CN115557871A - 一种抗病毒化合物pf-07321332的合成方法 - Google Patents
一种抗病毒化合物pf-07321332的合成方法 Download PDFInfo
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- CN115557871A CN115557871A CN202111422348.6A CN202111422348A CN115557871A CN 115557871 A CN115557871 A CN 115557871A CN 202111422348 A CN202111422348 A CN 202111422348A CN 115557871 A CN115557871 A CN 115557871A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 47
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 title claims abstract description 36
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
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- -1 (S) -4- ((tert-butoxycarbonyl) amino) -4-cyanobutyric acid methyl ester Chemical compound 0.000 claims abstract description 26
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 24
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 20
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 12
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 12
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 7
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Genetics & Genomics (AREA)
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Abstract
本发明提供了一种抗病毒药物PF‑07321332的合成方法,包括以(S)‑4‑((叔丁氧羰基)氨基)‑4‑氰基丁酸甲酯化合物1为起始原料,利用强碱拔氢后与1,2,3‑噁噻唑烷‑3‑甲酸苄酯2,2‑二氧化物化合物2完成烷基化反应得到化合物3,再经过一锅法氢化并环合得到化合物4,化合物4通过盐酸解脱Boc成盐反应得到化合物5;化合物6与化合物7经缩合后再水解,得到化合物9;最后将化合物5和化合物9在缩合剂作用下缩合得到目标产物PF‑07321332;该合成工艺路线简单、收率较高、成本低廉、适宜工业化生产。
Description
技术领域
本发明属于医药化工领域,具体涉及抗病毒药物PF-07321332的合成方法。
背景技术
2021年11月5日,美国辉瑞制药宣布,新型口服在抗病毒药物Paxlovid用于治疗新冠病毒肺炎的II/III期临床试验中达到终点,能显著降低新冠患者住院和死亡风险。Paxlovid的主要成分是化合物PF-07321332,它是由辉瑞制药研发的一种新型口服新冠病毒3CL蛋白酶抑制剂,它的作用机制与已经获批的抗新冠病毒药物瑞德西韦和Molnupiravir有明显不同,能通过抑制新冠病毒切割长多肽链从达到抑制病毒的效果。Paxlovid一旦获批,PF-07321332的市场前景极其巨大。
PF-07321332化学名为:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-甲酰胺,它的结构式如下:
Science 2020年第368卷6497期1331页报道了PF-07321332重要中间体(S)-2-((叔丁氧羰基)氨基)-3-((S)-2-氧代吡咯烷-3-基)丙酸甲酯的合成方法,利用N-Boc-L-谷氨酸二甲酯在LiHMDS拔氢后与溴乙腈完成烷基化反应,接着利用硼氢化钠再二氯化钴催化下还原氰基得到目标中间体。路线如下:
辉瑞制药在Science 2021年APSP文章中报道了PF-07321332的完整合成路线,先利用(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-甲酸甲酯盐酸盐与N-Boc-L-叔亮氨酸在HATU的作用下缩合,再经过酯基水解、酸解脱Boc成盐、氨酯交换得到关键中间体之一(1R,2S,5S)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-甲酸;接着利用(S)-2-((叔丁氧羰基)氨基)-3-((S)-2-氧代吡咯烷-3-基)丙酸甲酯经过氨解、酸解脱Boc成盐反应后得到另一关键中间体(S)-2-氨基-3-((S)-2-氧代吡咯烷-3-基)丙酰胺盐酸盐;然后将这两个关键中间体在EDCI作用下缩合,然后利用Burgess试剂将酰胺脱水生成氰基,最后以甲叔醚溶剂化合物的形式得到目标产物PF-07321332。
