WO2021147302A1 - 一种阿哌沙班的中间体及制备方法 - Google Patents

一种阿哌沙班的中间体及制备方法 Download PDF

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WO2021147302A1
WO2021147302A1 PCT/CN2020/108762 CN2020108762W WO2021147302A1 WO 2021147302 A1 WO2021147302 A1 WO 2021147302A1 CN 2020108762 W CN2020108762 W CN 2020108762W WO 2021147302 A1 WO2021147302 A1 WO 2021147302A1
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formula
ring
compound
preparation
heteroaryl group
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刘阿情
郭必豹
高照波
梅杰
何杨
于帅
刘声民
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浙江九洲药业股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/90Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical intermediate that can be used as a factor Xa inhibitor, in particular, to apixaban intermediates and a preparation method thereof, and a method for synthesizing apixaban by using these intermediates.
  • Apixaban (I) is a new generation of oral antithrombotic drugs. Among many coagulation factor Xa inhibitors, (I) shows a high degree of selectivity, good bioavailability and efficient therapeutic effects. Its main It is used for adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolic events (VTE). Apixaban was first discovered by Bristol-Myers Squibb in 2003. In 2007, it co-developed the drug with Pfizer. Since its launch in 2011, sales have increased year by year. For BMS & Pfizer, Eliquis (Apixa) Class) total sales in the first three quarters of 2019 were US$9.016 billion, a year-on-year increase of 25%. Eliquis is expected to have sales of US$12 billion in 2025.
  • the invention provides a new intermediate for synthesizing apixaban and a preparation method thereof.
  • the method is simple and easy to implement, is green and environmentally friendly, reduces the cost, and is convenient to implement industrialized production.
  • the present invention provides the following technical solutions:
  • an intermediate for preparing apixaban of formula (v) the structural formula is as follows:
  • A is a C 6-14 aryl group or a 5- to 14-membered heteroaryl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S, and when there are multiple heteroatoms, The heteroatoms are the same or different; the aryl or heteroaryl group may be further substituted with 0 to 5 R 2 , wherein when there are multiple substituents, the substituents are the same or different;
  • B is a 3- to 10-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S, and said heterocyclic ring may be further substituted with 0 to 5 substituents, said substitution
  • ring D When ring D exists, two atoms including ring E connected to it together form a 5- to 6-membered ring, said 5- to 6-membered ring contains 0 to 2 heteroatoms selected from N, O or S, said 5
  • the to 6-membered ring may be further substituted with 0 to 5 R 4 ;
  • the ring E is a phenyl group or a 5- to 6-membered heteroaryl group, the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S,
  • the phenyl or heteroaryl group may be further substituted with 0 to 3 R 4 ;
  • ring E is a phenyl group or a 5- to 6-membered heteroaryl group, the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, the phenyl group or heteroaryl group May be further substituted with 0 to 5 R 4 ;
  • R 4 , R 4a and R 4b are halogen, C 1-4 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, or phenyl and phenyl derivatives thereof; or, NR 4 R 4a is composed of C 3-8 membered ring composed of, N, and 0-1 O atoms;
  • n 0, 1, 2, 3 or 4;
  • P is 0, 1, or 2.
  • the present invention provides an intermediate for preparing apixaban of formula (iv), the structural formula is as follows:
  • R, R 4 , R 4a , R 4b , n and P are the same as above;
  • the present invention provides a method for preparing apixaban intermediate of formula (v), which is obtained by contacting lactam compound (iv) in the presence of a base.
  • the reaction formula is as follows:
  • A, B, ring D, ring E, R 3 , R 4 , R 5 , R 7 and R 9 are the same as above;
  • the base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine, DBU;
  • the present invention provides a method for preparing apixaban intermediate of formula (iv), which is obtained by contacting lactam compound formula (ii) with compound formula (iii) in the presence of a base and a catalyst, and reacting
  • the formula is as follows:
  • A, B, ring D, ring E, R 3 , R 4 , R 5 and R 7 have the same definitions as above;
  • R 8 is Cl, Br, Cl, I, OSO 2 Me, OSO 2 Ph, and OSO 2 Ph-p-Me;
  • the base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine, DBU;
  • the catalyst is selected from one or more of LiI, NaI, KI, LiBr, NaBr, KBr, tetrabutylamine bromide, and tetrabutylamine iodide;
  • the present invention provides a method for preparing compound (ii), which is obtained by contacting a compound of formula (i) in the presence of a base.
  • the reaction formula is as follows:
  • R 4 , R 4a , R 4b , n and P are the same as above;
  • the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide;
  • the present invention provides a method for preparing apixaban-containing compound of formula (v), comprising the following steps: 1) a compound of formula (i) is contacted in the presence of a base to obtain a compound of formula (ii); 2) Lactam compound formula (ii) is contacted with compound formula (iii) in the presence of a base and a catalyst to obtain a compound of formula (iv); 3) lactam compound (iv) is contacted in the presence of a base to obtain a compound of formula (v) ,
  • the reaction formula is as follows:
  • A, B, ring D, ring E, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 have the same definitions as above;
  • Step 1) The base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide;
  • Step 2) and 3) said base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine, DBU;
  • the catalyst is selected from one or more of LiI, NaI, KI, LiBr, NaBr, KBr, tetrabutylamine bromide, and tetrabutylamine iodide;
  • the beneficial effects of the present invention are: compared with the original process of apixaban, in the synthesis process of the present invention, no phosphorous waste water is produced, the three wastes are easy to treat, and the three wastes are less polluted; the reaction process is simple and easy to implement, and no expensive Metal catalyst.
