CN114957326A - 一种贝前列素钠膦叶立德中间体的合成方法 - Google Patents
一种贝前列素钠膦叶立德中间体的合成方法 Download PDFInfo
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- 229960002890 beraprost Drugs 0.000 title claims abstract description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 10
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 title claims abstract 6
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 32
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims abstract description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- NTFIXTWXHQHPTK-UHFFFAOYSA-N CC(CCC#C)C(CP(O)(O)=O)=O Chemical compound CC(CCC#C)C(CP(O)(O)=O)=O NTFIXTWXHQHPTK-UHFFFAOYSA-N 0.000 claims abstract description 3
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims abstract 2
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical group CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000013341 scale-up Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000011089 carbon dioxide Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- -1 3-methyl-2-oxo-5-ethynyl pentyl phosphonic acid dimethyl ester Chemical compound 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HCWFJBHPAYFCMP-UHFFFAOYSA-N methyl 2-methylhex-5-ynoate Chemical compound COC(=O)C(C)CCC#C HCWFJBHPAYFCMP-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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Abstract
本发明涉及一种贝前列素钠膦叶立德中间体的合成方法,主要解决现有合成方法存在的原料管制,以及反应条件苛刻不易放大生产的技术问题。技术方案为:一种贝前列素钠膦叶立德中间体的合成方法,在无水四氢呋喃中,N‑甲氧基‑N,2‑二甲基‑4‑炔酰胺与甲基磷酸二烷基酯、二异丙基氨基锂反应得到目标化合物:3‑甲基‑2‑氧代‑5‑乙炔基戊基膦酸二烷基酯。
Description
技术领域
本发明涉及贝前列素钠的合成,具体涉及一种贝前列素钠膦叶立德中间体的合成方法。
背景技术
贝前列素钠(商品名Dorner),是由日本东丽株式会社(Toray)开发的抗血小板药物。目前国内市售的贝前列素钠制剂分别是由日本东丽株式会社(Toray)和匈牙利奇诺英公司开发,以商品名德纳和凯那在中国上市。该原料药的合成工艺涉及9~10步的合成步骤,总收率低。所以研发有效的贝前列素钠及其中间体的制备方法具有非常重要的意义和价值。
目前大多数研究集中在关键中间体化合物1的用于优化合成探索,鲜有对Wittig反应磷叶立德化合物A (3-甲基-2-氧代-5-乙炔基戊基膦酸二甲酯 CAS 70073-58-4 )的研究报告,反应式如下:
化合物A 经典的路线有两条;
路线一:(专利WO2008/79383,WO2015/9991,US2016/60216等)用化合物4 (2-甲基-4-乙炔基丁酸甲酯,CAS:69691-19-6)和甲基膦酸二甲酯(DMMP,CAS 756-79-6),-78℃低温正丁基锂条件,收率30-40%。反应式如下:
路线二:(专利WO2015/179427以及Tetrahedron Letters; vol. 62; (2021);)化合物5(N-甲氧基-N,2-二甲基-4-炔酰胺)和甲基膦酸二甲酯(DMMP,CAS 756-79-6),-78℃低温丁基锂条件,反应条件苛刻,收率75%。反应式如下:
发明内容
本发明的目的是提供一种贝前列素钠膦叶立德中间体的合成方法,主要解决现有合成方法存在的原料管制,以及反应条件苛刻不易放大生产的技术问题。
本发明的技术方案为:一种贝前列素钠膦叶立德中间体的合成方法,其特征是:包括以下步骤,在无水四氢呋喃(THF)中,N-甲氧基-N,2-二甲基-4-炔酰胺与甲基磷酸二烷基酯、二异丙基氨基锂(LDA)反应得到目标化合物:3-甲基-2-氧代-5-乙炔基戊基膦酸二烷基酯;反应式如下:
本发明的有益效果:在研究中意外发现,如果在路线二化合物A合成中,使用LDA替代正丁基锂,可以很好解决正丁基锂的危险性以及反应过程中的锂盐的不稳定性,以及放大生产的局限性大, 而使用LDA 和Weinreb胺反应, 反应条件温和, 非常适合放大。在优化制备化合物A过程中,因原料甲基膦酸二甲酯(DMMP)自从2021年5月开始列入精神药品或易制毒化学品或管制类产品,不得非法销售或购买,经研究发现,甲基膦酸二乙酯 (DEMPCAS 683-08-0)可以替代。化合物B用 正丁基锂和LDA 反应条件,明显LDA 反应条件优越,并对LDA后处理条件优化后对类似化合物的合成提供了很高的参考价值。
