CN107089972A - 一种坎地沙坦酯的制备方法 - Google Patents
一种坎地沙坦酯的制备方法 Download PDFInfo
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- CN107089972A CN107089972A CN201710486005.3A CN201710486005A CN107089972A CN 107089972 A CN107089972 A CN 107089972A CN 201710486005 A CN201710486005 A CN 201710486005A CN 107089972 A CN107089972 A CN 107089972A
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- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- WLPATYNQCGVFFH-UHFFFAOYSA-N 2-phenylbenzonitrile Chemical group N#CC1=CC=CC=C1C1=CC=CC=C1 WLPATYNQCGVFFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- XWXQEBMBBDIGOQ-UHFFFAOYSA-N 2-ethoxy-1h-benzimidazole Chemical compound C1=CC=C2NC(OCC)=NC2=C1 XWXQEBMBBDIGOQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000005997 bromomethyl group Chemical group 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 150000002118 epoxides Chemical class 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 150000003536 tetrazoles Chemical group 0.000 claims description 6
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000012805 post-processing Methods 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 claims 1
- 238000010926 purge Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- -1 alkyl formate Chemical compound 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000029936 alkylation Effects 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- 238000012544 monitoring process Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VVQNAFBGAWCMLU-UHFFFAOYSA-N 1h-benzimidazole-4-carboxylic acid Chemical class OC(=O)C1=CC=CC2=C1N=CN2 VVQNAFBGAWCMLU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 3
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 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
- SEXZHJJUKFXNDY-UHFFFAOYSA-N 1-(bromomethyl)-2-phenylbenzene Chemical group BrCC1=CC=CC=C1C1=CC=CC=C1 SEXZHJJUKFXNDY-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- KKTUQAYCCLMNOA-UHFFFAOYSA-N 2,3-diaminobenzoic acid Chemical class NC1=CC=CC(C(O)=O)=C1N KKTUQAYCCLMNOA-UHFFFAOYSA-N 0.000 description 1
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical class OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 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
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 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
