CN101466673A - Process for making salts of n-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide - Google Patents
Process for making salts of n-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide Download PDFInfo
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- CN101466673A CN101466673A CNA2007800220599A CN200780022059A CN101466673A CN 101466673 A CN101466673 A CN 101466673A CN A2007800220599 A CNA2007800220599 A CN A2007800220599A CN 200780022059 A CN200780022059 A CN 200780022059A CN 101466673 A CN101466673 A CN 101466673A
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- Prior art keywords
- methyl
- ethyl
- phenyl
- amino
- indole
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- 238000000034 method Methods 0.000 title claims abstract description 56
- 150000003839 salts Chemical class 0.000 title claims description 127
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical class CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 title abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 158
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 158
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 167
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 157
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 156
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 146
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 111
- 238000003756 stirring Methods 0.000 claims description 78
- 239000003513 alkali Substances 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 239000000725 suspension Substances 0.000 claims description 56
- 239000002904 solvent Substances 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 38
- 239000004310 lactic acid Substances 0.000 claims description 37
- 235000014655 lactic acid Nutrition 0.000 claims description 37
- 150000004682 monohydrates Chemical class 0.000 claims description 36
- 238000001556 precipitation Methods 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 31
- 239000011541 reaction mixture Substances 0.000 claims description 30
- -1 2-Methyl-1H-indole-3-yl Chemical group 0.000 claims description 29
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 27
- 238000000926 separation method Methods 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 19
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 18
- 230000036571 hydration Effects 0.000 claims description 16
- 238000006703 hydration reaction Methods 0.000 claims description 16
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 16
- 239000000832 lactitol Substances 0.000 claims description 16
- 229960003451 lactitol Drugs 0.000 claims description 16
- 235000010448 lactitol Nutrition 0.000 claims description 16
- 229940095064 tartrate Drugs 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 7
- 229940114119 gentisate Drugs 0.000 claims description 7
- 229940049920 malate Drugs 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 235000019260 propionic acid Nutrition 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 150000003016 phosphoric acids Chemical class 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 229940050411 fumarate Drugs 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229960004592 isopropanol Drugs 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 229960005219 gentisic acid Drugs 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- SSONCJTVDRSLNK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;hydrochloride Chemical compound Cl.CC(=C)C(O)=O SSONCJTVDRSLNK-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 91
- 239000007787 solid Substances 0.000 description 58
- 229960000448 lactic acid Drugs 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 35
- 238000001914 filtration Methods 0.000 description 32
- 238000000634 powder X-ray diffraction Methods 0.000 description 29
- 229960004756 ethanol Drugs 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000843 powder Substances 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 14
- 229960005184 panobinostat Drugs 0.000 description 13
- 239000012453 solvate Substances 0.000 description 13
- 238000000354 decomposition reaction Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 230000004580 weight loss Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229940083608 sodium hydroxide Drugs 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000007614 solvation Methods 0.000 description 3
- STGNLGBPLOVYMA-MAZDBSFSSA-N (E)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O STGNLGBPLOVYMA-MAZDBSFSSA-N 0.000 description 2
- XVRIEWDDMODMGA-UHFFFAOYSA-N 5-chloropentan-2-one Chemical compound CC(=O)CCCCl XVRIEWDDMODMGA-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000004807 desolvation Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- KYTDZWJWCKFINO-UNOMPAQXSA-N CC1=C(C2=CC=CC=C2N1)CCN(CC3=CC=C(C=C3)/C(=C/C(=O)O)/C(=O)O)O Chemical compound CC1=C(C2=CC=CC=C2N1)CCN(CC3=CC=C(C=C3)/C(=C/C(=O)O)/C(=O)O)O KYTDZWJWCKFINO-UNOMPAQXSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229930195212 Fischerindole Natural products 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- MKYNHKOAYQRSBD-UHFFFAOYSA-N dioxouranium;nitric acid Chemical compound O=[U]=O.O[N+]([O-])=O.O[N+]([O-])=O MKYNHKOAYQRSBD-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to preparing N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide through a novel synthesizing method. The raw materials of the invention are (E)-3-(4-[[2-(2-methy-1H-indol-3-yl)-ethylamino]methyl]phenyl)methacrylate hydrochloride and 2-methyltrytamine.
Description
Background of invention
Invention field
The present invention relates to prepare N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the salt of 2E-2-acrylamide.
Related background art
Compound N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with following formula] amino] methyl] phenyl]-the 2E-2-acrylamide (perhaps, N-hydroxyl-3-(4-{[2-(2-Methyl-1H-indole-3-yl)-ethylamino]-methyl-phenyl)-acrylamide) be described among the WO 02/22577:
This compound has the valuable pharmacological performance; Therefore, it can be used for the treatment of the histone deacetylase activity is suppressed to have the disease of response as for example histone deacetylase inhibitors.WO 02/22577 is N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl openly] amino] methyl] phenyl]-any concrete salt or the salt hydrate or the solvate of 2E-2-acrylamide.
The invention summary
The present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the crystal salt of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is dissolved or suspended in the solvent of appropriate amount; (b) under suitable temperature, handle N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with salt forming agent] amino] methyl] phenyl]-2E-2-acrylamide free alkali, wherein salt forming agent is selected from the source of supply of hydrochloride, lactic acid salt, maleate, mesylate, tartrate, acetate, benzoate, Citrate trianion, fumarate, gentisate, malate, malonate, oxalate, phosphoric acid salt, propionic salt, vitriol, succinate, sodium, potassium, calcium or zine ion.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the hydrochloride of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethanol; (b) be added dropwise to hydrochloric acid in envrionment temperature with under stirring, wherein hydrochloric acid exists with the amount of 50% molar excess; (c) the reaction mixture stirring is enough to make the sedimentary time of hydrochloride; (d) reaction mixture; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide hydrochloride; (f) with the described salt of cold washing with alcohol; (g) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the L-tartrate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethanol; (b) at 60 ℃ and the following L-tartrate that is added dropwise to of stirring, wherein L-tartrate exists with the amount of 10% molar excess; (c) reaction mixture is stirred the time that is enough to make the L-tartrate precipitation; (d) reaction mixture; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide L-tartrate; (f) with the described salt of cold washing with alcohol; (g) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated method of single hydration of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone; (b) be added dropwise to lactic acid in envrionment temperature with under stirring, wherein lactic acid exists with equimolar amount; (c) the reaction mixture stirring is enough to make single sedimentary time of hydration lactic acid salt; (d) reaction mixture; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide list hydration lactic acid salt; (f) wash described salt with cold acetone; (g) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated method of 2E-2-acrylamide, it comprises the steps: that (a) provides lactic acid solution; (b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the water; (c) suspension is heated to suitable temp; (d) add lactic acid solution to form solution; (e) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution; (f) with the solution stirring certain hour; (g) solution is heated to second suitable temp; (h) with the solution stirring certain hour; (i) cooling solution; (j) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (k) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate; (l) wash described salt with water; (m) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated method of 2E-2-acrylamide, it comprises the steps: that (a) provides lactic acid solution; (b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the 1:1 mixture of second alcohol and water; (c) suspension is heated to suitable temp; (d) add lactic acid solution to form solution; (e) cooling solution; (f) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution; (g) with the solution stirring certain hour; (h) cooling solution; (i) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (j) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate; (k) wash described salt with water; (l) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the mesylate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethyl acetate; (b) be added dropwise to methylsulfonic acid in envrionment temperature with under stirring, wherein methylsulfonic acid exists with equimolar amount, to produce precipitation; (c) reaction mixture is heated to about 50 ℃ through about 4 hours of about 2-from about 40 ℃; (d) reaction mixture is with the precipitation mesylate; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide mesylate; (f) wash described salt with cold ethyl acetate; (g) dry salt.
