CN114573503A - 一种制备奥特康唑中间体的方法 - Google Patents
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims description 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J25/00—Catalysts of the Raney type
- B01J25/02—Raney nickel
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
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- B01J35/19—
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
Abstract
本发明提供了一种奥特康唑的式I中间体的制备方法，该方法通过将式II中间体经还原反应制备式I中间体。本发明的奥特康唑的式I中间体的制备方法反应更彻底，目标产物转化率高，杂质少，质量高，操作简单，易于工业应用
Description
技术领域
本发明属于药物化学领域，具体涉及一种制备奥特康唑中间体的方法。
背景技术
奥特康唑(VT-1161)，其英文名称为Oteseconazole，化学名称为(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四氮唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙烷-2-醇，CAS：1340593-59-0，其化学结构式如下：
奥特康唑是一款由美国Mycovia公司开发的新型口服小分子选择性真菌CYP51抑制剂，且对真菌CYP51的选择性显著优于其他常用唑类抗真菌药。从目前的临床研究来看，奥特康唑也表现出了优秀的药物动力学特征、疗效以及安全性。临床上用于复发性外阴阴道念珠菌病、侵袭性真菌感染和甲真菌病等疾病治疗。
中间体胺化物(其结构如下式I)是奥特康唑的关键中间体，它是由中间体硝基化物(其结构如下式II)还原而来。
CN108289457B提供了使用约0.40mol％Pt还原合成3-氨基-1-(5-溴吡啶-2-基)-2-(2,4-二氟苯基)-1,1-二氟丙-2-醇的方法，
但是该方法会产生较多的脱溴杂质(其结构如下式III)以及较多的还原中间态胺肟杂质(其结构如下式IV)，同时Pt价格昂贵，不利于产业化。
针对现有技术的不足，需要提供一种改进的能使中间体硝基化物(式II中间体)反应更彻底，并有效减少脱溴杂质(式III杂质)和胺肟杂质(式IV杂质)的适合产业化的奥特康唑中间体胺化物(式I中间体)的制备方法。
发明内容
针对现有技术的不足，本发明的目的在于提供一种改进的奥特康唑中间体胺化物(式I中间体)的制备方法，该方法能使中间体硝基化物(式II中间体)反应更彻底，并有效减少脱溴杂质(式III杂质)和胺肟杂质(式IV杂质)产生，目标产物转化率高，杂质少，质量高，操作简单，易于工业应用。
本发明的奥特康唑的式I中间体的制备方法包括以下步骤：
将式II中间体与醇类溶剂、乙酸、雷尼镍混合于高压釜中，通过氢气置换后进行加氢还原反应，反应结束后分离获得式I中间体。
根据本发明所述的制备方法，其中，所述醇类溶剂选自甲醇、乙醇、异丙醇及其混合溶剂，优选甲醇。
根据本发明所述的制备方法，其中，所述醇类溶剂与式II中间体的重量比为4～12：1(w/w)，优选4～10：1。
根据本发明所述的制备方法，其中，所述乙酸与式II中间体的摩尔比为0.2～0.8：1，优选0.3～0.6：1。
根据本发明所述的制备方法，其中，所述雷尼镍与式II中间体的重量比为0.05～0.3：1，优选0.1～0.2：1。
根据本发明所述的制备方法，其中，所述高压釜中氢气压力为0～1.0MPa，优选0.2～0.5MPa。
根据本发明所述的制备方法，其中，所述加氢还原反应的反应温度范围为15～40℃，优选20～35℃。
根据本发明所述的制备方法，其中，式I中间体与L-二对甲基苯甲酰酒石酸成盐，得到式I化合物的半L-二对甲基苯甲酰酒石酸盐。
根据本发明所述的制备方法，其中，式I中间体与L-二对甲基苯甲酰酒石酸成盐的步骤中使用醇类(例如，甲醇、乙醇、异丙醇、正丙醇中的一种或多种，优选异丙醇)作为溶剂。
本发明的有益效果包括：
现有技术制备方法中因式II中间体中氟的影响，硝基还原不易顺利进行，需采用价格昂贵的Pt催化剂，而且即使采用价格昂贵的Pt催化剂，反应产生的副产物还是较多。本发明通过使用雷尼镍+乙酸作为催化剂代替现有技术中的Pt催化剂，出乎意料地发现，中间体硝基化物(式II中间体)反应更彻底，特定用量范围的雷尼镍+乙酸作为催化剂能够显著抑制并有效减少脱溴杂质(式III杂质)和胺肟杂质(式IV杂质)的产生，目标产物转化率高，操作简单，显著降低生产成本，易于工业化应用；该方法制备得到的式I中间体杂质少、质量高，有较高的经济价值。
附图说明
图1为参考例1中以Pt为催化剂的反应液有关物质图谱。
图2为参考例2中以雷尼镍为催化剂、以甲醇为溶剂的反应液有关物质图谱。
图3为实施例1中以雷尼镍+乙酸为催化剂、以甲醇为溶剂的反应液有关物质图谱。
图4为实施例2中以雷尼镍+乙酸为催化剂、以乙醇为溶剂的反应液有关物质图谱。
具体实施方式
下面结合实施例对本发明做进一步阐述，但本发明的实施方式不限于此。
实施例部分
本发明实施例中使用的原料和试剂均为常规可购买获得。
参考例1：
参考CN108289457B实施例4的制备方法，以Pt为催化剂进行还原反应。还原反应完成后，取样检测反应液，有关物质图谱见图1，面积百分比报告见表1。
表1面积百分比报告
