CN1233244A - 制备氟苯尼考的中间体的方法 - Google Patents

制备氟苯尼考的中间体的方法 Download PDF

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CN1233244A
CN1233244A CN97198768A CN97198768A CN1233244A CN 1233244 A CN1233244 A CN 1233244A CN 97198768 A CN97198768 A CN 97198768A CN 97198768 A CN97198768 A CN 97198768A CN 1233244 A CN1233244 A CN 1233244A
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formula
compound
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florfenicol
reaction
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J·C·托森
D·B·瓦施
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Merck Sharp and Dohme Corp
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    • 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
    • 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
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical

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  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

本发明涉及制备式Ⅰ化合物的方法,其中R和R”的意义如文中所述。式Ⅰ的化合物可用作制备氟苯尼考的中间体。

Description

制备氟苯尼考的中间体的方法
发明领域
本发明涉及氟苯尼考的中间体及其新的制备方法。
发明背景
氟苯尼考{也称为[R-(R*,S*)]-2,2-二氯-N-[1-(氟甲基)-2-羟基-2-[4-(甲磺酰基)苯基]乙基]乙酰胺}是一种广谱抗菌剂，可用于治疗美国专利4361557(此中通过引用并入本文)中公开的革兰氏阳性、革兰氏阴性和立克次体引起的感染。本发明涉及氟苯尼考的中间体及其新的制备方法。正如可见于例如美国专利4876352(此中通过引用并入本文)中的那样，本说明书中所述的中间体可用于制备氟苯尼考。
简述
在一个实施方案中，本发明涉及制备式Ⅰ化合物的方法：
Figure A9719876800041
式中R是H、NO2、CH3S、CH3SO2或C4-C6烷基；R”是芳基、卤代芳基、苄基、取代苄基、C1-C6烷基、C3-C7环烷基以及卤代烷基，并且噁唑啉环的构型是4R反式：该方法包括a)使式Ⅱ的化合物：
Figure A9719876800051
式中R如上所述，并且R’为H、C1-C6烷基、C3-C7环烷基、苄基、取代苄基或芳基；与一种还原剂诸如硼氢化钾在一适合的反应容器中接触得到式Ⅲ的化合物：
Figure A9719876800052
式中R如上所述，并b)然后在相同的反应容器中，使式Ⅲ的化合物与式Ⅳ的化合物：
      R”-C≡N    Ⅳ式中R”如上所述，反应以便获得式Ⅰ的化合物。
本发明方法的优点在于它是制备氟苯尼考、其类似物和噁唑啉中间体的高效及经济的方法。
实施方案的详细说明
除非另外指明，本说明书和权利要求书使用的下列术语定义如下：
术语“质子溶剂”是指氢键键合溶剂，正如James B.Hendrickson,Cram,Donald J．和Hammond,George S．在Organic Chemistry,McgrawHill Book Company(New York,(1970)，第1279页)中所定义的溶剂。所述溶剂最好(但不必要)能将噁唑啉(Ⅰ)从溶液中沉淀出来。这种溶剂包括(但不限于)水，C1-C10链烷酸诸如甲酸、乙酸等，C1-C10醇诸如甲醇和乙醇及其混合物，C2-C10二元醇诸如乙二醇和C1-C10三元醇诸如丙三醇。或者，为了使式Ⅰ的噁唑啉化合物沉淀，可将质子溶剂和任何适合的共溶剂混合。这种共溶剂包括能与所述质子溶剂混溶的其他质子溶剂诸如C4-C10链烷烃，芳香溶剂诸如苯、甲苯、二甲苯，卤代苯诸如氯苯，和醚诸如二乙醚、叔丁基甲基醚、异丙基醚和四氢呋喃或任何上面溶剂或共溶剂的混合物。
术语“烷基”是指直链或支链烷基诸如甲基、乙基、丙基或仲丁基。或者，可具体指明烷基中的碳数。例如，C1-C6烷基指含1至6个碳原子的如上所述的烷基。“卤代烷基”是指一个或多个氢被卤素取代的上述的“烷基”。
术语“芳基”是指苯基或被C1-C6烷基或卤素取代的苯基。
取代苄基是指被C1-C6烷基或卤素取代的苄基。
术语“卤素”是指氟、氯、溴或碘。
术语“卤代芳基”是指被卤素取代的苯基。
在本说明书中，
Figure A9719876800061
上式为一种氨基二醇砜，被称为ADS。制备本发明化合物的步骤由下面所示：化学流程图式中R、R’、R”的意义同上。
根据上面的化学流程图，式Ⅰ的化合物可如下制备。将式Ⅱ的化合物
Figure A9719876800072
式中R和R’的意义同上，在约0-30℃的温度(优选室温)下、在一种质子溶剂诸如乙醇、乙二醇或更优选的甲醇中，用一种还原剂诸如NaBH4、Ca(BH4)2、LiBH4或更优选的KBH4处理约2-约8小时(更优选约4小时)，获得式Ⅲ的化合物：式中R的意义同上。
如果例如在上面所述的反应中，将甲醇用作还原反应的溶剂，那么可通过蒸馏回收供随后的反应再使用。除去甲醇也可提高式Ⅰ化合物的收率。
在同一反应容器中，使式Ⅲ的化合物与式Ⅳ的化合物接触
     R”-C≡N    Ⅳ式中R”的意义同上，式Ⅳ化合物的量与式Ⅲ化合物相比为约1.1-约2.5当量，优选为约1.7当量。
式Ⅳ的化合物可以是例如苄腈或二氯乙腈。该反应根据所用腈和溶剂的不同可以在25℃至115℃之间进行。该反应进行约6到约30小时，优选18小时。然后冷却该反应混合物，例如通过加入冷水，并通过常规方法诸如过滤和洗涤处理而得到式Ⅰ的化合物。最好该反应步骤在约6到约7的pH下进行。
本发明方法的一项优点是消除了分离ADS的需要，因为两个反应步骤在同一容器中进行。
优选形成二氯甲基噁唑啉，最优选形成苯基噁唑啉。
如下所示的丝氨酸乙酯是优选的式Ⅱ的原料：
Figure A9719876800081
下面实施例以可实践的方式说明了本发明，但是这并不意味着对本发明范围的限制。
实施例1
Figure A9719876800091
将KBH4(1g)置于约40mL甲醇中。在搅拌下加入D-苏对-甲基磺酰苯基丝氨酸乙基酯(5g)。还原为ADS的反应用几小时完成并可通过HPLC监测。当反应完成后，加入20mL甘油用以破坏过量还原剂，并且通过蒸馏去除甲醇。除去甲醇后，将产生的混合物加热到105℃，加入苄腈(3.1mL)，同时继续加热约18小时。所需的噁唑啉的形成可通过HPLC监测。将反应物冷却到室温，并进行下列处理：加入冷水、过滤产生的固体物、用甲醇洗涤固体物、然后在真空下干燥。与苯基噁唑啉真实样品一致的物质的产量为约4.7g(81％)。
实施例2
将KBH4(1g)置于约40mL甲醇中。在搅拌下加入D-苏对-甲基磺酰苯基丝氨酸乙基酯(5g)。还原为ADS的反应用几小时完成并可通过HPLC监测。当反应完成时，加入20mL甘油用以破坏过量还原剂并且通过蒸馏去除甲醇。除去甲醇后，将产生的混合物用硫酸酸化到约6到7的pH，并加入二氯乙腈(2.4g)。在50℃下搅拌反应物约18小时。所需的噁唑啉的形成可通过HPLC监测。将反应物冷却到室温并进行下列处理：过滤固体物、用异丙醇和2％NaHCO3洗涤固体物、然后在真空下干燥。与二氯噁唑啉真实样品一致的物质的产量为约3.8g(65％)。
原料
式(Ⅱ)和(Ⅳ)的原料是本领域技术人员熟知的。

