CN101772490A - 纯化形式的曲唑酮和盐酸曲唑酮 - Google Patents
纯化形式的曲唑酮和盐酸曲唑酮 Download PDFInfo
- Publication number
- CN101772490A CN101772490A CN200880101823A CN200880101823A CN101772490A CN 101772490 A CN101772490 A CN 101772490A CN 200880101823 A CN200880101823 A CN 200880101823A CN 200880101823 A CN200880101823 A CN 200880101823A CN 101772490 A CN101772490 A CN 101772490A
- Authority
- CN
- China
- Prior art keywords
- trazodone
- ammonium
- production method
- bromination
- chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 229960002301 trazodone hydrochloride Drugs 0.000 title claims abstract description 65
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960003991 trazodone Drugs 0.000 claims abstract description 73
- 239000012074 organic phase Substances 0.000 claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- 230000029936 alkylation Effects 0.000 claims description 35
- 238000005804 alkylation reaction Methods 0.000 claims description 35
- 230000031709 bromination Effects 0.000 claims description 30
- 238000005893 bromination reaction Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 12
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 12
- 238000005660 chlorination reaction Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- -1 aromatic amines compound Chemical class 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 6
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 claims description 4
- GODRVQNPPALOOT-UHFFFAOYSA-N C1(=CC=CC=C1)[P](CCCC)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)[P](CCCC)(C1=CC=CC=C1)C1=CC=CC=C1 GODRVQNPPALOOT-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- QSRFYFHZPSGRQX-UHFFFAOYSA-N benzyl(tributyl)azanium Chemical compound CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QSRFYFHZPSGRQX-UHFFFAOYSA-N 0.000 claims description 4
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 4
- VICYBMUVWHJEFT-UHFFFAOYSA-N dodecyltrimethylammonium ion Chemical compound CCCCCCCCCCCC[N+](C)(C)C VICYBMUVWHJEFT-UHFFFAOYSA-N 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 4
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000010306 acid treatment Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- HTZOGMBRKCPHSZ-UHFFFAOYSA-N (3-ethylphenyl)methanamine;hydrochloride Chemical compound Cl.CCC1=CC=CC(CN)=C1 HTZOGMBRKCPHSZ-UHFFFAOYSA-N 0.000 claims description 2
- QAQSNXHKHKONNS-UHFFFAOYSA-N 1-ethyl-2-hydroxy-4-methyl-6-oxopyridine-3-carboxamide Chemical compound CCN1C(O)=C(C(N)=O)C(C)=CC1=O QAQSNXHKHKONNS-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- NRWHGFUSXDSBSP-UHFFFAOYSA-N C(C)N(CC)CC[P](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(C)N(CC)CC[P](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 NRWHGFUSXDSBSP-UHFFFAOYSA-N 0.000 claims description 2