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 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
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一条新型的坎地沙坦酯合成路线，包括由2‑乙氧基苯并咪唑‑7‑甲酸烷基酯与4‑溴甲基‑2’‑氰基联苯发生烷基化反应，接着酯基水解后再与1‑卤代乙基环己基碳酸酯反应得到中间体1‑[(2′‑氰基联苯‑4‑基)甲基]‑2‑乙氧基‑1H‑苯并咪唑‑7‑羧酸烷基酯，再经过四氮唑化反应得到坎地沙坦酯。本发明可以通过一锅法完成烷基化、水解和成酯反应，合成步骤少，工艺简单；所用原料廉价易得，生产成本低；三废少，绿色环保。
Description
技术领域
本发明涉及一种降血压药物坎地沙坦酯的制备方法。
背景技术
坎地沙坦酯为坎地沙坦的前体药物，坎地沙坦酯在体内迅速被水解成活性代谢物坎地沙坦。坎地沙坦为选择性血管紧张素Ⅱ受体AT1拮抗剂，通过与血管平滑肌AT1受体结合而拮抗血管紧张素Ⅱ的血管收缩作用，从而降低末梢血管阻力。
坎地沙坦酯化学名为2-乙氧基-1-{[2'-(1H-四氮唑-5-基)(1,1'-联苯基)-4-基]甲基}苯并咪唑-7-甲酸-1-{[(环己氧基)羰基]氧基}乙酯，结构式如式I所示：
目前坎地沙坦酯的合成路线主要有两条。一条是以3-硝基苯二甲酸(化合物II)或2,3-二氨基苯甲酸甲酯(化合物III)为原料，经数步反应得到四氮唑化的中间体IV，再经过皂化、N-保护、成酯和脱保护最终得到坎地沙坦酯(EP459136，J.Med.Chem.1993,36:2182-2196、2343-2349)，如路线I所示。该路线需要使用分子量较大的三苯基甲基做为保护基团，且脱保护基时用到强酸，容易生成杂质。
CN1204125C报道了一条改进的合成路线。该路线以3-硝基-2-叔丁氧基氨基苯甲酸甲酯为起始原料，经多步反应后得到中间体IX，再经过环合、皂化、成酯和四氮唑化得到坎地沙坦酯，如路线II所示。该路线省去了N-保护和脱保护两步反应，合成步骤有所缩短，但依然略显冗长。
发明内容
本发明提供了一条简短高效、经济实用、绿色环保的合成坎地沙坦酯的方法，
具体包括以下步骤：
(1)2-乙氧基苯并咪唑-7-甲酸烷基酯(XIII)在碱性条件下，与4-溴甲基-2’-氰基联苯(XIV)在有机溶剂中反应得到1-[(2′-氰基联苯-4-基)甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸烷基酯(X’)；
(2)化合物X’在碱性条件下水解为1-[(2′-氰基联苯-4-基)甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸(XI)；
(3)化合物(XI)与1-卤代乙基环己基碳酸酯经亲核取代反应生成2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)；
(4)将化合物(XII)的氰基转变为四氮唑环后得到坎地沙坦酯(I)；
合成路线如下所示：
其中化合物XIII和X’中，R为C1-C4的烷基，优选为甲基或乙基；X为卤素，优选为氯，溴，碘。
优选步骤(1)和步骤(2)为一锅法完成，中间过程没有分离纯化过程。
进一步优选步骤(1)，步骤(2)和步骤(3)为一锅法完成，中间过程没有分离纯化过程。
步骤(1)所用有机溶剂为极性溶剂，优选DMF、THF、丙酮，乙腈、二氧六环，进一步优选丙酮。
步骤(1)所用的碱优选为Na2CO3、K2CO3、Cs2CO3、甲醇钠、叔丁醇钾、Na3PO4、Na2HPO4、K3PO4或K2HPO4，进一步优选K2CO3。
步骤(2)所用的碱优选LiOH、NaOH、KOH、CsOH或Ba(OH)2，进一步优选KOH。
步骤(3)反应结束后，优选的后处理方法为：将反应液降至室温，过滤除去无机盐，浓缩除去部分溶剂，继续降温析晶，得到化合物XII。
步骤(4)所用有机溶剂为二甲苯或DMF；所述四氮唑化反应试剂可以为NaN3与路易斯酸(AlCl3、CaCl2、ZnCl2、MgCl2、NH4Cl、三丁基氯化锡等)或小分子有机酸(乙酸、丙酸、丁酸等)或三乙胺盐酸盐，优选为路易斯酸，进一步优选为ZnCl2和三丁基氯化锡。
本合成路线的优点在于：
1.合成步骤少，工艺简单。可通过“一锅法”完成烷基化、皂化和成酯反应，生产周期短，收率高。
2.所用原料廉价易得，适合大规模生产。所用起始原料2-乙氧基苯并咪唑-7-甲酸烷基酯(XIII)可以由2,3-二氨基苯甲酸烃基酯与原碳酸酯四乙酯经环合反应制得，4-溴甲基-2’-氰基联苯(XIV)则是沙坦类药物合成中的常用原料。整条路线未使用昂贵难获取的试剂，所有用到的有机溶剂均可回收套用，生产成本低。
3.“三废”少，绿色环保。本发明步骤(3)反应结束后可通过过滤除盐代替提取水洗操作，仅在四氮唑化反应后处理时产生少量废水，且仅有一次蒸馏溶剂操作，废气量少。
下面结合实施例对本发明做进一步说明，但不对本发明构成任何限制。
具体实施方式
实施例1
2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)的制备：
