CN102827157A - Method for preparing lurasidone - Google Patents
Method for preparing lurasidone Download PDFInfo
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- CN102827157A CN102827157A CN2012103528918A CN201210352891A CN102827157A CN 102827157 A CN102827157 A CN 102827157A CN 2012103528918 A CN2012103528918 A CN 2012103528918A CN 201210352891 A CN201210352891 A CN 201210352891A CN 102827157 A CN102827157 A CN 102827157A
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- 238000000034 method Methods 0.000 title claims abstract description 57
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 title abstract description 6
- 229960001432 lurasidone Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- 239000002994 raw material Substances 0.000 claims abstract description 25
- -1 salt silicate Chemical class 0.000 claims abstract description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
- 230000002140 halogenating effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 118
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- 229940125904 compound 1 Drugs 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical group 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- 150000007530 organic bases Chemical class 0.000 claims description 20
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- 230000026030 halogenation Effects 0.000 claims description 16
- 238000005658 halogenation reaction Methods 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 235000015320 potassium carbonate Nutrition 0.000 claims description 14
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 4
- 150000008045 alkali metal halides Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 235000007164 Oryza sativa Nutrition 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 229940059936 lithium bromide Drugs 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 235000009566 rice Nutrition 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- 229960004418 trolamine Drugs 0.000 claims description 3
- 238000007039 two-step reaction Methods 0.000 claims description 3
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 21
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 abstract description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000003693 atypical antipsychotic agent Substances 0.000 abstract description 2
- 229940127236 atypical antipsychotics Drugs 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 description 24
- 238000011161 development Methods 0.000 description 13
- 238000012544 monitoring process Methods 0.000 description 13
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 125000001475 halogen functional group Chemical group 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- XDODWINGEHBYRT-UHFFFAOYSA-N [2-(hydroxymethyl)cyclohexyl]methanol Chemical compound OCC1CCCCC1CO XDODWINGEHBYRT-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000006103 sulfonylation Effects 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RIVOBMOBWMOLDJ-RNGGSSJXSA-N (3ar,4s,7r,7as)-hexahydro-1h-4,7-methanoisoindole-1,3(2h)-dione Chemical compound O=C1NC(=O)[C@@H]2[C@H]1[C@]1([H])C[C@@]2([H])CC1 RIVOBMOBWMOLDJ-RNGGSSJXSA-N 0.000 description 1
- UGUBTUIYPIDXLX-RLHNMQKVSA-N C=C[C@]1(C(C2)(C3)CCC23[C@@H]1/C(/N1)=[O]\C#C)C1=O Chemical compound C=C[C@]1(C(C2)(C3)CCC23[C@@H]1/C(/N1)=[O]\C#C)C1=O UGUBTUIYPIDXLX-RLHNMQKVSA-N 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- OHFAVTSIGMIBQJ-ZQTLJVIJSA-N OC[C@H](CCCC1)C1(C1)[C@@H]1O Chemical compound OC[C@H](CCCC1)C1(C1)[C@@H]1O OHFAVTSIGMIBQJ-ZQTLJVIJSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 150000004694 iodide salts Chemical group 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940036674 latuda Drugs 0.000 description 1
- 229940073577 lithium chloride Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940094035 potassium bromide Drugs 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229940075581 sodium bromide Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a method for preparing lurasidone and preparation of atypical antipsychotic compound lurasidone, and in particular relates to a method for preparing single salt silicate. The method comprises the following steps of: halogenating hydroxy by using a compound I as an initial raw material to prepare an intermediate compound II; reacting the intermediate compound II with a compound V under an alkalinity condition to generate an intermediate compound VI; and reacting the intermediate compound VI with a compound III under the alkalinity condition to prepare a target product of lurasidone. The method is short in process routine, easy to control and convenient to operate; and the generation of impurities is avoided, the reaction yield is obviously improved, the raw materials are cheap and easy to acquire, and the large-scale production is facilitated.
Description
Technical field
The present invention relates to a kind of compound Lu Laxi ketone (Lurasidone, preparation method Latuda) of atypical antipsychotic.
