GB948730A - Substituted cyclopropanes and related compounds - Google Patents

Substituted cyclopropanes and related compounds

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Publication number
GB948730A
GB948730A GB1184159A GB1184159A GB948730A GB 948730 A GB948730 A GB 948730A GB 1184159 A GB1184159 A GB 1184159A GB 1184159 A GB1184159 A GB 1184159A GB 948730 A GB948730 A GB 948730A
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United Kingdom
Prior art keywords
reduced
diphenyl
group
converted
cis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB1184159A
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Publication date
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Priority to GB1184159A priority Critical patent/GB948730A/en
Publication of GB948730A publication Critical patent/GB948730A/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/54—Preparation of carboxylic acid anhydrides
    • C07C51/56—Preparation of carboxylic acid anhydrides from organic acids, their salts, their esters or their halides, e.g. by carboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

The invention comprises a salt containing an ammonium cation of the formula: <FORM:0948730/C2/1> (wherein Ar is a phenyl, halophenyl, alkylphenyl or alkoxyphenyl group, the alkyl and alkoxy groups each containing at most 4 carbon atoms, or Ar2 is an o,o1-biphenylene group, R1 and R2 are hydrogen atoms or alkyl groups of at most 4 carbon atoms, W is a hydrogen atom or an alkyl group of at most 6 carbon atoms which may be substituted other than on the a -carbon atom with a dialkylamino group, the whole dialkylaminoalkyl group containing at most 12 carbon atoms, or an aralkyl group of 7 to 9 carbon atoms, X is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, or W and X together with the nitrogen atom may form a saturated cyclic amino group having 4 to 6 carbon atoms, Y is a hydrogen atom or an alkyl group of at most 4 carbon atoms, Z is an a -hydroxyalkyl group of at most 5 carbon atoms or an O-aryl derivative thereof, or an aryl group of 2 to 5 carbon atoms, or Z may be a hydrogen atom if the amine is a cyclic amine, or Y and Z together form a methylene group) and, unless the cation is quaternary, the secondary or tertiary amine corresponding thereto; and their preparation by (1) reduction with lithium aluminium hydride of a compound of the formula: <FORM:0948730/C2/2> (wherein W1 is as W but is not a hydrogen atom, X1 is as X, and Z1 is a hydrogen atom, a carboxyl group or its ester or an acyl group, or X1 and Z1 together form a carbonyl group in which event W1 may also be a carbamyl group), which reduction may be followed, if desired, by acylation of the a -hydroxyalkyl group, or by oxidation to an acyl group, or by N-quaternization or, when W is benzyl, by hydrogenative N-debenzylation; or (2) for preparing the bicyclic compounds by treating a compound of the formula: <FORM:0948730/C2/3> (wherein neither W nor X is a hydrogen atom) with p-toluene-sulphonyl chloride in the presence of a tertiary aliphatic amine. If W1 is a carbamyl group, W in the product is a hydrogen atom. In examples (1) 1,1-diphenylcyclopropane -2- carbonyl chloride (prepared from the acid and thionyl chloride) and pyrrolidine give 1,1-diphenyl -2- pyrrolidino carbonyl - cyclopropane and this on reduction gives 1,1-diphenyl -2-pyrrolidinomethylcyclopropane hydrochloride; (2) 1, 1-diphenyl -2- methyl -2- pyrrolidinocarbonyl cyclopropene is similarly prepared and reduced; (3) 1,1-diphenylcyclopropane -2,3-cis-dicarboxylic anhydride and dimethylamine give 1,1-diphenyl-cyclopropane -2,3-dicarboxylic acid mono-dimethylamide, this is reduced to 1,1-diphenyl -2-dimethylaminomethyl -3- hydroxymethylcyclopropane and this is converted to the acetate; (4) 1,1-diphenyl -2- piperidino carbonyl -3- ciscarboxy - cyclopropane is prepared similarly and is reduced to the piperidinomethyl compound which is converted to the acetate, cirramate and to the quaternary metho-p-toluene-sulphonate; (5) and (6) similarly are prepared 1,1-diphenyl -2-morpholinocarbonyl -3- cis-carboxycyclopropane and the corresponding pyrrolidide, which are reduced and the products converted into esters and quaternary salts; (7) The acid-amide of (4) is converted to the corresponding acid chloride, this with ethyl magnesium bromide gives 1,1-diphenyl -2- piperidinocarbonyl -3- cis-propionylcyclopropane