CN1412183A - 替米沙坦的一种新的制备路线 - Google Patents
替米沙坦的一种新的制备路线 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 6
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 23
- 229960005187 telmisartan Drugs 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical compound C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 7
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- ILXRSCZVHSZGCS-UHFFFAOYSA-N 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-1h-benzimidazole Chemical compound C1=CC=C2N(C)C(C3=CC(C)=C4N=C(NC4=C3)CCC)=NC2=C1 ILXRSCZVHSZGCS-UHFFFAOYSA-N 0.000 description 2
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- WTFUTSCZYYCBAY-SXBRIOAWSA-N 6-[(E)-C-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-N-hydroxycarbonimidoyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C/C(=N/O)/C1=CC2=C(NC(O2)=O)C=C1 WTFUTSCZYYCBAY-SXBRIOAWSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- 229950006323 angiotensin ii Drugs 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- SCQUWJNTFMIYAV-UHFFFAOYSA-N ethyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CCOC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 SCQUWJNTFMIYAV-UHFFFAOYSA-N 0.000 description 1
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- RMXGTMRDXKUUDJ-UHFFFAOYSA-N methyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 RMXGTMRDXKUUDJ-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种抗高血压药物的活性成分——替米沙坦的制备方法。其特征在于中间体I与4′－溴甲基联苯－2－腈经亲核取代反应制得替米沙坦的氰基衍生物(IV)后，IV的氰基再水解为羧基得最终产物替米沙坦(III)。本发明阐述的工艺中采用4′－溴甲基联苯－2－腈代替4′－溴甲基联苯－2－羧酸酯与I反应，由于4′－溴甲基联苯－2－腈已有市场供应，且较稳定，与I的反应速度快，所得产物IV杂质少，从而保证了终产物III的纯度。该路线总的反应步骤少于已有的文献报道路线，且反应条件易控制，操作简便，原料价廉易得，适合于大规模生产。
Description
技术领域
本发明涉及一种新的抗高血压药物替米沙坦(Telmisartan)的制备方法。
背景技术
替米沙坦为一种新型非肽类血管紧张素II(ATII)受体拮抗剂。其结构如下：
已有替米沙坦的合成路线(Scheme 1)主要是以3-甲基-4-氨基苯甲酸甲酯为起始原料经N-酰化、硝化、还原、环合、酯水解、缩合反应而得中间体2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑(I)，I与4′-溴甲基联苯-2-羧酸叔丁酯经亲核取代反应得到化合物II，II再水解为最终产物替米沙坦(III)(Ries U，Mihm G，Narr B等，J Med Chem，1993，36：4040-4051)。经过改进，也可采用4′-溴甲基联苯-2-羧酸甲酯或4′-溴甲基联苯-2-羧酸乙酯与I反应后再水解为替米沙坦(沈敬山，李剑峰，严铁马等，替米沙坦的合成新路线.Appl.No.：CN 01126367.9，2001)。在已有制备方法中，都是先用酯基保护4′-溴甲基联苯-2-羧酸的羧基，再与I反应，但4′-溴甲基联苯-2-羧酸酯需另行制备，从而使总的合成步骤较多，生产成本也较高。
Scheme 1 
发明内容
本发明目的是寻找替米沙坦的更为简便的工业制备方法。
本发明通过如下反应实施。
本发明采用4′-溴甲基联苯-2-腈代替4′-溴甲基联苯-2-羧酸酯与I进行亲核取代反应生成IV，再将IV的氰基水解为羧基得目的物III。路线如Scheme 2所示。
Scheme2
本发明包括下列步骤：
(1)2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑(I)与4′-溴甲基联苯-2-腈经亲核取代反应生成4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-腈(IV)。更具体地说，是采用有机碱(例如醇钠、三乙胺、三正丁胺、三丙基胺)或无机碱(例如NaOH、KOH、CsOH、Ba(OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3)为去酸剂，在20～80℃的温度范围内反应4～6小时，生成中间体IV。反应溶剂可选用DMF、DMSO、THF、二氧六环、吡咯烷酮类、六甲基磷酰胺、丙酮、乙二醇二甲醚、CH2Cl2、二氯乙烷等。
(2)IV的氰基水解为酸得4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-羧酸(III)，即替米沙坦。IV可在酸性条件(例如H2SO4、浓盐酸、氢溴酸、浓盐酸/冰醋酸、氢溴酸/冰醋酸等)下水解，反应温度可控制在室温至回流状态的范围内。IV也可在碱性条件下，更具体地说，是在无机碱(例如NaOH、KOH、CsOH、Ba(OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3)或有机碱(例如醇钠)存在下，以C1～C5低级醇(例如甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、异戊醇、乙二醇、丙二醇)与水(醇∶水＝1～9∶9～1，V∶V)的混合溶剂或其它溶剂(例如DMF、DMSO、THF、二氧六环、吡咯烷酮类)与水(其它溶剂∶水＝1～9∶9～1，V∶V)的混合溶剂为溶剂，在30～160℃的温度范围内反应10～20小时，水解为目的物III。
