WO2011043480A1 - Inhibiteur d'homocystéine synthase - Google Patents

Inhibiteur d'homocystéine synthase Download PDF

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Publication number
WO2011043480A1
WO2011043480A1 PCT/JP2010/067801 JP2010067801W WO2011043480A1 WO 2011043480 A1 WO2011043480 A1 WO 2011043480A1 JP 2010067801 W JP2010067801 W JP 2010067801W WO 2011043480 A1 WO2011043480 A1 WO 2011043480A1
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group
compound
mmol
methyl
reference example
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PCT/JP2010/067801
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Japanese (ja)
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朗 中尾
裕子 鈴木
亮 辰己
智文 説田
真紀 関
博司 岩▲崎▼
ゾングリ ゼン、
グラゴリー マカラ、
チャオヤン ダイ、
アーシャド シティキ、
ノリユキ カワハタ、
ヤン ナン、
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田辺三菱製薬株式会社
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Publication of WO2011043480A1 publication Critical patent/WO2011043480A1/fr

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a novel amide derivative. More specifically, the present invention relates to a homocysteine synthetase inhibitor containing an amide derivative or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • Homocysteine is a sulfur-containing amino acid and an important intermediate in the metabolism of the essential amino acid methionine. Homocysteine is maintained at a very low concentration in the cell and excess homocysteine is released extracellularly, ie into the blood. 30 years ago, Dr. McCully reported that this homocysteine causes vascular pathologies such as arteriosclerosis and myocardial infarction (Non-patent Document 1). Thereafter, clinical trials have shown that patients with arteriosclerosis in peripheral blood vessels and cerebral blood vessels have high homocysteine levels (Non-Patent Document 2).
  • Non-Patent Documents 3 to 8 In a large-scale study, a 25% increase in blood homocysteine levels (3 ⁇ M in absolute value) reported a 10% increase in the risk of coronary artery disease and a 20% increase in the risk of cerebral infarction (non-) Patent Document 9), which is now suggested to be an independent risk factor.
  • a homocysteine lowering therapy only intake of a coenzyme of a metabolic enzyme, that is, vitamin B6, vitamin B12, and folic acid has been tried.
  • Non-patent Document 10 The intake of these vitamins lowers blood homocysteine levels to some extent. Furthermore, improvement of vascular endothelial function and regression of carotid artery plaque by vitamin therapy have been reported (Non-Patent Documents 11 to 13). However, a recurrence prevention effect was not observed in a large-scale study (The Vitamin Intervention for Stroke Prevention (VISP)) in which the effect of vitamin therapy on the recurrence of cerebral infarction and myocardial infarction was observed. As a cause of this, it has been suggested that a sufficient decrease in homocysteine was not observed in vitamin therapy (Non-patent Document 14).
  • VISP Vitamin Intervention for Stroke Prevention
  • SAH S-Adenosyl-L-homocysteine
  • Ado Adenosine
  • Hcy Homocystine
  • adenine derivatives Patent Document 1
  • Patent Document 2 nitroprusside compounds
  • An object of the present invention is to provide a homocysteine synthetase inhibitor useful for the prevention or treatment of diseases related to homocysteine synthase.
  • the amide derivative of the present invention exhibits a homocysteine synthetase inhibitory action, and can be an effective drug for the prevention or treatment of diseases involving the enzyme.
  • the present invention relates to the following amide derivatives or pharmacologically acceptable salts thereof, or solvates thereof, and uses thereof.
  • (1 ′) The following general formula (I ′)
  • R 1 is a hydrogen atom or a C 1 -C 3 alkyl group
  • R 2 is An optionally substituted heterocycle group (the heterocycle group contains at least one nitrogen atom in the ring), or -N (R 2a ) (R 2b );
  • R 2a and R 2b are each independently selected.
  • R 3 is a hydrogen atom
  • R 4 , R 5 , R 6 , R 7 are each independently selected
  • L represents a linker represented by the following general formula
  • R 9 is An optionally substituted C 1 -C 6 alkyl group, An optionally substituted C 2 -C 6 alkenyl group, An optionally substituted C 2 -C 6 alkynyl group, An optionally substituted C 3 -C 8 cycloalkyl group, A heterocycle group which may be substituted, An aryl group which may be substituted, A heteroaryl group which may be substituted or an arylalkyl group which may be substituted;
  • R 10 is Halogen atoms, A cyano group, An optionally substituted C 1 -C 6 alkyl group, -CF 3 , —O—R 11 (wherein R 11 represents a hydrogen atom, a C 1 -C 4 alkyl group or —CF 3 ), —CO—R 12 (wherein R 12 represents a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group, a
  • n is an integer of 0-2, g is an integer of 0-2, h is an integer from 0 to 1, i is an integer of 1-2;
  • R 13 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a cyano group or a halogen atom,
  • R 14 is a C 1 -C 4 alkyl group, W is ⁇ CH— or ⁇ N—,
  • R 15 represents a hydrogen atom, a C 1 -C 4 alkyl group, an aryl group, a C 1 -C 4 alkylamino group, a C 1 -C 6 alkoxy group, an arylamino group or an aryloxy group.
  • A is An aryl group which may be substituted, An optionally substituted aryl-C 1 -C 4 alkyl group, Optionally substituted heteroaryl-C 1 -C 4 alkyl group, A C 3 -C 6 alkynyl group, An optionally substituted C 3 -C 8 cycloalkyl group, or any group represented by the following general formulas (III) to (VI):
  • n is an integer of 0-2, g is an integer of 0-2, h is an integer from 0 to 1, i is an integer of 1-2;
  • R 13 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a cyano group or a halogen atom,
  • R 14 is a C 1 -C 4 alkyl group, W is ⁇ CH— or ⁇ N—,
  • R 15 represents a hydrogen atom, a C 1 -C 4 alkyl group, an aryl group, a C 1 -C 4 alkylamino group, a C 1 -C 6 alkoxy group, an arylamino group or an aryloxy group.
  • L represents a linker represented by the following general formula;
  • R 8a , R 8b , R 8c , R 8d in the formula represents a hydrogen atom, and the other symbols have the same meaning as described above, or the amide derivative or a pharmaceutically acceptable salt thereof according to (5), Or a solvate thereof.
  • R 10 is Halogen atoms, A cyano group, -CO-R 12 (wherein R 12 is as defined above), An aryl group which may be substituted, The amide derivative or the pharmaceutically acceptable salt thereof or the solvate thereof according to (6), which is a heteroaryl group which may be substituted, or a heterocycle group which may be substituted.
  • a homocysteine synthase inhibitor comprising the amide derivative according to any one of (1) to (9) or a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • Treatment or prevention of hyperhomocysteinemia comprising, as an active ingredient, the amide derivative according to any one of (1) to (9) or a pharmacologically acceptable salt thereof, or a solvate thereof.
  • Pharmaceutical for. (12) Use of the amide derivative according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof, or a solvate thereof for producing a homocysteine synthetase inhibitor.
  • the amide derivative represented by the above general formula (I) is referred to as “compound (I)”, the amide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, or a solvate thereof.
  • the product may be referred to as “the compound of the present invention”.
  • A represents an optionally substituted aryl group, an optionally substituted aryl-C 1 -C 4 alkyl group, an optionally substituted heteroaryl-C 1 -C 4 alkyl group, C 3 A —C 6 alkynyl group, an optionally substituted C 3 -C 8 cycloalkyl group, or any group selected from general formulas (III) to (VI).
  • Examples of the group represented by the formula include a cyclopentenyl group and a 2,5-dihydro-1H-pyrrolyl group.
  • Examples of the group represented by the formula include morpholinyl group, 1-piperidinyl group, 4-piperidinyl group, piperazinyl group, thiomorpholinyl group, azepanyl group, cyclopentanyl group, cyclohexanyl group, and cycloheptanyl group.
  • alkyl group preferably has 1 to 6 carbon atoms and may be linear or branched.
  • the “C 1 -C 3 alkyl group” for R 1 is preferably methyl or ethyl, and more preferably methyl.
  • the “C 1 -C 6 alkyl group” for R 2a and R 2b is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, more preferably methyl, ethyl or isopropyl. is there.
  • the “C 1 -C 4 alkyl group” for R 4 , R 5 , R 6 and R 7 is preferably methyl.
  • As the “C 1 -C 3 alkyl group” for R 8a , R 8b , R 8c and R 8d methyl is preferable.
  • the “C 1 -C 6 alkyl group” for R 9 is preferably methyl, ethyl, n-propyl or isopropyl.
  • the “C 1 -C 6 alkyl group” for R 10 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and more preferably methyl.
  • the “C 1 -C 4 alkyl group” for R 11 is preferably methyl, ethyl, n-propyl or isopropyl, more preferably methyl.
  • the “C 1 -C 6 alkyl group” for R 12 is preferably methyl, ethyl, n-propyl or isopropyl, more preferably methyl or ethyl.
  • the “C 1 -C 4 alkyl group” for R 13 is preferably methyl or ethyl, and more preferably methyl.
  • the “C 1 -C 4 alkyl group” for R 14 is preferably methyl, ethyl, n-propyl or isopropyl, more preferably methyl.
  • the “C 1 -C 6 alkyl group” for R 15 is preferably a methyl group, an ethyl group, isopropyl or t-butyl, and more preferably methyl or ethyl.
  • substituent of the “optionally substituted C 1 -C 6 alkyl group” for R 9 include a halogen atom, a cyano group, a C 3 -C 7 cycloalkyl group, a 5- to 7 -membered heterocycle group, and a hydroxy group , A C 1 -C 4 alkoxy group, preferably a halogen atom, a C 3 -C 6 cycloalkyl group, or a C 1 -C 4 alkoxy group, and more preferably a fluorine atom.
  • Examples of the substituent of the “optionally substituted C 1 -C 6 alkyl group” for R 10 include a halogen atom, a hydroxy group, a cyano group, a C 3 -C 7 cycloalkyl group, and a 5- to 7 -membered heterocyclic group. , An aryl group and a C 1 -C 4 alkoxy group, preferably a halogen atom, a hydroxy group, a C 3 -C 6 cycloalkyl group and a C 1 -C 4 alkoxy group.
  • haloalkyl group is an alkyl group having 1 or more, preferably 1 to 3 halogen atoms, having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which may be linear or branched.
  • halogen atoms having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which may be linear or branched.
  • trifluoromethyl fluoroethyl, difluoroethyl, trifluoroethyl, trifluoro n-propyl, trifluoroisopropyl, trifluoro n-butyl, trifluoroisobutyl, trifluoro t-butyl, trifluoro n-pentyl, trifluoro and n-hexyl.
  • haloalkyl group for R 2a and R 2b is preferably fluoroethyl, difluoroethyl or trifluoroethyl, and more preferably 2-fluoroethyl, 2,2-difluoroethyl or trifluoroethyl.
  • the “alkenyl group” preferably has 2 to 6 carbon atoms and may be linear or branched and has at least one carbon double bond, and examples thereof include an ethenyl group, a propenyl group, and a butenyl group.
  • the “C 2 -C 6 alkenyl group” for R 9 includes ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, and the like, and more preferably ethenyl Group, 1-propenyl group and 2-propenyl group.
  • Examples of the substituent of the “optionally substituted C 2 -C 6 alkenyl group” for R 9 include a halogen atom, a cyano group, a C 3 -C 7 cycloalkyl group, a 5- to 7 -membered heterocycle group, and an aryl group , A hydroxy group, and a C 1 -C 4 alkoxy group, preferably a halogen atom, a C 3 -C 6 cycloalkyl group, and a C 1 -C 4 alkoxy group.
  • alkynyl group preferably has 2 to 6 carbon atoms and may be linear or branched and has at least one carbon triple bond, and examples thereof include an ethynyl group, a propynyl group, and a butynyl group.
  • the “C 2 -C 6 alkynyl group” for R 9 is preferably an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group or a 3-butynyl group, more preferably ethynyl. Group, 1-propynyl group, 2-propynyl group and 2-butynyl group.
  • the “C 3 -C 6 alkynyl group” of A is preferably a 2-propynyl group, a 1-methyl-2-propynyl group, a 2-butynyl group, a 3-butynyl group, or a 1-methyl-2-butynyl group, More preferred are 2-propynyl group and 2-butynyl group.
  • Examples of the substituent of the “optionally substituted C 2 -C 6 alkynyl group” of R 9 include a halogen atom, a cyano group, a C 3 -C 7 cycloalkyl group, a 5-7-membered heterocycle group, an aryl group , A hydroxy group, and a C 1 -C 4 alkoxy group, preferably a halogen atom, a C 3 -C 6 cycloalkyl group, and a C 1 -C 4 alkoxy group.
  • the “cycloalkyl group” is an alicyclic hydrocarbon having a saturated structure, and includes monocyclic hydrocarbons, condensed polycyclic hydrocarbons, and bridged hydrocarbons.
  • the number of carbon atoms is preferably 3 to 8, and examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • the “C 3 -C 8 cycloalkyl group” for R 9 is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and more preferably cyclopentyl or cyclohexyl.
  • the “C 3 -C 8 cycloalkyl group” of A is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and more preferably cyclohexyl.
  • Examples of the substituent of the “optionally substituted C 3 -C 8 cycloalkyl group” for R 9 include an aryl group, a heteroaryl group, a halogen atom, a cyano group, a C 1 -C 4 alkyl group, and a C 3 -C 7 group.
  • Examples of the substituent of the “optionally substituted C 3 -C 8 cycloalkyl group” for A include an aryl group, heteroaryl group, halogen atom, cyano group, C 1 -C 4 alkyl group, hydroxyl group, C 3 — C 7 cycloalkyl group, C 1 -C 4 alkoxy group, —CF 3 group, —OCF 3 group, preferably aryl group, halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group is there.
  • the “aryl group” is a cyclic hydrocarbon having aromaticity, and is a monocyclic hydrocarbon or polycyclic hydrocarbon having 6 to 10 carbon atoms, which includes a cycloalkyl group, a heterocycle group, It may be condensed or fused with a heteroaryl group.
  • the aryl group for R 2a and R 2b is preferably a phenyl group.
  • the “aryl group” for R 9 is preferably a phenyl group, a 2-naphthyl group, a 5-indanyl group or a 6-benzothiazolyl group, more preferably a phenyl group.
  • the “aryl group” for R 10 is preferably a phenyl group.
  • the “aryl group” for R 15 is preferably a phenyl group, a 1-naphthyl group, or a 2-naphthyl group.
  • the “aryl group” for A is preferably a phenyl group, a 1-naphthyl group, a 2-naphthyl group, or a 5-indanyl group.
  • substituent of the “optionally substituted aryl group” for R 2a and R 2b include a halogen atom, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, and a —CF 3 group. , —OCF 3 group.
  • Examples of the substituent for the “optionally substituted aryl group” for R 9 include a halogen atom, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group, —OCF group. 3 groups and a benzyloxy group are mentioned, Preferably a chlorine atom, a fluorine atom, and a methyl group are mentioned.
  • Examples of the substituent of the “optionally substituted aryl group” for R 10 include a halogen atom, cyano, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, —CF 3 group, and —OCF 3 group.
  • Examples of the substituent of the “optionally substituted aryl group” for A include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group, and a —OCF 3 group. It is done.
  • a “carbocycle group” is an alicyclic hydrocarbon having a saturated structure, an alicyclic hydrocarbon having an unsaturated structure, or a cyclic hydrocarbon having aromaticity. This includes hydrogen, condensed polycyclic hydrocarbons and bridged hydrocarbons. The number of carbon atoms is preferably 3 to 10, and these may be condensed or fused with a cycloalkyl group, a heterocycle group or a heteroaryl group. Furthermore, the carbon atom on the above cycloalkyl group may be partially substituted with an oxo group or a thioxo group, and the carbon atom or heteroatom on the above heterocycle group may be partially substituted with an oxo group or a thioxo group. It may be replaced. Examples of the carbocycle group include a cycloalkenyl group in addition to the substituents mentioned for the cycloalkyl group and aryl group.
  • a “heterocycle group” is a cyclic compound having at least one heteroatom (nitrogen, oxygen or sulfur) and a carbon atom, a completely saturated structure, or a partially unsaturated structure.
  • the heterocycle group may be a 3- to 8-membered monocyclic compound, or an 8- to 12-membered ring condensed, fused, or bonded to another heterocycle group, heteroaryl group, cycloalkyl group, or aryl group. Includes cyclic compounds or heterocyclic spiro compounds.
  • the carbon atom or heteroatom on the heterocycle group may be partially substituted with an oxo group or a thioxo group.
  • heterocycle group examples include tetrahydrofuranyl group, tetrahydropyranyl group, dioxolanyl group, dioxanyl group, pyrrolidinyl group, piperidinyl group, dihydropyridinyl group, tetrahydropyridinyl group, piperazinyl group, azepanyl group, azocanyl group , Morpholinyl group, thiomorpholinyl group, oxazolidinyl group, thiazolidinyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, dihydrooxadiazolyl group, dihydrotriazolyl group, dihydrobenzofuranyl group,
  • the “heterocycle group” of R 2 contains at least one nitrogen atom as a hetero atom, preferably a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, thiazolidinyl group, more preferably 1 -Pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 1-piperidinyl group, 2-piperidinyl group, 3-piperidinyl group, 4-piperidinyl group, 4-morpholinyl group.
  • the “heterocycle group” for R 9 is preferably a tetrahydrofuranyl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydrothienyl group, or a tetrahydrothiopyranyl group, more preferably a 3-tetrahydrofuranyl group, 4- Tetrahydropyranyl group.
  • the “heterocycle group” for R 10 is preferably a dihydrooxadiazolyl group or a dihydrotriazolyl group, more preferably a 1,2,4-dihydrooxadiazolyl group or a 1,3,4-dihydrooxadiazo group.
  • R 2 It is a ryl group.
  • substituent of the “optionally substituted heterocycle group” for R 2 include a halogen atom, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a hydroxy C 1 -C 4 alkyl group, and a C 3 -C 7.
  • Examples of the substituent of the “optionally substituted heterocycle group” for R 10 include an aryl group, heteroaryl group, halogen atom, cyano group, C 1 -C 4 alkyl group, C 3 -C 7 cycloalkyl group, C There are 1 -C 4 alkoxy groups, -CF 3 groups, and -OCF 3 groups, preferably C 1 -C 4 alkyl groups. “A ′ and R 1 may combine to form a heterocycle group which may be substituted with the adjacent nitrogen atom.” Examples of the substituent of the heterocycle group include an aryl group, an arylcarbonyl group and an arylalkyl group. Yes, preferably a phenyl group, a phenylcarbonyl group, or a benzyl group.
  • heteroaryl group is an aromatic cyclic compound having at least one heteroatom (nitrogen, oxygen or sulfur) and a carbon atom, a 5- to 6-membered monocyclic compound, or other It includes a condensed cyclic compound having 8 to 12 membered rings fused or fused with a heterocycle group, heteroaryl group, cycloalkyl group or aryl group.
  • heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, flazanyl , Pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group, indolizinyl group, isoindolyl group, indolyl group, indazolyl group, benzoimidazolyl group, purinyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinoxalinyl group, quinazolinyl group, cinolinyl group Group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzoxazolyl
  • the “heteroaryl group” for R 9 is preferably a thienyl group, a pyridyl group or a pyrimidyl group, more preferably a 2-thienyl group.
  • 1,3,4-thiadiazolyl group pyridyl group, pyrazinyl group, pyrimidyl group.
  • substituent of the “optionally substituted heteroaryl group” for R 9 include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group, and a —OCF 3 group. Is mentioned.
  • Examples of the substituent of the “optionally substituted heteroaryl group” for R 10 include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group, and a —OCF 3 group. And preferably a methyl group.
  • arylalkyl group means that the aryl part is the same as described above, and the alkyl part preferably has 1 to 4 carbon atoms and may be linear or branched.
  • the “arylalkyl group” for R 9 is preferably a benzyl group or a phenethyl group, and more preferably a benzyl group.
  • the “aryl-C 1 -C 4 alkyl group” for A is preferably a benzyl group, a phenethyl group or a 3-phenylpropyl group, more preferably a benzyl group or a phenethyl group.
  • substituent of the “optionally substituted arylalkyl group” for R 9 include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group, and a —OCF 3 group.
  • the aryl part of the arylalkyl group may be substituted.
  • Examples of the substituent of the “optionally substituted aryl-C 1 -C 4 alkyl group” of A include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CF 3 group , —OCF 3 group and nitro group, preferably a fluorine atom, a methyl group, a methoxy group and a nitro group.
  • the aryl part of the arylalkyl group may be substituted, and may be the same or different and may be substituted with 1 to 5 (preferably 1 or 2) substituents.
  • heteroarylalkyl group means that the heteroaryl part is the same as described above, and the alkyl part preferably has 1 to 4 carbon atoms and may be linear or branched.
  • pyridylmethyl, pyridylethyl examples include furylmethyl, furylethyl, thienylmethyl, thienylethyl and the like.
  • the “heteroaryl-C 1 -C 4 alkyl group” for A is preferably pyridylethyl, furylethyl or thienylethyl, more preferably 2- (2-furyl) ethyl or 2- (2-thienyl) ethyl. .
  • Examples of the substituent of the “optionally substituted heteroaryl-C 1 -C 4 alkyl group” of A include a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, and a CF 3 group , OCF 3 groups.
  • the heteroaryl part of the heteroarylalkyl group may be substituted.
  • the “alkoxy group” is a monovalent group generated by losing the hydrogen atom of the hydroxyl group of alcohols, and may have 1 to 6 carbon atoms and may be linear or branched.
  • methoxy, ethoxy, propoxy examples include butoxy, pentyloxy, hexyloxy and the like.
  • the “C 1 -C 6 alkoxy group” for R 12 is preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a t-butoxy group, more preferably a methoxy group or an ethoxy group.
  • the “C 1 -C 4 alkoxy group” for R 13 is preferably a methoxy group or an ethoxy group, more preferably a methoxy group.
  • the “C 1 -C 6 alkoxy group” for R 15 is preferably a methoxy group, an ethoxy group, or a t-butoxy group, and more preferably a methoxy group.
  • halogen atom examples include fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably fluorine or chlorine.
  • the halogen atom for R 13 is preferably fluorine or chlorine.
  • fluorine, chlorine and bromine are preferable.
  • Alkylamino group means an amino group in which one or two hydrogen atoms are substituted with an alkyl group.
  • the alkyl part preferably has 1 to 4 carbon atoms and may be linear or branched.
  • examples of the alkylamino group include methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino and the like.
  • the “C 1 -C 4 alkylamino group” for R 15 is preferably methylamino, dimethylamino, ethylamino or isopropylamino.
  • arylamino group refers to an amino group in which one or two hydrogen atoms are substituted with an aryl group, and the aryl moiety is the same as described above. For example, a phenylamino group is mentioned.
  • the “arylamino group” for R 15 is preferably a phenylamino group.
  • aryloxy group examples include a phenoxy group and a naphthyloxy group.
  • the “aryloxy group” for R 15 is preferably a phenoxy group.
  • Examples of the substituent of the “optionally substituted amino group” in R 10 include a C 1 -C 4 alkyl group, a C 1 -C 4 alkylsulfonyl group, a C 1 -C 4 acyl group, and a C 1 -C 4 alkoxycarbonyl.