The invention further relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the maleate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone; (b) 45 ℃ and stir under be added dropwise to toxilic acid, wherein toxilic acid exists with equimolar amount; (c) the reaction mixture stirring is enough to make the sedimentary time of maleate; (d) reaction mixture; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with optional (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide maleate; (f) wash described salt with cold acetone; (g) dry salt.
Detailed Description Of The Invention
" salt " that is used for this paper is meant the compound by organic acid or alkali medicine and pharmaceutically acceptable inorganic or organic acid or alkali reaction are prepared; " salt " that is used for this paper comprises the hydrate and the solvate of salt prepared in accordance with the present invention.Pharmaceutically acceptable example inorganic or organic acid or alkali is listed in Handbook ofPharmaceutical Salts (pharmaceutical salts handbook), P.H.Stahl and C.G.Wermuth (editor), and VHCA, Zurich 2002, the 334-345 pages or leaves are in the Table I-8.Application No. xx/xxx in application, xxx (attorney docket (Attorney Docket No.) 50249), itself and this paper apply for simultaneously, have proposed N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the real salt of 2E-2-acrylamide; The disclosure of described application in application is incorporated herein by reference fully." polymorphic form " that is used for this paper is meant unique " crystal formation " or " polymorphic form " or " crystalline form ", and they are different mutually aspect x-ray powder diffraction spectrogram, physical chemistry and/or pharmacokinetics performance and thermodynamic stability.Application No. xx/xxx in application, xxx (attorney docket 50249), itself and this paper apply for simultaneously, have proposed N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the various polymorphic forms of 2E-2-acrylamide and salt thereof; The disclosure of described application in application is incorporated herein by reference fully.
First embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the crystal salt of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is dissolved or suspended in the solvent of appropriate amount; (b) under suitable temperature, handle N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with salt forming agent] amino] methyl] phenyl]-2E-2-acrylamide free alkali, wherein salt forming agent is selected from the source of supply of hydrochloride, lactic acid salt, maleate, mesylate, tartrate, acetate, benzoate, Citrate trianion, fumarate, gentisate, malate, malonate, oxalate, phosphoric acid salt, propionic salt, vitriol, succinate, sodium, potassium, calcium or zine ion.
In the first step of the inventive method, with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is dissolved or suspended in the solvent of appropriate amount under suitable temp; Be applicable to N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali can be any hydrate, solvate or polymorphic form.In a preferred embodiment of the invention, use N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate form H
A
Be applicable to that solvent of the present invention includes but not limited to ethanol, Virahol, acetone, ethyl acetate, ethanol/water mixture, iso-propanol/water mixture, acetone, acetonitrile, tetrahydrofuran (THF), 2-propyl alcohol and composition thereof.
In second step of the inventive method, under suitable temperature, handle N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with salt forming agent] amino] methyl] phenyl]-2E-2-acrylamide free alkali, wherein salt forming agent is selected from the source of supply of hydrochloride, lactic acid salt, maleate, mesylate, tartrate, acetate, benzoate, Citrate trianion, fumarate, gentisate, malate, malonate, oxalate, phosphoric acid salt, propionic salt, vitriol, succinate, sodium, potassium, calcium or zine ion.Suitable temperature is generally about 0 ℃-Yue 60 ℃, and more preferably room temperature is to about 60 ℃.Most probable salt forming agent can at room temperature form salt; The source of supply of Citrate trianion, tartrate and propionic salt requires elevated temperature to form salt.
The suitable source of supply of hydrochloride, lactic acid salt, maleate, mesylate, tartrate, acetate, benzoate, Citrate trianion, fumarate, gentisate, malate, malonate, oxalate, phosphoric acid salt, propionic salt, vitriol, succinate, sodium, potassium, calcium or zine ion comprises corresponding acid, i.e. hydrochloric acid, lactic acid, toxilic acid, methylsulfonic acid, tartrate, acetate, phenylformic acid, citric acid, fumaric acid, gentisinic acid, oxysuccinic acid, propanedioic acid, oxalic acid, phosphoric acid, propionic acid, sulfuric acid, succsinic acid, NaOH, KOH, CaCl
2And ZnCl
2Suitable source of supply include but not limited to above listed those, and above listed those the respective compound of various replacements.Those skilled in the art are understandable to be that suitable source of supply is the salt forming agent that is used for the inventive method.
With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-consumption of 2E-2-acrylamide compares, and salt forming agent provides with equimolar amount usually.In other embodiments of the present invention, salt forming agent can provide with excessive, i.e. N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mol ratio of 2E-2-acrylamide and salt forming agent is the about 1:2 of about 1:1-.
In the optional step of the inventive method, reduce N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-temperature of the mixture of 2E-2-acrylamide and salt forming agent, by filtering or some other suitable measure separated salt, with isolating salt drying to remove residual solvent.For example, if N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mixture of 2E-2-acrylamide and salt forming agent provides clear solution, have been found that advantageously cool the temperature to about 4 ℃ to produce precipitation.
Importantly, notice that the parameter that changes the inventive method causes obtaining N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the various polymorphic forms of 2E-2-acrylamide.This embodiment hereinafter and the Application No. xx/xxx in application can find out among the xxx (attorney docket 50251).