文献报道的方法合成中间体(S)-2-((叔丁氧羰基)氨基)-3-((S)-2-氧代吡咯烷-3-基)丙酸甲酯的反应,要使用强刺激性化合物溴乙腈作为烷基化试剂,储存和放大都具有一定安全隐患;中间体涉及氰基的还原,而硼氢化钠还原的难度较大,反应收率较低,虽然还有专利报道利用钯碳或二氧化铂催化氢化还原氰基,但是收率也比较低,并且使用高负载量的贵金属催化剂又额外提高了生产成本。另外,在后续合成PF-07321332的步骤中,中间体(S)-2-((叔丁氧羰基)氨基)-3-((S)-2-氧代吡咯烷-3-基)丙酸甲酯引入的甲酯官能团仍然需要通过氨解、酰胺脱水等步骤才能转化为氰基,而在两个关键中间体对接后再进行酰胺脱水需要更加严苛的反应条件,再加上Burgess试剂性质活泼价格昂贵,反应收率较低副产物较多,不利于降低成本。
总之,现有用于合成PF-07321332的放大生产步骤较多、工艺放大困难、收率较低,工艺成本较高,仍然需要找到工艺路线简单、成本低廉、适宜工业化生产的合成方法。
发明内容
针对现有技术的不足,本发明的目的是提供一种PF-07321332的合成方法,该合成工艺路线简单、收率较高、成本低廉、适宜工业化生产。
本发明目的之一是提供一种PF-07321332关键中间体化合物5,所述化合物5的结构式为:
本发明目的之二是提供一种PF-07321332关键中间体化合物5的合成方法,采取如下的技术方案:
一种PF-07321332关键中间体化合物5的合成方法,包括如下步骤:
(1)将化合物1在碱作用下与化合物2完成烷基化反应得到化合物3;
(2)将化合物3在催化剂作用下进行氢化反应脱CBZ并一步成环得到化合物4;
(3)将化合物4经过酸解脱Boc并成盐反应得到化合物5;
作为优选,所述步骤(1)中碱选自二异丙基氨基锂、双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂;反应溶剂选自四氢呋喃、2-甲基四氢呋喃或甲苯;反应结束后用氯化铵溶液淬灭反应,水相用乙酸乙酯萃取,浓缩后加正庚烷,冷却析晶,过滤得目标产物。
作为优选,所述步骤(2)中催化剂选自钯碳或氢氧化钯;不加碱或加入碱促进关环反应,碱选自三乙胺、二异丙基乙胺、碳酸钾、碳酸钠、醋酸钠或醋酸钾;反应溶剂选甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯。
作为优选,所述步骤(3)中用到的反应溶剂为甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯、甲苯或水以及这些溶剂任意两种形成的混合溶剂;反应结束后,旋去部分溶剂后,加入乙酸乙酯冷却,过滤得目标产物。
本发明的目的之三是提供一种抗病毒药物PF-07321332的合成方法,采取如下的技术方案:
一种PF-07321332的合成方法,包括将化合物5在碱和缩合剂的作用下与化合物9完成缩合反应得到PF-07321332化合物10;
作为优选,所述缩合反应中选用缩合剂为羰基二咪唑(CDI)、氯甲酸异丁酯(ICBF)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)组合、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/2-羟基吡啶-N-氧化物组合、O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳二亚胺(DCC)或N,N'-二异丙基碳二亚胺(DIC);碱选自二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、三乙烯二胺或N-甲基吗啉;反应溶剂选自N,N-二甲基甲酰胺、二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环。
进一步地,上述化合物9的合成方法,包括如下步骤:
(1)将化合物6在碱和缩合剂的作用下与化合物7完成缩合反应得到化合物8;
(2)将化合物8在碱的作用下水解得到化合物9;
作为优选,所述步骤(1)的缩合反应选用缩合剂为羰基二咪唑(CDI)、氯甲酸异丁酯(ICBF)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)组合、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/2-羟基吡啶-N-氧化物组合、O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳二亚胺(DCC)或N,N'-二异丙基碳二亚胺(DIC);碱选自二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、三乙烯二胺或N-甲基吗啉;反应溶剂选自N,N-二甲基甲酰胺、二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环。
作为优选,所述步骤(2)的水解反应溶剂选自甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、二氯甲烷或甲苯;碱选自氢氧化钠、氢氧化锂或氢氧化钾。
本发明的目的之四是提供一种抗病毒药物PF-07321332的合成方法,采取如下的技术方案:
一种抗病毒药物PF-07321332的合成方法,包括如下步骤:
(1)以(S)-4-((叔丁氧羰基)氨基)-4-氰基丁酸甲酯化合物1为起始原料,利用强碱拔氢后与1,2,3-噁噻唑烷-3-甲酸苄酯2,2-二氧化物化合物2完成烷基化反应得到化合物3;
(2)所得化合物3经过一锅法氢化并环合得到化合物4,化合物4通过盐酸解脱Boc成盐反应得到化合物5;
(3)化合物6与N-三氟乙酰基叔亮氨酸化合物7经缩合后再水解,得到化合物9;
(4)将化合物5和化合物9在缩合剂作用下缩合得到目标产物PF-07321332;