- YBPOGTNTNFWOBQ-UHFFFAOYSA-M C(C)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1.I(=O)(=O)[O-] Chemical compound C(C)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1.I(=O)(=O)[O-] YBPOGTNTNFWOBQ-UHFFFAOYSA-M 0.000 claims description 2
- WXJVQQPLIMTRFK-UHFFFAOYSA-N C(CCC)[P](CCCC)(CCCC)CCCC Chemical compound C(CCC)[P](CCCC)(CCCC)CCCC WXJVQQPLIMTRFK-UHFFFAOYSA-N 0.000 claims description 2
- LGQBUDQNPLEVMZ-UHFFFAOYSA-M C(CCCCC)[N+](CCCCCC)(CCCCCC)CCCCCC.I(=O)(=O)[O-] Chemical compound C(CCCCC)[N+](CCCCCC)(CCCCCC)CCCCCC.I(=O)(=O)[O-] LGQBUDQNPLEVMZ-UHFFFAOYSA-M 0.000 claims description 2
- FXQYYFYMDDANJO-UHFFFAOYSA-N C(CCCCCCCCCCCCCCC)[P](CCCC)(CCCC)CCCC Chemical compound C(CCCCCCCCCCCCCCC)[P](CCCC)(CCCC)CCCC FXQYYFYMDDANJO-UHFFFAOYSA-N 0.000 claims description 2
- KYMUDEQLSUKRGO-UHFFFAOYSA-N C(c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1 Chemical compound C(c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1 KYMUDEQLSUKRGO-UHFFFAOYSA-N 0.000 claims description 2
- SJUKNQVWHYECAE-UHFFFAOYSA-N C1(=CC=CC=C1)[P](CC)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)[P](CC)(C1=CC=CC=C1)C1=CC=CC=C1 SJUKNQVWHYECAE-UHFFFAOYSA-N 0.000 claims description 2
- AUCVMXYVKNCUAO-UHFFFAOYSA-N CCCC[P+](C)(CCCC)CCCC.N Chemical compound CCCC[P+](C)(CCCC)CCCC.N AUCVMXYVKNCUAO-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- JGFDZZLUDWMUQH-UHFFFAOYSA-N Didecyldimethylammonium Chemical compound CCCCCCCCCC[N+](C)(C)CCCCCCCCCC JGFDZZLUDWMUQH-UHFFFAOYSA-N 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 claims description 2
- NTKVWOTYTNWGRK-UHFFFAOYSA-N P.Br.Br.Br Chemical compound P.Br.Br.Br NTKVWOTYTNWGRK-UHFFFAOYSA-N 0.000 claims description 2
- DGWFDTKFTGTOAF-UHFFFAOYSA-N P.Cl.Cl.Cl Chemical compound P.Cl.Cl.Cl DGWFDTKFTGTOAF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 2
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 2
- RLGQACBPNDBWTB-UHFFFAOYSA-N cetyltrimethylammonium ion Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)C RLGQACBPNDBWTB-UHFFFAOYSA-N 0.000 claims description 2
- KZVKZKHPBUOGDB-UHFFFAOYSA-N chloromethane N,N-dibutylbutan-1-amine Chemical compound ClC.CCCCN(CCCC)CCCC KZVKZKHPBUOGDB-UHFFFAOYSA-N 0.000 claims description 2
- 229940078672 didecyldimethylammonium Drugs 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- HZZUMXSLPJFMCB-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;acetate Chemical compound CC([O-])=O.C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 HZZUMXSLPJFMCB-UHFFFAOYSA-M 0.000 claims description 2
- 238000006197 hydroboration reaction Methods 0.000 claims description 2
