CN112079788A - 一种缬沙坦的制备方法 - Google Patents
一种缬沙坦的制备方法 Download PDFInfo
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- CN112079788A CN112079788A CN201910508659.0A CN201910508659A CN112079788A CN 112079788 A CN112079788 A CN 112079788A CN 201910508659 A CN201910508659 A CN 201910508659A CN 112079788 A CN112079788 A CN 112079788A
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- valsartan
- reaction
- azide
- zinc
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 61
- 229960004699 valsartan Drugs 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 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 2
- 238000000034 method Methods 0.000 claims abstract description 26
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 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 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- -1 valsartan nitrile compound Chemical class 0.000 claims description 29
- 239000012043 crude product Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- UJTNRXYTECQKFO-QHCPKHFHSA-N methyl (2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoate Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(=O)OC)=CC=C1C1=CC=CC=C1C1=NN=NN1 UJTNRXYTECQKFO-QHCPKHFHSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 150000003536 tetrazoles Chemical class 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- QFDUTPNKBRXHTC-UHFFFAOYSA-N zinc diazide Chemical compound [Zn++].[N-]=[N+]=[N-].[N-]=[N+]=[N-] QFDUTPNKBRXHTC-UHFFFAOYSA-N 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- JUXXCHAGQCBNTI-UHFFFAOYSA-N 1-n,1-n,2-n,2-n-tetramethylpropane-1,2-diamine Chemical compound CN(C)C(C)CN(C)C JUXXCHAGQCBNTI-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000004246 zinc acetate Substances 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- VCQWRGCXUWPSGY-UHFFFAOYSA-L zinc;2,2,2-trifluoroacetate Chemical compound [Zn+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F VCQWRGCXUWPSGY-UHFFFAOYSA-L 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 abstract description 28
- WBNQDOYYEUMPFS-UHFFFAOYSA-N N-nitrosodiethylamine Chemical compound CCN(CC)N=O WBNQDOYYEUMPFS-UHFFFAOYSA-N 0.000 abstract description 16
- 239000012535 impurity Substances 0.000 abstract description 10
- 231100000024 genotoxic Toxicity 0.000 abstract description 4
