CN101481363A - 一种制备瑞格列奈的方法 - Google Patents
一种制备瑞格列奈的方法 Download PDFInfo
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- 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 title claims abstract description 16
- 229960002354 repaglinide Drugs 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- -1 methoxy-benzyl Chemical group 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229940059260 amidate Drugs 0.000 claims description 3
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960005286 carbaryl Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种治疗糖尿病的药物瑞格列奈的制备方法。该制备方法步骤是：式(II)所示的(S)型化合物与式(III)所示的化合物在缩合剂存在的条件下进行酰胺化反应，生成式(IV)所示的(S)型化合物；式(IV)所示的(S)型化合物先在碱存在的条件下，脱去R2基团，然后在酸存在的条件下，脱去R1基团。式(II)、式(III)、式(IV)所示的(S)型化合物以及R1基团、R2基团如说明书中定义。在本制备方法中，由于R1基团的引入以及脱保护基步骤地改进，缩短了反应时间，提高了收率且安全性更好，更适合于工业化生产。
Description
技术领域
本发明涉及药物有机合成领域，特别是涉及一种治疗糖尿病的药物瑞格列奈的制备方法。
背景技术
瑞格列奈的化学名为S(+)-2-乙氧基-4-[N-{1-(2-哌啶基苯基)-3-甲基-1-丁基}氨基羰基甲基]苯甲酸，结构式为
这可以从美国专利(专利号：US5312924)中得知。研究表明，瑞格列奈是一种对映体，与R(-)-2-乙氧基-4-[N-{1-(2-哌啶基苯基)-3-甲基-1-丁基}氨基羰基甲基]苯甲酸相比，其在人体内具有长时间的生物活性，并且能更迅速的被消除，是一种新型的口服降糖药物，能促进胰岛素分泌，具有吸收快、作用时间短的特点，可在II型糖尿病患者中模拟生理性胰岛素分泌，有效控制餐后高血糖，有较高的蛋白结合率，不会在组织中蓄积，安全性良好。瑞格列奈既可以作为一线抗糖尿病药物单独使用，也可以与其他降糖药联合应用增加疗效，是一种治疗II型糖尿病的新型药物。
多种文献报道了瑞格列奈的合成，其路线主要是以式(ii)化合物与式(VI)化合物缩合得到化合物(VII)，再经水解得到产物(I)，其工艺流程如下：
其中R指甲基、乙基、苄基等羧基保护基团。
在各种文献报道(如US5312924或CN1571769)中，研究人员主要是针对式(II)与式(VI)的缩合工艺进行了研究，以提高收率，降低成本。但不可否认的是，在这些缩合反应中，使用的缩合剂多为DCC、三苯基膦+CCl4等，存在着反应时间长、毒性大等缺点，不利于工业化生产。
因此开发一条能解决上述难题的工艺路线具有重要的意义和价值。本发明提供了一条新的制备瑞格列奈的工艺路线，它具有反应时间短，收率高，低毒，低危险，操作简单等优点，是一条具有很好工业化前景的工艺路线。
发明内容
本发明的目的在于提供一种反应时间短，收率高且适合于工业上应用的瑞格列奈的制备方法。
本发明公开了一种制备式(I)所示瑞格列奈的制备方法，
所述方法包括：
式(II)所示的(S)型化合物与式(III)所示的化合物在缩合剂存在条件下进行酰胺化反应，生成式(IV)所示的(S)型化合物，即
其中，
R1选自苄基、对硝基苄基、对甲氧基苄基、对甲基苄基，优选对甲氧基苄基；
R2选自甲基、乙基、叔丁基、苄基、对硝基苄基或对甲氧基苄基，优选乙基。
进一步，式(IV)所示的(S)型化合物脱去R2和R1基团，制得式(I)所示的瑞格列奈产物。
其中化合物(II)以3-甲基-1-(2-哌啶-1-基)苯基)-1-丁酮为起始原料，经脱水、还原、拆分、游离得到，R1为对甲氧基苄基，具体路线如下：
化合物(III)外购得到，其中R2为乙基；
对本方案中的步骤(2)进一步优化，上述式(IV)所示的(S)型化合物先在碱存在的条件下，脱去R2基团，然后在酸存在的条件下，脱去R1基团。
上述优选方案中的碱选自有机碱或无机碱，其中有机碱选自甲醇钠、乙醇钠或叔丁醇钾；无机碱选自碳酸钠、碳酸钾、氢氧化钠或氢氧化钾，优选氢氧化钠或氢氧化钾。
上述优选方案中的酸选自三氟乙酸和甲磺酸的混合酸。
在本方案中，式(II)所示的(S)型化合物的优选的结构式为
在本方案中，“缩合剂”指酸或活化酯与氨基发生酰胺化反应所用的脱水剂或酸活化剂，选自DCC、DIC、HoBt+EDC、Ph3P+DIAD、Ph3P+DEAD、CDI等，优选CDI。