- 229930195733 hydrocarbon Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- ARRNBPCNZJXHRJ-UHFFFAOYSA-M hydron;tetrabutylazanium;phosphate Chemical compound OP(O)([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC ARRNBPCNZJXHRJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 229940050176 methyl chloride Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 2
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims description 2
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims description 2
- DTIFFPXSSXFQCJ-UHFFFAOYSA-N tetrahexylazanium Chemical compound CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC DTIFFPXSSXFQCJ-UHFFFAOYSA-N 0.000 claims description 2
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 2
- ZRVXFJFFJZFRLQ-UHFFFAOYSA-M tetramethylazanium;iodate Chemical compound [O-]I(=O)=O.C[N+](C)(C)C ZRVXFJFFJZFRLQ-UHFFFAOYSA-M 0.000 claims description 2
- LPSKDVINWQNWFE-UHFFFAOYSA-M tetrapropylazanium;hydroxide Chemical compound [OH-].CCC[N+](CCC)(CCC)CCC LPSKDVINWQNWFE-UHFFFAOYSA-M 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
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 15
- 239000008346 aqueous phase Substances 0.000 abstract description 6
- 230000002152 alkylating effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 150000007514 bases Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
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- 238000001914 filtration Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WUDPLCXQXVLVHD-UHFFFAOYSA-N ClCCCN(CCNC1C2=CC=CC=C2)C1Cl Chemical compound ClCCCN(CCNC1C2=CC=CC=C2)C1Cl WUDPLCXQXVLVHD-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
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- 230000001738 genotoxic effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 2
- MNHKUCBXXMFQDM-UHFFFAOYSA-N 4-[(4-nitrophenyl)methyl]pyridine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CC1=CC=NC=C1 MNHKUCBXXMFQDM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000588724 Escherichia coli Species 0.000 description 2
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
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Abstract
生产曲唑酮或盐酸曲唑酮的方法,包括下列步骤:(a)制备在至少一种有机溶剂中包含曲唑酮的有机相;(b)制备包含至少一种碱性化合物的水相;(c)混合所述水相与所述有机相;(d)在至少40℃的温度下加热至少30分钟;(e)回收所述曲唑酮;且任选(f)用盐酸处理所述曲唑酮而得到盐酸曲唑酮。曲唑酮或盐酸曲唑酮包含低于15ppm的烷基化物质,且药物组合物包含所述盐酸曲唑酮。
Description
发明领域
本发明涉及曲唑酮和盐酸曲唑酮的纯化形式及其制备方法。
本发明特别涉及包含低于15ppm的经证实或怀疑遗传毒性的烷基化物质的曲唑酮和盐酸曲唑酮纯化形式。
现有技术
曲唑酮或2-[3-[4-(3-氯苯基)-1-哌嗪基丙基]-1,2,4-三唑并[4,3-a]吡啶-3(2H)-酮是抗抑郁药,尽管对5-羟色胺受体具有显著作用,但是它既不是精神兴奋药,也不是MAO抑制剂,也不是三环抗忧郁药。此外,曲唑酮具有止痛特性。
曲唑酮缓解了抑郁症的特征性症状,特别是焦虑、躯体症状、精神运动迟延、忧郁症、情绪不稳、易怒、失眠、情感淡漠、疲劳感和缺乏精力、情绪沮丧。
还证实曲唑酮有效控制显著的原发性颤动,可能是因血清素能活性所致。
在医学上优选以药学上可接受的酸加成盐的形式使用曲唑酮。优选的形式是通过用盐酸处理游离碱获得的盐酸盐形式。
盐酸曲唑酮由如下结构式表示:
某些在经济上有利的制备盐酸曲唑酮的方法描述在专利US3,381,009和EP 1,108,722中。