- 230000001738 genotoxic effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000010791 quenching Methods 0.000 abstract description 3
- 230000000171 quenching effect Effects 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 15
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 239000012086 standard solution Substances 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 150000001540 azides Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- NWAUPHAHIDQCHS-UHFFFAOYSA-N 1,1'-biphenyl;2h-tetrazole Chemical compound C1=NN=NN1.C1=CC=CC=C1C1=CC=CC=C1 NWAUPHAHIDQCHS-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002262 Schiff base Substances 0.000 description 3
- 150000004753 Schiff bases Chemical class 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 239000007924 injection Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 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 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- YIRBOOICRQFSOK-NSHDSACASA-N benzyl (2s)-2-amino-3-methylbutanoate Chemical compound CC(C)[C@H](N)C(=O)OCC1=CC=CC=C1 YIRBOOICRQFSOK-NSHDSACASA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
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- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
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- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
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- 239000012074 organic phase Substances 0.000 description 1
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- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 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
- 229960004295 valine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种缬沙坦的制备方法,步骤包括:使用复合催化剂在非亲水性有机溶剂中催化联苯氰基化合物(Ⅱ)与叠氮化合物合成缬沙坦甲酯,然后在碱性条件下水洗除去催化剂和叠氮酸无机盐,有机相再在碱性条件下水解反应,反应结束分去甲苯层,水层酸化然后乙酸乙酯萃取,冷却结晶得缬沙坦粗品,本发明提供的方法避免了叠氮化钠在淬灭的过程中产生的基因毒性杂质NDMA、NDEA和潜在基因毒性杂质V320等杂质,且工艺操作简单方便,连续性好,溶剂回收率高,产品收率高,产品纯度好,降低了生产成本,提高了产品的市场竞争能力,具有较高的工业化价值。
Description
(一)技术领域
本发明涉及药物及药物中间体合成领域,具体涉及一种缬沙坦制备方法。
(二)背景技术
缬沙坦(Valsartan),化学名:N-戊酰基-N-[[2'-(1H-四氮唑-5-基)[1,1'-联苯]-4-基]甲基]-L-缬氨酸,具有降血压效果持久稳定,副作用少以及能与其他沙坦类药物联合使用等优点,是一种临床上使用广泛的抗高血压药物。缬沙坦结构式如下所示:
