CN103724253A - 一种米格列奈钙的制备方法 - Google Patents
一种米格列奈钙的制备方法 Download PDFInfo
- Publication number
- CN103724253A CN103724253A CN201310680671.2A CN201310680671A CN103724253A CN 103724253 A CN103724253 A CN 103724253A CN 201310680671 A CN201310680671 A CN 201310680671A CN 103724253 A CN103724253 A CN 103724253A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- cis
- raw material
- hydrolysis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960003365 mitiglinide Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- QEVLNUAVAONTEW-UZYHXJQGSA-L calcium;(2s)-4-[(3as,7ar)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxobutanoate;dihydrate Chemical compound O.O.[Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 QEVLNUAVAONTEW-UZYHXJQGSA-L 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- PMRVFZXOCRHXFE-FMEJWYFOSA-L Kad 1229 Chemical compound [Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 PMRVFZXOCRHXFE-FMEJWYFOSA-L 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 14
- 238000005804 alkylation reaction Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- DPJYJNYYDJOJNO-NRPADANISA-N camphorsultam Chemical compound C1S(=O)(=O)N[C@H]2C[C@H]3C(C)(C)[C@@]12CC3 DPJYJNYYDJOJNO-NRPADANISA-N 0.000 claims description 7
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 claims description 6
- 238000005580 one pot reaction Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- 238000010411 cooking Methods 0.000 claims description 5
- 239000013067 intermediate product Substances 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- ODSNARDHJFFSRH-OCAPTIKFSA-N (3as,7ar)-2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCC[C@@H]2CNC[C@@H]21 ODSNARDHJFFSRH-OCAPTIKFSA-N 0.000 description 2
- MUXOBHXGJLMRAB-UHFFFAOYSA-N Dimethyl succinate Chemical compound COC(=O)CCC(=O)OC MUXOBHXGJLMRAB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- -1 phenyl aldehyde Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006600 Stobbe condensation reaction Methods 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-M [O-]C([C@H](CC(N(C1)C[C@@H]2[C@H]1CCCC2)=O)Cc1ccccc1)=O Chemical compound [O-]C([C@H](CC(N(C1)C[C@@H]2[C@H]1CCCC2)=O)Cc1ccccc1)=O WPGGHFDDFPHPOB-BBWFWOEESA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种米格列奈钙的新制备方法,该方法包括:以顺-六氢异吲哚为原料,经酰化反应、烃化反应、水解反应和成盐反应,制得米格列奈钙。所述烃化反应和水解反应采用“一勺烩”的方法完成,产品纯度达到99.8%以上,收率36%以上。本发明所述的制备方法具有原料易得,反应条件温和,操作简单易行,收率较高,具有较高工业生产价值,目前已实现产业化。
Description
技术领域
本发明涉及医药领域,具体而言,本发明涉及一种米格列奈钙的制备方法。
背景技术
双〔(2s)-2-苄基-3-(顺-六氢异吲哚-2-羰基)丙酸〕单钙二水合物(米格列奈钙),分子式为C38H48CaN2O6·2H2O,英文名为Mitiglinide Calcium Hydrate,结构式(I)如下:
米格列奈钙是由日本橘生药品工业株式会社合成,2004年4月在日本上市,用于经饮食和运动疗法不能有效控制高血糖的Ⅱ型糖尿病病人。米格列奈钙是继瑞格列奈、那格列奈后第三个美格列脲类药物,属于苯丙氨酸的衍生物。米格列奈钙通过关闭胰腺β细胞膜上的ATP依赖性K通道,造成Ca内流,使细胞内Ca浓度增加而使细胞外含胰岛素的囊泡脱粒,从而刺激胰岛素的分泌。并且只是在进餐时才会迅速而短暂的刺激胰腺分泌胰岛素,与传统的磺酰脲类药物相比起效迅速而作用时间短,抑制Ⅱ型糖尿病特征性的餐后高血糖,避免了低血糖反应的发生,是早期及轻度糖尿病患者的一线治疗药物,且耐受性好。
根据文献和专利报道,米格列奈钙的制备主要有以下几种方法。
方法一:以2-(S)-苄基丁二酸为原料,经酰胺化、还原、成盐得到米格列奈钙此方法虽然步骤较少,但原料为手性化合物,价格昂贵,使生产成本较高,不适于工业化生产。【参考文献:Sorbera L A,Leeson P A,Castaner R M,et al.Mitiglinide calcium(KAD-1229)[J].Drugs Future,2000,25(10):1034-1042.