  • Examples of the substituent of the “optionally substituted amino group” in R 12 include a C 1 -C 4 alkyl group and a C 1 -C 4 alkylsulfonyl group, and a methyl group and the like are preferable.
  • C 1 -C 4 alkylsulfonyl group means that the alkyl part may have 1 to 4 carbon atoms and may be linear or branched.
  • a methylsulfonyl group an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group Etc.
  • C 1 -C 4 alkoxycarbonyl group means that the alkoxy part thereof has 1 to 4 carbon atoms and may be linear or branched.
  • methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n -Butoxycarbonyl, t-butoxycarbonyl and the like can be mentioned.
  • C 1 -C 4 alkylaminocarbonyl group means that the alkyl part thereof has 1 to 4 carbon atoms and may be linear or branched.
  • a methylaminocarbonyl group an ethylaminocarbonyl group, a propylaminocarbonyl group And butylaminocarbonyl group.
  • arylsulfonyl group has the same aryl moiety as the above “aryl group”, and examples thereof include a group in which the group exemplified in the above “aryl group” and a sulfonyl group are bonded.
  • s is preferably an integer of 0, 1 and 2.
  • t is preferably an integer of 0 and 1.
  • X is preferably an oxygen atom and a sulfur atom
  • l is preferably an integer of 1 and 2
  • m is preferably an integer of 0 and 2.
  • n is preferably an integer of 0 and 1
  • g is preferably an integer of 0, 1, and 2.
  • h is preferably an integer of 0 and 1
  • i is preferably an integer of 1 and 2
  • W is preferably ⁇ CH— and ⁇ N—
  • D is preferably an oxygen atom, a sulfur atom, ⁇ N—
  • E u—R 15 and ⁇ CH—R 15
  • u is preferably an integer of 0 and 1
  • E is preferably —SO 2 — or —CO—.
  • the pharmacologically acceptable salts of Compound (I) include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, citric acid Salts with organic acids such as acids, malic acid and fumaric acid; Salts with alkali metals such as sodium and potassium; Salts with alkaline earth metals such as magnesium; Ammonia, ethanolamine, 2-amino-2-methyl- And salts with amines such as 1-propanol.
  • the type of salt is not particularly limited as long as it is pharmacologically acceptable.
  • solvate of compound (I) examples include solvates with water, ethanol, ethyl acetate and the like.
  • type of solvate is not particularly limited as long as it is pharmacologically acceptable.
  • “Homocysteine synthetase inhibition” refers to reversibly inhibiting the activity of SAHH, and this reversible inhibition includes competitive inhibition, non-antagonistic inhibition, and non-antagonistic inhibition. Enzyme inhibition includes reversible inhibition that binds reversibly and inhibits reactions that should proceed originally, and irreversible inhibition that makes amino acids in the vicinity of the deficient site strong bonds such as covalent bonds, making the substrate unable to bind. is there. There are three types of reversible inhibition. The first is competitive inhibition, which forms an enzyme-inhibitor complex (EI) between the enzyme (E) and the inhibitor (I) and antagonizes the binding of the substrate to the enzyme.
  • EI enzyme-inhibitor complex
  • the competitive inhibitor binds to the substrate binding site of the enzyme instead of the substrate and reversibly inhibits the enzyme activity. Therefore, even if a competitive inhibitor is present, the inhibitory activity naturally disappears if the substrate concentration is sufficiently increased.
  • the inhibition constant Ki is defined as [E] [I] / [EI].
  • the second reversible inhibition is an antagonistic inhibition, where the inhibitor does not affect the free enzyme and does not affect the stage at which the substrate binds to the enzyme. It binds reversibly only to the enzyme-substrate complex (ES) and exhibits an inhibitory action. Therefore, increasing the substrate concentration has no effect on the inhibition strength.
  • the inhibition constant Ki is [ES] [I] / [ESI].
  • [ESI] is the concentration of enzyme-substrate-inhibitor complex.
  • the third reversible inhibition is non-competitive inhibition, and the inhibitor reversibly binds both a free enzyme and an enzyme-substrate complex to exhibit an inhibitory action.
  • Non-competitive inhibitors bind to an enzyme at a site different from the binding site of the substrate, and inhibit it by changing the structure of the enzyme molecule.
  • Ki EI [E] [I] / [EI]
  • Ki ESI [ES] [I] / [ESI].
  • Disease related to homocysteine synthase refers to a disease for which symptoms can be expected to be prevented or ameliorated by reversibly inhibiting the activity of homocysteine synthase. Blood pressure or its complications.
  • the compound of the present invention can be synthesized by adapting various known synthesis methods using characteristics based on the basic skeleton or the type of substituent. Although the typical manufacturing method is illustrated below, it is not limited only to the method as described below. Depending on the type of functional group, it may be effective in terms of production technology to change the functional group to a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. Yes, the protecting group can be removed as necessary to obtain the desired compound.
  • Examples of such a functional group include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of the protecting group include those by Greene and Wutt, Protective Groups in Organic Synthesis 3rd edition “ Protective groups described in “Protective Groups in Organic Synthesis (third edition)” can be used, and these may be appropriately used depending on the reaction conditions.
  • room temperature usually indicates 0 to 30 ° C.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and L are as defined above.
  • G represents a halogen atom
  • P represents a protecting group for an amino group
  • R 21 represents C. 1-4 represents an alkyl group
  • the reaction is preferably carried out using the compound (8) in which the nitrogen atom is protected, and after completion of the reaction, Perform deprotection.
  • Step 1 (alkylation reaction) This step is carried out under heating in the presence of compound (1), 2 equivalents or more of compound (2), and 2 equivalents or more of a base in an inert solvent or without a solvent.
  • the base include alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate, alkali metal phosphates such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate and tripotassium phosphate, triethylamine N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (hereinafter referred to as DBU) And the like.
  • DBU decane
  • the amount of the base used is 2 equivalents or more, preferably 2 to 20 equivalents, relative to compound (1).
  • the halogen atom of compound (2) represents chlorine, bromine, iodine, fluorine or the like, and the amount used is 2 equivalents or more, preferably 2 to 20 equivalents, relative to compound (1).
  • the “inert solvent” include ethers such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbons such as chloroform, carbon tetrachloride and 1,2-dichloroethane, hydrocarbons such as hexane, benzene, toluene and xylene.
  • Nitriles such as acetonitrile, amides such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and the like. May be mixed in an appropriate ratio, and the reaction can be carried out without using a solvent.
  • the reaction temperature is usually 40 to 200 ° C., preferably 50 to 150 ° C.
  • Step 2 Ester hydrolysis reaction
  • This step is usually performed in a water-containing solvent in the presence of an acid or a base.
  • the acid include formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid and the like.
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal hydroxides such as potassium hydroxide, lithium hydroxide and sodium hydroxide.
  • the amount of acid or base used is usually an excess amount relative to compound (3).
  • the amount of acid used is 2 to 100 equivalents relative to compound (3)
  • the amount of base used is 2 to 10 equivalents relative to compound (3).
  • the water-containing solvent examples include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, a mixed solvent of one or more solvents selected from dimethyl sulfoxide and acetone, and the like.
  • R 21 is a tert-butyl group
  • acid decomposition can be performed.
  • the acid for example, formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid and the like are used.
  • the solvent may be mixed in an appropriate ratio.
  • halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like are used.
  • the amount of the acid used is usually an excess amount relative to the compound (3), and preferably 2 to 200 equivalents relative to the compound (3).
  • the reaction temperature is usually ⁇ 20 to 150 ° C., preferably ⁇ 10 to 100 ° C.
  • Step 3 (acid anhydride reaction) This step is usually performed using a dehydrating condensing agent in an inert solvent.
  • the “inert solvent” include ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide and N-methylpyrrolidone, and sulfoxides such as dimethylsulfoxide are used. You may mix and use these 2 or more types in a suitable ratio.
  • the reaction temperature is usually about ⁇ 20 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is usually about 30 minutes to about 24 hours.
  • the dehydrating condensing agent include dicyclohexylcarbodiimide (hereinafter referred to as DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (hereinafter referred to as WSC), and WSC is particularly preferable.
  • the amount of the condensing agent to be used is usually 1 to 3 equivalents relative to compound (4), but a liquid separation operation can be performed in the middle from step 3 to step 4 (amidation reaction).
  • a water-soluble condensing agent such as is used for the reaction, it is possible to separate the condensing agent into an aqueous layer and the product (5) into an organic layer.
  • 1 to 1.2 equivalents of the condensing agent is added. It is preferable.
  • Step 4 (Amidation reaction)
  • the dehydrating condensing agent is removed by separating the reaction solution in step 3 and the extraction solvent is concentrated and then dissolved again in an “inert solvent” (described in step 3) or in the reaction solution in step 3
  • the reaction solution is used as it is without performing the extraction operation.
  • a free form or a salt such as hydrochloride is used.
  • a tertiary amine such as DBU, N, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine is used as a neutralizing agent.
  • Organic bases such as N-methylmorpholine, pyridine and 2,6-lutidine
  • inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and the like, and the like. But organic bases are preferred.
  • Step 5 (Amidation reaction) Examples of the method in this step include the following i) a method using a dehydration condensing agent and ii) a method using a reactive derivative of a carboxyl group.
  • the reaction time is usually about 1 hour to about 72 hours, preferably about 1 hour to about 24 hours.
  • This reaction may be carried out in the presence of about 1 to 2 equivalents of 1-hydroxybenzotriazole (hereinafter referred to as HOBt) or 1-hydroxy-7-azabenzotriazole (hereinafter referred to as HOAt) as necessary. Good.
  • this reaction may be performed in the presence of a base, if necessary.
  • base examples include tertiary amines such as DBU, N, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, and 2,6-lutidine, alkali metal or alkaline earth metal carbonates ( Examples thereof include sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.). Of these, triethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, and the like are preferable.
  • tertiary amines such as DBU, N, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, and 2,6-lutidine
  • alkali metal or alkaline earth metal carbonates examples thereof include sodium carbonate, potassium carbonate, cesium carbonate
  • a reactive derivative of compound (7) and about 1 to 5 equivalents (preferably 1 to 3 equivalents) of compound (8) are reacted in an inert solvent.
  • the reactive derivative in the “reactive derivative of compound (7)” include acid halide (eg, acid chloride, acid bromide), mixed acid anhydride (eg, C 1-6 alkyl-carboxylic acid or C 1 -1). And anhydrides with 6 alkyl carbonic acid), and active esters (eg, esters with optionally substituted phenol, HOBt, HOAt, N-hydroxysuccinimide, etc.).
  • Examples of the “substituent” in the “optionally substituted phenol” include a halogen atom and a nitro group.
  • the number of substituents is 1 to 5, and specific examples of “optionally substituted phenol” include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the like.
  • the reactive derivative is preferably an acid halide.
  • Examples of the “inert solvent” include the solvents described in Step 1. Two or more of these may be mixed and used at an appropriate ratio. Of these, tetrahydrofuran, dichloromethane, acetonitrile and the like are preferable.
  • the reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is usually about 1 hour to 72 hours, preferably about 1 hour to 24 hours.
  • This reaction may be carried out in the presence of about 1 to 10 equivalents, preferably about 1 to 3 equivalents of a base, if necessary.
  • bases those exemplified in the above-mentioned i) “method using a dehydration condensing agent” can be used.
  • Step 6 (amino group deprotection reaction)
  • This step and the protection reaction of the amino group are performed according to a known method, for example, a method described in Protective Groups in Organic Synthesis edition (1999).
  • the amino-protecting group include formyl, C 1-6 alkyl-carbonyl optionally substituted with a halogen atom (eg, acetyl, propionyl, trifluoroacetyl, etc.), optionally substituted with a halogen atom.
  • C 1-6 alkoxy-carbonyl eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.
  • benzoyl C 7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), C 7-10 aralkyloxy-carbonyl (eg, , Benzyloxycarbonyl, etc.), trityl, silyl (eg, trimethylsilyl, tert-butyldimethylsilyl, etc.), C 2-6 alkenyl (eg, 2-propenyl, etc.), substituted benzenesulfonyl (eg, 2-nitrobenzenesulfonyl), etc.
  • tert-butoxycarbonyl trifluoroacetyl, benzyloxycarbonyl, 2-nitrobenzenesulfonyl and the like.
  • the protecting group for compound (8) is preferably tert-butoxycarbonyl, trifluoroacetyl, benzyloxycarbonyl, 2-nitrobenzenesulfonyl or the like.
  • Step 7 (Amidation reaction) This step can be manufactured by the same method as in step 5.
  • the target compound (10) can be obtained by reacting the compound (7) with the compound (11) under the various conditions described in Step 5.
  • step 4 and step 5 (or 7) of production method 1 compound (6) and compound (8) to be added or compound (6) and compound (11) may be exchanged. That is, in step 4, compound (8) or compound (11) can be added, and in step 5, compound (6) can be added.
  • Step 8 (Amidation reaction) This step is a reaction for obtaining the compound (15) by amidation reaction of the compound (6) and the compound (14) or (14 ′). This step can be performed by the same method as in steps 5 and 7.
  • Step 9 alkylation reaction
  • This step is an alkylation reaction using compound (1) and compound (2) to obtain compound (16).
  • This reaction can be carried out in the same manner as in Step 1, but when the reaction is carried out using 1 equivalent or more of compound (2), compound (3) may be formed as a by-product, and therefore compound (3
  • the number of equivalents of 2) is preferably less than 2 equivalents, more preferably 1 to 1.2 equivalents.
  • Step 10 alkylation reaction
  • This step is an alkylation reaction for synthesizing compound (17) from compounds (16) and (15). This reaction can be carried out by the same method as in Step 1.
  • Compound (15) is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to Compound (16).
  • Step 11 Ester hydrolysis reaction
  • This reaction can be carried out according to the same method as in Step 2.
  • the steps after the compound (18) obtained in this step are the same as the method shown in [Production Method 1].
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 21 , Ar, A, and G are as defined above.
  • the steps 9 and 10 shown in the production method 4 can be carried out by changing their order. That is, compound (1) can be reacted with (15) to obtain compound (19), and then compound (2) can be reacted to obtain compound (17).
  • Step 12 (Amidation reaction) This step is a reaction for obtaining the compound (21) by amidation reaction of the compound (8) and the compound (20) or (20 ′). This step can be performed by the same method as in steps 5 and 7.
  • Step 13 alkylation reaction
  • This step is an alkylation reaction using compound (1) and compound (22) to obtain compound (23).
  • This reaction can be carried out by the same method as in Step 9.
  • the number of equivalents of compound (22) is preferably less than 2 equivalents, more preferably 1 to 1.2 equivalents.
  • Step 14 (alkylation reaction) This step is an alkylation reaction for synthesizing compound (24) from compounds (23) and (21). This reaction can be carried out in the same manner as in Step 10.
  • Compound (21) is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to Compound (23).
  • Step 15 Ester hydrolysis reaction
  • This reaction can be carried out according to the same method as in Step 2.
  • Step 16 (Amidation reaction) This step is an amidation reaction in which the compounds (25) and (6) are reacted to synthesize the compound (9). This step can be performed by the same method as in step 5. The steps after compound (9) are the same as in [Production Method 1].
  • Step 17 is a reaction for converting compound (27) into compound (28) by nitration reaction, and can be synthesized by a known method.
  • a mixed acid method using concentrated sulfuric acid and nitric acid a method using nitric acid in an acetic acid solvent, acetic acid, trifluoroacetic acid, or a nitrite (for example, sodium nitrite, tetrafluoroborate nitrite, etc.) or nitrate (for example, , Sodium nitrate, potassium nitrate, etc.).
  • Step 18 Reduction of nitro group
  • a known method is a step of converting the amino group, for example, Comprehensive Organic Transformations's, 3rd edition, 821-828 pages (Comprehensive Organic Transformations, 3 rd edition , (page 821-828, VCH Publishers Inc.) published in 1999 or the like, or a method analogous thereto.
  • a hydrogen source eg, ammonium formate, hydrazine, etc.
  • a hydrogenation reaction using palladium carbon, Raney nickel, etc. as a catalyst using iron, tin chloride, etc. under acidic conditions
  • It can be synthesized by a reaction, a reaction using hydrazine and a catalytic amount of ferric chloride in the presence of activated carbon, and the like.
  • LG means a leaving group (for example, a halogen atom or —OSO 2 R 22 ), and R 22 denotes a C 1-4 alkyl group. Represents a C 1-4 haloalkyl group or an aryl group.
  • Step 19 This step is usually performed in an inert solvent in the presence of a base.
  • the equivalent amount of compound (31) is 1 to 100 molar equivalents relative to compound (30). 1 to 10 molar equivalents are preferred.
  • the base include alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide and hydroxide.
  • Alkali metal hydroxides such as lithium, metal hydrides such as potassium hydride and sodium hydride, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine and DBU Used.
  • the amount of the base used is preferably 1 to 10 molar equivalents relative to compound (31).
  • the reaction temperature is usually ⁇ 50 to 200 ° C., preferably ⁇ 20 to 150 ° C.
  • the inert solvent examples include ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl
  • ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • hydrocarbons such as hexane, benzene and toluene
  • amides such as formamide and N-methylpyrrolidone
  • sulfoxides such as dimethyl sulfoxide
  • nitriles such as acetonitrile.
  • Step 20 Reduction of nitro group
  • This step is a reaction for reducing a nitro group to an amino group, and can be carried out by the same method as in Step 18.
  • Step 21 This step is an alkylation reaction in which the compound (34) is reacted with the compound (33).
  • the equivalent amount of compound (34) is 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents relative to compound (33), and the amount of base is preferably 1 to 10 relative to compound (33). Molar equivalent.
  • the base and solvent used are the same as those described in Step 19.
  • Step 22 This step is a step of synthesizing the compound (29) by reacting the compound (34) with the functional group XH group contained in the compound (35).
  • the equivalent amount of compound (34) is 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (35).
  • the reaction solvent and the base are the same as those described in Step 19.
  • Step 23 This step can be performed in the same manner as in step 21.
  • Step 24 This step is an ester hydrolysis reaction and can be carried out in the same manner as in Step 2.
  • Step 25 This step is a reaction for converting a carboxylic acid into a carbamate-protected amino group by a rearrangement reaction, and is a known method, for example, Comprehensive Organic Transformations, 3rd edition, pages 867-869. (Comprehensive Organic Transformations, 3 rd edition , page 867-869, VCH Publishers Inc.) can be synthesized according to the method described in 1999 annual like or a method analogous thereto.
  • a method in which a carboxylic acid is converted to an aminocarbonyl group and then converted to an amino group by Hoffman rearrangement a carboxylic acid is converted to an acid azide and then converted to an amino group, or diphenylphosphoryl azide (hereinafter referred to as DPPA).
  • DPPA diphenylphosphoryl azide
  • Curtius rearrangement that converts to a carbamate group.
  • Step 26 This step is a deprotection reaction of a carbamate group which is a protective group for an amino group, and can be carried out by a known method. For example, it can be carried out by the method described in Protective Groups in Organic Synthesis, 3rd edition, pages 503 to 550 (Protective Groups in Organic Synthesis, third edition, pages 503-550).
  • a and R 21 are as defined above, and R 22 represents a methyl or ethyl group.
  • the compound (40) is converted into an alkyl carbamate (41a) and an amide (42b), and then converted into an alkyl group by a reduction reaction (for example, a reduction reaction using lithium aluminum hydride).
  • a reduction reaction for example, a reduction reaction using lithium aluminum hydride.
  • Or (6b) can be obtained, and the compound (6c) in which the isopropyl group is substituted can be synthesized by subjecting the compound (40) and acetone to a reductive amination reaction. .
  • R 23 represents a C 1 -C 3 alkyl group.
  • a production method of the compound (6d) when R 1 of the compound (6) is a C 1 -C 3 alkyl group is shown.
  • compound (6d) indicates that when A is (III) to (V), W is —CH ⁇ . It is possible to obtain the compound (6d) by reductive amination reaction after deriving from the alcohol form of the compound (42) to the ketone or aldehyde form (43a) by oxidation reaction.
  • the compound (6d) After conversion to a leaving group such as methanesulfonyloxy, paratoluenesulfonyloxy, trifluoromethanesulfonyloxy group (for example, chlorine, bromine, iodine, etc.), the compound (6d) can be obtained by an alkylation reaction. .
  • a leaving group such as methanesulfonyloxy, paratoluenesulfonyloxy, trifluoromethanesulfonyloxy group (for example, chlorine, bromine, iodine, etc.
  • R 13 , R 21 , R 22 , i and n are as defined above.
  • TBS tert-butyldimethylsilyl group
  • the compound is induced to the compound (48) by a reduction reaction with boron, and the amino group is converted into a carbamate or amide,
  • the hydroxyl group is reduced with triethylsilane or the like in the presence of a Lewis acid to induce compound (50a) or (50b).
  • compound (6e * ) or (6e) is prepared according to [Production Method 3 of Compound (6)]. ** ) can be produced.
  • the secondary amine is denoted as (51) for convenience.
  • Nitroso form (52) is obtained by reacting (51) with sodium nitrite under acidic conditions, and the nitroso group is reduced using lithium aluminum hydride, zinc, titanium trichloride or the like to obtain compound (53) Get.
  • an R 22 group is introduced by a reduction reaction, whereby the compound (6f) can be synthesized.
  • R 13 , R 14 , and n are as defined above, and R 24 represents hydrogen, a hydroxyl group, and an alkoxy group.
  • R 24 represents hydrogen, a hydroxyl group, and an alkoxy group.
  • R 14 , R 23 and n are as defined above, and R 25 represents hydrogen, C 1 -C 4 alkyl, aryl, C 1 -C 6 alkoxy group or aryloxy group.
  • Compound (6j) can be synthesized, for example, by the method shown below.
  • R 14 , R 23 , R 25 , n, P, and LG are as defined above.
  • an organic base such as triethylamine or N, N-diisopropylethylamine within the range below the boiling point of the organic base.
  • the target compound (6j) can be synthesized by obtaining the compound (62) and carrying out a deprotection reaction.
  • R 2 , R 3 , L, P, P * are as defined above, and the amino group contained in R 2 is a primary or secondary amino group, and P * is different from P Amino protecting group is shown.
  • the production method of the compound (8) includes, for example, the amino group of (R 3 ) NH— in the compound (11a).
  • the protecting group P * is protected, and then the amino group contained in R 2 is protected with the protecting group P. Thereafter, the desired compound (8) can be synthesized by deprotecting the protecting group P * . Examples where P * is a 2-nitrobenzenesulfonyl group and P is a tert-butoxycarbonyl group are shown below.
  • R 2 , R 3 and L are as defined above, and the amino group contained in R 2 represents a primary or secondary amino group.
  • the compound (11a) and 2-nitrobenzenesulfonyl chloride are selectively (R 3 ) in the presence of a base (eg, triethylamine) in an inert solvent (eg, dichloromethane, tetrahydrofuran, etc.) at ⁇ 20 ° C. to room temperature.
  • a base eg, triethylamine
  • an inert solvent eg, dichloromethane, tetrahydrofuran, etc.
  • the compound (64a) and benzenethiol are used in an inert solvent (eg, acetonitrile, dichloromethane, N, N-dimethylformamide, etc.) in the presence of a base (potassium carbonate, cesium carbonate, triethylamine, etc.) at room temperature or if necessary.
