CN101045712A - Synthesis method of valsartan - Google Patents
Synthesis method of valsartan Download PDFInfo
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- CN101045712A CN101045712A CN 200710090688 CN200710090688A CN101045712A CN 101045712 A CN101045712 A CN 101045712A CN 200710090688 CN200710090688 CN 200710090688 CN 200710090688 A CN200710090688 A CN 200710090688A CN 101045712 A CN101045712 A CN 101045712A
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- Prior art keywords
- reaction
- trityl
- val
- tetrazole
- methyl ester
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 33
- 229960004699 valsartan Drugs 0.000 title claims abstract description 33
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title abstract 4
- 238000001308 synthesis method Methods 0.000 title 1
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 claims abstract description 32
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 24
- 239000001301 oxygen Substances 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 9
- 238000010189 synthetic method Methods 0.000 claims abstract description 7
- 230000020477 pH reduction Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 44
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000003536 tetrazoles Chemical class 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- -1 inorganic acid salt Chemical class 0.000 claims description 8
- SQCZQTSHSZLZIQ-UHFFFAOYSA-N 1-chloropentane Chemical compound CCCCCCl SQCZQTSHSZLZIQ-UHFFFAOYSA-N 0.000 claims description 7
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 235000010755 mineral Nutrition 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 3
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000004904 shortening Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PCTNAMGLSYHIPL-UHFFFAOYSA-N tin(4+) tetraazide Chemical compound [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] PCTNAMGLSYHIPL-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229950004288 tosilate Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
- 229940005605 valeric acid Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention relates to a new synthetic method of valsartan, includes preparation method of intermediate N - ( 1 - oxygen amyl) - N - [ [ 2' - trityl - tetrazolium - 5 - group) - ( 1, 1' - dibenzyl) - 4 - group] - methyl] - L - valine. 2' - ( N - trityl) tetrazolium - 4 - bromoethyl Biphenyl and valine methyl ester ( or other salt) carry out alkylation reaction, after acidylation, by alkaline hydrolysis and acidification to obtain intermediate N - ( 1 - oxygen amyl) - N - [ [ 2' - trityl - tetrazolium - 5 - group) - ( 1, 1' - dibenzyl) - 4 - group] - methyl] - L - valine, then by protection solution to gain Valsartan. This invention belong to pharmaceutical chemistry and organic chemistry region, possess merits of raw material stabilization, yield higher, valsartan optical purity high, industrialization operating easy and so on.
Description
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, particularly, the present invention relates to valsartan (Valsartan, 1) novel synthesis, and intermediate---N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation method of L-Xie Ansuan (2).
Background technology
Valsartan (Valsartan) is a kind of non-peptide class Angiotensin II (ATII) receptor antagonist, the chemistry of valsartan is called N-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-the L-Xie Ansuan, the chemical structure of valsartan is as the formula (1).
Known valsartan and (or) synthetic method such as the patent US 5,399,578 of intermediate, US 5,965, and 592, WO 02/006253, and CN 1317485, and WO 04/026847, WO 04/111018, WO 05/049586, WO05/049587 and J.Med.Chem.1991,34 (8), 2525-2574, Bioorganic ﹠amp; Med.Lett.1994,4 (1), 29-34.
U.S. Pat 5; 399; the 578 valsartan synthetic methods of describing are shown in reaction formula (1); with 2 '-cyano group-4-formyl biphenyl (3) is raw material; with the tosilate (4) of L-Xie Ansuan benzyl ester through reductive amination process; positive valeryl reaction becomes tetrazole, go to protect valsartan (2).The shortcoming of this method is: one, adopts trialkyl azide tin and cyano group to react down at 120-140 ℃ and generate tetrazole, but trialkyl azide tin toxicity is big.1317485 pairs of tetrazole synthetic methods of patent CN are improved, the employing sodiumazide is a raw material, the polyoxyethylene glycol that trialkyl azide tin and terminal hydroxy group are silylated is a catalyzer, though reduced the consumption of trialkyl azide tin, sodiumazide danger is bigger.Its two, adopt the method for shortening to slough benzyl protecting group, need use hydrogenation unit.In addition, 04/111018 pair of method of sloughing benzyl of world patent WO is improved, and adopts hydrolysis under the alkaline condition, has avoided shortening; But the optical purity of valsartan crude product is not appeared in the newspapers, and yield is lower.