The preferred embodiments of the invention relate to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the hydrochloride of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethanol; (b) be added dropwise to hydrochloric acid in envrionment temperature with under stirring, wherein hydrochloric acid exists with the amount of 50% molar excess; (c) the reaction mixture stirring is enough to make the sedimentary time of hydrochloride; (d) reaction mixture.The optional step of this embodiment of the present invention comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide hydrochloride; (f) with the described salt of cold washing with alcohol; (g) dry salt.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the L-tartrate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethanol; (b) 60 ℃ and stir under be added dropwise to L-tartrate, wherein L-tartrate exists with the amount of 10% molar excess; (c) reaction mixture is stirred the time that is enough to make the L-tartrate precipitation; (d) reaction mixture; The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide L-tartrate; (f) with the described salt of cold washing with alcohol; (g) dry salt.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated method of single hydration of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone; (b) be added dropwise to lactic acid in envrionment temperature with under stirring, wherein lactic acid exists with equimolar amount; (c) the reaction mixture stirring is enough to make single sedimentary time of hydration lactic acid salt; (d) reaction mixture.The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide list hydration lactic acid salt; (f) wash described salt with cold acetone; (g) dry salt.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated method of 2E-2-acrylamide, it comprises the steps: that (a) provides lactic acid solution; (b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the water; (c) suspension is heated to 48 ℃ according to appointment of suitable temps; (d) add lactic acid solution to form solution; (e) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution; (f) with the solution stirring certain hour; (g) solution is heated to second suitable temp; (h) with the solution stirring certain hour; (i) cooling solution; (j) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide.Preferably provide lactic acid with about 1.1 molar equivalents to the amount of about 1.3 molar equivalents with respect to free alkali.Preferably lactic acid solution was slowly added as 30 minutes through for some time.Preferred crystallization is carried out about 15 ℃-Yue 50 ℃ temperature range.The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (k) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate; (l) wash described salt with water; (m) dry salt.Drying is preferably carried out under about 50 ℃ temperature in a vacuum.In preferred embodiments, step (a) is by dilute with water DL-lactic acid, is heated to about 90 ℃ temperature and keeps about 15 hours, cools off then and carries out.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated alternative method of 2E-2-acrylamide, it comprises the steps: that (a) provides lactic acid solution; (b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the 1:1 mixture of second alcohol and water; (c) suspension is heated to 60 ℃ according to appointment of suitable temps; (d) add lactic acid solution to form solution; (e) cooling solution; (f) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution; (g) with the solution stirring certain hour; (h) cooling solution; (i) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide.Preferably lactic acid solution was slowly added as 30 minutes through for some time.The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (j) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate; (k) wash described salt with water; (l) dry salt.Drying is preferably carried out under about 45 ℃ temperature in a vacuum.In preferred embodiments, step (a) is by dilute with water DL-lactic acid, is heated to about 90 ℃ temperature and keeps about 15 hours, cools off then and carries out.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the mesylate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethyl acetate; (b) be added dropwise to methylsulfonic acid in envrionment temperature with under stirring, wherein methylsulfonic acid exists with equimolar amount, to produce precipitation; (c) reaction mixture is heated to about 50 ℃ through about 4 hours of about 2-from about 40 ℃; (d) reaction mixture.The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide mesylate; (f) wash described salt with cold ethyl acetate; (g) dry salt.Notice in step (b) and at first form yellow powder; Yellow powder is the polymorphic form of mesylate, and it contains the methylsulfonic acid above equimolar amount.The result is the very height moisture absorption of this solid.Yet through mild heat in step (c), yellow powder is converted into the white crystal solid that contains the equimolar amount methylsulfonic acid.This salt is non-hygroscopic.Importantly add methylsulfonic acid at ambient temperature, increase temperature then; The adding methylsulfonic acid is given the salt precipitation as soft and cohesive material immediately under comparatively high temps.
Another preferred embodiment of the present invention relates to a kind of preparation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the maleate of 2E-2-acrylamide, it comprises the steps: that (a) is with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone; (b) 45 ℃ and stir under be added dropwise to toxilic acid, wherein toxilic acid exists with equimolar amount; (c) the reaction mixture stirring is enough to make the sedimentary time of maleate; (d) reaction mixture.The optional step of this embodiment comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of (e) precipitation separation] amino] methyl] phenyl]-2E-2-acrylamide maleate; (f) wash described salt with cold acetone; (g) dry salt.
With reference now to following embodiment, specific embodiments of the present invention is described.Be understood that these embodiment only disclose and should not limit the scope of the invention by any way by setting forth mode of the present invention.
In following embodiment, for degree of crystallinity, " excellence " is meant to have the material that sharp-pointed and intensity surpasses the XRPD main peaks of 70 countings; " well " is meant that material has sharp-pointed and intensity is the material of the XRPD main peak of 30-70 counting; " poor " is meant to have the material that wide and intensity is lower than the XRPD main peaks of 30 countings.In addition, " drying loss " (LOD) is meant the weight loss of measuring between envrionment temperature and decomposition temperature.Decomposition temperature is approximately the starting point of the first order derivative of thermogravimetric curve (to temperature).It is not real starting point, because for all salt, weightlessness can not take place with the phase same rate.Therefore, real decomposition temperature may be lower than described temperature.Salt formation, stoichiometry and existence or do not exist solvent by observing corresponding salt forming agent and reaction solvent
1H-NMR chemical shift (table contains the characterization displacement study of salt forming agent or solvent) and confirming.Water-content can not be obtained by the NMR data, because the water peak is wide.The protonated degree of free alkali is by benzene (H
Bz) proton chemical shifts changes and estimate.In addition, salt of the present invention precipitates with free flowing powder (FFP), viscosity amorphous material (SAM) (it has and tends to reunite, and forms spherical monolithic or is bonded at viscosity denseness on the reactor wall) or unformed gel (AG).At last, "-" expression is not measured.
Embodiment 1
The preparation acetate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 1.Stoichiometric acetate is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 1.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％T Decompose (T Desolvation) | 1H-NMR |
| Acetone | Envrionment temperature | FFP | Excellent S A | 13.5(107.9)147.9 | 1.89 (acetate, 3H) 2.08 (acetone, 6H) 3.74 (H bz) |
| IPA | 60 | FFP | Good A | ～10.5(72.5)148.7 | — |
| AcOEt | 60 | FFP | Good A | 9.3(105.1)147.9 | 1.89 (acetate, 3H) 3.73 (H bz) |
Salt-forming reaction in acetone has produced the salt of high-crystallinity, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-ratio of 2E-2-acrylamide and acetate is 1:1, differentiates to be stoichiometric acetone solvate S
AProduced the not acetate of solvation (form A) of identical crystalline at Virahol with salt-forming reaction in the ethyl acetate.105 ℃ the weight loss of following of being higher than is because loss (if salt is hydrate) or acetate or both losses of water.
Embodiment 2
The preparation benzoate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 2.Stoichiometric phenylformic acid is added in the suspension subsequently.Mixture is stirred at ambient temperature (, then continuing to stir down) at 4 ℃ if form clear solution.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 2.
| Solvent | T/℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | Envrionment temperature | FFP | Excellent S A | 1.5 before decomposing under 110 ℃ | — |
| IPA:H 2O (1:0.05) | Envrionment temperature | FFP | Excellent S B | 6.3 ＊(at 120 ℃ of following isothermals) | 1.02(IPA，6H)3.83(H bz) |
| EtOH | Envrionment temperature | FFP | Excellent S A | 5.2 ＊(at 120 ℃ of following isothermals) | 1.04 (EtOH, 5H) 3.43 (EtOH, 1H) 7.93 (benzoate, 2H) 3.85 (H bz) |
| IPA | Envrionment temperature | FFP | Excellent S B | 1.5% before decomposing under 100 ℃ | — |
| Acetone | Envrionment temperature | FFP | Excellent A | 0.5％160.2 | 7.93 (benzoate, 2H) 3.84 (H bz) |
*Kept isothermal 10 minutes down at 120 ℃.