  • an inert solvent eg, dichloromethane, etc.
  • benzenethiol are used in an inert solvent (eg, acetonitrile, dichloromethane, N, N-dimethylformamide, etc.) in the presence of a base (potassium carbonate, cesium carbonate, triethylamine, etc.) at room temperature or if necessary.
  • the target compound (8a) can be synthesized by reacting under heating.
  • Compound (8) can be synthesized by condensing known compound (65) or compound (65) that can be easily synthesized by a known method and phthalimide by Mitsunobu reaction and then deprotecting with hydrazine or the like. .
  • R 2a , R 2b , L, and LG are as defined above.
  • R 2 is —N (R 2a ) (R 2b ) and R 2a and R 2b are both substituents other than hydrogen
  • Compound (11b) can be synthesized by condensing (67) and compound (68) by an alkylation reaction to obtain compound (69), followed by a deprotection reaction.
  • R 2a and L are as defined above.
  • R 2 is —N (R 2a ) (R 2b ) and at least one of R 2a and R 2b is hydrogen (for convenience, at least R 2b is hydrogen)
  • the compound (67 ) And compound (70) are condensed by an alkylation reaction to obtain compound (71), and then phthalimide side is deprotected to synthesize compound (8b) substituted with 2-nitrobenzenesulfonyl group as a substituent. Is possible.
  • a substituent is a halogen atom (chlorine, bromine, iodine, etc.)
  • an alkyl group an alkenyl group, an alkynyl group, a cyano group, an aryl group by a cross-coupling reaction using a derivative such as boron or tin and a transition metal catalyst
  • a derivative such as boron or tin and a transition metal catalyst
  • the carboxyl group can be converted to an amino group by a rearrangement reaction, converted to an aminocarbonyl group (amide) by amidation, and converted to an aldehyde by subjecting it to a reduction reaction. Moreover, it can be converted into a heteroaryl group, a heterocycle group, etc. by subjecting the aminocarbonyl group to a cyano group by subjecting it to a dehydration reaction, and carrying out a ring formation reaction using the aminocarbonyl group or cyano group. . In addition, conversion to a hydroxyalkyl group or an alkyl group is possible by reducing a carboxyl group or a carbonyl group.
  • the amino group can be converted to an alkylamino group by alkylation, to a carbonylamino group or a sulfonylamino group by amidation, to a halogen atom, a phenolic hydroxyl group, or a cyano group via a diazonium salt.
  • the phenolic hydroxyl group is converted to an alkoxy group by an alkylation reaction with an alkyl halide or a Mitsunobu reaction with an alkyl alcohol, and a phenolic hydroxyl group is converted to a trifluoromethylsulfonyloxy group, followed by a cross-coupling reaction.
  • the following production methods can be given as examples of the method for introducing and converting the substituent R 10 .
  • M 1 represents an atomic group capable of cross-coupling reaction (for example, an atomic group bonded by boron, tin, etc.), and LG * represents chlorine, bromine. , Iodine or a triflate group, and R 26 represents an aryl group, a heteroaryl group, a heterocycle group, an alkynyl group or the like.
  • a halogen atom capable of cross-coupling reaction such as chlorine, bromine, iodine, etc.
  • a compound R 26 -M 1 is used to carry out a cross coupling reaction (for example, a Suzuki coupling reaction, a Stille coupling reaction, etc.) in the presence of a metal catalyst, whereby R 10 is an aryl group, a heteroaryl group. It is possible to synthesize (II-2) which is a heterocycle group or an alkynyl group. This reaction is usually performed in an inert solvent in the presence of a metal catalyst. At this time, a base may be added.
  • Examples of the metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel.
  • examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium
  • examples of the divalent palladium catalyst include palladium acetate and dichlorobis (triphenylphosphine).
  • the zero-valent nickel catalyst such as palladium
  • 1,1′-bis (diphenylphosphino) ferrocene nickel and the like can be mentioned.
  • Monodentate ligands such as triphenylphosphine and tris (ortho-tolyl) phosphine, and bidentate ligands such as diphenylphosphinopropane and diphenylphosphinobutane may be added.
  • the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate, and alkali metal phosphates such as tripotassium phosphate.
  • M 1 is an atomic group bonded with tin, it is not necessary to use a base.
  • the amount of the metal catalyst used is, for example, 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent, relative to (II-1).
  • the amount of the base used is 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to (II-1).
  • the reaction temperature is usually from room temperature to the reflux temperature of the solvent.
  • the inert solvent include alcohols such as methanol, ethanol, isopropanol and tert-butanol, ethers such as tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate, dichloromethane, chloroform, dichloroethane, and carbon tetrachloride.
  • Halogenated hydrocarbons such as hexane, benzene, toluene, xylene and other hydrocarbons, N, N-dimethylformamide, N-methylpyrrolidone, amides such as N, N-dimethylacetamide, nitriles such as acetonitrile, Sulfoxides such as dimethyl sulfoxide, water, and the like are used, and these may be mixed and used at an appropriate ratio.
  • M 1 is an atomic group containing tin, it is preferable to carry out in a non-aqueous solvent.
  • the amount of compound R 26 -M 1 to be used is, for example, 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to (II-1).
  • (II-1) by subjecting (II-1) to a Suzuki coupling reaction or a still coupling reaction using a diborane derivative such as bis (pinacolato) diborane or a ditin derivative such as hexabutylditine (II- After conversion to 3), (II-2) can be synthesized by reacting again with compound R 26 -LG * .
  • a diborane derivative such as bis (pinacolato) diborane or a ditin derivative such as hexabutylditine
  • (II-1) and zinc cyanide are added in a solvent such as N, N-dimethylformamide or N-methylpyrrolidone in the presence of a transition metal catalyst (eg, tetrakistriphenylphosphine palladium (0)).
  • a transition metal catalyst eg, tetrakistriphenylphosphine palladium (0).
  • (II-4) can be converted into (II-5) in which R 10 is a tetrazole group using, for example, sodium azide, trimethyltin azide and the like.
  • (II-4) is reacted with hydroxylamine or a salt thereof to convert to (II-6), then acylated with a hydroxyl group and subjected to a dehydration reaction, whereby R 10 is 1,2,4-oxadi It can be converted to (II-7) which is an azol-3-yl group.
  • (II-6) is reacted with N, N-dimethylacetamide dimethyl acetal under heating, whereby R 10 is a 5-methyl-1,2,4-oxadiazol-3-yl group ( II-7 * ) can also be converted.
  • (II-6) can be converted to (II-8) by reacting with ethyl chloroformate or the like under basic conditions, and further converted to (II-9) by alkylation. Is possible.
  • (II-6) can be converted to (II-10) by reacting with 1,1′-thiocarbonyldiimidazole or the like.
  • (II-11) can be converted to an aminocarbonothioyl group to give (II-12), and then R 10 can be converted to a thiazole group (II-13).
  • R 10 is 1,2,4-oxadiazol-5-yl group (II-15) to, by reaction with hydrazine or hydrazinium salt, R 10 is 1,2,4-triazol-3-yl It is possible to convert to the group (II-16).
  • R 10 can be converted to (II-21) in which R 10 is a 1,3,4-thiadiazole group using a Lawson reagent or the like. is there.
  • (II-20) can be converted to (II-22) where R 10 is a 1,3,4-oxadiazole group using polyphosphoric acid or the like.
  • R 9 and R 27 are as defined above, and R 29 represents hydrogen or a C 1-4 alkyl group.
  • R 29 represents hydrogen or a C 1-4 alkyl group.
  • the compound (I) and each intermediate obtained as described above are isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization and various chromatography.
  • the salt of the compound (I) an acid addition salt or a base addition salt can be used, but the type of the salt is not particularly limited as long as it is physiologically acceptable.
  • a salt of compound (I) or a solvate thereof can be produced from compound (I) by a known method.
  • compound (I) or a salt thereof contains an optically active substance, it can be separated into individual optical isomers by an ordinary optical resolution means.
  • an optically active compound (I) or a salt thereof may be synthesized using an optically pure starting material or a compound having a known configuration.
  • the compound of the present invention has a homocysteine synthetase inhibitory action and is useful as a homocysteine synthetase inhibitor, particularly as a medicament for treating or preventing hyperhomocysteinemia.
  • the amide derivative represented by the above formula (I ′) or a pharmacologically acceptable salt thereof, or a solvate thereof has the same effect as the compound of the present invention.
  • the compound of the present invention is involved in homocysteine synthase in a subject by administering an effective amount to the subject (eg, mammals such as humans, dogs, cats, cows, horses, pigs, monkeys, mice, etc., preferably humans). It can be used for prevention or treatment of diseases. Examples of diseases involving homocysteine synthase include hyperhomocysteinemia.
  • One or more of the compounds of the present invention may be administered to a patient as they are, but preferably, an active ingredient and a pharmacologically and pharmaceutically acceptable additive are added to form a form well known to those skilled in the art. It can be provided as a formulation.
  • the compound of the present invention is prepared in an appropriate dosage form (powder, injection, tablet, capsule, topical preparation, etc.) together with an appropriate diluent and other additives that are usually used, and then according to the dosage form. It can be administered to humans or animals by an appropriate administration method (for example, intravenous administration, oral administration, transdermal administration, topical administration, etc.).
  • excipients As pharmacologically and pharmaceutically acceptable additives, excipients, disintegrants, binders, lubricants, coating agents, dyes, diluents, bases, tonicity agents, etc. should be used. I can do it.
  • preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, syrups, etc.
  • preparations suitable for parenteral administration include injections and infusions. Or a suppository.
  • excipients, disintegrants, binders, lubricants, coating agents or bases can be used as additives.
  • another compound suitable for the treatment of the target disease and the compound of the present invention may be used in combination.
  • 1 H-NMR proto nuclear magnetic resonance spectrum
  • TMS tetramethylsilane
  • ⁇ relative delta
  • Coupling constant (J) indicates trivial multiplicity in hertz (Hz)
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • quintet is a quintet line
  • m is a multiple line
  • dd represents a double doublet
  • dt represents a double triplet
  • broad represents a broad absorption peak
  • brs represents a broad single absorption peak.
  • Reference example 2 tert-Butyl (2-aminoethyl) ethylcarbamate N-ethylethylenediamine (21.02 g, 238 mmol) and triethylamine (51 ml, 366 mmol) were dissolved in dichloromethane (200 ml), and the mixture was cooled to -20 ° C. with stirring, and 2-nitrobenzenesulfonyl chloride (54.45 g, 246 mmol) was dissolved. The mixture was gradually added, followed by stirring at 0 ° C. for 8 hours.
  • the reaction solution was diluted with water, concentrated under reduced pressure, most of acetonitrile was distilled off, and the aqueous layer was extracted with dichloromethane.
  • the obtained organic layer was dried over potassium carbonate, the insoluble material was filtered off, and the solvent was concentrated under reduced pressure.
  • the obtained oil was dissolved in toluene and extracted with 500 ml of 10% aqueous citric acid solution.
  • a sodium hydroxide aqueous solution was added to the aqueous layer to form a strong alkaline solution, and then the floating oily substance was extracted.
  • the aqueous layer was extracted with dichloromethane, and the oily substance and the dichloromethane solution were mixed and dried over potassium carbonate.
  • Step A tert-Butyl isopropyl [2- ⁇ [(2-nitrophenyl) sulfonyl] amino ⁇ ethyl] carbamate N-isopropylethylenediamine (8.44 g, 82.60 mmol) and triethylamine (18 ml, 129 mmol) were dissolved in dichloromethane (80 ml) and stirred under ice-cooling.
  • Step B tert-butyl (2-aminoethyl) isopropylcarbamate 34.21 g (82.60 mmol) of the compound obtained in Step A was dissolved in 300 ml of acetonitrile, and 52.38 g (161 mmol) of cesium carbonate and 12 ml (117 mmol) of benzenethiol were added at room temperature. Stir all day and night. After the reaction solution was diluted with water, the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over potassium carbonate, insoluble matters were filtered, and the solution was concentrated under reduced pressure.
  • the obtained oil was dissolved in toluene and extracted with 1N aqueous potassium hydrogen sulfate solution.
  • An aqueous sodium hydroxide solution was added to the aqueous layer to make a strong alkaline solution, and then the floating oil was extracted.
  • the aqueous layer was extracted with dichloromethane, and the oil and dichloromethane were mixed and dried over sodium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound as a pale yellow oil (15.0 g, yield 79%).
  • Step B N- [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl] -N-isopropyl-2-nitrobenzenesulfonamide 6.29 g (25.75 of the compound obtained in Step A mmol) was dissolved in 100 ml of N-methylpyrrolidone and stirred under ice cooling. To this, 1.21 g (30 mmol) of 60% sodium hydride was added and stirred at room temperature for 20 minutes, then 8.31 g (31.0 mmol) of N- (3-bromopropyl) phthalimide was further added and stirred at 70 ° C. for 90 minutes.
  • the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of diethyl ether-hexane and dried under reduced pressure to give 8.11 g (yield 73%) of the title compound as a colorless solid.
  • Step C N- (3-Aminopropyl) -N-isopropyl-2-nitrobenzenesulfonamide 8.11 g (18.80 mmol) of the compound obtained in Step B and 5 ml of hydrazine monohydrate were added to 200 ml of ethanol, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled and diluted with diethyl ether. Insoluble matter was filtered off, and the solution was concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane and extracted with hydrochloric acid. An aqueous sodium hydroxide solution was added to the aqueous layer to make it alkaline, followed by extraction with dichloromethane, and the organic layer was dried over potassium carbonate.
  • Step A Using 12.4 g of N-methyl-2-nitrobenzenesulfonamide methylamine hydrochloride according to the method of Reference Example 4, step A, 7.39 g (yield 32%) of the title compound was obtained as a colorless solid.
  • Step B N- [3- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl] -N-methyl-2-nitrobenzenesulfonamide 3.10 g (14.34) of the compound obtained in Step A mmol) and 3.80 g (14.17 mmol) of N- (3-bromopropyl) phthalimide were obtained according to the method of Reference Example 4, Step B to obtain 4.19 g (yield 73%) of the title compound as a pale yellow solid.
  • Step C N- (3-Aminopropyl) -N-methyl-2-nitrobenzenesulfonamide hydrochloride Using the compound obtained in Step B, 4.18 g (10.36 mmol), N- (3- Aminopropyl) -N-methyl-2-nitrobenzenesulfonamide (3.20 g) was obtained as a crude oil. This was dissolved in 50 ml of dichloromethane, 3 ml of 4N hydrochloric acid-dioxane solution was added, and then diluted with diethyl ether to precipitate a solid. The precipitated solid was filtered and dried under reduced pressure to obtain 3.18 g (yield 99%) of the title compound as a pale yellow solid.
  • Step A N- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] -N-methyl-2-nitrobenzenesulfonamide
  • Reference Example 5 4.26 g (19.7 mmol), 5.05 g (19.9 mmol) of N- (2-bromoethyl) phthalimide, and according to the method of Reference Example 4, Step B, 1.64 g (yield 21%) of the title compound was obtained as pale yellow crystals.
  • Step B N- (2-Aminoethyl) -N-methyl-2-nitrobenzenesulfonamide Using 1.63 g (4.19 mmol) of the compound obtained in Step A and according to the method of Reference Example 4, Step C, 0.95 g of the title compound ( (88% yield) was obtained as a yellow oil.
  • Step A tert-Butyl [2- ⁇ [(2-nitrophenyl) sulfonyl] amino ⁇ ethyl] carbamate Using 4.61 g of tert-butyl (2-aminoethyl) carbamate according to the method of Reference Example 4 Step A, 2.22 g of the title compound (22% yield) was obtained as a yellow oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.42 (s, 9H), 3.2-3.4 (m, 4H), 4.84 (brs, 1H), 5.71 (brs, 1H), 7.73-7.79 (m , 2H), 7.85-7.90 (m, 1H), 8.11-8.15 (m, 1H).
  • Step B N- (2-Aminoethyl) -N-isopropyl-2-nitrobenzenesulfonamide 2.22 g (6.43 mmol) of the compound obtained in Step A, 0.65 ml (8.46 mmol) of isopropanol and 1.85 g (7.05 mmol) of triphenylphosphine It melt
  • reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and the precipitated colorless solid was filtered.
  • the oil obtained by concentrating the mother liquor under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to give tert-butyl [2- ⁇ isopropyl [(2-nitrophenyl) sulfonyl] amino ⁇ ethyl].
  • a colorless crude oil of 3.75 g of carbamate was obtained. This was dissolved in 10 ml of dichloromethane, 10 ml of 4N hydrochloric acid-dioxane solution was added at room temperature, and the mixture was stirred for 1 hour.
  • the reaction mixture was diluted with diethyl ether and extracted with water.
  • the aqueous layer was made alkaline with aqueous sodium hydroxide, extracted with dichloromethane, dried over sodium sulfate, insolubles were filtered, and the solution was concentrated under reduced pressure to give 1.39 g (yield 75%) of the title compound as a yellow oil. Obtained.
  • Step A [(2R) -1-glycylpyrrolidin-2-yl] methanol N- (tert-butoxycarbonyl) glycine 5.00 g (28.5 mmol), D-prolinol 3.50 g (34.2 mmol) in N, N-dimethylformamide 10 ml , Dissolved in 100 ml of dichloromethane and stirred at room temperature.
  • Step B [(2R) -1- (2-aminoethyl) pyrrolidin-2-yl] methanol 720 mg (19.0 mmol) of lithium aluminum hydride was added to 30 ml of tetrahydrofuran, followed by stirring under ice cooling. Next, 20 ml of a tetrahydrofuran solution containing 1.00 g (6.32 mmol) of the compound obtained in Step A was slowly added, followed by heating under reflux for 2 hours. After cooling the reaction solution, 0.72 ml of water, 1.44 ml of 1N aqueous sodium hydroxide solution and 0.72 ml of water were slowly added in this order while stirring, and then stirred at room temperature for 1 hour.
  • Step A 4.88 g (48.2 mmol) of tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate 4-hydroxypiperidine was dissolved in 50 ml of dichloromethane, added with 6.7 ml (48.1 mmol) of triethylamine, and stirred under ice cooling. . To this was added 10.11 g (46.3 mmol) of di-tert-butyl dicarbonate dissolved in 30 ml of dichloromethane.
  • Step B tert-Butyl 4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-1-carboxylate 2.43 g (8.70 mmol) of the compound obtained in step A, potassium phthalimide 2.40 g (12.96 mmol) was used, and the title compound 846 mg (yield 29%) was obtained as a colorless solid according to the method of Reference Example 4, Step B.
  • Step C tert-Butyl 4-aminopiperidine-1-carboxylate hydrochloride
  • 837 mg (2.53 mmol) of the compound obtained in Step B and 0.31 ml (6.4 mmol) of hydrazine monohydrate were added and heated under reflux for 1 hour. .
  • the reaction solution was cooled, and diethyl ether was added thereto to precipitate a solid.
  • the precipitated solid was filtered, and the resulting solution was concentrated under reduced pressure to obtain a colorless oil.
  • Step A tert-butyl 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-1-carboxylate tert-butyl 3-hydroxypiperidine-1-carboxylate 4.38 in 60 ml of tetrahydrofuran g (21.76 mmol), 4.82 g (32.76 mmol) of phthalimide, and 8.62 g (32.86 mmol) of triphenylphosphine were slowly added to a 15% 40% diethyl azodicarboxylate-toluene solution while stirring at room temperature. Stir overnight.
  • reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and the precipitated colorless solid was filtered.
  • the mother liquor was concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2.04 g (yield 28%) of the title compound as a colorless solid.
  • Step B tert-Butyl 3-aminopiperidine-1-carboxylate hydrochloride Using the compound obtained in Step A (2.04 g, 6.17 mmol) according to the method of Reference Example 9, Step C, 1.45 g (99% yield) of the title compound was obtained as a colorless solid.
  • 1 H-NMR 300MHz, DMSO-d 6 ); ⁇ (ppm) 1.3-1.6 (m, 2H), 1.43 (s, 9H), 1.6-1.8 (m, 1H), 1.9-2.0 (m, 1H) , 2.7-3.1 (m, 3H), 3.6-3.8 (m, 1H), 3.9-4.0 (m, 1H), 8.23 (brs, 3H).
  • This was dissolved in 70 ml of methanol, and 14.46 g of potassium carbonate dissolved in 50 ml of water was added under ice cooling, followed by stirring at room temperature for 5 hours.
  • the reaction mixture was concentrated under reduced pressure, diluted with diethyl ether, washed with saturated brine, and dried over sodium sulfate.
  • Step A tert-butyl ⁇ 2-[(trifluoroacetyl) amino] ethyl ⁇ carbamate
  • tert-butyl 2-[(trifluoroacetyl) amino] ethyl ⁇ carbamate
  • Step B tert-Butyl ⁇ 2-[(2,2,2-trifluoroethyl) amino] ethyl ⁇ carbamate 6.57 g (25.6 mmol) of the compound obtained in Step A was dissolved in 100 ml of tetrahydrofuran and stirred under ice cooling. Next, a suspension of lithium aluminum hydride 1.94 g (51.2 mmol) in tetrahydrofuran (50 ml) was slowly added dropwise. Then, it was left overnight at room temperature.
  • Step C tert-butyl ⁇ 2-[(trifluoroacetyl) (2,2,2-trifluoroethyl) amino] ethyl ⁇ carbamate Using 4.56 g (18.8 mmol) of the compound obtained in Step B, Reference Example 14 Step A In this manner, 3.05 g (yield 48%) of the title compound was obtained as a pale yellow oil.
  • 1 H-NMR 300MHz, DMSO-d 6 ); ⁇ (ppm) 1.36 (s, 9H), 3.20-3.32 (m, 2H), 3.43-3.58 (m, 2H), 4.25-4.40 (m, 2H) , 7.04 (brs, 1H).
  • Step D N- (2-Aminoethyl) -2,2,2-trifluoro-N- (2,2,2-trifluoroethyl) acetamide hydrochloride 3.05 g (9.02 mmol) of the compound obtained in Step C was added to ethyl acetate. After dissolving in 20 ml, 10 ml of 4N hydrochloric acid-ethyl acetate solution was added and stirred at room temperature for 6 hours. The precipitated solid was filtered, and the obtained solid was washed with ethyl acetate and dried under reduced pressure to obtain 1.51 g (yield 61%) of the title compound as a light brown solid.
  • Step A [Benzyl (tert-butyl) amino] acetonitrile 10.0 g (61.3 mmol) of benzyl (tert-butyl) amine is dissolved in 100 ml of acetonitrile, and stirred at room temperature, 4.5 ml (64.6 mmol) of bromoacetonitrile, 16.9 g (122.3 mmol) of potassium carbonate. ) And sodium iodide 9.2 g (61.4 mmol) were sequentially added, and the mixture was stirred overnight at the same temperature.
  • Step B N-benzyl-N- (tert-butyl) ethane-1,2-diamine
  • the compound 5.00 g (24.7 mmol) obtained in Step A was dissolved in 100 ml of tetrahydrofuran and stirred under ice cooling. At the same temperature, 1.87 g (49.4 mmol) of lithium aluminum hydride was slowly added, and then stirred at room temperature for 2 hours. After ice cooling again, 1.9 ml of water, 3.8 ml of 1N aqueous sodium hydroxide solution and 1.9 ml of water were slowly added in this order, and then stirred at room temperature for 1 hour.