Reaction formula (1):
The valsartan synthetic method that world patent WO 04/026847 describes is shown in reaction formula (2); 2 '-tetrazole base-4-formyl biphenyl (4) with the protected mistake of tetrazole is a raw material; generate Schiff's base with L-Xie Ansuan or derivative (5) condensation; again through shortening or metal hydride reduction; gained secondary amine and n-amyl chloride carry out acylation reaction in the presence of water, obtain the valsartan (1) of high-optical-purity.The shortcoming of this method is: one, 2 '-tetrazole base-4-formyl biphenyl (or 2 '-tetrazole of the protected mistake of tetrazole base-4-formyl biphenyl) need preparation separately, cost height.Its two, need to adopt adopt shortening or metal hydride reduction Schiff's base.Its three, in the positive valeryl reaction, the existence of water can improve the optical activity of product valsartan on the one hand; But causing the n-amyl chloride partial hydrolysis simultaneously is positive valeric acid, influences the crystallization purifying of valsartan.
Reaction formula (2):
The valsartan synthetic method that existing patent WO 05/049586 describes is shown in reaction formula (3); 2 '-tetrazole base-4-bromomethylbiphenyl (7) with the protected mistake of tetrazole is a raw material; L-Xie Ansuan (6) condensation prepared secondary amine with the esterified protection of carboxyl; through positive valeryl reaction; slough the protecting group of tetrazole; and then, obtain valsartan (1) by the hydrolysis of ester group reaction.In this patent report, separating tetrazole protective group and hydrolysis of ester group reaction two rapid step by step yields is 50%, and the chiral purity of gained valsartan is not reported.
Reaction formula (3):
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of preparation valsartan (1).Another object of the present invention has provided a kind of N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation method of L-Xie Ansuan (2).
The inventor is through research, find a kind of effectively synthetic N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-method of L-Xie Ansuan (2), and this method is applied to the preparation of valsartan (1), research and develop the variation route of a preparation valsartan, finished the present invention thus.
According to the present invention, it is characterized in that, among the present invention, valsartan (1) is through intermediate N (1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (2), by following steps preparations, shown in reaction formula (4).
Reaction formula (4):
According to the present invention, alkylated reaction described in the above-mentioned preparation process is meant 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) (or its salt) synthetic N-[[2 '-(N-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl under alkaline condition]-methyl]-reaction of L-valine methyl ester (Val-1).
According to the present invention, described valine methyl ester salt is meant the inorganic acid salt of valine methyl ester, example hydrochloric acid salt, vitriol; Or organic acid salt, as tosilate.
Specifically, alkylated reaction of the present invention is in the presence of organic bases (for example triethylamine, diisopropylethylamine etc.), in organic solvent, nucleo philic substitution reaction obtains compound (Val-1) by 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) or its salt.Wherein, temperature of reaction is in-20-80 ℃ temperature range; Reaction times is in 1-24 hour; Organic solvent is selected from THF, dioxane, methylene dichloride, ethylene dichloride, toluene, acetonitrile etc.
According to the present invention; acylation reaction described in the above-mentioned preparation process is meant N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1; 1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-1) and n-amyl chloride synthetic N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl under alkaline condition]-methyl]-reaction of L-valine methyl ester (Val-2).
Specifically; acylation reaction of the present invention is at organic bases (for example triethylamine, diisopropylethylamine etc.); perhaps mineral alkali (for example salt of wormwood, yellow soda ash) exists down, in organic solvent, obtains compound (Val-2) through acylation reaction by compound (Val-1) and n-amyl chloride.Wherein, temperature of reaction is in-20-80 ℃ temperature range; Organic solvent is selected from N, dinethylformamide, tetrahydrofuran (THF), dioxane, methylene dichloride, ethylene dichloride, toluene, acetonitrile etc.; Reaction times is in 1-24 hour.
According to the present invention, it is characterized in that, the reaction of alkaline hydrolysis described in the above-mentioned preparation process is meant N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-2) hydrolysis methyl esters under alkaline condition, obtain intermediate (Val-2 ').
According to the present invention, it is characterized in that described alkaline hydrolysis reaction is in the presence of excessive mineral alkali, carries out in the mixture of organic solvent and water.Wherein, organic solvent is selected from polar solvent, as lower aliphatic alcohols, and methyl alcohol, ethanol, propyl carbinol; Or aprotic polar solvent, as 1,4-dioxane, tetrahydrofuran (THF), N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO); Or the mixture of two or more solvents wherein.According to the difference of selecting organic solvent for use, the ratio of water and organic solvent changes in 1: 1000 to 5: 1 scope, is preferably 1: 10 to 5: 1.The consumption of organic solvent is 1-100 a times of compound (Val-2), is preferably 1-30 doubly.
