TWI628185B - 一種製備曲前列尼爾的中間體、其製備方法以及藉由其製備曲前列尼爾的方法 - Google Patents
一種製備曲前列尼爾的中間體、其製備方法以及藉由其製備曲前列尼爾的方法 Download PDFInfo
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- TWI628185B TWI628185B TW102142937A TW102142937A TWI628185B TW I628185 B TWI628185 B TW I628185B TW 102142937 A TW102142937 A TW 102142937A TW 102142937 A TW102142937 A TW 102142937A TW I628185 B TWI628185 B TW I628185B
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- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title claims abstract description 38
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- -1 wherein P 1 Chemical compound 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 230000009471 action Effects 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 229910052736 halogen Inorganic materials 0.000 claims description 5
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 239000012069 chiral reagent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 150000003752 zinc compounds Chemical class 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 3
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- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 150000002900 organolithium compounds Chemical class 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
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- MQIKJSYMMJWAMP-UHFFFAOYSA-N dicobalt octacarbonyl Chemical group [Co+2].[Co+2].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] MQIKJSYMMJWAMP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 8
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
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- 238000006606 decarbonylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940001440 flolan Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003174 prostaglandin I2 derivatives Chemical class 0.000 description 1
- 230000008704 pulmonary vasodilation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 229940118867 remodulin Drugs 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- DCGLONGLPGISNX-UHFFFAOYSA-N trimethyl(prop-1-ynyl)silane Chemical compound CC#C[Si](C)(C)C DCGLONGLPGISNX-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本發明涉及一種製備曲前列尼爾的中間體、其製備方法以及藉由其製備曲前列尼爾的方法。具體地,本發明涉及用於製備曲前列尼爾(treprostinil,如式(I)所示)的式(VI)所示化合物,其製備方法,以及藉由該化合物製備曲前列尼爾的方法。該製備曲前列尼爾的方法為:藉由如式(VI)所示的化合物的還原和羥基脫保護得到如式(III)所示的化合物,如式(III)所示的化合物與氯乙腈反應後水解製得如式(I)所示的曲前列尼爾。該方法操作簡便,合成收率高,適於大規模生產。