  • Step C N- (tert-butyl) ethane-1,2-diamine 2.65 g (12.8 mmol) of the compound obtained in Step B was dissolved in 30 ml of ethanol and stirred at room temperature. Next, 500 mg of 10% palladium carbon (containing water) was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The insoluble material was filtered through Celite, and the obtained solution was concentrated under reduced pressure to give the title compound (850 mg, yield 57%) as a pale-yellow oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.00 (s, 9H), 2.40-2.46 (m, 2H), 2.49-2.56 (m, 2H), 2.75-4.00 (broad, 3H).
  • Step A tert-Butyl 1-methylhydrazinecarboxylate Journal of Heterocyclic Chemistry, 2000, 37, 1, 47-55 (Journal of Heterocyclic Chemistry, 2000, 37 (1), 47-55)
  • 122.7 g of the title compound was obtained as a colorless oil from 44.1 g of N-methylhydrazine.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.48 (s, 9H), 3.06 (s, 3H), 4.06 (brs, 2H).
  • Step B tert-Butyl 1,3-dihydro-2H-isoindol-2-yl (methyl) carbamate
  • the reaction was carried out according to the method described in US Pat. No. 4,272,284. 160 g (606 mmol) of xylylene dibromide and 88.52 g (606 mmol) of the compound obtained in Step A were dissolved in 550 ml of N-methylpyrrolidone. While maintaining the reaction solution at 50 ° C. to 60 ° C., 190 ml (1.36 mol) of triethylamine was gradually added with a dropping funnel with stirring, and after completion of the addition, the reaction solution was left at room temperature overnight.
  • Step C N-methyl-1,3-dihydro-2H-isoindole-2-amine hydrochloride 126 g of the compound obtained in Step B was dissolved in a mixed solvent of 150 ml of dichloromethane and 150 ml of ethanol. While stirring at room temperature, 500 ml of 4N hydrochloric acid-dioxane solution was added and stirred at the same temperature for 5 hours. The reaction solution was diluted with dichloromethane and water, and then the aqueous layer was extracted. An ice-cooled sodium hydroxide aqueous solution was added to the ice-cooled aqueous layer to make the aqueous layer strongly alkaline, and then the aqueous layer was extracted with dichloromethane.
  • Step A tert-Butyl (4-fluoro-1,3-dihydro-2H-isoindol-2-yl) methylcarbamate 1.60 g of 3-fluoro-ortho-xylene (16.03 mmol) in 60 ml of carbon tetrachloride, N-bromosuccinic acid 6.98 g (39.22 mmol) of imide and 0.24 g of benzoyl peroxide were added, and the mixture was heated to reflux for 45 minutes. After cooling the reaction solution, it was diluted with hexane, insolubles were filtered, and the resulting solution was concentrated under reduced pressure. The reaction was carried out using the resulting oil according to the method of Reference Example 17, Step B.
  • Step B 4-Fluoro-N-methyl-1,3-dihydro-2H-isoindol-2-amine hydrochloride 806 mg (3.03 mmol) of the compound obtained in Step A was dissolved in 3 ml of dichloromethane and 0.3 ml of ethanol. While stirring at room temperature, 3 ml of 4N hydrochloric acid-dioxane solution was added and stirred at the same temperature for 100 minutes. Diethyl ether was added to the reaction solution, the precipitated solid was filtered, and the solid obtained after washing with diethyl ether was dried under reduced pressure to obtain 433 mg (yield 71%) of the title compound as a gray solid.
  • Step A Using 20.05 g (161.5 mmol) of tert-butyl (5-fluoro-1,3-dihydro-2H-isoindol-2-yl) methylcarbamate 4-fluoro-ortho-xylene according to the method of Reference Example 18 Step A The title compound (13.04 g, 30% yield) was obtained as a tan oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.41 (s, 9H), 3.08 (s, 3H), 4.39 (s, 2H), 4.43 (s, 2H), 6.85-6.95 (m, 2H ), 7.07-7.13 (m, 1H).
  • Step B 5-Fluoro-N-methyl-1,3-dihydro-2H-isoindole-2-amine hydrochloride Using 13.04 g (48.97 mmol) of the compound of Step A and following the method of Reference Example 18 Step B, the title compound 7.61 g (77% yield) was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.77 (s, 3H), 4.39 (s, 2H), 4.42 (s, 2H), 7.09-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.34-7.40 (m, 1H), 10.9 (brs, 2H).
  • Step A tert-butyl (5-methoxy-1,3-dihydro-2H-isoindol-2-yl) methylcarbamate 4-methoxy-ortho-xylene 6.85 g (50.3 mmol) was used according to the method of Reference Example 18 Step A The title compound (2.11 g, yield 15%) was obtained as a brown oil.
  • Step B 5-Methoxy-N-methyl-1,3-dihydro-2H-isoindol-2-amine hydrochloride Using 2.10 g (7.54 mmol) of the compound obtained in Step A, according to the method of Reference Example 18 Step B, The title compound (1.23 g, yield 76%) was obtained as a pale yellow solid.
  • Step A Using 5.88 g (31.77 mmol) tert-butyl (5-cyano-1,3-dihydro-2H-isoindol-2-yl) methylcarbamate 4-bromo-ortho-xylene according to the method of Reference Example 18 Step A 2.52 g of 5-bromo-1,3-dihydro-2H-isoindol-2-yl (methyl) carbamate was obtained as a brown crude oil.
  • This oily substance 734 mg (6.25 mmol) of zinc cyanide, and 1.74 g of tetrakis (triphenylphosphine) palladium (0) were added to 25 ml of N, N-dimethylformamide, and the reaction solution was heated and stirred at 100 ° C. for 7 hours. .
  • the reaction mixture was cooled, diluted with ethyl acetate, and insolubles were filtered off. The filtrate was washed with aqueous ammonia and saturated brine, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the solution was concentrated under reduced pressure.
  • Step B 5-Cyano-N-methyl-1,3-dihydro-2H-isoindole-2-amine hydrochloride Using 370 mg (1.35 mmol) of the compound of Step A and according to the method of Reference Example 18 Step B, 200 mg of the title compound ( Yield 70%) was obtained as a gray solid.
  • Step A tert-Butyl 1-ethylhydrazinecarboxylate Journal of Heterocyclic Chemistry, 2000, 37, 1, 47-55 (Journal of Heterocyclic Chemistry, 2000, 37 (1), 47-55)
  • the title compound (64.8 g) was obtained as a colorless oil from 25.0 g of N-ethylhydrazine.
  • Step B tert-Butyl 1,3-dihydro-2H-isoindol-2-yl (ethyl) carbamate Using 6.0 g (38 mmol) of the compound obtained in Step A according to the method of Reference Example 17 Step B, the title compound 6.5 g (66% yield) was obtained as a light brown crude solid.
  • Step C N-ethyl-1,3-dihydro-2H-isoindole-2-amine hydrochloride Using the compound 6.10 g (23 mmol) obtained in Step B, according to the method of Reference Example 18, Step B, 4.15 g of the title compound ( Yield 90%) was obtained as a gray solid.
  • 1 H-NMR 300MHz, DMSO-d 6 ); ⁇ (ppm) 1.26 (brs, 3H), 3.19 (brs, 2H), 4.43 (s, 4H), 7.3-7.4 (m, 4H), 10.9 (brs , 2H).
  • Step A tert-Butyl (2,3-dihydro-1H-inden-2-yl) carbamate 3.10 g (23.3 mmol) of 2-aminoindane was dissolved in 50 ml of dichloromethane, and 5.20 g of di-tert-butyl dicarbonate under ice-cooling ( 23.8 mmol) and 5 ml of triethylamine were added and stirred at room temperature for 2 hours.
  • the solution was concentrated under reduced pressure to give 4.68 g (yield 86%) of the title compound as a colorless oil.
  • Step B N-methylindan-2-amine hydrochloride
  • 2.56 g (67.46 mmol) of lithium aluminum hydride and 4.63 g (19.84 mmol) of the compound obtained in Step A were added and heated under reflux for 3 hours.
  • the reaction mixture was ice-cooled, and 2.56 ml of water, 2.56 ml of 15% aqueous sodium hydroxide, 7.68 ml of water and anhydrous magnesium sulfate were successively added with stirring.
  • the insoluble material was filtered through celite, and the solution was concentrated under reduced pressure to give 3.15 g of an oil.
  • Step A N- (2,3-dihydro-1H-inden-2-yl) acetamide 2-aminoindane (1.07 g, 8.03 mmol) was dissolved in dichloromethane (20 ml) and acetic anhydride (0.76 ml, 8.04 mmol) and triethylamine (1.7 ml) were cooled with ice And stirred at room temperature for 50 minutes.
  • Step A 6-Methyl-1H-indene-1,2 (3H) -dione 2-oxime
  • the precipitated solid was filtered and washed with diisopropyl ether to obtain 5.36 g (yield 89%) of the title compound as a pale yellow solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.39 (s, 3H), 3.72 (s, 2H), 7.45-7.60 (m, 3H), 12.59 (s, 1H).
  • Step B 6-Methyl-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇
  • the compound obtained in Step A (4.36 g, 24.9 mmol), imidazole (5.10 g, 74.7 mmol), tert-butyldimethylsilyl chloride (5.60 g, 37.4 mmol) was added to 50 ml of N, N-dimethylformamide at room temperature, and 95. Stir for 2 hours at ° C.
  • Step C Ethyl (1-hydroxy-6-methyl-2,3-dihydro-1H-indene- 2-yl) carbamate
  • the compound obtained in Step B (6.00 g, 20.7 mmol) was dissolved in 100 ml of tetrahydrofuran, and heated and stirred at 63 ° C. At the same temperature, 41.4 ml (41.4 mmol) of a 1 mol / L borane-tetrahydrofuran complex / tetrahydrofuran solution was slowly added dropwise. After stirring at the same temperature for 2.5 hours, the mixture was cooled to room temperature, and methanol was slowly added dropwise with stirring.
  • reaction solution was concentrated under reduced pressure, methanol and toluene were added again, and the solution was concentrated under reduced pressure. After repeating this four times, the obtained colorless solid and 3.5 ml (24.8 mmol) of triethylamine were dissolved in 50 ml of dichloromethane and stirred under ice cooling. Next, 2.2 ml (22.8 mmol) of ethyl chloroformate was added, and the mixture was allowed to stand overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Step D Ethyl (5-methyl-2,3-dihydro-1H-inden-2-yl) carbamate 3.90 g (13.9 mmol) of the compound obtained in Step C, triethylsilane in 90 ml of 1,2-dichloroethane with stirring at room temperature 4.4 ml (27.8 mmol) and 3.4 ml (27.8 mmol) of boron trifluoride-diethyl ether complex dissolved in 20 ml of 1,2-dichloroethane were added, followed by stirring at 83 ° C. for 1 hour. After cooling to room temperature, the reaction solution was diluted with water and extracted with dichloromethane.
  • Step E 5, N-Dimethylindan-2-amine hydrochloride Using 2.76 g (12.6 mmol) of the compound obtained in Step D, according to the method of Reference Example 23, Step B, 1.52 g (yield 61%) of the title compound was obtained. Obtained as a yellow solid.
  • Step A 4-methyl-1H-indene-1,2 (3H) -dione 2-oxime Using 5.00 g (34.2 mmol) of 4-methylindan-1-one according to the method of Reference Example 25, step A, 4.03 g of the title compound (Yield 67%) was obtained as a light brown solid.
  • Step B 4-Methyl-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇
  • Step B 4-Methyl-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇
  • Step C Ethyl (1-hydroxy-4-methyl-2,3-dihydro-1H-inden-2-yl) carbamate According to the method of Reference Example 25, Step C, using 6.24 g (21.6 mmol) of the compound obtained in Step B This gave 2.73 g (54% yield) of the title compound as a light brown solid.
  • Step D Ethyl (4-methyl-2,3-dihydro-1H-inden-2-yl) carbamate Using 2.73 g (11.6 mmol) of the compound obtained in Step C, according to the method of Reference Example 25, Step D, the title compound 2.36 g (93% yield) was obtained as a light brown solid.
  • Step E 4, N-dimethylindan-2-amine hydrochloride Using 2.36 g (10.8 mmol) of the compound obtained in Step D, according to the method of Reference Example 23, Step B, 1.85 g (yield 87%) of the title compound was obtained. Obtained as a brown solid.
  • Step A 5-Fluoro-1H-indene-1,2 (3H) -dione 2-oxime Using 5.00 g (33.3 mmol) of 5-fluoroindan-1-one according to the method of Reference Example 25, Step A, 4.45 g of the title compound (75% yield) was obtained as a light brown solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 3.78 (s, 2H), 7.21-7.37 (m, 1H), 7.40-7.51 (m, 1H), 7.75-7.90 (m, 1H) , 12.67 (s, 1H).
  • Step B 5-Fluoro-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇ Using the compound 4.45 g (24.8 mmol) obtained in Step A and according to the method of Reference Example 25, Step B, 5.15 g (yield 71%) of the title compound was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 0.27 (s, 6H), 0.97 (s, 9H), 3.82 (s, 2H), 7.02-7.18 (m, 2H), 7.85-7.98 (m , 1H).
  • Step C Ethyl (1-hydroxy-5-fluoro-2,3-dihydro-1H-inden-2-yl) carbamate According to the method of Reference Example 25, Step C, using 5.15 g (17.6 mmol) of the compound obtained in Step B 1.84 g (44% yield) of the title compound was obtained as a colorless solid.
  • Step D 5-Fluoro-N-methylindan-2-amine hydrochloride Using 1.84 g (7.69 mmol) of the compound obtained in Step C, according to the method of Reference Example 25 Step D and Reference Example 23 Step B, 1.06 g of the title compound (Yield 68%) was obtained as a light brown solid.
  • Step A 5-Chloro-1H-indene-1,2 (3H) -dione 2-oxime Using 5.00 g (30.0 mmol) of 5-chloroindan-1-one according to the method of Reference Example 25, Step A, 4.67 g of the title compound (Yield 80%) was obtained as a light brown solid.
  • Step B Ethyl (1-hydroxy-5-chloro-2,3-dihydro-1H-inden-2-yl) carbamate Using 4.45 g (24.8 mmol) of the compound obtained in Step A, using Reference Example 25 Steps B and C According to the method, 2.78 g (yield 39%) of the title compound was obtained as a brown oil.
  • Step C Ethyl (5-chloro-2,3-dihydro-1H-inden-2-yl) carbamate Using 2.78 g (10.87 mmol) of the compound obtained in Step B, according to the method of Reference Example 25, Step D, the title compound 2.31 g (89% yield) was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.20-1.28 (m, 3H), 2.70-2.85 (m, 2H), 3.15-3.32 (m, 2H), 4.02-4.21 (m, 2H) , 4.43-4.52 (m, 1H), 4.85 (brs, 1H), 7.11-7.22 (m, 3H).
  • Step D 5-Chloro-N-methylindan-2-amine hydrochloride Using 2.31 g (9.64 mmol) of the compound obtained in Step C, according to the method of Reference Example 23, Step B, 1.79 g of the title compound (yield 85%) Was obtained as a pale green solid.
  • Step A 5-methoxy-1H-indene-1,2 (3H) -dione 2-oxime Using 5.00 g (30.8 mmol) of 5-methoxyindan-1-one according to the method of Reference Example 25, Step A, 5.35 g of the title compound (Yield 91%) was obtained as a brown solid.
  • Step B 5-Methoxy-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇ Using 3.40 g (17.8 mmol) of the compound obtained in Step A and according to the method of Reference Example 25, Step B, 4.91 g (yield 90%) of the title compound was obtained as a light brown solid.
  • Step C Ethyl (1-hydroxy-5-methoxy-2,3-dihydro-1H-inden-2-yl) carbamate According to the method of Reference Example 25, Step C, using 4.91 g (16.1 mmol) of the compound obtained in Step B 3.05 g (yield 81%) of the title compound was obtained as a pale yellow solid.
  • Step D Ethyl (5-methoxy-2,3-dihydro-1H-inden-2-yl) carbamate Using 3.05 g (13.0 mmol) of the compound obtained in Step C according to the method of Reference Example 25, Step D, the title compound 2.35 g (77% yield) was obtained as a light brown solid.
  • Step E 5-methoxy-N-methylindan-2-amine hydrochloride 1.98 g of the title compound (93% yield) using 2.35 g (9.99 mmol) of the compound obtained in Step D according to the method of Reference Example 23, Step B was obtained as a light brown solid.
  • Step A According to the method of Reference Example 25, Step A using 10.0 g (52.0 mmol) of 5,6-dimethoxy-1H-indene-1,2 (3H) -dione 2-oxime 5,6-dimethoxyindan-1-one, The title compound (11.64 g, yield 100%) was obtained as a light brown solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 3.66 (s, 2H), 3.83 (s, 3H), 3.90 (s, 3H), 7.18 (s, 1H), 7.19 (s, 1H ), 12.40 (s, 1H).
  • Step B 5,6-Dimethoxy-1H-indene-1,2 (3H) -dione 2- ⁇ O- [tert-butyl (dimethyl) silyl] oxime ⁇ Using 11.64 g (52.0 mmol) of the compound obtained in Step A and according to the method of Reference Example 25, Step B, 16.70 g (yield 96%) of the title compound was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 0.29 (s, 6H), 0.98 (s, 9H), 3.75 (s, 2H), 3.93 (s, 3H), 3.99 (s, 3H), 6.90 (s, 1H), 7.32 (s, 1H).
  • Step C Ethyl (5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl) carbamate According to the method of Reference Example 25, Steps C and D using 10.0 g (29.8 mmol) of the compound obtained in Step B This gave 3.31 g (42% yield) of the title compound as a brown solid.
  • Step D 5,6-Dimethoxy-N-methylindan-2-amine hydrochloride Using 3.31 g (12.48 mmol) of the compound obtained in Step C and according to the method of Reference Example 23, Step B, 3.03 g of the title compound (yield 100) %) As a light brown solid.
  • Step A Using tert-butyl (3,4-dichlorophenyl) carbamate 3,4-dichloroaniline 5.00 g (30.9 mmol) according to the method of Reference Example 23, Step A, 4.62 g (yield 59%) of the title compound was obtained as a colorless solid. Obtained.
  • Step B 3,4-Dichloro-N-methylaniline hydrochloride Using 4.62 g (17.6 mmol) of the compound obtained in Step A and according to the method of Reference Example 23, Step B, 3.38 g (yield 100%) of the title compound is colorless. Obtained as a solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.67-2.71 (m, 3H), 6.51-7.18 (m, 2H), 7.25-7.40 (m, 1H), 9.2-10.9 (broad, 2H).
  • Step A Using tert-butyl (2,3-dihydro-1H-inden-5-yl) carbamate 5-aminoindane (4.10 g, 30.9 mmol) according to the method of Reference Example 23, Step A, 6.98 g (yield 97 %) As a brown solid.
  • Step B N-methylindan-5-amine hydrochloride Using 6.98 g (29.9 mmol) of the compound obtained in Step A and according to the method of Reference Example 23, Step B, 3.91 g (yield 71%) of the title compound as a brown solid Obtained.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 1.97-2.09 (m, 2H), 2.79-2.93 (m, 4H), 2.86 (s, 3H), 7.23-7.41 (m, 3H) , 11.10 (brs, 2H).
  • Step A tert-Butyl (trans-4-phenylcyclohexyl) carbamate Journal of Organic Chemistry, 1952, 17: 1017-1022 (Journal of Organic Chemistry, 1952, 17, 1017-1022) Using 4.02 g (16.15 mmol) of phenylcyclohexylamine hydrochloride and 4.8 ml (34 mmol) of triethylamine according to the method of Reference Example 23, Step A, 4.06 g (yield 91%) of the title compound was obtained as a colorless solid.
  • Step B Trans-N-methyl-4-phenylcyclohexaneamine hydrochloride Using 3.92 g (14.23 mmol) of the compound obtained in Step A and according to the method of Reference Example 23, Step B, 3.11 g of the title compound (yield 97%) was obtained. Obtained as a colorless solid.
  • Step A tert-Butyl (1,2,3,4-tetrahydronaphthalen-2-yl) carbamate Journal of Medicinal Chemistry, 1980, 23, 745-749 (Journal of Medicinal Chemistry, 1980, 23, 745-749)
  • Step A using 2.50 g (13.61 mmol) of 1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, which is the described compound, and 2.01 ml (15.0 mmol) of triethylamine, the title compound 3.06 g (91% yield) was obtained as a light brown solid.
  • Step B N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride Using the compound obtained in Step A (3.00 g, 12.13 mmol) according to the method of Reference Example 23, Step B, 1.66 g of the title compound (Yield 69%) was obtained as a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 1.71-1.85 (m, 1H), 2.20-2.30 (m, 1H), 2.60 (s, 3H), 2.73-2.95 (m, 3H) , 3.13-3.24 (m, 1H), 3.31-3.41 (m, 1H), 7.09-7.19 (m, 4H), 9.36 (brs, 2H).
  • Step A tert-butyl methyl (pyrrolidin-1-yl) carbamate N, N-diisopropylethylamine 25 ml (144 mmol), 5.00 g (34.2 mmol) of the compound obtained in Reference Example 17 Step A and 1,4-dibromobutane 7.40 g (34.2 mmol) was added, and the mixture was heated with stirring at 130 ° C. for 5 hours. The reaction solution was cooled, diluted with ethyl acetate, the precipitated solid was filtered, and the resulting solution was concentrated under reduced pressure.
  • Step B N-methylpyrrolidin-1-amine hydrochloride 3.43 g (17.1 mmol) of the compound obtained in Step A was dissolved in 40 ml of ethyl acetate, and then 20 ml (80.0 mmol) of 4N hydrochloric acid-ethyl acetate solution was added at room temperature. After standing overnight at the same temperature, the solvent was concentrated under reduced pressure to give 3.42 g (yield> 100%) of the title compound as a brown oil.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 1.83-1.92 (m, 4H), 2.64 (s, 3H), 3.19 (brs, 4H), 5.4-6.8 (br, 2H).
  • Step A tert-butyl 2,5-dihydro-1H-pyrrol-1-yl (methyl) carbamate tert-butyl 1-methylhydrazinecarboxylate 5.00 g (34.2 mmol) and (2Z) -1,4-dichloro-2-butene 3.6 According to the method of Reference Example 35, Step A, 5.85 g (yield 86%) of the title compound was obtained as a yellow oil using ml (34.2 mmol).
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 1.39 (s, 9H), 2.90 (s, 3H), 3.77 (s, 4H), 5.74 (s, 2H).
  • Step B N-methyl-2,5-dihydro-1H-pyrrol-1-amine hydrochloride Using the compound 5.85 g (29.5 mmol) obtained in Step A according to the method of Reference Example 35 Step B, 3.07 g of the title compound ( Yield 77%) was obtained as a reddish brown solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.64 (s, 3H), 3.95 (s, 4H), 5.87 (s, 2H), 7.83 (brs, 2H).