Background technology
The chemistry of Lu Laxi ketone by name (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-[4-(1 for 2-; 2-benzisothiazole-3-yl) piperazinyl] methyl] cyclohexyl methyl } six hydrogen-4,7-methylene radical-2H-isoindole-1,3-dione hydrochloride, English chemistry (3aR, 4S by name; 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazinyl] methyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1; 3-dionehydrochloride also has document to be called: N-[4-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]-(2R, 3R)-2; 3-tetramethylene-butyl]-(1 ' R, 2 ' S, 3 ' R, 4 ' S)-2; 3-two ring [2,2,1] heptane imide hydrochlorides, molecular formula is C
28H
36N
4O
2SHCl, molecular weight are 529.14; Its chemical structural formula is:
The synthetic route of the I that existing bibliographical information is crossed is summarized has two kinds, specific as follows:
The main raw material of this route is compound I, compound III and compound V.Compound I obtains comprising the midbody compound II of methylsulfonyl functional group at methylsulfonyl chloride/triethylamine (MsCl/TEA) environment carapax et plastruw testudinis sulfonylation
*, then at K
2CO
3Following and the compound III reaction of alkaline condition generates midbody compound IV, continues at K
2CO
3Alkaline condition descends and compound V reaction obtains title product Lu Laxi ketone (referring to document US 5532372A).
English chemical being called of compound I (1R, 2R)-cyclohexanedimethanol, molecular formula is C
8H
16O
2, CAS number is 65376-05-8, its chemical structural formula is:
English chemical being called of compound III (3aR, 4S, 7R, 7aS) 4,7-Methano-1H-isoindole-1,3 (2H)-dione, molecular formula is C
9H
11NO
2, CAS number is 14805-29-29, its chemical structural formula is:
formula III
English chemistry N-(3-Benzisothiazolyl) piperazine by name of compound V, molecular formula is C
11H
13N
3S, CAS number is 87691-87-0, its chemical structural formula is:
The main raw material of this route still is compound I, compound III and compound V.Compound I obtains comprising the midbody compound II of methylsulfonyl functional group at methylsulfonyl chloride/triethylamine (MsCl/TEA) environment carapax et plastruw testudinis sulfonylation
*, then at K
2CO
3Alkaline condition generates the midbody compound VI that comprises methylsulfonyl functional group with compound V reaction down
*, continue at K
2CO
3Alkaline condition descends and the compound III reaction, obtains the Lu Laxi ketone of the free type of title product.
But synthetic route 2 is at preparation midbody VI
*Process in; Owing to contain an impurity (accounting for 40-65%) that is dissolved in solvent acetonitrile in the product of preceding step reaction; This impurity causes the yield of this operational path very low; Generally can only reach about 35-42%, even change the minimizing that different solvents, alkali, temperature of reaction, reaction times and protection of inert gas can not be avoided this impurity.Because synthetic route 2 productive rates are seriously on the low side, cause Lu Laxi ketone final production cost very high.
It is thus clear that the operational path to synthetic Lu Laxi ketone still has improved demand at present, the deficiency that existing method exists need manage to overcome.
Summary of the invention
The objective of the invention is to seek a generation that can effectively reduce side reaction, midbody and the finished product yield significantly improve, and the Lu Laxi ketone synthetic route of integrated artistic easy handling realization.
The inventor finds; With the compound I is the intermediate compound II that starting raw material halogenation hydroxyl obtains comprising halogen functional group; Under alkaline condition, react then with compound V; Generation comprises the midbody compound VI of halogen functional group, continues under alkaline condition, to react with compound III, obtains the Lu Laxi ketone of the free type of title product.This synthetic route can realize above-mentioned at least one purpose of the present invention fully.
Summary of the invention
First aspect present invention provides:
1. prepare method with following formula VII compound and pharmacologically acceptable salt thereof,
It may further comprise the steps:
1) making with the following formula I compound is that starting raw material carries out the halogenation hydroxyl reaction
Obtain intermediate compound with Formula Il:
2) formula II compound is reacted under alkaline environment Yu with following formula V compound
Obtain intermediate compound with following formula VI:
3) formula VI compound is continued and following formula III compound reaction under alkaline environment
Obtain shown in the formula VII (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1 ylmethyl] cyclohexyl methyl } six hydrogen-4,7-methylene radical-2H-isoindole-1,3-diketone;
And optional step:
Formula VII product and acid-respons are prepared its pharmaceutically acceptable salt,
Wherein:
X is selected from halogen, for example I, Br, Cl.
2, according to the method for project 1; Wherein said step 1) Chinese style I compound carries out the hydroxyl halogenating reaction with halide salt, haloid acid or halogen simple substance; Preferred halide salt is selected from halogenation lithium salts, sodium halogen salt, halogenation sylvite, halogenation thionyl salt, magnesium halide salts, silver halide salt, halogenation ammonia salt etc.; Preferred haloid acid is selected from HCl, HBr and HI, and preferred halogen simple substance is selected from Cl
2, Br
2And I
2
2 ', according to the method for project 1, be used in the wherein said step 1) hydroxyl is selected from the halide reagent of the substituted halogenating reaction of halogen: halogen simple substance (Cl for example
2, Br
2And I
2), alkyl sulphonyl halogenide (for example methylsulfonyl chloride), alkali metal halide (for example sodium halide such as Soiodin, for example lithium halide such as lithiumbromide), hydrogen halide (for example hydrogen bromide).
