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WO2021209269A1 - Procédé de préparation de composés énamine substitués - Google Patents

Procédé de préparation de composés énamine substitués Download PDF

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Publication number
WO2021209269A1
WO2021209269A1 PCT/EP2021/058580 EP2021058580W WO2021209269A1 WO 2021209269 A1 WO2021209269 A1 WO 2021209269A1 EP 2021058580 W EP2021058580 W EP 2021058580W WO 2021209269 A1 WO2021209269 A1 WO 2021209269A1
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WO
WIPO (PCT)
Prior art keywords
acid
compound
formula
methyl
ethyl
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.)
Ceased
Application number
PCT/EP2021/058580
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English (en)
Inventor
Werner Bonrath
Le DAI
Xixiang DAI
Qiangqiang LIU
Marc-André Mueller
Kun Peng
Liuhai WU
Lei Zhang
Zili Zhang
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
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DSM IP Assets BV
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Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Priority to EP21717374.9A priority Critical patent/EP4136066A1/fr
Priority to CN202180027529.0A priority patent/CN115397807B/zh
Priority to CN202411047416.9A priority patent/CN118993936A/zh
Publication of WO2021209269A1 publication Critical patent/WO2021209269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

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 EtOH 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.
  • substituted refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -N0 2 , cyano or isocyano.
  • the present invention provides a process for producing a compound of formula (I), comprising: a) reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (la); and b) converting the compound of formula (la) into the compound of formula (I),
  • 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 4 and R 4 ' 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-Ce 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.
  • the rest one is hydroxyl, methoxyl, ethoxyl, or NR 4 R 4 ' (wherein R and R ' are dependently H, methyl or ethyl), optionally substituted by one or more substituents.
  • R', Ri, R 2 and R 3 together with the carbon they connect, form carbon monoxide (Co0).
  • 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 4 R 4 ' (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 (la) and (II) may be in a form of any salt of formula (la') and (IG) respectively:
  • X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), postassium (K), rubidium (Rb), caesium (Cs) and francium (Fr)); or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra)); and Iron (ll/lll), nickel and cobalt.
  • X is Na or K.
  • the compound of formula (III) may be added in an amount of from 0.01 moles to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10 moles, per 1 mole of the compound of formula (II).
  • the step a) of the process of the present invention may be carried out in the presence of a solvent.
  • the solvent preferably is a polar organic solvent such as toluene, tetrahydrofuran (THF), methyl tert-butyl ether (TBME), alcohol (i.e., ethanol) and benzene, or mixture thereof.
  • the reaction of the step a) of the present invention may be carried out at the temperature from -30°C to 110°C, preferably from -20°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.
  • 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 (la) may be converted into the compound of formula (I) by any suitable way, for example, by adding water, an acid, an acidic salt or an alcohol.
  • the acid include but are not limited to organic acid such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid and maleic acid; inorganic acid such as hydrochloric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, chloric acid, hypochlorous acid, perchloric acid, sulfonic acid, hydrobromic acid and hydrofluoric acid; and acidic resin such as sulfonic acid resin.
  • the examples of the acidic salt include but are not limited to ammonium chloride, monopotassium phosphate, monosodium phosphate, sodium hydrogen sulfate and potassium hydrogen sulfate.
  • the examples of the alcohol include but are not limited to methanol, ethanol and phenol.
  • the compound of formula (la) is converted into the desired compound of formula (I) by adding an acid as defined above.
  • the acid may be added in an amount of from 0.1 mol to 10 mol, preferably from 0.5 mol to 8 mol, more preferably from 1 mol to 5 mol such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 mol, per 1 mol of the compound of formula (la).
  • the compound of formula (la) is converted into the desired compound of formula (I) by adding water.
  • the water may be added in an amount of from 10 mL to 1000 mL, preferably from 18 mL to 500 mL, more preferably from 20 mL to 100 mL, per 1 mol of the compound of formula (la).
  • a solvent may be used when necessary.
  • suitable solvent include but are not limited to ethyl acetate, ethyl butyrate, butyl acetate, tetrahydrofuran, toluene, 1,4-dioxane, 2,5-dimethyltetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diethyl ether, acetonitrile, methyl tert-butyl ether, and mixture thereof.
  • the step b) of the process of the present invention may be carried out at the temperature from 0°C to 50°C, preferably from 10°C to 40°C, such as 10, 15, 20, 25, 30, 35 and 40°C.
  • the obtained compound of formula (I) may be directly used for industrial application, or purified by known process such as extraction, crystallization and/or filtration.
  • the reaction mixture of the step a) containing the compound of formula (la) is preferably used to the step b) directly without isolation and purification.
  • the process of the present application may be carried out in one pot.
  • the present invention also provides a one-pot process for the preparation of the compound of formula (I), which comprises adding the compound of formula (II) as defined above, the compound of formula (III) as defined above, optionally the solvent as defined above, and water or an acid or an acidic salt or an alcohol as defined above into one pot for reaction to obtain the compound of formula (I).
  • 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 (lla) with a strong base such as sodium (Na), Sodium hydride (NaH) or sodium amide.
  • a strong base such as sodium (Na), Sodium hydride (NaH) or sodium amide.
  • the compounnd of formula (II) may be produced from nitriles as disclosed in US 5187297 A.
  • the processes of the present invention avoid toxic and unsafe reagents while providing high yield and high selectivity.
  • the obtained products of the processes of the present invention can be used for producing oxazole compounds directly without any purification.
  • the present invention provides a process for producing an oxazole compound comprising the step for producing the compound of formula (la) and/or the compound of formula (I) as described 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.
  • 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).
  • the filter cake obtained according to Example 3 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, 92% yield).
  • the filter cake obtained according to Example 3 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (50 mL) was added and H 2 0 (20 mL) was added dropwise in 5 mins. The reaction mixture was stirred for 10 mins at room temperature and then extracted with butyl acetate (50 mL x 3). The organic phase was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (7.0 g, 53% yield based on acetonitrile).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un composé énamine substitué de formule (I), et un procédé de production de composés oxazole à partir du composé de formule (I). Selon les procédés de la présente invention, on peut produire des composés énamine substitués avec un rendement et une sélectivité élevés tout en évitant des réactifs toxiques ou dangereux pour produire des composés oxazole. Dans la formule, R représente H, un alkyle ou aryle inférieurs, éventuellement substitués par un ou plusieurs substituants.
PCT/EP2021/058580 2020-04-17 2021-04-01 Procédé de préparation de composés énamine substitués Ceased WO2021209269A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP21717374.9A EP4136066A1 (fr) 2020-04-17 2021-04-01 Procédé de préparation de composés énamine substitués
CN202180027529.0A CN115397807B (zh) 2020-04-17 2021-04-01 用于制备取代的烯胺化合物的方法
CN202411047416.9A CN118993936A (zh) 2020-04-17 2021-04-01 用于制备取代的烯胺化合物的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2020085419 2020-04-17
CNPCT/CN2020/085419 2020-04-17