Description
本發明涉及一種製備曲前列尼爾的中間體、其製備方法以及藉由其製備曲前列尼爾的方法。
肺動脈高壓是由各種原因引起的靜息狀態下右心導管測得的肺動脈平均壓大於或等於25mmHg的一組臨床病理生理綜合症。作為一種臨床常見的心血管疾病,肺動脈高壓藉由肺小動脈的血管痙攣,內膜增生和重構導致肺血管阻力增加,最終可導致右心衰竭,甚至死亡。
作為治療肺動脈高壓的標靶藥物,前列環素(PGI2)可以促進肺血管舒張,抑制血小板聚集和血栓形成,刺激血栓溶解,抑制肺血管重塑,從而降低肺動脈壓力和肺血管阻力,對肺動脈高壓具有顯著療效。2003年,以PGI2的鈉鹽為主要成分的依前列醇(Flolan)是美國食物藥品管理局(FDA)批准的第一種用於治療肺動脈高壓的前列環素類藥物。但是由於PGI2在25攝氏度、pH值7.6的環境中半衰期約為10分鐘,依前列醇在人體循環中有
效的作用時間為3-5分鐘,因此這種治療需要靜脈持續給藥,並且輸注前要低溫避光保存。這在一定程度上限制了依前列醇的廣泛應用,同時也促進了對具有更好穩定性和生物活性的PGI2衍生物的探索。考慮到PGI2結構中的烯基醚在弱酸環境中的水解可能是導致PGI2不穩定性的主要原因,科學研究者藉由修飾或者改變烯基醚來尋找化學性質穩定的替代衍生物。藉由用酚基醚的官能團來替代烯基醚,人們發現曲前列尼爾(Treprostinil,化學結構如式(I)所示)是治療肺動脈高壓的合適替代品。曲前列尼爾具有很好的穩定性,在循環中的半衰期達到4個小時,在25攝氏度條件下可保存五年不會分解;並且藥物在藉由肺部時也不會分解。同時曲前列尼爾具有很好的生物活性,在治療肺動脈高壓,外周血管疾病,缺血性病變,治療改善腎功能,神經性足部潰瘍,哮喘,甚至治療癌症方面都有很好的療效。特別在治療肺動脈高壓方面,以曲前列尼爾的鈉鹽為主要成分的新藥Remodulin在2004年獲得美國食物藥品管理局(FDA)批准上市。
由於曲前列尼爾分子具有稠環結構並且具有多個手性中心,其合成過程比較複雜。Aristoff等人首次報導了曲前列尼爾的合成方法(Tetrahedron Lett.1982,23,2067-2070),其合成策略是首先合成C環(五員環),然後藉由1,4-加成反應引入A環(芳香環),最後Friedel-Crafts反應閉環形成B環(六員環)(如方案1所
示)。多步合成得到化合物1,烯烴化反應將化合物1中的酮轉化為烯烴2;硼氫化反應從立體阻礙較小的正面進攻得到化合物3,同時構建了C環上的手性中心;Friedel-Crafts反應閉環構建了B環,從而最終成功合成曲前列尼爾的主要骨架。此手性合成路線共需要36步反應,過於冗長,不利於大規模合成。
隨後,Aristoff等人又開發了另外一種合成方法(J.Am.Chem.Soc.1985,107,7967-7974),即藉由易購原料5來引入A環和B環,再用Wadsworth-Emmons-Wittig反應來合成C環(如方案2所示)。藉由化合物5的卞位羰基化得到化合物6;在羰基鄰位上烯丙基化,然後卞位脫羰基得到消旋化合物7;烯烴氧化從而得到內酯8;Wadsworth-Emmons-Wittig反應最後形成C環(無手性),氫化反應和硼氫化鈉在鹼性條件下的還原反應確定了C環上的另兩個手性中心,從而構建曲前列尼爾的主要骨架。此合成路線共十四步反應,合成相對簡潔,但得到的是消旋的曲前列尼爾,由於沒有找到合適的手性拆分試劑,故無法大量合成光學純
的曲前列尼爾。
在Aristoff合成方法的基礎上,Fuchs等人報導了曲前列尼爾合成方法(Bioorg.Med.Chem.Lett.1991,1,79-82),其合成策略為:首先合成C環,然後藉由1,4-加成反應引入A環,再一次藉由1,4-加成反應閉環形成B環(如方案3所示)。多步合成得到手性化合物13,與銅試劑12的1,4-加成反應引入A環;脫保護形成卞基氯15;再一次1,4-加成反應閉環形成B環得到化合物16;最後脫苯磺醯基可以成功構建曲前列尼爾的主要骨架(2:1的順反異構比)。此手性合成路線相對簡短,但是脫苯磺醯基的反應過程中,C環上的手性中心會消除,僅能得到2:1的順反異構比,由於沒有發現經濟有效的分離手段,也無法大量合成光學純的曲前列尼爾。
Moriarty等人報導了利用Pauson-Khand環化反應合成曲前列尼爾的方法(J.Org.Chem.2004,69,1890-1902),合成策略為:藉由易購原料來引入A環,然後用Pauson-Khand環化反應同時構建B環和C環(如方案4所示)。藉由對多步合成得到的化合物18的CBS不對稱還原構建一手性中心,得到環化反應前體化合物19;Pauson-Khand環化反應得到B環和C環,並且在已有手性中心的作用下構建了C環上的另一手性中心;氫化還原脫掉了卞位的手性控制基團,同時還原了不飽和烯酮得到順式化合物21(羰基的鄰位4:1的正反異構化);硼氫化鈉在鹼性條件下的還原反應既還原了羰基又確定了其鄰位的手性中心,從而得到曲前列
尼爾的主要骨架。此手性合成路線有很好手性控制,但需要用過量的昂貴的手性CBS試劑和八羰基二鈷,合成成本較高。
由於曲前列尼爾在醫學上的重要意義和曲前列尼爾分子的合成複雜性,迫切需要開發更多適用於大規模生產的有效方法。
本發明提供了一種如式(VI)所示的化合物,該化合物可用於製備曲前列尼爾,
