CN102702171B - 多元碱化合物的酸加成盐的制造方法 - Google Patents
多元碱化合物的酸加成盐的制造方法 Download PDFInfo
- Publication number
- CN102702171B CN102702171B CN201210189482.0A CN201210189482A CN102702171B CN 102702171 B CN102702171 B CN 102702171B CN 201210189482 A CN201210189482 A CN 201210189482A CN 102702171 B CN102702171 B CN 102702171B
- Authority
- CN
- China
- Prior art keywords
- piperazine
- ethyl
- pyridyl
- methyl
- ethanamide
- 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.)
- Expired - Fee Related
Links
- 239000002253 acid Substances 0.000 title abstract description 75
- 150000003839 salts Chemical class 0.000 title abstract description 50
- 238000000034 method Methods 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 title description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 87
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 128
- 239000005864 Sulphur Substances 0.000 claims description 126
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 126
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 101
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 79
- DSFVQIUBODXRLL-UHFFFAOYSA-N acetamide;dihydrochloride Chemical compound Cl.Cl.CC(N)=O DSFVQIUBODXRLL-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 56
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 28
- 150000007514 bases Chemical class 0.000 abstract 4
- 239000002585 base Substances 0.000 description 94
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- 238000004519 manufacturing process Methods 0.000 description 61
- 235000002639 sodium chloride Nutrition 0.000 description 52
- 239000000243 solution Substances 0.000 description 30
- 238000002425 crystallisation Methods 0.000 description 27
- 230000008025 crystallization Effects 0.000 description 26
- 239000013078 crystal Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
- 238000002386 leaching Methods 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 238000001035 drying Methods 0.000 description 14
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- -1 coenzyme A cholesterol ester Chemical class 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 150000004885 piperazines Chemical class 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- HENAPIDDJSZTEF-UHFFFAOYSA-N S(=O)(=O)(O)S(=O)(=O)O.C(C)(=O)N Chemical compound S(=O)(=O)(O)S(=O)(=O)O.C(C)(=O)N HENAPIDDJSZTEF-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000010612 desalination reaction Methods 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 201000009925 nephrosclerosis Diseases 0.000 description 4
- AUYNWRLEXAPZAJ-UHFFFAOYSA-N piperazine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CNCCN1 AUYNWRLEXAPZAJ-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000004455 differential thermal analysis Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RBVNKYIVVWTKNO-UHFFFAOYSA-N 6-methyl-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine Chemical compound CC1=CC=C([N+]([O-])=O)C(OCC(F)(F)F)=N1 RBVNKYIVVWTKNO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- GJWSUKYXUMVMGX-UHFFFAOYSA-N citronellic acid Chemical compound OC(=O)CC(C)CCC=C(C)C GJWSUKYXUMVMGX-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- UIEVSGOVFXWCIK-UHFFFAOYSA-N 2-chloro-6-methyl-3-nitropyridine Chemical compound CC1=CC=C([N+]([O-])=O)C(Cl)=N1 UIEVSGOVFXWCIK-UHFFFAOYSA-N 0.000 description 1
- KHEVPDFAQFJIGK-UHFFFAOYSA-N 2-sulfooxyethanesulfonic acid Chemical compound OS(=O)(=O)CCOS(O)(=O)=O KHEVPDFAQFJIGK-UHFFFAOYSA-N 0.000 description 1
- CSDBFIYGLRXUDX-UHFFFAOYSA-N 4-fluoro-1,3-dihydrobenzimidazole-2-thione Chemical compound FC1=CC=CC2=C1N=C(S)N2 CSDBFIYGLRXUDX-UHFFFAOYSA-N 0.000 description 1
- IZVFFXVYBHFIHY-SKCNUYALSA-N 5alpha-cholest-7-en-3beta-ol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CC[C@H]33)C)C3=CC[C@H]21 IZVFFXVYBHFIHY-SKCNUYALSA-N 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 229930008398 Citronellate Natural products 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 201000008562 aortic malignant tumor Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000004670 arteriolosclerosis Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JDCBWJCUHSVVMN-UHFFFAOYSA-N but-3-en-2-amine Chemical compound CC(N)C=C JDCBWJCUHSVVMN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940075933 dithionate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- VRXIOAYUQIITBU-UHFFFAOYSA-N tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCO)CC1 VRXIOAYUQIITBU-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明涉及多元碱化合物的酸加成盐或者其水加成物。通过本发明可简单适当地将多元碱化合物酸加成盐的酸的加成数变换为适合于该多元碱化合物的数。