第一种方法包括使式I的s-三唑并-[4,3-a]-吡啶-3-酮与式II的N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪反应:
第二种方法包括使式III的2-(3-氯丙基)-s-三唑并-[4,3-a]-吡啶-3-酮与式IV的N-(3-氯苯基)-哌嗪反应:
第三种方法包括使式V的2-(γ-吗啉代-丙基)-s-三唑并-[4,3-a]-吡啶-3-酮与式VI的3-氯苯胺反应:
第四种方法包括使式VII的2-(3-氨基丙基)-s-三唑并[4,3-a]-吡啶-3-酮与式VIII的3-氯-N,N′-二氯乙基苯胺反应:
第五种方法包括使式IX的2-{3-[双-(2-氯乙基)-氨基]-丙基}2H-[1,2,4]三唑并[4,3-a]吡啶-3-酮与式VI的3-氯苯胺反应:
一旦获得曲唑酮,那么易于通过与盐酸反应,例如通过如例如专利EP 1,108,722中所述用盐酸水溶液处理曲唑酮的有机溶液,获得盐酸曲唑酮。
制备从I至IX上述中间体需要使用具有经证实遗传毒性的烷基化物质,例如2,2-二氯乙胺,用于通过与化合物V1反应获得化合物IV;1-溴-3-氯丙烷,用于通过与化合物IV反应获得化合物II。
化合物II,III,VIII和IX也是烷基化物质且由此可能具有遗传毒性。除上述烷基化物质外,在可替代选择的生产曲唑酮的方法中,可以使用类似的烷基化物质,例如2,2-二溴乙胺或1,3-二氯丙烷。
曲唑酮和盐酸曲唑酮代表的终产物中所述烷基化物质的含量应降至最少可能的量。特别地,将摄入这些烷基化物质的毒理学阈值测定为1.5ug/天。
因此,由于推定了100mg的盐酸曲唑酮每日剂量,所以产物中作为杂质存在的烷基化物质的量应低于15ppm。然而,如果我们考虑600mg盐酸曲唑酮的最大每日剂量,那么产物中作为杂质存在的烷基化物质的量甚至应低于2.5ppm。
令人遗憾的是,上述专利US 3,381,009和EP 1,108,722中所述的制备方法未使得这些烷基化物质的含量降至低于15ppm,更不用说低于2.5ppm。
因此,申请人抓住了设计生产曲唑酮和盐酸曲唑酮的方法的问题,该生产方法使终产物中这些烷基化物质的含量降至低于15ppm成为可能。此外,所述生产方法必须在经济上有利且必须得到高产率的终产物。
定义
在本说明书和随后给出的权利要求中,表述″曲唑酮″意旨游离碱形式的曲唑酮,而表述″盐酸曲唑酮″意旨通过将盐酸加成到曲唑酮上形成的盐。
此外,在本说明书和随后给出的权利要求中,表述″烷基化物质″用于表示能够将烷基引入用于合成曲唑酮或其中间体的化合物上的物质。
本发明的描述
令人意外地,申请人发现将包含碱性化合物的水溶液加入到曲唑酮在有机溶剂中的溶液中将终产物中烷基化物质的量降至低于15ppm。
因此,本发明涉及生产曲唑酮或盐酸曲唑酮的方法,包括下列步骤:
(a)制备在至少一种有机溶剂中包含曲唑酮的有机相;
(b)制备包含至少一种碱性化合物的水相;
(c)混合所述水相与所述有机相;
(d)在至少40℃的温度下加热至少30分钟;
(e)回收所述曲唑酮;且任选
(f)用盐酸处理所述曲唑酮而得到盐酸曲唑酮。
本发明的生产方法使得将曲唑酮或盐酸曲唑酮代表的终产物中烷基化物质的量降至低于15ppm,优选低于10ppm和更优选低于2.5ppm成为可能。
有利的是,根据本发明的优选方面,本发明的生产方法使得将终产物中烷基化物质的量降至低于1ppm成为可能。
已经证实本发明的方法在经济上有利,保持了高于85%和优选高于90%的终产物产率。
优选所述有机相由曲唑酮在所述有机溶剂中的溶液为代表。
有利的是,所述有机溶剂可以选自任意对曲唑酮而言为惰性并且能够溶解曲唑酮的有机溶剂。
优选所述有机溶剂选自,醇类,例如乙醇,丙醇,异丁醇,己醇和苄醇;醚类,例如乙醚,丙醚;烃类,例如甲苯,苯,二甲苯;酮类,例如丙酮,甲基乙基酮,甲基异丁基酮;酯类,如乙酸乙酯。制备有机相的优选有机溶剂是异丁醇。
优选所述有机相包含10g至50g/100克有机相的用量的曲唑酮,更优选20g至35g/100克有机相且甚至更优选25g至30g/100克有机相。
优选所述水相由碱性化合物在水中的溶液代表。
有利地,所述水相包含至少一种碱性化合物,其选自至少一种无机碱、至少一种有机碱或其混合物。
无机碱的有用实例是氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾、氢氧化铵、氧化镁、肼和羟基胺。
有机碱的有用实例是脂族或芳族胺类化合物,例如甲胺、乙胺、丙胺、丁胺、二乙胺、三甲胺、三乙胺、乙醇胺、二乙醇胺、三乙醇胺、N,N-二甲基乙醇胺、N-甲基乙醇胺、乙二胺、哌啶、喹啉、咪唑、苯并咪唑、组氨酸、吡啶、甲基吡啶、二甲基吡啶、可力丁、吗啉、N-甲基吗啉、苄胺和环己胺。
优选所述碱性化合物的添加量在0.05至1mol/mol曲唑酮,更优选0.2至0.8mol/mol曲唑酮且甚至更优选0.4至0.6mol/mol曲唑酮。
有利地,所述水相的添加量在30g至100g/100克有机相,更优选40g至90g/100克有机相且甚至更优选50g至80g/100克有机相。
优选所述水相包含相转移催化剂。有利地,所述相转移催化剂选自季铵盐和季磷鎓盐。
优选所述季铵盐选自溴化苄基三丁基铵、氯化苄基三丁基铵、溴化苄基三乙基铵、氯化苄基三乙基铵、氯化苄基三甲基铵、溴化鲸蜡基吡啶鎓、氯化鲸蜡基吡啶鎓、溴化鲸蜡基三甲基铵、氯化二癸基二甲基铵、溴化十二烷基三甲基铵、氯化十二烷基三甲基铵、氯化甲基三丁基铵、硫酸氢甲基三丁基铵、氯化甲基三辛酰基铵、氯化甲基三辛基铵、氯化苯基三甲基铵、硼氢化四丁基铵、溴化四丁基铵、氯化四丁基铵、氟化四丁基铵、硫酸氢四丁基铵、氢氧化四丁基铵、碘化四丁基铵、高氯酸四丁基铵、溴化四乙基铵、氯化四乙基铵、氢氧化四乙基铵、溴化四己基铵、碘化四己基铵、溴化四甲基铵、氯化四甲基铵、氟化四甲基铵、氢氧化四甲基铵、碘化四甲基铵、溴化四辛基铵、溴化四丙基铵、氯化四丙基铵、氢氧化四丙基铵、氯化三丁基甲基铵和氯化三乙基苄基铵。
有利地,所述季铵盐选自溴化四丁基铵、氯化四丁基铵、溴化苄基三乙基铵、氯化苄基三乙基铵、氯化苄基三甲基铵、溴化苄基三甲基铵、溴化苄基三丁基铵和氯化苄基三丁基铵。
优选所述季磷鎓盐选自溴化苄基三苯基磷鎓、氯化苄基三苯基磷鎓、溴化丁基三苯基磷鎓、氯化丁基三苯基磷鎓、乙酸乙基三苯基磷鎓、溴化乙基三苯基磷鎓、碘化乙基三苯基磷鎓、溴化十六烷基三丁基磷鎓、溴化甲基三苯基磷鎓、溴化四丁基磷鎓和溴化四苯基磷鎓。
