WO2022032927A1 - 噁拉戈利钠关键中间体的有机胺盐以及其制备方法 - Google Patents

噁拉戈利钠关键中间体的有机胺盐以及其制备方法 Download PDF

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WO2022032927A1
WO2022032927A1 PCT/CN2020/131054 CN2020131054W WO2022032927A1 WO 2022032927 A1 WO2022032927 A1 WO 2022032927A1 CN 2020131054 W CN2020131054 W CN 2020131054W WO 2022032927 A1 WO2022032927 A1 WO 2022032927A1
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fluoro
methyl
trifluoromethyl
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陈剑
张现强
李耀强
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南京桦冠生物技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to 1,1,3,3-tetramethylguanidine (R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxybenzene) as an intermediate for preparing medicines yl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidin-1(2H)-yl) -1-Phenylethyl) sulfamate and preparation method.
  • Elagolix sodium (structural formula V) is an orally administered non-peptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling. Administration produces dose-dependent inhibition of luteinizing hormone and follicle-stimulating hormone, and reduces plasma concentrations of ovarian sex hormones, estradiol, and progesterone. In July 2018, the drug was approved by the FDA for the treatment of women with moderate-to-severe endometriosis pain. It is worth mentioning that Elagolix sodium is the first oral therapy approved by the FDA for this indication in ten years.
  • GnRH gonadotropin-releasing hormone
  • the multi-step intermediate is an oily substance, which cannot be purified by recrystallization, resulting in difficulty in purification.
  • the original research AbbVie developed the process patent route of this compound (patent WO2009062087) as follows:
  • the multi-step method is to directly obtain the crude product solution and then perform the subsequent reaction, which is important for the quality control of the API and the process stability. brought some challenges.
  • the present invention provides the compound 1,1,3,3-tetramethylguanidine (R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3- (2-Fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidin-1(2H)-yl)-1-phenyl ethyl) sulfamate, the structure is shown in formula I.
  • the present invention provides the compound 1,1,3,3-tetramethylguanidine (R)-(tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxybenzene) according to the above technical solutions yl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dicarbonyl-3,6-dihydropyrimidin-1(2H)-yl)
  • the preparation method of -1-phenylethyl) sulfamic acid ester comprises the following steps:
  • the organic solvent is acetonitrile, tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide.
  • the temperature of the reaction is 60°C, and the time is 16 hours.
  • the reaction also includes: concentrating the reaction solution to dryness, adding 2-methyltetrahydrofuran for recrystallization to obtain 1,1,3,3-tetramethylguanidine (R)-(tert-butoxycarbonyl )(2-(5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-di Carbonyl-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)sulfamate.
  • R 1-(tert-butoxycarbonyl )(2-(5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-di Carbonyl-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)sulfamate.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯(结构式I)，以及其制备方法。该化合物具有良好的结晶性能从而可以得到较好的纯度，对于其进一步得到API噁拉戈利钠提供了良好的基础。