方法二:丁二酸二甲酯与苯甲醛为原料,经Stobble缩合、水解、脱水成酸酐,与顺-全氢异吲哚缩合后还原得到消旋酸,再经拆分、成盐等得米格列奈钙。此法操作相对复杂,缩合反应时杂质多,产物难以分离提纯,成本较高,且手性拆分时收率较低。【参考文献:郑德强,刘文涛,毋立华等.米格列奈钙的合成[J].食品与药品,2007,9(11):13-15.】
方法三:丁二酸二甲酯与苯甲醛为原料,经Stobbe缩合、还原、拆分,用对硝基苯酚和二环己基碳二亚胺活化,成盐得到米格列奈钙,此生产成本比较高,而且用到柱层析,不适于工业化生产。【参考文献:张红梅,陈立功,曹小辉.米格列奈的合成工艺研究[J],现代化工,2008,28(8):56-59.】
随着社会经济的发展和人们生活水平的不断提高,糖尿病患病率正在急剧增加,已成为影响人类身体健康的主要疾病之一。米格列奈钙作为优秀的速效降糖药,虽然合成路线报道较多,但多不适合工业化生产,寻找一条经济有效的方法制备方法,具有重要意义。
发明内容
本发明的目的是提供一种适于工业化生产的米格列奈钙的制备方法。
为了实现本发明的目的,本发明提供了一种米格列奈钙的制备方法,如下所示,该方法包括如下步骤:
米格列奈钙的合成工艺路线
1)以顺-六氢异吲哚为原料依次进行酰化反应、烃化反应、水解反应来制备米格列奈,所述烃化反应、水解反应通过“一勺烩”的方法来制备;
2)通过成盐反应由所述步骤1)中制得的米格列奈来制备米格列奈钙。
目前,米格列奈钙通常是依次通过缩合、水解、脱水成酸酐,与顺-全氢异吲哚缩合后还原得到消旋酸,再经拆分、成盐等制得米格列奈钙,本发明人发现,在米格列奈钙制备过程中,烃化反应和水解反应可通过“一锅法”来制备,无需分离中间产物。在本领域中,术语“一锅法”(one-pot process,俗称“一勺烩法”)是指将多步反应简化到一起依次进行,中间无需分离中间产物。具体到本发明是指烃化反应、水解反应依次进行,而无需分离中间产物,这样就大大简化了操作条件和过程,提高了产品收率和质量,降低了成本。
本发明中:以顺-六氢异吲哚为原料,经与氯乙酰氯反应得顺-N-氯乙酰基六氢异吲哚,然后与N-苯丙酰基樟脑磺内酰胺进行烃化反应,所得产物经水解、成盐得目标产物。
本发明的酰化反应中,反应温度为0-30℃,反应时间为1-6小时。
所述的烃化反应采用N-苯丙酰基樟脑磺内酰胺作为手性诱导基团,所用溶剂以极性非质子溶剂如N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜,反应温度为25-100℃,反应时间10-24小时,投料比为顺-N-氯乙酰基六氢异吲哚:N-苯丙酰基樟脑磺内酰胺=1:1~2为最佳。
所述的水解反应温度20-50℃,反应时间10-20小时。
所述成盐反应是通过由制得的米格列奈和氯化钙反应来进行的,成盐时反应温度为20-45℃,反应时间为0.5-3小时。
与现有技术相比本发明有如下优点:
1、采用顺-六氢异吲哚为原料,经与氯乙酰氯反应得顺-N-氯乙酰基六氢异吲哚,然后与N-苯丙酰基樟脑磺内酰胺进行烃化反应,所得产物经水解、成盐得目标产物,该合成路线具有原料易得,反应条件温和,操作简单易行,收率较高,具有较高工业生产价值。
2、采用樟脑磺内酰胺作为手性诱导基团,立体选择性地进行烃化反应,从而实现手性合成。
3、采用“一勺烩”的方法,简化了操作,提高了收率,四步反应总收率达到36%。
具体实施方式
下面的实施例将对本发明予以进一步的说明,但并不因此而限制本发明。
实施例1:
将顺-六氢异喹啉(250.4g,2mol),无水碳酸钾(304.0g,2.2mol),二氯甲烷(1000ml)加入到反应瓶中,保持温0-5℃,剧烈搅拌下,滴加氯乙酰氯(271.0g,2.4mol)的二氯甲烷(500ml)溶液,滴毕,室温反应2.5h,点板监测,反应毕,补加水1000ml,分出有机层,水洗(1000ml),饱和食盐水(1000ml)洗,无水硫酸钠干燥过夜,减压蒸出二氯甲烷,得顺-N-氯乙酰基六氢异吲哚(2)357.4g油状物,收率:88.6%。
将顺-N-氯乙酰基六氢异吲哚(302.5g,1.5mol),N-苯丙酰基樟脑磺内酰胺(573.0g,1.65mol),70%氢化钠(56.6g,1.65mol),N,N-二甲基甲酰胺(900ml)加入到反应瓶中,在50℃下,剧烈搅拌反应12h,得到烃化产物,放置至室温备用。
向上述体系中缓慢滴加水100ml,滴毕,加入氢氧化锂(39.5g,1.65mol),四氢呋喃(600ml),在0-5℃下滴加30%过氧化氢溶液680ml,滴毕,转移至室温下继续反应18h,点板监测,反应毕,补加水1200ml,调pH至2-3左右,用二氯甲烷(900ml×3)提取,合并有机相,饱和食盐水(1500ml)洗,无水硫酸钠干燥过夜,减压蒸出溶剂得粘稠状液体,向其中加入乙酸乙酯250ml,室温搅拌,抽滤,滤饼用乙酸乙酯(150ml)洗涤,干燥,得(2s)-2-苄基-3-(顺-六氢异吲哚-2-羰基)-丙酸(6),得白色固体231.8g,两步收率:49%。