EP4323333A1 - Verfahren zur herstellung von substituierten enaminverbindungen - Google Patents

Verfahren zur herstellung von substituierten enaminverbindungen

Info

Publication number
EP4323333A1
EP4323333A1 EP22720626.5A EP22720626A EP4323333A1 EP 4323333 A1 EP4323333 A1 EP 4323333A1 EP 22720626 A EP22720626 A EP 22720626A EP 4323333 A1 EP4323333 A1 EP 4323333A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
methyl
ethyl
carbon
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.)
Pending
Application number
EP22720626.5A
Other languages
English (en)
French (fr)
Inventor
Werner Bonrath
Le DAI
Xixiang DAI
Qi Gu
Qiangqiang LIU
Maurus Marty
Marc-André Mueller
Kun Peng
Liuhai WU
Zili Zhang
Florian ZIEGLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP4323333A1 publication Critical patent/EP4323333A1/de
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton

Definitions

  • the present invention is related to a new process for producing substituted enamine compounds.
  • Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials.
  • the wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity.
  • oxazole derivatives are important intermediates for preparation of biological compounds such as vitamin B 6 .
  • oxazole compounds Various processes for the preparation of oxazole compounds have been developed.
  • One preferred process in industry is from alanine and oxalic acid in ethanol carried out by azeotropic distillation with benzene.
  • the ring closure reaction to obtain 5-ethoxy-4-methyloxazole can also be carried out using phosgene or triphosgene, which is toxic and not environment friendly (see CN 104725262 B, CN 102898321 A and CN 105985297 A)
  • the present invention provides a substituted enamine compound of formula (I), which can be converted to an oxazole compound, wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.
  • the present invention also provides a process for producing the compound of formula (I) and a process for producing oxazole compounds from the compound of formula (I).
  • the term "lower alkyl” as used refers to Ci-Cio alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms.
  • the "lower alkyl” is Ci-C 6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclon
  • aryl refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.
  • lower alkoxyl refers to the structure represented by (lower alkyl)-0-, wherein the lower alkyl is defined as above.
  • halo or halogen refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.
  • substitutedine or substituted refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -N0 2 , cyano or isocyano.
  • a compound represented by a formula or a name also cover stereoisomers thereof, including diastereomers and enantiomers, such as cis/trans-isomers or E/Z-isomers.
  • the present invention provides a process for producing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) to produce the compound of formula (I), wherein
  • R is H, lower alkyl or aryl, optionally substituted by one or more substituents
  • R' is H; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR 4 R 4 ' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R 2 and R 3 , together with the carbon they connect, form carbon monoxide (Co0).
  • R is H or Ci-C 6 alkyl, optionally substituted by one or more substituents. More preferably, R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents. The most preferably, R is H or methyl.
  • the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR 4 R 4 ' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents.
  • R is H, methyl, ethyl or phenyl; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR R ' (wherein R and R ' are dependently H, methyl or ethyl).
  • R is H, methyl, ethyl or phenyl
  • the compound of formula (III) is carbon monoxide.
  • R is H or methyl; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH 2 or -NHCH 3 .
  • the compound of formula (I) and (II) may be in a form of any salt of formula (G) and (IG) respectively: wherein R is defined as above, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH ) or substituted ammonium.
  • X and Y are dependently Na or K.
  • the compound of formula (III) may be added in an amount of from 0.01 mols to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10 moles such as 0.2, 0.5, 0.8, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10 moles, per 1 mole of the compound of formula (II).
  • the process of the present invention may be carried out in the presence of a solvent.
  • the solvent may be an inorganic solvent such as liquid ammonia, or an organic solvent including but not limited to alkane such as pentane, hexane, heptane, cyclopentane and cyclohexane, aromatic hydrocarbon such as benzene and toluene, ester such as methyl formate and ethyl formate, alcohol such as ethanol, ether such as methyl tert-butyl ether (TBME) and cyclopentyl methyl ether, tertiary amine such as N,N-diethylaniline, triethylamine and tributylamine, amide such as dimethylformamide (DMF), diethylformamide (DEF) and dibutylformamide (DBF), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), or
  • the solvent is liquid ammonia, toluene, THF, heptane, acetonitrile, methyl formate, N,N- diethylaniline, triethylamine, TBME, cyclopentyl methyl ether, toluene, ethanol, or mixture thereof.
  • the solvent is liquid ammonia, toluene, heptane, acetonitrile, methyl formate, TBME, or mixture thereof.
  • the compound of formula (III) is methyl formate
  • the solvent is selected from the group consisting of liquid ammonia, heptane, acetonitrile, methyl formate, N,N-diethylaniline, triethylamine, TBME, cyclopentyl methyl ether and toluene, and mixture thereof.
  • the compound of formula (III) is ethyl formate
  • the solvent is selected from the group consisting of liquid ammonia, toluene, THF and heptane, and mixture thereof.
  • the solvent may be added in an amount of from 0.05 mL to 10 mL, preferably from 0.1 mL to 9 mL, more preferably from 0.15 mL to 5 mL such as 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4 and 5 mL, per 1 mmol of the compound of formula (II).
  • the reaction of the present invention may be carried out at the temperature from -50°C to 110°C, preferably from -40°C to 100°C, more preferably from -10°C to 50°C such as -10, -5, 0, 10, 15, 20, 25, 30, 35, 40, 45 and 50°C, under a pressure at 1-20 bar, preferably 2-15 bar, more preferably 3-10 bar such as 3, 4, 5, 6, 7, 8, 9 and 10 bar.
  • the obtained compound of formula (la) may be used to the next step b) directly or purified by known process such as crystallization and/or filtration.
  • the compound of formula (II) may be prepared by any process known in the art in-situ or ex-situ, for example, by treating the compound of formula (I la) with a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.
  • a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.
  • the compound of formula (II) maybe produced from nitriles such as acetonitrile as disclosed in US 5187297 A.
  • R is defined as above.
  • the compound of formula (I) according to the present invention can be used for producing oxazole compounds.
  • the whole process for producing oxazole compounds avoid toxic and unsafe reagents while providing high yield and high selectivity.
  • the present invention provides a process for producing an oxazole compound comprising the step of producing the compound of formula (I) as defined above.
  • the process of the present invention avoids toxic phosphate reagents and saves steps compared to the processes known in the art and thus provides a new process.
  • the present invention will be further illustrated by the following examples.
  • a dried four necked round bottom flask was charged with liquid ammonia (15 mL, 0.615 mol, 11 eq). After the flask was flushed with argon, sodium (1.5 g, 65 mmol, 1.1 eq) was added and stirred for 30 mins at - 40°C to -50°C. At the same temperature compound 1 (4.85 g, 59 mmol, 1 eq) in THF (20 mL) was added dropwise in 15 mins. Then the reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a white suspension of the compound 2.
  • This suspension was filtrated over a paper filter (7 cm diameter) and washed with TBME (200 mL) to obtain filter cake containing the compound 2 (19.40 g, 67.1wt% purity, 97% yield).
  • a dried autoclave was charged at -40°C to -50°C with liquid ammonia (887 mL, 36 mol, 46 eq) and iron nitrate nonahydrate (210 mg, 0.97 mmol, 0.001 eq). Then sodium (18.0 g, 783 mmol, 1.0 eq) was added, and the reaction mixture stirred for 30 min at -40°C to -50°C until complete cessation of hydrogen evolution. The reaction mixture was heated to 20°C over a period of 45 min, whereas a pressure of 8 bar formed. At the same temperature anhydrous acetonitrile (64.2 g, 1,564 mmol, 2.0 eq) was pumped over a period of 15 min, and the reaction mixture was stirred for 150 min.
  • Example 9 The filter cake obtained according to the same procedures of Example 9 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (100 mL) was added and acetic acid (7.75 g, 129 mmol, 1.0 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (13.22 g, 98.8wt% purity,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP22720626.5A 2021-04-15 2022-04-04 Verfahren zur herstellung von substituierten enaminverbindungen Pending EP4323333A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2021087509 2021-04-15
PCT/EP2022/058839 WO2022218734A1 (en) 2021-04-15 2022-04-04 A process for preparation of substituted enamine compounds

