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WO2003093221A1 - Preparation de d-(-)-1-substitue-phenyl-2-dichloroacetoamino-3-fluoro-1-propanol a partir d'ester substitue de phenylserine de type l - Google Patents

Preparation de d-(-)-1-substitue-phenyl-2-dichloroacetoamino-3-fluoro-1-propanol a partir d'ester substitue de phenylserine de type l Download PDF

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Publication number
WO2003093221A1
WO2003093221A1 PCT/CN2002/000354 CN0200354W WO03093221A1 WO 2003093221 A1 WO2003093221 A1 WO 2003093221A1 CN 0200354 W CN0200354 W CN 0200354W WO 03093221 A1 WO03093221 A1 WO 03093221A1
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WO
WIPO (PCT)
Prior art keywords
substituted phenyl
threo
substituted
fluoro
propanol
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PCT/CN2002/000354
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English (en)
Chinese (zh)
Inventor
Guoqiang Lin
Xinsheng Lei
Hao Huang
Xiaoming Yu
Rong Li
Original Assignee
Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences
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Publication date
Application filed by Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences
Priority to AU2002311147A priority Critical patent/AU2002311147A1/en
Publication of WO2003093221A1 publication Critical patent/WO2003093221A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol from L-substituted phenylserine ester. Furthermore, it is a kind of purified L-isomer from the waste liquid of the substituted phenylserine ester, which is purified to obtain D- (-)-threo-1-R-substitution by D-type inversion and fluorination. Convenient method for phenyl-2-dichloroacetamino-3-fluoropropanol. Background technique
  • Drugs such as chloramphenicol, methylsulfomycin, and fluconi are a broad-spectrum antibiotic, and they are particularly effective against Gram-negative bacteria.
  • the synthesis of this broad class of drugs usually involves the resolution of D, L-type-1-R-substituted phenyl-2-aminopropanediol or D, L-substituted phenylserine esters, of which only the D-type isomer is synthesized as described above Prodrugs of the drug, L-isomers are discarded (Cutler, RA, et al, J. Am. Chem.
  • the object of the present invention is to provide a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol from L-substituted phenylserine ester. . It is based on the extraction and purification of L-type substituted phenylserine esters from the separated waste liquid in industrial production, and converts the L-type isomers into oxazoline cyclates; and then converts into high-value-added D- (-)-Threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol. Summary of invention
  • the method of the present invention is to extract and purify L-type substituted phenylserine ester 1 from the separated waste liquid in industrial production, and use D as the raw material to form D-(-)-threo through acylation and isomerization reaction.
  • the molar ratio of the L-substituted phenylserine ester 1, the acid halide, the compound containing a lone electron on the nitrogen atom, and the dichlorosulfoxide is 1: 0.8 ⁇ 1.5: 0 ⁇ 5: 0.5 ⁇ 3, and the recommended molar ratios are in order It is 1: 0.8 ⁇ 1.2: 0.04 ⁇ 4: 0.5 ⁇ 2.
  • D_threo_ ( 4 5 ⁇ -2- -4-oxoacyl-5-R-substituted phenyl-2-oxazoline 2a and basic substances After 0.5 ⁇ 5 hours of reaction, compound D- (-)-threo- (4 & 5-2--4-oxoacyl-5-R-substituted phenyl-2-oxazoline 2b can be obtained.
  • 2a and basic The molar ratio of the substance is 1: 1 to 10, and the recommended molar ratio is 1: 1 to 3.
  • R 2 is the aforementioned R 2 and X is halogen.
  • the basic substance may be sodium carbonate or Potassium, sodium or potassium bicarbonate, ammonium carbonate, diethylamine, triethylamine, sodium or potassium methoxide, sodium or potassium ethoxide, and the like.
  • Compound 2b is reduced to D- (-)-threo- (4S, 5i?)-2-R 2 -4-hydroxymethyl-5-R- with potassium borohydride or sodium borohydride in a polar solvent.
  • Substituted phenyl-2-oxazoline 2c the reaction temperature is -10 Q C to 50 ° C, the reaction time is 1-12 hours, and the molar ratio of compound 2b to potassium borohydride or sodium during the reaction is 1: 1 to 10 The recommended molar ratio is 1: 1 ⁇ 3.
  • Potassium borohydride or sodium can be directly added to the reaction system in the form of solid particles, or it can be formulated as a solution to be added to the reaction system.
  • the recommended solvent is water.
  • Compound 2c can also be reacted with a fluorinating reagent to prepare D- (-)-threo- (4 & 5i?)-2-R 2 -4-fluoromethyl-5-R- substituted phenyl-2-oxazoline 2d and 2d were hydrolyzed and ring-opened under acidic conditions to obtain D--1-R-substituted phenyl-2-amino-3-fluoro-1-propanol 3a, and finally subjected to dichloroacetylation to obtain D- (-)- Threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol 4a.
  • compound 2c is reacted with a fluorinating agent to obtain compound 2d.
  • the reaction can be carried out under normal pressure or under a closed pressure.
  • the reaction is preferably in an inert atmosphere.
  • the recommended solvent is acetonitrile.
  • the reaction is performed in a closed pressure-resistant container, the recommended solvent is dichloromethane.
  • the reaction temperature is 0 ⁇ 120 ° C, the recommended temperature is 10 (20 ° C, the reaction time is 0.5 ⁇ 10 hours, the recommended time is 1 ⁇ 3 hours; the molar ratio of compound 2c to the fluorinating reagent is 1: 0.5 ⁇ 3, it is recommended molar ratio is 1: 1 to 3, said fluorinating agent may be known and disclosed, of the formula et 2 NSF DAST reagent (Nagabhushan, TL, US 4235892, 1980), Yarovenko reagent (Shart, CM, et al, Org. React., 21, 158, 1974), Ishikawa reagent (Takaoka, A "et al, Bull. Chem. Soc.