将化合物6(230g,0.73mol)、水1150ml,加入到反应瓶中,全溶后,加入2mol/L氢氧化钠溶液400ml,室温搅拌30min,剧烈搅拌下缓慢滴加氯化钙(162.0g,1.46mol)的水(320ml)溶液,滴毕,继续反应1.5h,抽滤,水(200ml×2)洗滤饼,得白色固体,60℃下减压干燥3h,滤饼用95%乙醇(2300ml)重结晶,得米格列奈钙(Ⅰ)430g,收率:83.6%,m.p.:178~183℃,FAB-MS:m/z316[M+1]+;[α]D 20=+5.45°(C=1,甲醇)[文献:m.p.:179~185℃,[α]D 20=+5.64°(C=1.0,甲醇)];纯度:99.8%[HPLC归一化法:色谱柱C18,流动相1.00mol/L磷酸二氢钾缓冲盐-乙腈—水(20∶35∶30)(调节pH=2.10);检测波长210nm];1H-NMR(CDCl3,400M),δ:1.1~1.5(16H,m),1.8~2.4(6H,m),2.5~3.1(14H,m)3.3~3.8(6H,m)7.4~7.6(10H,m);元素分析(%):C64.68,H7.35,N3.94,理论值:C64.75,H7.44,N3.97.收率:36.05%,纯度99.8%。
与文献方法(见下表)相比,本发明的收率有了大幅度的提高,且终产品纯度达到了99.8%
方法 | 方法一 | 方法二 | 方法三 | 实施例1 |
总收率 | 6.26% | 9.50% | 9.26% | 36.05% |
Claims (9)
1.一种米格列奈钙的制备方法,其特征在于: 以顺-六氢异吲哚为原料依次进行酰化反应、烃化反应、水解反应来制备米格列奈,所述烃化反应、水解反应通过 “一勺烩”的方法来制备。
2.根据权利要求1所述的制备方法,其特征在于,以顺-六氢异吲哚为原料,经与氯乙酰氯反应得顺-N-氯乙酰基六氢异吲哚,然后与N-苯丙酰基樟脑磺内酰胺进行烃化反应,所得产物经水解、成盐即得。
3.根据权利要求1或2所述的制备方法,其特征在于,所述烃化反应、水解反应,是在无需分离中间产物的情况下通过“一勺烩”来进行的。
4.根据权利要求1或2所述的制备方法,其特征在于,所述酰化反应是以对顺-六氢异吲哚为原料与氯乙酰氯进行反应。
5.根据权利要求1或2或4所述的制备方法,其特征在于,所述酰化反应的反应温度为0-30℃,反应时间为1-6小时。
6.根据权利要求1或2或3所述的制备方法,其特征在于,所述的烃化反应采用N-苯丙酰基樟脑磺内酰胺作为手性诱导基团,所用溶剂选自N,N-二甲基甲酰胺、四氢呋喃或二甲基亚砜。
7.根据权利要求5所述的制备方法,其特征在于,所述的烃化反应的反应温度为25-100℃,反应时间10-24小时,投料比为顺-N-氯乙酰基六氢异吲哚:N-苯丙酰基樟脑磺内酰胺=1:1~2。
8.根据权利要求1所述的制备方法,其特征在于,所述水解反应温度为20-50℃,反应时间为10-20小时。
9.根据权利要求2所述的米格列奈钙的制备方法,其特征在于,所述成盐反应是通过由制得的米格列奈和氯化钙反应来进行的,成盐时反应温度为20-45℃,反应时间为0.5-3小时。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310680671.2A CN103724253B (zh) | 2013-12-11 | 2013-12-11 | 一种米格列奈钙的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310680671.2A CN103724253B (zh) | 2013-12-11 | 2013-12-11 | 一种米格列奈钙的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103724253A true CN103724253A (zh) | 2014-04-16 |
CN103724253B CN103724253B (zh) | 2016-06-15 |
Family
ID=50448587
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310680671.2A Expired - Fee Related CN103724253B (zh) | 2013-12-11 | 2013-12-11 | 一种米格列奈钙的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103724253B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1616427A (zh) * | 2003-11-13 | 2005-05-18 | 中国科学院上海药物研究所 | 一种制备抗糖尿病药物米格列奈的新方法 |
CN101270074A (zh) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | 一种高纯度米格列奈钙的制备方法 |
WO2009047797A2 (en) * | 2007-10-08 | 2009-04-16 | Ind-Swift Laboratories Limited | Process for the preparation of perhydroisoindole derivative |
CN101492411A (zh) * | 2008-01-22 | 2009-07-29 | 北京华禧联合科技发展有限公司 | 一种改进的制备米格列奈的方法 |
-
2013