  • the synthesis scheme has a high yield per step and a controllable cost, which is suitable for large-scale industrial production.

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

Abstract

本发明涉及一种可用作Xa因子抑制剂的药物中间体,具体涉及一种阿哌沙班的中间体式(iv)和式(v)及其制备方法,以及利用这些中间体合成阿哌沙班的方法。该方法反应式如式(iii)。本发明合成过程中,三废污染较少;反应过程简单易行,不会用到昂贵的金属催化剂。合成方案每步收率较高,成本可控,适合大规模工业化生产。

Description

一种阿哌沙班的中间体及制备方法
本申请要求于2020年1月21日提交中国专利局、申请号为202010068239.8、发明名称为“一种阿哌沙班的中间体及制备方法”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
本发明涉及一种可用作Xa因子抑制剂的药物中间体,具体说,涉及阿哌沙班的中间体及其制备方法,以及利用这些中间体合成阿哌沙班的方法。
背景技术
阿哌沙班(I)是一种新一代的口服抗血栓药物,在众多凝血因子Xa抑制剂中,(I)表现出高度的选择性、良好的生物利用度和高效的治疗效果,其主要用于髋关节或膝关节择期置换术的成年患者,预防静脉血栓栓塞事件(VTE)。阿哌沙班2003年最初由百时美施贵宝公司发现,2007年与辉瑞共同研发该药,从2011年上市到现在,销售额逐年增加,BMS&辉瑞方面,艾乐妥(Eliquis)(阿哌沙班)2019年前3季度总销售额为90.16亿美元,同比增长25%。Eliquis预计在2025年的销售额达120亿美元。
Figure PCTCN2020108762-appb-000001
美国专利号US2003181466A1首次公开报道了阿哌沙班的一种合成路线:用4-碘苯胺和5-溴戊酰氯合成化合物(VII),化合物(VII)用五氯化磷氯代、过量吗啉处理得到化合物(VI),进一步和化合物(V)反应关环得到4,5-二氢吡唑并[3,4-c]吡啶-2-酮的衍生物(IV),接着与δ-戊内酰胺发生类似Ullmann缩合的反应合成化合物(II),最后乙酯氨解得到阿哌沙班。该路线的缺点是反应过程中使用了五氯化磷,易产生大量的盐酸气和含磷副产物,对环境危害较大。
Figure PCTCN2020108762-appb-000002
鉴于已有的路线存在的一些缺陷,有必要进一步开发对环境友好,适用于商业化生产的阿哌沙班路线。
发明内容
本发明提供了一种合成阿哌沙班的新的中间体及其制备方法,该方法简单易行,绿色环保,降低了成本,方便实施工业化生产。
为了实现本发明的目的,本发明提供了如下技术方案:
第一方面,一种制备阿哌沙班式为(v)的中间体,结构式如下:
Figure PCTCN2020108762-appb-000003
其中,A为C 6-14芳基或5至14元杂芳基,所述杂芳基含有1至4个选自N、O或S的杂原子,其中,当具有多个杂原子时,各杂原子相同或者不同;芳基或杂芳基可进一步被0至5个R 2取代,其中当具有多个取代基时,各取代基相同或者不同;
当B不存在时,A为H、F、Cl、Br、I、羟基、-C(=O)OR 4、C 1-4烷基或C 1-4烷氧羰基的取代基所取代;
B为3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,且所述杂环可进一步被0至5个取代基所取代,所述取代基选自(=O)、(=S)或者R 4a
Figure PCTCN2020108762-appb-000004
表示环D存在或不存在;
当环D存在时,包括环E与之相连的两个原子一起形成5至6元环,所述5至6元环含有0至2个选自N、O或S的杂原子,所述5至6元环可进一步被0至5个R 4取代;环E为苯基或5至6元杂芳基,所述杂芳基含有1至3个选自N、O或S的杂原子,所述苯基或杂芳基可进一步被0至3个R 4取代;
当环D不存在时,环E为苯基或5至6元杂芳基,所述杂芳基含有1至3个选自N、O或S的杂原子,所述苯基或杂芳基可进一步被0至5个R 4取代;
R 3为F、Cl、Br、I、羟基、巯基、氨基、硝基、氰基、三氟甲基、C 1-4烷氧基、-(CR 4R 4a) nNR 4R 4a、-(CR 4R 4a) nNR 4R 4a、-(CH 2) nC(=NR 4b)NR 4R 4a、-(CR 4R 4a) n-C(=O)NR 4R 4a、-(CR 4R 4a) nNR 4C(=O)R 4a、-(CR 4R 4a) nOR 4、-(CH 2) nC(=O)R 4、或-(CH 2) nS(=O) PR 4b
R 7为H、F、Cl、Br、I、氰基、三氟甲基、-(CR 4R 4a) nOR、-(CR 4R 4a) nNR 4R 4b、-C(=O)R 4R 4a) n、-(CH 2) nS(=O) nR 4R 4a、-C(R 4R 4a)R;
R 9为H、F、Cl、Br、I、羟基、巯基、氨基、硝基、氰基、三氟甲基、C 1-4烷氧基、-(CR 4R 4a) nNR 4R 4a、-(CR 4R 4a) nNR 4R 4a、-(CH 2) nC(=NR 4b)NR 4R 4a、-(CR 4R 4a) n-C(=O)NR 4R 4a、-(CR 4R 4a) nNR 4C(=O)R 4a、-(CR 4R 4a) nOR 4、-(CH 2) nC(=O)R 4、或-(CH 2) nS(=O) PR 4b