3, according to the method for project 2 or 2 '; Wherein said step 1) is in suitable organic solvent, to carry out; Preferably under the non-existent condition of organic bases, carry out; Preferably under the condition that organic bases exists, carry out, preferred organic solvent is selected from acetonitrile, methylene dichloride, acetic acid, chloroform, tetracol phenixin and ethylene dichloride, and preferred organic bases is selected from triethylamine, trolamine, tripropyl amine, Tributylamine, triphenylphosphine and triphenylcarbinol.Can be through TLC development process monitoring reaction, developer for example is the phospho-molybdic acid developer.
4, according to the method for project 2, wherein said step 1) is a single step reaction, formula I compound and organic bases are dissolved in organic solvent after, add the intermediate compound that halogen-containing halide reagent obtains formula II;
Or single step reaction, formula I compound is dissolved in organic solvent after, add the intermediate compound that halogen-containing halide reagent obtains formula II;
Or two-step reaction, the first step adds reductive agent hydroxyl is taken off after earlier formula I compound and organic bases being dissolved in organic solvent, and second step added alkali metal halide, reacted the intermediate compound that obtains formula II.
5, according to the method for project 4, wherein said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), triphenylphosphine (PPh
3) 1 ~ 1.5 equivalent (for example about 1.2 equivalents), the greenhouse stirs, and adds iodine (I
2) 1 ~ 1.5 equivalent (for example about 1.2 equivalents), finish to reacting (for example pass through, TLC development process monitoring reaction, developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish), column chromatography for separation obtains the iodine intermediate compound of formula II.This intermediate compound is a white powder;
Or said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), triethylamine (TEA) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), and temperature is controlled at below 0 ℃, adds methylsulfonyl chloride (MsCl) 2 ~ 2.5 equivalents (for example about 2.2 equivalents); Extremely reaction finishes (for example through TLC development process monitoring reaction, developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish), adds entry; Methylene dichloride (DCM) extraction obtains solid after concentrating, and in this solid, adds Soiodin (NaI) 2 ~ 3 equivalents (for example about 2.5 equivalents); With the proper amount of acetone dissolving, the lucifuge reaction adds entry; Wash rice goes out solid, filters, and obtains the iodine intermediate compound of formula II.This intermediate compound is a white powder;
Or said step 1) be with acetic acid (AcOH) as solvent, add formula I compound 1 equivalent, 40% Hydrogen bromide (HBr) 5-10 equivalent; About 0.1 equivalent of sulfuric acid, 60-80 ℃ of reaction finishes to reacting (for example through TLC development process monitoring reaction; Developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish), add entry; Methylene dichloride (DCM) extracts, and gets the bromine intermediate compound of formula II after concentrating.This intermediate compound is an oily matter;
Or said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), triethylamine (TEA) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), and temperature is controlled at below 0 ℃; Add methylsulfonyl chloride (MsCl) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), make reaction, finish to reaction and (for example monitor reaction through the TLC development process; Developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish), add entry; Methylene dichloride (DCM) extraction obtains solid after concentrating, and in this solid, adds lithiumbromide (LiBr) 2 ~ 3 equivalents (for example about 2.5 equivalents); With the proper amount of acetone dissolving, the lucifuge reaction, aftertreatment obtains the bromine intermediate compound of formula II.This intermediate compound is an oily matter;
Or said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), and temperature is controlled at below 0 ℃, adds sulfur oxychloride (SOCl
2) 4 ~ 6 equivalents (for example about 5 equivalents) make reaction, finishing to reaction, (for example through TLC development process monitoring reaction, developer is the phospho-molybdic acid developer; Finish to raw material formula I compound reaction); Add entry, methylene dichloride (DCM) extracts, and obtains the chlorine intermediate compound of formula II after concentrating.This intermediate compound is an oily matter.
6. according to the method for project 1; Wherein said step 2) the neutral and alkali environment is to realize through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal; Step 2) is through extraction after said reaction is accomplished and/or filters the intermediate compound that obtains formula VI that preferred extraction agent is selected from MTBE (MTBE), ETHYLE ACETATE, ether, sherwood oil and normal hexane.
7. the solvent that reaction is used according to the method for project 6, step 2 wherein) is N (DMF), acetonitrile, methylene dichloride, acetic acid, chloroform, tetracol phenixin and ethylene dichloride.
8. according to the method for project 1; Wherein said step 3) neutral and alkali environment is to realize that through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal the solvent that reaction is used is N (DMF), acetonitrile, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
9. according to the method for project 8, temperature of reaction is 80-150 ℃ in the wherein said step 3), and the reaction times is 5-80 hour.