  • Step A (3aR, 7aS) -Nitrosooctahydro-1H-isoindole tetrahedron, 55, 1999, 9439-9454 (Tetrahedron, 55 (1999), 9439-9454) is a compound described in cis-octahydro- Dissolve 1.81 g (14.5 mmol) of 1H-isoindole in 16 ml of 1N hydrochloric acid, gradually add 6.22 g (90.1 mmol) of sodium nitrite dissolved in 20 ml of water with stirring on ice, and then add 3 ml at the same temperature. Stir for hours.
  • Step B (3aR, 7aS) -N-methyleneoctahydro-2H-isoindole-2-amine 50 ml of diethyl ether was added to 0.89 g (23 mmol) of lithium aluminum hydride, and 1.20 g of the compound of Step A was stirred with stirring under ice cooling. 7.78 mmol) was added and stirred at room temperature for 4 hours. After cooling the reaction solution with ice, 0.89 ml of water, 0.89 ml of 15% aqueous sodium hydroxide, 2.67 ml of water and sodium sulfate were successively added with stirring.
  • Step C (3aR, 7aS) -N-methyloctahydro-2H-isoindole-2-amine 50 ml of diethyl ether was added to 204 mg (5.38 mmol) of lithium aluminum hydride, and the mixture was stirred under ice cooling. Thereto was added 505 mg (3.39 mmol) of the compound obtained in Step B, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, and then 0.204 ml of water, 0.204 ml of 15% aqueous sodium hydroxide solution, 0.615 ml of water and sodium sulfate were successively added with stirring.
  • Step A (3aR, 6aS) -cis-N-methylenehexahydrocyclopenta [c] pyrrol-2 (1H) -amine 3-amino-3-azabicyclo [3.3.0] octane hydrochloride to 2.50 g (15.4 mmol) Then, 4.5 ml of water and 1.26 g (15.4 mmol) of sodium acetate were added and stirred under ice cooling. To this, 1.37 ml of 37% formalin was added and stirred for 5 minutes, and then a diluted aqueous sodium hydroxide solution was added to the reaction solution.
  • Step B (3aR, 6aS) -cis-N-methylhexahydrocyclopenta [c] pyrrole-2 (1H) -amine
  • the title compound 2.53 g (yield> 100%) was obtained as a colorless oil.
  • Step A N-Methylenemorpholin-4-amine Using 2.50 g (24.5 mmol) of N-aminomorpholine and according to the method of Reference Example 38, Step A, 1.89 g (yield 68%) of the title compound was obtained as a pale yellow oil.
  • Step A 4-Nitrosothiomorpholine Using 11.53 g (111.7 mmol) of thiomorpholine, 7.26 g (yield 49%) of the title compound was obtained as a yellow solid by the method of Reference Example 37, Step A.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 2.57-2.61 (m, 2H), 2.4-2.89 (m, 2H), 4.05-4.10 (m, 2H), 4.49-4.53 (m, 2H) .
  • Step C N-methylthiomorpholin-4-amine Using 3.38 g of the compound obtained in Step B, following the method of Reference Example 37, Step C, 3.50 g (yield> 100%) of the title compound was obtained as a pale yellow oil.
  • Step A Using 2.50 g (21.9 mmol) of N-methylenepiperidin-1-amine N-nitrosopiperidine according to the method of Reference Example 37, Step B, 1.63 g (yield 66%) of the title compound was obtained as a pale yellow oil.
  • Step B N-methylpiperidin-1-amine Using 1.63 g (14.5 mmol) of the compound obtained in Step A and according to the method of Reference Example 37, Step C, 1.65 g (yield> 100%) of the title compound as a yellow oil Obtained.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.39-1.42 (m, 2H), 1.60-1.68 (m, 4H), 1.83-1.90 (m, 4H), 2.59 (s, 3H).
  • Step A 2-nitroso-1,2,3,4-tetrahydroisoquinoline Using 3.3 g of 1,2,3,4-tetrahydroisoquinoline (37.5 mmol) according to the method of Reference Example 37, step A, 3.33 g of the title compound (yield) 55%) as a pale yellow solid.
  • Step B N-methylene-3,4-dihydroisoquinoline-2 (1H) -amine Using 3.00 g (18.5 mmol) of the compound obtained in Step A and following the method of Reference Example 37, Step B, 2.86 g (yield) 95%) as a pale yellow oil.
  • Step C N-methyl-3,4-dihydroisoquinoline-2 (1H) -amine Using 2.86 g (17.9 mmol) of the compound obtained in Step B and following the method of Reference Example 37, Step C, 2.65 g (yield) 92%) as a yellow oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 2.68 (s, 3H), 2.98 (s, 4H), 3.87 (s, 2H), 7.01-7.27 (m, 4H).
  • Step A Using 2.00 g (17.5 mmol) of N-methyleneazepan-1-amine 1-aminohomopiperidine according to the method of Reference Example 38, Step A, 1.88 g (yield 85%) of the title compound was obtained as a reddish brown oil. .
  • Step B N-methylazepan-1-amine hydrochloride Using 1.20 g (9.5 mmol) of the compound obtained in Step A, the pale yellow oil obtained in accordance with Reference Example 37, Step C was dissolved in 15 ml of diethyl ether and stirred on ice. The lower 4N hydrochloric acid-dioxane solution (1.8 ml) was added, and the solution was concentrated under reduced pressure to give the title compound (0.85 g, yield 53%) as a pale yellow oil.
  • Step A Using 5.00 g (30.8 mmol) of 1-phenylpiperazine 1-phenylpiperazine according to the method of Reference Example 37, Step A, 1.10 g (yield 19%) of the title compound was obtained as a pale yellow oil.
  • Step B N-methylene-4-phenylpiperazin-1-amine Using 1.10 g (5.8 mmol) of the compound obtained in Step A, according to the method of Reference Example 37, Step B, 1.35 g (yield> 100%) of the title compound. Obtained as a yellow oil.
  • Reference example 45 (2-Fluorobenzyl) methylamine 1.00 g (5.29 mmol) of 2-fluorobenzyl bromide dissolved in 5 ml of 40% aqueous methylamine solution and 2 ml of tetrahydrofuran was added to 5 ml of tetrahydrofuran with stirring under ice-cooling, and the mixture was heated at the same temperature for 1 hour. Stir. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Reference Example 46 tert-Butyl 4- (methylamino) piperidine-1-carboxylate tert-Butyl 4-oxo-1-piperidinecarboxylate 3.99 g (20 mmol) and 30 ml of ethanol were added under ice-cooling and stirring. 2.70 g (40 mmol) of methylamine hydrochloride ), 5.6 ml (40 mmol) of triethylamine, and 11.8 ml (40 mmol) of titanium (IV) isopropoxide, and then stirred at room temperature for 8 hours. Next, 1.14 g (30 mmol) of sodium borohydride was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours.
  • Step A 1-Benzylideneamino-piperazine
  • the title compound 5.9 g was obtained as a pale yellow solid from 20.0 g of piperazine according to the method described in the specification of DE-A-2127171.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 3.05-3.09 (m, 4H), 3.14-3.19 (m, 4H), 7.2-7.4 (m, 3H), 7.57-7.62 (m, 3H) .
  • Step B 1-Benzylideneamino-4-[(2-nitrophenyl) sulfonyl] piperazine 3.45 g (18.24 mmol) of the compound obtained in Step A is dissolved in 50 ml of dichloromethane, and 3.8 ml (27 mmol) of triethylamine and 4.45 of 2-nitrobenzenesulfonyl chloride. g (20.1 mmol) was added, and the mixture was stirred at room temperature for 8 hours, and then allowed to stand overnight. The reaction solution was diluted with 200 ml of dilute aqueous sodium hydroxide solution and extracted with 200 ml of diethyl ether.
  • Step C 4-[(2-Nitrophenyl) sulfonyl] piperazin-1-amine 1N hydrochloric acid was added to 6.61 g (17.67 mmol) of the compound obtained in Step B, and a Dean-Stark trap was installed. The resulting benzaldehyde was distilled off azeotropically in the flask for 6 hours. The reaction solution was cooled and washed with diethyl ether, and then the aqueous layer was made alkaline by adding potassium carbonate.
  • Step D N-methylene-4-[(2-nitrophenyl) sulfonyl] piperazin-1-amine Using 4.85 g (16.94 mmol) of the compound obtained in Step C and according to the method of Reference Example 38, Step A, 4.93 g of the title compound (Yield 98%) was obtained as a pale yellow oil.
  • Step E N-methyl-4-[(2-nitrophenyl) sulfonyl] piperazin-1-amine
  • a mixed solvent of 50 ml of methanol and 30 ml of tetrahydrofuran was added 4.93 g (16.53 mmol) of the compound obtained in Step D, followed by stirring under ice cooling.
  • 1.35 g (21.49 mmol) of sodium cyanoborohydride 1 ml of acetic acid and 10 ml of methanol were added dropwise in small portions. After completion of dropping, the mixture was further stirred at the same temperature for 30 minutes.
  • the reaction solution was poured into dilute aqueous sodium hydroxide solution and extracted with chloroform.
  • Step A 1-Benzyl-4- (methylsulfonyl) piperazine
  • dichloromethane 10.0 g (56.73 mmol) of 1-benzylpiperazine was added, and 4.4 ml (56.85 mmol) of methanesulfonyl chloride was added while stirring under ice-cooling. For 1 hour.
  • the reaction mixture was diluted with 10% aqueous sodium carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (9.58 g, yield 66%) as a pale yellow solid.
  • Step B 1- (Methylsulfonyl) piperazine hydrochloride Into 70 ml of dichloromethane was added 9.58 g (37.66 mmol) of the compound obtained in Step A, and while stirring under ice cooling, 1-chloroethyl chloroformate (4.53 ml, 41.43 mmol) was added. Then, it stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in 70 ml of methanol and heated to reflux for 30 minutes. The reaction solution was cooled to room temperature, and the precipitated solid was filtered and washed with a small amount of methanol.
  • Step C 1- (Methylsulfonyl) -4-nitrosopiperazine Using 6.65 g (33.14 mmol) of the compound obtained in Step B and according to the method of Reference Example 37, Step A, 3.75 g (yield 59%) of the title compound was pale yellow. Obtained as a solid.
  • Step D N-methylene-4- (methylsulfonyl) piperazin-1-amine Using 3.75 g (19.41 mmol) of the compound obtained in Step C and according to the method of Reference Example 37, Step B, 2.12 g of the title compound (57% yield) ) Was obtained as a colorless solid.
  • Step E N-methyl-4- (methylsulfonyl) piperazin-1-amine Using 2.12 g (11.08 mmol) of the compound obtained in Step D according to the method of Reference Example 37, Step C, 1.73 g of the title compound (yield 81%) ) Was obtained as a yellow oil.
  • Step A tert-Butyl [2- (2-thienyl) ethyl] carbamate Using 2.00 g (15.72 mmol) of [2- (2-thienyl) ethyl] amine, according to the method of Reference Example 23, Step A, 3.86 g of the title compound was yellow. Obtained as an oil.
  • Step B Methyl [2- (2-thienyl) ethyl] amine hydrochloride Using 3.86 g of the compound obtained in Step A, 2.44 g of the title compound in the method of Reference Example 23, Step B (total yield of 87% from Step A) Was obtained as a colorless solid.
  • Step A [2- (2-Furyl) ethyl] amine 50 ml of tetrahydrofuran was added to 2.05 g (53.91 mmol) of lithium aluminum hydride and stirred under ice cooling. Thereto was added a solution of 2- (2-nitrovinyl) furan 2.50 g (17.97 mmol) in 30 ml of tetrahydrofuran, and the mixture was heated to reflux for 1 hour. The reaction mixture was ice-cooled, and 80 ml of hydrous diethyl ether, 80 ml of tetrahydrofuran, and 14 ml of a saturated aqueous sodium sulfate solution were sequentially added while stirring.
  • Step C [2- (2-Furyl) ethyl] methylamine 40 ml of tetrahydrofuran was added to 1.79 g (47.16 mmol) of lithium aluminum hydride, and the mixture was stirred under ice cooling. Thereto was added 20 ml of a tetrahydrofuran solution containing 3.94 g of the compound obtained in Step B, and the mixture was heated to reflux for 3 hours. The reaction solution was ice-cooled, and 60 ml of hydrous diethyl ether, 60 ml of tetrahydrofuran, and 12 ml of a saturated aqueous sodium sulfate solution were successively added while stirring.
  • Step A tert-butyl [2- (2-methoxyphenyl) ethyl] carbamate Using 2.00 g (13.23 mmol) of [2- (2-methoxyphenyl) ethyl] amine according to the method of Reference Example 23, step A, 4.44 g of the title compound was obtained as a pale yellow oil.
  • Step B [2- (2-Methoxyphenyl) ethyl] methylamine hydrochloride Using the compound obtained in Step A, 4.44 g, according to the method of Reference Example 23, Step B, 2.47 g of the title compound (total yield from Step A: 93 %) As a colorless solid.
  • Step A tert-Butyl [2- (3-methoxyphenyl) ethyl] carbamate Using 2.00 g (13.23 mmol) of [2- (3-methoxyphenyl) ethyl] amine according to the method of Reference Example 23, step A, 4.53 g of the title compound was obtained as a pale yellow oil.
  • Step B [2- (3-Methoxyphenyl) ethyl] methylamine hydrochloride Using 4.53 g of the compound obtained in Step A and according to the method of Reference Example 23, Step B, 2.15 g of the title compound (total yield from Step A: 81 %) As a colorless solid.
  • Step A tert-Butyl [2- (4-methoxyphenyl) ethyl] carbamate Using 2.00 g (13.23 mmol) of [2- (4-methoxyphenyl) ethyl] amine according to the method of Reference Example 23, Step A, 3.98 g of the title compound was obtained as a pale yellow oil.
  • Step B [2- (4-Methoxyphenyl) ethyl] methylamine hydrochloride Using 3.98 g of the compound obtained in Step A, according to the method of Reference Example 23, Step B, 2.15 g of the title compound (total yield from Step A: 81 %) As a colorless solid.
  • Step A 1-Methyl-2- (2-nitrovinyl) benzene Ortho-tolualdehyde (10.00 g, 83.23 mmol) was dissolved in acetic acid (50 ml), ammonium acetate (6.93 g, 89.89 mmol) and nitromethane (7 ml, 129 mmol) were added. After stirring for hours, it was left overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (12.71 g, yield 94%) as a brown oil.
  • Step B [2- (2-Methylphenyl) ethyl] amine hydrochloride Using the compound obtained in Step A 12.71 g (77.89 mmol) and following the procedure of Reference Example 50 Step A, [2- (2-Methylphenyl) ethyl A crude amine product was obtained. This was dissolved in 200 ml of ethyl acetate, 20 ml of 4N hydrochloric acid-dioxane solution was added, the precipitated solid was filtered, washed with diisopropyl ether, and dried under reduced pressure to give 4.30 g (yield 32%) of the title compound as colorless. Obtained as a solid. 1 H-NMR (300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.30 (s, 3H), 2.92 (brs, 4H), 7.12-7.20 (m, 4H), 8.23 (brs, 3H).
  • Step C tert-Butyl [2- (2-methylphenyl) ethyl] carbamate
  • the title compound according to the method of Reference Example 23, Step A, using 2.50 g (14.56 mmol) of the compound obtained in Step B and 3 ml (21.8 mmol) of triethylamine 3.73 g was obtained as a pale yellow oil.
  • Step D [2- (2-Methylphenyl) ethyl] methylamine hydrochloride Using 3.73 g of the compound obtained in Step C and according to the method of Reference Example 23, Step B, 2.35 g of the title compound (total yield from Step C: 87 %) As a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.31 (s, 3H), 2.56 (s, 3H), 2.93-3.04 (m, 4H), 7.13-7.20 (m, 4H), 9.24 (brs, 2H).
  • Step A Using 10.00 g (83.23 mmol) of 1-methyl-3- (2-nitrovinyl) benzene meta-tolualdehyde according to the method of Reference Example 54, step A, 12.75 g (yield 94%) of the title compound was obtained as a brown oil. Obtained.
  • Step B [2- (3-Methylphenyl) ethyl] amine hydrochloride Using the compound obtained in Step A, 12.75 g (78.14 mmol), according to the method of Reference Example 50, Step A, [2- (3-Methylphenyl) ethyl A crude amine product was obtained. This was dissolved in 100 ml of ethyl acetate, 21 ml of 4N hydrochloric acid-dioxane solution was added, the precipitated solid was filtered, washed with diethyl ether, and dried under reduced pressure to give 3.27 g (yield 24%) of the title compound as a pale salt. Obtained as a yellow solid.
  • Step C tert-Butyl [2- (3-methylphenyl) ethyl] carbamate Using 2.50 g (14.56 mmol) of the compound obtained in Step B and 3 ml (21.9 mmol) of triethylamine according to the method of Reference Example 23, Step A, the title compound 3.78 g was obtained as a yellow oil.
  • Step D [2- (3-Methylphenyl) ethyl] methylamine hydrochloride Using 3.78 g of the compound obtained in Step C, according to the method of Reference Example 23, Step B, 2.24 g of the title compound (total yield from Step C: 83 %) As a colorless solid.
  • Step A tert-butyl [2- (4-methylphenyl) ethyl] carbamate Using 3.63 g (26.85 mmol) of [2- (4-methylphenyl) ethyl] amine according to the method of Reference Example 23, step A, 7.13 g of the title compound was obtained as a yellow oil.
  • Step B [2- (4-Methylphenyl) ethyl] methylamine hydrochloride Using the compound 7.13 g obtained in Step A, according to the method of Reference Example 23, Step B, 3.85 g of the title compound (total yield from Step A: 77 %) As a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 2.28 (s, 3H), 2.53 (s, 3H), 2.87-2.94 (m, 2H), 3.03-3.09 (m, 2H), 7.14 (s, 4H), 9.13 (brs, 2H).
  • Step A N- (trans-2-phenylcyclopropyl) formamide 2.74 g (16.15 mmol) of trans-2-phenylcyclopropylamine hydrochloride was dissolved in 50 ml of water, made alkaline with potassium carbonate, and extracted with ethyl acetate. . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, insolubles were filtered, and the solution was concentrated under reduced pressure. 18.5 ml of formic acid was added to the residue, and the mixture was ice-cooled. Then, 7 ml of acetic anhydride was added dropwise with stirring.
  • Step B Trans-N-methyl-2-phenylcyclopropanamine A solution of 2.36 g (14.64 mmol) of the compound obtained in Step A in a suspension of 0.66 g (17.57 mmol) of sodium borohydride in 55 ml of tetrahydrofuran at room temperature in 32 ml of tetrahydrofuran was dripped. Then, a solution of iodine 1.86 g (7.33 mmol) in 63 ml of tetrahydrofuran was added dropwise, and then heated under reflux overnight. The reaction mixture was ice-cooled, 125 ml of methanol was added, and the mixture was concentrated under reduced pressure.
  • Step A tert-Butyl (trans-2-phenylcyclopropyl) carbamate Trans-2-phenylcyclopropylamine Hydrochloride 1.12 g (6.60 mmol) and triethylamine 1.0 ml (7.17 mmol) were used according to the method of Reference Example 23, Step A. The title compound (944 mg, yield 61%) was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 1.10-1.19 (m, 2H), 1.45 (s, 9H), 2.00-2.07 (m, 1H), 2.73 (brs, 1H), 4.85 (brs) , 1H), 7.11-7.29 (m, 5H).
  • Step A tert-butyl 4,6-dihydro-5H-thieno [2,3-c] pyrrol-5-yl (methyl) carbamate Journal of Organic Chemistry, Vol. 31, pages 3592-3595, 1966 2,3-bis (bromomethyl) thiophene 3.59 g (13.3 mmol) and 1.94 g (13.3 mmol) of the compound of Step 17 of Reference Example 17 were dissolved in 100 ml of N-methylpyrrolidone, and the temperature of the reaction solution was 80 to 85 ° C. While stirring, 5.0 ml (35.9 mmol) of triethylamine was slowly added with stirring. The mixture was heated and stirred at the same temperature for 10 hours, and then left overnight at room temperature.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • the obtained oil was purified by silica gel chromatography (ethyl acetate-hexane) to give 1.31 g (yield 39%) of the title compound as an orange oil. It was.
  • Step B N-methyl-4,6-dihydro-5H-thieno [2,3-c] pyrrol-5-amine hydrochloride Using 1.31 g (5.15 mmol) of the compound obtained in Step A, According to the method, 764 mg (yield 78%) of the title compound was obtained as a pale purple solid.
  • Step B N- (2-phenoxyphenyl) iminodiacetic acid 11.6 g (32 mmol) of the compound obtained in Step A was dissolved in 150 ml of methanol. While stirring at room temperature, 150 ml of 1N sodium hydroxide was added and stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and 160 ml of 1N hydrochloric acid was added. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (8.19 g, yield 85%) as a colorless solid.
  • Step A 4-Chloro-1- (4-chlorophenoxy) -2-nitrobenzene 14.42 g (112 mmol) of 4-chlorophenol is dissolved in 200 ml of N, N-dimethylformamide, and 4.50 g (113 mmol) of 60% sodium hydride is dissolved at room temperature. In addition, the mixture was stirred at the same temperature for 40 minutes. Next, 19.74 g (103 mmol) of 1,4-dichloro-2-nitrobenzene was added, and the mixture was heated and stirred at 80 ° C. for 1 hour. The reaction solution was cooled and poured into ice water.
  • Step B 5-Chloro-2- (4-chlorophenoxy) aniline 3.25 g (11.44 mmol) of the compound obtained in Step A is dissolved in 100 ml of methanol, and a catalytic amount of ferric chloride (FeCl 3 ) and activated carbon are added thereto. Stir at room temperature. Next, 1.7 ml (35 mmol) of hydrazine monohydrate was added, and then heated under reflux for 40 minutes. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained oil was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • FeCl 3 ferric chloride
  • activated carbon activated carbon
  • Step D N- [5-Chloro-2- (4-chlorophenoxy) phenyl] iminodiacetic acid Using 4.80 g (11.26 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 3.95 g of the title compound ( Yield 95%) was obtained as a colorless solid.
  • a mixed solvent 12.07 g (48.35 mmol) of the compound obtained in Step A and 14.08 g (252 mmol) of reduced iron were added, and 100 The mixture was heated and stirred at ° C for 2 hours.
  • the reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered through celite. The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step C N- [2- (4-Chlorophenoxy) phenyl] iminodiacetic acid diethyl ester 10.0 g (45.52 mmol) of the compound obtained in Step B and 15 ml (135 mmol) of ethyl bromoacetate are dissolved in 100 ml of acetonitrile, and hydrogen phosphate is added thereto. 22.81 g (131 mmol) of dipotassium and 3.38 g (23 mmol) of sodium iodide were added and heated under reflux for 28 hours. The reaction solution was cooled, diluted with toluene, washed with water, sodium hydrogensulfite and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step D N- [2- (4-Chlorophenoxy) phenyl] iminodiacetic acid 5.64 g (89% yield) of the title compound according to the method of Reference Example 60, Step B using 7.44 g (19.0 mmol) of the compound obtained in Step C ) was obtained as a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 4.03 (s, 4H), 6.84-6.92 (m, 5H), 7.05-7.11 (m, 1H), 7.31-7.36 (m, 2H) , 12.46 (brs, 2H).