优选所述水相包含如下用量的相转移催化剂:0.05g至0.5g/100克水相,更优选0.1g至0.3g/100克水相且甚至更优选0.15g至0.2g/100克水相。
优选所述加热步骤(d)在40℃至有机相与水相混合物沸点之间的温度下进行30分钟至300分钟、优选60至240分钟、更优选90至180分钟时间期限。
优选回收步骤(e)通过下列步骤进行:从包含曲唑酮的有机相中分离水相并且将有机相冷却至低于30℃,优选低于20℃且甚至更优选低于10℃,以便促进结晶和沉淀曲唑酮,最终例如通过过滤分离。
有利地,在最终的处理步骤(f)中,优选将曲唑酮溶于适当的有机溶剂,例如选自上述用于制备有机相的那些。在该步骤中优选的溶剂是丙酮。用盐酸水溶液如专利EP 1,108,722中所述处理由此获得的溶液。然后根据本领域技术人员公知的常规技术过滤、洗涤并且干燥盐酸曲唑酮沉淀。
通过本发明方法获得的曲唑酮和盐酸曲唑酮的特征在于具有经证实或怀疑的遗传毒性的烷基化物质含量低于15ppm。
根据为生产曲唑酮和盐酸曲唑酮选择的生产方法的不同,作为杂质存在的烷基化物质例如是2,2-二氯乙胺,1-溴-3-氯-丙烷,N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪(式II),2-(3-氯丙基)-s-三唑并-[4,3-a]-吡啶-3-酮(式III),3-氯-N,N′-二氯乙基-苯胺(式VIII),2-{3-[双-(2-氯乙基)-氨基]-丙基}-2H-[1,2,4]三唑并[4,3-a]吡啶-3-酮(式IX),2,2-二溴乙胺和1,3-二氯丙烷。
特别地,最频繁遇到的烷基化物质以2,2-二氯乙胺,1-溴-3-氯-丙烷和N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪为代表。
2,2-二氯乙胺(CAS No.334-22-5)和1-溴-3-氯-丙烷(CAS No.109-70-6)是如TOXNET中报告的已知遗传毒性物质,TOXNET是由National Library of Medicine,US出版的数据库,其互联网网址是http://toxnet.nlm.nih.gov/。
已经通过接触N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪在二甲亚砜(DMSO)中的溶液并且使用DMSO作为阴性对照评价了N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪对鼠伤寒沙门菌(Salmonella typhimurium)菌株TA1535,TA1537,TA98和TA100的组氨酸-依赖性营养缺陷型的突变体和大肠埃希氏杆菌(Escherichia coli)菌株WP2uvrA(pKM101)的色氨酸-依赖性突变体的遗传毒性活性。在有和没有用苯巴比妥和5,6-苯并黄酮处理的大鼠肝微粒体部分(S9混合物)存在下进行两种独立的突变试验。试验以标准平板掺入测定法并且根据最新的管理指导原则进行。在有S9混合物存在下在菌株TA1535上获得了返回至原养型的显著增加。在两种测定中,增加是浓度相关性的并且在接触1500μg/平板的N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪后达到对照值的6.4和5.1倍。因此,推断N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪在代谢活化后在所述细菌系统中表现出遗传毒性。
令人意外的是,使用本发明方法获得的曲唑酮或盐酸曲唑酮中所述烷基化物质的总含量低于15ppm,优选低于10ppm且甚至更优选低于2.5ppm。在该优选的实施方案中,使用本发明方法获得的曲唑酮或盐酸曲唑酮中烷基化物质各自的含量低于1ppm。
因此,本发明还涉及包含低于15ppm,优选低于10ppm且甚至更优选低于2.5ppm的烷基化物质的曲唑酮或盐酸曲唑酮。
在一个优选的实施方案中,本发明还涉及包含低于1ppm且优选低于0.5ppm的各烷基化物质的曲唑酮或盐酸曲唑酮。
优选所述烷基化物质选自2,2-二氯乙胺,1-溴-3-氯-丙烷;和N-(3-氯-苯基)-N′-(3-氯丙基)-哌嗪(式II),2-(3-氯丙基)-s-三唑并-[4,3-a]-吡啶-3-酮(式III),3-氯-N,N′-二氯乙基-苯胺(式VIII),2-{3-[双-(2-氯乙基)-氨基]-丙基}-2H-[1,2,4]三唑并[4,3-a]吡啶-3-酮(式IX),2,2-二溴乙胺和1,3-二氯-丙烷。
甚至更优选所述烷基化物质选自2,2-二氯乙胺,1-溴-3-氯丙烷和N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪。
本发明的盐酸曲唑酮可以有利地用于制备混合了至少一种药学上可接受的赋形剂的药物组合物。
因此,本发明还涉及药物组合物,其包含如上所述的本发明的盐酸曲唑酮与至少一种药学上可接受的赋形剂。
术语″药学上可接受的赋形剂″意旨适合于制备对生物给药的药物组合物的任意物质,但没有特别限定。
本领域技术人员公知的这类物质是,例如抗粘着剂、粘合剂、崩解剂、填充剂、稀释剂、矫味剂、着色剂、助流剂、润滑剂、防腐剂、湿润剂、吸收剂和甜味剂。
药学上可接受的赋形剂的有用的实例是糖类,例如乳糖、葡萄糖或蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素和纤维素衍生物,例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;黄蓍树胶;麦芽;明胶;滑石粉;可可脂;蜡;油,例如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,例如丙二醇;多元醇类,例如甘油、山梨醇、甘露糖醇和聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;藻酸;水;等渗溶液;乙醇,缓冲溶液;聚酯类;聚碳酸酯类;聚酸酐类等。
本发明的药物组合物可以以可以用于给予本发明的盐酸曲唑酮的任意组合物为代表,优选用于口服或胃肠外给药的组合物,例如片剂、锭剂、胶囊、溶液、混悬液、分散液和糖浆剂。
本发明由下列实施例示范,但不限于此。
实施例1
强碱(NaOH)存在下的制备
