CN108727213B - 一种沙库必曲的制备方法 - Google Patents
一种沙库必曲的制备方法 Download PDFInfo
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- CN108727213B CN108727213B CN201810697086.6A CN201810697086A CN108727213B CN 108727213 B CN108727213 B CN 108727213B CN 201810697086 A CN201810697086 A CN 201810697086A CN 108727213 B CN108727213 B CN 108727213B
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- 239000007983 Tris buffer Substances 0.000 description 1
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- WXZIKFXSSPSWSR-UHFFFAOYSA-N [Li]CCCCC Chemical compound [Li]CCCCC WXZIKFXSSPSWSR-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FYXKZNLBZKRYSS-UHFFFAOYSA-N benzene-1,2-dicarbonyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C(Cl)=O FYXKZNLBZKRYSS-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229960000359 chromic chloride Drugs 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- XZQOHYZUWTWZBL-UHFFFAOYSA-L chromium(ii) bromide Chemical compound [Cr+2].[Br-].[Br-] XZQOHYZUWTWZBL-UHFFFAOYSA-L 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- UZDWIWGMKWZEPE-UHFFFAOYSA-K chromium(iii) bromide Chemical compound [Cr+3].[Br-].[Br-].[Br-] UZDWIWGMKWZEPE-UHFFFAOYSA-K 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- SZAVVKVUMPLRRS-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].C[CH-]C SZAVVKVUMPLRRS-UHFFFAOYSA-N 0.000 description 1
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000692 natriuretic peptide Substances 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- WKGDNXBDNLZSKC-UHFFFAOYSA-N oxido(phenyl)phosphanium Chemical compound O=[PH2]c1ccccc1 WKGDNXBDNLZSKC-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000005049 silicon tetrachloride Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