Description
本申请是国际申请号为PCT/JP2004/002375、国际申请日为2004年2月27日、进入中国国家阶段的申请号为CN 200480005262.1、发明名称为“多元碱化合物的酸加成盐的制造方法”的中国专利申请的分案申请。
技术领域
本发明涉及能简单将所需数的酸加成到多元碱化合物上的多元碱化合物的酸加成盐或者其水加成物的制造方法。
背景技术
人们公知的是:在药物组合物中,即使原体是同一游离体,也因其盐的种类和盐的结晶类型的不同,其溶解性、口服吸收性、药效和制剂的稳定性等都有很大的差异。因此,在对药物组合物进行开发之际,对原体的化学稳定性、生物有效性、物理稳定性(结晶化度、水合度)、制剂特性产生的影响(硬度、崩解度、溶出性)、对原体的制造性产生的影响(成形性、流动性、填充性)等进行了综合研究,选择满足最佳条件的原体是极其重要的。
多元碱化合物的一种,即以2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺为代表的哌嗪衍生物作为酶(酰化辅酶A胆固醇脂酰基转移酶(ACAT)的抑制剂)是有用的,该酶可催化由胆固醇向胆固醇酯的合成(国际公开第98/54153号手册)。
认为若ACAT被抑制的话,由于肠道内的胆固醇吸收受到抑制,并且在肝脏内的向血中所进行的极低密度脂蛋白(VLDL)的分泌也受到抑制,所以该抑制造成了血中的胆固醇的下降。另外,还因为抑制了血管壁中的巨噬细胞的泡沫化,所以粥样动脉硬化病变可期望得到控制。所以期待着ACAT抑制剂可适用于对高血脂、动脉硬化、颈部和脑动脉硬化、脑血管意外、缺血性心脏病、冠状动脉硬化、肾硬化、动脉硬化性肾硬化、细动脉硬化性肾硬化、恶性肾硬化、缺血性肠道病、急性肠系膜血管闭塞症、慢性肠道绞痛、缺血性大肠炎、大动脉癌、闭塞性动脉硬化(ASO)等各种疾病的治疗和预防,进行了大量的研究开发。
但是,因为在作为上述ACAT抑制剂的有用的哌嗪衍生物中,例如2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺以游离碱的状态结晶,其结晶不均一,物理上的稳定性和水溶性都低,存在口服吸收性显著低等的问题。
为了改善口服吸收性,通常上述多元碱化合物加成酸,用作酸加成盐。例如,2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺使用过量的盐酸形成四盐酸盐·2水加成物,以显著改善水溶性和口服吸收性。
但是,存在如下的问题点:酸的加成数对生成的多元碱化合物的酸加成盐的物性产生影响,上述四盐酸盐·2水加成物经粉末X射线衍射测定确认结晶化度差,差示热分析测定确定容易引起脱水和脱盐酸、吸湿性试验确定有高吸湿性。另外,还考虑到过剩使用的酸的残存、四盐酸盐之类酸碱度高的盐产生的对压片机和铝的金属腐蚀的问题,可能对制剂和制剂的稳定性产生影响。为此,在制造时,必须对干燥温度、真空减压度、干燥量等因素进行充分管理,很难高效稳定提供恒定保持物性的药物组合物作为该组合物的原体。
为了解决上述问题点,虽然考虑到制造可控制加成酸的数的酸加成盐,但是采用盐酸等作为酸时,很难正确称量要加成于1摩尔多元碱化合物中的摩尔数的酸量,很难简便制造加成了所需数的酸的多元碱化合物的酸加成盐或其水加成物。
因此,期望这样的制造方法,即简便适当地将多元碱化合物的酸加成盐的酸的加成数改变为适合于其多元碱化合物的数。
发明内容
因此本发明的目的在于提供一种制造方法,该制造方法可简便将多元碱化合物的酸加成盐或者其水加成物的酸的加成数达到所需的数目。
本发明者鉴于上述问题,进行深入研究的结果发现:通过使多元碱化合物与吡啶和酸所形成的吡啶的酸式盐(acid salt)反应,对于强于吡啶的碱性的部位,可简便制得加成了所需的数目的酸的多元碱化合物的酸加成盐。并且,还发现通过该方法制得的各种哌嗪衍生物的酸加成盐,例如2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物,其结晶化度高,无吸湿性,没有脱水和脱盐酸等产生的重量变化,热稳定性好,也无多晶型现象的问题,另外,也无残余盐酸的影响,是理想的酸加成盐,作为药物原体是有用的,完成了本发明。
即,本发明提供一种多元碱化合物的酸加成盐或者其水加成物的制造方法,其特征在于,使具有强于吡啶的碱性部位的多元碱化合物和吡啶的酸式盐反应。
本发明还提供2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物或者2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物。
本发明的制造方法可简便制造多元碱化合物加成所需数目的酸的盐。通过该制造方法,不仅可控制加成酸的数目,还可稳定制造对酸不稳定的多元碱化合物的酸加成盐。
通过使用吡啶的酸式盐可相对减弱酸的酸度,明显缓和以往方法通过添加强酸等将系统内的局部pH降低所引起的分解和杂质生成等的问题。
附图说明
图1是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物的粉末X射线衍射图。
图2是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物的TG-DSC测定的结果图。
图3是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·四盐酸盐·2水加成物的粉末X射线衍射的图。
图4是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·四盐酸盐·2水加成物的TG-DSC测定的结果图。
图5是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二硫酸盐·1.5水加成物的粉末X射线衍射的图。
图6是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二硫酸盐·1.5水加成物的TG-DSC测定的结果图。
图7是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐·4水加成物的粉末X射线衍射的图。
图8是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐·4水加成物的TG-DSC测定的结果图。
图9是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐的粉末X射线衍射的图。
图10是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐TG-DSC测定的结果图。
图11是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺二马来酸盐的粉末X射线衍射的图。
图12是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二马来酸盐的TG-DSC测定的结果图。
图13和图14是2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定的结果图。
图15和图16是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其二盐酸盐的TG-DTA测定的结果图。
图17和图18是2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定的结果图。
图19和图20是2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺和其二盐酸盐的TG-DTA测定的结果图。
图21和图22是2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定的结果图。
图23和图24是2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定的结果图。
具体实施方式
本发明所用的多元碱化合物是具有一个或者一个以上强于吡啶的碱性部位的化合物,例如可以是同一分子中具有多个哌嗪基、叔氨基、仲氨基、伯氨基等的含氮化合物。作为多元碱化合物,较好是含氮有机化合物,更好是哌嗪衍生物。
作为哌嗪衍生物,较好是式(1)所示的物质:
(式中,X表示-NH-、氧原子或者硫原子;Y1、Y2和Y3分别独立表示氢、卤素、低级烷基或者低级卤代烷基;R1、R2和R3分别独立表示氢、卤素、低级烷基、低级卤代烷基、低级烷硫基、低级卤代烷氧基或者低级烷氧基烷氧基;l表示1-2的整数;m表示2-4的整数;n表示1-3的整数)。这里的低级表示指碳原子数为1-5,特好是1-3。
另外,作为哌嗪衍生物,更好采用式(2)所示的物质:
(式中,X表示-NH-、氧原子或者硫原子;Y1和Y2分别独立表示氢、卤素、三氟甲基;R1和R2分别独立表示甲基、三氟甲基、甲硫基、三氟乙氧基或者甲氧基乙氧基)。特好采用2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺、2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺、2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺、2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺、2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-甲基-4-三氟甲基-3-吡啶基]乙酰胺、2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺和2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺。该化合物由国际公开第98/54153号记载的方法制得。
本发明所用的吡啶的酸式盐是吡啶和无机酸或有机酸的盐,对于与吡啶形成盐的酸无特别限制,可用盐酸、硫酸、硝酸、磷酸、亚硫酸、亚硝酸、氢溴酸、氢碘酸等无机酸,以及乙酸、丁酸、硬脂酸等脂肪酸;草酸、马来酸、琥珀酸、富马酸等多元酸;柠檬酸、乳酸、酒石酸、苹果酸、扁桃酸、水杨酸、香茅酸(pamoic acid)、泛酸、葡糖酸等的羟基羧酸;乙二磺酸、苯磺酸、对甲苯磺酸、甲磺酸等磺酸;谷氨酸、天冬氨酸等酸性氨基酸;三氟乙酸、鞣酸等。
较好采用盐酸、硫酸、马来酸、富马酸、酒石酸、苹果酸、柠檬酸、甲磺酸等,更好采用盐酸、硫酸和马来酸;特好采用盐酸。
