CN114075144A - 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 PDFInfo
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- CN114075144A CN114075144A CN202010828575.8A CN202010828575A CN114075144A CN 114075144 A CN114075144 A CN 114075144A CN 202010828575 A CN202010828575 A CN 202010828575A CN 114075144 A CN114075144 A CN 114075144A
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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
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- 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
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- 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
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- 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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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
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。
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:
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:
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
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,我们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。
即,本发明为以下记载的发明。
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(结构式I)及其制备方法。
2.权利要求1所述制备方法,其包括在碱的存在下使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。
3.权利要求2中所述制备方法,其中,碱为1,1,3,3-四甲基胍。
4.权利要求2中所述制备方法,其中,有机溶剂为乙腈、四氢呋喃、N,N- 二甲基甲酰胺以及二甲基亚砜。
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:
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,d6-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:
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(300 mL)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%)。
Claims (4)
2.权利要求1所述制备方法,其包括在碱的存在下使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。
3.权利要求2中所述制备方法,其中,碱为1,1,3,3-四甲基胍。
4.权利要求2中所述制备方法,其中,有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺以及二甲基亚砜。
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CN202010828575.8A CN114075144B (zh) | 2020-08-12 | 2020-08-12 | 噁拉戈利钠关键中间体的有机胺盐以及其制备方法 |
US17/426,522 US20220242830A1 (en) | 2020-08-12 | 2020-11-24 | Organic amine salt of key intermediate of elagolix sodium and preparation method thereof |
PCT/CN2020/131054 WO2022032927A1 (zh) | 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 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
CN109651171A (zh) * | 2019-01-13 | 2019-04-19 | 苏州鹏旭医药科技有限公司 | 依拉戈利及其钠盐的中间体及其盐的制备方法和应用 |
WO2020023459A1 (en) * | 2018-07-23 | 2020-01-30 | Abbvie Inc. | Elagolix sodium compositions and processes |
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- 2020-11-24 WO PCT/CN2020/131054 patent/WO2022032927A1/zh active Application Filing
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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 |
WO2020023459A1 (en) * | 2018-07-23 | 2020-01-30 | Abbvie Inc. | Elagolix sodium compositions and processes |
CN109651171A (zh) * | 2019-01-13 | 2019-04-19 | 苏州鹏旭医药科技有限公司 | 依拉戈利及其钠盐的中间体及其盐的制备方法和应用 |
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WO2022032927A1 (zh) | 2022-02-17 |
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