CN114736151B - 一种帕罗韦德关键中间体制备方法及化合物的结构式 - Google Patents
一种帕罗韦德关键中间体制备方法及化合物的结构式 Download PDFInfo
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- 239000005416 organic matter Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- 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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Abstract
本发明提供一种帕罗韦德关键中间体制备方法及化合物的结构式,L‑丝氨酸的氨基用BOC保护,与三甲氧基膦反应生成化合物4;化合物4与叔丁基二甲基硅氧基乙醛,反应得到的化合物5与2,2‑二氯丙烷环丙烷化,得到化合物6;将化合物6脱硅基保护得到的化合物7的羟基卤代,得到化合物8,化合物8环合得到化合物9后脱BOC保护,得到帕罗韦德关键中间体的化合物2。本发明以廉价的L‑丝氨酸和叔丁基二甲基硅保护的羟基乙醛为原料,通过构建Z式双键,经过环丙烷化,脱硅基保护,最后环合得到制备帕罗韦德的关键中间体。本发明该方法操作简单,该方法原料便宜,合成步骤简单,有效避免了双键位置异构以及手性消旋的问题,其工艺方法适合工业化生产。
Description
技术领域
本发明涉及有机物合成制药技术领域,更具体地说,尤其涉及一种帕罗韦德关键中间体制备方法及化合物结构式。
背景技术
帕罗韦德(Paxlovid)是辉瑞开发的用于新冠肺炎治疗的药物,已获多个国家批准上市,其主要有效成分结构如化合物1所示。
化合物1合成过程中,化合物2(环丙基的脯氨酸片段)是其关键中间体,也是主要的合成技术难点和制约产品成本控制的关键所在,现有技术中,该化合物的合成方法如下:
方法一:文献synthesis(1982,753)以手性羟脯氨酸为原料,甲酯化,氨基上Boc保护,然后将羟基做成离去基团,例如碘,砜基,三氟甲磺酰基,苯硒基;再用碱消除获得双键,环丙烷化得到环丙基脯氨酸。该方法不仅路线长,在消除获得双键的时候会产生位置异构,用苯硒基消除虽然不会产生位置异构,但是硒试剂剧毒,三氟甲磺酰基消除时还会发生手性消旋,如下式:
方法二:文献synthesis(2001,46)先合成Boc-二氢吡咯,然后合成消旋的Boc-二氢脯氨酸甲酯,酶水解拆分得到脯氨酸,然后再甲酯化,环丙烷化。该方法缺点在于Boc-二氢吡咯合成不容易,手性拆分后有一半的异构体无用,还要对羧基再次进行甲酯化,如下式:
方法三:文献Journal of Medicinal Chemistry(2006,6074) 从焦谷氨酸出发,还原羧基到羟基,苯甲醛保护,构建烯烃,环丙烷化,然后还原酰胺,保护氨基,氧化羟基到羧酸并酯化。该路线很长,要采用低温,四氢铝锂等高危险操作,如下式:
发明内容
针对现有技术的上述缺陷和问题,本发明提供一种帕罗韦德关键中间体制备方法及化合物的结构式。
为了达到上述目的,本发明提供如下技术方案:
一种帕罗韦德关键中间体的制备方法,包括步骤:
步骤一、将L-丝氨酸的氨基用BOC保护,与三甲氧基膦反应生成化合物4;
步骤二、化合物4与叔丁基二甲基硅氧基乙醛,反应得到化合物 5;
步骤三、化合物5与2,2-二氯丙烷环丙烷化,得到化合物6;
步骤四、化合物6脱硅基保护,得到化合物7;
步骤五、将化合物7的羟基卤代得到化合物8;
步骤六、将化合物8环合得到化合物9;
步骤七,化合物9脱BOC保护,得到帕罗韦德关键中间体的化合物2。
上述技术方案中,所述BOC保护剂包括Boc-醋酐、(Boc)2O。
上述技术方案中,所述三甲氧基膦用三乙氧基磷替代。