参考例2：以雷尼镍为催化剂，甲醇为溶剂
加入20g式II中间体，加入100g(5w/w)乙醇，加入2g(0.1w/w)雷尼镍，氮气置换，氢气置换，加压至0.1MPa，于20～25℃保温反应10小时，通过HPLC确认反应完成。取样检测反应液，有关物质图谱见图2，面积百分比报告见表2。参考CN108289457B实施例4进行后处理得到14.6g式I化合物的半L-DTTA盐，收率52％。
表2面积百分比报告
实施例1：以雷尼镍+乙酸为催化剂，甲醇为溶剂
加入20g式II中间体，加入200g(10w/w)甲醇，加入1.8g(0.6eq)乙酸，加入4g(0.2w/w)雷尼镍，氮气置换，氢气置换，加压至0.3MPa，于20～30℃保温反应8小时，通过HPLC确认反应完成。取样检测反应液，有关物质图谱见图3，面积百分比报告见表3。反应液过滤后减压脱溶至干，加入60g异丙醇继续脱溶，再加入160g异丙醇，升温溶解，加入11.4g的L-DTTA，升温至50～55℃保温4小时，降温至20～30℃保温16小时，过滤，干燥得21.3g式I化合物的半L-DTTA盐，收率76％。
表3面积百分比报告
实施例2：以雷尼镍+乙酸为催化剂，乙醇为溶剂
加入20g式II中间体，加入80g(4w/w)乙醇，加入0.9g(0.3eq)乙酸，加入6g(0.3w/w)雷尼镍，氮气置换，氢气置换，加压至0.5MPa，于25～35℃保温反应10小时，通过HPLC确认反应完成。取样检测反应液，有关物质图谱见图4，面积百分比报告见表4。反应液过滤后减压脱溶至干，加入60g异丙醇继续脱溶，再加入140g异丙醇，升温溶解，滴加入9.5g的L-DTTA的40g异丙醇溶液，升温至50～55℃保温4小时，降温至20～30℃保温16小时，过滤，干燥得17.7g式I中间体的半L-DTTA盐，收率63％。
表4面积百分比报告
实验部分
有关物质检测方法：
溶液配制
流动相A：0.03mol/L KH2PO4溶液，pH3.0
流动相B：乙腈
稀释液：乙腈/水(50:50,v/v)
HPLC检测条件如下表1所示。
表1
上述各实施方案中反应液的检测结果如下表2所示。
表2
本发明的发明人在研究过程中，尝试用多种试剂进行还原，如锌粉等。发现通过使用本发明的特定用量范围的雷尼镍+乙酸作为催化剂才能达到预期的效果。另一方面，本发明制备方法中各物料的用量比在发明内容公开的用量比范围内，且其效果近似。
Claims (9)
1.一种奥特康唑的式I中间体的制备方法，包括以下步骤：
将式II中间体与醇类溶剂、乙酸、雷尼镍混合于高压釜中，通过氢气置换后进行加氢还原反应，反应结束后分离获得式I中间体。
2.根据权利要求1所述的制备方法，其中，所述醇类溶剂选自甲醇、乙醇、异丙醇及其混合溶剂，优选甲醇。
3.根据权利要求1或2所述的制备方法，其中，所述醇类溶剂与式II中间体的重量比为4～12：1，优选4～10：1。
4.根据权利要求1或2所述的制备方法，其中，所述乙酸与式II中间体的摩尔比为0.2～0.8：1，优选0.3～0.6：1。
5.根据权利要求1或2所述的制备方法，其中，所述雷尼镍与式II中间体的重量比为0.05～0.3：1，优选0.1～0.2：1。
6.根据权利要求1或2所述的制备方法，其中，所述高压釜中氢气压力为0～1.0MPa，优选0.2～0.5MPa。
7.根据权利要求1或2所述的制备方法，其中，所述加氢还原反应的反应温度范围为15～40℃，优选20～35℃。
8.根据权利要求1或2所述的制备方法，其中，式I中间体与L-二对甲基苯甲酰酒石酸成盐，得到式I化合物的半L-二对甲基苯甲酰酒石酸盐。
9.根据权利要求1或2所述的制备方法，其中，式I中间体与L-二对甲基苯甲酰酒石酸成盐的步骤中使用醇类作为溶剂。
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| CN102060719A (zh) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | 盐酸米多君中间体1-(2,5-二甲氧基苯基)-2-氨基乙醇的制备方法 |
| CN108289457A (zh) * | 2015-09-18 | 2018-07-17 | 迈科维亚医药公司 | 抗真菌化合物制备方法 |
| CN109651287A (zh) * | 2019-01-18 | 2019-04-19 | 吕东 | 一种4-(4-氨基苯基)吗啉酮的制备方法 |
| CN109678791A (zh) * | 2014-03-19 | 2019-04-26 | Vps-3有限公司 | 1-(2,4-二氟苯)-2,2-二氟-2-(5-取代吡啶-2-基)乙酮及制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102060719A (zh) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | 盐酸米多君中间体1-(2,5-二甲氧基苯基)-2-氨基乙醇的制备方法 |
| CN109678791A (zh) * | 2014-03-19 | 2019-04-26 | Vps-3有限公司 | 1-(2,4-二氟苯)-2,2-二氟-2-(5-取代吡啶-2-基)乙酮及制备方法 |
| CN108289457A (zh) * | 2015-09-18 | 2018-07-17 | 迈科维亚医药公司 | 抗真菌化合物制备方法 |
| CN109651287A (zh) * | 2019-01-18 | 2019-04-19 | 吕东 | 一种4-(4-氨基苯基)吗啉酮的制备方法 |
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