国内外公开的有关很多有关缬沙坦合成的文献和专利,主要有两种路线: 1)、后环合路线,Arlesheim等报道的以2,-氰基-4-甲酰基联苯为原料,与L-缬氨酸苄酯的对甲苯磺酸盐经还原胺化反应,正戊酰化反应,成四氮唑环,去保护得缬沙坦。该方法的缺点主要是:①需要采用三烷基叠氮化锡与氰基在120~140℃下反应生成四氮唑,三烷基叠氮化锡毒性很大;②采用催化加氢的方法脱去苄基保护基,需要加氢设备。2)、后环合路线,Donatienne等报道以四氮唑被保护过的2,-四氮唑基-4-甲酰基联苯为原料,与L-缬氨酸或其衍生物缩合生成席夫碱,再经催化加氢或金属氢化物还原,所得仲胺与正戊酰氯在水存在下进行酰化反应,最后得到缬沙坦。该方法的缺点:①2,-四氮唑基-4-甲酰基联苯(或四氮唑被保护的2,-四氮唑基-4-甲酰基联苯)需要另行制备,原料成本高;②需要采用催化加氢或金属氢化物还原席夫碱;③正戊酰化反应中,水的存在一方面可提高缬沙坦的光学活性,但同时也导致正戊酰氯的部分水解,所得副产物正戊酸影响产品缬沙坦的纯化。
缬沙坦药物分子中联苯四氮唑的合成是缬沙坦合成工艺中的关键步骤,在工业化生产中通常采用联苯氰基化合物(Ⅱ)与叠氮化合物在Lewis酸催化下进行环加成反应合成联苯四氮唑环(Ⅲ),商业化生产路线如下式所示:
在联苯四氮唑环合反应中亲油性脂类化合物缬沙坦氰基中间体(II)和亲水性无机盐类叠氮化合物进行不均相反应,为了提高反应收率通常采用DMF,DMAC,NMP,二乙二醇二甲基醚等极性非亲水性有机溶剂,同时使用过量的叠氮化合物,反应结束后需要使用到亚硝酸钠或次氯酸钠等氧化剂对叠氮化和物进行无害化淬灭处理;这样的工艺操作存在两个缺点,一是叠氮化合物的淬灭过程中不可避免的会有一定量的基因毒性杂质(NDMA和NDEA)和潜在基因毒性杂质V320产生;二是极性有机溶剂在水相难以回收和处理,同时也会带走一部分产品造成产率下降;因此,开发一种具有高收率、三废少且不含NDMA、NDEA和V320等杂质的缬沙坦制备工艺是非常有必要的。
(三)发明内容
本申请发明人在研究上述缬沙坦四氮唑环合反应,针对以往缬沙坦四氮唑环合的两个重要缺点,设计使用复合催化剂在非亲水性有机溶剂中催化联苯氰基化合物(Ⅱ)与叠氮酸无机盐的四氮唑环合反应,然后在碱性条件下水洗除去催化剂和叠氮酸无机盐,有机相碱性条件下水解后分去甲苯层,水层酸化然后乙酸乙酯萃取,冷却结晶得缬沙坦粗品,本发明溶剂回收率高,操作简单方便,产品收率高且不含NDMA、NDEA和V320等杂质,具有较高的工业化价值。
本发明公开了一种缬沙坦的制备方法,包括如下步骤:
(1)中间体缬沙坦甲酯 (Ⅲ)的制备
将缬沙坦腈基化合物(II)溶于非亲水性有机溶剂中,然后分批依次加入叠氮化合物、Lewis酸和相转移催化剂,进行四氮唑环合反应,反应结束后,冷却加水,再加入无机碱,碱水洗涤,得到缬沙坦中间体(Ⅲ)的反应混合物;
(2)缬沙坦粗品的制备
向缬沙坦甲酯(Ⅲ)的反应混合物中加入碱液,加热搅拌进行水解反应,反应结束,得缬沙坦粗品;
(3)缬沙坦成品的制备
将缬沙坦粗品加入到乙酸乙酯中,升温搅拌至溶清,然后搅拌降温析晶,离心,干燥,得到缬沙坦成品;
反应路线如下:
作为对上述缬沙坦的制备方法的进一步改进,进一步设置如下:
其中步骤(1)中,所述的叠氮化合物选自叠氮化钠,叠氮化钾,叠氮化锂及叠氮化锌等中一种或其任意组合;优选为叠氮化钠,其用量为1.0~5.0当量;
步骤(1)中,所述的Lewis酸选自氯化锌,溴化锌,碘化锌,三氟甲磺酸锌,乙酸锌,三氟乙酸锌,叠氮化锌等中一种或其任意组合,其用量为0.5~2当量;
步骤(1)中,所述的溶剂选自甲苯,二甲苯,邻二甲苯,间二甲苯,对二甲苯,氯苯和二氯苯等中一种或其任意组合;
步骤(1)中,所述的相转移催化剂选自三乙胺,三正丁胺,四甲基乙二胺,四甲基丙二胺,DMF和DMAC等中一种或其任意组合,其用量为0.5~2当量;
步骤(1)中,所述的四氮唑环合反应温度为70~150℃,反应时间为10~60小时;
步骤(1)中,所述的无机碱选自氢氧化钠,碳酸钠,碳酸氢钠,碳酸钾和氨水等中一种或其任意组合;
步骤(1)中,所述的碱水洗涤的PH值为8~12;
步骤(2)中,所述的碱液选自氢氧化钠,氢氧化锂,氢氧化钾以及碳酸钠等中一种或其任意组合的水溶液,浓度为1~20%,其用量为1~5当量;
步骤(2)中,所述的缬沙坦甲酯的水解反应温度为10~60℃,反应时间为1~6小时;
步骤(3)中,所述的降温结晶的度为-10~10℃。
本发明所提供的缬沙坦的制备方法,环合反应溶剂选用非亲水类有机溶剂,易于从水相中提取出产物,同时采用在碱性条件下水洗分离出叠氮化合物和催化剂,从根源上避免了N-亚硝基二甲胺NDMA、N-亚硝基二乙胺NDEA和V320等杂质的产生;碱性条件下叠氮化合物在水溶液中安全稳定,工业生产的安全性好,操作方便,连续性好,同时提高了缬沙坦的收率和纯度,保证了缬沙坦用药的安全性,具有较高的工业化应用价值。
(四)具体实施方式
为使本发明的目的、技术方案和有益效果更加清楚,下面将结合具体实施例对本发明进行进一步描述,这些实施例仅供举例说明和特例代表,但本发明的保护范围并不仅限于此。下面进一步提供具体实施例的技术方案。
在本发明的下述各实施实例及对比例中,用GC-MS方法对缬沙坦成品中的N-亚硝基二甲胺(NDMA)和N-亚硝基二乙胺(NDEA)进行检测,用LC -MS方法对缬沙坦成品中的缬沙坦杂质V320进行检测;首先,对本发明下述实施例及对比例所采用的GC-MS(气相色谱-质谱联用)及LC -MS(液相色谱-质谱联用)测试方法进行说明。
1、GC-MS的色谱条件及检测方法:
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制:称取适量N-亚硝基二甲胺(NDMA)对照品,用稀释液稀释至NDMA浓度分别为:0.2、0.8、3.2、6.4、20 μg/mL,振摇至完全溶解后备用。