and this is reduced to 1,1-diphenyl -2- piperidinomethyl -3- cis-(1-hydroxypropyl)-cyclopropane which is converted to the acetate and is also oxidized to 1,1-diphenyl -2- piperidinomethyl -3- cis-propionylcyclopropane; (8) to (11) 1,1-diphenyl -2- dimethylaminocarbonyl -3- cis-carboxy -3- trans - methylcyclopropane, the corresponding di-nbutyamino compound and the corresponding piperidide and pyrrolidide are prepared and reduced as in (3) and one of the products is converted to various esters; (12) diphenyldiazomethane (from benzophenone hydrazone) and methyl N-pentamethylenemaleamate give a pyrazoline, this on heating gives 1,1-diphenyl -2-piperidinocarbonyl -3- trans - methoxycarbonylcyclopropane and this is reduced; (13) p,p1-dimethylbenzophenone hydrazone is reacted with mercuric oxide and XOH and then with maleic anhydride to give 1,1-bis-p-tolylcyclopropane -2, 3-cis-dicarboxylic anhydride and this with piperidine gives a mono-piperidide which is then reduced and the product converted to a methiodide; (14) to (16) the corresponding monopyrrolidide and morpholide are similarly prepared and reduced; (17) bis-p-tolyldiazomethane and citraconic anhydride give 1,1-bis-p-tolyl -3-methylcyclopropane -2, 3-cis-dicarboxylicanhydride, this is converted to the corresponding mono-dimethylamide and this is reduced and then acetylated; (18) the corresponding mono-piperidide is similarly prepared and reduced; (19) p, p1-dimethoxybenzophenone hydrazone is oxidized to the diazo compound and this reacted with maleic anhydride to give 1,1-bis-p-methoxyphenylcyclopropane -2,3-cis-dicarboxylic anhydride, this is converted to the mono-dimethylamide, this is converted to the methyl ester and this is reduced; (20) to (23) by the above described methods 1,1-bisp - chlorophenylcyclopropane -2, 3 - cis - dicarboxylic anhydride and the corresponding mono-piperidide, and the corresponding monopyrrolidide and mono-isopropylamide are prepared and reduced; (24) 9-diazofluorene (from fluorenone hydrazone) and maleic anhydride give 1,1 -obiphenylenecyclopropane -2, 3 - cis - dicarboxylic anhydride, this is converted to the mono-piperidide and this reduced; (25) to (28) the corresponding dimethylamide, diethylamide, pyrrolidide and morpholide are similarly prepared and reduced; (29) diazofluorene and citraconic anhydride give 1,1-o-biphenylene -3- methylcyclopropane -2, 3 - cis - dicarboxylic anhydride, this converted to the mono-pyrrolidide and this reduced and the product esterified; (30) to (38) other products of the invention are prepared similarly; (39) diphenyldiazomethane and N-methylmaleimide give 6,6-diphenyl -2, 4- dioxo - 3-methyl -3- azabicyclo [3.1.0]-hexane and this is reduced and the product converted to the methiodide, and, via the quaternary hydroxide, to the methopicrate; (40) the corresponding 3-ethyl compound is similarly prepared and reduced; (41) 6,6-diphenyl 2, 4 - dioxo -1- methyl -3- b -diethylaminoethyl -3- azabicyclo [3.1.0] hexane is prepared from the appropriate anhydride and diamine and then reduced and the product converted to a bis-methiodide; (42) and (43) diphenyldiazomethane and N-benzylmaleimide give a pyrazoline, this on heating gives 6,6-diphenyl -2,4-dioxo -3- benzyl -3- azabicyclo - [3.1.0] hexane and this is reduced 6,6-diphenyl -3- benzyl -3- azabicyclo- [3.1.0]-hexane which is then debenzylated; (44) 6,6-diphenyl 2,4-dioxo-3-carbamyl -3- azabicyclo [3.1.0] hexane is similarly prepared and reduced; (45) the pyrazoline of the formula: <FORM:0948730/C2/4> is similarly prepared, heated to form the azabicyclo compound and this reduced and the product quaternized; (46) the corresponding N-n-butylpyrazoline is similarly prepared and heated to give the azabicyclo compound and the latter reduced; (47) and (48) 9-diazofluorene and N-methylmaleimide give 6,6-o-biphenylene -2, 4-dioxo -3- methyl -3- azabicyclo [3.1.0] hexane and this is reduced and the product quaternized; (49) the corresponding 3-ethyl compound is similarly prepared and reduced; (50) to (63) process (2) of the invention is illustrated. Some of these processes are also described in more general terms.
GB1184159A 1959-04-08 1959-04-08 Substituted cyclopropanes and related compounds Expired GB948730A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB1184159A GB948730A (en) 1959-04-08 1959-04-08 Substituted cyclopropanes and related compounds