吡啶的酸式盐无论是以结晶或者非结晶的形式都可使用。
在结晶性的吡啶的酸式盐的制造中,虽然理论上可以等当量反应吡啶和酸制得吡啶的酸式盐,但是,实际上,在无水或者含水有机溶剂中等,较好相对于酸过量使用吡啶,吡啶对酸的量是1.0-1.5倍当量,更好以1.0-1.2倍当量使用。生成的吡啶的酸式盐可通过采用溶剂的通常的结晶化方法等进行精制。
在本发明中,在使结晶性吡啶的酸式盐与多元碱化合物反应时,通常使用的吡啶的酸式盐的量采用能提供与加成在1摩尔多元碱化合物中的酸的摩尔数同摩尔的酸的吡啶的酸式盐。具体地说,依赖于所用溶剂的种类和量,较好使用能提供通常的加成酸的摩尔数的1.0-3.0倍的量,较好1.0-2.5倍量的酸的吡啶的酸式盐。
采用非结晶性的吡啶的酸式盐制造多元碱化合物的酸加成盐时,在无水或含水有机溶剂中,在多元碱化合物中添加对应于加成在1摩尔多元碱化合物的酸的摩尔数的酸量的1.0-2.5倍量,更好为1.0-1.2倍量的酸和是使用酸量的1.0-1.5倍当量,更好是1.0-1.2倍当量的吡啶进行,较为理想。
多元碱化合物的酸加成盐的制造方法是:在有机溶剂中在0-120℃、更好为室温-100℃,特好以使用的有机溶剂的回流温度将与多元碱化合物加成的酸的量所需的吡啶的酸式盐加热溶解时,在多元碱化合物和吡啶的酸式盐之间发生盐交换,生成多元碱化合物的酸加成盐。
作为这里使用的有机溶剂,可采用甲醇、乙醇、异丙醇等低级醇;二烷、四氢呋喃等醚;丙酮、乙腈等。还可使用添加水到有机溶剂内的混合溶剂。
对于这里使用的溶剂的种类和量无特别限制,较好适当选择其种类和量,以使多元碱化合物的酸加成盐的收率最大化。
生成的多元碱化合物的酸加成盐或者其水加成物可根据需要一边搅拌,一边放置0.5-24小时,使其结晶后,取出析出的晶体而制得。
本发明所用的吡啶的酸式盐可相对减弱所用的酸的酸度,所以在多元碱化合物的游离体对酸不稳定时,明显缓和以往方法通过添加强酸等将系统内的局部pH降低所引起的分解和杂质生成等的问题。
本发明的制造方法,在制造上述哌嗪衍生物的酸加成盐时,特别在制造如下物质时是极其有利的:2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物或者2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物。即在制造2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的四盐酸盐·2水加成物时,只要以过量使用盐酸作为前提,什么问题都没有,但是,在如一盐酸盐或者其水加成物的制造那样,必须正确无误地称量盐酸的量时,该操作通常是困难的,要制造希望的均一的盐酸盐或者其水加成物是极其困难的。
在制造2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物、2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·二盐酸盐或者其水加成物、2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物以及2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐或者其水加成物时,较好使用含水低级醇作为有机溶剂。
上述制得的物质,特别是2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物,其结晶化度高,也无吸湿性,没有脱水和脱盐酸等产生的重量变化,热稳定性好,也无多晶型现象的问题,另外,也无残余盐酸的影响,是理想的酸加成盐。
实施例
以下列举实施例对本发明进-步详细说明,但本发明不限于这些实施例。
实施例1
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物的制造
(1)在回流温度下将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的游离碱(2.00kg、3.98mol)和吡啶盐酸盐(0.92kg、7.96mol)加热溶解于乙醇(12L)后,在75-87℃下将水(20L)滴加到反应液中。冷却至室温后,搅拌1小时,滤取析出的晶体。以水洗净晶体后,80℃下减压干燥,制得无色针状晶体的2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐水加成物(通过1H-NMR测定含有2%的乙醇)(1.96kg、89.0%)。
(2)将(1)制得的2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐水加成物(1.96kg)悬浮于水(40L),在回流温度下常压蒸馏除去溶剂(20L)。冷却至室温后,滤取析出的晶体,以水洗净晶体后,80℃下减压干燥,制得无色针状晶体的目标化合物(1.70kg、84.2%)。
熔点:194-196℃
IR(KBr)cm-1:3431,1674,1625,1564,1520.
1H-NMR(400MHz,DMSO-d6)δ:2.32(3H,s),2.40(3H,s),2.45(3H,s),2.75-3.75(14H,m),6.92(1H,m),7.08-7.20(2H,m),7.42-7.53(2H,m),9.38(1H,br,s).
通过水分含量试验2.84%,进行C23H30N6OS2·HCl·0.9H2O的元素分析
计算值:C,49.74;H,5.95;N,15.13;Cl,6.38;S,17.32
实测值:C,49.97;H,6.00;N,15.24;Cl,6.48;S,17.26
参考例1
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·四盐酸盐·2水加成物的制造
将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的游离碱(134.31g、0.267mol)溶解于甲醇(500ml)中,0℃下搅拌,同时滴加10%(w/v)氯化氢甲醇(607.6g,1.666mol)15分钟后,添加乙醚(700ml),放置2小时。滤取析出的晶体,依次以甲醇-乙醚(1∶1)混合溶剂(500ml)和乙醚(500ml)洗净,室温下减压干燥3小时,制得无色结晶的目标化合物(133.54g、73.0%)。
熔点:193-196℃
IR(KBr)cm-1:3405,2922,1699,1614,1564,1516.
1H-NMR(400MHz,DMSO-d6)δ:2.42(3H,s),2.43(3H,s),2.46(3H,s),3.66-3.84(10H,m),3.91(2H,t,J=7.3Hz),4.09(2H,br.s),6.95(1H,s),7.33-7.43(2H,m),7.63-7.69(2H,m),10.16(1H,br.s).
C23H30N6OS2·4HCl·2H2O的元素分析
计算值:C,40.35;H,5.59;N,12.28;Cl,20.71;S,14.05.
实测值:C,40.12;H,5.83;N,12.13;Cl,20.59;S,14.27.
参考例2
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二硫酸盐·1.5水加成物的制造
以水(1.5ml)稀释硫酸(纯度96%,799.9mg,7.83mmol),室温下将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的游离碱(1.94g、3.86mmol)添加在上述溶液中,室温下溶解。添加乙醇(4.5ml)加热溶解生成的粘性物质后,室温下搅拌10分钟,在其添加乙醇(9ml)。冰水中冷却搅拌,滤取生成的晶体,80℃下加热减压干燥3小时,制得无色粉末的目标化合物(2.64g、94.3%)。
熔点:204-208℃
IR(KBr)cm-1:3403,1700,1617,1567,1521.
1H-NMR(400MHz,DMSO-d6,120℃)δ:2.44(3H,s),2.46(3H,s),2.48(3H,s),3.05-3.14(4H,m),3.26-3.53(8H,m),3.60(2H,m),6.92(1H,m),7.16-7.19(2H,m),7.48-7.52(2H,m),9.18(1H,br.s).
C23H30N6OS3·2H2SO4·1.5H2O的元素分析
计算值:C,38.06;H,5.14;N,11.58;S,22.09
实测值:C,37.99;H,5.20;N,11.39;S,22.27
参考例3
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐·4水加成物的制造
80℃下花2分钟将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺游离碱(2.95g,5.86mmol)加热溶解于1mol/L硫酸(6ml,6.00mmol),室温下放置3天,进行晶体析出。倾析后,添加水(15ml)滤取晶体,依次以水(15ml)和异丙醇(10ml+5ml)洗净晶体。在室温常压下以开放系统放置(风干)24小时,制得无色棱晶的目标化合物(3.71g、94.1%)。
熔点:不明确
IR(KBr)cm-1:3431,1674,1625,1564,1520.
1H-NMR(400MHz,DMSO-d6)δ:2.40(6H,s),2.45(3H,s),2.80-3.72(14H,m),6.92(1H,m),7.11-7.18(2H,m),7.43-7.53(2H,m),9.38(1H,br.s).
C23H30N6OS3·H2SO4·4H2O的元素分析
计算值:C,41.06;H,5.99;N,12.49;S,19.06
实测值:C,40.92;H,5.85;N,12.35;S,19.07
参考例4
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐的制造
加热回流下溶解参考例3制得的2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐·4水加成物(3.25g,4.83mmol)到97.5%乙醇(120ml)后,室温下放置3天进行晶体析出。滤取晶体,以乙醇(30ml+20ml)洗净后,80℃加热减压干燥6小时,制得无色微小针状晶体的目标化合物(2.70g、93.0%)。
熔点:170-171℃
IR(KBr)cm-1:3431,1674,1625,1564,1520.