N-亚硝基二乙胺(NDEA)对照品的标准溶液配制:称取适量N-亚硝基二乙胺(NDEA)对照品,用稀释液稀释至NDEA浓度分别为:0.05、0.2、0.8、3.2、6.4 ug/mL,振摇至完全溶解后备用。
待测样品(下述各实施实例及对比例中缬沙坦成品)中NDMA和NDEA含量检测:
称取400mg待测样品,配置成20 mL溶液,振摇至完全溶解后待检测。用下述的GC-MS方法对待测品溶液及不同浓度的NDMA和NDEA标准溶液进行检测,并用标准曲线法计算待测样品中NDMA和NDEA的含量;
仪器与设备:气相色谱仪、电子轰击离子源(EI)和质谱检测器
方法:GC-MS(气相色谱-质谱联用)
色谱条件:色谱柱 VF-WAX ms ( 30 m×0.25 mm,0.25μm)或等效色谱柱
载气:氦气(He)
载气流速:2.0 mL/min
分流比无
质谱检测器条件
离子源 | 电子轰击离子源(EI) |
碰撞气体 | 氩气 |
离子源温度 | 200℃ |
接口温度 | 240℃ |
气体流速 | 11 L/min |
雾化压力 | 45psi |
检测器电压 | 相对协调电压+0.3KV |
溶剂切除时间 | 7min |
2、LC-MS的色谱条件及检测方法:
空白溶液:甲醇
标准溶液:精密称取VAL320对照品约10mg,置50mL容量瓶中,加入甲醇适量使溶解并稀释至刻度,摇匀;精密移取1mL,置100mL容量瓶中,用甲醇稀释至刻度,摇匀;精密移取1mL,置10mL容量瓶中,用甲醇稀释至刻度,摇匀。(VAL320:0.2μg/mL)
样品溶液:精密称取本品约100mg,置10mL容量瓶中,加入甲醇适量使溶解,并用甲醇稀释至刻度,摇匀,平行配制2份溶液。(缬沙坦:10.0mg/mL)
进样序列:
序号 | 溶液名称 | 进样针数 |
1 | 空白溶液 | 2 |
2 | 标准溶液 | 3 |
3 | 样品溶液(1) | 1 |
4 | 样品溶液(2) | 1 |
系统适应性评估:
项目 | 溶液名称 | 可接受标准 |
重复性,RSD%(n<sub>SS</sub>=3) | 标准溶液 | ≤10.0% |
计算:
按下式计算缬沙坦中VAL320含量:
VAL320 (ppm)
其中:
ASas=样品溶液中VAL320的峰面积;
ASs= 标准溶液中VAL320的峰面积;
CSas=样品溶液的浓度 (mg/mL);
CSs= 标准溶液中VAL320的浓度 (mg/mL);
备注:若空白溶液中有残留,扣除空白。
限度:VAL320: ≤20ppm
仪器与设备:液相色谱仪、电子轰击离子源(EI)和质谱检测器
方法:LC-MS(液相色谱-质谱联用)
色谱条件:Agilent poroshell Infinity 120-EC-C18, 4.6mm×50mm, 2.7μm
流动相A:精密移取0.5mL甲酸,加水1000mL使溶解,混匀,超声脱气。
流动相B:乙腈
‐梯度洗脱表:
时间(min) | MP A% | MP B% |
0 | 60 | 40 |
18 | 60 | 40 |
18.2 | 20 | 80 |
23.7 | 20 | 80 |
24 | 60 | 40 |
30 | 60 | 40 |
‐检测波长:225nm
‐流速:0.5mL/min
‐进样体积:5μL
‐柱温:25°C
MS条件:
‐离子源:电子喷雾ESI
‐雾化气:氮气
‐气体温度:350°C
‐气体流速:12L/min
‐雾化压力:50psi
‐毛细管电压:4kV
‐扫描模式:MRM
‐极性:正
采集参数:
时间分割:
序号 | 开始时间(min) | 化合物信号 | 扫描模式 | 控制阀 |
1 | 0 | / | MRM | To Waste |
2 | 10 | VAL320 | MRM | To MS |
3 | 20 | / | MRM | To Waste |
实施例1:缬沙坦粗品的制备
在500mL的四口反应瓶中加入34g(83.7mmol)N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC:N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98%),120g甲苯,搅拌均匀,依次分批加入16.3g(263mmol)叠氮化钠、14.8g(108.8mmol)无水氯化锌和12.6g(108.4mmol)四甲基乙二胺,搅拌均匀,然后升温至90~100℃,反应约40小时,HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1%,停止反应,冷却至40~50℃,加入200g水和11.5g碳酸钠,分去水层,然后用20%食盐水200g洗涤两次,有机层加入50g 32%的氢氧化钠溶液和200g水,控温40~45℃反应3~6小时,HPLC检测缬沙坦甲酯(Ⅲ) 残留≤1%,分去甲苯层,水层调节PH值小于1,析出大量白色固体,然后加入250g乙酸乙酯搅拌溶清,分去水层,有机层用200g水洗涤两次,乙酸乙酯层蒸干,加入150g乙酸乙酯升温溶清,冷却搅拌结晶得缬沙坦粗品30.7g,收率84.3%。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测,结果均为未检出;用LC-MS方法对缬沙坦粗品中的V320进行定量检测,结果为未检出;叠氮根残留定量检测为未检出。
实施例2:缬沙坦粗品的制备