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Abstract
本发明公开了一种沙库必曲的制备方法,包括如下合成路线中的步骤a~e:
Description
技术领域
本发明涉及一种沙库必曲的制备方法,属于化学药物合成技术领域。
背景技术
心衰是一种危及生命的致衰性疾病,患者的心脏泵出的血液不足以供给全身,而导致呼吸困难、乏力和体液潴留等症状的缓慢出现,严重时可能影响生活质量。由诺华(Novartis)公司首创的Entresto(又名LCZ696),结合了血管紧张素IIAT1受体拮抗剂缬沙坦(Diovan)和脑啡肽酶(Neprilysin)受体抑制剂沙库必曲(sacubitril,又称AHU-377),可增强机体对抗心衰的自然防御力,同时可增加利钠肽和其他内源性血管活性肽的水平,并抑制肾素-血管紧张素-醛固酮系统(RAAS),被认为能够减少衰竭心脏的应变。鉴于该药物在治疗心力衰竭方面表现出更高的安全性和更好的疗效,该药物于2015年7月被FDA批准上市,商品名为Entresto(以前叫LCZ696)。
沙库必曲(sacubitril,又称AHU-377),其化学名为4-[[(1S,3R)-1-([1,1'-联苯基]-4-基甲基)-4-乙氧基-3-甲基-4-氧代丁基]氨基]-4氧代丁酸(英文名为4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid),其结构式如下:
目前关于沙库必曲的合成报道,主要有以下几种合成路线:
1)诺华公司公开的原研药路线:
该路线以3-联苯基-3-氨基-丙醇为起始原料,经过氨基的保护反应、醇的氧化反应、Wittig反应、不对称氢化反应、氨基脱除保护基反应、酰胺化反应一共六步反应得到目标化合物;并且该路线中的起始原料没有工业化,需要从其他原料合成得到,所以该路线起始原料较为昂贵,另外,该路线中的不对称氢化采用了金属钌化合物作为反应催化剂,成本高昂,不适用工业化生产。
2)世界专利WO2007106708和WO2008083967公开的合成路线:
该路线以L-酪氨酸为起始原料,通过氨基和羧基的保护反应、酚羟基的活化反应、Suzuki偶联反应、酰胺酯交换反应、还原反应、Wittig反应、双键加成反应、脱除氨基保护反应、酰胺化反应一共10步反应得到目标化合物;该路线中采用了较为昂贵的起始原料L-酪氨酸,且活化酚羟基的反应中,使用了价格昂贵的三氟甲磺酸酯,酰胺酯交换反应和还原反应的产率较低,且使用了较为危险的化学试剂四氢铝锂,反应条件苛刻,也不适用工业化生产。
3)世界专利WO2014198195公开的合成路线:
该路线以L-焦谷氨酸为起始原料,经过羟基保护反应、格氏反应、氨基的保护反应、焦谷氨酸的不对称取代反应、脱除保护反应、Boc第二次保护反应、酰胺键断裂开环反应、脱除氨基保护基反应、酰胺化取代反应一共九步反应的到目标化合物;该条路线中使用了剧毒的化学试剂氰化铜,以及多次的氨基上保护基反应和脱除保护基反应增加了反应的步骤,同时该路线中的不对称取代反应工业化成本较高,不对称取代反应中的催化剂不容易得到,也不适用工业化生产。
4)中国专利CN201510039610.7中公开的合成路线:
该路线(S)-1-(α-氨基苄基)-2-萘芬和2R-甲基4-氧代-丁酸为起始原料,经过环合反应、格氏试剂加成反应、苄基脱除反应、开环反应、酯化反应、酰胺化反应一共六步反应得到目标化合物,该路线的反应步骤虽然较少,但是该路线中的起始原料来源困难,也不适用工业化生产。
发明内容
针对现有技术存在的上述问题,本发明的目的是提供一种沙库必曲的制备方法。
为实现上述发明目的,本发明采用的技术方案如下:
一种沙库必曲的制备方法,包括如下合成路线中的步骤a~e:
其中R为羟基保护基。
作为优选方案,所述的R为三甲基硅基(TMS)、叔丁基二甲基硅基(TBS)或叔丁基二苯基硅基(TBDPS)。