上述技术方案中,所述步骤三中,化合物5在锌铜偶联剂的作用下与2,2-二氯丙烷成环得到化合物6。
上述技术方案中,所述步骤四中,用四丁基氟化铵脱去化合物6 中硅基保护。
上述技术方案中,所述步骤六中,化合物8到化合物9的成环反应方式为:在无水四氢呋喃中加入粉末状碳酸钠成环。
上述技术方案中,所述X1包括-OMs、-OTs、-Cl、-Br、-I、-OTf,保护基团包括BOC、FMOC,链烃基团包括甲基、乙基、丙基。
本发明以廉价的L-丝氨酸和叔丁基二甲基硅保护的羟基乙醛为起始原料,通过构建Z式双键,经过环丙烷化,脱硅基保护,最后环合得到制备帕罗韦德的关键中间体。本发明该方法操作简单,该方法原料便宜,合成步骤简单,有效避免了双键位置异构以及手性消旋的问题,其工艺方法适合工业化生产。
具体实施方式
下面将结合本发明的实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
一种帕罗韦德关键中间体的制备方法,包括步骤为:
步骤一、将L-丝氨酸的氨基用BOC保护,与三甲氧基膦反应生成化合物4;
步骤二、化合物4与叔丁基二甲基硅氧基乙醛,反应得到化合物 5;
步骤三、化合物5与2,2-二氯丙烷环丙烷化,得到化合物6;
步骤四、化合物6脱硅基保护,得到化合物7;
步骤五、将化合物7的羟基卤代得到化合物8;
步骤六、将化合物8环合得到化合物9;
步骤七,化合物9脱BOC保护,得到帕罗韦德关键中间体的化合物2。
具体合成路线见下式:
具体实施例1:
将丝氨酸50g,碳酸钠100g,加入300g水中,室温下搅拌溶解澄清,然后滴加Boc酸酐115g,然后在室温下搅拌24小时,加入醋酸调节pH值至6~7,然后加入乙酸乙酯300ml萃取产品,萃取两次,无水硫酸钠干燥好,浓缩干得到粗品101.1g。
将上述得到的粗品101.1g,88.5g三甲氧基膦,274.5g三苯基膦,加入至1000ml四氢呋喃中,搅拌溶解澄清,降温至-10℃以下,缓慢滴加偶氮二甲酸二乙酯182.3g/100ml四氢呋喃溶液,滴加完毕后保温2小时,然后减压浓缩过柱纯化得到74.5g化合物4。
将叔丁醇钾11.2g溶于300ml无水四氢呋喃中,冰水浴下慢慢滴加31.1g化合物4溶于50ml无水四氢呋喃的溶液,控制温度不超过 10℃,加毕,搅拌半小时,再滴加叔丁基二甲基硅氧基乙醛17.4g溶于50ml无水四氢呋喃的溶液,加毕,慢慢升温至25℃,搅拌至TLC 显示反应完全,慢慢倒入冰水中,分液,水相乙酸乙酯萃取,合并有机相,干燥浓缩,柱层析得到31.5g化合物5。
将锌铜偶联剂3.2g,17.9g化合物5,锌粉6.35g和溴化锌 11.18g分别加到100ml无水四氢呋喃中,25℃下搅拌半小时后慢慢滴加2,2-二氯丙烷11.3g,加毕,在25℃下搅拌至检测反应完全,加入冰水,过滤分液,水相乙酸乙酯提取,合并有机相,干燥浓缩,柱层析得16.6g化合物6。
将16g化合物6溶解于80ml二氯甲烷中,加入四丁基氟化铵 10.44g,搅拌至反应结束,碳酸氢钠溶液水洗有机相,干燥浓缩干,得到化合物7,加入四氢呋喃100ml,四溴化碳13.28g和三苯基膦 10.48g,搅拌至原料消失,过滤,浓缩至干,柱层析得到12.8g化合物8。
将12g化合物8溶于50ml无水四氢呋喃中,加入粉状碳酸钾 13.8g,搅拌至反应完全,过滤,浓缩柱层析得到8.5g化合物9。
将8g化合物9溶于50ml无水甲醇中,加入浓盐酸6g,搅拌至反应完全,过滤,浓缩至干,得到6.8g化合物2。
具体实施例2:
将丝氨酸50g,碳酸钠100g,加入300g水中,室温下搅拌溶解澄清,然后滴加(Boc)2O 106g,然后在室温下搅拌20小时,加入醋酸调节pH值至6~7,然后加入乙酸乙酯300ml萃取产品,萃取两次,无水硫酸钠干燥好,浓缩干得到粗品100.4g。将上述得到的粗品100.4g,88.1g三乙氧基膦,272.3g三苯基膦,加入至1000ml四氢呋喃中,搅拌溶解澄清,降温至-10℃以下,缓慢滴加偶氮二甲酸二乙酯181.1g/100ml四氢呋喃溶液,滴加完毕后保温2小时,然后减压浓缩过柱纯化得到76.3.6g固体。