其中,P1,P2和P3各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基,P3為氫或-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、或取代或非取代的C6-10芳基。
本發明另一方面提供了化合物(VI)的製備方法,其可以採用下列合成路線,
其中,P1,P2和P3各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基,P3為氫或-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、或取代或非取代的C6-10芳基。
化合物(VI)可以藉由化合物(VII)與八羰基二鈷(Co2(CO)8)反應得到(Pauson-Khand反應,參考文獻:J.Org.Chem.2004,69,1890);也可以藉由化合物(VII)在氯化鈀催化作用下與一氧化碳反應得到(鈀催化Pauson-Khand反應,參考文獻:J.Org.Chem.2009,74,1657),使用鈀催化Pauson-Khand反應可以避免使用昂貴的危險試劑八羰基二鈷,從而使得合成過程更加安全,並且可以降低合成成本。
在本發明的一個較佳的實施方案中,式(VI)和(VII)中,P1較佳為THP,P2較佳為苄基,P3為TBS。
本發明還提供了一條以化合物(VI)為起始原料的合成曲前列尼爾的新方法,即化合物(VI)經過鈀碳催化加氫還原得到化合物(V),化合物(V)經過硼氫化鈉還原和脫除保護基後得到化合物(III),化合物(III)與氯乙腈反應然後水解製備曲前列尼爾,
其中,P1,P2和P3各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基,P3為氫或-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、或取代或非取代的C6-10芳基。
化合物(VII)藉由化合物(VIII)的羥基保護得到,
其中,P1、P2各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基。
本發明再一方面提供了一種如式(VIII)所示的化合物及其製備方法,如式(VIII)所示的化合物可用於製備曲前列尼爾,
其中,P1、P2各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基。
在本發明提供的化合物(VIII)的製備方法中,其可以採用下述方法:由化合物(IX)在手性化合物和有機鋅化合物的作用下與化合物(X)反應得到化合物(VIII),
其中,P1、P2各自獨立地分別為氫或羥基保護基;較佳P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基。
該有機鋅化合物為ZnR’2,其中R’為取代或非取代的C1-6烷基,較佳為甲基。
該手性化合物為如式XIII所示的化合物,
其中,Ar1和Ar2為取代或非取代的芳基,該芳基選自苯基或萘基,其視需要被1至5個選自鹵素、三氟甲基、甲氧基、胺基、氰基、硝基、苯基或C1-6烷基的取代基取代;R為取代或非取代的C1-6烷基,較佳R為甲基。
在本發明的一個較佳的實施方案中,式(X)和(VIII)中,P1為THP;式(X)和(VIII)中,P2為苄基;式XIII中,Ar1和Ar2
為苯基,R為甲基,所用的有機鋅試劑為二甲基鋅。
化合物(IX)可參照文獻合成:J.Am.Chem.Soc.1985,107,1421。
化合物XIII可參照文獻合成:Tetrahedron:Asymmetry 2005,16,1953。
藉由該方法,可以從由化合物(IX)和(X)一步合成得到手性中間體(VIII),從而可以避免Moritary合成方法中的多步反應(即:先加成,再氧化,然後CBS不對稱還原),避免使用昂貴的CBS試劑。因此,該方法提高了合成效率,降低了合成成本。
化合物(VIII)還可採用下列合成方法,
該方法包括如下步驟:1)化合物(X)在鹼的作用下與化合物(IX)反應得到化合物(XIV),2)化合物(XIV)經過氧化得到化合物(XV),3)化合物(XV)在手性試劑的作用下不對稱還原得到化合物(VIII)。
步驟1)中的鹼為有機鋰化合物,較佳為正丁基鋰;步驟2)中氧化反應可以是Swern氧化或藉由氯鉻酸吡啶鹽氧化;步驟3)中的手性試劑為(R)-CBS試劑。
使用CBS試劑控制不對稱還原是把酮還原成手性醇
的常用方法,可參見文獻:J.Am.Chem.Soc.1987,109,5551。
本發明還提供了一種如式(X)所示的化合物及其製備方法,如式(X)所示的化合物可用於製備曲前列尼爾,
其中,P1為氫或羥基保護基,較佳P1為氫、取代或非取代的C1-10烷基。
化合物(X)的製備方法可採用下列合成方法,
其中,P1為氫或羥基保護基,較佳P1為氫、取代或非取代的C1-10烷基;R4為-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、取代或非取代的C6-10芳基。
該方法包括如下步驟:1)化合物(XVI)在鹼的作用下與化合物(XII)反應得到化合物(XI),2)化合物(XI)在鹼的作用下得到化合物(X)。
步驟1)中的鹼為有機鋰化合物,較佳為正丁基鋰;步驟2)中的鹼為無機鹼,較佳為氫氧化鈉。
化合物(XII)可參照文獻合成:Tetrahedron,2010,66,2351.