- 2013-12-11 CN CN201310680671.2A patent/CN103724253B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1616427A (zh) * | 2003-11-13 | 2005-05-18 | 中国科学院上海药物研究所 | 一种制备抗糖尿病药物米格列奈的新方法 |
CN101270074A (zh) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | 一种高纯度米格列奈钙的制备方法 |
WO2009047797A2 (en) * | 2007-10-08 | 2009-04-16 | Ind-Swift Laboratories Limited | Process for the preparation of perhydroisoindole derivative |
CN101492411A (zh) * | 2008-01-22 | 2009-07-29 | 北京华禧联合科技发展有限公司 | 一种改进的制备米格列奈的方法 |
Non-Patent Citations (1)
Title |
---|
张永亮,等: "米格列奈合成方法研究", 《化工中间体》, no. 1, 31 December 2009 (2009-12-31), pages 16 - 22 * |
Also Published As
Publication number | Publication date |
---|---|
CN103724253B (zh) | 2016-06-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104974060A (zh) | 一种8-(2-羟基苯甲酰胺基)辛酸钠的制备方法 | |
CN101941969B (zh) | 盐酸莫西沙星的制备方法 | |
CN105330609B (zh) | 一种制备lcz696的方法 | |
JP2018158936A (ja) | β‐ヒドロキシ‐β‐メチル酪酸の精製方法 | |
CN104478877B (zh) | 制备雷迪帕韦中间体的方法 | |
CN103420881B (zh) | 一种新的药用消旋羟蛋氨酸钙的制备方法 | |
CN103570638A (zh) | 一种氟苯尼考中间体环合物的合成方法 | |
CN107573310A (zh) | 一种科立内酯二醇的制备方法 | |
CN108069901B (zh) | 一种瑞巴派特合成新工艺 | |
CN103724253A (zh) | 一种米格列奈钙的制备方法 | |
CN113582880A (zh) | 一种(3-氨基二环[1.1.1]戊烷-1-基)氨基甲酸叔丁酯的制备方法 | |
CN102030707A (zh) | 布南色林中间体的制备方法 | |
CN104628518A (zh) | 一种合成瑞格列奈关键中间体的方法 | |
CN104311471A (zh) | 一种改进的米格列奈钙的工业化制备方法 | |
CN104876911A (zh) | 一种简易的方法合成德拉沙星 | |
CN102659639B (zh) | 一种益母草碱的制备工艺 | |
CN107151246A (zh) | 一种(r)-吡喹酮胺盐及左旋吡喹酮的制备方法 | |
CN105732613B (zh) | 一种9‑去甲基‑(+)‑α‑二氢丁苯那嗪的合成方法 | |
WO2017152539A1 (zh) | 一种4-五氟化硫苯酚类化合物及制备方法以及五氟化硫取代苯并吡喃类化合物的制备方法 | |
CN105646472A (zh) | 一种盐酸阿罗洛尔的制备方法 | |
CN102731437A (zh) | 一种4-哌嗪-3-三氟甲基苯胺盐酸盐的制备方法 | |
CN104177271A (zh) | 一种氯化乙酰左卡尼汀的制备方法 | |
CN104163769A (zh) | 一种氯化丙酰左卡尼汀的制备方法 | |
CN103709092B (zh) | 米格列奈钙的制备方法 | |
CN103981248A (zh) | 一种拆分外消旋亮氨酸的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20190827 Address after: 118000 No. 19 Shijing Street, Zhenxing District, Dandong City, Liaoning Province Patentee after: No. 966 Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army Address before: 118000 No. 19 Shijing Street, Zhenxing District, Dandong City, Liaoning Province Patentee before: Yuan Zhenting |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160615 Termination date: 20191211 |