Separately salt-forming reaction in ethanol and the identical solvate S of salt-forming reaction generation in ethanol and water
AThe protonated base that is obtained by NMR: benzoate: the alcoholic acid stoichiometry is 1:1:0.5.Solvent loss and decomposition are very near at interval incident heat under the heating rate of 10 ℃/min, can not record ethanol content at first.At last, by keeping down measuring in 10 minutes at 120 ℃.5.2% LOD is corresponding to 0.5 mole of ethanol of every general formula unit.Separately salt-forming reaction in Virahol and identical Virahol (IPA) the solvate S of salt-forming reaction generation in Virahol and water
BThe protonated base that is obtained by NMR: the stoichiometry of benzoate is 1:1.Solvent loss and decomposition are very near at interval incident heat under the heating rate of 10 ℃/min, can not at first record isopropanol content.At last, by keeping down measuring in 10 minutes at 120 ℃.6.3% LOD is corresponding to 0.5 mole of Virahol of every general formula unit.Based on solvent and XRPD spectrogram, two kinds of solvate S
AAnd S
BShow isomorphism.Salt-forming reaction in acetone produces the benzoate that does not contain any solvent or water, and 1:1 stoichiometry salt has excellent degree of crystallinity and high decomposition temperature (form A).
Embodiment 3
Embodiment 3
Form hydrochloride
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 3.Stoichiometric hydrochloric acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 3.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | Clear solution is to FFP | Excellent A | 0.5 | 4.20(H bz) |
| EtOH | Envrionment temperature | Clear solution is to FFP | Excellent A | 1.1 232.3 | 4.19(H bz) |
| IPA | Envrionment temperature | The FFP yellow is to white powder | Excellent A | — | 4.18(H bz) |
| Acetone | Envrionment temperature | FFP to SAM is to FFP | Excellent A | — | 4.18(H bz) |
| AcOEt | Envrionment temperature | FFP to SAM is to FFP | Excellent A | — | — |
All above-mentioned 5 reactions produce identical crystal salt.Salt is anhydrous and at high temperature decomposes.
Embodiment 4
Form half-Citrate trianion
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 4.Stoichiometric citric acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 4.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| IPA:H 2O | 60 | SAM extremely | Excellent | 0.4 | 3.98(H bz) |
| (1:0.05) | FFP | A | 184.3 | ||
| Acetone | Envrionment temperature 60 | FFP to SAM is to FFP | Excellent A | 5.0-5.8 | — |
| EtOH | 60 | SAM to FFP | Excellent A | — | — |
| IPA:H 2O (1:0.025) | 60 | SAM to FFP | Excellent A | 0.3 181.0 | — |
| IPA:H 2O (1:0.05) | 60 | SAM to FFP | Excellent A | — | — |
| Acetone: H 2O (1:0.025) | 60 | SAM to FFP | Excellent A | — | — |
| Acetone: H 2O?(1:0.05) | 60 | SAM to FFP | Excellent A | 0.7 177.0 | — |
Be heated to 60 ℃ (acetone and ethanol) and introduce water (at 60 ℃ of following Virahols and water, acetone and water) and produce the high-crystallinity salt that does not contain any solvent or water.For the high LOD value under envrionment temperature/60 of acetone ℃ is owing to there is amorphous material in crystal powder.The stoichiometry of salt can not be by DMSO-d
6In
1H-NMR measures, because the peak of desired citrate ion is identical with solvent peak.Yet,
13The C-NMR wave spectrum shows and has two 177.3 and 171.6ppm
13The C=O signal.The former is owing to protonated carboxylic acid, and the latter is owing to protonated carboxylic acid root not.Therefore, the stoichiometry of salt is 2:1 (most probable) or 1:1.
Embodiment 5
Form half-fumarate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 5.Stoichiometric fumaric acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 5.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH | Envrionment temperature | FFP to SAM is to FFP | Excellent B | (1.1+1.7 2 step) 213.2 | 3.93(H bz) 6.50 (1H, fumarates) |
| IPA | Envrionment temperature | FFP | Form H by a strong peak A | (3.4+6.0 2 step) 159.8 | 3.91(H bz) the only a small amount of IPA of 6.50 (1H, fumarates) |
| EtOH:H 2 O(1:0.05) | Envrionment temperature | FFP to SAM is to FFP | Excellent A | 0.7 217.4 | 3.90(H bz) 6.49 (1H, fumarates) |
| IPA:H 2O (1:0.05) | Envrionment temperature | FFP | Excellent A | 1.5 208.2 | — |
| IPA:H 2O (1:0.05) | Envrionment temperature | FFP | Excellent A | — | — |
| EtOH:H 2 O (1:0.025) | Envrionment temperature | FFP to SAM is to FFP | Difference A | 0.7 154.8 | — |
| EtOH:H 2 O(1:0.05) | Envrionment temperature | FFP to SAM is to FFP | Excellent A | 0.9 217.1 | 3.90(H bz) 6.49 (1H, fumarates) |
Salt-forming reaction produces stoichiometry 2:1 (protonated base: fumarate fumarate), i.e. half-fumarate in Virahol and acetone at ambient temperature.Although they all are not solvates, they have poor degree of crystallinity and low decomposition temperature.For the Virahol under the envrionment temperature, relevant (the most probable H of LOD most probable with dehydration
AForm).All the salt-forming reaction under envrionment temperature or 60 ℃ produces stoichiometry 2:1 (emprotid: fumarate fumarate), i.e. half-fumarate in ethanol, second alcohol and water and Virahol and water.Salt-forming reaction in second alcohol and water and Virahol and water (1:0.05) under envrionment temperature or 60 ℃ produces identical XRPD spectrogram (anhydrous form A).Though the spectrogram of the salt that forms by ethanol is similar but show the difference that some are little at ambient temperature, and can present half-fumarate polymorphic form (form B) of the uniqueness of similar structures.
Embodiment 6
Form gentisate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 6.With stoichiometric 2,5-resorcylic acid (gentisinic acid) adds in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 6.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％ T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | Clear solution is to FFP | Excellent A | 0.3 235.5 | 4.18(H bz) 6.61 (1H, gentisates) |
Prepared gentisate is a highly crystalline, anhydrous and decompose under very high temperature.According to NMR, the stoichiometry of salt is 1:1.