Publications (1)

Publication Number Publication Date
EP4323333A1 true EP4323333A1 (de) 2024-02-21

Family

ID=81579557

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22720626.5A Pending EP4323333A1 (de) 2021-04-15 2022-04-04 Verfahren zur herstellung von substituierten enaminverbindungen

Country Status (3)

Country Link
EP (1) EP4323333A1 (de)
CN (1) CN117136179A (de)
WO (1) WO2022218734A1 (de)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2985435B2 (ja) 1990-11-05 1999-11-29 ロンザ リミテッド ３−アミノクロトンニトリルの製造方法
CN102898321B (zh) 2011-07-24 2015-10-28 上海海嘉诺医药发展股份有限公司 一种制备n-丁氧草酰丙氨酸丁酯的方法
CN104725262B (zh) 2013-12-23 2018-05-15 大丰海嘉诺药业有限公司 一种连续制备n-乙氧基草酰丙氨酸乙酯的方法
CN105985297B (zh) 2015-01-30 2018-08-10 湖北得正医药科技有限公司 维生素b6中间体4-甲基-5-乙氧基-2-噁唑酸乙酯的合成工艺
CN111848449A (zh) * 2019-04-30 2020-10-30 帝斯曼知识产权资产管理有限公司 一种新的酰氧基烯胺化合物
EP4136066A1 (de) * 2020-04-17 2023-02-22 DSM IP Assets B.V. Verfahren zur herstellung substituierter enaminverbindungen

Also Published As

Publication number Publication date
CN117136179A (zh) 2023-11-28
WO2022218734A1 (en) 2022-10-20

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