Description

噁拉戈利钠关键中间体的有机胺盐以及其制备方法
本申请要求于2020年08月12日提交中国专利局、申请号为202010828575.8、发明名称为“噁拉戈利钠关键中间体的有机胺盐以及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及用作制备药物的中间体1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯以及制备方法。
背景技术
噁拉戈利钠(结构式V)是一种口服给药的非肽小分子促性腺激素释放激素(GnRH)受体拮抗剂，通过与脑垂体中的GnRH受体竞争性结合来抑制内源性GnRH信号传导。给药会对黄体生成素和卵泡刺激素产生剂量依赖性抑制，降低卵巢性激素、雌二醇和黄体酮的血药浓度。2018年7月，该药获得FDA批准，用于治疗患有中度至重度子宫内膜异位症疼痛的女性。值得一提的是，噁拉戈利钠是十年来首个获FDA批准用于该适应症的口服疗法。
Figure PCTCN2020131054-appb-000001
目前噁拉戈利钠的主要合成路线为专利CN100424078C报道的化合物合成路线如下：
Figure PCTCN2020131054-appb-000002
化合物报道路线中，多步骤中间体为油状物，无法进行重结晶精制操作，从而导致纯化困难。进一步，原研艾伯维开发了该化合物的工艺专利路线(专利WO2009062087)如下：
Figure PCTCN2020131054-appb-000003
该路线在化合物专利的基础上对于多步骤进行了工艺改进，但依旧无法解决中间体纯化的问题，多步骤为直接得到粗品溶液后进行随后反应，这对于原料药的质量控制以及工艺稳定性都带来了一定挑战。
发明内容
本发明提供了化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢 嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯，结构如式I所示。
Figure PCTCN2020131054-appb-000004
本发明提供了以上技术方案所述化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯的制备方法，包括以下步骤：
在碱的存在下使5-(2-氟-3-甲氧苯基)-1-(2-氟-6-(三氟甲基)苯甲基)-6-甲基嘧啶-2,4(1H,3H)-二酮(结构式II)和叔-丁基(R)-4-苯基-1,2,3-氧杂噻唑烷-3-羧酸酯2,2-二氧化(结构式III)在有机溶剂中反应得到；所述碱为1,1,3,3-四甲基胍；
Figure PCTCN2020131054-appb-000005
优选地，所述有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺或二甲基亚砜。
优选地，所述反应的温度为60℃，时间为16小时。
优选地，所述反应后还包括：将反应液浓缩至干，加入2-甲基四氢呋喃重结晶，得到1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯。
基于目前噁拉戈利钠工艺路线中多步骤中间体为油状物导致纯化困难的问题，本申请发明人对于工艺路线进行了研究，意外发现得到中间体 1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯(结构式I)为结晶性能良好的固体，且制备条件简单，转化率以及原子经济性好。由于化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯(结构式I)具有良好的结晶性能，从而可以使用重结晶的方式纯化而得到高纯度的中间体，这对于随后的反应以及转化可以提供一个良好的基础，进而能够得到质量更好且可控性更高的噁拉戈利钠(API)。
具体实施方式
以下举出的实施例和制备例说明本发明，但本发明不限定于此。
本发明具体实施方案中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1：
Figure PCTCN2020131054-appb-000006
在2L的三口反应瓶中，依次加入5-(2-氟-3-甲氧苯基)-1-(2-氟-6-(三氟甲基)苯甲基)-6-甲基嘧啶-2,4(1H,3H)-二酮(结构式II，70.06g，1.0当量)、叔-丁基(R)-4-苯基-1,2,3-氧杂噻唑烷-3-羧酸酯2,2-二氧化(结构式III，54.06g，1.1当量)和乙腈(350mL)体系室温搅拌，随后加入1,1,3,3-四甲基胍(28.36g，1.5当量)，体系加热至60℃反应16小时，TLC显示原料转化完全后，浓缩反应液至干随后加入2-甲基四氢呋喃(200mL)重结晶，得到产物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯(结构式I，122.8g收率：89％类 白色固体)。
1H-NMR(300MHz,d 6-DMSO)δ7.77-7.14(m,11H),7.00-6.93(d,1H),5.76(s,1H),5.51-5.39(m,1H),5.27-5.14(m,1H),5.08-4.87(m,1H),4.39-4.24(m,1H),3.85(s,3H),2.88(s,12H),2.06(s,3H),1.10(s,9H)。
LCMS(ESI)m/z,645.6(M+1) +。
实施例2：
Figure PCTCN2020131054-appb-000007
在2L的反应瓶中加入1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯(结构式I，70g)依次加入乙醇(385mL)、水(300mL)以及浓盐酸(97mL)。体系50℃搅拌4小时，随后加入碳酸钠调节pH＝7-8，使用醋酸异丙酯萃取浓缩，油状物加入溴代丁酸乙酯(16g)以及碳酸钾(20g)体系加入DMF(300mL)。随后体系加热至70℃反应48小时。体系降温至室温，加入NaOH(1N，300mL)室温搅拌3小时，随后醋酸异丙酯萃取，水相使用甲基异丁基酮再次萃取。收集甲基异丁基酮相，浓缩，得到产品噁拉戈利钠(44.6g，类白色固体，收率82.0％)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (6)

  1. 化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯，结构如式I所示：
    Figure PCTCN2020131054-appb-100001
  2. 权利要求1所述化合物1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯的制备方法，其特征在于，包括以下步骤：
    在碱的存在下使式II所示的5-(2-氟-3-甲氧苯基)-1-(2-氟-6-(三氟甲基)苯甲基)-6-甲基嘧啶-2,4(1H,3H)-二酮和式III所示的叔-丁基(R)-4-苯基-1,2,3-氧杂噻唑烷-3-羧酸酯2,2-二氧化在有机溶剂中反应得到；所述碱为1,1,3,3-四甲基胍；
    Figure PCTCN2020131054-appb-100002
  3. 根据权利要求2所述的制备方法，其特征在于，所述有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺或二甲基亚砜。
  4. 根据权利要求2所述的制备方法，其特征在于，所述反应的温度为60℃，时间为16小时。
  5. 根据权利要求2～4任意一项所述的制备方法，其特征在于，所述反应后还包括：将反应液浓缩至干，加入2-甲基四氢呋喃重结晶，得到1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲 基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯。
  6. 一种制备噁拉戈利钠的方法，其特征在于，包括以下步骤：
    在70g权利要求1所述1,1,3,3-四甲基胍(R)-(叔-丁氧基羰基)(2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二羰基-3,6-二氢嘧啶-1(2H)-基)-1-苯基乙基)氨基磺酸酯中依次加入乙醇385mL、水300mL以及浓盐酸97mL，所得体系50℃搅拌4小时，随后加入碳酸钠调节pH＝7-8，使用醋酸异丙酯萃取浓缩，所得油状物加入溴代丁酸乙酯16g以及碳酸钾20g和DMF300mL；随后体系加热至70℃反应48小时，将体系降温至室温，加入300mL、浓度1N的NaOH室温搅拌3小时，随后醋酸异丙酯萃取，所得水相使用甲基异丁基酮再次萃取，收集甲基异丁基酮相，浓缩，得到噁拉戈利钠。
PCT/CN2020/131054 2020-08-12 2020-11-24 噁拉戈利钠关键中间体的有机胺盐以及其制备方法 WO2022032927A1 (zh)

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WO2018198086A1 (en) * 2017-04-28 2018-11-01 Lupin Limited Process for the preparation of elagolix and pharmaceutically acceptable salts thereof

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Publication number Priority date Publication date Assignee Title
WO2020023459A1 (en) * 2018-07-23 2020-01-30 Abbvie Inc. Elagolix sodium compositions and processes
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