Embodiment 7
Form single hydration lactic acid salt
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 7.Stoichiometric lactic acid is added in the suspension subsequently.Mixture stirred at ambient temperature and when forming clear solution, and continue down to stir at 4 ℃.By solid collected by filtration and by XRPD, TGA and
1H-NMR analyzes solid.
Table 7.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD% (T desolvation) T Decompose | 1H-NMR |
| IPA | 4 | FFP | Excellent H A | 4.3(79.3)156.3 | — |
| Acetone | 4 | FFP | Excellent H A | 4.5(77.8)149.5 | 4.18(H bz) |
Salt-forming reaction in Virahol and acetone under 4 ℃ has produced stoichiometric (1:1) single hydration lactic acid salt.Salt is crystal, begins dehydration under 77 ℃ and decomposes down being higher than 150 ℃ being higher than.
Embodiment 8
Form maleate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 8.Stoichiometric toxilic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 8.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH | Room temperature to 4 | Clear solution is to FFP | Excellent H A？ | (6.2 room temperature) 150 | 4.22(H bz) 6.01 (2H, maleate) |
| IPA | 60 | SAM to FFP | Excellent A | 0.2 178.1 | 4.22(H bz) 6.01 (2H, maleate) |
| Acetone | 60 | SAM to FFP | Excellent A | 0.2 176.1 | 4.22(H bz) 6.01 (2H, maleate) |
Salt-forming reaction in Virahol and acetone under 60 ℃ has produced the anhydrous solid of highly crystalline, and this solid is being higher than approximately～180 ℃ of decomposition down.Toxilic acid is only and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide produces the dicarboxylic acid of 1:1 salt.Its
1The H-NMR spectrogram is presented at the 6.01ppm place resonance, and corresponding to two olefinic protons, and the resonance at the 10.79ppm place is because a unprotonated carboxylic acid.Toxilic acid also is formed on the salt that loses high water content under the mild heat condition.Salt-forming reaction in ethanol (room temperature to 4 ℃) produces hydrate (form H equally
A).
Embodiment 9
Form half-malate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 9.Stoichiometric oxysuccinic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 9.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | SAM to FFP | Excellent A | 1.9 206.0 | 3.96(H bz) 3.83 (0.5H, malates) |
| EtOH | 60 | SAM to FFP | Excellent A | 0.4 199.3 | — |
| IPA | 60 | SAM to FFP | Excellent A | — | — |
| Acetone | 60 | SAM to FFP | Excellent S A | 0.695? | 3.97(H bz) 3.84 (0.5H, malates) |
| EtOH:H 2O (1:0.05) | Envrionment temperature | SAM to FFP | Excellent A | — | — |
Salt-forming reaction in second alcohol and water, ethanol and Virahol produces identical crystallization and anhydrous half-malate.LOD difference between second alcohol and water (1:0.05) and ethanol can reflect the variation of the amount of amorphous material in two kinds of samples.Salt-forming reaction in the acetone is given and being higher than approximately～95 ℃ of weightless continuously down difference half-malates.This salt is acetone solvate (form S
A).Solvent loss and decomposition are very near at interval incident heats.
Embodiment 10
Form half-malonate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 10.Stoichiometric propanedioic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 10.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH | 60 | SAM to FFP | Difference A | 1.0 169.5 | |
| IPA | 60 | SAM to FFP | Good A | 1.5 174.1 | 4.00(H bz) 2.69 (1H, malonates) |
| Acetone | 60 | SAM to FFP | Good A | — | — |
| Acetone | Envrionment temperature | FFP to SAM is to FFP | Good A | — | — |
Respond and give identical half-malonate.Degree of crystallinity is good usually, although unformed ring also can be seen in the XRPD spectrogram.The water relevant with these materials may be the absorption because unformed component moisturizes.Ambient temperature conditions in building-up process shows and produces higher-quality salt.
Embodiment 11
Form mesylate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 11.Stoichiometric methylsulfonic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 11.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| Acetone | 60 | SAM to FFP | Excellent A+B? | 1.6 172.8 | 4.22(H bz) 2.33 (～5H, mesylates) |
| AcOEt | Envrionment temperature | FFP | Excellent A | (1.3+1.3 2 step) 170.9 | 4.22(H bz) 2.36 (～5H, mesylates) |
Yellow salt is given in the salt-forming reaction of at room temperature stirring in ethyl acetate.Salt (form A) is crystal, shows 2 step weight loss and does not contain any solvent according to NMR, has the 1 molecule mesylate of surpassing but show.Salt-forming reaction in acetone is given isolating white powder after the heating down at 60 ℃.It shows excellent degree of crystallinity, but can be the mixture that surpasses a kind of polymorphic form (form A and B).Do not contain any solvent according to NMR, have the 1 molecule mesylate of surpassing but show.Wherein initiation reaction at ambient temperature, isolating new form B is given in another salt-forming reaction in ethyl acetate that then gained pale yellow powder suspension is heated to 50 ℃, as shown in Figure 5.
Embodiment 12
Form oxalate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the listed solvent of 1ml table 12.Stoichiometric salt forming agent oxalic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 12.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | FFP | Difference | — | — |
| IPA:H 2O (1:0.05) | 60 | FFP | Difference | — | — |
| EtOH | Envrionment temperature | Waxy solid | Unformed | — | — |
| IPA | Envrionment temperature | Waxy solid | Unformed | — | — |
| Acetone | Envrionment temperature | Waxy solid | Unformed | — | — |
Although oxalic acid is being added N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-precipitating immediately during 2E-2-acrylamide suspension, oxalate is difficult to separate and show in filtration procedure absorb water.
Embodiment 13
Form phosphoric acid salt
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 13.Stoichiometric phosphoric acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 13.
| Solvent | T/℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | FFP | Excellent H A | 7.0 179.6 | 3.94(H bz) |
| EtOH | Envrionment temperature | FFP | Good S A | ～6.6 | (1.1～1.5H，EtOH)4.00(H bz) |
| IPA | Envrionment temperature | FFP | Excellent S B | ～7.0 | 1.02(3-4H，IPA)4.00(H bz) |
| Acetone | Room temperature to 60 | SAM to FFP | Excellent A | 1.0 187.4 | 4.00(H bz) |
| AcOEt | Room temperature to 60 | SAM to FFP | Good A | 1.2 175.5 | — |
Half solvate that salt-forming reaction in ethanol and Virahol obtains ethanol and Virahol (is respectively form S
AAnd S
B).In the second alcohol and water,, only detect trace ethanol by NMR although LOD is big.Material is absorptive or hydrate (the form H of dehydration when mild heat and under the vacuum condition
A) (recording complete dehydration with 10 ℃/min at～60 ℃ by TGA).Salt-forming reaction in acetoneand ethyl acetate produces the phase syncrystallization and anhydrous phosphoric acid salt (form A).The stoichiometry most probable is 1:1.Salt shows high decomposition temperature.