将根据专利US 3,381,009的实施例1获得的37.1g曲唑酮(等于约0.100mol)与140ml异丁醇放入500-ml烧瓶。然后加入100ml2%的NaOH水溶液并且将得到的混合物加热至约80℃并且保持在该温度下,同时搅拌约3小时。
然后从水相中分离有机相且然后用水洗涤。通过共沸蒸馏除去有机相中残留的水。将得到的溶液冷却至5℃以便沉淀曲唑酮碱的结晶,通过过滤分离。
将湿产物(约40g)溶于约270ml丙酮,加热至发生溶解且然后将12N HCI水溶液加入到该溶液中至pH 3至4,以便使曲唑酮碱成盐且获得相应的盐酸盐。
将得到的溶液冷却至5℃以便沉淀盐酸曲唑酮结晶。过滤由此获得的盐酸曲唑酮,用丙酮洗涤并且在减压下干燥。在干燥结束时,获得35.5g盐酸曲唑酮(等于约0.087mol),产物产率等于约87%。
表1
实施例2
弱碱(Na
2
CO
3
)存在下的制备
将根据专利US 3,381,009的实施例1获得的37.1g曲唑酮(等于约0.100mol)与140ml异丁醇放入500-ml烧瓶。然后加入100ml含5.3g Na2CO3的水溶液并且将得到的混合物加热至约80℃并且保持在该温度下,同时搅拌约4小时。
然后从水相中分离有机相且然后用水洗涤。通过共沸蒸馏除去存在于有机相中残留的水。将得到的溶液冷却至5℃以便沉淀曲唑酮碱的结晶,通过过滤分离。
将湿产物(约42g)溶于约270ml丙酮,加热至发生溶解且然后将12N HCI水溶液加入到该溶液中至pH 3至4,以便使曲唑酮碱成盐且获得相应的盐酸盐。
将得到的溶液冷却至5℃以便沉淀盐酸曲唑酮结晶。过滤由此获得的盐酸曲唑酮,用丙酮洗涤并且在减压下干燥。在干燥结束时,获得37.0g盐酸曲唑酮(等于约0.091mol),产物产率等于约91%。
表2
实施例3
弱碱(Na
2
CO
3
)和相转移催化剂(氯化苄基三乙基铵)存在下的制备
将根据专利US 3,381,009的实施例1获得的37.1g曲唑酮(等于约0.100mol)与140ml异丁醇放入500-ml烧瓶。然后加入100ml含5.3g Na2CO3和150mg氯化苄基三乙基铵的水溶液并且将得到的混合物加热至约80℃并且保持在该温度下,同时搅拌约2小时。
然后从水相中分离有机相且然后用水洗涤。通过共沸蒸馏除去存在于有机相中残留的水。将得到的溶液冷却至5℃以便沉淀曲唑酮碱的结晶,通过过滤分离。
将湿产物(约38.5g)溶于约270ml丙酮,加热至发生溶解且然后将12N HCI水溶液加入到该溶液中至pH 3至4,以便使曲唑酮碱成盐且获得相应的盐酸盐。
将得到的溶液冷却至5℃以便沉淀盐酸曲唑酮结晶。过滤由此获得的盐酸曲唑酮,用丙酮洗涤并且在减压下干燥。在干燥结束时,获得36.7g盐酸曲唑酮(等于约0.090mol),产物产率等于约90%。
表3
实施例4
强碱(KOH)存在下的制备
将根据专利US 3,381,009的实施例1获得的37.1g曲唑酮(等于约0.100mol)与140ml甲基异丁基酮放入500-ml烧瓶。然后加入100ml含2.8g KOH的水溶液并且将得到的混合物加热至约80℃并且保持在该温度下,同时搅拌约3小时。
然后从水相中分离有机相且然后用水洗涤。通过共沸蒸馏除去存在于有机相中残留的水。将得到的溶液冷却至5℃以便沉淀曲唑酮碱的结晶,通过过滤分离。
将湿产物(约38g)溶于约270ml丙酮,加热至发生溶解且然后将12N HCI水溶液加入到该溶液中至pH 3至4,以便使曲唑酮碱成盐且获得相应的盐酸盐。
将得到的溶液冷却至5℃以便沉淀盐酸曲唑酮结晶。过滤由此获得的盐酸曲唑酮,用丙酮洗涤并且在减压下干燥。在干燥结束时,获得35.5g盐酸曲唑酮(等于约0.087mol),产物产率等于约87%。
表4
根据下列方法测定表1至4中所示烷基化物质的起始和最终含量。
通过UV/Vis分光光度测定法测定在盐酸曲唑酮中的2,2-二氯乙
胺的测定法
该测定法基于根据如Anal.Chem.33,906-910,1961,″Colorimetric estimation of nitrogen mustards in aqueous media″中所述的改进的Friedman-Boger方法的2,2-二氯乙胺与4-(4-硝基苄基)-吡啶的反应。
简言之,将4-(4-硝基苄基)吡啶在丙酮中的溶液加入到盐酸曲唑酮水溶液(0.25g/ml)中。将得到的混合物加热至100℃下20分钟且然后在冰浴上快速冷却。向该溶液中加入1ml丙酮和3ml 1N氢氧化钠。然后用氯仿(3ml)萃取着色的衍生物。对着空白样品记录544nm处的吸收度值且然后根据得到的值计算二阶导数(δ)。通过使用外标法测定以ppm计的盐酸曲唑酮中2,2-二氯乙胺含量。
该反应对2,2-二氯乙胺而言是特异性的,因为在对其它烷基化试剂,例如1-溴-3-氯丙烷和N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪所述的条件下未获得着色的衍生物。
从1至10ppm的2,2-二氯乙胺验证线性。校准器的准确度始终在理论值的85至115%。
基于空白的精密度值(测定为标准偏差σ)将定量下限(LLOQ)设定在1ppm,如下:δLLOQ=δ空白+10*σ=0.00048+10*0.00024=0.00288,相当于1.1ppm。
基于空白的精密值(测定为标准偏差σ)将检测限(LOD)设定在0.46ppm,如下:δLLOQ=δ空白+3*σ=0.00048+10*0.00024=0.00288,相当于0.46ppm。
通过计算6次测定的变异系数(CV%)评估精密度。在5ppm处的CV%等于12.2%且在10ppm处它等于11.2%。
通过顶部空间技术测定盐酸曲唑酮中1-溴-3-氯丙烷的测定法
将盐酸曲唑酮溶于水/甲醇溶液。在完全溶解后,将该溶液放入顶部空间自动采样器并且通过气相色谱法,使用中度极性的毛细管柱测定1-溴-3-氯丙烷的含量。使用火焰离子化检测器监测柱流出液。将1-溴-3-氯丙烷的含量测定为相对于具有已知含量(2ppm)的标准样品的含量测定限。
色谱条件
气相色谱 | 痕量Ultra |
分析柱 | 毛细管柱,L=30m,内径0.53mm,3μm(RTX1301或等效物) |
固定相 | 6%氰基丙基苯基,94%二甲基聚硅氧烷 |
烘箱温度 | 90℃/2min,然后以10℃/min增加至130℃并且维持在130℃下1min |
流动相(压力) | 氮气(100kPa) |
检测器 | FID(空气350kPa,氢气35kPa) |
保留时间 | 约3.5min,1-溴-3-氯丙烷 |