According to the present invention, in the alkaline hydrolysis reaction, used alkali is selected from alkali metal hydroxide or alkaline earth metal hydroxides, as potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide etc.
According to the present invention, in the alkaline hydrolysis reaction, the consumption of alkali is N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-5 to 1000 times (mol ratio) of L-valine methyl ester (Val-2), be preferably 10 to 100 times (mol ratio).
According to the present invention, can get compound (2) after the acidifying of above-mentioned alkaline hydrolysis reaction product; Wherein, the required acid of acidification reaction is preferably from organic acid, as acetate, formic acid, citric acid etc.
According to the present invention, prepared N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-optical purity of L-Xie Ansuan (2) is more than 95%.
According to the present invention, separate protective reaction in the described reaction formula (4), be meant the reaction of sloughing trityl-protecting group.Can be undertaken by known method of separating trityl.
Among the present invention, compound (Val-2) is earlier at alkaline condition hydrolysis ester group, and acidifying obtains compound (2) again, and compound (2) is sloughed trityl-protecting group at last and obtained valsartan (1), and total recovery is more than 67%, and chiral purity can reach more than 99%.And existing patent WO 05/049586 takes to slough earlier trityl-protecting group, uses the method for trimethyl silicane potassium alcoholate ester hydrolysis base again, and the yield of example 10 reports only is 50% in this patent, and the optical purity of this patented method products therefrom valsartan is not reported.Compare with WO 05/049586, this patent method yield is higher, and can obtain the valsartan of high-optical-purity.The present invention has also that raw material stable is easy to get, advantage such as industrialization operation easily.
Embodiment
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention; Under design prerequisite of the present invention, preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention.
In the following example, the optical purity of compound records with chirality HPLC.
Example 1.N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-1)
Drying tube is being housed, and thermometer in the 1000mL four-hole bottle of dropping funnel and mechanical stirring slurry, adds valine methyl ester (Val-OMe, 24.3g, 0.185mol), and diisopropylethylamine (18.7g, 0.185mol), and methylene dichloride (300mL), stirring and dissolving, cooling.Under-10～0 ℃, drip N-trityl-2 '-tetrazole base-4-bromomethylbiphenyl (BBTT, 100g, 0.179mol) methylene dichloride (300mL) solution, finish, under 0～10 ℃, continue reaction 4 to 5 hours, TLC (developping agent, normal hexane: ethyl acetate=5: 1) show that raw material disappears substantially, the sodium bicarbonate aqueous solution washing of adding 5%, saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester crude product 110g (the HPLC analytical results shows that the content of Val-1 is 90% in the crude product).This crude product need not to be further purified, and directly carries out the next step.
Example 2.N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-1)
Drying tube is being housed, thermometer, in the 100mL there-necked flask of dropping funnel, the adding valine methyl ester hydrochloride (the Val-OMe hydrochloride, 3.1g, 18.5mmol), diisopropylethylamine (3.74g, 37mmol), and methylene dichloride (30mL), stirring and dissolving, cooling.Under-10～0 ℃, drip N-trityl-2 '-tetrazole base-4-bromomethylbiphenyl (BBTT, 9.98g, 0.179mol) methylene dichloride (30mL) solution, finish, under 0～10 ℃, continue about 5 hours of reaction, TLC shows that raw material disappears substantially, adds 5% sodium bicarbonate aqueous solution washing, the saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-valine methyl ester crude product 12.1g, this crude product and example 1 products therefrom are identical.
Example 3.N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-valine methyl ester (Val-2)
Drying tube is being housed, thermometer, in dropping funnel and the churned mechanically 1000mL four-hole bottle, add example 1 gained crude product successively, ethyl acetate (500mL), and triethylamine (21.2g, 0.21mol) after the stirring and dissolving, be cooled to about-10 ℃, slowly drip n-amyl chloride (24.2g, 0.20mol).Finish, under this temperature, reacted 3 hours; Heat up then, continue reaction 5 hours at 35 ℃, TLC demonstration reaction is finished.Reaction solution is used saturated aqueous common salt, phosphoric acid buffer (pH=7), deionized water wash successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester crude product 110g (the HPLC analytical results shows that the content of Val-2 is 85.1% in the crude product).This crude product can directly carry out the next step.