本發明還提供了一種如式(XI)所示的化合物,
其中,P1和R4如化合物(X)中定義。
本發明的曲前列尼爾的製備方法具有操作安全,合成效率高,合成成本較低,適合工業化生產等特點,具有顯著的社會效益和經濟效益。
本發明所使用的術語,除有相反的表述外,具有如下的含義:
“烷基”指飽和的脂族烴基團,包括1至10個碳原子的直鏈和支鏈基團,較佳包括1至6個碳原子。非限制性實施例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上被取代,較佳為一個或多個以下基團,獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基。
“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至10個碳原子,較佳為C3-8環烷基,更佳為C3-6環烷基,最佳為5員或6員環烷基。單環環烷基的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等。多環環烷基包括
螺環、稠環和橋環的環烷基。環烷基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個以下基團,獨立地選自烷基、烷氧基、鹵素、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基。
“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團,較佳為6至10員,更較佳苯基和萘基。芳基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個以下基團,獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。
“羥基保護基”是本領域已知的適當的用於羥基保護的基團,參見文獻(“Protective Groups in Organic Synthesis”,5Th Ed.T.W.Greene & P.G.M.Wuts)中的羥基保護基團。作為示例,較佳地,該羥基保護基可以是(C1-10烷基或芳基)3矽烷基,例如:三乙基矽基,三異丙基矽基,第三丁基二甲基矽基,第三丁基二苯基矽基等;可以是C1-10烷基或取代烷基,例如:甲基,第三丁基,烯丙基,苄基,甲氧基甲基,乙氧基乙基,2-四氫吡喃基(THP)等;可以是(C1-10烷基或芳香基)醯基,例如:甲醯基,乙醯基,苯甲醯基等;可以是(C1-6烷基或C6-10芳基)磺醯基;也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。
以下將結合具體實施例詳細地說明本發明,以使得本專業技術人員更全面地理解本發明,具體實施例僅用於說明本發明的技術方案,並不以任何方式限定本發明。
下表為實施例中所涉及的化合物的結構式
氮氣保護下,於0℃向1-(三甲基矽基)丙炔(XVIa,購自上海瑞一醫藥科技有限公司)(74克)的無水四氫呋喃(200毫升)溶液中滴加正丁基鋰(250毫升,2.5M己烷溶液)。在0℃攪拌3小時後,滴加化合物XIIa(65.8克,參照文獻合成:Tetrahedron 2010,66,2351)的無水四氫呋喃(100毫升)溶液,將反應混合物緩慢升溫至20℃,並在20℃攪拌12小時。用飽和氯化銨水溶液淬滅反應,加入乙酸乙酯和水分層,收集有機相。將有機相濃縮得到黃色油狀粗產物XIa,不純化直接用於下一步反應。
氮氣保護下,於20℃向粗產物XIa的乙醇溶液中緩慢加入氫氧化鈉(39.2克)。20℃攪拌12小時後,將反應混合物濃縮。藉由管柱層析分離得到化合物Xa(59克,兩步收率88%)。