1H-NMR(400MHz,DMSO-d6)δ:2.40(6H,s),2.45(3H,s),2.80-3.72(14H,m),6.92(1H,m),7.11-7.18(2H,m),7.43-7.53(2H,m),9.38(1H,br.s).
C23H30N6OS3·H2SO4的元素分析
计算值:C,45.98;H,5.37;N,13.99;S,21.35
实测值:C,45.73;H,5.40;N,13.75;S,21.38
参考例5
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二马来酸盐的制造
将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的游离碱(23.75g、47.2mmol)溶解于乙醇200ml,添加马来酸(11.4g、98.2mmol)进行加热溶解,形成均一溶液。减压浓缩反应液,将获得的残渣从乙醇-乙酸乙酯中结晶出来,滤取,制得无色结晶的目标化合物(30.95g、89.1%)。
熔点:127-130℃
IR(KBr)cm-1:3424,1687,1624,1576,1492.
1H-NMR(400MHz,DMSO-d6)δ:2.43(3H,s),2.45(3H,s),2.47(3H,s),2.93-3.00(4H,m),3.08-3.17(4H,m),3.25(2H,t,J=6.8Hz),3.37(2H,br.s),3.55(2H,t,J=6.8Hz),6.14(4H,s),6.91(1H,s),7.13-7.16(2H,m),7.44-7.50(2H,m),9.04(1H,br.s).
C23H30N6OS3·2C4H4O4(马来酸)的元素分析
计算值:C,50.67;H,5.21;N,11.44;S,13.09.
实测值:C,50.49;H,5.37;N,11.20;S,13.36。
图1显示制得的2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物的粉末X射线衍射的图;图2显示TG(热重量分析)-DSC(差示扫描热量分析)测定结果。图3显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·四盐酸盐·2水加成物的粉末X射线衍射的图;图4显示了TG-DSC测定结果;图5显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二硫酸盐·1.5水加成物的粉末X射线衍射的图;图6显示TG-DSC测定结果;图7显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐·4水加成物的粉末X射线衍射的图;图8显示了TG-DSC测定结果;图9显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一硫酸盐的粉末X射线衍射的图,图10是TG-DSC测定结果,图11显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·二马来酸盐的粉末X射线衍射的图,图12显示了TG-DSC测定结果。
表1
(注)
℃保热稳定性:80℃保存10天的多元碱化合物的酸加成盐相对于保存前的HPLC测定值求出纯度。但是,二硫酸盐·1.5水加成物、二马来酸盐60存7天后,于80℃保存10天。
吸湿性:测定25℃、83%相对湿度的条件下保存4天后的重量变化。
TG:热重量分析
DSC:差示扫描热量分析
从表1可知,通过本发明,2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.9水加成物的结晶化度高,也无吸湿性,没有脱水和脱盐酸等产生的重量变化,热稳定性好,也无多晶型现象的问题,另外,也无残余盐酸的影响,是理想的酸加成盐。
实施例2
2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
(1)1-叔丁氧基碳基-4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪的制造
在1-叔丁氧基羰基-4-(2-羟基乙基)哌嗪(7.40g、32.13mmol)的THF(100ml)溶液中,冰冷搅拌下,依次添加三乙胺(4.36g、43.09mmol)、4-二甲基氨基吡啶(200mg、1.64mmol)和甲磺酰氯(7.40g、38.76mmol)。恢复到室温搅拌50分钟。过滤反应液,减压浓缩滤液,将获得的残渣溶解于DMF(200ml)中,室温下依次添加5,6-二氟-2-巯基苯并咪唑(5.00g、26.86mmol)、碳酸钾(8.64g、62.51mmol)和18-冠-6(500mg、1.92mmol),80℃搅拌90分钟。将反应液减压浓缩,以硅胶柱色谱法(硅胶200g、己烷∶丙酮=8∶1→1∶1)精制获得的残渣。通过丙酮-乙醚-己烷进行结晶化,制得无色结晶的目标化合物(7.26g、68%)。
熔点:192.3-193.0℃
IR(KBr)cm-1:3061,2976,2836,1672,1475,1427.
1H-NMR(400MHz,CDCl3)δ:1.50(9H,s),2.51-2.68(4H,m),2.94(2H,t,J=5.4Hz),3.28(2H,t,J=5.4Hz),3.45-3.65(4H,m),6.85-7.62(2H,m).
(2)1-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪·3三氟乙酸盐的制造
冰冷下搅拌花15分钟滴加1-叔丁氧基羰基-4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪(7.26g、18.22mmol)到三氟乙酸(50ml)中,溶解。冰冷下搅拌10分钟后,添加乙醚(100ml)和己烷(100ml)到反应液中,滤取生成的晶体。通过乙醇-乙醚再结晶获得的结晶,制得淡黄色粉末的目标化合物(9.58g、82%)。
熔点:141.2-142.9℃
IR(KBr)cm-1:3417,3026,2749,2483,1671,1484.
1H-NMR(400MHz,DMSO-d6)δ:2.78-3.26(10H,m),3.49(2H,t,J=7.2Hz),
7.51(2H,t,J=9.0Hz),8.76(2H,m).
(3)2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-硝基吡啶的制造
将2,4-二氯-6-甲基-3-硝基吡啶(30g、144.9mmol)溶解于2,2,2-三氟乙醇(250ml)中,添加碳酸钾(50g、361.8mmol),进行21小时加热回流。通过氯仿-水萃取反应液,以饱和食盐水洗净有机层后,用无水硫酸钠干燥,减压浓缩,制得淡黄色油状物质的目标化合物(45.40g、94%)。
熔点:72.8-73.2℃
IR(KBr)cm-1:3432,3111,2975,1610,1585,1535.
1H-NMR(400MHz,CDCl3)δ:2.50(3H,s),4.49(2H,q,J=7.7Hz),4.85(2H,q,J=8.3Hz),6.53(1H,s).
C10H8F6N2O4的元素分析
计算值:C,35.94;H,2.41;N,8.38,
实测值:C,35.94;H,2.45;N,8.49.
(4)3-氨基-2,4-双(2,2,2-三氟乙氧基)-6-甲基吡啶的制造
将2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-硝基吡啶(45.00g、134.7mmol)溶解于异丙醇(300ml)内,80℃搅拌,并且添加连二亚硫酸钠(78.00g、448.0mmol)的水(300ml)溶液,搅拌15分钟。再添加连二亚硫酸钠(16.50g、94.8mmol)的水(51ml)溶液,搅拌10分钟,再添加连二亚硫酸钠(11.10g、63.8mmol)的水(51ml)的溶液,10分钟搅拌。添加4mol/L硫酸水溶液(201ml),90℃搅拌30分钟。将反应液放置冷却至室温后,冰浴中,添加28%氨水(310ml),搅拌30分钟,以氯仿萃取。以饱和食盐水洗净有机层后,用无水硫酸钠干燥,减压浓缩,以己烷对获得的残渣再结晶,制得淡黄色针状晶体的目标化合物(32.91g、80%)。
熔点:53.5-53.8℃
IR(KBr)cm-1:3453,3314,2968,1603,1505,1456.
1H-NMR(400MHz,CDCl3)δ:2.34(3H,s),3.66(2H,br.s),4.39(2H,q,J=8.0Hz),4.79(2H,q,J=8.6Hz),6.35(1H,s).