本发明具有如下优点：
1. 4′-溴甲基联苯-2-腈比4′-溴甲基联苯-2-羧酸酯尤其是4′-溴甲基联苯-2-羧酸叔丁酯更稳定，且已有市场原料供应，价格低廉，不需另行制备，从而使总的反应步骤少于已有的文献报道路线，也降低了成本。
2. 4′-溴甲基联苯-2-腈与I的反应速度快，反应条件温和，所得中间体IV稳定性好，纯度高，使最终产品III的质量和收率得到了保证。
3.反应条件易控制，操作简便，适于大规模生产。
具体实施方式
下面各实施例进一步说明本发明，但不作任何限制。
实施例1 4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-腈(IV)
将I(30.4g，0.10mol)、4′-溴甲基联苯-2-腈(29.9g，0.11mol)、K2CO3细粉(或如前所述其它无机碱)(41.4g，0.3mol)与DMF(或如前所述其它溶剂)(300ml)混合，40℃反应约5小时。TLC检测无原料后将反应液倒入到冰水(600g)中，以乙酸乙酯提取(300ml×3)，合并有机相，水沈(300ml×2)，饱和食盐水洗(300ml)。无水硫酸钠干燥后减压浓缩至小体积，搅拌下滴加石油醚至固体析出。得IV粗品(45.5g，91.9％)。可不经纯化直接用于下步反应。分析样品以乙酸乙酯-石油醚重结晶，得白色固体。1HNMR(CDCl3)：1.05(3H，t，CH2CH3)，1.88(2H，m，CH2CH2CH3)，2.79(3H，s，Ar-CH3)，2.92(2H，t，CH2CH2CH3)，3.86(3H，s，NCH3)，5.44(2H，s，ArCH2)，7.17～7.82(14H，m，ArH)。MS(EI)m/z：495(M+，基峰)，480，467，452，303，274，192，165。
实施例2 4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-腈(IV)
将I(30.4g，0.10mol)、4′-溴甲基联苯-2-腈(29.9g，0.11mol)、乙醇钠(或如前所述其它有机碱)(20.4g，0.3mol)与干燥DMF(或如前所述其它溶剂)(300ml)混合，80℃反应3小时。后处理同实施例1。
实施例3 4′-[(1，4′-二甲基2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-羧酸(III)
取上步所得IV(24.8g，0.05mol)与冰乙酸(150ml)和浓盐酸(300ml)(或如前所述其它酸)混合，100℃反应10小时。减压浓缩去大部分混酸，余物慢慢倒入到水(500g)中，搅拌，即有固体析出，过滤，少量水洗，得III粗品，以DMF重结晶得III(22.2g，86.4％，HPLC＞99.0％)。mp 261～263℃。1HNMR(DMSO-d6)：0.98(3H，t，CH2CH3)，1.80(2H，m，CH2CH2CH3)，2.61(3H，s，Ar-CH3)，2.92(2H，t，CH2CH2CH3)，3.81(3H，s，NCH3)，5.62(2H，s，ArCH2)，7.15～7.73(14H，m，ArH)。MS(EI)m/z：515(M+1)，469(基峰)，442，303，274，165，77。
实施例4 4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-羧酸(III)
IV(24.8g，0.05mol)加入乙醇(或如前所述其它溶剂)(200ml)，NaOH(8.0g，0.2mol)(或如前所述其它碱)，水(100ml)，回流反应10小时。减压回收乙醇至余留液体积约为60ml，滴加盐酸(1∶1)至pH为5～6，有固体析出，过滤，水洗，得III粗品，以DMF重结晶得III(20.4g，79.5％)。
实施例5 4′-[(1，4′-二甲基2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-羧酸(III)
IV(24.8g，0.05mol)加入乙二醇(100ml)和水(150ml)(或如前所述其它混合溶剂)、乙醇钠(或如前所述其它醇钠)(13.6g，0.2mol)，回流反应10小时。TLC检测无原料后冷至室温，滴加盐酸(1∶1)至pH为5～6，有固体析出，过滤，水洗，得III。
Claims (10)
1.一种反应步骤如下的替米沙坦合成方法：
经由起始原料2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑与4′-溴甲基联苯-2-腈在有机碱或无机碱的存在下，在反应溶剂中、一定温度下，进行数小时的亲核取代反应制得关键中间体4′-[(1，4′-二甲基-2′-丙基[2，6′-二-1H-苯并咪唑]-1′-基)甲基]-[1，1′-联苯]-2-腈，然后水解为替米沙坦。
2.根据权利要求1所述替米沙坦合成方法其特征在于亲核取代反应以有机碱为去酸剂，有机碱为醇钠、三乙胺、三正丁胺、三丙基胺。
3.根据权利要求1所述替米沙坦合成方法其特征在于无机碱去酸剂，无机碱为NaOH、KOH、CsOH、Ba(OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3。
4.根据权利要求1所述替米沙坦合成方法其特征在于亲核取代反应温度为20～80℃，反应时间为4～6小时。
5.根据权利要求1所述替米沙坦合成方法其特征在于亲核取代反应溶剂为DMF、DMSO、THF、二氧六环、吡咯烷酮类、六甲基磷酰胺、丙酮、乙二醇二甲醚、CH2Cl2、二氯乙烷。
6.根据权利要求1所述替米沙坦合成方法其特征在于氰基水解在酸性条件下进行，可用H2SO4、浓盐酸、氢溴酸、浓盐酸/冰醋酸、氢溴酸/冰醋酸水解，水解温度为室温至回流状态之间。
7.根据权利要求1所述替米沙坦合成方法其特征在于氰基水解在碱性条件下进行，以C1～C5低级醇与水的混合溶剂或其他溶剂与水的混合溶剂为溶剂，在30～160℃反应10～20小时。
8.根据权利要求7所述替米沙坦合成方法其特征在于无机碱为NaOH、KOH、CsOH、Ba(OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3。
9.根据权利要求7所述替米沙坦合成方法其特征在于有机碱为醇钠。
1O.根据权利要求7所述替米沙坦合成方法其特征在于水解反应的溶剂为C1～C5低级醇与水的混合溶剂，其比例为醇∶水＝1～9∶9～1(V∶V)，或DMF、DMSO、THF、二氧六环、吡咯烷酮类等其他溶剂与水的混合溶剂，其比例为其他溶剂∶水＝1～9∶9～1(V∶V)。
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| WO2006044648A1 (en) * | 2004-10-15 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing telmisartan |
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