R为H、-C(R 4R 4a)R 4b、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b
R 2为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
R 4、R 4a和R 4b为卤素、C 1-4烷基、环丙基、环戊基、环己基、苄基或苯基及其苯基衍生物;或者,NR 4R 4a为由C、N、和0-1个O原子组成的3-8元环;
n为0、1、2、3或者4;
P为0、1或者2。
第二方面,本发明提供了一种制备阿哌沙班式为(iv)的中间体,结构式如下:
Figure PCTCN2020108762-appb-000005
其中A、B、环D、环E、R 3和R 7的定义与权利要求1中的相同;
R 4为H、OH、CN、NO 2、卤素、-S(=O) nR、-NR 1R 2、-C(=O)OR、-C(=O)NR 1R 2、-OR;
R 5为H、OH、CN、NO 2、卤素、-S(=O) nR、-NR 1R 2、-C(=O)OR、-C(=O)NR 1R 2、-OR;
R 1为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
R 2为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
R、R 4、R 4a、R 4b、n和P的定义与上述相同;
第三方面,本发明提供了一种阿哌沙班中间体式为(v)的制备方法,由内酰胺类化合物(iv)在碱的存在下接触得到,反应式如下:
Figure PCTCN2020108762-appb-000006
其中A、B、环D、环E、R 3、R 4、R 5、R 7和R 9的定义与上述相同;
所述碱选自三乙胺、二异丙基乙胺、吡啶、哌啶、DBU;
第四方面,本发明提供了一种阿哌沙班中间体式为(iv)的制备方法,由内酰胺类化合物式(ii)与化合物式(iii)在碱和催化剂的存在下接触得到,反应式如下:
Figure PCTCN2020108762-appb-000007
其中A、B、环D、环E、R 3、R 4、R 5和R 7的定义与上述相同;
R 8为Cl、Br、Cl、I、OSO 2Me、OSO 2Ph和OSO 2Ph-p-Me;
所述碱选自三乙胺、二异丙基乙胺、吡啶、哌啶、DBU;
所述催化剂选自LiI、NaI、KI、LiBr、NaBr、KBr、四丁基溴化胺、四丁基碘化胺中的一种或多种;
第五方面,本发明提供了一种化合物(ii)的制备方法,由式(i)化合物在碱存在下接触得到,反应式如下:
Figure PCTCN2020108762-appb-000008
其中A、B、R 3、R 4和R 5的定义与上述相同;
R 2为氰基、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
R 4、R 4a、R 4b、n和P的定义与上述相同;
所述碱选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾;
第六方面,本发明提供了一种含阿哌沙班的化合物式(v)的制备方法,包括以下步骤:1)式(i)化合物在碱存在下接触得到式(ii)化合物;2)内酰胺类化合物式(ii)与化合物式(iii)在碱和催化剂的存在下接触得到式(iv)化合物;3)内酰胺类化合物(iv)在碱的存在下接触得到式(v)化合物,反应式如下:
Figure PCTCN2020108762-appb-000009
其中A、B、环D、环E、R 2、R 3、R 4、R 5、R 7、R 8和R 9定义与上述相同;
步骤1)所述碱选自甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾;
步骤2)和3)所述碱选自三乙胺、二异丙基乙胺、吡啶、哌啶、DBU;
步骤2)所述催化剂选自LiI、NaI、KI、LiBr、NaBr、KBr、四丁基溴化胺、四丁基碘化胺中的一种或多种;
本发明的有益效果在于:相对于阿哌沙班的原有工艺,本发明合成过程中,未有产生含磷废水,三废易于处理三废污染较少;反应过程简单易行,不会用到昂贵的金属催化剂。合成方案每步收率较高,成本可控,适合大规模工业化生产。
具体实施方式
在以下实例中进一步定义本发明。应理解,这些实例虽然指示本发明的优选实施例,但是仅以说明方式给出,并不限制本发明的权利要求。
实施例1
Figure PCTCN2020108762-appb-000010
4-(苯胺)丁酸乙酯的制备
于苯胺(4.0g,0.043mol)中,加入4-溴丁酸乙酯(8.4g,0.043mol),加入三乙胺(5.2g,0.052mol),于20~30℃保温搅拌15h-20h,当HPLC和TLC显示反应完成时,加入50ml水调PH至3-5,用二氯甲烷提取,分层,有机层弃;水层调PH至12-14,用二氯甲烷 提取,分层,有机层加入无水硫酸钠干燥。减压蒸馏得到产品(8.2g,理论值8.9g,收率92%)。对于3,LCMS m/z 208(M ++H,C 12H 17NO 2)。
实施例2
Figure PCTCN2020108762-appb-000011
4-((4-硝基苯基)氨基)丁酸乙酯的制备