在500mL的四口反应瓶中加入34g(83.7mmol)N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC:N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98%),120g甲苯,搅拌均匀,依次分批加入16.3g(263mmol)叠氮化钠、14.8g(108.8mmol)无水氯化锌和12.6g(108.4mmol)四甲基乙二胺,搅拌均匀,然后升温至90~100℃,反应约40小时,HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1%,停止反应,冷却至40~50℃,加入200g水和50g氨水,分去水层,然后用20%食盐水200g洗涤两次,有机层加入50g32%的氢氧化钠溶液和200g水,控温40~45℃反应3~6小时,HPLC检测缬沙坦甲酯(Ⅲ) 残留≤1%,分去甲苯层,水层调节PH值小于1,析出大量白色固体,然后加入250g乙酸乙酯搅拌溶清,分去水层,有机层用200g水洗涤两次,乙酸乙酯层蒸干,加入150g乙酸乙酯升温溶清,冷却搅拌结晶得缬沙坦粗品32.1g,收率88.2%。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测,结果均为未检出;用LC-MS方法对缬沙坦粗品中的V320进行定量检测,结果为未检出;叠氮根残留定量检测为未检出。
实施例3:缬沙坦粗品的制备
在1500L的反应釜中加入235.2kg(579.3mol)N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC:N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98%),800kg甲苯,搅拌均匀,依次分批加入113.5kg叠氮化钠、98.2kg无水氯化锌和83.6kg四甲基乙二胺,搅拌均匀,然后升温至90~100℃,反应约40小时,HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1%,停止反应,冷却至40~50℃,加入1200kg水和330kg氨水,分去水层,然后用20%食盐水1200kg洗涤两次,有机层加入330kg32%的氢氧化钠溶液和1200kg水,控温40~45℃反应3~6小时,HPLC检测缬沙坦甲酯(Ⅲ) 残留≤1%,分去甲苯层,水层调节PH值小于1,析出大量白色固体,然后加入1600kg乙酸乙酯搅拌溶清,分去水层,有机层用1200kg水洗涤两次,乙酸乙酯层蒸干,加入1000kg乙酸乙酯升温溶清,冷却搅拌结晶得缬沙坦粗品227.1kg,收率89.8%。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测,结果均为未检出;用LC-MS方法对缬沙坦粗品中的V320进行定量检测,结果为未检出;叠氮根残留定量检测为未检出。
实施例4:缬沙坦成品的制备
在250mL的四口反应瓶中加入上述得到的32.1g缬沙坦粗品,加入150g乙酸乙酯升温至50℃,搅拌至溶清,然后搅拌降温结晶,过滤,干燥,得到缬沙坦成品27.4g,收率85.3%。(杂质A:0.04%;单个未知杂质≤0.10%;总杂质≤0.1%;乙酸乙酯残留:2218ppm;戊酸残留:75ppm;重金属<10ppm;NDMA(GC-MS):未检出;NDEA(GC-MS):未检出; V320(LC-MS):未检出),叠氮根残留定量检测为未检出。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,其中步骤(1)中,所述的叠氮化合物选自叠氮化钠,叠氮化钾,叠氮化锂及叠氮化锌中一种或其任意组合。
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,所述的Lewis酸选自氯化锌,溴化锌,碘化锌,三氟甲磺酸锌,乙酸锌,三氟乙酸锌,叠氮化锌中一种或其任意组合,其用量为0.5~2当量。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,所述的溶剂选自甲苯,二甲苯,邻二甲苯,间二甲苯,对二甲苯,氯苯和二氯苯中一种或其任意组合。
5.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,所述的相转移催化剂选自三乙胺,三正丁胺,四甲基乙二胺,四甲基丙二胺,DMF和DMAC等中一种或其任意组合,其用量为0.5~2当量。
6.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,所述的四氮唑环合反应温度为70~150℃,反应时间为10~60小时。
7.根据权利要求1所述的制备方法,其特征在于,步骤(1)中,所述的无机碱选自氢氧化钠,碳酸钠,碳酸氢钠,碳酸钾和氨水中一种或其任意组合。
8.根据权利要求1所述的合成方法,其特征在于,步骤(1)中,所述的碱水洗涤的pH值为8~12。
9.根据权利要求1所述的制备方法,其特征在于,步骤(2)中,所述的碱液选自氢氧化钠,氢氧化锂,氢氧化钾以及碳酸钠中一种或其任意组合的水溶液,浓度为1~20wt%,其用量为1~5当量。
10.根据权利要求1所述的制备方法,其特征在于,步骤(2)中,所述的缬沙坦甲酯(Ⅲ)的水解反应温度为10~60℃,反应时间为1~6小时。
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