Claims (4)

1．制备式Ⅰ化合物的方法：
Figure A9719876800021
式中R是H、NO2、CH3S、CH3SO2或C4-C6烷基；R”是芳基、卤代芳基、苄基、取代苄基、C1-C6烷基、C3-C7环烷基以及卤代烷基，并且噁唑啉环的构型是4R反式；该方法包括a)使式Ⅱ的化合物：
Figure A9719876800022
式中R如上所述，并且R’为H、C1-C6烷基、C3-C7环烷基、苄基、取代苄基或芳基；与一种还原剂在适合的反应容器接触以便获得式Ⅲ的化合物：式中R如上所述，和b)然后在相同的反应容器中，使式Ⅲ的化合物与式Ⅳ的化合物：
     R”-C≡N    Ⅳ反应以便获得式Ⅰ的化合物。
2．按照权利要求1的方法，其中所述还原剂是硼氢化钾。
3．按照权利要求1的方法，其中被形成的式Ⅰ化合物是：
Figure A9719876800032
4．按照权利要求1的方法，其中被形成的式Ⅰ化合物是：
Figure A9719876800033
CN97198768A 1996-08-19 1997-08-18 制备氟苯尼考的中间体的方法 Expired - Lifetime CN1097583C (zh)

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WO2003093221A1 (fr) * 2001-06-01 2003-11-13 Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences Preparation de d-(-)-1-substitue-phenyl-2-dichloroacetoamino-3-fluoro-1-propanol a partir d'ester substitue de phenylserine de type l
CN102911133A (zh) * 2012-10-31 2013-02-06 绍兴民生医药有限公司 (4r,5r)-2-二氯甲基-4,5-二氢-5-(4-甲砜基苯基)-4-恶唑甲醇的纯化方法
CN102911133B (zh) * 2012-10-31 2014-07-02 绍兴民生医药有限公司 (4r,5r)-2-二氯甲基-4,5-二氢-5-(4-甲砜基苯基)-4-恶唑甲醇的纯化方法
CN103254147A (zh) * 2013-04-19 2013-08-21 浙江科技学院 一种d-苏式-2-(二氯甲基)-4,5-二氢-5-[对-（甲砜基）苯基]-4-噁唑甲醇的制备方法
CN103254147B (zh) * 2013-04-19 2016-04-06 浙江科技学院 一种d-苏式-2-(二氯甲基)-4,5-二氢-5-[对-（甲砜基）苯基]-4-噁唑甲醇的制备方法
CN106631872A (zh) * 2016-12-13 2017-05-10 浙江普洛家园药业有限公司 一种氟苯尼考类似物中间体的合成方法

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