运行时间 | 7min |
注射器温度 | 250℃ |
检测器温度 | 250℃ |
氢气压力 | 35kPa |
大气压 | 350kPa |
自动采样器条件
顶部空间自动采样器 | Perkin Elmer YurboMatrix 40 |
操作模式 | 连续 |
转移管直径 | 0.25mm |
样品温度 | 90℃ |
针头温度 | 150℃ |
转移管温度 | 170℃ |
恒温控制时间 | 15分钟 |
加压时间 | 1分钟 |
将100mg盐酸曲唑酮精确称入22-ml试管,然后加入0.025%(v/v)的甲醇水溶液。用波纹铝帽和PTFE涂敷的丁基橡胶塞密封试管,且然后放入顶部空间自动采样器。
从0.2至9.3ppm的1-溴-3-氯丙烷验证线性,得到等于0.992的相关系数(通过最小二乘法回归分析)。
检测限(LOD)和定量下限(LLOQ)获自信/噪比(S/N),如下:
LOD=3xS/N=0.2ppm
LLOQ=10xS/N=0.5ppm
发现基于6次重复测定的精密度在0.5ppm下等于3.6%(CV)。
将准确度测定为回收%。在线性范围内,在涉及理论浓度时它始终是100%。
通过高效液相色谱法结合串联质谱法(HPLC/MS/MS)测定盐酸曲唑
酮中的1-(3-氯苯基)-4-(3-氯丙基)哌嗪(CCP)的测定法
将盐酸曲唑酮溶于水并且注入分析仪。使用烷基酰胺类型的反相分析柱获得色谱分离。
通过正离子质谱法,使用″Multiple Reaction Monitoring″(MRM)技术监测来自柱的洗脱液。
色谱条件
HPLC系统 | Agilent系列1200(或等效物) |
分析柱 | ABZ+,75×4.6mm,3μm(Supelco) |
烘箱温度 | 40℃ |
溶剂A | 甲醇 |
溶剂B | 乙酸铵5mM+0.1%(v/v)甲酸 |
操作流速 | 2ml/min,狭缝用于将离子源的流速降至0.3ml/min |
洗脱 | 等度溶剂A/B=12/88(v/v)3min |
净化 | 等度溶剂A/B=80/20(v/v)5min |
注射体积 | 5μl |
保留时间 | 约2.5min,CCP |
HPLC系统 | Agilent系列1200(或等效物) |
运行时间 | 10.0min |
质谱条件
从0.4至8ppm的1-(3-氯苯基)-4-(3-氯丙基)哌嗪验证线性,得到等于0.9987的相关系数(通过最小二乘法回归分析)。
准确度始终在理论值的85%至115%。
基于获自6次测定的准确度(85%)和精密度(CV=6.7%)值将定量下限(LLOQ)设定在0.4ppm。
基于信/噪比(S/N)值将检测限(LOD)设定在0.04ppm∶LOD =3xS/N=0.04ppm。
Claims (28)
1.生产曲唑酮和盐酸曲唑酮的方法,其特征在于它包括下列步骤:
(a)制备在至少一种有机溶剂中包含曲唑酮的有机相;
(b)制备包含至少一种碱性化合物的水相;
(c)混合所述水相与所述有机相;
(d)在至少40℃的温度下加热至少30分钟;
(e)回收所述曲唑酮;且任选
(f)用盐酸处理所述曲唑酮而得到盐酸曲唑酮。
2.权利要求1的生产方法,其特征在于所述曲唑酮或盐酸曲唑酮包含低于15ppm的烷基化物质。
3.权利要求1的生产方法,其特征在于所述曲唑酮或盐酸曲唑酮包 含低于10ppm的烷基化物质。
4.权利要求1的生产方法,其特征在于所述曲唑酮或盐酸曲唑酮包含低于2.5ppm的烷基化物质。
5.权利要求1的生产方法,其特征在于所述曲唑酮或盐酸曲唑酮包含低于1ppm的烷基化物质。
6.任一上述权利要求的生产方法,其特征在于所述有机溶剂选自醇类、醚类、烃类、酮类和酯类。
7.权利要求6的生产方法,其特征在于所述有机溶剂选自乙醇,丙醇,异丁醇,己醇,苄醇,乙醚,丙醚,甲苯,苯,二甲苯,丙酮,甲基乙基酮,甲基异丁基酮和乙酸乙酯。
8.任一上述权利要求的生产方法,其特征在于所述有机相包含10g至50g/100克有机相的用量的曲唑酮。
9.任一上述权利要求的生产方法,其特征在于所述水相包含至少一种选自至少一种无机碱、至少一种有机碱或其混合物的碱性化合物。
10.权利要求9的生产方法,其特征在于所述无机碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾、氢氧化铵、氧化镁、肼和羟基胺。
11.权利要求9的生产方法,其特征在于所述有机碱选自脂族胺类化合物和芳族胺类化合物。
12.任一上述权利要求的生产方法,其特征在于加入0.05至1mol/mole曲唑酮用量的所述碱性化合物。
13.任一上述权利要求的生产方法,其特征在于加入30g至100g/100克有机相用量的所述水相。
14.任一上述权利要求的生产方法,其特征在于所述水相包含相转移催化剂。
15.权利要求14的生产方法,其特征在于所述相转移催化剂选自季铵盐和季磷鎓盐。
16.权利要求15的生产方法,其特征在于所述季铵盐选自溴化苄基三丁基铵、氯化苄基三丁基铵、溴化苄基三乙基铵、氯化苄基三乙基铵、氯化苄基三甲基铵、溴化鲸蜡基吡啶鎓、氯化鲸蜡基吡啶鎓、溴化鲸蜡基三甲基铵、氯化二癸基二甲基铵、溴化十二烷基三甲基铵、氯化十二烷基三甲基铵、氯化甲基三丁基铵、硫酸氢甲基三丁基铵、氯化甲基三辛酰基铵、氯化甲基三辛基铵、氯化苯基三甲基铵、硼氢化四丁基铵、溴化四丁基铵、氯化四丁基铵、氟化四丁基铵、硫酸氢四丁基铵、氢氧化四丁基铵、碘化四丁基铵、高氯酸四丁基铵、溴化四乙基铵、氯化四乙基铵、氢氧化四乙基铵、溴化四己基铵、碘化四己基铵、溴化四甲基铵、氯化四甲基铵、氟化四甲基铵、氢氧化四甲基铵、碘化四甲基铵、溴化四辛基铵、溴化四丙基铵、氯化四丙基铵、氢氧化四丙基铵、氯化三丁基甲基铵和氯化三乙基苄基铵。
17.权利要求15的生产方法,其特征在于所述季铵盐选自溴化四丁基铵、氯化四丁基铵、溴化苄基三乙基铵、氯化苄基三乙基铵、氯化苄基三甲基铵、溴化苄基三甲基铵、溴化苄基三丁基铵和氯化苄基三丁基铵。
18.权利要求15的生产方法,其特征在于所述季磷鎓盐选自溴化苄基三苯基磷鎓、氯化苄基三苯基磷鎓、溴化丁基三苯基磷鎓、氯化丁基三苯基磷鎓、乙酸乙基三苯基磷鎓、溴化乙基三苯基磷鎓、碘化乙基三苯基磷鎓、溴化十六烷基三丁基磷鎓、溴化甲基三苯基磷鎓、溴化四丁基磷鎓和溴化四苯基磷鎓。
19.生产任一权利要求15至18的方法,其特征在于所述水相包含0.05g至0.5g/100克水相的用量的相转移催化剂。