C10H10F6N2O2·0.55H2O的元素分析
计算值:C,38.24;H,3.56;N,8.92,
实测值:C,37.96;H,3.19;N,8.94
(5)2-溴-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的制造
将3-氨基-2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-硝基吡啶(42.29g、139.0mmol)溶解于二氯甲烷(600ml)中,添加N,N-二甲基苯胺(20.46g、16.8mmol),在冰浴中搅拌,同时滴加溴乙酰溴(28.73g、142.3mmol)的二氯甲烷(100ml)溶液,室温下搅拌10分钟。通过氯仿-水对反应液进行萃取,以饱和食盐水洗净有机层后,使用无水硫酸钠,干燥,减压浓缩,通过氯仿-己烷将获得的残渣再结晶,制得无色针状晶体的目标化合物(50.25g、85%)。
熔点:152.8-154.0℃
IR(KBr)cm-1:3250,3053,1677,1597,1541,1456.
1H-NMR(400MHz,CDCl3):2.43(3H,s),4.02(2H,s),4.42(2H,q,J=7.9Hz),4.78(2H,q,J=8.5Hz),6.47(1H,s),7.49(1H,br s).
C12H11BrF6N2O3的元素分析
计算值:C,33.90;H,2.61;N,6.59,
实测值:C,34.13;H,2.66;N,6.65.
(6)2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的制造
在1-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪·3三氟乙酸盐(4.00g、6.25mmol)和碳酸钾(4.32g、31.26mmol)的乙腈(100ml)和水(30ml)的混合溶液中,冰冷下搅拌,同时花15分钟添加2-溴-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺(2.20g、5.22mmol)。室温下搅拌15小时后,通过氯仿-水萃取反应液,以饱和食盐水洗净有机层后,用无水硫酸钠干燥,减压浓缩,残渣以硅胶柱色谱法(硅胶150g,展开剂己烷∶丙酮=4∶1→2∶1→1∶1)精制,通过氯仿-己烷再结晶,制得淡黄色粉末的目标化合物(3.04g、91%)。
熔点:191-192℃
IR(KBr)cm-1:3275,1686,1604,1591,1509.
1H-NMR(400MHz,DMSO-d6)δ:2.38(3H,s),2.42-2.62(8H,m),2.67(2H,t,J=6.7Hz),3.30(2H,s),3.40(2H,t,J=6.7Hz),4.82(2H,q,J=8.8Hz),4.90(2H,q,J=8.8Hz),6.91(1H,s),7.47(2H,m),8.77(1H,s),12.82(1H,br.s)
进行C25H26F8N6O3S的元素分析
计算值:C,46.73;H,4.08;N,13.08
实测值:C,46.55;H,4.12;N,12.94
(7)2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺盐酸盐的制造
将2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺(1.00g、1.56mmol)溶解于乙醇(20ml)后,添加吡啶盐酸盐(360g、3.12mmol)。将反应溶液浓缩,从乙醇中再结晶获得的残渣,制得无色结晶性粉末的目标化合物(787mg、78%,按1H-NMR测定含有40%当量的乙醇)。
(8)将(7)制得的结晶性粉末(300mg)悬浮于水(3ml)中,进行1小时的加热回流。将反应液冷却至室温后,滤取晶体,以水(2ml×2)洗净后,50℃下加热减压干燥7小时,制得无色结晶性粉末的除去了乙醇的目标化合物(144mg、48%)。
在图13和图14中显示了2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG(热重量分析)-DTA(差示热分析)的测定结果。
熔点:186-187℃
IR(KBr)cm-1:3389,3263,1686,1592,1514,1479,1274.
1H-NMR(400MHz,DMSO-d6)δ:2.41(3H,s),2.80-3.74(14H,m),4.87(2H,q,J=8.8Hz),4.94(2H,q,J=9.0Hz),6.96(1H,s),7.50(2H,t,J=9.0Hz),9.11(1H,br).
进行C25H27ClF8N6O3S·1.6H2O的元素分析
计算值:C,42.42;H,4.30;N,11.87;Cl,5.01.
实测值:C,42.72;H,4.62;N,11.23;Cl,4.98.
实施例3
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐的制造
(1)2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的制造
用1-[2-(苯并咪唑-2-基硫)乙基]哌嗪·三盐酸盐代替1-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪·3三氟乙酸盐,与实施例2同样进行处理,制得无色结晶性粉末的目标化合物(91%)。
熔点:152-153℃
1H-NMR(400MHz,CDCl3)δ:2.43(3H,s),2.65-2.97(8H,m),3.01(2H,t,J=5.0Hz),3.23(2H,t,J=5.0Hz),3.31(2H,s),4.42(2H,q,J=8.0Hz),4.75(2H,q,J=8.5Hz),6.48(1H,s),7.60-7.24(2H,m),7.41-7.65(2H,m),8.26(1H,s).
(2)2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐的制造
将2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的游离碱(1.00g、1.65mmol)溶解于乙醇(20ml)后,添加吡啶盐酸盐(381mg,3.30mmol)。浓缩反应溶液,添加乙醇(0.5ml)、水(5ml)到获得的残渣内,滤取析出物,制得无色结晶性粉末的2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐(545mg、52%)。将该盐酸盐(250mg)悬浮于水(2.5ml)内,加热至80℃,使其溶解。将反应液冷却至室温后,滤取晶体,以水(1ml×2)洗净后,50℃下加热减压干燥7小时,制得无色结晶性粉末的目标化合物(183mg、73%)。
在图15和图16中显示了2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其二盐酸盐的TG-DTA测定结果。
熔点:153-154℃
IR(KBr)cm-1:3407,1691,1592,1513,1274,1168.
1H-NMR(400MHz,CD3CN)δ:2.40(3H,s),2.90-3.19(4H,m),3.26(2H,s),3.27-3.42(4H,m),3.46(2H,t,J=7.1Hz),3.81(2H,t,J=7.1Hz),4.57(2H,q,J=8.3Hz),4.83(2H,q,J=8.8Hz),6.71(1H,s),7.34(2H,dd,J=3.2,6.1Hz),7.64(2H,dd,J=3.2,6.1Hz),8.31(1H,br).
进行C25H30Cl2F6N6O3S·1.3H2O的元素分析
计算值:C,42.72;H,4.67;N,11.96;Cl,10.09.
实测值:C,42.73;H,4.88;N,11.86;Cl,10.01.
实施例4
2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
(1)2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的制造
使用1-[2-(苯并唑-2-基硫)乙基]哌嗪·二三氟乙酸盐代替1-[2-(苯并咪唑-2-基硫)乙基]哌嗪·三盐酸盐,与实施例3同样进行反应和处理,制得目标化合物。
熔点:141-142℃
1H-NMR(400MHz,CDCl3)δ:2.42(3H,s),2.54-2.76(8H,m),2.84(2H,t,J=6.9Hz),3.15(2H,s),3.49(2H,t,J=6.9Hz),4.41(2H,q,J=8.0Hz),4.75(2H,q,J=8.5Hz),6.46(1H,s),7.25-7.35(2H,m),7.43(1H,d,J=7.8Hz),7.59(1H,d,J=7.8Hz),8.38(1H,s).