在本制备方法中，由于R1基团的引入，不仅避免了在氨基上发生副反应，而且增加了氨基的亲核性，使得式(II)所示的(S)型化合物与式(III)所示的化合物进行的缩合反应更加容易，缩短了反应时间，提高了产品的纯度；同时，本发明中，式(IV)所示的(S)型化合物先在碱存在的条件下脱去R2基团，然后在酸存在的条件下脱去R1基团，和传统的脱保护基反应相比，反应更完全，收率更高，更适合于工业化生产。
具体实施方式
为了更详细地说明本发明，给出下述制备实例。但本发明的范围并非限定于此。
实施例一
(S)-N-(4-甲氧基苄基)-3-甲基-1-[2-(1-哌啶基)苯基]丁基-1-胺的制备
将原料3-甲基-1-(2-哌啶-1-基)苯基)-1-丁酮(3.3Kg，13.4mol)，甲苯(30L)，对甲苯磺酸(330g)，4-甲氧基苄胺(4.5Kg，32.5mol)投入反应釜中，回流分水反应五小时。加入无水硫酸钠约(1.6Kg)，继续反应过夜。次日，将反应液冷却至室温，冲入饱和碳酸氢钠溶液(20L)中，分层，水层用乙酸乙酯(10L)提取，合并有机层，干燥，浓缩干得油状物：8.0Kg。
TLC：石油醚/乙酸乙酯＝20/1，Rf原料＝0.7，Rf产物＝0.3
将上步油状物(8.0Kg)，甲醇(30L)，六水合氯化镍(7Kg)投入反应釜中，冷却到0℃。于0℃以下分批加入硼氢化钠(4.5Kg)。反应液颜色变黑，产生大量气泡，放热明显。加料完毕后自然升温反应五小时。反应液用浓盐酸调PH＝1～2，然后碳酸钾溶液调PH＝9～10，乙酸乙酯(20L×3)提取，合并有机层，无水硫酸镁干燥，浓缩干，柱层析得油状物：3.6Kg。
展开剂：石油醚/乙酸乙酯＝3/1，Rf原料＝0.9，Rf产物＝0.6
将上步油状物(3.6Kg，9.7mol)、L-扁桃酸(1.5Kg，9.4mol)、异丙醇/水(1：1)的混合溶剂(17L)投入到反应釜中，加热至回流，溶清后，自然放置析晶，过滤，干燥得粗品：3.2Kg；
将上步固体投入到反应釜中，加入甲醇/水(1：1)的混合溶剂(26L)加热至回流溶清，放冷自然析晶，过滤，干燥，得固体：1.53Kg。
将氢氧化钠(120g，3.0mol)和纯化水(1.1L)投入到20L反应釜中，加入甲苯(6.8L)以及所得固体(1.53Kg，2.95mol)，室温搅拌反应45分钟。
分层，有机层用水(4L×2)洗涤，无水硫酸镁干燥。过滤，得目标化合物滤液，直接用于下步反应。
实施例二
(S)-4-(2-((4-甲氧基苄基)(3-甲基-1-(2-(1-哌啶基)苯基)丁基)氨基)-2-氧代乙基)-2-乙氧基苯甲酸乙酯的制备
将上步中的(S)-N-(4-甲氧基苄基)-3-甲基-1-[2-(1-哌啶基)苯基]丁基-1-胺甲苯干燥液、CDI(640g)、侧链酸2-(3-乙氧基-4-(乙氧基羰基)苯基)乙酸(750g)投入到50L反应釜中，加入乙腈(4L)，室温搅拌反应8小时。加入水(6L)搅拌，分层，水层用乙酸乙酯(6L×2)提取，合并有机层，用饱和盐水洗涤，无水硫酸镁干燥。过滤，滤液减压浓缩干，残余物柱层析纯化(洗脱剂为：二氯甲烷/甲醇＝100：1)，合格组分浓缩干，得油状物：1.34Kg。
TLC：石油醚：乙酸乙酯＝3：1，Rf原料＝0.6，Rf产物＝0.7
CDI：N，N-羰基二咪唑
实施例三
(S)-2-乙氧基-4-{2-[(3-甲基-1-(2-(1-哌啶基)苯基)丁基)氨基]-2-氧代乙基}苯甲酸(瑞格列奈)的制备
1)碱解
将上步中间体3(1.34Kg)，甲醇(8L)、氢氧化钠水溶液(氢氧化钠/水＝560g/2.2L)投入到20L反应釜中，加热至回流反应2小时。减压浓缩除去甲醇，残余液用10％的盐酸调PH＝4～5，二氯甲烷提取(2.8L×2)，合并有机层，无水硫酸镁干燥。过滤，滤液减压浓缩干，所得中间体直接用于下步投料。
TLC：石油醚/乙酸乙酯＝3/1，Rf产物＝0.3，Rf原料＝0.8；
2)酸解
向上步中间体中加入三氟乙酸(5.4L)，搅拌20分钟后，滴加入甲磺酸(0.92L)，室温搅拌反应1.5小时。加入水(8.5L)，用40％的氢氧化钾溶液调PH＝6，搅拌20分钟，乙酸乙酯(5L)提取，水层用乙酸乙酯(5L)反提，合并有机层，用5％的氢氧化钾溶液(5L)提取，有机层再用5％的氢氧化钾溶液(2.5L×2)提取，合并水层，用盐酸调PH＝5，乙酸乙酯(6L×2)提取，合并有机层，饱和盐水(5L×2)洗涤，无水硫酸镁干燥。过滤，滤液减压浓缩至体积2.0L左右，冷却析晶，过滤，干燥得瑞格列奈：610g。
Claims (9)
1、一种制备式(I)所示瑞格列奈的方法，
所述方法包括：
(1)、式(II)所示的(S)型化合物与式(III)所示的化合物在缩合剂存在下进行酰胺化反应，生成式(IV)所示的(S)型化合物，即
其中，
R1选自苄基、对硝基苄基、对甲氧基苄基、对甲基苄基；
R2选自甲基、乙基、叔丁基、苄基、对硝基苄基或对甲氧基苄基；(2)、式(IV)所示的(S)型化合物脱去R2和R1基团，制得式(I)所示的瑞格列奈产物。