于4-硝基苯胺(5.6g,0.043mol)中,加入4-溴丁酸乙酯(8.4g,0.043mol),加入三乙胺(5.2g,0.052mol),于20~30℃保温搅拌15h-20h,当HPLC和TLC显示反应完成时,加入50ml水调PH至3-5,用二氯甲烷提取,分层,有机层弃;水层调PH至12-14,用二氯甲烷提取,分层,有机层加入无水硫酸钠干燥。减压蒸馏得到产品(9.8g,理论值10.9g,收率90%)。对于5,LCMS m/z 253(M ++H,C 12H 16N 2O 4)。
实施例3
Figure PCTCN2020108762-appb-000012
4-((4-溴苯基)氨基)丁酸乙酯的制备
于4-溴苯胺(7.4g,0.043mol)中,加入4-溴丁酸乙酯(8.4g,0.043mol),加入三乙胺(5.2g,0.052mol),于20~30℃保温搅拌15h-20h,当HPLC和TLC显示反应完成时,加入50ml水调PH至3-5,用二氯甲烷提取,分层,有机层弃;水层调PH至12-14,用二氯甲烷提取,分层,有机层加入无水硫酸钠干燥。减压蒸馏得到产品(10.8g,理论值12.3g,收率88%)。对于7,LCMS m/z 286(M ++H,C 12H 16BrNO 2)。
实施例4
Figure PCTCN2020108762-appb-000013
4-((4-碘苯基)氨基)丁酸乙酯的制备
于4-碘苯胺(9.4g,0.043mol)中,加入4-溴丁酸乙酯(8.4g,0.043mol),加入三 乙胺(5.2g,0.052mol),于20~30℃保温搅拌15h-20h,当HPLC和TLC显示反应完成时,加入50ml水调PH至3-5,用二氯甲烷提取,分层,有机层弃;水层调PH至12-14,用二氯甲烷提取,分层,有机层加入无水硫酸钠干燥。减压蒸馏得到产品(13.0g,理论值14.3g,收率91%)。对于9,LCMS m/z 334(M ++H,C 12H 16INO 2)。
实施例5
Figure PCTCN2020108762-appb-000014
4-((4-(2-氧代哌啶-1-基)苯基)氨基)丁酸乙酯的制备
于50ml二氯甲烷中加入4-(2-氧代哌啶-1-基)苯氨(8.17g,0.043mol),4-溴丁酸乙酯(8.4g,0.043mol),加入三乙胺(5.2g,0.052mol),于30~40℃保温搅拌15~20h,当HPLC和TLC显示反应完成时,加入30ml水,再调pH至3~5,萃取分层。有机层弃;水层调pH至12~14,用二氯甲烷萃取,分层。有机层加入五水硫酸镁干燥,减压蒸馏得到产品(11.64g,理论值13.08g,收率89%),对于11,LCMS m/z 305(M+H +,C 17H 24N 2O 3)
实施例6
Figure PCTCN2020108762-appb-000015
4-(2-乙氧基-N-(4-硝基苯基)-2-氧代乙酰氨基)丁酸乙酯(i-1)的制备
在0~20℃,于4-((4-硝基苯基)氨基)丁酸乙酯(7.92g,31.4mmol)的二氯甲烷溶液(50ml)中,加入三乙胺(3.81g,37.7mmol),滴加草酰氯单乙酯(4.5g,33.0mmol),滴毕,于20~30℃保温2-4h,当HPLC和TLC显示反应完成时,加入水,用二氯甲烷萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到产品,(10.5g,理论值11.06g,收率95%)。对于i-1,LCMS m/z 353(M ++H,C 16H 20N 2O 7)。
实施例7
Figure PCTCN2020108762-appb-000016
4-(2- 乙氧基-N-(4-苯基)-2-氧代乙酰氨基)丁酸乙酯(i-2)的制备
在0~20℃,于4-((4-苯基)氨基)丁酸乙酯(6.51g,31.4mmol)的二氯甲烷溶液(50ml)中,加入三乙胺(3.81g,37.7mmol),滴加草酰氯单乙酯(4.5g,33.0mmol),滴毕,于20~30℃保温2-4h,当HPLC和TLC显示反应完成时,加入水,用二氯甲烷萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到产品,(9.4g,理论值9.6g,收率98%)。对于i-2,LCMS m/z 308(M ++H,C 16H 21NO 5)。
实施例8
Figure PCTCN2020108762-appb-000017
4-(2-乙氧基-N-(4-苯基)-2-氧代乙酰氨基)丁酸乙酯(i-3)的制备
在0~20℃,于4-((4-溴苯基)氨基)丁酸乙酯(8.98g,31.4mmol)的二氯甲烷溶液(50ml)中,加入三乙胺(3.81g,37.7mmol),滴加草酰氯单乙酯(4.5g,33.0mmol),滴毕,于20~30℃保温2-4h,当HPLC和TLC显示反应完成时,加入水,用二氯甲烷萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到产品,(11.5g,理论值12.1g,收率95%)。对于i-3,LCMS m/z 386(M ++H,C 16H 20BrNO 5)。
实施例9
Figure PCTCN2020108762-appb-000018
4-(2-乙氧基-N-(4-苯基)-2-氧代乙酰氨基)丁酸乙酯(i-4)的制备