(2)2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
将2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺(1.00g、1.65mmol)溶解于乙醇(20ml)后,添加吡啶盐酸盐(380mg、3.29mmol)。浓缩反应溶液,添加乙醇(0.5ml)、水(5ml)到获得的残渣内,滤取析出物,制得无色结晶性粉末的2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐(786mg、74%)。将该盐酸盐(300mg)悬浮于水(1.5ml)内,加热至80℃,使其溶解。将反应液冷却至室温后,滤取晶体,以水(0.5ml×2)洗净晶体后,50℃下加热减压干燥7小时,制得无色结晶性粉末的目标化合物(84mg、28%)。
在图17和图18中显示了2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定结果。
熔点:174-176℃
IR(KBr)cm-1:3431,1690,1591,1508,1454,1274,1169,1139.
1H-NMR(400MHz,DMSO-d6)δ:2.39(3H,s),2.66-3.82(14H,m),4.87(2H,q,J=8.5Hz),4.94(2H,q,J=9.0Hz),6.96(1H,s),7.33(2H,t,J=3.4Hz),7.60-7.69(2H,m),8.17(1H,br).
进行C25H28ClF6N5O4S·0.4H2O的元素分析
计算值:C,46.11;H,4.46;N,10.75;Cl,5.44.
实测值:C,46.17;H,4.44;N,10.74;Cl,5.30.
实施例5
2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·二盐酸盐的制造
(1)2,6-二甲基-4-三氟甲基吡啶-3-羧酸甲酯的制造
将1,1,1-三氟-2,4-戊二酮(25.01g、135.3mmol)溶解于乙腈(230ml)内,添加3-氨基丁烯酸甲酯(15.57g、135.2mmol),进行20小时加热回流。将反应液放置冷却至室温后,减压浓缩,用硅胶柱色谱法(硅胶400g、展开剂己烷∶丙酮=10∶1)精制获得的残渣,制得了黄色油状物质的目标化合物(22.30g、71%)。
(2)2,6-二甲基-4-三氟甲基吡啶-3-羧酸盐酸盐的制造
将2,6-二甲基-4-三氟甲基吡啶-3-羧酸甲酯(23.30g、99.9mmol)溶解于乙醇(50ml),添加5mol/L氢氧化钾水溶液(50ml、250mmol),加热回流2天。将反应液放置冷却至室温后,添加浓盐酸(15ml),减压浓缩,通过乙醇和甲苯对获得的残渣共沸3次。在乙醇内将获得的残渣加热悬浮后,过滤,减压浓缩滤液。用甲苯将获得的残渣共沸2次后,添加乙醚,滤取,制得无色粉末的目标化合物(25.24g、99%)。
(3)3-叔丁氧基羰基氨基-2,6-二甲基-4-三氟甲基吡啶的制造
将2,6-二甲基-4-三氟甲基吡啶-3-羧酸盐酸盐(23.17g、90.6mmol)悬浮于叔丁醇(175ml),添加二苯基磷酰基叠氮(DPPA)(35.25g、128.1mmol)和三乙胺(31.36g、309.9mmol),加热回流3小时。添加水(100ml)到反应液内,通过氯仿萃取。以无水硫酸钠干燥有机层后,减压浓缩,用硅胶柱色谱法(硅胶400g、展开剂己烷∶丙酮=10∶1)对获得的残渣进行精制,制得淡黄色油状物质的目标化合物(18.01g、68%)。
(4)3-氨基-2,6-二甲基-4-三氟甲基吡啶·二盐酸盐的制造
将3-叔丁氧基羰基氨基2,6-二甲基-4-三氟甲基吡啶(21.12g、72.8mmol)溶解于甲醇(70ml)内,添加10%氯化氢甲醇(140ml),60℃下搅拌12小时。减压浓缩反应液,将获得的残渣悬浮于乙酸乙酯和乙醚,滤取,以乙醚洗净,制得无色粉末的目标化合物(15.64g,82%)。
(5)2-溴-N-(2,6-二甲基-4-三氟甲基-3-吡啶基)乙酰胺的制造
将3-氨基-2,6-二甲基-4-三氟甲基吡啶·二盐酸盐(15.60g、59.30mmol)溶解于甲醇(100ml),冰浴中添加饱和氨甲醇溶液(300ml),形成均一的溶液。以氯仿-水萃取反应液,以饱和食盐水洗净有机层后,用无水硫酸钠干燥,减压浓缩将获得的残渣溶解于二氯甲烷(200ml),添加N,N-甲基苯胺(10.80g、89.12mmol),冰浴中搅拌并滴加溴乙酰溴(15.52g、76.90mmol)的二氯甲烷(40ml)溶液,室温下搅拌2小时。将反应液减压浓缩,残渣以硅胶柱色谱法(硅胶400g、展开剂己烷∶丙酮=10∶1→4∶1→3∶1)精制,用乙酸乙酯-己烷再结晶,制得无色针状晶体的目标化合物(17.68g、96%)。
(6)2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺的制造
用2-溴-N-(2,6-二甲基-4-三氟甲基-3-吡啶基)乙酰胺代替2-溴-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺,用1-[2-(苯并咪唑-2-基硫)乙基]哌嗪·二盐酸盐代替1-[2-(苯并咪唑-2-基硫)乙基]哌嗪·三盐酸盐,与实施例3一样,进行反应和处理,制得作为游离碱的目标化合物。
(7)2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·2盐酸盐的制造
将2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺(500mg、0.98mmol)溶解于乙醇(10ml)后,添加吡啶盐酸盐(227mg、1.96mmol)。浓缩反应溶液,在获得的残渣内添加乙醇(0.2ml)、水(2ml),滤取析出物,制得无色结晶性粉末的目标化合物(295mg、55%)。
在图19和图20内显示了2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺和其二盐酸盐的TG-DTA测定结果。
熔点:221-212℃
IR(KBr)cm-1:3427,1692,1430,1389,1240,1177,1154.
1H-NMR(400MHz,CD3OD)δ:2.68(3H,s),2.81(3H,s),3.32-3.45(4H,m),3.62-3.73(6H,m),3.82(2H,t,J=6.6Hz),4.89(2H,s),7.37(1H,dt,J=1.0,8.1Hz),7.47(1H,dt,J=1.0,8.1Hz),7.85-7.93(2H,m),8.26(1H,s).
进行C23H28Cl2F3N5OS2·0.6H2O的元素分析
计算值:C,46.56;H,4.96;N,11.80;Cl,11.95.
实测值:C,46.46;H,5.07;N,11.66;Cl,12.04.
实施例6
2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
(1)用4-三氟甲基苯酚代替2-巯基-5-三氟甲基苯并唑的制造WO98/54153号说明书的实施例85中的2-三氟甲基苯酚,同样进行反应和处理,制得目标化合物。
(2)用2-巯基-5-三氟甲基苯并唑代替1-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪·2三氟乙酸盐的制造WO98/54153号说明书的实施例22的2-巯基苯并唑,同样进行反应和处理,制得目标化合物。
1H-NMR(400MHz,DMSO-d6)δ:2.60-3.20(10H,m),3,57(2H,t,J=6.7Hz),7.61(1H,d,J=8.6Hz),7.89(1H,d,J=8.6Hz),8.04(1H,s),8.66(2H,s)。
(3)2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺的制造
用1-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪·2三氟乙酸盐代替1-[2-(苯并唑-2-基硫)乙基]哌嗪·2三氟乙酸盐,与WO98/54153号说明书的实施例24同样进行反应和处理,制得无色结晶性粉末的目标化合物。
熔点:103-104℃
1H-NMR(400MHz,CDCl3)δ:2.42(3H,s),2.49(3H,s),2.52(3H,s),2.60-2.82(8H,m),2.86(2H,t,J=6.8Hz),3.21(2H,s),3.51(2H,t,J=6.8Hz),6.67(1H,s),7.51-7.53(2H,m),7.85(1H,s),8.55(1H,s).