  • Compound 2d can also undergo a hydrolysis ring-opening reaction with an inorganic or organic acid to obtain 3a.
  • the solvent used can be water, methanol, ethanol, isopropanol, glacial acetic acid, etc.
  • the recommended solvent is water.
  • the molar ratio of compound 2d to the inorganic or organic acid is 1: 1 to 100.
  • the acid used may be an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as formic acid, glacial acetic acid, p-toluenesulfonic acid, and methanesulfonic acid. Hydrochloric acid is recommended.
  • the reaction temperature can be room temperature to 120 ° C, the recommended temperature is 80 to 120 ° C, the reaction time is 4 hours to 18 hours, and the recommended reaction time is 10 to 18 hours.
  • the reaction solution of 2d hydrolysis to 3a needs to be neutralized with alkali and extracted with organic solvent.
  • the extraction method can be used to extract 3a by liquid separation or continuous liquid-liquid extractor.
  • the extraction solution used can be ether, ethyl acetate, chloroform, dichloromethane, etc.
  • the recommended solvent is dichloromethane.
  • Compound 3a undergoes an acylation reaction to obtain the target 4a. That is, 3a can undergo an acylation reaction with an acylating agent in a polar solvent. If a basic substance is added to the reaction, such as: a compound containing a lone electron on the nitrogen atom, and Inorganic bases or sodium alkoxides of valent or divalent metals will facilitate the reaction.
  • the reaction temperature can be 0 ⁇ 100 ° C, the recommended temperature is room temperature, the reaction time is 5 ⁇ 36 hours, and the recommended reaction time is 10 ⁇ 18 hours.
  • the molar ratio of acylating agent and basic substance is 1: 1 ⁇ 10: 1 ⁇ 100.
  • the recommended molar ratio is 1: 1.5 ⁇ 3: 3 ⁇ 6.
  • the acylating agent used is dichloroacetyl chloride, dichloroacetyl bromide, methyl dichloroacetate or ethyl dichloroacetate.
  • the recommended acylating agent is methyl dichloroacetate.
  • the compound containing a lone pair electron on the nitrogen atom in the present invention is a tertiary amine, a secondary amine, a primary amine, a pyridine, a bipyridine, a diethylamine compound, and NH 3 having a hydrocarbon group of 24 .
  • the polar solvent described in the present invention may be one or more kinds of diethyl ether, tetrahydrofuran, chloroform, dichloromethane, dichloroacetamidine, trichloroacetamidine, methanol, ethanol, pyridine, triethylamine, toluene, Acetonitrile and water.
  • the method of the present invention can be used to synthesize compound 2 from compound 1 in a stepwise manner, or compound 2 can be directly synthesized by a continuous one-pot method, and compound 4a can be synthesized from compound 2 by a stepwise method.
  • Example 1 Extraction and purification of L-(-)-threo-3- (4-methylsulfonyl) phenylserine ethyl ester 500 ml of the industrial waste liquid (L-isomer: ee> 80%) ), Concentrated under reduced pressure to obtain a viscous liquid, dissolved in 400 ml of water, added 10 g of activated carbon, stirred at room temperature for 0.5 hours, and filtered. The filtrate was adjusted to a pH of 8 to 9 with concentrated ammonia water, a solid was precipitated, left to stand, filtered, and 100 ml of filter cake was used. Wash gently with ice-cold water.
  • Example 3 D- (-)-threo-2-phenyl-4-fluoromethyl-5- (4 - preparation methylsulfonyl) phenyl-2-oxazoline product obtained from example 2 30g (recrystallized from isopropanol, P 2 0 5 and dried overnight), placed in sealed pressure bottle, sealed The bottle was evacuated, replaced with nitrogen, 300 ml of dry dichloromethane, and finally 21.4 ml of freshly distilled Ishikawa reagent (Takaoka, A., et al, Bull. Chem. Soc. Jpn., 52, 3377, 1979) .
  • Example 5 D- (-)-threo-l- (4-methylsulfone) Preparation of phenyl-2-dichloroacetamino-3-fluoro-1-propanol Take 5.55 g of the product obtained in Example 4 and dissolve it in 55 ml of dry methanol, add 3.06 ml of triethylamine and 11.4 ml of methyl dichloroacetate. Stir at room temperature for 18 hours, evaporate the solvent, add a mixed solvent of toluene and water, let it stand, filter, and obtain the crude product. Recrystallize in isopropanol-water to obtain a white solid, 6.7 g, yield 84%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne la préparation de D-(-)-1-substitué-phényl-2-dichloroacétoamino-3-fluoro-1-propanol, le procédé impliquant l'utilisation d'ester substitué de phénylsérine de type L, extrait et purifié à partir de liquide de résolution utilisé comme matière première, en plusieurs étapes. Le procédé est simple, économique, donne des rendements élevés avec une transformation complète de configuration et constitue un procédé efficace et simple de conversion d'ester substitué de phénylsérine de type L en fluorothiamphénicol de type D. L'invention permet d'empêcher le rejet de l'énantiomère produit dans le procédé de résolution du Florfénicol, de réduire la pollution de l'environnement et présente un certain intérêt.
PCT/CN2002/000354 2001-06-01 2002-05-27 Preparation de d-(-)-1-substitue-phenyl-2-dichloroacetoamino-3-fluoro-1-propanol a partir d'ester substitue de phenylserine de type l WO2003093221A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002311147A AU2002311147A1 (en) 2001-06-01 2002-05-27 Preparation of d-(-) -1-substituted phenyl-2-dichloro-acetoamino-3fluoro-1-propanol from l type substituted phenyl serine ester