作为优选方案,所述的步骤a是由式1化合物与式2化合物(丁二酰亚胺)在磷试剂和偶氮试剂的存在下发生Mitsunobu反应(又称:光延反应)得到式3化合物。
作为进一步优选方案,步骤a中,所述磷试剂选自三苯基膦、苯基氧膦(例如:三苯基氧膦、4-(二羟苯基)苯基氧膦等)中的任意一种。
作为进一步优选方案,步骤a中,所述偶氮试剂选自偶氮二甲酸二异丙酯(简称:DIAD)、偶氮二甲酸二乙酯(简称:DEAD)中的任意一种。
作为进一步优选方案,步骤a中,式1化合物与式2化合物的摩尔比为1:1~:1:5。
作为进一步优选方案,步骤a中,式1化合物与偶氮试剂的摩尔比为1:1~:1:5。
作为进一步优选方案,步骤a中,反应溶剂选自四氢呋喃、苯、二氯甲烷、甲醇、乙醇、甲苯、N,N-二甲基甲酰胺中的任意一种。
作为优选方案,所述的步骤b是由式3化合物在脱保护试剂的作用下发生脱除羟基保护反应得到式4化合物。
作为进一步优选方案,步骤b中,所述脱保护试剂选自四丁基氟化铵、对甲苯磺酸、无水三氯化铁、三氟甲烷磺酸钪、三氯乙酸中的任意一种。
作为进一步优选方案,步骤b中,式3化合物与脱保护试剂的摩尔比为1:1~1:20。
作为进一步优选方案,步骤b中,反应溶剂选自甲醇、乙醇、二氯甲烷、乙腈、四氢呋喃中的任意一种。
作为进一步优选方案,步骤b中,反应温度为20~100℃。
作为优选方案,所述的步骤c是由式4化合物在氧化剂的作用下发生醇的氧化反应得到式5化合物。
作为进一步优选方案,步骤c中,所述氧化剂选自三氯化钌/高碘酸钠、硝酸、氢氧化钠/高锰酸钾中的任意一种。
作为进一步优选方案,步骤c中,式4化合物与氧化剂的摩尔比为1:1~1:5。
作为进一步优选方案,步骤c中,反应溶剂选自乙腈、水、四氢呋喃中的至少一种。
作为进一步优选方案,步骤c中,反应温度为0~30℃。
作为优选方案,所述的步骤d是由式5化合物与酰基化试剂发生酯化反应得到式6化合物。
作为进一步优选方案,步骤d中,所述酰基化试剂为酰氯化试剂,所述酰氯化试剂选自氯化亚砜、邻苯二甲酰氯、草酰氯、四氯化硅、五氯化磷中的任意一种。
作为进一步优选方案,步骤d中,式5化合物和酰基化试剂的摩尔比为1:1~1:4。
作为进一步优选方案,步骤d中,反应溶剂为乙醇。
作为进一步优选方案,步骤d中,反应温度为0~30℃。
作为优选方案,所述的步骤e是由式6化合物在开环试剂的作用下发生开环反应得到所述沙库必曲。
作为进一步优选方案,步骤e中,所述开环试剂选自氢氧化锂、烷基锂(例如:甲基锂、乙基锂、丙基锂、异丙基锂、正丁基锂、仲丁基锂、叔丁基锂、戊基锂等)中的任意一种。
作为进一步优选方案,步骤e中,式6化合物和开环试剂的摩尔比为1:1~1:5。
作为进一步优选方案,步骤e中,反应溶剂为四氢呋喃、正己烷中的至少一种。
作为进一步优选方案,步骤e中,反应温度为-78~30℃。
作为一种实施方案,式1的制备,包括如下合成路线中的步骤A~G:
其中R为羟基保护基。以廉价易得的式1-1化合物(即联苯-4-乙酸)为起始原料,经过几步常规反应即可制得式1化合物,成本低廉、操作简单、易于工业化生产。
作为优选方案,所述的步骤A是由式1-1化合物(即联苯-4-乙酸)在还原剂的作用下发生还原反应得到式1-2化合物。
作为进一步优选方案,步骤A中,所述的还原剂为硼氢化物(例如:硼氢化钠)或复合氢化物(例如:氢化铝锂)。
作为进一步优选方案,步骤A中,式1-1化合物与还原剂的摩尔比为1:1~1:5。
作为进一步优选方案,步骤A中,反应溶剂为醚类溶剂,例如:四氢呋喃,乙醚等。
作为进一步优选方案,步骤A中,反应温度为0~50℃。
作为优选方案,所述的步骤B是由式1-2化合物在氧化剂的作用下发生醇的氧化反应得到式1-3化合物。
作为进一步优选方案,步骤B中,所述的氧化剂选自铬酸、三氧化硫-吡啶络合物、重铬酸盐-硫酸、二氧化锰、戴斯-马丁氧化剂中的任意一种。
作为进一步优选方案,步骤B中,式1-2化合物与氧化剂的摩尔比为1:1~1:5。
作为进一步优选方案,步骤B中,反应溶剂选自二氯甲烷、三氯甲烷、乙腈、甲苯、二氧六环中的至少一种。