(4)2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
将2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺(200mg、0.35mmol)溶解于乙醇(4ml)后,添加吡啶盐酸盐(82mg、0.70mmol)。浓缩反应溶液,在获得的残渣内添加乙醇(0.5ml)和水(5ml),滤取析出物,制得无色结晶性粉末的目标化合物(180mg、85%)。
在图21和图22中显示了2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA的测定结果。
熔点:195-196℃
IR(KBr)cm-1:3427,1685,1501,1437,1327,1143,1123.
1H-NMR(400MHz,DMSO-d6)δ:2.42(3H,s),2.43(3H,s),2.46(3H,s),2.70-3.84(14H,m),6.94(1H,s),7.72(1H,d,J=8.3Hz),7.91(1H,d,J=8.3Hz),8.06(1H,s).
进行C24H29ClF3N5O2S3·0.5H2O的元素分析
计算值:C,46.71;H,4.90;N,11.35.
实测值:C,46.67;H,4.89;N,11.33.
实施例7
2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
(1)2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺的制造
用2-溴-N-[2-(2-甲氧基乙氧基)-6-甲基-4-(2,2,2-三氟乙氧基)-3-吡啶基]乙酰胺代替2-溴-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺,用1-[2-(苯并唑-2-基硫)乙基]哌嗪·二盐酸盐代替1-[2-(苯并咪唑-2-基硫)乙基]哌嗪·三盐酸盐,与实施例3同样进行反应和处理,制得目标化合物。
(2)2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐的制造
将2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺(500mg、0.86mmol)溶解于乙醇(10ml)后,添加吡啶盐酸盐(198mg、1.71mmol)。浓缩反应溶液,在获得的残渣内添加乙醇(0.2ml)和水(2ml),滤取析出物,制得无色结晶性粉末的目标化合物(134.0mg、25.2%)。
在图23和图24内显示了2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺和其一盐酸盐的TG-DTA测定结果。
熔点:181-182℃
IR(KBr):3432,1686,1593,1507,1454,1170,1137(cm-1).
1H-NMR(400MHz,CD3CN)δ:2.38(3H,s),2.92-3.26(8H,m),3.31(3H,s),3.42-3.59(4H,m),3.62(2H,t,J=4.9Hz),3.72-3.84(2H,m),4.38(2H,t,J=4.9Hz),4.54(2H,q,J=8.3Hz),6.61(1H,s),7.28-7.36(2H,m),7.54(2H,dd,J=2.2,5.6Hz),8.19(1H,br).
进行C26H33ClF3N5O5S·0.4H2O的元素分析
计算值:C,49.78;H,5.43;N,11.16;Cl,5.65.
实测值:C,49.76;H,5.31;N,11.25;Cl,5.78.
Claims (1)
1.2-[4-[2-(5,6-二氟苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·1.6水加成物、
2-[4-[2-(苯并咪唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·二盐酸盐·1.3水加成物、
2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.4水加成物、
2-[4-[2-(苯并噻唑-2-基硫)乙基]哌嗪-1-基]-N-[2,6-二甲基-4-三氟甲基-3-吡啶基]乙酰胺·二盐酸盐·0.6水加成物、
2-[4-[2-(5-三氟甲基苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2,4-双(甲硫基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.5水加成物,或者
2-[4-[2-(苯并唑-2-基硫)乙基]哌嗪-1-基]-N-[2-(2-甲氧基乙氧基)-4-(2,2,2-三氟乙氧基)-6-甲基-3-吡啶基]乙酰胺·一盐酸盐·0.4水加成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-052700 | 2003-02-28 | ||
JP2003052700 | 2003-02-28 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2004800052621A Division CN1753886B (zh) | 2003-02-28 | 2004-02-27 | 多元碱化合物的酸加成盐的制造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102702171A CN102702171A (zh) | 2012-10-03 |
CN102702171B true CN102702171B (zh) | 2014-09-10 |
Family
ID=32923406
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2004800052621A Expired - Fee Related CN1753886B (zh) | 2003-02-28 | 2004-02-27 | 多元碱化合物的酸加成盐的制造方法 |
CN201210189482.0A Expired - Fee Related CN102702171B (zh) | 2003-02-28 | 2004-02-27 | 多元碱化合物的酸加成盐的制造方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2004800052621A Expired - Fee Related CN1753886B (zh) | 2003-02-28 | 2004-02-27 | 多元碱化合物的酸加成盐的制造方法 |
Country Status (21)
Country | Link |
---|---|
US (2) | US7750150B2 (zh) |
EP (1) | EP1598346B1 (zh) |
JP (2) | JP4594863B2 (zh) |
KR (1) | KR101106127B1 (zh) |
CN (2) | CN1753886B (zh) |
AT (1) | ATE554083T1 (zh) |
AU (1) | AU2004215523B2 (zh) |
BR (1) | BRPI0407908A (zh) |
CA (1) | CA2516822C (zh) |
DK (1) | DK1598346T3 (zh) |
EA (1) | EA009045B1 (zh) |
ES (1) | ES2384517T3 (zh) |
IL (1) | IL170093A (zh) |
IS (1) | IS7978A (zh) |
MX (1) | MXPA05009129A (zh) |
MY (1) | MY140618A (zh) |
NO (1) | NO331272B1 (zh) |
NZ (1) | NZ541716A (zh) |
PL (1) | PL378292A1 (zh) |
TW (2) | TWI374136B (zh) |
WO (1) | WO2004076441A1 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI324600B (en) * | 2003-07-07 | 2010-05-11 | Kowa Co | 2,4-bis (trifluoroethoxy) pyridine compound and drug containing the compound |
JPWO2005020996A1 (ja) * | 2003-08-29 | 2007-11-01 | 興和株式会社 | リピド・リッチ・プラークの安定化方法及び破裂予防方法 |
TW200619204A (en) * | 2004-12-10 | 2006-06-16 | Kowa Co | Method for reduction, stabilization and prevention of rupture of lipid rich plaque |
AU2006285915B2 (en) * | 2005-08-30 | 2011-02-24 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
US8415372B2 (en) * | 2007-02-27 | 2013-04-09 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
CN101622243B (zh) * | 2007-02-28 | 2013-12-04 | 旭化成制药株式会社 | 磺酰胺衍生物 |
JP5234825B2 (ja) | 2007-07-02 | 2013-07-10 | 旭化成ファーマ株式会社 | スルホンアミド化合物及びその結晶 |
WO2009068755A1 (en) * | 2007-11-30 | 2009-06-04 | Braggone Oy | Novel siloxane polymer compositions |
US20130035344A1 (en) * | 2009-12-29 | 2013-02-07 | Kowa Co., Ltd. | Pharmaceutical composition for oral administration |
US20120289517A1 (en) * | 2009-12-29 | 2012-11-15 | Kowa Co., Ltd. | Solid pharmaceutical composition for oral administration |
CA2798735A1 (en) * | 2010-05-19 | 2011-11-24 | Haruki Shibata | Prophylactic and/or therapeutic agent for non-alcoholic steatohepatitis |
US9777028B2 (en) * | 2015-06-17 | 2017-10-03 | Gilead Sciences, Inc. | Co-crystals, salts and solid forms of tenofovir alafenamide |