在0~20℃,于4-((4-碘苯基)氨基)丁酸乙酯(10.46g,31.4mmol)的二氯甲烷溶液(50ml)中,加入三乙胺(3.81g,37.7mmol),滴加草酰氯单乙酯(4.5g,33.0mmol),滴毕,于20~30℃保温2-4h,当HPLC和TLC显示反应完成时,加入水,用二氯甲烷萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到产品,(13.1g,理论值13.6g,收率96%)。对于i-4,LCMS m/z 434(M ++H,C 16H 20INO 5)。
实施例10
Figure PCTCN2020108762-appb-000019
1-(4-硝基苯基)哌啶-2,3-二酮-4-羧酸乙酯(ii-1)的制备
N 2保护下,于4-(2-乙氧基-N-(4-硝基苯基)-2-氧代乙酰氨基)丁酸乙酯(10.27g,29.1mmol)的叔丁醇溶液(200ml)中,加入叔丁醇钾(4.90g,43.7mmol),于20~50℃保温2-5h,当HPLC和TLC显示反应完成时,抽滤,滤饼加入盐酸水溶液中,用乙酸乙酯提取,有机层用无水硫酸钠干燥,减压浓缩得到产品,(7.85g,理论值8.92g,收率88%)。对于ii-1,LCMS m/z 307(M ++H,C 14H 14N 2O 6)。
实施例11
Figure PCTCN2020108762-appb-000020
1-(4-苯基)哌啶-2,3-二酮-4-羧酸乙酯(ii-2)的制备
N 2保护下,于4-(2-乙氧基-N-(4-苯基)-2-氧代乙酰氨基)丁酸乙酯(8.95g,29.1mmol)的叔丁醇溶液(180ml)中,加入叔丁醇钾(4.90g,43.7mmol),于20~50℃保温2-5h,当HPLC和TLC显示反应完成时,抽滤,滤饼加入盐酸水溶液中,用乙酸乙酯提取,有机层用无水硫酸钠干燥,减压浓缩得到产品,(6.93g,理论值7.61g,收率91%)。对于ii-2,LCMS m/z 262(M ++H,C 14H 15NO 4)。
实施例12
Figure PCTCN2020108762-appb-000021
1-(4-溴苯基)哌啶-2,3-二酮-4-羧酸乙酯(ii-3)的制备
N 2保护下,于4-(2-乙氧基-N-(4-溴苯基)-2-氧代乙酰氨基)丁酸乙酯(11.25g,29.1mmol)的叔丁醇溶液(230ml)中,加入叔丁醇钾(4.90g,43.7mmol),于20~50℃保温2-5h, 当HPLC和TLC显示反应完成时,抽滤,滤饼加入盐酸水溶液中,用乙酸乙酯提取,有机层用无水硫酸钠干燥,减压浓缩得到产品,(9.41g,理论值9.91g,收率95%)。对于(ii-3),LCMS m/z 340(M ++H,C 14H 14BrNO 4)。
实施例13
Figure PCTCN2020108762-appb-000022
1-(4-碘苯基)哌啶-2,3-二酮-4-羧酸乙酯(ii-4)的制备
N 2保护下,于4-(2-乙氧基-N-(4-碘苯基)-2-氧代乙酰氨基)丁酸乙酯(11.25g,29.1mmol)的叔丁醇溶液(230ml)中,加入叔丁醇钠(4.20g,43.7mmol),于20~50℃保温2-5h,当HPLC和TLC显示反应完成时,抽滤,滤饼加入盐酸水溶液中,用乙酸乙酯提取,有机层用无水硫酸钠干燥,减压浓缩得到产品,(11.74g,理论值12.62g,收率93%)。对于ii-4,LCMS m/z 388(M ++H,C 14H 14INO 4)。
实施例14
Figure PCTCN2020108762-appb-000023
(E)-乙基-4-(2-乙氧基-1-(2-(4-甲氧基苯基)肼基)2-氧代乙基)-2,3-二氧代-1-(4-硝基苯基)哌啶-4羧酸酯(iv-1)的制备
N 2保护下,于1-(4-硝基苯基)哌啶-2,3-二酮-4-羧酸乙酯(6.56g,21.43mmol)的甲苯溶液(66ml)中,加入三乙胺(3.25g,32.14mmol)、KI(0.36g,2.14mmol)和氯代[(4-甲氧基苯基)亚肼基]乙酸乙酯(5.5g,21.43mmol),于20~50℃保温8-15h,当HPLC和TLC显示反应完成时,加入1%盐酸水溶液(20ml)洗,分层,有机层用无水硫酸钠干燥,旋干直接通过柱色谱纯化(SiO 2,5-50%EtOAc/庚烷梯度洗脱),得到所需的产品(9.60g,理论值11.28g,收率85%)。对于iv-1,LCMS m/z 527(M ++H,C 25H 26N 4O 9)。
实施例15
Figure PCTCN2020108762-appb-000024
(E)-乙基-4-(2-乙氧基-1-(2-(4-甲氧基苯基)肼基)2-氧代乙基)-2,3-二氧代-1-苯基哌啶-4羧酸酯(iv-2)的制备
N 2保护下,于1-(4-苯基)哌啶-2,3-二酮-4-羧酸乙酯(5.6g,21.43mmol)的甲苯溶液(66ml)中,加入二异丙基乙胺(4.15g,32.14mmol)、KI(0.36g,2.14mmol)和氯代[(4-甲氧基苯基)亚肼基]乙酸乙酯(5.5g,21.43mmol),于20~50℃保温10-14h,当HPLC和TLC显示反应完成时,加入1%盐酸水溶液(20ml)洗,分层,有机层用无水硫酸钠干燥,旋干直接通过柱色谱纯化(SiO 2,5-50%EtOAc/庚烷梯度洗脱),得到所需的产品(8.80g,理论值10.32g,收率85%)。对于iv-2,LCMS m/z 482(M ++H,C 25H 27N 3O 7)。
实施例16