作为进一步优选方案,步骤B中,反应温度为0~50℃。
作为优选方案,所述的步骤C是由式1-3化合物与式1-4化合物发生NHK反应得到式1-5化合物。
作为进一步优选方案,所述的步骤C是由式1-3化合物与式1-4化合物在碱存在下、在铬催化剂、手性配体、协同催化剂、还原剂和添加剂的作用下发生NHK反应得到式1-5化合物。
作为进一步优选方案,步骤C中,所述的碱为有机碱,所述的有机碱选自三乙胺、1,8-双二甲氨基萘(PS)、N,N-二异丙基乙胺(DIPEA)中的任意一种。
作为进一步优选方案,步骤C中,所述的铬催化剂选自二氯化铬、三氯化铬、二溴化铬、三溴化铬中的任意一种,所述的手性配体为双噁唑啉配体,所述的协同催化剂为酞氰钴(CoPc)、、三(2,2,6,6-四甲基-3,5-庚二酮酸)铁(Fe(TMHD)3)中的任意一种。
作为进一步优选方案,步骤C中,所述的还原剂选自锰粉、铁粉、锌粉中的任意一种。
作为进一步优选方案,步骤C中,所述的添加剂为卤化锂(例如:氯化锂、氟化锂、溴化锂、碘化锂等)和二氯二茂锆。
作为进一步优选方案,步骤C中,式1-3化合物与式1-4化合物的摩尔比为1:1~1:5。
作为进一步优选方案,步骤C中,反应溶剂选自乙腈、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、N,N-二甲基甲酰胺、二甲基亚砜、1,3-二甲基-2-咪唑啉酮、1,2-二氯乙烷、二甲基乙酰胺中的任意一种。
作为进一步优选方案,步骤C中,反应温度为0~40℃。
作为优选方案,所述的步骤D是由式1-5化合物在酸性条件下发生分子内关环反应得到式1-6化合物。
作为进一步优选方案,步骤D中,使用的酸选自甲酸、乙酸、高氯酸、三氟甲磺酸、三氟乙酸中的任意一种。
作为进一步优选方案,步骤D中,式5化合物与酸的摩尔比为1:1.5~1:5。
作为进一步优选方案,步骤D中,反应溶剂选自二氯甲烷、三氯甲烷、甲醇、异丙醇、二氧六环中的至少一种。
作为进一步优选方案,步骤D中,反应温度为-20~100℃。
作为优选方案,所述的步骤E是由式1-6化合物在催化剂存在下与氢气发生加氢还原反应得到式1-7化合物。
作为进一步优选方案,步骤E中,所述的催化剂选自钯碳、硼氢化钠中的任意一种。
作为进一步优选方案,步骤E中,反应溶剂选自甲醇、乙醇、四氢呋喃中的任意一种。
作为进一步优选方案,步骤E中,反应温度为20~100℃。
作为优选方案,所述的步骤F是由式1-7化合物在开环试剂的作用下发生分子内开环反应得到式1-8化合物。
作为进一步优选方案,步骤F中,所述开环试剂为复合氢化物(例如:四氢铝锂)硼氢化物(例如:硼氢化钠)或二异丁基氢化铝。
作为进一步优选方案,步骤F中,式1-7化合物和开环试剂的摩尔比为1:1~1:5。
作为进一步优选方案,步骤F中,反应溶剂选自四氢呋喃、乙醚、水、甲醇、乙醇、异丙醇、二氯甲烷中的至少一种。
作为进一步优选方案,步骤F中,反应温度为0~100℃。
作为优选方案,所述的步骤G是由式1-8化合物在碱存在下与羟基保护试剂发生反应得到式1化合物。
作为进一步优选方案,步骤G中,所述的羟基保护试剂为三甲基氯硅基(TMSCl)、叔丁基二甲基氯硅烷(TBSCl)或叔丁基二苯基氯硅烷(TBDPSCl)。
作为进一步优选方案,步骤G中,所述的碱为有机碱,所述的有机碱选自三乙胺、4-二甲氨基吡啶(DMAP)、吡啶、咪唑、1,8-二氮杂二环十一碳-7-烯(DBU)中的任意一种。
作为进一步优选方案,步骤G中,反应溶剂选自二氯甲烷、三氯甲烷、甲醇、异丙醇、二氧六环中的至少一种。
作为进一步优选方案,步骤G中,反应温度为0~100℃。
与现有技术相比,本发明具有如下显著性有益效果:
本发明通过易得的式1化合物和式2化合物进行Mitsunobu反应,接着通过脱除羟基保护反应、氧化反应、酯化反应、开环反应即可制得本发明所述的沙库必曲,整个路线操作简单、安全无污染、对设备无特殊要求、生产成本低,适用于工业化生产,相对于现有技术具有显著性进步。
具体实施方式
下面结合实施例对本发明技术方案做进一步详细、完整地说明。