Second aspect present invention provide with 1 to 9 each the said method preparation of beginning a project with following formula VII compound:
11. second aspect present invention also provides the compound with following formula VII:
Detailed Description Of The Invention
According to each method of first aspect present invention, wherein said step 1) is in suitable organic solvent, to carry out.In one embodiment, suitable organic solvent described in the step 1) can be to be selected from following one or more: acetonitrile, methylene dichloride, acetic acid, chloroform, tetracol phenixin and ethylene dichloride.In one embodiment, step 1) is carried out under the non-existent condition of organic bases.In one embodiment, step 1) is carried out under the condition that organic bases exists.In one embodiment, organic bases described in the step 1) can be to be selected from following one or more: triethylamine, tripropyl amine, Tributylamine, N, N-diisopropylethylamine.In one embodiment, step 1) is that preferred developer is the phospho-molybdic acid developer through TLC development process monitoring reaction.In one embodiment, step 1) can be in the scope of-30 to 100 ° of C, to carry out, and preferably carries out at ambient temperature, preferably in the scope of-30 to 0 ° of C, carries out, and preferably in 60-80 ℃ scope, carries out.In one embodiment, step 1) is formula I compound 1 equivalent, organic bases 0.2-10 equivalent; Halogen-containing reactant 0.5-20 equivalent; Preferred organic bases 1.0-5 equivalent, preferred organic bases 1.2 equivalents, preferred organic bases 2.2 equivalents; Preferred halogen-containing reactant 1-12 equivalent, preferred halogen-containing reactant 5-10 equivalent.In one embodiment, step 1) is after formula I compound and organic bases are dissolved in organic solvent, to add the single step reaction that halogen-containing reactant carries out.In one embodiment, step 1) is a single step reaction, formula I compound is dissolved in organic solvent after, add the intermediate compound that halogen-containing reactant obtains formula II, preferred halogen-containing reactant is sulfur oxychloride (SOCl
2).In one embodiment, step 1) is a two-step reaction, after the first step earlier is dissolved in organic solvent with formula I compound and organic bases; Add sulphonating agent hydroxyl is become sulphonate, second step added halogenated alkali metal salt, and reaction obtains the intermediate compound of formula II; Preferred organic solvent is a methylene dichloride; Organic bases is a triethylamine, and sulphonating agent is a methylsulfonyl chloride, and preferred halogenated alkali metal salt is selected from Soiodin, potassiumiodide, lithiumbromide, Sodium Bromide, Potassium Bromide and lithium chloride.
According to each method of first aspect present invention, wherein said step 2) the neutral and alkali environment is to realize through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal.In one embodiment, step 2) be formula I compound 1 equivalent, alkaline environment additive 0.2-10 equivalent, preferred alkaline environment additive 0.5-5 equivalent, preferred alkaline environment additive 0.8-1.2 equivalent, preferred alkaline environment additive 1 equivalent.In one embodiment, the solvent that reaction is used step 2) is for can being to be selected from following one or more: N (DMF), acetonitrile, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.In one embodiment, step 2) temperature of reaction is 40-100 ℃, and preferable reaction temperature is 60-80 ℃.In one embodiment, step 2) reaction times is 1-100 hour, preferred 2-10 hour, and preferred 4-8 hour, preferred 5 hours, preferred 40-90 hour, preferred 60-80 hour.In one embodiment, step 2) is through extraction after said reaction is accomplished and/or filters the intermediate compound that obtains formula VI that preferred extraction agent is selected from MTBE (MTBE), ETHYLE ACETATE, ether, sherwood oil and normal hexane.In one embodiment, step 2) react the halogeno salt solution that obtains formula IV midbody compound, directly be used for the step 3) reaction.
According to each method of first aspect present invention, wherein said step 3) neutral and alkali environment is to realize through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal.The solvent that reaction is used in the step 3) is for can being to be selected from following one or more: N (DMF), acetonitrile, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.In one embodiment, step 3) is that preferred developer is the phospho-molybdic acid developer through TLC development process monitoring reaction.In one embodiment, the step 3) temperature of reaction is 40-250 ℃, and preferable reaction temperature is 80-150 ℃, and preferable reaction temperature is 80-100 ℃.In one embodiment, step 2) reaction times is 1-100 hour, preferred 5-90 hour, and preferred 5-80 hour, preferred 60-80 hour.
Second aspect present invention provides a kind of formula VII compound, and it is made by each described method of first aspect present invention.