2.根据权利要求1所述的方法，其中所述缩合剂选自DCC、DIC、HoBt和EDC的组合、Ph3P和DIAD的组合、Ph3P和DEAD的组合或CDI。
3、根据权利要求2的制备方法，其特征在于所用的缩合剂为CDI。
4.根据权利要求1所述的方法，其中R1为对甲氧基苄基。
5.根据权利要求1所述的方法，其中R2为乙基。
6、根据权利要求1的制备方法，其特征在于式(IV)所示的(S)型化合物
先在碱存在的条件下脱去R2基团，然后在酸存在的条件下脱去R1基团。
7、根据权利要求6的制备方法，其特征在于所述的碱选自甲醇钠、乙醇钠、叔丁醇钾、碳酸钠、碳酸钾、氢氧化钠或氢氧化钾
8.根据权利要求7所述的制备方法，所述的碱为氢氧化钠或氢氧化钾。
9、根据权利要求6的制备方法，其特征在于所述的酸为三氟乙酸和甲磺酸的混合酸。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101781272A (zh) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | 一种瑞格列奈胺的制备方法及其中间体 |
| CN102267959A (zh) * | 2011-07-06 | 2011-12-07 | 海南锦瑞制药股份有限公司 | 一种瑞格列奈晶体、其制备方法及含有该晶体的固体口服制剂 |
| CN103012319A (zh) * | 2011-09-20 | 2013-04-03 | 浙江九洲药业股份有限公司 | 瑞格列奈中间体的合成工艺改进 |
| CN108129419A (zh) * | 2017-12-22 | 2018-06-08 | 陈益德 | 一种瑞格列奈合成方法 |
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| WO2012071374A1 (en) * | 2010-11-23 | 2012-05-31 | Abbott Laboratories | Methods of treatment using selective bcl-2 inhibitors |
| CN102786498A (zh) * | 2011-05-20 | 2012-11-21 | 江苏豪森医药集团连云港宏创医药有限公司 | 一种制备瑞格列奈的方法 |
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| IN192527B (zh) * | 2001-09-25 | 2004-04-24 | Ranbaxy Lab | |
| US7915421B2 (en) * | 2003-05-14 | 2011-03-29 | Cilag Ltd. | Method for preparing phenyl acetic acid derivatives |
| US20070123565A1 (en) * | 2004-07-23 | 2007-05-31 | Aher Umesh P | Donepezil Hydrochloride Form VI |
| CN100445275C (zh) * | 2006-06-21 | 2008-12-24 | 浙江大学 | 一种合成瑞格列奈的工艺 |
| CN100537552C (zh) * | 2007-05-16 | 2009-09-09 | 江苏豪森药业股份有限公司 | 一种制备瑞格列奈的方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101781272A (zh) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | 一种瑞格列奈胺的制备方法及其中间体 |
| CN101781272B (zh) * | 2010-02-11 | 2012-12-05 | 上海百灵医药科技有限公司 | 一种瑞格列奈胺的制备方法及其中间体 |
| CN102267959A (zh) * | 2011-07-06 | 2011-12-07 | 海南锦瑞制药股份有限公司 | 一种瑞格列奈晶体、其制备方法及含有该晶体的固体口服制剂 |
| CN102267959B (zh) * | 2011-07-06 | 2013-05-01 | 海南锦瑞制药股份有限公司 | 一种瑞格列奈晶体、其制备方法及含有该晶体的固体口服制剂 |
| CN103012319A (zh) * | 2011-09-20 | 2013-04-03 | 浙江九洲药业股份有限公司 | 瑞格列奈中间体的合成工艺改进 |
| CN103012319B (zh) * | 2011-09-20 | 2015-06-10 | 浙江九洲药业股份有限公司 | 瑞格列奈中间体的合成工艺改进 |
| CN108129419A (zh) * | 2017-12-22 | 2018-06-08 | 陈益德 | 一种瑞格列奈合成方法 |
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