实施例1:式1化合物的制备
步骤A:制备式1-2化合物:
将LiAlH4(1.1eq)溶于无水THF中,冰浴条件下,缓慢加入式1-1化合物(联苯-4-羧酸,1.0eq)的THF溶液,加料完毕后,反应液升温至搅拌反应12小时,结束反应,加入15%的NaOH溶液淬灭反应,所得混合液用乙酸乙酯萃取,合并有机相,干燥,过滤,浓缩后柱层析,得白色片状晶体,即为式1-2化合物,收率70%。
经测试:1H NMR(400MHz,CDCl3):δ7.59-7.55(m,4H),7.46-7.42(m,2H),7.36-7.31(m,3H),3.91(q,J=8.0Hz,2H),2.92(t,J=8.0Hz,2H),1.48(t,J=4.0Hz,1H)。
步骤B:制备式1-3化合物:
将式1-2化合物(1.0eq)溶于二氯甲烷中,冰浴条件下,缓慢加入戴斯-马丁氧化剂(2.5eq),加料完毕后,反应液升温至搅拌反应2.5小时,结束反应,缓慢向反应体系中加入饱和NaS2O3溶液和饱和NaHCO3溶液,所得混合液用乙酸乙酯萃取,合并有机相,干燥,过滤,浓缩后柱层析,得淡黄色固体,即为式1-3化合物,收率56%。
经测试:1H NMR(400MHz,CDCl3):δ9.80(s,1H),7.60-7.53(m,4H),7.47-7.41(m,2H),7.38-7.29(m,3H),3.75(s,2H)。
步骤C:制备式1-5化合物:
无水无氧环境下,将CrCl2(5mol%)和手性双噁唑啉配体(8mol%)溶于15mL THF中,室温搅拌2小时,向体系中依次加入式1-3化合物(1.0eq),锰粉(2.0eq),二氯二茂锆(1.2eq),氯化锂(2.0eq),酞氰钴(5mol‰),然后0℃条件下向体系中缓慢加入然后加入式1-4化合物(2-溴甲基丙烯酸乙酯,1.0eq),加料完毕后于0℃搅拌36小时,结束反应,加入弗罗里硅土,搅拌20分钟,抽滤,滤液浓缩后柱层析,得到黄绿色液体,即为式1-5化合物,收率90%,ee=94%(立体选择性强,为后续化合物及最终产物沙库必曲的高立体选择性提供了基础)。
经测试:1H NMR(400MHz,CDCl3):δ7.59-7.54(m,4H),7.45-7.42(m,2H),7.36-7.30(m,3H),6.28(s,1H),5.68(s,1H),4.22(q,J=8.0Hz,2H),4.09-4.04(m,1H),2.90-2.78(m,2H),2.67(dd,J=4.0,16.0Hz,1H),2.44(dd,J=8.0,16.0Hz,1H),1.31(t,J=8.0Hz,3H)。
步骤D:制备式1-6化合物:
将式1-5化合物(1.0eq)溶于二氯甲烷中,加入TFA(2.0eq),室温搅拌反应4小时,反应液减压浓缩后柱层析,得到黄绿色液体,即为式1-6化合物,收率85%。
经测试:1H NMR(400MHz,CDCl3):δ7.59-7.54(m,4H),7.46-7.42(m,2H),7.36-7.29(m,3H),6.21(s,1H),5.60(s,1H),4.82-4.78(m,1H),3.14(dd,J=4.0,8.0Hz,1H),3.04-2.93(m,2H),2.71(dd,J=4.0,8.0Hz,1H)。
步骤E:制备式1-7化合物:
将式1-6化合物(1.0eq)溶于乙醇中,加入10%钯碳,在H2氛围下室温搅拌16小时,结束反应,抽滤,滤液浓缩后柱层析,即得式1-7化合物,收率92%。
经测试:1H NMR(400MHz,CDCl3):δ7.59-7.53(m,4H),7.46-7.42(m,2H),7.36-7.30(m,3H),4.63-4.56(m,1H),3.15(dd,J=8.0,16.0Hz,1H),2.95(dd,J=8.0,12.0Hz,1H),1.63(q,J=12.0Hz,1H),1.25(d,J=8.0Hz,3H)。
步骤F:制备式1-8化合物:
将式1-7化合物(1.0eq)溶于THF中,室温下分批加入LiAlH4(4.0eq),室温搅拌10分钟,然后加热至回流状态搅拌反应2小时,结束反应,冷至室温,加少量水淬灭至无气泡,向其中再加入与锂铝氢等当量的氢氧化钠,搅拌10分钟,硅藻土过滤,滤液浓缩后柱层析,即得式1-8化合物,收率77%。
经测试:1H NMR(400MHz,CDCl3):δ7.59-7.54(m,4H),7.46-7.42(m,2H),7.36-7.28(m,3H),3.99-3.92(m,1H),3.57-3.55(m,1H),3.42-3.40(m,1H),2.86-2.72(m,2H),1.56-1.53(m,2H),0.91(d,J=8.0Hz,3H)。
步骤G:制备式1化合物:
将式1-8化合物(1.0eq)溶于DCM中,冰浴条件下,依次加入三乙胺(3.0eq)、TBSCl(2.0eq)和DMAP(0.1eq),加料完毕后,室温反应12小时,结束反应,加水淬灭反应,反应液用乙酸乙酯萃取,合并有机相,有机相用无水NaSO4干燥,过滤,浓缩,柱层析,即得式1化合物,收率90%。
经测试:1H NMR(400MHz,CDCl3):δ7.62-7.55(m,4H),7.47-7.44(m,2H),7.37-7.32(m,3H),3.99-3.96(m,1H),3.56-3.55(m,1H),3.48-3.46(m,1H),3.21-3.19(m,1H),2.86-2.81(m,2H),1.89-1.85(m,1H),1.53-1.49(m,2H),0.95(s,9H),0.91(d,J=8.0Hz,3H),0.11(s,6H)。
实施例2:式3化合物的制备
将式1化合物(1.0eq)溶于THF中,冰浴条件下,加入式2化合物(丁二酰亚胺,3.0eq)和PPh3(3.0eq),搅拌均匀,缓慢滴加DIAD(3.0eq),室温反应12小时,结束反应,加水淬灭反应,反应液用乙酸乙酯萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,即得式3化合物,所得化合物直接用于下一步反应。
实施例3:式4化合物的制备
将式3化合物(1.0eq)溶于THF中,加入TBAF溶液(1.0M in THF,2.0eq),室温搅拌反应12小时,结束反应,加饱和氯化胺淬灭反应,反应液用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析,即得到式4化合物,两步收率80%。
经测试:1H NMR(400MHz,CDCl3):δ7.56-7.47(m,4H),7.42-7.39(m,2H),7.33-7.20(m,3H),4.59-4.55(m,1H),3.31-3.25(m,1H),3.07-3.02(m,1H),2.72-2.26(m,8H),2.15-2.02(m,1H),1.23(d,J=8.0Hz,3H)。
实施例4:式5化合物的制备
将式4化合物(1.0eq)溶于混合溶剂(乙腈/四氯化碳/水=1:1:1.5,体积比)中,冰浴条件下,分别加入三氯化钌水合物(0.1eq)和高碘酸钠(4.0eq),搅拌混合均匀后室温反应5小时,结束反应,用饱和亚硫酸钠溶液淬灭反应,反应液用二氯甲烷萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,即得式15化合物,所得化合物直接用于下一步反应。
实施例5:式6化合物的制备
将式5化合物(1.0eq)溶于乙醇中,室温缓慢滴入氯化亚砜(2.0eq),室温搅拌约7小时,结束反应,加饱和碳酸钠淬灭反应,反应液减压蒸去乙醇后用乙酸乙酯萃取,合并有机相,有机相用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析,即得式6化合物,两步收率91%。
经测试:1H NMR(400MHz,CDCl3):δ7.57-7.47(m,4H),7.43-7.40(m,2H),7.34-7.18(m,3H),4.49-4.46(m,1H),4.17-4.07(m,2H),3.27-3.21(m,1H),3.05-3.01(m,1H),2.47-2.30(m,6H),2.09-2.04(m,1H),1.25(t,J=8.0Hz,3H),1.18(d,J=8.0Hz,3H)。