Embodiment 14
Form propionic salt
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 14.Stoichiometric propionic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 14.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| IPA | 60 | FFP | Excellent S A | 15.1 | (0.97 3H, propionic acid) 1.02 (～4H, IPA) 3.73 (H bz) |
| Acetone | 60 | FFP | Excellent A | 7.0?98.9 | (0.97 3H, propionic acid) 3.73 (Hbz) |
| AcOEt | 60 | FFP | Excellent A | 6.3 ～100 | — |
Unreacted free alkali (the most probable form H of being is given in salt-forming reaction in ethanol
B).Virahol produces IPA solvate (the form S of propionic salt
A).Based on NMR, IPA content is～0.5.Salt shows 15% weight loss, and this adds the loss of unidentified component corresponding to IPA.Salt-forming reaction in acetoneand ethyl acetate produces identical crystalline and the salt of solvation (form A) not.In the weight loss of the 6.3-7% of～100 ℃ of beginnings owing to water (if salt is hydrate), propionic acid or degradation production cause.When weight loss finishes (～140 ℃), salt decomposes.Be to be noted that when material being dissolved in DMSO being used for NMR, detect the free propionic acid and the propionic salt of trace only.
Embodiment 15
Form vitriol
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 15.Stoichiometric sulfuric acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 15.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| IPA | 60 | SAM extremely | Excellent | 8.9-12 | 1.02(6H，IPA) |
| FFP | SA | 162 | 1.10(3H，IPA +)4.22(H bz) | ||
| AcOEt | Envrionment temperature | FFP | Difference A | ～6.7 ～160 | 4.22(H bz) |
Isolating white crystals salt is given in salt-forming reaction in Virahol.It is differentiated and is isopropanol solvate (form S
A), every general formula unit contains 1.5mol IPA.In DMSO, that 0.5mol IPA is protonated.Isolating yellow hygroscopic powder (form A) is given in salt-forming reaction in ethyl acetate.In filtration procedure, can see that sample absorbs moisture, the degree of crystallinity of its difference acts on owing to this.
Embodiment 16
Form half-succinate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 16.Stoichiometric succsinic acid is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 16.
| Solvent | T，℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | 60 | SAM to FFP | Excellent A | 1.1 203.7 | (2.31 2H, succinate) 3.86 (H bz) |
| IPA:H 2O (1:0.05) | 60 | SAM to FFP | Excellent H A | 4.6 | (2.31 2H, succinate) 3.85 (H bz) |
| EtOH | Envrionment temperature | FFP to SAM is to FFP | Excellent A | 1.1 194.6 | (2.31 2H, succinate) 3.85 (H bz) |
| IPA | Envrionment temperature | FFP | Good S A | 2.8+4.6 (90.6) (2 step) 155.8 | 1.02 (～3H, IPA) 2.32 (2H, succinates), 3.88 (H bz) |
| Acetone | The environment temperature | FFP | Well | (1.5+1.3 2 step) | (2.31 2H, succinate) |
| Degree | B | 162.3 | 3.86(H bz) | ||
| AcOEt | Envrionment temperature | FFP | Good B | 1.3+2.9154.5 | — |
| EtOH | 60 | SAM to FFP | Excellent A | — | — |
| EtOH:H 2O (1:0.025) | 60 | SAM to FFP | Excellent A | 1.0 197.3 | (2.31 2H, succinate) 3.85 (H bz) |
| EtOH:H 2O (1:0.05) | 60 | SAM to FFP | Excellent A | — | — |
Isolate four kinds of remarkable different hemisuccinic acid salt: half solvate (form S of monohydrate (form A) (in ethanol at ambient temperature), Virahol
A) (Virahol) and two kinds not solvation form A and B.Form A shows higher crystallinity, until 200 ℃ minimum weight loss with than high decomposition temperature.In addition, can be as in ethanol and second alcohol and water, reproducing synthetic down at 60 ℃.
Embodiment 17
Form half-tartrate
Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the listed solvent of 1ml table 17.Stoichiometric tartrate is added in the suspension subsequently.Mixture is stirred (, then continuing down to stir) at 4 ℃ if form clear solution under 60 ℃ or envrionment temperature.By solid collected by filtration and by XRPD, TGA and sometimes
1H-NMR analyzes solid.
Table 17.
| Solvent | T/℃ | Physical appearance | Degree of crystallinity and form | LOD％?T Decompose | 1H-NMR |
| EtOH:H 2O (1:0.05) | Room temperature to 60 | FFP to SAM is to FFP | Excellent A | 0.5 206.9 | (3.86 1H, tartrate) 3.95 (H bz) |
| EtOH:H 2O (1:0.025) | 60 | SAM to FFP | Excellent A | — | — |
| EtOH:H 2O | 60 | SAM extremely | Excellent | 0.5 | (3.86 1H, tartrate) |
| (1:0.05) | FFP | A | 207.6 | 3.95(H bz) | |
| EtOH | 60 | SAM to FFP | Excellent A | — | — |
| IPA:H 2O?(1:0.05 | 60 | SAM to FFP | Good B | 1.9 and 3.4〉160 ℃ | (3.90 1H, tartrate) 3.96 (H bz) |
Free alkali and tartaric salt-forming reaction need be heated to elevated temperature.The high crystal anhydrous salt that decompose under being higher than 200 ℃ are as the separation of half tartrate and be labeled as form A.Form B separates under 60 ℃ in Virahol and water immediately, although be very similar to the structure of A, sees remarkable difference on its XRPD spectrogram.
Embodiment 18
Form the anhydrous lactitol hydrochlorate
Water (27.2g) dilution DL-lactic acid (4.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 3.4g), and solution is heated to 90 ℃ (internal temperatures) kept 15 hours.Solution is cooled to room temperature and is used for following salify step as lactic acid solution.
With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali (10.0g) places the 4 neck reaction flasks of being furnished with mechanical stirrer.Add softening water (110.5g) and suspension was heated to 65 ℃ (internal temperatures) through 30 minutes.The DL-lactic acid solution was being added in this suspension through 30 minutes under 65 ℃.In the process that adds lactate solution, suspension is converted into solution.With softening water (9.1g) rinsing feed hopper, and with solution extra stirring 30 minutes under 65 ℃.Solution is cooled to 45 ℃ (internal temperatures) and under this temperature, add kind brilliant (10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide list hydration lactic acid salt).With suspension be cooled to 33 ℃ and under this temperature extra the stirring 20 hours.With suspension reheat to 65 ℃, under this temperature, stirred 1 hour and be cooled to 33 ℃ through 1 hour.33 ℃ down extra stir 3 hours after, by the filtering separation product, and with softening water (2 * 20g) washing leaching cakes.Filter cake is obtained anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl as crystallized product in vacuum and 50 ℃ of following dryings] amino] methyl] phenyl]-2E-2-acrylamide lactic acid salt.HPLC and
1Among the H-NMR, this product is equal to monohydrate salt (form H
A), difference is
1Water signal integration in the H-NMR spectrogram.