Figure PCTCN2020108762-appb-000025
(E)-乙基-4-(2-乙氧基-1-(2-(4-甲氧基苯基)肼基)2-氧代乙基)-2,3-二氧代-1-(4-溴苯基)哌啶-4羧酸酯(iv-3)的制备
N 2保护下,于1-(4-溴苯基)哌啶-2,3-二酮-4-羧酸乙酯(7.3g,21.43mmol)的甲苯溶液(73ml)中,加入二异丙基乙胺(4.15g,32.14mmol)、KI(0.36g,2.14mmol)和氯代[(4-甲氧基苯基)亚肼基]乙酸乙酯(5.5g,21.43mmol),于20~50℃保温10-14h,当HPLC和TLC显示反应完成时,加入1%盐酸水溶液(20ml)洗,分层,有机层用无水硫酸钠干燥,旋干直接通过柱色谱纯化(SiO 2,5-50%EtOAc/庚烷梯度洗脱),得到所需的产品(8.80g,理论值10.0g,收率83%)。对于iv-3,LCMS m/z 560(M ++H,C 25H 26BrN 3O 7)。
实施例17
Figure PCTCN2020108762-appb-000026
(E)-乙基-4-(2-乙氧基-1-(2-(4-甲氧基苯基)肼基)2-氧代乙基)-2,3-二氧代-1-(4-碘苯基)哌啶-4羧酸酯(iv-4)的制备
N 2保护下,于1-(4-碘苯基)哌啶-2,3-二酮-4-羧酸乙酯(8.3g,21.43mmol)的甲苯溶液(73ml)中,加入二异丙基乙胺(4.15g,32.14mmol)、KI(0.36g,2.14mmol)和氯代[(4-甲氧基苯基)亚肼基]乙酸乙酯(5.5g,21.43mmol),于20~50℃保温10-14h,当HPLC和TLC显示反应完成时,加入1%盐酸水溶液(20ml)洗,分层,有机层用无水硫酸钠干燥,旋干直接通过柱色谱纯化(SiO 2,5-50%EtOAc/庚烷梯度洗脱),得到所需的产品(8.80g,理论值10.0g,收率83%)。对于iv-4,LCMS m/z 608(M ++H,C 25H 26IN 3O 7)。
实施例18
Figure PCTCN2020108762-appb-000027
(E)-乙基-4-(2-乙氧基-1-(2-(4-甲氧基苯基)肼基)2-氧代乙基)-2,3-二氧代-1-((1-哌啶)-4-苯基)哌啶-4羧酸酯(iv-5)的制备
N 2保护下,于1-((1-哌啶)-苯基)哌啶-2,3-二酮-4-羧酸乙酯(7.68g,21.43mmol)的甲苯溶液(77ml)中,加入二异丙基乙胺(4.15g,32.14mmol)、KI(0.36g,2.14mmol)和氯代[(4-甲氧基苯基)亚肼基]乙酸乙酯(5.5g,21.43mmol),于20~50℃保温10-14h,当HPLC和TLC显示反应完成时,加入1%盐酸水溶液(20ml)洗,分层,有机层用无水硫酸钠干燥,旋干直接通过柱色谱纯化(SiO 2,5-50%EtOAc/庚烷梯度洗脱),得到所需的产品(11.9g,理论值12.4g,收96%)。对于iv-5,LCMS m/z 579(M ++H,C 30H 34N 4O 8)。
实施例19
Figure PCTCN2020108762-appb-000028
二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-(1-哌啶基苯基)-3a,4,5,6,7,7a-六氢-1H-吡啶并[3,4-c]吡啶-3,3a-二羧酸酯(v-5)的制备
于式iv-5(8.58g,14.8mmol)的甲苯溶液(86ml)中,加入三乙胺(1.5g,14.8mmol),于110℃保温1-4h,当HPLC和TLC显示反应完成时,旋干溶剂,直接通过柱色谱纯化(SiO 2,15-35%EtOAc/庚烷梯度洗脱),得到所需的产品(8.2g,理论值8.58g,收率95%)。对于v-5,LCMS m/z 579(M ++H,C 30H 34N 4O 8)。
实施例20
Figure PCTCN2020108762-appb-000029
二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-(4-硝基苯基)-3a,4,5,6,7,7a-六氢-1H-吡啶并[3,4-c]吡啶-3,3a-二羧酸酯(v-1)的制备
于式iv-1(7.8g,14.8mmol)的甲苯溶液(78ml)中,加入三乙胺(1.5g,14.8mmol),于110℃保温1-4h,当HPLC和TLC显示反应完成时,旋干溶剂,直接通过柱色谱纯化(SiO 2,15-35%EtOAc/庚烷梯度洗脱),得到所需的产品(7.3g,理论值7.8g,收率93%)。对于v-1,LCMS m/z 527(M ++H,C 25H 26IN 4O 9)。
实施例21
Figure PCTCN2020108762-appb-000030
二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-苯基-3a,4,5,6,7,7a-六氢-1H-吡啶并[3,4-c]吡啶-3,3a-二羧酸酯(v-2)的制备
于式iv-2(7.14g,14.8mmol)的甲苯溶液(78ml)中,加入三乙胺(1.5g,14.8mmol),于110℃保温1-4h,当HPLC和TLC显示反应完成时,旋干溶剂,直接通过柱色谱纯化(SiO 2,15-35%EtOAc/庚烷梯度洗脱),得到所需的产品(6.93g,理论值7.14g,收率97%)。对于v-2,LCMS m/z 482(M ++H,C 25H 27N 3O 7)。