The present invention makes the starting raw material halogenation of formula I, obtains containing the formula II compound of halogen functional group, makes the reaction of this formula II compound and formula V compound obtain containing the formula VI compound of halogen functional group then.Find that unexpectedly when formula II compound reacted, the yield that obtains formula VI compound will be far above formula II in acetonitrile
*Compound reacts acquisition formula VI in acetonitrile
*The yield of compound.In addition; Although end product expectation of the present invention is carried out purifying through many methods; Yet the formula II compound and/or the formula VI compound of trace may remaining be arranged in the formula VII end product (comprising its acid salt) inevitably, and expectation is certainly, and the remaining micro-formula II compound and the total amount of formula VI compound are lower than 0.5%; For example be lower than 0.25%, for example be lower than 0.1%; As long as exist, these residual impurity are can be through for example the HPLC method is detected.
Therefore,, can contain total amount in the wherein said formula VII compound or pharmaceutically acceptable salt thereof and be lower than 0.5%, for example be lower than 0.25%, for example be lower than 0.1% remaining formula II compound and formula VI compound according to the compound of second aspect present invention.As pharmaceutical raw material, allow to contain total amount in the formula VII compound or pharmaceutically acceptable salt thereof and be lower than 0.5%, for example be lower than 0.25%, for example be lower than 0.1% remaining formula II compound and formula VI compound.In the formula VII compound or pharmaceutically acceptable salt thereof that each embodiment of hereinafter of the present invention obtains,, wherein contain total amount and be lower than 0.05% remaining formula II compound and formula VI compound through detecting.Theoretically, based on the inventive method, inevitably, more or less formula II compound and/or formula VI compound can residually be arranged in the end product formula VII compound or pharmaceutically acceptable salt thereof of the present invention.
In context of the present invention; Mention that formula VII compound and some raw material that in the process of synthesis type VII compound, uses or midbody are for example during formula
compound; Relate to chiral carbon atom in these compounds; The below of writing paper sheet of planar is pointed in key wherein
expression, promptly with the opposite direction of key
expression; That for example formula
compound is represented is supply (1R; 2R)-1,2-cyclohexanedimethanol.
The present invention with (1R, 2R)-1, the 2-cyclohexanedimethanol is a starting raw material, carries out the intermediate compound that the halogenation hydroxyl reaction obtains formula II; Formula II compound is reacted with formula V compound under alkaline environment, obtain the intermediate compound of formula VI; Formula VI compound is continued under alkaline environment and the reaction of formula III compound, obtain formula VII product (3aR, 4S; 7R, 7aS)-2-{ (1R, 2R)-[4-(1 for 2-; 2-benzisothiazole-3-yl) piperazine-1 ylmethyl] cyclohexyl methyl } six hydrogen-4,7-methylene radical-2H-isoindole-1,3-diketone.An exemplary synthetic route of the said method of first aspect present invention is shown in synthetic route 3.
In the present invention, in the process by formula I compound formula II compound, mentioning " halogenation hydroxyl " perhaps similar terms such as " hydroxyl halogenations ", is to instigate the hydroxyl in the formula I compound to replace with halogen, obtains comprising the formula II compound of halogen functional group.
The present invention has following advantage:
(1) synthetic route 1 of the present invention and bibliographical information is compared the midbody reaction and is easy to control, and is easy to operate; Compare with the synthetic route 2 of bibliographical information and to have avoided the impurity generation, reaction yield obviously improves
(2) the present invention has avoided the costliness and the special reagent that use in the document, and raw material is cheap and easy to get, helps scale operation.
Description of drawings
Fig. 1 and Fig. 2 have shown the carbon-13 nmr spectra and the hydrogen spectrum of Lu Laxi ketone free alkali respectively.
Embodiment
Further specify the present invention through concrete midbody and embodiment below, still, be to be understood that into, these midbodys and embodiment are only used for the usefulness of explanation more in detail particularly, are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the TP that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Embodiment 1: the preparation of the iodide of formula II midbody
Disposable adding formula I compound 1 equivalent in methylene dichloride (DCM), triphenylphosphine (PPh
3) 1.2 equivalents, the greenhouse stirs, and adds iodine (I in batches
2) 1.2 equivalents, the monitoring reaction of TLC development process, developer is the phospho-molybdic acid developer, finishes to the reaction of raw material formula I compound, and column chromatography for separation obtains containing the formula II midbody compound of iodine functional group, and this intermediate compound is a white powder.Yield about 95%.