Xa:1H NMR(400MHz,CDCl3)δ 5.80(ddd,J=17.1,10.1,6.9Hz,1H),4.98(dd,J=22.2,13.1Hz,2H),4.65(dd,J=6.9,4.0Hz,1H),3.90(dd,J=10.7,6.2Hz,1H),3.73(dd,J=10.3,4.3Hz,1H),3.50(dd,J=11.0,5.6Hz,1H),2.33(dt,J=7.5,4.0Hz,1H),2.24(td,J=7.3,2.5Hz,1H),2.05(dd,J=13.5,6.8Hz,2H),1.93(dt,J=5.3,2.6Hz,1H),1.82-1.30(m,12H)。
氮氣保護下,於20℃向化合物Xa(47.3克)的甲苯(200毫升)溶液中加二甲基鋅(200毫升,1.0M)的甲苯溶液,然後加入化合物XIIIa(3.80克,參照文獻合成:Tetrahedron:Asymmetry 2005,16,1953)的甲苯溶液。該混合物冷卻至-10℃,滴加化合物IXa(12.6克,參照文獻合成:J.Am.Chem.Soc.1985,107,1421)的甲苯溶液。在-10℃攪拌6小時後,用飽和氯化銨水溶液淬滅反應,加入乙酸乙酯和水分層,收集有機相。將有機相濃縮,藉由管柱層析分離得到化合物VIIIa(23.2克,收率95%)。
VIIIa:1H NMR(400MHz,CDCl3)δ 7.46-7.16(m,7H),6.91(d,J=8.2Hz,1H),6.05-5.95(m,1H),5.87-5.71(m,1H),5.64(s,1H),5.08(s,2H),5.05-4.89(m,4H),4.70-4.60(m,1H),3.90-3.42(m,5H),2.50-1.27(m,16H)。
步驟一:
氮氣保護下,於-78℃向化合物Xa(39克)的無水四氫呋喃(150毫升)溶液中滴加正丁基鋰(61毫升,2.5M己烷溶液)。在-78℃攪拌1小時後,滴加化合物IXa(30克,參照文獻合成:J.Am.Chem.Soc.1985,107,1421.)的無水四氫呋喃(100毫升)溶液。在-78℃攪拌1小時後,用水淬滅,加入乙酸乙酯和水分層,收集有機相。將有機相濃縮,藉由管柱層析分離得到化合物XIVa(53.0克,收率91%)。
XIVa:1H NMR(400MHz,CDCl3)δ 7.46-7.16(m,7H),6.91(d,J=8.2Hz,1H),6.05-5.95(m,1H),5.87-5.71(m,1H),5.64(s,1H),5.08
(s,2H),5.05-4.89(m,4H),4.70-4.60(m,1H),3.90-3.42(m,5H),2.50-1.27(m,16H)。
步驟二:
氮氣保護下,於0℃向化合物XIVa(45.4克)的無水二氯甲烷(200毫升)溶液中加入氯鉻酸吡啶鹽(40克)。將反應混合物緩慢升溫至20℃並攪拌2小時。反應混合物藉由矽藻土過濾。將濾液濃縮,藉由管柱層析分離得到化合物XVa(38.3克,收率85%)。
XVa:1H NMR(400MHz,CDCl3)δ 7.72(dd,J=11.3,7.8Hz,1H),7.45-7.26(m,5H),7.22(d,J=7.5Hz,1H),7.07(dd,J=8.0,1.9Hz,1H),6.06-5.90(m,1H),5.80-5.70(m,1H),5.08(s,2H),5.03-4.87(m,4H),4.65-4.55(m,1H),3.95-3.78(m,3H),3.76-3.66(m,1H),3.52-3.38(m,1H),2.60-1.26(m,16H)。
步驟三:
氮氣保護下,將化合物XVa(24.3克)溶於無水四氫呋喃(250毫升),於0℃滴加(R)-2-甲基-CBS-噁唑硼烷(55毫升,1M甲苯溶液)。將反應混合物降溫至-30℃,加入硼烷-二甲硫醚絡合物(30毫升,2M四氫呋喃溶液)。在-30℃攪拌1小時後,加入甲醇淬滅。加入5%氯化銨水溶液和乙酸乙酯,收集有機相。將有機相濃縮,藉由管柱層析分離得到化合物VIIIa(24.5克,99%)。