  • Step A 4-Chloro-2- (4-chlorophenoxy) -1-nitrobenzene Using 10.65 g (60.67 mmol) of 4-chloro-2-fluoro-1-nitrobenzene according to the method of Reference Example 62, Step A, 5.38 g of the title compound (Yield 31%) was obtained as a yellow solid.
  • Step B 4-Chloro-2- (4-chlorophenoxy) aniline Using 5.33 g (18.76 mmol) of the compound obtained in Step A, according to the method of Reference Example 61, Step B, 4.30 g (yield 90%) of the title compound was obtained. Obtained as a yellow solid.
  • Step C N- [4-Chloro-2- (4-chlorophenoxy) phenyl] iminodiacetic acid diethyl ester Using the compound obtained in Step B, 4.30 g (16.92 mmol), according to the method of Reference Example 60, Step A, the title compound 6.95 g (96% yield) was obtained as a pale yellow oil.
  • Step D N- [4-Chloro-2- (4-chlorophenoxy) phenyl] iminodiacetic acid
  • Step B using 6.95 g (16.3 mmol) of the compound obtained in Step C, 5.07 g of the title compound ( Yield 84%) was obtained as a colorless solid.
  • Step A 2- (4-Chlorophenoxy) -5-trifluoromethylaniline 1-chloro-2-nitro-4-trifluoromethylbenzene 12.32 g (54.62 mmol) and 4-chlorophenol 7.80 g (60.67 mmol) Reference Example 61 According to the method of Steps A and B, 8.86 g (yield 56%) of the title compound was obtained as a yellow oil.
  • Step B N- [2- (4-Chlorophenoxy) -5-trifluoromethylphenyl] iminodiacetic acid diethyl ester Using 3.47 g (12.06 mmol) of the compound obtained in Step A, the procedure described in Reference Example 60, Step A is used. 3.45 g (62% yield) of compound was obtained as a yellow oil.
  • Step C N- [2- (4-Chlorophenoxy) -5-trifluoromethylphenyl] iminodiacetic acid Using the compound obtained in Step B, 3.45 g (7.50 mmol), according to the method of Reference Example 60, Step B, the title compound 2.69 g (90% yield) was obtained as a colorless solid.
  • Step A 1- (4-chlorophenoxy) -4-fluoro-2-nitrobenzene Using 21.21 g (165 mmol) of 4-chlorophenol and 25.00 g (157.1 mmol) of 1,4-difluoro-2-nitrobenzene, Step A in Reference Example 62 In this manner, 39.04 g (yield 93%) of the title compound was obtained as a dark red oily substance.
  • Step B 2- (4-Chlorophenoxy) -5-fluoroaniline Using 39.04 g (145.87 mmol) of the compound obtained in Step A, according to the method of Reference Example 61, Step B, 31.95 g of the title compound (yield 92%) was obtained. Obtained as a light brown solid.
  • Step C N- [2- (4-Chlorophenoxy) -5-fluorophenyl] iminodiacetic acid diethyl ester Using 15.98 g (67.2 mmol) of the compound obtained in Step B and according to the method of Reference Example 61, Step C, the title compound 18.36 g (yield 67%) was obtained as a colorless solid.
  • Step D N- [2- (4-Chlorophenoxy) -5-fluorophenyl] iminodiacetic acid 15.24 g (44.65 mmol) of the compound obtained in Step C was used according to the method of Reference Example 60, Step B, and 15.24 g ( Yield 97%) was obtained as a colorless solid.
  • Step A 1- (4-Chlorophenoxy) -4-methoxy-2-nitrobenzene
  • the title compound (3.50 g, yield 67%) was obtained as a pale yellow solid.
  • Step B 2- (4-Chlorophenoxy) -5-methoxyaniline Using 3.50 g (12.5 mmol) of the compound obtained in Step A, according to the method of Reference Example 61, Step B, 3.00 g of the title compound (yield 96%) was obtained. Obtained as a pale yellow oil.
  • Step C N- [2- (4-Chlorophenoxy) -5-methoxyphenyl] iminodiacetic acid diethyl ester Using 3.00 g (12.01 mmol) of the compound obtained in Step B, according to the method of Reference Example 60, Step A, the title compound 5.00 g (99% yield) was obtained as a colorless oil.
  • Step D N- [2- (4-Chlorophenoxy) -5-methoxyphenyl] iminodiacetic acid 5.00 g (11.9 mmol) of the compound obtained in Step C and 3.56 g of the title compound according to the method of Reference Example 60, Step B ( Yield 83%) was obtained as a colorless solid.
  • Step A 1- (4-Chlorophenoxy) -4-methyl-2-nitrobenzene
  • the title compound (4.20 g, yield 79%) was obtained as a pale yellow solid.
  • Step B 2- (4-Chlorophenoxy) -5-methylaniline Using 4.20 g (15.9 mmol) of the compound obtained in Step A, according to the method of Reference Example 61, Step B, 3.70 g of the title compound (yield 99%) was obtained. Obtained as a pale yellow oil.
  • Step C N- [2- (4-Chlorophenoxy) -5-methylphenyl] iminodiacetic acid diethyl ester Using 3.70 g (15.8 mmol) of the compound obtained in Step B, according to the method of Reference Example 60, Step A, the title compound 5.71 g (89% yield) was obtained as a colorless oil.
  • Step D N- [2- (4-Chlorophenoxy) -5-methylphenyl] iminodiacetic acid According to the method of Reference Example 60, Step B, using the compound 5.70 g (14.1 mmol) obtained in Step C, 4.50 g of the title compound ( The yield was 92%) as a colorless solid.
  • Step A 1- (4-Chlorophenoxy) -4- (methylthio) -2-nitrobenzene Using 15.69 g (77.04 mmol) of 1-chloro-4- (methylthio) -2-nitrobenzene and 11.31 g (87.97 mmol) of 4-chlorophenol Then, according to the method of Reference Example 61, Step A, 18.03 g (yield 79%) of the title compound was obtained as a bright yellow solid.
  • Step B 2- (4-Chlorophenoxy) -5- (methylthio) aniline Using 8.83 g (29.86 mmol) of the compound obtained in Step A and following the method of Reference Example 61, Step B, 7.71 g of the title compound (yield 97%) ) Was obtained as an orange oil.
  • Step C N- [2- (4-Chlorophenoxy) -5- (methylthio) phenyl] iminodiacetic acid diethyl ester Using 3.28 g (12.34 mmol) of the compound obtained in Step B, the procedure described in Reference Example 60, Step A is used. 714 mg (yield 11%) of the compound was obtained as a colorless oil.
  • Step D N- [2- (4-Chlorophenoxy) -5- (methylthio) phenyl] iminodiacetic acid 860 mg (1.96 mmol) of the compound obtained in Step C was used according to the method of Reference Example 60 Step B and 637 mg of the title compound ( Yield 85%) was obtained as a colorless solid.
  • Step A 4,5-dichloro-2- (4-chlorophenoxy) aniline
  • 653 mg (yield 34%) of the title compound was obtained as a pale yellow solid.
  • Step B N- [4,5-Dichloro-2- (4-chlorophenoxy) phenyl] iminodiacetic acid diethyl ester Using 642 mg (2.23 mmol) of the compound obtained in Step A, according to the method of Reference Example 60, Step A, the title compound 454 mg (44% yield) was obtained as a colorless oil.
  • Step C N- [4,5-dichloro-2- (4-chlorophenoxy) phenyl] iminodiacetic acid 605 mg (1.31 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Step B, and the title compound 429 mg ( Yield 81%) was obtained as a colorless solid.
  • Reference example 70 N- [5- (tert-butoxycarbonyl) -2- (4-chlorophenoxy) phenyl] iminodiacetic acid
  • Step A 4-chloro-3-nitrobenzoic acid tert-butyl ester 4-chloro-3-nitrobenzoic acid 18.0 g (89.3 mmol), 4-dimethylaminopyridine 21.8 g (178.4 mmol), WSC 34.2 g (178.4 mmol) in dichloromethane Dissolved in 180 ml. While stirring at room temperature, 13.5 g (182 mmol) of tert-butanol was added, and the mixture was stirred overnight at the same temperature. The reaction solution was washed with water, and the organic layer was concentrated.
  • Step B 4- (4-Chlorophenoxy) -3-nitrobenzoic acid tert-butyl ester Step of Reference Example 62 using 10.0 g (38.8 mmol) of the compound obtained in Step A and 5.54 g (43.1 mmol) of 4-chlorophenol According to the method of A, 12.1 g (yield 89%) of the title compound was obtained as a pale yellow solid.
  • Step C 3-Amino-4- (4-chlorophenoxy) benzoic acid tert-butyl ester Using 6.0 g (17.2 mmol) of the compound obtained in Step B and according to the method of Reference Example 61, Step B, 6.54 g of the title compound Ratio> 100%) as a pale yellow oil.
  • Step D N- [5- (tert-butoxycarbonyl) -2- (4-chlorophenoxy) phenyl] iminodiacetic acid diethyl ester
  • Step E N- [5- (tert-butoxycarbonyl) -2- (4-chlorophenoxy) phenyl] iminodiacetic acid 1.87 g (3.8 mmol) of the compound obtained in Step D was used according to the method of Reference Example 60, Step B. The title compound (1.64 g, yield 99%) was obtained as a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 1.56 (s, 9H), 4.16 (s, 4H), 6.79-6.91 (m, 4H), 7.2-7.28 (m, 3H), 9.58 (brs, 2H).
  • Step A 4- (4-Chlorophenoxy) -3-nitrobenzoic acid methyl ester 4-chloro-3-nitrobenzoic acid methyl ester 4.00 g (18.6 mmol) and 4-chlorophenol 2.65 g (20.6 mmol) were used as reference examples. According to the method of 62 Step A, the title compound (4.90 g, yield 87%) was obtained as a pale yellow solid.
  • Step B 3-Amino-4- (4-chlorophenoxy) benzoic acid methyl ester Using 4.90 g (16.1 mmol) of the compound obtained in Step A and according to the method of Reference Example 61, Step B, 4.48 g (yield 100) %) As a pale yellow oil.
  • Step C N- [2- (4-Chlorophenoxy) -5- (methoxycarbonyl) phenyl] iminodiacetic acid diethyl ester Using 4.48 g (16.1 mmol) of the compound obtained in Step B, according to the method of Reference Example 60, Step A, This gave 4.10 g (57% yield) of the title compound as a colorless oil.
  • Step D N- [2- (4-Chlorophenoxy) -5- (methoxycarbonyl) phenyl] iminodiacetic acid
  • the title compound according to the method of Reference Example 60, Step B, using 3.00 g (6.67 mmol) of the compound obtained in Step C 1.51 g (57% yield) was obtained as a colorless solid.
  • Step A 1- (4-Chlorophenoxy) -4- (1-oxopropyl) -2-nitrobenzene 4-chlorophenol 3.08 g (23.95 mmol), obtained according to the method described in the published German Patent Application No. 1168917 Using 10.00 g (47.25 mmol) of compound 1- (4-chloro-3-nitrophenyl) propan-1-one according to the method of Reference Example 62, step A, 5.07 g of the title compound (yield 35%) was obtained as a yellow solid. Got as.
  • Step B 1- (4-Chlorophenoxy) -4- (2-ethyl-1,3-dioxolan-2-yl) -2-nitrobenzene 60 ml of toluene in a flask equipped with a Dean-Stark water removal device (Dean-Stark trap) Then, 5.00 g (16.36 mmol) of the compound obtained in Step A, 2.00 g (32.22 mmol) of ethylene glycol and 312 mg (1.64 mmol) of p-toluenesulfonic acid monohydrate were added and heated under reflux for 5 hours.
  • the reaction mixture was cooled, diluted aqueous sodium hydroxide solution was added, and the mixture was extracted with 100 ml of ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography (ethyl acetate-hexane) to give 6.04 g of the title compound as a yellow oil.
  • Step C 2- (4-Chlorophenoxy) -5- (2-ethyl-1,3-dioxolan-2-yl) aniline
  • Step B using 6.04 g of the compound obtained in Step B 5.11 g of compound (total yield from Step B: 98%) was obtained as a colorless solid.
  • Step D N- [2- (4-Chlorophenoxy) -5- (2-ethyl-1,3-dioxolan-2-yl) phenyl] iminodiacetic acid diethyl ester Using 5.11 g (15.98 mmol) of the compound obtained in Step C According to the method of Reference Example 60, step A, the title compound (6.69 g, yield 85%) was obtained as a yellow oil.
  • Step E N- [2- (4-Chlorophenoxy) -5- (2-ethyl-1,3-dioxolan-2-yl) phenyl] iminodiacetic acid Using 6.69 g (13.60 mmol) of the compound obtained in Step D, Reference Example 60 According to the method of Step B, 4.84 g (yield 82%) of the title compound was obtained as a pale red solid.
  • Step A 4- (4-Chlorophenoxy) -3-nitroacetophenone According to the method of Reference Example 62, Step A using 3.54 g (27.6 mmol) of 4-chlorophenol and 5.00 g (25.1 mmol) of 4-chloro-3-nitroacetophenone. , 3.47 g (yield 48%) of the title compound was obtained as a pale yellow solid.
  • Step B N- [2- (4-Chlorophenoxy) -5- (2-methyl-1,3-dioxolan-2-yl) phenyl] iminodiacetic acid 2.99 g (10.6 mmol) of the compound obtained in Step A, ethylene glycol 1.2
  • Step B N- [2- (4-Chlorophenoxy) -5- (2-methyl-1,3-dioxolan-2-yl) phenyl] iminodiacetic acid 2.99 g (10.6 mmol) of the compound obtained in Step A, ethylene glycol 1.2
  • Reference Example 61 Step B Reference Example 60 Steps A and B using ml (21.2 mmol) and p-toluenesulfonic acid monohydrate 0.20 g, the title compound 1.41 g (Yield 32%) was obtained as a light brown solid.
  • Step A 1- (4-Chlorophenoxy) -4- (methylsulfonyl) -2-nitrobenzene 4-chlorophenol 3.08 g (23.95 mmol), 1-fluoro-4- (methylsulfonyl) -2-nitrobenzene 5.00 g (22.81 mmol) According to the method of Reference Example 62, step A, the title compound (5.93 g, yield 79%) was obtained as a yellow-green solid.
  • Step B 2- (4-Chlorophenoxy) -5- (methylsulfonyl) aniline Using 5.93 g (18.09 mmol) of the compound obtained in Step A and according to the method of Reference Example 61, Step B, 4.42 g of the title compound (yield 82 %) As a red oil.
  • Step C N- [2- (4-Chlorophenoxy) -5- (methylsulfonyl) phenyl] iminodiacetic acid diethyl ester Using 4.42 g (14.84 mmol) of the compound obtained in Step B, according to the method of Reference Example 60, Step A, This gave 4.94 g (yield 71%) of the title compound as a yellow oil.
  • Step D N- [2- (4-Chlorophenoxy) -5- (methylsulfonyl) phenyl] iminodiacetic acid
  • the title compound according to the method of Reference Example 60, Step B, using 4.94 g (10.51 mmol) of the compound obtained in Step C 3.19 g (yield 73%) was obtained as a yellow amorphous solid.
  • Step A N- [5-carboxyl-2- (4-chlorophenoxy)] phenyliminodiacetic acid diethyl ester 3.00 g (4.57 mmol) of the compound obtained in Reference Example 70 Step D was dissolved in 10 ml of dichloromethane, and the mixture was stirred at room temperature. 7 ml of fluoroacetic acid was added and stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with dilute sodium bicarbonate water and 10% aqueous citric acid solution, and dried over anhydrous magnesium sulfate.
  • Step B N- [2- (4-Chlorophenoxy) -5- (methoxycarbonylamino) phenyl] iminodiacetic acid diethyl ester 500 mg (1.15 mmol) of the compound obtained in Step A at room temperature in 5 ml of toluene, diphenyl phosphate azide 0.27 ml (1.26 mmol) and triethylamine 0.17 ml (1.26 mmol) were added, and then the mixture was heated to reflux for 1 hour. Next, 0.93 ml of methanol was added to the reaction solution, and the mixture was subsequently heated to reflux for 21 hours.
  • Step C N- [2- (4-Chlorophenoxy) -5- (methoxycarbonylamino) phenyl] iminodiacetic acid Using the compound 358 mg (0.77 mmol) obtained in Step B, according to the method of Reference Example 60, Step B, the title compound 338 mg (yield 100%) was obtained as a pale yellow solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 3.64 (s, 3H), 3.99 (s, 4H), 6.77-6.87 (m, 3H), 6.93-6.97 (m, 1H), 7.09 (s, 1H), 7.28-7.34 (m, 2H), 9.58 (s, 1H), 12.41 (brs, 2H).
  • Step A N- [5- (tert-butoxycarbonylamino) -2- (4-chlorophenoxy) phenyl] iminodiacetic acid diethyl ester 1.50 g (3.44 mmol) of the compound obtained in Reference Example 75 Step A, 6.6 ml of tert-butanol Using, according to the method of Reference Example 75, Step B, 1.09 g (yield 63%) of the title compound was obtained as a colorless solid.
  • Step B N- [5- (tert-butoxycarbonylamino) -2- (4-chlorophenoxy) phenyl] iminodiacetic acid 1.09 g (2.15 mmol) of the compound obtained in Step A was used according to the method of Reference Example 60, Step B. 948 mg (98% yield) of the title compound was obtained as a colorless solid.
  • Step A N- [5- ⁇ (2-acetylhydrazino) carbonyl ⁇ -2- (4-chlorophenoxy) phenyl] iminodiacetic acid diethyl ester 800 mg (1.84 mmol) of the compound obtained in Reference Example 75 Step A in 10 ml of tetrahydrofuran 1,1′-carbonyldiimidazole (387 mg, 2.39 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. Next, 143 mg (1.93 mmol) of acetohydrazide was added while stirring the reaction solution under ice cooling, and then stirred at room temperature for 3 hours.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride was added to the residue, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (methanol-dichloromethane) to obtain 373 mg (yield 41%) of the title compound as a colorless amorphous solid.
  • Step B N- [2- (4-Chlorophenoxy) -5- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] iminodiacetic acid diethyl ester
  • Compound obtained in step A in 7.5 ml toluene 370 mg (0.75 mmol) and Lawson reagent 365 mg (0.90 mmol) were added, and the mixture was heated and stirred for 3 hours.
  • the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Step C N- [2- (4-Chlorophenoxy) -5- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] iminodiacetic acid Using 260 mg (0.53 mmol) of the compound obtained in Step B According to the method of Reference Example 60, step B, the title compound (226 mg, yield 98%) was obtained as a colorless solid.
  • Step A 3-amino-4- (4-chlorophenoxy) benzonitrile 4-chloro-3-nitrobenzonitrile 5.00 g (27.39 mmol) and 4-chlorophenol 3.70 g (28.76 mmol) were used to obtain Reference Example 61, Step A, According to the method of B, 4.63 g (yield 69%) of the title compound was obtained as a colorless solid.
  • Step B N- [2- (4-Chlorophenoxy) -5-cyanophenyl] iminodiacetic acid diethyl ester Using 4.63 g (18.92 mmol) of the compound obtained in Step A and according to the method of Reference Example 61, Step C, the title compound 4.45 g (56% yield) was obtained as a colorless solid.
  • Step C N- [2- (4-Chlorophenoxy) -5-cyanophenyl] iminodiacetic acid 3.40 g (10.56 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Step B, and 3.75 g of the title compound ( Yield 99%) as a colorless solid.
  • Step A 1- (4-Chlorophenoxy) -5-cyano-2-nitrobenzene Chemical and Pharmaceutical Bulletin, 1992, 40, 2399-2409 (Chemical & Pharmaceutical Bulletin, 1992, 40, 2399-2409)
  • the compound 3-chloro-4-nitrobenzonitrile 5.00 g (27.39 mmol), 4-chlorophenol 3.85 g (30.0 mmol) and potassium carbonate 4.15 g (30.0 mmol) were added to 70 ml of xylene, and the mixture was heated to reflux for 6 hours.
  • the reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Step B 4-Amino-3- (4-chlorophenoxy) benzonitrile 4.96 g (99% yield) of the title compound according to the method of Reference Example 61, Step B, using 5.61 g (20.43 mmol) of the compound obtained in Step A was obtained as a pale yellow solid.
  • Step C N- [2- (4-Chlorophenoxy) -4-cyanophenyl] iminodiacetic acid Using the compound obtained in Step B, 4.96 g (20.27 mmol), according to the method of Reference Example 60, Steps A and B, the title compound 1.60 g (22% yield) was obtained as a colorless solid.
  • Step A 3-amino-4- (3-chlorophenoxy) benzonitrile Using 7.53 g (41.25 mmol) 4-chloro-3-nitrobenzonitrile and 5.81 g (45.19 mmol) 3-chlorophenol, step A in Reference Example 61, According to the method of B, 8.97 g (yield 89%) of the title compound was obtained as a colorless solid.
  • Step B N- [2- (3-Chlorophenoxy) -5-cyanophenyl] iminodiacetic acid diethyl ester Using 8.93 g (36.5 mmol) of the compound obtained in Step A and according to the method of Reference Example 60, Step A, the title compound 5.49 g (yield 36%) was obtained as a colorless solid.
  • Step C N- [2- (3-Chlorophenoxy) -5-cyanophenyl] iminodiacetic acid According to the method of Reference Example 60, Step B, using 5.49 g (13.17 mmol) of the compound obtained in Step B, 4.59 g of the title compound ( Yield 97%) was obtained as a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 4.11 (s, 4H), 6.93-7.00 (m, 2H), 7.06-7.08 (m, 1H), 7.2-7.3 (m, 3H) , 7.38-7.44 (m, 1H), 12.59 (brs, 2H).
  • Step A 3-amino-4- (4-fluorophenoxy) benzonitrile 4-chloro-3-nitrobenzonitrile 7.51 g (41.14 mmol) and 4-fluorophenol 5.06 g (45.14 mmol) According to the method of B, 8.70 g (yield 93%) of the title compound was obtained as a colorless solid.
  • Step B N- [5-cyano-2- (4-fluorophenoxy) phenyl] iminodiacetic acid diethyl ester Using the compound obtained in Step A, 8.67 g (37.99 mmol), according to the method of Reference Example 60, Step A, the title compound 7.62 g (yield 50%) was obtained as a colorless solid.
  • Step C N- [5-Cyano-2- (4-fluorophenoxy) phenyl] iminodiacetic acid Using the compound 7.31 g (18.26 mmol) obtained in Step B according to the method of Reference Example 60 Step B, 5.55 g of the title compound ( (88% yield) was obtained as a colorless solid.
  • Step A 4- (4-Methylphenoxy) -3-nitrobenzonitrile
  • Method of Reference Example 62 Step A using 10.0 g (54.8 mmol) of 4-chloro-3-nitrobenzonitrile and 6.58 g (60.8 mmol) of p-cresol To give 14.0 g (yield> 100%) of the title compound as a pale yellow solid.
  • Step B 3-Amino-4- (4-methylphenoxy) benzonitrile 14.1 g (yield> 100%) of the title compound was obtained as a colorless oil according to the method of Reference Example 61, Step B using 14.0 g of the compound obtained in Step A. Obtained as a thing.
  • Step C N- [5-Cyano-2- (4-methylphenoxy) phenyl] iminodiacetic acid diethyl ester Using 14.1 g of the compound obtained in Step B, according to the method of Reference Example 60, Step A, 17.0 g of the title compound (Step A Yield 78%) as a colorless oil.