实施例22
Figure PCTCN2020108762-appb-000031
二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-(4-溴苯基)-3a,4,5,6,7,7a-六氢-1H-吡啶并[3,4-c]吡啶-3,3a-二羧酸酯(v-3)的制备
于式iv-3(8.31g,14.8mmol)的甲苯溶液(83ml)中,加入三乙胺(1.5g,14.8mmol),于110℃保温1-4h,当HPLC和TLC显示反应完成时,旋干溶剂,直接通过柱色谱纯化(SiO 2,15-35%EtOAc/庚烷梯度洗脱),得到所需的产品(7.12g,理论值8.58g,收率83%)。对于v-3,LCMS m/z 560(M ++H,C 25H 26BrN 3O 7)。
实施例23
Figure PCTCN2020108762-appb-000032
二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-(4-碘苯基)-3a,4,5,6,7,7a-六氢-1H-吡啶并[3,4-c]吡啶-3,3a-二羧酸酯(v-4)的制备
于式iv-4(9.0g,14.8mmol)的甲苯溶液(78ml)中,加入三乙胺(1.5g,14.8mmol),于110℃保温1-4h,当HPLC和TLC显示反应完成时,旋干溶剂,直接通过柱色谱纯化(SiO 2,15-35%EtOAc/庚烷梯度洗脱),得到所需的产品(7.12g,理论值9.0g,收率83%)。对于v-4,LCMS m/z 608(M ++H,C 25H 26IN 3O 7)。
实施例24
Figure PCTCN2020108762-appb-000033
乙基1-(4-甲氧基苯基)-7-氧代-6-(4-(2-氧代哌啶-1-基)苯基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]3-羧酸吡啶(vi-5)的制备
将二乙基7a-羟基-1-(4-甲氧基苯基)-7-氧代-6-(4-(2-氧代哌啶-1-基)苯基)-1,4,5,6,7,7a-六氢-3aH-吡唑并[3,4-c]吡啶-3,3a-二羧酸酯(8.67g,15mmol)溶于50ml甲苯中,加入溴化氢乙酸溶液(33%)(1.33g,5.5mmol),于40℃保温搅拌1~2h,当HPLC和TLC显示反应完成时,加入20ml饱和碳酸氢钠溶液,萃取分层。有机层加入五水硫酸镁干燥,减压蒸馏得到产品(6.88g,理论值7.32g,收率94%),对于vi-5,LCMS m/z 489(M+H +,C 27H 28N 4O 5)。

Claims (9)

  1. 一种制备阿哌沙班式为(v)的中间体,结构式如下:
    Figure PCTCN2020108762-appb-100001
    其中,A为C 6-14芳基或5至14元杂芳基,所述杂芳基含有1至4个选自N、O或S的杂原子,其中,当具有多个杂原子时,各杂原子相同或者不同;芳基或杂芳基可进一步被0至5个R 2取代,其中当具有多个取代基时,各取代基相同或者不同;
    当B不存在时,A为H、F、Cl、Br、I、羟基、-C(=O)OR 4、C 1-4烷基或C 1-4烷氧羰基的取代基所取代;
    B为3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,且所述杂环可进一步被0至5个取代基所取代,所述取代基选自(=O)、(=S)或者R 4a
    Figure PCTCN2020108762-appb-100002
    表示环D存在或不存在;
    当环D存在时,包括环E与之相连的两个原子一起形成5至6元环,所述5至6元环含有0至2个选自N、O或S的杂原子,所述5至6元环可进一步被0至5个R 4取代;环E为苯基或5至6元杂芳基,所述杂芳基含有1至3个选自N、O或S的杂原子,所述苯基或杂芳基可进一步被0至3个R 4取代;
    当环D不存在时,环E为苯基或5至6元杂芳基,所述杂芳基含有1至3个选自N、O或S的杂原子,所述苯基或杂芳基可进一步被0至5个R 4取代;
    R 3为F、Cl、Br、I、羟基、巯基、氨基、硝基、氰基、三氟甲基、C 1-4烷氧基、-(CR 4R 4a) nNR 4R 4a、-(CR 4R 4a) nNR 4R 4a、-(CH 2) nC(=NR 4b)NR 4R 4a、-(CR 4R 4a) n-C(=O)NR 4R 4a
    -(CR 4R 4a) nNR 4C(=O)R 4a、-(CR 4R 4a) nOR 4、-(CH 2) nC(=O)R 4、或-(CH 2) nS(=O) PR 4b
    R 7为H、F、Cl、Br、I、氰基、三氟甲基、-(CR 4R 4a) nOR、-(CR 4R 4a) nNR 4R 4b、-C(=O)R 4R 4a) n、-(CH 2) nS(=O) nR 4R 4a、-C(R 4R 4a)R;
    R 9为H、F、Cl、Br、I、羟基、巯基、氨基、硝基、氰基、三氟甲基、C 1-4烷氧基、-(CR 4R 4a) nNR 4R 4a、-(CR 4R 4a) nNR 4R 4a、-(CH 2) nC(=NR 4b)NR 4R 4a、-(CR 4R 4a) n-C(=O)NR 4R 4a、-(CR 4R 4a) nNR 4C(=O)R 4a、-(CR 4R 4a) nOR 4、-(CH 2) nC(=O)R 4、或-(CH 2) nS(=O) PR 4b