将叔丁醇钾20g溶于300ml无水四氢呋喃中,冰水浴下慢慢滴加 36g上述固体溶于50ml无水四氢呋喃的溶液,控制温度不超过10℃,加毕,搅拌半小时,再滴加叔丁基二甲基硅氧基乙醛19.6g溶于50ml 无水四氢呋喃的溶液,加毕,慢慢升温至25℃,搅拌至TLC显示反应完全,慢慢倒入冰水中,分液,水相乙酸乙酯萃取,合并有机相,干燥浓缩,柱层析得到34.1g化合物5。
将锌铜偶联剂3.2g,17.9g化合物5,锌粉6.35g和溴化锌11.18g 分别加到100ml无水四氢呋喃中,25℃下搅拌半小时后慢慢滴加2,2- 二氯丙烷11.3g,加毕,在25℃下搅拌至检测反应完全,加入冰水,过滤分液,水相乙酸乙酯提取,合并有机相,干燥浓缩,柱层析得16.6g化合物6。
将16g化合物6溶解于80ml二氯甲烷中,加入四丁基氟化铵 10.44g,搅拌至反应结束,碳酸氢钠溶液水洗有机相,干燥浓缩干,得到化合物7,加入四氢呋喃100ml,四溴化碳13.28g和三苯基膦 10.48g,搅拌至原料消失,过滤,浓缩至干,柱层析得到12.8g化合物8。
将12g化合物8溶于50ml无水四氢呋喃中,加入粉状碳酸钾 13.8g,搅拌至反应完全,过滤,浓缩柱层析得到8.5g化合物9。
将8g化合物9溶于50ml无水甲醇中,加入浓盐酸6g,搅拌至反应完全,过滤,浓缩至干,得到6.8g化合物2。
本发明还提供了一种用于合成化合物2的中间体结构式,其结构式如化合物10所示,其中X1为卤素基团或其他可以和氨基成环的基团,优选-OMs、-OTs、-Cl、-Br、-I、-OTf;X2为甲基、乙基、丙基或者其他链烃基团;X3为保护基团,用于保护氨基的结构,优选 BOC、FMOC。化合物10可以通过简单的成环反应,制备得到化合物2,是合成化合物2的一种关键中间体。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应所述以权利要求的保护范围为准。
Claims (7)
2.根据权利要求1所述一种帕罗韦德关键中间体的制备方法,其特征在于:步骤一中,所述BOC保护剂包括Boc-醋酐、(Boc)2O。
3.根据权利要求1或2所述一种帕罗韦德关键中间体的制备方法,其特征在于:步骤一中,所述三甲氧基膦用三乙氧基磷替代。
4.根据权利要求3所述一种帕罗韦德关键中间体的制备方法,其特征在于:所述步骤三中,化合物5在锌铜偶联剂的作用下与2,2-二氯丙烷成环得到化合物6。
5.根据权利要求4所述一种帕罗韦德关键中间体的制备方法,其特征在于:所述步骤四中,用四丁基氟化铵脱去化合物6中硅基保护。
6.根据权利要求5所述一种帕罗韦德关键中间体的制备方法,其特征在于:所述步骤六中,化合物8到化合物9的成环反应方式为:在无水四氢呋喃中加入粉末状碳酸钠成环。
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Denomination of invention: A key intermediate preparation method for Parovide and structural formula of its compound Granted publication date: 20230421 Pledgee: Agricultural Bank of China Xiangtan County Branch Pledgor: Hunan Furui Biomedical Technology Co.,Ltd. Registration number: Y2024980000042 |