VIIIa:1H NMR(400MHz,CDCl3)δ 7.46-7.16(m,7H),6.91(d,J=8.2Hz,1H),6.05-5.95(m,1H),5.87-5.71(m,1H),5.64(s,1H),5.08(s,2H),5.05-4.89(m,4H),4.70-4.60(m,1H),3.90-3.42(m,5H),2.50-1.27(m,16H)。
氮氣保護下,將化合物VIIIa(24.4克)溶於無水二氯甲烷(100毫升)。於20℃依次加入第三丁基二甲基氯矽烷(11.3克)和咪唑(8.5克)。反應混合物在20℃下攪拌2小時後,用冰水淬滅。溶液分層後收集二氯甲烷相。將有機相濃縮,用管柱層析分離得到化合物VIIa(25.1克,收率83%)。
VIIa:1H NMR(400MHz,CDCl3)δ 7.44(d,J=7.5Hz,2H),7.39(t,J=7.4Hz,2H),7.35-7.27(m,2H),7.20(t,J=8.0Hz,1H),6.87(d,J=8.1Hz,1H),6.05-5.91(m,1H),5.85-5.72(m 1H),5.61(s,1H),5.07(s,2H),5.04-4.90(m,4H),4.65-4.55(m,1H),3.90-3.39(m,5H),2.35-1.35(m,16H),0.93(s,9H),0.12(d,J=11.9Hz,6H)。
氮氣保護下,在20℃將化合物VIIa(25.1克)溶於無水二氯甲烷(80毫升),然後加入八羰基二鈷(15.6克)。在20℃攪拌1小時後,濃縮除去二氯甲烷。粗品溶於無水乙腈(80毫升),氮氣保護下反應混合物加熱至回流並攪拌2小時。將反應混合物降溫至20℃,濃縮。粗品藉由管柱層析分離得到化合物VIa(26.0克,收率99%)。
VIa:1H NMR(400MHz,CDCl3)δ 7.44-7.16(m,6H),6.95(d,J=7.2Hz,1H),6.85(d,J=7.6Hz,1H),5.85-5.69(m,1H),5.60-5.45(m,1H),5.06(s,2H),5.01-4.87(m,2H),4.56-4.48(m,1H),3.90-3.30(m,5H),2.69(dd,J=18.8,6.3Hz,1H),2.50-1.25(m,18H),0.82(s,9H),0.13(m,6H)。
在60℃將化合物VIIa(2.9克),氯化鈀(0.1克),四甲基硫脲(0.1克)和氯化鋰(0.2克)的四氫呋喃混合物與一氧化碳反應60小時。將混合物降溫至20℃,加水淬滅反應,加乙酸乙酯萃取,收集有機相。將有機相濃縮,藉由管柱層析分離得到化合物VIa(2.5克,收率85%)。
VIa:1H NMR(400MHz,CDCl3)δ 7.44-7.16(m,6H),6.95(d,J=7.2Hz,1H),6.85(d,J=7.6Hz,1H),5.85-5.69(m,1H),5.60-5.45(m,1H),5.06(s,2H),5.01-4.87(m,2H),4.56-4.48(m,1H),3.90-3.30(m,5H),2.69(dd,J=18.8,6.3Hz,1H),2.50-1.25(m,18 H),0.82(s,9H),0.13(m,6H)。
步驟一:
在20℃,向化合物VIa(26克)的乙醇(170毫升)溶液中依次加入無水碳酸鉀(1.3克)和10%鈀碳(6.5克)。反應混合物在60psi氫氣壓力和20℃下氫化15小時。藉由矽藻土過濾反應混合物。將乙醇濾液濃縮至120毫升得化合物Va乙醇溶液,無需純化直接用於下一步反應。
步驟二:
氮氣保護下,將上述化合物Va的乙醇溶液降溫至-10℃,加入硼氫化鈉(1.55克),在-10℃繼續攪拌3小時。反應完畢,用飽和氯化銨水溶液淬滅,加入二氯甲烷分層。收集有機相,有機相濃縮得到黃色油狀粗產物IVa,粗產物溶於甲醇後,直接用於下一步。
步驟三:
氮氣保護下,將上述化合物IVa的甲醇溶液降溫至0℃,加入對甲苯磺酸(780毫克)。反應混合物升溫至20℃並攪拌2小時。反應完畢,加入飽和碳酸氫鈉水溶液淬滅,加入二氯甲烷分層。收集有機相,將有機相濃縮,用甲苯再結晶後得到白色固體IIIa(10.5克,3步收率75%)。
IIIa:1H NMR(400MHz,CD3OD)δ 6.90(t,J=7.7Hz,IH),6.62(d,J=7.9Hz,2H),3.61(td,J=9.9,6.2Hz,1H),3.52(s,1H),2.73-2.42(m,4H),2.30-2.20(m,1H),2.11-2.01(m,1H),1.99-1.84(m,1H),1.77-1.23(m,13H),1.23-1.14(m,1H),1.14-1.02(m,1H),0.91(t,J=6.6Hz,3H);13C NMR(100MHz,CD3OD)δ 155.2,141.9,127.0,126.1,120.5,113.9,77.7,73.0,52.7,42.4,42.0,38.3,36.1,34.6,34.2,33.2,29.6,26.6,26.5,23.7,14.4。
步驟四:
氮氣保護下,將化合物IIIa(3克)溶於丙酮,依次加入氯乙腈(5.8毫升),四丁基溴化銨(290毫克)和碳酸鉀(12.4克)。反應混合物加熱至70℃,並在70℃反應14小時。反應完畢,將反應混合物冷卻至20℃,經矽藻土過濾,濃縮濾液。管柱層析分離後得到化合物IIa(3.6克,99%)。
IIa:1H NMR(400MHz,CDCl3)δ 7.14(t,J=7.8Hz,1H),6.90(d,J=7.4Hz,1H),6.82(d,J=8.2Hz,1H),4.75(s,2H),3.80-3.70(m,1H),3.80-3.70(m,1H),2.84-2.69(m,2H),2.56-2.44(m,2H),2.31-1.20(m,17H),0.90(t,J=6.7Hz,3H)。
步驟五:
氮氣保護下,將化合物IIa(3.6克)溶於甲醇(80毫
升),緩慢加入30%氫氧化鉀水溶液。將反應混合物加熱至60℃,並在60℃反應3小時,減壓濃縮除去甲醇,得到淺褐色粗產物。
在乙醇-水中結晶得到白色固體純產物曲前列尼爾(3.0克,收率86%)。
I:[α]25 D+45.2(c 10mg/mL,MeOH);1H NMR(400MHz,CD3OD)δ 7.05(t,J=7.9Hz,1H),6.79(d,J=7.4Hz,1H),6.70(d,J=8.3Hz,1H),4.62(s,2H),3.67-3.57(m,1H),3.56-3.46(m,1H),2.80-2.45(m,4H),2.33-2.23(m,1H),2.13-2.02(m,1H),1.97-1.87(m,1H),1.76-1.04(m,15H),0.92(t,J=6.7Hz,3H);13C NMR(100MHz,CD3OD)δ 173.0,156.6,142.2,128.7,127.2,122.5,110.9,77.7,72.9,66.7,52.8,42.3,42.0,38.3,36.1,34.6,34.1,33.2,29.6,26.6,26.5,23.7,14.4。
由於已根據其特殊的實施方案描述了本發明,某些修飾和等價變化對於精通此領域的技術人員是顯而易見的且包括在本發明的範圍內。
Claims (25)
- 一種式(VI)所示的化合物,其中,P1,P2和P3各自獨立地分別為氫或羥基保護基。
- 如申請專利範圍第1項所述的化合物,其中P1為氫、取代或非取代的C1-10烷基,P2為氫、取代或非取代的C1-10烷基,P3為氫或-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、或取代或非取代的C6-10芳基。