In the extra salify experiment of carrying out according to said procedure, product solution is filtered down at 65 ℃, be cooled to 45 ℃ subsequently, add kind of crystalline substance and crystallization.In all cases, obtain form A (anhydrous form) as product.
Embodiment 19
Form the anhydrous lactitol hydrochlorate
Water (13.6g) dilution DL-lactic acid (2.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 1.7g), and solution is heated to 90 ℃ (internal temperatures) kept 15 hours.Make solution be cooled to room temperature and be used for following salify step as lactic acid solution.
With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali (5.0g) places the 4 neck reaction flasks of being furnished with mechanical stirrer.Add softening water (54.85g) and suspension was heated to 48 ℃ (internal temperatures) through 30 minutes.The DL-lactic acid solution was being added in this suspension through 30 minutes under 48 ℃.Form solution.Adding kind of crystalline substance (5mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-suspension of 2E-2-acrylamide lactic acid salt (anhydrous form A) in 0.25g water) and 48 ℃ of extra down lasting stirrings 2 hours.Temperature was risen to 65 ℃ (internal temperatures) through 30 minutes, with suspension extra stirring 2.5 hours under this temperature.Then temperature was cooled to 48 ℃ through 2 hours, and extra the continuation stirred 22 hours under this temperature.Also use softening water (2 * 10g) washing leaching cakes by the filtering separation product.Wet cake is obtained anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl as crystallized product in vacuum and 50 ℃ of following dryings] amino] methyl] phenyl]-2E-2-acrylamide lactic acid salt (form A).
Embodiment 20
Single hydration lactic acid salt is converted into the anhydrous lactitol hydrochlorate
Water (4.1g) dilution DL-lactic acid (0.59g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 0.5g), and solution is heated to 90 ℃ (internal temperatures) kept 15 hours.Solution is cooled to room temperature and is used for following salify step as lactic acid solution.
With 10g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide list hydration lactic acid salt places 4 neck reaction flasks.Add entry (110.9g), add lactic acid solution subsequently.The feed hopper of water (15.65g) rinsing lactic acid.Suspension is heated to 82 ℃ (internal temperatures) obtains solution.Solution is obtained clear solution in 82 ℃ of following stirrings 15 minutes and heat filtering to another reaction flask.Temperature is cooled to 50 ℃, and adding kind of crystalline substance (10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-suspension of 2E-2-acrylamide lactic acid salt (anhydrous form) in 0.5g water).With temperature be cooled to 33 ℃ and under this temperature extra the continuation stirred 19 hours.The suspension that forms through 45 minutes reheat to 65 ℃ (internal temperature), was stirred 1 hour down and was cooled to 33 ℃ through 1 hour at 65 ℃.After 3 hours, product is passed through filtering separation 33 ℃ of extra down stirrings, and water (50g) washing wet cake.Product drying under 50 ℃ and vacuum is obtained the anhydrous N-hydroxyl-3-[4-[[[2-of crystalline (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide lactic acid salt (form A).
Embodiment 21
Form the anhydrous lactitol hydrochlorate
Water (54.4g) dilution DL-lactic acid (8.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 6.8g).Solution is heated to 90 ℃ (internal temperatures) and kept 15 hours.Make solution be cooled to room temperature and be used for following salify step as lactic acid solution.
With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide (20g) places the 1L glass reactor, and adding ethanol/water (mixture of 209.4g 1:1 weight ratio).Faint yellow suspension was heated to 60 ℃ (internal temperatures) through 30 minutes, and under this temperature, added lactic acid solution through 30 minutes.Water (10g) rinsing feed hopper.With solution be cooled to through 2 hours 38 ℃ and 38 ℃ add down kind brilliant (20mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide lactic acid salt, anhydrous form).After 2 hours, mixture was cooled to 25 ℃ through 6 hours 38 ℃ of extra down stirrings.Continued to be cooled to 10 ℃ through 5 hours, be cooled to 5 ℃ and be cooled to 2 ℃ from 5 ℃ from 10 ℃ through 1 hour through 4 hours from 25 ℃.Suspension was additionally stirred 2 hours down at 2 ℃, and by the filtering separation product.Water (2 * 30g) washing wet cakes obtain the anhydrous N-hydroxyl-3-[4-[[[2-of crystalline (2-Methyl-1H-indole-3-yl) ethyl with product in vacuum and 45 ℃ of following dryings] amino] methyl] phenyl]-2E-2-acrylamide lactic acid salt (form A).
Embodiment 22
Form sodium salt
Will about 50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the 1ml methyl alcohol.Stoichiometric sodium hydroxide is added in the suspension subsequently.Mixture is stirred down at 50 ℃.In case the formation clear solution continues down to stir at 4 ℃.Analyze by solid collected by filtration and by XRPD and TGA.Separate N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl as xanchromatic height hygroscopic powder] amino] methyl] phenyl]-sodium salt of 2E-2-acrylamide, it absorbs moisture in filtration procedure.
Embodiment 23
Form sylvite
Will about 50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the 1ml methyl alcohol.Stoichiometric potassium hydroxide is added in the suspension subsequently.Mixture is stirred down at 50 ℃.In case the formation clear solution continues down to stir at 4 ℃.Analyze by solid collected by filtration and by XRPD and TGA.Separate N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl as xanchromatic height hygroscopic powder] amino] methyl] phenyl]-sylvite of 2E-2-acrylamide, it absorbs moisture in filtration procedure.
Embodiment 24
Form calcium salt
Will about 50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the 1ml methyl alcohol.Stoichiometric sodium hydroxide is added in the suspension subsequently.Mixture is stirred down at 50 ℃.In case the formation clear solution adds stoichiometric U-Ramin MC and causes the faint yellow solid precipitation immediately.Analyze by solid collected by filtration and by XRPD and TGA.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-water absorbability of the calcium salt of 2E-2-acrylamide is less than N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sodium salt of 2E-2-acrylamide or sylvite and can be easy to separate.
Embodiment 25
Form zinc salt
Will about 50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the 1ml methyl alcohol.Stoichiometric sodium hydroxide is added in the suspension subsequently.Mixture is stirred down at 50 ℃.In case the formation clear solution adds stoichiometric zinc sulfate and causes the faint yellow solid precipitation immediately.Analyze by solid collected by filtration and by XRPD and TGA.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-water absorbability of the zinc salt of 2E-2-acrylamide is less than N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sodium salt of 2E-2-acrylamide or sylvite and can be easy to separate.