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Application Number Priority Date Filing Date Title
GB1184159A GB948730A (en) 1959-04-08 1959-04-08 Substituted cyclopropanes and related compounds

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340268A (en) * 1964-02-26 1967-09-05 Ciba Geigy Corp 1-[piperidyl]-2, 2-di(monocyclic hexacyclic aryl)-cyclopropane
US4103030A (en) * 1974-12-11 1978-07-25 Sumitomo Chemical Company, Limited Novel cyclopropylmethylamine derivatives
FR2492383A1 (en) * 1980-10-16 1982-04-23 Bristol Myers Co SPIRO-QUATERNARY AMMONIUM HALIDES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN PROCESS FOR PRODUCING N- (2-PYRIMIDINYL) PIPERAZINYL-ALKYLAZOSPIRO-ALKANEDIONES
WO2005033080A1 (en) * 2003-10-06 2005-04-14 Pfizer Products Inc. Process for preparing an azabicyclo[3.1.0]hexane compound
EP1140828B1 (en) * 1998-12-23 2006-08-09 Pfizer Limited 3-azabicyclo¬3.1.0|hexane derivatives as opiate receptors ligands

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340268A (en) * 1964-02-26 1967-09-05 Ciba Geigy Corp 1-[piperidyl]-2, 2-di(monocyclic hexacyclic aryl)-cyclopropane
US4103030A (en) * 1974-12-11 1978-07-25 Sumitomo Chemical Company, Limited Novel cyclopropylmethylamine derivatives
FR2492383A1 (en) * 1980-10-16 1982-04-23 Bristol Myers Co SPIRO-QUATERNARY AMMONIUM HALIDES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN PROCESS FOR PRODUCING N- (2-PYRIMIDINYL) PIPERAZINYL-ALKYLAZOSPIRO-ALKANEDIONES
NL8104660A (en) * 1980-10-16 1982-05-17 Bristol Myers Co SPIRO-QUATERARY AMMONIUM HALOGENIDES AND N- (2-PYRIMIDINYL) PIPERAZINYL ALKYLAZAPIROALKANDION PROCESS.
EP1140828B1 (en) * 1998-12-23 2006-08-09 Pfizer Limited 3-azabicyclo¬3.1.0|hexane derivatives as opiate receptors ligands
AP1852A (en) * 1998-12-23 2008-05-29 Pfizer '3-Azabicyclo{3.1.0] hexane derivatives as opiate receptors ligands.
WO2005033080A1 (en) * 2003-10-06 2005-04-14 Pfizer Products Inc. Process for preparing an azabicyclo[3.1.0]hexane compound
KR100767895B1 (en) 2003-10-06 2007-10-17 화이자 프로덕츠 인코포레이티드 Process for preparing an azabicyclo[3.1.0]hexane compound

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