Embodiment 2: the preparation of the iodide of formula II midbody
Disposable adding formula I compound 1 equivalent in methylene dichloride (DCM), triethylamine (TEA) 2.2 equivalents, temperature is controlled at below 0 ℃, adds methylsulfonyl chloride (MsCl) 2.2 equivalents; TLC development process monitoring reaction, developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish, and adds entry; Methylene dichloride (DCM) extraction obtains solid after concentrating, and in this solid, adds Soiodin (NaI) 2.5 equivalents, proper amount of acetone (Acetone) dissolving; Lucifuge reaction 10 hours adds the entry wash rice and goes out solid, filters; Obtain containing the formula II midbody compound of iodine functional group, this intermediate compound is a white powder, and yield is about 87%.
Embodiment 3: the preparation of the bromide of formula II midbody
As solvent, add formula I compound 1 equivalent, 40% Hydrogen bromide (HBr) 5-10 equivalent, sulfuric acid 0.1 equivalent with acetic acid (AcOH); 60-80 ℃ of reaction, TLC development process monitoring reaction, developer is the phospho-molybdic acid developer; Finish to raw material formula I compound reaction, add entry, methylene dichloride (DCM) extraction; Obtain containing the formula II midbody compound of bromo functional groups after concentrating, this compound is an oily matter, and yield is about 92-98%.
Embodiment 4: the preparation of the bromide of formula II midbody
Disposable adding formula I compound 1 equivalent, trolamine (TEA) 2.2 equivalents in methylene dichloride (DCM), temperature is controlled at below 0 ℃, adds methylsulfonyl chloride (MsCl) 2.2 equivalents; TLC development process monitoring reaction, developer is the phospho-molybdic acid developer, reacts to raw material formula I compound to finish; Add entry, methylene dichloride (DCM) extraction obtains solid after concentrating; In this solid, add lithiumbromide (LiBr) 2.5 equivalents, proper amount of acetone dissolving, lucifuge reaction 10 hours; Aftertreatment obtains containing the formula II midbody compound of bromo functional groups, and this compound is an oily matter, and yield is about 93%.
Embodiment 5: the muriatic preparation of formula II midbody
Disposable adding formula I compound 1 equivalent in methylene dichloride (DCM), temperature is controlled at below 0 ℃, adds sulfur oxychloride (SOCl
2) 5.0 equivalents, TLC development process monitoring reaction, developer is the phospho-molybdic acid developer; Finish to raw material formula I compound reaction, add entry, methylene dichloride (DCM) extraction; Obtain the chlorine intermediate compound of formula II after concentrating, this intermediate compound is an oily matter, and yield is about 98%.
Embodiment 6: the preparation of formula VI midbody
Get iodide 1 equivalent, salt of wormwood 1 equivalent, formula V compound 1 equivalent that obtain in embodiment 1 or 2, acetonitrile is a solvent, and 60-80 ℃ was reacted 5 hours, and reaction finishes, and adds MTBE, and obtaining formula VI midbody is iodide, is white solid.
Embodiment 7: the preparation of formula VI midbody
Get bromide 1 equivalent, salt of wormwood 1 equivalent, formula V compound 1 equivalent that obtain in embodiment 3 or 4, acetonitrile is a solvent, and 60-80 ℃ was reacted 40 hours, and reaction finishes, and adds MTBE, and obtaining formula VI midbody is bromide, is white solid.
Embodiment 8: the preparation of formula VI midbody
Embodiment 9: the preparation of formula VI midbody
Embodiment 10: the preparation of formula VI midbody
Embodiment 11: the preparation of formula VI midbody
Among the above embodiment 6-11, the yield of the one-step reaction of preparation formula VI compound is between 85% ~ 95%, and for example the yield of embodiment 6 about 91%.
The inventor finds, according to the described synthetic route 2 of this paper background technology part, obtains intermediate II
*This intermediate II then
*In acetonitrile, react the formula VI that obtains comprising methylsulfonyl functional group with formula V
*Compound, this preparation formula VI
*The yield of the one-step reaction of compound is lower than 50%.
Embodiment 12-17: the preparation of Lu Laxi ketone free alkali
With embodiment 6 resulting midbody or midbody solutions, add 1 normal salt of wormwood, 1 normal formula III midbody compound, DMF is a solvent, reacts 5-80 hour the TLC monitoring down at 80-150 ℃.Add entry after reaction finishes, stir 1 hour after-filtration, obtain Lu Laxi ketone free alkali,, can directly be used for next step salify for field gray solid (yield 91%).The carbon-13 nmr spectra of this free alkali and hydrogen spectrum are seen Fig. 1 and Fig. 2 respectively, and the information that wherein shows shows that product and Lu Laxi ketone free alkali coincide.
In addition, use gained midbody or the midbody solution of embodiment 7-11 respectively, prepare Lu Laxi ketone free alkali, yield 86 ~ 93% with reference to above step.