    R为H、-C(R 4R 4a)R 4b、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b
    R 2为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
    R 4、R 4a和R 4b为卤素、C 1-4烷基、环丙基、环戊基、环己基、苄基或苯基及其苯基衍生物;或者,NR 4R 4a为由C、N、和0-1个O原子组成的3-8元环;
    n为0、1、2、3或者4;
    P为0、1或者2。
  2. 一种制备阿哌沙班式为(iv)的中间体,结构式如下:
    Figure PCTCN2020108762-appb-100003
    其中A、B、环D、环E、R 3和R 7的定义与权利要求1中相同;
    R 4为H、OH、CN、NO 2、卤素、-S(=O) nR、-NR 1R 2、-C(=O)OR、-C(=O)NR 1R 2、-OR;
    R 5为H、OH、CN、NO 2、卤素、-S(=O) nR、-NR 1R 2、-C(=O)OR、-C(=O)NR 1R 2、-OR;
    R 1为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
    R 2为H、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
    R、R 4、R 4a、R 4b、n和P的定义与权利要求1中相同;
  3. 一种阿哌沙班中间体式为(v)的制备方法,其特征在于,内酰胺类化合物(iv)在碱的存在下接触得到,反应式如下:
    Figure PCTCN2020108762-appb-100004
    其中A、B、环D、环E、R 3、R 4、R 5、R 7和R 9的定义与上述相同;
  4. 一种阿哌沙班中间体式为(iv)的制备方法,其特征在于,内酰胺类化合物式(ii)与化合物式(iii)在碱和催化剂的存在下接触得到,反应式如下:
    Figure PCTCN2020108762-appb-100005
    其中A、B、环D、环E、R 3、R 4、R 5和R 7的定义与权利要求1中的相同;
    R 8为Cl、Br、Cl、I、OSO 2Me、OSO 2Ph和OSO 2Ph-p-Me;
  5. 根据权利要求4所述的制备方法,其特征在于,所述式(ii)化合物由式(i)化合物在碱存在下接触得到,反应式如下:
    Figure PCTCN2020108762-appb-100006
    其中A、B、R 3、R 4和R 5的定义与上述相同;
    R 2为氰基、-(CR 4R 4a) nOR 4、-(CR 4R 4a) nNR 4R 4a、-C(=O)NR 4R 4a、-(CH 2) nS(=O) PR 4b、-C(R 4R 4a)R 4b
    R 4、R 4a、R 4b、n和P的定义与上述相同;
  6. 一种阿哌沙班中间体式为(v)的制备方法,其特征在于,包括以下步骤:1)式(i)化合物在碱存在下接触得到式(ii)化合物;2)内酰胺类化合物式(ii)与化合物式(iii)在碱和催化剂的存在下接触得到式(iv)化合物;3)内酰胺类化合物(iv)在碱的存在下接触得到式(v)化合物,反应式如下:
    Figure PCTCN2020108762-appb-100007
    其中A、B、环D、环E、R 2、R 3、R 4、R 5、R 7、R 8和R 9定义与上述相同;
  7. 根据权利要求4,5和6所述的制备方法,其特征在于,所述第1)步的碱为甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾;
  8. 根据权利要求3,4和6所述的制备方法,其特征在于,所述第2)步和第3)碱为三乙胺、二异丙基乙胺、吡啶、哌啶、DBU;
  9. 根据权利要求4和6所述的制备方法,其特征在于,所述所述第2)步催化剂为LiI、NaI、KI、LiBr、NaBr、KBr、四丁基溴化胺、四丁基碘化胺中的一种或多种;
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049681A2 (en) * 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2014044113A1 (zh) * 2012-09-18 2014-03-27 上海恒瑞医药有限公司 吡唑并[3,4-c]吡啶类衍生物、其制备方法及其在医药上的应用

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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049681A2 (en) * 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2014044113A1 (zh) * 2012-09-18 2014-03-27 上海恒瑞医药有限公司 吡唑并[3,4-c]吡啶类衍生物、其制备方法及其在医药上的应用

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