向500mL烧瓶中加入200mL DMF、2-乙氧基苯并咪唑-7-甲酸甲酯(XIII，22.0g，0.10mol)、K2CO3(17.9g，0.13mol)和4-溴甲基-2’-氰基联苯(28.6g，0.105mol)。升温至50～60℃，反应至TLC监测化合物XIII消失(约5～8小时)。
再向反应液加入KOH(11.8g，0.21mol)，继续保温50～60℃反应至TLC监测水解完成(约2～4小时)。加入1-氯代乙基环己基碳酸酯(31.0g，0.15mol)，升温至65～75℃，反应至TLC监测反应完成(约6～8小时)。
反应液降至室温，过滤除去无机盐。浓缩除去约120g溶剂，降温至0℃，析晶1h，得到2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)47.7g，收率84.0％(相对于XIII)，纯度95.11％。
实施例2
2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)的制备：
向500mL烧瓶中加入200mL丙酮、2-乙氧基苯并咪唑-7-甲酸甲酯(XIII，22.0g，0.10mol)、K2CO3(17.9g，0.13mol)和4-溴甲基-2’-氰基联苯(28.6g，0.105mol)。升温至回流，反应至TLC监测化合物XIII消失(约5～8小时)。
再向反应液加入KOH(11.8g，0.21mol)，继续回流反应至TLC监测皂化完成(约3～5小时)。加入1-氯代乙基环己基碳酸酯(31.0g，0.15mol)，升温至回流，反应至TLC监测成反应完成(约8～10小时)。
反应液降至室温，过滤除去无机盐。浓缩除去约100g溶剂，降温至0℃，析晶1h，得到2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)51.8g，收率91.3％(相对于XIII)，纯度97.43％。
实施例3坎地沙坦酯(I)的制备
向250mL烧瓶中加入75mL二甲苯、NaN3(6.5g，0.1mol)和三丁基氯化锡(32.6g，0.1mol)，升温至138～142℃回流反应5h。反应结束，冷却温度至70～80℃，加入化合物XII(28.4g，0.05mol)，将料液加热至138～142℃回流反应至TLC确认反应完全(约11～13h)。
降至室温，加入50mL水和4.3g(0.05mol，1eq)NaNO2，搅拌30分钟，滴加2N稀盐酸，调节pH至6，室温搅拌2小时，冷至10℃，析晶1h，过滤，滤饼用少量饮用水洗涤，烘干得坎地沙坦酯23.8g，收率87.9％，纯度96.58％。
实施例4坎地沙坦酯(I)的制备
向250mL烧瓶中加入75mL DMF、NaN3(6.5g，0.1mol)和ZnCl2(13.6g，0.1mol)，升温至138～142℃回流反应5h。反应结束，冷却温度至70～80℃，加入化合物XII(28.4g，0.05mol)，将料液加热至138～142℃回流反应至TLC确认反应完全(约10～11h)。浓缩除去约60mLDMF。
降至室温，加入50mL水和4.3g(0.05mol，1eq)NaNO2，搅拌30分钟，滴加2N稀盐酸，调节pH至6，室温搅拌2小时，冷至10℃，析晶1h，过滤，滤饼用少量饮用水洗涤，烘干得坎地沙坦酯21.5g，收率80.4％，纯度94.17％。
Claims (8)
1.一种坎地沙坦酯(I)的制备方法，其特征在于包括以下步骤：
(1)2-乙氧基苯并咪唑-7-甲酸烷基酯(XIII)在碱性条件下，与4-溴甲基-2’-氰基联苯(XIV)在有机溶剂中反应得到1-[(2′-氰基联苯-4-基)甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸烷基酯(X’)；
(2)化合物X’在碱性条件下水解为1-[(2′-氰基联苯-4-基)甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸(XI)；
(3)化合物(XI)与1-卤代乙基环己基碳酸酯(XV)经亲核取代反应生成2-乙氧基-1-[(2′-氰基联苯-4-基)甲基]-1H-苯并咪唑-7-甲酸－1-[[(环己氧基)羰基]氧基]乙酯(XII)；
(4)将化合物XII的氰基转变为四氮唑环后得到坎地沙坦酯(I)；
合成路线如下所示：
其中化合物XIII和X’中，R为C1-C4的烷基；X为卤素，选自氯，溴或碘。
2.根据权利要求1所述的方法，其中R为甲基或乙基。
3.根据权利要求1所述的方法，其中步骤(1)和步骤(2)为一锅法完成，中间过程没有分离纯化过程。
4.根据权利要求3所述的方法，其中步骤(1)，步骤(2)和步骤(3)为一锅法完成，中间过程没有分离纯化过程。
5.根据权利要求1-4任一项所述的方法，其中步骤(1)所用有机溶剂选自DMF、THF、丙酮，乙腈、二氧六环，进一步优选丙酮。
6.根据权利要求1-4任一项所述的方法，步骤(1)所用的碱为Na2CO3、K2CO3、Cs2CO3、甲醇钠、叔丁醇钾、Na3PO4、Na2HPO4、K3PO4或K2HPO4，进一步优选K2CO3。
7.据权利要求1-4任一项所述的方法，步骤(2)所用的碱为LiOH、NaOH、KOH、CsOH或Ba(OH)2，进一步优选KOH。
8.据权利要求1-4任一项所述的方法，步骤(3)后处理方法为：将反应液降至室温，过滤除去无机盐，浓缩除去部分溶剂，继续降温析晶，得到化合物XII。
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