Embodiment 18: the preparation of Lu Laxi ketone dihydrochloride
Lu Laxi ketone free alkali bullion 100 grams of embodiment 12 add anhydrous propanone 1000ml, and the dissolving back adds hydrochloric acid (2-3 equivalent concentrated hydrochloric acid); Stir, separate out a large amount of off-white color solids, filter; Solid washs with small amount of acetone; Get white solid, be Lu Laxi ketone dihydrochloride, HPLC purity is greater than 99.5%.
Embodiment 19: the preparation of the pure article of Lu Laxi ketone free alkali
Lu Laxi ketone dihydrochloride 100 gram adds salt of wormwood 1 equivalent, water 500ml, and methylene dichloride 500ml, stirring at room 1 hour, separatory, the organic layer dried over sodium sulfate is concentrated into driedly, obtains the pure article of Lu Laxi ketone free alkali, is the off-white color solid.
Embodiment 20: the preparation of Lu Laxi ketone mono-hydrochloric salts
Pure article 100 grams of Lu Laxi ketone free alkali add anhydrous propanone 1000ml, dissolve the back and add hydrochloric acid (1.05 equivalent concentrated hydrochloric acids), stir, and separate out a large amount of off-white color solids, filter, and solid washs with small amount of acetone, gets white solid, is Lu Laxi ketone mono-hydrochloric salts.
Other conversion pattern of embodiment:
Above embodiment 1 to embodiment 20 is with formula I compound (1R; 2R)-1; The 2-cyclohexanedimethanol obtains intermediate compound II as starting raw material halogenation hydroxyl; Under alkaline condition, generate midbody compound VI then, continue under alkaline condition, to obtain title product Lu Laxi ketone with the compound III reaction with compound V reaction.
The contriver also finds, used organic solvent, step 2 in the step 1)) with 3) used solvent and basic additive are under different value condition, under reaction conditions of the present invention, reaction yield is substantially the same with the productive rate of embodiment 1 to embodiment 20.
Therefore, application the present invention does not partly detail other optional condition of synthesis type VII compound at embodiment, but those skilled in the art can easily realize the present invention with spirit according to aforesaid method of the present invention fully.
Claims (10)
1. prepare method with following formula VII compound and pharmacologically acceptable salt thereof,
This method may further comprise the steps:
1) making with the following formula I compound is that starting raw material carries out the halogenation hydroxyl reaction
Obtain intermediate compound with Formula Il:
2) formula II compound is reacted under alkaline environment Yu with following formula V compound
Obtain intermediate compound with following formula VI:
3) formula VI compound is continued and following formula III compound reaction under alkaline environment
Obtain shown in the formula VII (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1 ylmethyl] cyclohexyl methyl } six hydrogen-4,7-methylene radical-2H-isoindole-1,3-diketone;
And optional following steps:
Formula VII product and acid-respons are prepared its pharmaceutically acceptable salt,
Wherein X is selected from halogen, for example I, Br, Cl.
2. according to the process of claim 1 wherein:
Said step 1) Chinese style I compound carries out the hydroxyl halogenating reaction with halide salt, haloid acid or halogen simple substance; Preferred halide salt is selected from halogenation lithium salts, sodium halogen salt, halogenation sylvite, halogenation thionyl salt, magnesium halide salts, silver halide salt, halogenation ammonia salt etc., and preferred haloid acid is selected from HCl, HBr, HI and HF, and preferred halogen simple substance is selected from Cl
2, Br
2And I
2Perhaps
Be used in the said step 1) hydroxyl is selected from the halide reagent of the substituted halogenating reaction of halogen: halogen simple substance (Cl for example
2, Br
2And I
2), alkyl sulphonyl halogenide (for example methylsulfonyl chloride), alkali metal halide (for example sodium halide such as Soiodin, for example lithium halide such as lithiumbromide), hydrogen halide (for example hydrogen bromide).
3. according to the method for claim 2; Wherein said step 1) is in suitable organic solvent, to carry out; Preferably under the non-existent condition of organic bases, carry out, preferably under the condition that organic bases exists, carry out, preferred organic solvent is selected from acetonitrile, methylene dichloride, acetic acid, chloroform, tetracol phenixin and ethylene dichloride; Preferred organic bases is selected from triethylamine, tripropyl amine, Tributylamine, N, the N-diisopropylethylamine.
4. according to the method for claim 2, wherein:
Said step 1) is a single step reaction, formula I compound and organic bases are dissolved in organic solvent after, add the intermediate compound that halogen-containing halide reagent obtains formula II; Perhaps
Said step 1) is a single step reaction, formula I compound is dissolved in organic solvent after, add the intermediate compound that halogen-containing halide reagent obtains formula II;
Said step 1) is a two-step reaction, and the first step adds reductive agent hydroxyl is taken off after earlier formula I compound and organic bases being dissolved in organic solvent, and second step added alkali metal halide, reacted the intermediate compound that obtains formula II.