Example 4.N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (2)
In that being housed, temperature takes into account in the churned mechanically 1000mL there-necked flask, adding example 3 gained Val-2 crude products (110g, content 85.1%, 0.135mol), tetrahydrofuran (THF) (500ml), after the stirring and dissolving, and the adding lithium hydroxide aqueous solution (concentration 10%, 250ml), in 45 ℃ of following stirring reactions 12 hours, TLC (developping agent, normal hexane: ethyl acetate: acetate=63: 35: 2) show that raw material disappears, and divides the phase of anhydrating; It is 7-8 that the gained organic phase is regulated pH with Glacial acetic acid, is evaporated to small volume, adds ethyl acetate (1000ml), the saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure is separated out solid.Gained solid re-crystallizing in ethyl acetate, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-Xie Ansuan (2) 68.2g, yield is 74.5% (in Val-2).Fusing point: 160-161 ℃, optical purity 97.1%.
Ultimate analysis:
Molecular formula: C43H43N5O3
Calculated value (%): C, 76.16; H, 6.35; N, 10.33
Measured value (%): C, 76.17; H, 6.47; N, 10.47
1H-NMR(400MHz，DMSO-d6)0.845(t，6H)，0.969(d，J＝6.4Hz，3H)，1.288～1.230(m，2H)，1.599～1.562(m，2H)，2.345～2.279(m，2H)，2.630～2.605(m，1H)，3.791(d，J＝10Hz，1H)，4.470(dd，2H)，7.017～6.948，7.448～7.225(m，18H)，6.957(d，J＝7.6Hz，2H)，7.130(d，J＝7.6Hz，2H)，7.938(d，J＝7.6Hz，1H)，～11(brs，1H)ppm.
Example 5.N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (2)
In that being housed, temperature takes into account in the churned mechanically 1000mL there-necked flask, add example 3 gained Val-2 crude product (110g, content 85.1%, 0.135mol), tetrahydrofuran (THF) (400ml), after the stirring and dissolving, add lithium hydroxide (26.4g, 1.1mol) and water (40ml), in 60 ℃ of following stirring reactions 24 hours, TLC shows that raw material disappears, and divides the phase of anhydrating; It is 7-8 that the gained organic phase is regulated pH with Glacial acetic acid, is evaporated to small volume, adds ethyl acetate (1000ml), the saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure is separated out solid.Gained solid re-crystallizing in ethyl acetate, N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-L-Xie Ansuan (2) 73.2g, yield is 79% (in Val-2).Fusing point: 160-161 ℃, optical purity 96.9%.
Example 6.N-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-preparation of L-Xie Ansuan (valsartan, 1)
N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (2,67.8g, 0.1mol) be dissolved in the methylene dichloride (250ml), add hydrochloric acid (1N, 50ml), stirring reaction to raw material disappears under room temperature, divides the phase of anhydrating; Organic phase saturated common salt water washing adds entry (300ml) again, and the ice-water bath cooling is regulated pH=9 to 10, standing demix with aqueous sodium hydroxide solution (1N) down.Water intaking is placed in the 1000ml there-necked flask, adds methylene dichloride (300ml), stirs down, regulate pH=3 to 4 with hydrochloric acid (6N), tell organic phase after, water layer extracts twice with methylene dichloride (150ml), merge organic phase, anhydrous sodium sulfate drying, be evaporated to small volume after, add the ethyl acetate crystallization, get valsartan (1) 38.3g, yield 88.1%, fusing point 116.3-117.2 ℃, purity (HPLC) 99.1%.
Claims (14)
1, the synthetic method of a kind of valsartan (1), and intermediate N (1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-preparation method of L-Xie Ansuan (2), it is characterized in that reactions steps is shown in reaction formula 4:
Reaction formula 4
In the described reaction formula 4; with 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) or valine methyl ester salt is raw material; through alkylated reaction; acylation reaction; alkaline hydrolysis reaction and acidification reaction make intermediate N (1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1; 1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (2), described intermediate (2) makes valsartan (1) through separating protective reaction again.
2, method according to claim 1 is characterized in that, described valine methyl ester salt can be the inorganic acid salt of valine methyl ester, also can be the organic acid salt of valine methyl ester.
3, method according to claim 1, it is characterized in that, described alkylated reaction is in the presence of organic bases, by 2 '-(N-trityl) tetrazole base-4-bromomethylbiphenyl (BBTT) and valine methyl ester (Val-OMe) or valine methyl ester salt are in organic solvent, and nucleo philic substitution reaction obtains compound (Val-1); Wherein, temperature of reaction is in-20-80 ℃ temperature range; Reaction times is in 1-24 hour.