20.任一上述权利要求的生产方法,其特征在于所述加热步骤(d)在40℃至有机相和水相混合物的沸点之间的温度下进行30分钟至300分钟时间期限。
21.曲唑酮和盐酸曲唑酮,其特征在于它们包含低于15ppm的烷基化物质。
22.权利要求21的曲唑酮和盐酸曲唑酮,其特征在于它们包含低于10ppm的烷基化物质。
23.权利要求21的曲唑酮和盐酸曲唑酮,其特征在于它们包含低于2.5ppm的烷基化物质。
24.任一权利要求21至23的曲唑酮和盐酸曲唑酮,其特征在于所述烷基化物质选自2,2-二氯乙胺,1-溴-3-氯-丙烷,N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪,2-(3-氯丙基)-s-三唑并-[4,3-a]-吡啶-3-酮,3-氯-N,N′-二氯乙基-苯胺,2-{3-[双-(2-氯乙基)-氨基]-丙基}-2H-[1,2,4]三唑并[4,3-a]吡啶-3-酮,2,2-二溴乙胺和1,3-二氯丙烷。
25.任一权利要求21至24的曲唑酮和盐酸曲唑酮,特征在于它们包含低于1ppm的各自烷基化物质。
26.权利要求25的曲唑酮和盐酸曲唑酮,其特征在于所述烷基化物质选自2,2-二氯乙胺,1-溴-3-氯丙烷,N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪,2-(3-氯丙基)-s-三唑并-[4,3-a]-吡啶-3-酮,3-氯-N,N′-二氯乙基苯胺,2-{3-[双-(2-氯乙基)-氨基]-丙基]-2H-[1,2,4]三唑[4,3-a]吡啶-3-酮,2,2-二溴乙胺和1,3-二氯丙烷。
27.权利要求25或26的曲唑酮和盐酸曲唑酮,其特征在于所述烷基化物质选自2,2-二氯乙胺,1-溴-3-氯-丙烷和N-(3-氯苯基)-N′-(3-氯丙基)-哌嗪。
28.药物组合物,包含任一权利要求21至27的盐酸曲唑酮与至少一种药学上可接受的赋形剂。
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IT001603A ITMI20071603A1 (it) | 2007-08-03 | 2007-08-03 | Trazodone e trazodone cloridrato in forma purificata |
US97653507P | 2007-10-01 | 2007-10-01 | |
US60/976,535 | 2007-10-01 | ||
PCT/EP2008/059640 WO2009019133A1 (en) | 2007-08-03 | 2008-07-23 | Trazodone and trazodone hydrochloride in purified form |
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CN105777745A (zh) * | 2016-03-29 | 2016-07-20 | 深圳市泛谷药业股份有限公司 | 一种盐酸曲唑酮的制备方法 |
CN111886235A (zh) * | 2018-02-07 | 2020-11-03 | 方济各安吉利克化学联合股份有限公司 | 用于制备曲唑酮的连续方法 |
CN117517545A (zh) * | 2023-12-08 | 2024-02-06 | 重庆锐恩医药有限公司 | 一种盐酸曲唑酮有关物质检测方法 |
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ITMI20071573A1 (it) | 2007-07-31 | 2009-02-01 | Acraf | Composizione farmaceutica liquida stabile a base di trazodone |
ITMI20071603A1 (it) * | 2007-08-03 | 2009-02-04 | Acraf | Trazodone e trazodone cloridrato in forma purificata |
WO2012072665A1 (en) | 2010-11-30 | 2012-06-07 | Pharmaneuroboost N.V. | Compositions comprising pipamperone and serotonin antagonist reuptake inhibitors |
CN103853790B (zh) * | 2012-12-06 | 2016-04-06 | 腾讯科技(深圳)有限公司 | 移动终端浏览器的上传信息处理方法及装置 |
JP2017505302A (ja) * | 2014-01-21 | 2017-02-16 | ピラマル エンタープライジーズ リミテッド | トラゾドンおよびその塩酸塩を製造するための改良法 |
RU2706700C1 (ru) | 2019-09-24 | 2019-11-20 | Общество с ограниченной ответственностью "Научно-производственная компания "СКиФФ" | Фармацевтическая композиция для коррекции поведения кошек и собак в стрессовых ситуациях |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105777745A (zh) * | 2016-03-29 | 2016-07-20 | 深圳市泛谷药业股份有限公司 | 一种盐酸曲唑酮的制备方法 |
CN111886235A (zh) * | 2018-02-07 | 2020-11-03 | 方济各安吉利克化学联合股份有限公司 | 用于制备曲唑酮的连续方法 |
CN111886235B (zh) * | 2018-02-07 | 2023-06-30 | 方济各安吉利克化学联合股份有限公司 | 用于制备曲唑酮的连续方法 |
CN117517545A (zh) * | 2023-12-08 | 2024-02-06 | 重庆锐恩医药有限公司 | 一种盐酸曲唑酮有关物质检测方法 |
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