本发明关于PF-07321332的合成方法中关键中间体化合物5具有易于重结晶精制,纯度较高,并且性质稳定利于保存的特点,可以十分方便地应用于合成PF-07321332后续工艺中;整条合成路线工艺简单、成本低廉,适宜工业化生产。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1
三口烧瓶中加入化合物1(24.23g,100mmol)和四氢呋喃(121mL),搅拌溶解,并真空切换氮气3次并冷至-55~-50℃,氮气保护下将二异丙基氨基锂(2.0M,105mL)四氢呋喃/正庚烷溶液缓慢滴入反应瓶中,滴完后保温反应1小时,缓慢将化合物2的溶液(28.30g,110mmol,溶于60mL四氢呋喃)滴入反应瓶中,缓慢升温至室温反应。反应结束加入饱和氯化铵溶液淬灭反应(242mL)淬灭反应,水相用乙酸乙酯(121mL)萃取3次,合并有机相饱和水洗1次(121mL),浓缩后缓慢加正庚烷194mL,缓慢冷却至-5~0℃析晶,过滤,冷的正庚烷洗涤,过滤,得中间体化合物3(36.01g,收率85.8%)。
MS(ESI)[M+H]+=420.1
1H NMR(400MHz,CDCl3)δ7.38-7.45(m,4H),7.30-7.38(m,1H),5.04-5.21(m,2H),5.12(s,2H),4.34-4.45(m,1H),3.65(s,3H),3.25-3.40(m,1H),3.10-3.18(m,1H),2.45-2.52(m,1H),1.75-2.02(m,4H),1.39(s,9H)。
实施例1中的二异丙基氨基锂可用双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂代替;四氢呋喃可用2-甲基四氢呋喃或甲苯代替。
实施例2
氢化瓶中加入化合物3(41.95g,100mmol)和无水甲醇(270mL),加入3%钯碳(0.42g干计),加入醋酸钾(9.81g,100mmol),水泵抽真空切换氢气3次,40~45℃常压加氢反应10~16小时。反应结束过滤除去钯碳和盐,浓缩蒸出部分溶剂,加热至55~60℃,缓慢加入水(270mL),缓慢冷至0~10℃打浆1小时,过滤,得化合物4(22.87g,收率90.3%)。
MS(ESI)[M+Na]+=276.2
1H NMR(400MHz,CDCl3)δ6.56(s,1H),6.32(br,0.18H),6.00(br,0.82H),4.61-4.79(m,1H),3.34-3.43(m,2H),2.47-2.57(m,1H),2.39-2.47(m,1H),2.26-2.34(m,1H),1.90-1.97(m,1H),1.82-1.90(m,1H),1.48(s,9H)。
实施例2中,钯碳可用氢氧化钯代替;醋酸钾可不加,或者醋酸钾用三乙胺、二异丙基乙胺、碳酸钾、碳酸钠或醋酸钠代替;甲醇可用乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯代替。
实施例3
三口烧瓶中加入化合物4(25.33g,100mmol)和无水甲醇(127mL),加入盐酸溶液(7N,30mL),加热至55~60℃反应4~6小时。旋去部分溶剂后,缓慢加入乙酸乙酯(200mL),缓慢冷却至0~5℃,过滤,收集滤饼真空干燥得目标化合物5(17.56g,收率92.6%)。
MS(ESI)m/z(游离碱)=154.2[M+H]+
1H NMR(400MHz,MeOD)δ4.73(t,J=6.0Hz,1H),3.28-3.34(m,2H),2.66-2.74(m,1H),2.33-2.41(m 1H),2.11-2.16m(2H),1.79-1.88(m,1H)。
实施例3中,甲醇可用乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯、甲苯或水以及这些溶剂任意两种形成的混合溶剂。
实施例4
三口烧瓶加入化合物6(20.57g,100mmol),化合物7(10.51g,120mmol),加入N,N-二甲基甲酰胺103mL搅拌溶解,加入缩合试剂O-苯并三氮唑-四甲基脲六氟磷酸盐HBTU(45.51g,120mmol)。室温缓慢滴加N-甲基吗啉(20.23g,200mmol),滴完后室温反应4-6小时。反应结束后加入206mL乙酸乙酯和206mL0.5N稀盐酸,分液,水相再用103mL乙酸乙酯萃取2次,合并有机相先后再用103mL水洗,103mL 5%碳酸氢钠洗,103mL水洗,干燥,浓缩,加入甲醇41mL,50~55℃缓慢滴入水206mL,缓慢冷却析晶,过滤,收集滤饼干燥得化合物式8(33.98g,收率89.8%)。
实施例4中,缩合剂O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)可用羰基二咪唑(CDI)、氯甲酸异丁酯(ICBF)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)组合、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/2-羟基吡啶-N-氧化物组合、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳二亚胺(DCC)或N,N'-二异丙基碳二亚胺(DIC)代替;N-甲基吗啉可用二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯DBU或三乙烯二胺代替;溶剂N,N-二甲基甲酰胺可用二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环代替。
实施例5