附图说明
图1为本发明化合物B的核磁谱图。
图2为本发明化合物B的HPLC谱图。
具体的实施方式
实施例1:
氮气保护下,干燥的无水四氢呋喃(140毫升)三口反应瓶加入,加入甲基磷酸二甲酯(DMMP) (14.67克,118毫摩尔),干冰/丙酮浴降温到-50℃,搅拌10分钟,滴加LDA(2M inTHF,59毫升,118毫摩尔)并控温不超过-50℃(大约15 分钟),滴加完毕,在该温度下反应10到15分钟,滴加化合物5(N-甲氧基-N,2-二甲基-4-炔酰胺(10 克,59.2 毫摩尔) 的无水四氢呋喃溶液(100 毫升),控制温度小于-40℃ 到-50℃ (大约15分钟加完),反应液在温度下反应1小时。
TLC/LCMS监测反应原料5反应完全,撤去干冰丙酮浴,温度回升到-20℃左右,滴加100毫升冰水淬灭反应,加入质量百分浓度为20%柠檬酸调节pH =5,加入乙酸乙酯萃取三次, 合并有机相,有机相饱和盐水洗涤,无水硫酸钠干燥,浓缩干得到粗品,柱层析纯化得到目标化合物A(13.23克,淡黄色油, 收率86%) MS (ESI) M/Z: 233.1 [M+H+]。
实施例2:
对比例:
氮气保护下,干燥的无水四氢呋喃(140毫升)三口反应瓶加入,加入甲基磷酸二乙酯DEMP (10克,65.8毫摩尔),干冰/丙酮浴降温到-78℃,搅拌10分钟,滴加正丁基锂(2.5 Min THF,26毫升,65.8毫摩尔)并控温不超过-70℃(大约15 分钟),滴加完毕,在该温度下反应10到15分钟,滴加化合物5(N-甲氧基-N,2-二甲基-4-炔酰胺(5.56 克,32.9 毫摩尔) 的无水四氢呋喃溶液(100 毫升),控制温度小于-70℃到-78℃(大约5分钟加完),反应液在温度下反应1小时。
TLC/LCMS监测反应原料5反应完全,撤去干冰丙酮浴,温度回升到-20℃左右,滴加100毫升冰水淬灭反应,加入质量百分浓度为20%柠檬酸调节pH =5,加入乙酸乙酯萃取三次, 合并有机相,有机相饱和盐水洗涤,无水硫酸钠干燥,浓缩干得到粗品,柱层析纯化得到目标化合物B (2.9克, 淡黄色油,收率34.1%)MS (ESI) M/Z: 261.2 [M+H+]。
本发明:
氮气保护下,干燥的无水四氢呋喃(140毫升)三口反应瓶加入,加入甲基磷酸二乙酯DEMP (10克,65.8毫摩尔),干冰/丙酮浴降温到-50℃,搅拌10分钟,滴加LDA(2.0 M inTHF,33毫升,65.8毫摩尔)并控温不超过-50℃(大约15 分钟),滴加完毕,在该温度下反应10到15分钟,滴加化合物5(N-甲氧基-N,2-二甲基-4-炔酰胺(5.56 克,32.9 毫摩尔) 的无水四氢呋喃溶液(100 毫升),控制温度小于-40℃ 到-50℃(大约5分钟加完),反应液在温度下反应1小时。
TLC/LCMS监测反应原料5反应完全,撤去干冰丙酮浴,温度回升到-20℃左右,滴加100毫升冰水淬灭反应,加入质量百分浓度为20%柠檬酸调节pH =5,加入乙酸乙酯萃取三次, 合并有机相,有机相饱和盐水洗涤,无水硫酸钠干燥,浓缩干得到粗品,柱层析纯化得到目标化合物B (7.01克, 淡黄色油,收率82%)。MS (ESI) M/Z: 261.2 [M+H+]。
1HNMR (400 MHz, CDCl3) δ 4.18 (q, J =7.2 Hz , 4H), 3.24-3.15 (m,2H), 2.97-2.92 (m, 1H),2.38-2.36 (m, 2H),1.76(s, 3H), 1.35 (t, J = 7.2 Hz,6H),1.18 (d,J=1.2 Hz, 3H); 31P NMR, δ 19.6。
后处理优化:
TLC/LCMS监测反应原料反应完全,撤去干冰丙酮浴,温度回升到-20℃左右,滴加100毫升冰水淬灭反应,加入400毫升石油醚,分液,水相用质量百分浓度为20%柠檬酸调节pH =5,加入乙酸乙酯萃取两次, 合并有机相,有机相饱和盐水洗涤,无水硫酸钠干燥,浓缩干得到目标化合物B (64克, 淡黄色油,收率74.9%)。核磁谱图见图1,HPLC谱图见图2。
实施例3:(放大反应)
氮气保护下,干燥的无水四氢呋喃(5升)三口反应瓶加入,加入甲基磷酸二乙酯DEMP (500克,6.58摩尔),干冰/丙酮浴降温到-50℃,搅拌20分钟,滴加LDA(2.0 M in THF,33升,6.58毫摩尔)并控温不超过-50℃(大约30分钟),滴加完毕,在该温度下反应30分钟,滴加化合物5(N-甲氧基-N,2-二甲基-4-炔酰胺(556 克,3.2摩尔) 的无水四氢呋喃溶液(2升),控制温度小于-40℃ 到-50℃(大约20分钟加完),反应液在温度下反应1小时。
TLC/LCMS监测反应原料反应完全,撤去干冰丙酮浴,温度回升到-20℃左右,滴加10升冰水淬灭反应,加入50升石油醚,分液,水相用质量百分浓度为20%柠檬酸调节pH =5,加入乙酸乙酯萃取两次, 合并有机相,有机相饱和盐水洗涤,无水硫酸钠干燥,浓缩干得到目标化合物B (655克, 淡黄色油,收率75%)。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (3)
2.根据权利要求1所述的一种贝前列素钠膦叶立德中间体的合成方法,其特征是:当R为甲基时,甲基磷酸二甲酯和二异丙基氨基锂-50℃下先反应10-15分钟,然后加入N-甲氧基-N,2-二甲基-4-炔酰胺-40℃ 到-50℃反应1小时。
3.根据权利要求1所述的一种贝前列素钠膦叶立德中间体的合成方法,其特征是:当R为乙基时,甲基磷酸二乙酯和二异丙基氨基锂-50℃下先反应10-15分钟,然后加入N-甲氧基-N,2-二甲基-4-炔酰胺-40℃ 到-50℃反应1小时。
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