  • Step D N- [5-Cyano-2- (4-methylphenoxy) phenyl] iminodiacetic acid Using 17.0 g (42.9 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 10.9 g of the title compound ( (75% yield) was obtained as a colorless solid.
  • Step A 4- (4-Benzyloxyphenoxy) -3-nitrobenzonitrile 4-chloro-3-nitrobenzonitrile 5.00 g (27.4 mmol) and 4-benzyloxyphenol 6.0 g (30.1 mmol) were used in Reference Example 62 steps. According to the method A, 8.01 g (yield 84%) of the title compound was obtained as a yellow solid.
  • Step B 3-Amino-4- (4-benzyloxyphenoxy) benzonitrile 5.78 g (yield 90%) of the title compound according to the method of Reference Example 62, Step B, using 7.00 g (20.2 mmol) of the compound obtained in Step A ) Was obtained as a light brown solid.
  • Step C N- [2- (4-Benzyloxyphenoxy) -5-cyanophenyl] iminodiacetic acid
  • the title compound according to the method of Reference Example 60, Steps A and B, using 4.91 g (15.5 mmol) of the compound obtained in Step B 3.58 g (53% yield) was obtained as a colorless solid.
  • 1 H-NMR (300MHz, DMSO-d 6 ); ⁇ (ppm) 4.12 (s, 4H), 5.09 (s, 2H), 6.69 (d, J 8.4, 1H), 6.97-7.08 (m, 4H) , 7.14-7.22 (m, 2H), 7.35-7.48 (m, 5H), 12.22-13.58 (br, 2H).
  • Step A N- [2- (Phenylthio) phenyl] iminodiacetic acid diethyl ester Using 5.22 g (25.93 mmol) of 2- (phenylthio) aniline, according to the method of Reference Example 60, Step A, 3.68 g (yield 38%) of the title compound Obtained as a pale yellow oil.
  • Step B N- [2- (Phenylthio) phenyl] iminodiacetic acid Using 3.66 g (9.80 mmol) of the compound obtained in Step A and according to the method of Reference Example 60, Step B, 2.03 g of the title compound (yield 65%) was colorless. Obtained as a solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 4.09 (s, 4H), 6.85-6.95 (m, 2H), 7.1-7.2 (m, 2H), 7.3-7.4 (m, 5H) , 12.47 (brs, 2H).
  • Step A N- ⁇ 2-[(4-Chlorophenyl) thio] phenyl ⁇ iminodiacetic acid diethyl ester Using 4.55 g (18.88 mmol) of 2-[(4-chlorophenyl) thio] aniline according to the method of Reference Example 60, Step A, the notation 1.25 g (yield 16%) of the compound was obtained as a pale yellow oil.
  • Step B N- ⁇ 2-[(4-chlorophenyl) thio] phenyl ⁇ iminodiacetic acid Using the compound 1.24 g (3.04 mmol) obtained in Step A and according to the method of Reference Example 60, Step B, 641 mg of the title compound (yield 60 %) As a colorless solid.
  • Step A 1-[(4-Fluorophenyl) thio] -2-nitrobenzene 11.42 g (80.94 mmol) of 1-fluoro-2-nitrobenzene, 10.81 g (84.34 mmol) of 4-fluorobenzenethiol in 100 ml of N, N-dimethylformamide and 19.02 g (137.6 mmol) of potassium carbonate was added, and the mixture was stirred with heating at 70 ° C. for 40 minutes. After cooling the reaction solution, water was added and the precipitated solid was filtered, washed with an aqueous sodium hydroxide solution and water, and then dried under reduced pressure to obtain 18.86 g (yield 93%) of the title compound as a yellow solid.
  • Step B 2-[(4-Fluorophenyl) thio] aniline Using 15.38 g (61.70 mmol) of the compound obtained in Step A and according to the method of Reference Example 61, Step B, 12.57 g (yield 93%) of the title compound is colorless. Obtained as an oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 4.29 (brs, 2H), 6.7-6.8 (m, 2H), 6.91-6.97 (m, 2H), 7.05-7.11 (m, 2H), 7.20 -7.24 (m, 1H), 7.41-7.45 (m, 1H).
  • Step C N- ⁇ 2-[(4-Fluorophenyl) thio] phenyl ⁇ iminodiacetic acid diethyl ester 11.18 g (69.23 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Step A and 11.71 g of the title compound. (43% yield) was obtained as a pale yellow oil.
  • Step D N- ⁇ 2-[(4-Fluorophenyl) thio] phenyl ⁇ iminodiacetic acid Using 11.71 g (29.91 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 6.97 g Yield 69%) as a colorless solid.
  • 1 H-NMR 300 MHz, DMSO-d 6 ); ⁇ (ppm) 4.09 (s, 4H), 6.81-6.84 (m, 1H), 6.89-6.95 (m, 1H), 7.15-7.28 (m, 4H) , 7.41-7.47 (m, 2H), 12.47 (brs, 2H).
  • Step A 5-chloro-2-[(4-chlorophenyl) thio] aniline Reference Example 86 Step A using 12.96 g (67.50 mmol) of 1,4-dichloro-2-nitrobenzene and 10.25 g (70.88 mmol) of 4-chlorobenzenethiol In accordance with the method of Reference Example 62, Step B, the title compound (17.71 g, yield 97%) was obtained as a colorless solid.
  • Step B N- ⁇ 5-Chloro-2-[(4-chlorophenyl) thio] phenyl ⁇ iminodiacetic acid diethyl ester Using 3.40 g (12.6 mmol) of the compound obtained in Step A, following the procedure of Reference Example 61, Step C, the notation 1.57 g (yield 28%) of the compound was obtained as a pale yellow oil.
  • Step C N- ⁇ 5-Chloro-2-[(4-chlorophenyl) thio] phenyl ⁇ iminodiacetic acid Using 1.57 g (3.55 mmol) of the compound obtained in Step B and according to the method of Reference Example 60, Step B, the title compound 1.31 g (96% yield) was obtained as a pale yellow solid.
  • Step A 3-amino-4-[(4-fluorophenyl) thio] benzonitrile 1,4-dichloro-2-nitrobenzene 16.99g (93.07mmol), 4-fluorobenzenethiol 12.57g (98.07mmol)
  • the title compound (16.69 g, yield 73%) was obtained as a colorless solid.
  • Step B N- ⁇ 5-cyano-2-[(4-fluorophenyl) thio] phenyl ⁇ iminodiacetic acid 14.01 g (57.35 mmol) of the compound obtained in Step A was used according to the method of Reference Example 60, Steps A and B. The title compound (1.51 g, yield 7%) was obtained as a pale yellow solid.
  • Step A Using 3.06 g (19.42 mmol) of N- (5-chloro-2-methoxyphenyl) iminodiacetic acid diethyl ester 5-chloro-2-methoxyaniline according to the method of Reference Example 60, step A, 6.64 g (yield) > 100%) as a colorless oil.
  • Step B N- (5-Chloro-2-methoxyphenyl) iminodiacetic acid 2.26 g (yield 85%) of the title compound according to the method of Reference Example 60, Step B using 3.21 g (9.73 mmol) of the compound obtained in Step A was obtained as a colorless solid.
  • Step A 2-methoxy-5- (2-methyl-1,3-dioxolan-2-yl) aniline 3-nitro-4-methoxyacetophenone 10.14 g (51.95 mmol), ethylene glycol 4.4 ml, p-toluenesulfonic acid, 1 water
  • Step B 14.1 g of a brown oil was obtained using 0.67 g of the Japanese product.
  • step B the title compound (6.13 g, yield 56%) was obtained as a yellow oil.
  • Step B N- [2-methoxy-5- (2-methyl-1,3-dioxolan-2-yl) phenyl] iminodiacetic acid diethyl ester Using 6.13 g (29.3 mmol) of the compound obtained in Step A, Reference Example 60 According to the method of Step A, 11.99 g (yield> 100%) of the title compound was obtained as a yellow oil.
  • Step D N- (5-acetyl-2-methoxyphenyl) iminodiacetic acid 1.63 g (yield 37%) of the title compound according to the method of Reference Example 60, Step B using 5.32 g (15.77 mmol) of the compound obtained in Step C was obtained as a colorless solid.
  • Step A 1- (4-Methoxy-3-nitrophenyl) propan-1-one 1- (4-Methoxyphenyl) propan-1-one Using 13.62 g (82.95 mmol), a chemical abstract, 49, 3879, 1955 According to the method described in the year (Chemical Abstract Vol. 49, 3879 (1955)), 16.93 g (yield 98%) of the title compound was obtained as a colorless solid.
  • Step B 5- (2-Ethyl-1,3-dioxolan-2-yl) -2-methoxyaniline
  • the title compound according to the method of Reference Example 91, Step A, using 16.93 g (80.93 mmol) of the compound obtained in Step A 17.31 g (96% yield) was obtained as a yellow solid.
  • Step C N- (2-methoxy-5-propionylphenyl) iminodiacetic acid diethyl ester Using the compound obtained in Step B, 17.31 g (77.53 mmol), according to the method of Reference Example 60 Step A and Reference Example 91 Step C, the title compound 26.19 g (96% yield) was obtained as a yellow oil.
  • Step D N- (2-methoxy-5-propionylphenyl) iminodiacetic acid 26.19 g (74.53 mmol) of the compound obtained in Step C was used according to the method of Reference Example 60, Step B, 21.50 g of the title compound (yield 98%) Was obtained as a pale yellow solid.
  • Step A 4-methoxy-3-nitrobenzoic acid tert-butyl ester Using 15.0 g (76.1 mmol) of 4-methoxy-3-nitrobenzoic acid according to the method of Reference Example 70, step A, 18.9 g of the title compound (yield 95%) ) Was obtained as a colorless solid.
  • Step C N- [5- (tert-butoxycarbonyl) -2-methoxyphenyl] iminodiacetic acid diethyl ester Using 8.44 g of the compound obtained in Step B, according to the method of Reference Example 60, Step A, 19.7 g of the title compound is obtained as a colorless oil Obtained as a thing.
  • Step D N- [5- (tert-butoxycarbonyl) -2-methoxyphenyl] iminodiacetic acid Using 3.5 g (8.9 mmol) of the compound obtained in Step C, according to the method of Reference Example 60, Step B, 1.42 g of the title compound ( Yield 48%) was obtained as a colorless solid.
  • Step A 4-Methoxy-3-nitrobenzonitrile 21.09 g (115.5 mmol) of 4-chloro-3-nitrobenzonitrile is dissolved in 300 ml of N-methylpyrrolidone, and 50 ml of 28% sodium methoxide-methanol solution is stirred at ⁇ 10 ° C. Slowly added and stirred at the same temperature for 2 hours. The reaction solution was poured into 700 ml of water, and the precipitated solid was filtered, washed with dilute sodium hydroxide aqueous solution and water, and dried under reduced pressure to obtain 16.61 g (yield 81%) of the title compound as a pale yellow solid. .
  • Step C N- (5-Cyano-2-methoxyphenyl) iminodiacetic acid diethyl ester Using the compound obtained in Step B (13.30 g, 89.77 mmol) according to the method of Reference Example 60, Step A, 20.93 g (yield 73) %) As a pale yellow solid.
  • Step D N- (5-cyano-2-methoxyphenyl) iminodiacetic acid Using 2.56 g (7.99 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 1.50 g of the title compound (yield 71%) was obtained as a colorless solid.
  • Step A 5-Bromo-3-fluoro-2-methoxyaniline Using 5.10 g (20.4 mmol) of 5-bromo-1-fluoro-2-methoxy-3-nitrobenzene according to the method of Reference Example 61, Step B, 4.85 g of the title compound (Yield> 100%) was obtained as a colorless oil.
  • 1 H-NMR 300 MHz, CDCl 3 ); ⁇ (ppm) 3.89 (s, 3H), 3.98 (brs, 2H), 6.60-6.65 (m, 2H).
  • Step B N- (5-Bromo-3-fluoro-2-methoxyphenyl) iminodiacetic acid diethyl ester Using 4.85 g of the compound obtained in Step A according to the method of Reference Example 61, Step C, 7.12 g of the title compound (yield 89 %) As a colorless oil.
  • Step C N- (5-cyano-3-fluoro-2-methoxyphenyl) iminodiacetic acid diethyl ester
  • N, N-dimethylformamide 5.04 g (12.85 mmol) of the compound obtained in Step B, 1.51 g of zinc cyanide ( 12.86 mmol) and 3.18 g (2.75 mmol) of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated and stirred at 100 ° C. for 1 hour.
  • the insoluble material was filtered off, the solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (3.48 g, yield 80%) as an orange oil. Obtained.
  • Step D N- (5-Cyano-3-fluoro-2-methoxyphenyl) iminodiacetic acid Using 3.43 g (10.14 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 2.46 g 86%) was obtained as a colorless solid.
  • Step A N- [3-Fluoro-2-methoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] iminodiacetic acid diethyl ester
  • Reference Example 95 17.5 g of the compound obtained in Step C (51.7 mmol) was dissolved in 350 ml of ethanol and stirred at room temperature. Next, 5.03 g (72.4 mmol) of hydroxylammonium chloride and 5.94 g (72.4 mmol) of sodium acetate were added, and the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
  • Step B N- [3-Fluoro-2-methoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] iminodiacetic acid 16.37 g (41.4 mmol) of the compound obtained in Step A Using, according to the method of Reference Example 60, Step B, 13.99 g (yield 100%) of the title compound was obtained as a colorless solid.
  • Step A N- [2-methoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] iminodiacetic acid diethyl ester in a mixed solvent of 90 ml of ethanol and 20 ml of water in Reference Example 94 Step C 6.02 g (18.8 mmol) of the obtained compound, 4.94 g (60.2 mmol) of sodium acetate and 4.14 g (59.6 mmol) of hydroxylammonium chloride were added, and the mixture was heated to reflux for 3.5 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step B N- [2-methoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] iminodiacetic acid 3.66 g (9.70 mmol) of the compound obtained in Step A was used as a reference.
  • Example 60 According to the method of step B, the title compound (3.04 g, yield 98%) was obtained as a colorless solid.
  • Step A 5-Bromo-2-methoxyaniline Using 5.0 g (21.5 mmol) of 4-bromo-1-methoxy-2-nitrobenzene according to the method of Reference Example 62, Step B, 4.17 g (yield 96%) of the title compound was colorless. Obtained as a solid.
  • Step B N- (5-Bromo-2-methoxyphenyl) iminodiacetic acid 4.26 g (20.6 mmol) of the compound obtained in Step A was used according to the method of Reference Example 60, Steps A and B, and 5.26 g (yield 80) %) As a pale pink solid.
  • Step A N- (5-Carboxy-2-methoxyphenyl) iminodiacetic acid diethyl ester 10.3 g (25.5 mmol) of the compound obtained in Reference Example 93 Step C was dissolved in 100 ml of dichloromethane and stirred at room temperature, and then 62 ml (0.817 mol) of trifluoroacetic acid. And stirred at the same temperature overnight. The reaction mixture was concentrated, water was added to the residue, and the mixture was vigorously stirred at room temperature. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 7.26 g (yield 84%) of the title compound as a pale yellow solid.
  • Step B N- ⁇ 5-[(2-acetylhydrazino) carbonyl] -2-methoxyphenyl ⁇ iminodiacetic acid diethyl ester 4.00 g (11.8 mmol) of the compound obtained in Step A was dissolved in 100 ml of dichloromethane and stirred under ice cooling. . Next, 1.52 ml (17.7 mmol) of oxalyl chloride and a catalytic amount of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting oil was again dissolved in 100 ml of dichloromethane.
  • Step C N- [2-methoxy-5- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] iminodiacetic acid diethyl ester 2.00 g (5.06 mmol) of the compound obtained in Step B and 2.25 g Lawesson's reagent (5.56 mmol) was added to 80 ml of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure. The obtained oil was purified by silica gel chromatography (using NH silica gel, dichloromethane) to give 2.12 g (yield> 100%) of the title compound as a yellow oil. It was.
  • Step D N- [2-Methoxy-5- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] iminodiacetic acid Method of Reference Example 60 Step B using 2.12 g of the compound obtained in Step C The title compound (1.52 g, yield 89%) was obtained as a colorless solid.
  • Step A 5-Chloro-2-ethoxyaniline 1.00 g (6.97 mmol) of 2-amino-4-chlorophenol was dissolved in 15 ml of N, N-dimethylformamide and stirred under ice cooling. Next, 307 mg (7.66 mmol) of 60% sodium hydride was added, and the mixture was stirred at the same temperature for 30 minutes. Next, 0.58 ml (7.31 mmol) of ethyl iodide was added, followed by stirring at the same temperature for 2 hours. Water was added to the reaction solution, extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Step B N- (5-Chloro-2-ethoxyphenyl) iminodiacetic acid diethyl ester Using 970 mg (5.65 mmol) of the compound obtained in Step A and according to the method of Reference Example 60, Step A, 1.86 g of the title compound (yield 96%) ) was obtained as a yellow oil.
  • Step C N- (5-Chloro-2-ethoxyphenyl) iminodiacetic acid 1.41 g (yield 90%) of the title compound according to the method of Reference Example 60, Step B using 1.86 g (5.41 mmol) of the compound obtained in Step B was obtained as a pale yellow solid.
  • Step A 5-Chloro-2-propoxyaniline 2-amino-4-chlorophenol 1.50 g (10.5 mmol) and 1.1 ml (11.0 mmol) of n-propyl iodide were used according to the method of Reference Example 101, step A, and the title compound 1.59 g (82% yield) was obtained as a brown oil.
  • Step B N- (5-Chloro-2-propoxyphenyl) iminodiacetic acid diethyl ester Using 1.58 g (8.51 mmol) of the compound obtained in Step A and according to the method of Reference Example 60, Step A, 2.82 g (yield 92 %) As a pale yellow oil.
  • Step C N- (5-Chloro-2-propoxyphenyl) iminodiacetic acid 2.20 g (7.85 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Step B. 2.20 g of the title compound (yield 93%) was obtained as a colorless solid.
  • Step B 3-Amino-4-ethoxybenzonitrile 2.67 g (yield 95%) of the title compound as a pale yellow solid was obtained according to the method of Reference Example 61, Step B using 3.67 g (19.1 mmol) of the compound obtained in Step A. Obtained.
  • Step C N- (5-Cyano-2-ethoxyphenyl) iminodiacetic acid 4.92 g (18.0 mmol) of the compound obtained in Step B was used in accordance with the method of Reference Example 60, Steps A and B. %) As a colorless solid.
  • Step A 3-amino-4-isopropoxybenzonitrile Using 3.11 g of 2-propanol and 4.33 g (23.72 mmol) of 4-chloro-3-nitrobenzonitrile, according to the method of Reference Example 103, Step A, Reference Example 61, Step B, The title compound (1.10 g, yield 26%) was obtained as a yellow solid.
  • Step B N- (5-Cyano-2-isopropoxyphenyl) iminodiacetic acid 1.28 g (yield) of the title compound according to the method of Reference Example 60, steps A and B, using 1.10 g (6.24 mmol) of the compound obtained in step A 70%) as a colorless solid.
  • Step A 3-amino-4-propoxybenzonitrile 1-propanol 2.87 g and 4-chloro-3-nitrobenzonitrile 4.19 g (22.95 mmol) are used according to the method of Reference Example 103, Step A and Reference Example 61, Step B. 2.82 g (yield 70%) of compound was obtained as a pale yellow solid.
  • Step B N- (5-Cyano-2-propoxyphenyl) iminodiacetic acid Using 2.82 g (16.00 mmol) of the compound obtained in Step A and according to the method of Reference Example 60, Steps A and B, 3.58 g of the title compound (yield 77 %) As a colorless solid.
  • Step A 4-Chloro-2-nitro-1- (2-propynyloxy) benzene 17.36 g (100.0 mmol) of 4-chloro-2-nitrophenol was dissolved in 100 ml of acetone, and 13.82 g (100.0 mmol) of potassium carbonate was added to propargyl. 15.0 g (126 mmol) of bromide and a catalytic amount of ferric chloride (FeCl 3 ) were added, and the mixture was heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and dilute aqueous sodium hydroxide solution was added to the residue.
  • FeCl 3 ferric chloride
  • Step B 5-Chloro-2- (2-propynyloxy) aniline
  • 12.33 g 58.27 mmol
  • Step B 10.33 g (yield 98%) of the title compound is obtained. Obtained as a brown solid.
  • Step C N- [5-Chloro-2- (2-propynyloxy) phenyl] iminodiacetic acid 1.44 g (7.93 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Steps A and B, and the title compound 1.56 g (66% yield) was obtained as a colorless solid.
  • Step A 1- (2-butynyloxy) -4-chloro-2-nitrobenzene 4-chloro-2-nitrophenol 5.18 g (29.84 mmol) and 1-bromo-2-butyne 5.00 g (37.60 mmol) were used to give Reference Example 106 According to the method of Step A, 6.26 g (yield 93%) of the title compound was obtained as a pale green solid.
  • Step B 2- (2-butynyloxy) -5-chloroaniline Using 6.26 g (27.74 mmol) of the compound obtained in Step A and according to the method of Reference Example 62, Step B, 5.77 g of the title compound was obtained as a brown oil.
  • Step C N- [2- (2-butynyloxy) -5-chlorophenyl] iminodiacetic acid Using 5.77 g of the compound obtained in Step B, according to the method of Reference Example 60, Steps A and B, 6.37 g of the title compound (from Step B) A total yield of 74%) was obtained as pale yellow crystals.
  • Step A 1- (Benzyloxy) -4-chloro-2-nitrobenzene 4-chloro-2-nitrophenol 5.00 g (28.81 mmol) is dissolved in 100 ml of ethanol, and 5.97 g (43.22 mmol) of potassium carbonate and 4.79 g of benzyl bromide are dissolved therein. (28.00 mmol) was added and heated to reflux for 2 hours. After cooling the reaction solution, insoluble matter was filtered off, and the solution was concentrated under reduced pressure. A dilute aqueous sodium hydroxide solution was added to the residue, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 5.52 g (yield 74%) of the title compound as a pale yellow solid.
  • Step B N- [2- (Benzyloxy) -5-chlorophenyl] iminodiacetic acid Using 5.52 g (20.93 mmol) of the compound obtained in Step A, according to the method of Reference Example 61 Step B, Reference Example 60 Steps A and B, The title compound (5.87 g, yield 80%) was obtained as a colorless solid.
  • Step A 4- (Benzyloxy) -3-nitrobenzonitrile 6.22 g (57.5 mmol) of benzyl alcohol was dissolved in 100 ml of N, N-dimethylformamide, and 2.52 g (63.0 mmol) of 60% sodium hydride was added under ice cooling. Stir at warm for 20 minutes. Next, 10.0 g (54.8 mmol) of 4-chloro-3-nitrobenzonitrile was added, and the mixture was stirred at the same temperature for 90 minutes. The reaction solution was poured into ice water, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 13.91 g (yield 100%) of the title compound as a yellow solid.
  • Step B 3-amino-4- (benzyloxy) benzonitrile Using the compound obtained in Step A (13.91 g, 54.7 mmol) according to the method of Reference Example 61, Step B, 10.73 g (yield 88%) of the title compound was yellow. Obtained as an oil.