JPWO2018092765A1 (ja) * | 2016-11-15 | 2019-10-17 | 学校法人同志社 | 経鼻投与用医薬組成物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054153A1 (fr) * | 1997-05-26 | 1998-12-03 | Kowa Company, Ltd. | Nouveaux composes de diamine cycliques et medicament contenant ces composes |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL112152A (en) * | 1994-12-26 | 2000-11-21 | Identa Ltd | Process and test kit for cocaine detection |
US6969711B2 (en) * | 1997-05-26 | 2005-11-29 | Kowa Company, Ltd. | Cyclic diamine compounds and medicine containing the same |
GB9826180D0 (en) | 1998-11-30 | 1999-01-20 | Smithkline Beecham Plc | Novel process |
US20060165605A1 (en) * | 2001-12-28 | 2006-07-27 | Ye-Mon Chen | Process to regenerate fcc spent catalyst |
JP4745666B2 (ja) * | 2002-12-12 | 2011-08-10 | 興和株式会社 | ヒドロキシアルキル環状ジアミン化合物 |
TWI324600B (en) * | 2003-07-07 | 2010-05-11 | Kowa Co | 2,4-bis (trifluoroethoxy) pyridine compound and drug containing the compound |
-
2004
- 2004-02-25 MY MYPI20040608A patent/MY140618A/en unknown
- 2004-02-27 BR BRPI0407908-6A patent/BRPI0407908A/pt not_active Application Discontinuation
- 2004-02-27 CN CN2004800052621A patent/CN1753886B/zh not_active Expired - Fee Related
- 2004-02-27 CN CN201210189482.0A patent/CN102702171B/zh not_active Expired - Fee Related
- 2004-02-27 DK DK04715495.0T patent/DK1598346T3/da active
- 2004-02-27 TW TW100135167A patent/TWI374136B/zh not_active IP Right Cessation
- 2004-02-27 AT AT04715495T patent/ATE554083T1/de active
- 2004-02-27 NZ NZ541716A patent/NZ541716A/en not_active IP Right Cessation
- 2004-02-27 WO PCT/JP2004/002375 patent/WO2004076441A1/ja active Search and Examination
- 2004-02-27 JP JP2005502951A patent/JP4594863B2/ja not_active Expired - Fee Related
- 2004-02-27 ES ES04715495T patent/ES2384517T3/es not_active Expired - Lifetime
- 2004-02-27 AU AU2004215523A patent/AU2004215523B2/en not_active Ceased
- 2004-02-27 PL PL378292A patent/PL378292A1/pl not_active IP Right Cessation
- 2004-02-27 EP EP04715495A patent/EP1598346B1/en not_active Expired - Lifetime
- 2004-02-27 MX MXPA05009129A patent/MXPA05009129A/es active IP Right Grant
- 2004-02-27 EA EA200501379A patent/EA009045B1/ru not_active IP Right Cessation
- 2004-02-27 CA CA2516822A patent/CA2516822C/en not_active Expired - Fee Related
- 2004-02-27 US US10/545,200 patent/US7750150B2/en not_active Expired - Fee Related
- 2004-02-27 TW TW093105174A patent/TWI355384B/zh not_active IP Right Cessation
- 2004-02-27 KR KR1020057015048A patent/KR101106127B1/ko not_active IP Right Cessation
-
2005
- 2005-08-04 IL IL170093A patent/IL170093A/en not_active IP Right Cessation
- 2005-08-12 IS IS7978A patent/IS7978A/is unknown
- 2005-09-02 NO NO20054100A patent/NO331272B1/no not_active IP Right Cessation
-
2010
- 2010-04-16 US US12/762,111 patent/US8518936B2/en not_active Expired - Fee Related
- 2010-07-15 JP JP2010160354A patent/JP5180998B2/ja not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054153A1 (fr) * | 1997-05-26 | 1998-12-03 | Kowa Company, Ltd. | Nouveaux composes de diamine cycliques et medicament contenant ces composes |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5180998B2 (ja) | 多酸性塩基化合物の酸付加塩の製造方法 | |
RU2186778C2 (ru) | Натриевая соль омепразола формы б, способ ее получения (варианты) и фармацевтический препарат, содержащий натриевую соль омепразола формы б | |
CN101326175B (zh) | C-met/hgfr抑制剂的多晶型物 | |
DE69720719T2 (de) | Mesylat des trihydrats des 5-(2-(4-(1,2-benzothiazol-3-yl)-1-piperazinyl)ethyl)-6-chlor-1,3-dihydro-2(1h)-indol-2-ons (=ziprasidon), seine herstellung und seine anwendung als dopamin d2 antagonist | |
JP2018520205A (ja) | レンバチニブメシル酸塩の新規結晶形及びその製造方法 | |
JP2010090128A (ja) | 結晶質の化合物ビス[(e)−7−[4−(4−フルオロフェニル)−6−イソプロピル−2−[メチル(メチルスルホニル)アミノ]ピリミジン−5−イル](3r,5s)−3,5−ジヒドロキシ−6−ヘプテン酸]カルシウム塩 | |
PT1755596E (pt) | Processo para a preparação de bissulfato de atazanavir e novas formas | |
US10464946B2 (en) | Crystalline forms of thienopyrimidine compound | |
JP7355834B2 (ja) | 固体形態のfgfr阻害剤化合物およびその製造方法 | |
JPH09221479A (ja) | アミノベンゼンスルホン酸誘導体一水和物及びその製造方法 | |
JPS63295561A (ja) | 2−キノロン誘導体 | |
TWI333856B (en) | Crystals of taxane and process for their production | |
CN113840605B (zh) | N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(3-异丙基-2-甲基-2h-吲唑-5-基)嘧啶-2-胺盐酸盐的结晶形式及其用途 | |
JP5628816B2 (ja) | リコフェロンのコリンおよびトロメタミン塩 | |
EA004862B1 (ru) | Кальцийдикарбоксилатные эфиры, способы их получения, фармацевтические композиции и способ лечения | |
JPH05213980A (ja) | 抗新生物作用を有する薬剤、オクタデシル−[2−(n−メチルピペリジノ)−エチル−ホスフェートの製造及び精製法及び薬剤の製法 | |
JPH02292217A (ja) | 糖尿病治療薬 | |
JP2024527207A (ja) | トリアゾロピラジン誘導体の新規なマレイン酸塩、組成物、使用方法及びこれの製造方法 | |
KR20240110861A (ko) | 키나아제 억제제로 사용되는 화합물 및 이의 용도 | |
EP0771798A1 (en) | Novel polymorphs of lesopitron dichlorohydrate and its hydrated forms, preparation methods and compositions containing them | |
JP2010518011A (ja) | 化学化合物、医薬組成物および方法 | |
JPS63316772A (ja) | イミダゾ−ル化合物およびそれを有効成分とする高脂血症治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140910 Termination date: 20170227 |
|
CF01 | Termination of patent right due to non-payment of annual fee |