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN01113056.3 2001-06-01
CNB011130563A CN1173933C (zh) 2001-06-01 2001-06-01 一种从l型取代苯丝氨酸酯制备d－（－）－苏式1－r－取代苯基－2－二氯乙酰氨基－3－氟－1－丙醇的方法

Publications (1)

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WO2003093221A1 true WO2003093221A1 (fr) 2003-11-13

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CN (1) CN1173933C (fr)
AU (1) AU2002311147A1 (fr)
WO (1) WO2003093221A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7126005B2 (en) 2003-10-06 2006-10-24 Aurobindo Pharma Limited Process for preparing florfenicol
WO2008150406A1 (fr) * 2007-05-30 2008-12-11 Schering-Plough Ltd. Procédé de préparation de composés aminodiol protégés par oxazoline utiles comme intermédiaires du florfénicol
US20110166359A1 (en) * 2008-07-30 2011-07-07 Paquette Leo A Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1331849C (zh) * 2005-08-12 2007-08-15 中国科学院上海有机化学研究所 甲砜霉素和氟苯尼考的新合成方法及其关键中间体
CN103965085B (zh) * 2014-04-17 2016-02-24 上海恒晟药业有限公司 一种取代1,2-氨基醇药物的制备方法
CN107417585B (zh) * 2017-06-22 2019-05-03 浙江海翔川南药业有限公司 一种药物中间体的合成方法
CN108752185A (zh) * 2018-07-17 2018-11-06 成都道合尔医药技术有限公司 一种1-氟-环戊甲酸的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1233244A (zh) * 1996-08-19 1999-10-27 先灵公司 制备氟苯尼考的中间体的方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1233244A (zh) * 1996-08-19 1999-10-27 先灵公司 制备氟苯尼考的中间体的方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CLARK JON E. ET AL.: "An enzymic route to florfenicol", accession no. STN Database accession no. 116:128730 *
DATABASE CA [online] KAPTEIN B. ET AL.: "Synthesis of 4-sulfur-substituted (2S,3R)-3-phenylserines by enzymic resolution. Enantiopure precursors for thiamphenicol and florfenicol", accession no. STN Database accession no. 128:23109 *
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 2, no. 1, 1998, pages 10 - 17 *
SYNTHESIS, no. 10, 1991, pages 891 - 894 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7126005B2 (en) 2003-10-06 2006-10-24 Aurobindo Pharma Limited Process for preparing florfenicol
WO2008150406A1 (fr) * 2007-05-30 2008-12-11 Schering-Plough Ltd. Procédé de préparation de composés aminodiol protégés par oxazoline utiles comme intermédiaires du florfénicol
US20110166359A1 (en) * 2008-07-30 2011-07-07 Paquette Leo A Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol
US8314252B2 (en) * 2008-07-30 2012-11-20 Intervet Inc. Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol

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AU2002311147A1 (en) 2003-11-17
CN1326926A (zh) 2001-12-19
CN1173933C (zh) 2004-11-03

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