  • Step C N- [2- (Benzyloxy) -5-cyanophenyl] iminodiacetic acid diethyl ester 10.73 g (47.87 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Step A, and 10.23 g ( Yield 57%) was obtained as a colorless solid.
  • Step D N- [2- (Benzyloxy) -5-cyanophenyl] iminodiacetic acid Using 2.0 g (47.87 mmol) of the compound obtained in Step C and according to the method of Reference Example 60, Step B, 1.62 g (Yield) 94%) as a colorless solid.
  • Step A 3- [4- (Difluoromethoxy) phenyl] -5-methyl-1,2,4-oxadiazole 4- (difluoromethoxy) benzonitrile (5.44 g, 32.2 mmol) was dissolved in 60 ml of ethanol and stirred at room temperature. . Next, 3.40 g (48.9 mmol) of hydroxylammonium chloride and 4.02 g (49.0 mmol) of sodium acetate were added, followed by heating under reflux for 80 minutes. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
  • Step B 3- [4-Difluoromethoxy-3-nitrophenyl] -5-methyl-1,2,4-oxadiazole 4.46 g (19.7 mmol) of the compound obtained in Step A was added to 10 ml of concentrated sulfuric acid under ice-cooling. Subsequently, a mixed solution of 1.5 ml of 69% nitric acid and 4 ml of concentrated sulfuric acid was added dropwise over 5 minutes so that the internal temperature did not exceed 20 ° C., and the mixture was stirred at the same temperature for 10 minutes. The reaction solution was poured into an ice-cooled dilute aqueous sodium hydroxide solution and extracted with ethyl acetate.
  • Step C 2-Difluoromethoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) aniline 3.54 g (13.1 mmol) of the compound obtained in Step B is dissolved in 25 ml of ethanol and then tin chloride is added.
  • (II) (SnCl 2 ) 12.0 g (63.3 mmol) and concentrated hydrochloric acid 10 ml were added, and the mixture was heated at 60 ° C. for 20 minutes. The reaction solution was cooled to room temperature and then poured into 250 ml of 1N aqueous sodium hydroxide solution. Further, solid sodium hydroxide was added until the pH of the solution reached 10 or more, and the precipitated solid was filtered.
  • Step D N- [2-Difluoromethoxy-5- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] iminodiacetic acid Using 2.96 g (12.3 mmol) of the compound obtained in Step C, Reference Example 60 According to the method of Steps A and B, 2.24 g (yield 51%) of the title compound was obtained as a colorless solid.
  • Step A 1- [4-Difluoromethoxy-3-nitrophenyl] ethanone 1- [4- (Difluoromethoxy) phenyl] ethanone 3.87 g (20.8 mmol) was dissolved in 12 ml of concentrated sulfuric acid, and 2.33 g (23.0 g) of potassium nitrate was stirred with ice cooling. mmol) was added and stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Step B 1- [3-Amino-4- (difluoromethoxy) phenyl] ethanone Using 3.96 g (17.1 mmol) of the compound obtained in Step A and according to the method of Reference Example 62, Step B, 3.40 g of the title compound (yield 99 %) As a yellow oil.
  • Step C N- [5-acetyl-2- (difluoromethoxy) phenyl] iminodiacetic acid 2.39 g (16.9 mmol) of the compound obtained in Step B was used according to the method of Reference Example 60, Steps A and B, and 2.72 g of the title compound ( Yield 51%) was obtained as a colorless solid.
  • Step A N- [5-Chloro-2- (4-chlorophenoxy) phenyl] -N- [2-oxo-2- (4-phenylpiperidin-1-yl) ethyl] glycine 1.13 g (3.05 mmol) of the compound of Reference Example 61 ), 4-phenylpiperidine hydrochloride 1.18 g (5.97 mmol) was used to give 1.41 g (yield 90%) of the title compound as a colorless solid according to the method of Example 1, Step A.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2-oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - (2-pyrrolidin - 1-ylethyl) glycinamide Using 990 mg (1.93 mmol) of the compound obtained in Step A and 0.34 ml (2.71 mmol) of 1- (2-aminoethyl) pyrrolidine, according to the method of Example 1, Step B, the title compound 1.08 g (92% yield) was obtained as a colorless amorphous solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - [1- (tert -Butoxycarbonyl) piperidin-4-yl] glycinamide
  • 412 mg (0.802 mmol) of the compound obtained in Reference Example 112 Step A 259 mg (1.09 mmol) of the compound of Reference Example 9, and 0.17 ml (1.2 mmol) of triethylamine, Example 1
  • the title compound (423 mg, yield 76%) was obtained as a colorless amorphous solid.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - piperidin-4-yl Glycinamide hydrochloride Using the compound 394 mg (0.566 mmol) obtained in Step A, the title compound 334 mg (yield 93%) was obtained as a colorless solid according to the method of Example 2, Step B.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - [(2S) - 1- (tert-Butoxycarbonyl) pyrrolidin-2-ylmethyl] glycinamide
  • Reference Example 112 Compound 411 mg (0.801 mmol) obtained in Step A, Reference Example 12 Compound 279 mg (1.18 mmol), Triethylamine 0.165 ml (1.18 mmol)
  • Step B 500 mg (yield 90%) of the title compound was obtained as a colorless amorphous solid.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - [(2S) - Pyrrolidin-2-ylmethyl] glycinamide hydrochloride Using the compound 481 mg (0.691 mmol) obtained in Step A, the title compound 429 mg (yield 98%) was obtained as a colorless solid according to the method of Example 2, Step B. .
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - [(2R) - 1- (tert-Butoxycarbonyl) pyrrolidin-2-ylmethyl] glycinamide
  • Example 1 Step using 405 mg (0.789 mmol) of the compound obtained in Reference Example 112 Step A and 273 mg (1.15 mmol) of the compound of Reference Example 13 According to the method of B, the title compound (498 mg, yield 91%) was obtained as a colorless amorphous solid.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- oxo-2- (4-phenyl-piperidin-1-yl) ethyl] -N 1 - [(2R) - Pyrrolidin-2-ylmethyl] glycinamide hydrochloride Using the compound 481 mg (0.691 mmol) obtained in Step A, the title compound 429 mg (yield 98%) was obtained as a colorless solid according to the method of Example 2, Step B. .
  • Step A N- [2- (4-Benzoylpiperidin-1-yl) -2-oxoethyl] -N- [5-chloro-2- (4-chlorophenoxy) phenyl] glycine 455 mg (1.23 mmol) of the compound of Reference Example 61, According to the method of Example 1, Step A, 489 mg (yield 73%) of the title compound was obtained as a colorless solid using 555 mg (2.46 mmol) of 4-benzoylpiperidine hydrochloride.
  • Step B N 2 - [2- (4- benzoyl-1-yl) -2-oxoethyl] -N 2 - [5- chloro-2- (4-chlorophenoxy) phenyl] -N 1 - (2-pyrrolidin -1 -Ilethyl) glycinamide
  • 328 mg Yield 65% was obtained as a colorless amorphous solid.
  • Step A N- [2- (4-Benzylpiperidin-1-yl) -2-oxoethyl] -N- [5-chloro-2- (4-chlorophenoxy) phenyl] glycine 455 mg (1.23 mmol) of the compound of Reference Example 61, According to the method of Example 1, Step A, 472 mg (yield 73%) of the title compound was obtained as a colorless solid using 4-benzylpiperidine hydrobromide 692 mg (2.70 mmol).
  • Step B N 2 - [2- (4- benzyl-piperidin-1-yl) -2-oxoethyl] -N 2 - [5- chloro-2- (4-chlorophenoxy) phenyl] -N 1 - (2-pyrrolidin -1 -Ilethyl) glycinamide Using 398 mg (0.755 mmol) of the compound obtained in Step A and 0.13 ml (1.04 mmol) of 1- (2-aminoethyl) pyrrolidine, according to the method of Example 1, Step B, 449 mg of the title compound ( Yield 95%) was obtained as a colorless amorphous solid.
  • Step A N- [5-Chloro-2- (4-chlorophenoxy) phenyl] -N- [2- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl] glycine 437 mg of the compound of Reference Example 61 (1.18 mmol) and 0.5 ml of 1,2,3,4-tetrahydroisoquinoline were used to give 472 mg (yield 82%) of the title compound as a colorless solid according to the method of Example 1, Step A.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- (3,4- dihydro-isoquinoline -2 (IH) - yl) -2-oxoethyl] -N 1 - ( 2-pyrrolidin-1-ylethyl) glycinamide
  • Step B using 464 mg (0.956 mmol) of the compound obtained in Step A and 0.165 ml (1.31 mmol) of 1- (2-aminoethyl) pyrrolidine. 548 mg (99% yield) of the title compound was obtained as a colorless amorphous solid.
  • Step A N- [5-Chloro-2- (4-chlorophenoxy) phenyl] -N- [2- (3,4-dihydroquinolin-1 (2H) -yl) -2-oxoethyl] glycine Compound 0.85 of Reference Example 61 According to the method of Example 1, Step A, 0.94 g (yield 90%) of the title compound was obtained as a colorless solid using g (2.16 mmol) and 0.57 ml (4.54 mmol) of 1,2,3,4-tetrahydroquinoline. It was.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - [2- (3,4- dihydro-quinoline -1 (2H) - yl) -2-oxoethyl] -N 1 - ( 2-pyrrolidin-1-ylethyl) glycinamide
  • the method of Example 1, Step B using 0.94 g (1.94 mmol) of the compound obtained in Step A and 0.34 ml (2.67 mmol) of 1- (2-aminoethyl) pyrrolidine.
  • 0.97 g (yield 86%) of the title compound was obtained as a colorless amorphous solid.
  • the insoluble material was filtered off, and the reaction solution was concentrated under reduced pressure.
  • the obtained oil was dissolved in 20 ml of dichloromethane, and the mixture was stirred under ice-cooling while stirring 942 mg (5.10 mmol) of the compound of Reference Example 17 and 1.2 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene ( 8.0 mmol) was added and stirred at room temperature overnight.
  • the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • Step B N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - (2-pyrrolidin - 1-ylethyl) glycinamide 453 mg (1.05 mmol) of the compound obtained in Step A, 0.17 ml (1.36 mmol) of 1- (2-aminoethyl) pyrrolidine, 181 mg (1.34 mmol) of 1-hydroxybenzotriazole were added to N, N— Dissolved in a mixed solvent of 1 ml of dimethylformamide and 10 ml of dichloromethane, 265 mg (1.38 mmol) of WSC was added under ice cooling, and then stirred at room temperature for 3 hours.
  • Step C N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - (2-pyrrolidin - 1-ylethyl) glycinamide dihydrochloride 352 mg (0.667 mmol) of the compound obtained in Step B was dissolved in 1.5 ml of dichloromethane. While stirring at room temperature, 0.55 ml (2.2 mmol) of 4N hydrochloric acid-dioxane solution was added.
  • Step A N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - ⁇ 2 - [ ( tert-Butoxycarbonyl) (methyl) amino] ethyl ⁇ glycinamide
  • Example 1 Using 440 mg (1.02 mmol) of the compound obtained in Step A, 274 mg (1.30 mmol) of the compound of Reference Example 1, and 0.2 ml (1.4 mmol) of triethylamine According to the method of Example 1, Step B, the title compound (502 mg, yield 84%) was obtained as a pale-yellow amorphous solid.
  • Step B N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - [2- (methyl Amino) ethyl] glycinamide dihydrochloride 483 mg (0.822 mmol) of the compound obtained in Step A was dissolved in 2 ml of dichloromethane. At room temperature, 4 ml of 4N hydrochloric acid-dioxane solution (2.0 ml, 8.0 mmol) was added and stirred at the same temperature for 90 minutes.
  • Step A N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - ⁇ 2 - [ ( tert-Butoxycarbonyl) (isopropyl) amino] ethyl ⁇ glycinamide
  • Step B N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 2 - (2-phenoxyphenyl) -N 1 - [2- (isopropyl Amino) ethyl] glycinamide dihydrochloride
  • the compound 518 mg (yield 100%) was obtained as a colorless solid according to the method of Example 2, Step B, using 527 mg (0.856 mmol) of the compound obtained in Step A.
  • Step A N- [5-Chloro-2- (4-chlorophenoxy) phenyl] -N- ⁇ 2- [1,3-dihydro-2H-isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ glycine Reference Using 2.27 g (6.13 mmol) of the compound of Example 61 and 1.42 g (7.69 mmol) of the compound of Reference Example 17 and according to the method of Example 1, Step A, 2.35 g (yield 77%) of the title compound was obtained as a colorless solid. It was.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1 - (2-pyrrolidin-1-ylethyl) glycinamide step the compound obtained in a 274mg (0.548mmol), 1- ( 2- aminoethyl) - using pyrrolidine 0.11 ml (0.88 mmol), example According to the method of Step B, 310 mg (yield 95%) of the title compound was obtained as a colorless amorphous solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- ⁇ 2-[(tert-butoxycarbonyl) (methyl) amino] ethyl ⁇ glycinamide
  • Example 4 412 mg (0.823 mmol) of the compound obtained in Step A, 270 mg (1.28 mmol) of the compound of Reference Example 1, The title compound (407 mg, yield 75%) was obtained as a colorless oil according to the method of Example 1, Step B using 0.18 ml (1.3 mmol) of triethylamine.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- [2- (methylamino) ethyl] glycinamide dihydrochloride 337 mg (yield 91%) of the title compound according to Example 2, Step B, using 387 mg (0.589 mmol) of the compound obtained in Step A was obtained as a colorless solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- ⁇ 2- [Ethyl (trifluoroacetyl) amino] ethyl ⁇ glycinamide
  • Example 4 Compound 402 mg (0.803 mmol) obtained in Step A, Reference Example 15 Compound 332 mg (1.51 mmol), Triethylamine 0.21 ml (1.5 mmol) was used to give the title compound 546 mg (yield> 100%) as a colorless amorphous solid according to the method of Example 1, Step B.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1- [2- (Ethylamino) ethyl] glycinamide dihydrochloride 529 mg (0.794 mmol) of the compound obtained in Step A was dissolved in 6 ml of methanol, then 2 ml of 1N aqueous sodium hydroxide solution was added, And stirred for 3 hours. Saturated brine was added during the reaction, extracted with dichloromethane, and dried over sodium sulfate.
  • Example 7 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1 -[(2S) -pyrrolidin-2-ylmethyl] glycinamide dihydrochloride
  • Step A N 2 - [5-chloro-2- (4-chloro) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2- yl (methyl) amino] -2-oxoethyl ⁇ —N 1 -[(2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-ylmethyl] glycinamide
  • Example 4 Compound 396 mg (0.791 mmol) obtained in Step A, Reference Example 12 Compound 312 mg (1.32 mmol) ) And 0.185 ml (1.33 mmol) of triethylamine were obtained according to the method of Example 1, Step B to obtain 490 mg (yield 91%) of the title compound as a colorless amorphous solid.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1 -[(2S) -Pyrrolidin-2-ylmethyl] glycinamide dihydrochloride 479 mg (0.702 mmol) of the compound obtained in Step A and according to Example 2, Step B, 433 mg (yield 94) %) As a colorless solid.
  • Example 8 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1 -[(2R) -pyrrolidin-2-ylmethyl] glycinamide dihydrochloride
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1 -[(2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-ylmethyl] glycinamide
  • Example 4 301 mg (0.602 mmol) of the compound obtained in Step A, 195 mg (0.824 mmol) of the compound of Reference Example 13 ) And 0.12 ml (0.86 mmol) of triethylamine were used to give 383 mg (yield 93%) of the title compound as a colorless amorphous solid according to the method of Example 1, Step B.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1 -[(2R) -Pyrrolidin-2-ylmethyl] glycinamide dihydrochloride 375 mg (0.549 mmol) of the compound obtained in Step A is used according to Example 2, Step B and 339 mg (yield 94) %) As a colorless solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1 - [1- (tert- butoxycarbonyl) pyrrolidin-3-yl] glycinamide example 4 compound obtained in step a 297 mg (0.594 mmol), the compound of reference example 11 199 mg (0.894 mmol), triethylamine 0.12 According to the method of Example 1, Step B, 393 mg (yield 99%) of the title compound was obtained as a colorless amorphous solid using ml (0.86 mmol).
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- (Pyrrolidin-3-yl) glycinamide dihydrochloride Using the compound 381 mg (0.570 mmol) obtained in Step A, according to Example 2, Step B, the title compound 322 mg (yield 88%) is colorless. Obtained as a solid.
  • Example 10 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- ⁇ 2-[(3R) -3-hydroxypyrrolidin-1-yl] ethyl ⁇ glycinamide
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- (2-Bromoethyl) glycinamide 1.96 g (3.92 mmol) of the compound obtained in Example 4 Step A, 2-bromoethylamine hydrobromide 985 mg (4.81 mmol), N, N-diisopropylethylamine 0.80 According to the method of Example 1, Step B, 2.03 g (yield 85%) of the title compound was obtained as a colorless amorphous solid using ml (4.82 mmol).
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1- ⁇ 2-[(3R) -3-hydroxypyrrolidin-1-yl] ethyl ⁇ glycinamide 592 mg (0.976 mmol) of the compound obtained in Step A and 0.4 ml of (R) -3-pyrrolidinol This was dissolved in 10 ml of N-dimethylformamide and stirred at 60 ° C. for 1 hour.
  • the reaction mixture was cooled, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • the insoluble material was filtered off, and the solution was concentrated under reduced pressure.
  • the obtained oil was purified by silica gel column chromatography (ammonia-containing methanol-dichloromethane) to obtain the title compound (347 mg, yield 58%) as a colorless amorphous solid.
  • Example 11 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ —N 1- ⁇ 2-[(3S) -3-hydroxypyrrolidin-1-yl] ethyl ⁇ glycinamide
  • Example 10 Compound 690 mg (1.14 mmol) obtained in Step A, (S) -3-pyrrolidinol 0.4 ml In accordance with the method of Example 10, Step B, the title compound (397 mg, yield 57%) was obtained as a colorless amorphous solid.
  • Example 12 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [1,3- dihydro -2H- isoindol-2-yl (methyl) amino] -2-oxoethyl ⁇ -N 1- [2- (4-Hydroxypiperidin-1-yl) ethyl] glycinamide
  • Example 10 Using 685 mg (1.13 mmol) of the compound obtained in Step A and 640 mg (6.33 mmol) of 4-hydroxypiperidine, Example 10 According to the method of Step B, the title compound (339 mg, yield 48%) was obtained as a colorless amorphous solid.
  • Example 13 N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- [2- (Methylamino) ethyl] glycinamide hydrochloride
  • Step A N- [5-Chloro-2- (4-chlorophenoxy) phenyl] -N- ⁇ 2- [2,3-dihydro-1H-inden-2-yl (methyl) amino] -2-oxoethyl ⁇ glycine Reference Example According to the method of Example 1, Step A, 1.12 g (yield 85%) of the title compound was obtained as a colorless solid using 977 mg (2.64 mmol) of the 61 compound and 605 mg (3.29 mmol) of the compound of Reference Example 23.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- ⁇ 2-[(tert-butoxycarbonyl) (methyl) amino] ethyl ⁇ glycinamide
  • Example 13 667 mg (1.34 mmol) of the compound obtained in Step A, 464 mg (2.20 mmol) of the compound of Reference Example 1, triethylamine Using 0.35 ml (2.51 mmol) and according to the method of Example 1, Step B, 772 mg (yield 88%) of the title compound was obtained as a colorless amorphous solid.
  • Step C N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- [2- (Methylamino) ethyl] glycinamide hydrochloride Using the compound 746 mg (1.14 mmol) obtained in Step B, according to the method of Example 2, Step B, the title compound 625 mg (yield 93%) was obtained as a colorless solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- ⁇ 2- [Ethyl (trifluoroacetyl) amino] ethyl ⁇ glycinamide
  • Example 13 360 mg (0.721 mmol) of the compound obtained in Step A, 248 mg (1.12 mmol) of the compound of Reference Example 15, triethylamine 0.16 ml ( 1.15 mmol) was used to give 453 mg (94% yield) of the title compound as a colorless amorphous solid according to the method of Example 1, Step B.
  • Step B N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- [2- (Ethylamino) ethyl] glycinamide hydrochloride Using the compound 442 mg (0.664 mmol) obtained in Step A, according to the method of Example 6, Step B, 394 mg of the title compound (yield 98%) was obtained as a colorless solid.
  • Step A N 2 - [5-chloro-2- (4-chlorophenoxy) phenyl] -N 2 - ⁇ 2- [2,3- dihydro -1H- inden-2-yl (methyl) amino] -2-oxoethyl ⁇ - N 1- [2- ⁇ (Isopropyl) [(2-nitrophenyl) sulfonyl] amino ⁇ ethyl] glycinamide 408 mg (0.817 mmol) of the compound obtained in Example 13 Step A, 286 mg (0.995 mmol) of the compound of Reference Example 7 ) To give the title compound 596 mg (yield 95%) as a colorless amorphous solid according to the method of Example 1, Step B.

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Abstract

L'inhibiteur d'homocystéine synthase ci-décrit est utile pour prévenir ou pour traiter les maladies liées à une homocystéine synthase. Plus spécifiquement, cette invention concerne un composé représenté par la formule générale (I) [chaque symbole de ladite formule étant tel que défini dans la description], un sel pharmacologiquement acceptable de celui-ci, ou un solvate dudit composé ou sel pharmacologiquement acceptable de celui-ci, qui peut être utilisé à titre d'inhibiteur d'homocystéine synthase.
PCT/JP2010/067801 2009-10-09 2010-10-08 Inhibiteur d'homocystéine synthase WO2011043480A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104011019A (zh) * 2011-12-05 2014-08-27 莱斯特大学 新的吡咯衍生物
CN104277002A (zh) * 2013-07-01 2015-01-14 上海医药工业研究院 甘氨酰胺衍生物、中间体、制备方法、药物组合物及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003095959A (ja) * 2001-09-21 2003-04-03 Kokuritsu Seishin Shinkei Center ホモシステイン血症治療剤
WO2008012524A1 (fr) * 2006-07-24 2008-01-31 Ucb Pharma S.A. Dérivés d'aniline substitués
JP2008515994A (ja) * 2004-10-13 2008-05-15 ジェネラル アトミクス Ｓ−アデノシル−ｌ−ホモシステイン加水分解酵素の可逆的阻害剤およびその使用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003095959A (ja) * 2001-09-21 2003-04-03 Kokuritsu Seishin Shinkei Center ホモシステイン血症治療剤
JP2008515994A (ja) * 2004-10-13 2008-05-15 ジェネラル アトミクス Ｓ−アデノシル−ｌ−ホモシステイン加水分解酵素の可逆的阻害剤およびその使用
WO2008012524A1 (fr) * 2006-07-24 2008-01-31 Ucb Pharma S.A. Dérivés d'aniline substitués

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104011019A (zh) * 2011-12-05 2014-08-27 莱斯特大学 新的吡咯衍生物
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
CN104011019B (zh) * 2011-12-05 2016-08-24 莱斯特大学 吡咯衍生物
CN104277002A (zh) * 2013-07-01 2015-01-14 上海医药工业研究院 甘氨酰胺衍生物、中间体、制备方法、药物组合物及应用

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