5. according to the method for claim 4, wherein:
Said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), triphenylphosphine (PPh
3) 1 ~ 1.5 equivalent (for example about 1.2 equivalents), the greenhouse stirs, and adds iodine (I
2) 1 ~ 1.5 equivalent (for example about 1.2 equivalents), finishing to reacting, column chromatography for separation obtains the iodine intermediate compound of formula II; Perhaps
Said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), triethylamine (TEA) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), and temperature is controlled at below 0 ℃; Add methylsulfonyl chloride (MsCl) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), finish, add entry to reacting; Methylene dichloride (DCM) extraction obtains solid after concentrating, and in this solid, adds Soiodin (NaI) 2 ~ 3 equivalents (for example about 2.5 equivalents); With the proper amount of acetone dissolving, the lucifuge reaction adds entry; Wash rice goes out solid, filters, and obtains the iodine intermediate compound of formula II; Perhaps
Said step 1) be with acetic acid (AcOH) as solvent, add formula I compound 1 equivalent, 40% Hydrogen bromide (HBr) 5-10 equivalent; About 0.1 equivalent of sulfuric acid, 60-80 ℃ of reaction finishes to reacting; Add entry, methylene dichloride (DCM) extracts, and gets the bromine intermediate compound of formula II after concentrating; Perhaps
Said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), trolamine (TEA) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), and temperature is controlled at below 0 ℃; Add methylsulfonyl chloride (MsCl) 2 ~ 2.5 equivalents (for example about 2.2 equivalents), make reaction, finish to reacting; Add entry, methylene dichloride (DCM) extraction obtains solid after concentrating; In this solid, add lithiumbromide (LiBr) 2 ~ 3 equivalents (for example about 2.5 equivalents); With the proper amount of acetone dissolving, the lucifuge reaction, aftertreatment obtains the bromine intermediate compound of formula II; Perhaps
Or said step 1) is adding formula I compound 1 equivalent in methylene dichloride (DCM), and temperature is controlled at below 0 ℃, adds sulfur oxychloride (SOCl
2) 4 ~ 6 equivalents (for example about 5 equivalents) make reaction, finish to reaction, add entry, methylene dichloride (DCM) extraction obtains the chlorine intermediate compound of formula II after concentrating.
6. according to the method for claim 1; Wherein said step 2) the neutral and alkali environment is to realize through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal; Step 2) is through extraction after said reaction is accomplished and/or filters the intermediate compound that obtains formula VI that preferred extraction agent is selected from MTBE (MTBE), ETHYLE ACETATE, ether, sherwood oil and normal hexane.
7. the solvent that reaction is used according to the method for claim 6, step 2 wherein) is N (DMF), acetonitrile, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
8. according to the method for claim 1; Wherein said step 3) neutral and alkali environment is to realize that through the oxyhydroxide that adds sodium hydroxide, salt of wormwood or other earth alkali metal the solvent that reaction is used is N (DMF), acetonitrile, methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
9. according to Claim 8 method, temperature of reaction is 80-150 ℃ in the wherein said step 3), the reaction times is 5-80 hour.
10. with following formula VII compound:
It prepares like each said method of claim 1 to 9; Perhaps
Wherein comprise be lower than 0.5% with Formula Il compound and/or formula VI compound:
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| CN106146486A (en) * | 2015-04-21 | 2016-11-23 | 上海医药集团股份有限公司 | A method for preparing lurasidone with high purity and high yield |
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| CN115043830A (en) * | 2022-07-01 | 2022-09-13 | 浙江美诺华药物化学有限公司 | Preparation method of lurasidone dihydrochloride crystal form |
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| CN103724238A (en) * | 2013-12-31 | 2014-04-16 | 无锡万全医药技术有限公司 | Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate |
| US10196400B2 (en) | 2015-01-08 | 2019-02-05 | Piramal Enterprises Limited | Process for the preparation of lurasidone and its intermediate |
| CN106146486A (en) * | 2015-04-21 | 2016-11-23 | 上海医药集团股份有限公司 | A method for preparing lurasidone with high purity and high yield |
| CN113185508A (en) * | 2015-04-21 | 2021-07-30 | 上海医药集团股份有限公司 | Method for preparing lurasidone with high purity and high yield |
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| CN110734434A (en) * | 2019-11-19 | 2020-01-31 | 湖南洞庭药业股份有限公司 | Method for preparing lurasidone and salt thereof |
| CN110734434B (en) * | 2019-11-19 | 2022-11-11 | 湖南洞庭药业股份有限公司 | Method for preparing lurasidone and salt thereof |
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