- 一種曲前列尼爾的製備方法,其特徵在於包括如下步驟,化合物(VI)經過還原得到化合物(V),化合物(V)經過還原得到化合物(IV),化合物(IV)脫除保護基後得到化合物(III),化合物(III)與氯乙腈反應得到化合物(II),化合物(II)水解得到曲前列尼爾,其中,P1,P2和P3如申請專利範圍第1或2項中所定義。
- 如申請專利範圍第3項所述的製備方法,其中該化合物(VI)還原得到化合物(V)為鈀碳催化加氫還原。
- 如申請專利範圍第3或4項所述的製備方法,其中該化合物(V)還原得到化合物(IV)使用的還原劑為硼氫化鈉。
- 一種如申請專利範圍第1項所述的式(VI)所示的化合物的製備方法,其特徵在於,包括化合物(VII)的閉環反應得到化合物(VI)的步驟,其中,P1、P2、P3如申請專利範圍第1或2項中所定義。
- 如申請專利範圍第6項所述的製備方法,其中該化合物(VII)與八羰基二鈷反應得到化合物(VI),或者化合物(VII)在鈀催化劑作用下與一氧化碳反應得到化合物(VI)。
- 如申請專利範圍第7項所述的製備方法,其中該鈀催化劑為氯化鈀。
- 如申請專利範圍第6項所述的製備方法,其中,該化合物(VII)為式(VIII)所示的化合物,其中,P1、P2如申請專利範圍第1或2項中所定義。
- 一種如申請專利範圍第9項所述的式(VIII)所示的化合物的製備方法,其特徵在於,包括化合物(X)在手性化合物和有機鋅化合物的作用下與化合物(IX)反應得到化合物(VIII)的步驟,其中,P1、P2如申請專利範圍第1或2項中所定義,該手性化合物為如式XIII所示的化合物,其中,Ar1和Ar2為取代或非取代的芳基,該芳基選自苯基或萘基,其視需要被1至5個選自鹵素、三氟甲基、甲氧基、胺基、氰基、硝基、苯基或C1-6烷基的取代基取代;R為取代或非取代的C1-6烷基。
- 如申請專利範圍第10項所述的式(VIII)所示的化合物的製備方法,其中,該芳基為苯基。
- 如申請專利範圍第10項所述的式(VIII)所示的化合物的製備方法,其中,R為甲基。
- 如申請專利範圍第10項所述的製備方法,其中該有機鋅化合物為ZnR’2,其中R’為取代或非取代的C1-6烷基。
- 如申請專利範圍第13項所述的製備方法,其中R’為甲基。
- 一種如申請專利範圍第9項所述的式(VIII)所示的化合物的製備方法,其特徵在於包括如下步驟,1)化合物(X)與化合物(IX)反應得到化合物(XIV),2)化合物(XIV)經過氧化得到化合物(XV),3)化合物(XV)在手性試劑的作用下不對稱還原得到化合物(VIII);其中,P1、P2如申請專利範圍第1或2項中所定義。
- 如申請專利範圍第15項所述的製備方法,其中該步驟1)的反應在鹼的作用下進行。
- 如申請專利範圍第16項所述的製備方法,其中該步驟1)的鹼為有機鋰化合物。
- 如申請專利範圍第17項所述的製備方法,其中該步驟1)的鹼為正丁基鋰。
- 如申請專利範圍第15至18任意一項所述的製備方法,其中該步驟3)中的手性試劑為(R)-CBS試劑。
- 如申請專利範圍第10項所述的式(VIII)所示的化合物的製備方法,其中,式(X)所示的化合物的製備方法,包括如下步驟,1)化合物(XVI)與化合物(XII)反應得到化合物(XI),2)化合物(XI)在鹼的作用下得到化合物(X),其中,P1如申請專利範圍第1或2項中所定義,R4為-SiR1R2R3,其中R1、R2和R3各自分別為C1-10的直鏈或支鏈烷基、C3-10的環烷基、或取代或非取代的C6-10芳基。
- 如申請專利範圍第20項所述的製備方法,其中該步驟1)的反應在鹼的作用下進行。
- 如申請專利範圍第21項所述的製備方法,其中該步驟1)的鹼為有機鋰化合物。
- 如申請專利範圍第22項所述的製備方法,其中該步驟1)的鹼為正丁基鋰。
- 如申請專利範圍第20至23任意一項所述的製備方法,其中該步驟2)中的鹼為無機鹼。
- 如申請專利範圍第24項所述的製備方法,其中該步驟2)中的鹼為氫氧化鈉。
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