4, method according to claim 3 is characterized in that, described organic bases is selected from triethylamine or diisopropylethylamine; Described organic solvent is selected from a kind of in THF, dioxane, methylene dichloride, ethylene dichloride, toluene, the acetonitrile.
5, method according to claim 1, described acylation reaction is meant N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-1) and n-amyl chloride be in the presence of organic bases or mineral alkali, in organic solvent, obtain compound (Val-2) by compound (Val-1) and n-amyl chloride through acylation reaction; Wherein, temperature of reaction is in-20-80 ℃ temperature range, and the reaction times is in 1-24 hour.
6, method according to claim 5 is characterized in that, described organic bases is selected from triethylamine or diisopropylethylamine; Described mineral alkali is selected from salt of wormwood or yellow soda ash; Described organic solvent is selected from N, a kind of in dinethylformamide, tetrahydrofuran (THF), dioxane, methylene dichloride, ethylene dichloride, toluene, the acetonitrile.
7, method according to claim 1, the reaction of described alkaline hydrolysis is meant N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-valine methyl ester (Val-2) is in the presence of mineral alkali, hydrolysis methyl esters in the mixture of organic solvent and water obtains alkaline hydrolysis reaction product (Val-2 ');
The consumption of above-mentioned alkali is N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-5 to 1000 times (mol ratio) of L-valine methyl ester (Val-2); According to the difference of selecting organic solvent for use, the ratio of water and organic solvent changes in 1: 1000 to 5: 1 scope, and the consumption of organic solvent is 1-100 a times of compound (Val-2).
8, method according to claim 7, used mineral alkali is selected from alkali metal hydroxide or alkaline earth metal hydroxides, can be a kind of in potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, the calcium hydroxide.
9, method according to claim 7, the consumption of described alkali are preferably 10 to 100 times (mol ratio).
10, method according to claim 7, described organic solvent can be selected from polar solvent, can be lower aliphatic alcohols, a kind of in methyl alcohol, ethanol, the propyl carbinol; But also aprotic polar solvent, can one be 1,4-dioxane, tetrahydrofuran (THF), N, a kind of in dinethylformamide, N,N-dimethylacetamide, the dimethyl sulfoxide (DMSO); It also can be the mixture of above-mentioned two or more solvents.
11, method according to claim 7, the ratio of described water and organic solvent is preferably 1: 10 to 5: 1.
12, method according to claim 7, the consumption of described organic solvent are preferably 1-30 doubly.
13, method according to claim 1, the required acid of described acidification reaction be preferably from organic acid, can be a kind of in acetate, formic acid, the citric acid.
14, method according to claim 1, prepared N-(1-oxygen amyl group)-N-[[2 '-(N '-trityl-tetrazole-5-yl)-(1,1 '-phenylbenzene)-4-yl]-methyl]-optical purity of L-Xie Ansuan (2) is more than 95%.
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| JP2010077077A (en) * | 2008-09-26 | 2010-04-08 | Tokuyama Corp | Method for producing n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-l-valine |
| CN101475540B (en) * | 2009-01-22 | 2011-05-11 | 江苏德峰药业有限公司 | Preparation of Valsartan |
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| WO2006067216A2 (en) * | 2004-12-22 | 2006-06-29 | Enantia, S. L. | Intermediate compounds for the preparation of an angiotensin ii receptor and process for the preparation of valsartan |
| WO2007005967A2 (en) * | 2005-07-05 | 2007-01-11 | Teva Pharmaceutical Industries Ltd. | Process for preparing valsartan |
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| CN101475540B (en) * | 2009-01-22 | 2011-05-11 | 江苏德峰药业有限公司 | Preparation of Valsartan |
| CN102010381B (en) * | 2009-09-05 | 2012-02-08 | 山东新时代药业有限公司 | Improved preparation method of valsartan |
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| CN102351804B (en) * | 2011-09-30 | 2013-07-31 | 浙江新赛科药业有限公司 | Method for recovering valsartan racemate |
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| CN113717118A (en) * | 2021-09-06 | 2021-11-30 | 安徽美诺华药物化学有限公司 | Synthesis process of valsartan |
| CN113717118B (en) * | 2021-09-06 | 2022-03-01 | 安徽美诺华药物化学有限公司 | Synthesis process of valsartan |
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