三口烧瓶中加入化合物8(37.84g,100mmol)和四氢呋喃(189mL),加入氢氧化钠溶液(20%,60mL),室温反应2~3小时。旋去部分溶剂后,加入甲基叔丁醚(90mL),分液,收集水相缓慢冷却至0~5℃,缓慢滴入稀盐酸(10%,150mL),0~5℃打浆30min,过滤,收集滤饼真空干燥得目标化合物9(34.10g,收率93.6%)。
实施例5中,溶剂四氢呋喃可用甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、2-甲基四氢呋喃、1,4-二氧六环、二氯甲烷或甲苯代替;氢氧化钠可用氢氧化锂或氢氧化钾代替。
实施例6
三口烧瓶加入化合物5(18.96g,100mmol),化合物9(38.26g,105mmol),加入N,N-二甲基甲酰胺95mL搅拌溶解,加入缩合试剂EDCI(23.0g,120mmol)和HOBt(16.22g,120mmol)。冷却至0~10℃缓慢滴加二异丙基乙胺DIPEA(38.77g,300mmol),滴完后升温至室温反应4-6小时。反应结束后加入190mL乙酸乙酯和190mL 0.5N稀盐酸,分液,水相再用95mL乙酸乙酯萃取2次,合并有机相先后再用95mL水洗,95mL 5%碳酸氢钠洗,95mL水洗,干燥,浓缩除部分乙酸乙酯,加热至50~55℃,缓慢加入正庚烷190mL,缓慢冷却至0~5℃析晶,过滤,收集滤饼真空干燥得目标化合物10(44.46g,收率89.0%)。
实施例6中,1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI和1-羟基苯并三唑HOBT的组合可用羰基二咪唑CDI、氯甲酸异丁酯ICBF、、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI/2-羟基吡啶-N-氧化物组合、O-苯并三氮唑-四甲基脲六氟磷酸盐HBTU、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU、二环己基碳二亚胺DCC或N,N'-二异丙基碳二亚胺DIC代替;二异丙基乙胺可用三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯DBU、三乙烯二胺或N-甲基吗啉代替;N,N-二甲基甲酰胺可用二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环代替。
Claims (10)
3.根据权利要求2所述的化合物5的合成方法,其特征在于所述步骤(1)中碱选自二异丙基氨基锂、双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂;反应溶剂选自四氢呋喃、2-甲基四氢呋喃或甲苯。
4.根据权利要求2所述的化合物5的合成方法,其特征在于所述步骤(2)中催化剂选自钯碳或氢氧化钯;不加碱或加入碱促进关环反应,碱选自三乙胺、二异丙基乙胺、碳酸钾、碳酸钠、醋酸钠或醋酸钾;反应溶剂选甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯;所述步骤(3)中用到的反应溶剂选自甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯、甲苯或水以及这些溶剂任意两种形成的混合溶剂。
6.根据权利要求5所述的一种抗病毒药物PF-07321332的合成方法,其特征在于所述缩合反应中选用的缩合剂选自羰基二咪唑CDI、氯甲酸异丁酯ICBF、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI/1-羟基苯并三唑HOBT组合、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI/2-羟基吡啶-N-氧化物组合、O-苯并三氮唑-四甲基脲六氟磷酸盐HBTU、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU、二环己基碳二亚胺DCC或N,N'-二异丙基碳二亚胺DIC;碱选自二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯DBU、三乙烯二胺或N-甲基吗啉;反应溶剂选自N,N-二甲基甲酰胺、二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环。
8.根据权利要求7所述的一种抗病毒药物PF-07321332的合成方法,其特征在于所述步骤(1)的缩合反应选用缩合剂选自羰基二咪唑CDI、氯甲酸异丁酯ICBF、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI/1-羟基苯并三唑HOBT组合、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI/2-羟基吡啶-N-氧化物组合、O-苯并三氮唑-四甲基脲六氟磷酸盐HBTU、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU、二环己基碳二亚胺DCC或N,N'-二异丙基碳二亚胺DIC;碱选自二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、三乙烯二胺或N-甲基吗啉;反应溶剂选自N,N-二甲基甲酰胺、二甲基乙酰胺、二氯甲烷,乙腈或1,4-二氧六环。
9.根据权利要求7所述的一种抗病毒药物PF-07321332的合成方法,其特征在于所述步骤(2)的水解反应溶剂选自甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、二氯甲烷或甲苯;碱选自氢氧化钠、氢氧化锂或氢氧化钾。
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