实施例6:沙库必曲的制备
将式6化合物(1.0eq)溶于混合溶剂(THF:H2O=3:1,体积比)中,加入氢氧化锂(1.2eq),室温反应1.5小时,加水淬灭反应,反应液用乙酸乙酯萃取,水相用5%稀HCl酸化后再用乙酸乙酯萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,柱层析,即得沙库必曲,收率为70%。
经测试:1H NMR(400MHz,CDCl3):δ7.57-7.50(m,4H),7.43-7.40(m,2H),7.34-7.22(m,3H),5.92(d,J=8.0Hz,1H).4.26-4.22(m,1H),4.11(q,J=8.0Hz,2H),2.84-2.81(m,2H),2.64-2.55(m,3H),2.43-2.40(m,2H),1.93-1.90(m,1H),1.56-1.49(m,1H),1.22(t,J=8.0Hz,3H),1.15(d,J=8.0Hz,3H);
13C NMR(400MHz,CDCl3):δ176.50,176.46,171.81,140.74,139.40,136.55,129.84,128.75,127.18,127.09,126.95,60.67,48.80,40.42,37.23,36.47,30.82,29.77,17.61,14.15;
HRMS(EI(+),70eV):C24H29O5N[M]+:calcd.410.1973,found 410.1983。
综上所述,本发明以易得的式1化合物和式2化合物为起始原料,经过5步反应即可制得本发明所述的沙库必曲,整个路线操作简单、安全无污染、对设备无特殊要求、生产成本低、收率高(单步骤收率至少为70%),适用于工业化生产。
最后需要在此指出的是:以上仅是本发明的部分优选实施例,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
Claims (9)
2.根据权利要求1所述的制备方法,其特征在于:所述的R为三甲基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基。
3.根据权利要求1所述的制备方法,其特征在于:所述的步骤a是由式1化合物与式2化合物在磷试剂和偶氮试剂的存在下发生Mitsunobu反应得到式3化合物。
4.根据权利要求1所述的制备方法,其特征在于:所述的步骤b是由式3化合物在脱保护试剂的作用下发生脱除羟基保护反应得到式4化合物。
5.根据权利要求1所述的制备方法,其特征在于:所述的步骤c是由式4化合物在氧化剂的作用下发生醇的氧化反应得到式5化合物。
6.根据权利要求1所述的制备方法,其特征在于:所述的步骤d是由式5化合物与酰基化试剂发生酯化反应得到式6化合物。
7.根据权利要求1所述的制备方法,其特征在于:所述的步骤e是由式6化合物在开环试剂的作用下发生开环反应得到所述沙库必曲。
8.根据权利要求1所述的制备方法,其特征在于:所述的步骤A是由式1-1化合物在还原剂的作用下发生还原反应得到式1-2化合物;所述的步骤B是由式1-2化合物在氧化剂的作用下发生醇的氧化反应得到式1-3化合物;所述的步骤C是由式1-3化合物与式1-4化合物发生NHK反应得到式1-5化合物。
9.根据权利要求1所述的制备方法,其特征在于:所述的步骤D是由式1-5化合物在酸性条件下发生分子内关环反应得到式1-6化合物;所述的步骤E是由式1-6化合物在催化剂存在下与氢气发生加氢还原反应得到式1-7化合物;所述的步骤F是由式1-7化合物在开环试剂的作用下发生分子内开环反应得到式1-8化合物;所述的步骤G是由式1-8化合物在碱存在下与羟基保护试剂发生反应得到式1化合物。
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