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WO2021209269A1 true WO2021209269A1 (fr) 2021-10-21

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WO (1) WO2021209269A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022218733A1 (fr) * 2021-04-15 2022-10-20 Dsm Ip Assets B.V. Procédé de préparation de composés énamine substitués
WO2022218734A1 (fr) * 2021-04-15 2022-10-20 Dsm Ip Assets B.V. Procédé de préparation de composés énamine substitués

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5187297A (en) 1990-11-05 1993-02-16 Lonza Ltd. Process for the production of 3-aminocrotononitrile
WO2007112317A1 (fr) * 2006-03-24 2007-10-04 University Of Notre Dame Du Lac Procédé et dispositif de prédiction d'un excès énantiomère
CN102898321A (zh) 2011-07-24 2013-01-30 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
CN104725262A (zh) 2013-12-23 2015-06-24 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
CN105985297A (zh) 2015-01-30 2016-10-05 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

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WO2007112317A1 (fr) * 2006-03-24 2007-10-04 University Of Notre Dame Du Lac Procédé et dispositif de prédiction d'un excès énantiomère
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022218733A1 (fr) * 2021-04-15 2022-10-20 Dsm Ip Assets B.V. Procédé de préparation de composés énamine substitués
WO2022218734A1 (fr) * 2021-04-15 2022-10-20 Dsm Ip Assets B.V. Procédé de préparation de composés énamine substitués

Also Published As

Publication number Publication date
CN115397807A (zh) 2022-11-25
CN118993936A (zh) 2024-11-22
CN115397807B (zh) 2024-08-13
EP4136066A1 (fr) 2023-02-22

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