Embodiment 26
Form hydrochloride
With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and the 40ml dehydrated alcohol pack in the 3 neck flasks of the 250ml that is furnished with magnetic stirring apparatus and feed hopper.In the suspension that stirs, be added dropwise to 7.5ml 2M HCl (15mmol, excessive 50%), obtain clear solution.In 10 minutes, be settled out white solid, and continue extra the stirring 2 hours at ambient temperature.Mixture was approximately cooled off 30 minutes in ice bath, by the filtered and recycled white solid.With cold ethanol (10ml) washing once and vacuum-drying spend the night obtain 3.72g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-hydrochloride (96.2%) of 2E-2-acrylamide.
It should be noted, although equimolar amount HCl obtains surpassing 80% productive rate, with HCl with excessive use to improve productive rate.Even, do not take place via the protonated formation disalt of the ring of Methyl-1H-indole-3-base as HCl during with excessive greatly use.Obtain identical mono-hydrochloric salts as product with 1,1.5 and 2 equivalent HCl reaction.In addition, the NMR data do not show any displacement of the contiguous proton of ring, and this can take place when protonated.
Embodiment 27
Form the L-tartrate
With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and the 50ml dehydrated alcohol pack in the 3 neck flasks of the 250ml that is furnished with magnetic stirring apparatus and feed hopper.With mixture heating up to 60 ℃, and be added dropwise to 0.83g (5.5mmol, excessive 10%) the L-tartrate that is dissolved in the 15ml dehydrated alcohol in the hot suspension.At first, form a large amount of yellow aggregates and stop enough stirrings, but they are converted into yellow powder free-pouring and that can stir after a while.Continue down to stir 2 hours at 60 ℃.Subsequently mixture is cooled to room temperature and mixture was approximately placed 30 minutes in ice bath.By the filtered and recycled yellow powder, once with cold dehydrated alcohol (10ml) washing.Vacuum-drying is spent the night and is obtained 4.1g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the L-tartrate of 2E-2-acrylamide (half-tartrate) (96.6%).
Embodiment 28
Form single hydration lactic acid salt
With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and 75ml acetone pack in the 3 neck flasks of the 250ml that is furnished with magnetic stirring apparatus and feed hopper.In the suspension that stirs, be added dropwise to the 10ml1M lactic acid aqueous solution (10mmol) that is dissolved in the 20ml acetone, obtain clear solution.Continue at ambient temperature to stir and go out white solid at about 1 hour postprecipitation.Mixture is cooled off in ice bath and extra the stirring 1 hour.By the filtered and recycled white solid.With cold acetone (15ml) washing once.Drying obtains 3.94g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl under vacuum subsequently] amino] methyl] phenyl]-single hydration lactic acid salt (86.2%) of 2E-2-acrylamide.
Embodiment 29
Form mesylate
With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and the 75ml ethyl acetate pack in the 3 neck flasks of the 250ml that is furnished with mechanical stirrer and feed hopper.In the suspension that stirs, be added dropwise to 0.65ml (10mmol) methylsulfonic acid that is dissolved in the 20ml ethyl acetate, but obtain the stirred suspension of unrestricted flow yellow powder.With mixture heating up to 50 ℃ and keep spending the night, yellow powder is converted into white solid during this period.Suspension is cooled to room temperature and passes through the filtered and recycled white solid.With cold ethyl acetate (15ml) washing once and under the vacuum dried overnight obtain 4.38g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mesylate (98.3%) of 2E-2-acrylamide.
Notice that the yellow powder that originally forms is the polymorphic form of mesylate, it contains the methylsulfonic acid above equimolar amount.The result is the very height moisture absorption of this solid.Mild heat to 40 or 50 ℃ and through 2-4 hour, yellow powder is converted into the white crystalline solid of the methylsulfonic acid that contains equimolar amount.This solid is non-hygroscopic.Also suggestion adds methylsulfonic acid, elevated temperature subsequently at ambient temperature.Observe, under comparatively high temps, add the precipitation that obtains salt immediately as soft and sticking material.
Embodiment 30
Form maleate
With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and 75ml acetone pack in the 3 neck flasks of the 250ml that is furnished with mechanical stirrer and feed hopper.With mixture heating up to 45 ℃, and be added dropwise to 1.16g (10mmol) toxilic acid that is dissolved in the 25ml acetone in the hot suspension.Although slowly reinforced, be settled out the salt that hinders stirring as soft cementation body.Continue down to stir to spend the night at 45 ℃, during this period, solid is converted into white free flowing powder.Mixture is cooled to room temperature and in ice bath, placed about 30 minutes.By the filtered and recycled white solid, with cold acetone (15ml) washing once and under the vacuum dried overnight obtain 4.21g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-maleate (90.5%) of 2E-2-acrylamide.
Notice that to synthetic preferred solvent be the 2-propyl alcohol.Yet, in optimizing process, observe except that desired form, can from the 2-propyl alcohol, separate other polymorphic form with low decomposition temperature (118.9 ℃) as yellow powder.
The present invention has carried out above description with reference to specific embodiments, obviously can make many changes, improvement and variation not breaking away from scope disclosed in this invention.Therefore, be intended to comprise that all drop on all these changes, improvement and variation in the claims spirit and scope.All patent applications that this paper quoted, patent and other publication all are incorporated herein by reference fully.
Embodiment 31
Form lactic acid salt
The synthetic Lactated schema of LBH589 is provided among the figure A.The name benchmark index of intermediate provides with following name benchmark index:
The name benchmark index
The compound chemistry name
1 4-bromo-phenyl aldehyde
2 methyl acrylates
3 (2E)-3-(formyl radical phenyl)-2-methyl acrylate
4 3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2-methyl acrylate mono-hydrochloric salts
5 (2E)-N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2-acrylamide
6 and 2 (E)-N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2 hydroxy propanoic acid of 2-acrylamide compounding
Z3a 2-Methyl-1H-indole-3-ethamine
Z3b 5-chloro-2 pentanone
The Z3c phenyl hydrazine
Figure A: synthetic LBH589 lactic acid salt
LBH589 lactic acid salt (6) drug substance is via convergent synthesis production; Rendezvous Point is indoles-amine Z3a and aldehyde 3 condensations.
Make 5-chloro-2 pentanones (Z3b) and phenyl hydrazine (Z3c) reaction under refluxing (the Fischer indoles of variation is synthetic) in ethanol synthetic the comprising of indoles-amine Z3a.
Product separates by the extraction aftertreatment, and subsequent crystallisation carries out.Aldehyde 3 is by palladium catalysis 4-bromo-phenyl aldehyde (1) and vinylated (the Heck type reaction of methyl acrylate (2); Pd (OAc)
2/ P (o-tolyl)
3/ Bu
3N, the CH that is refluxing
3Among the CN) and prepare via precipitate and separate product from rare HCl solution.Be imine intermediate with intermediate Z3a and 3 condensations then, and use sodium borohydride in methyl alcohol, being lower than under 0 ℃ its reduction (reduction amination).Need, will be by product K-281 4 recrystallize from methanol of precipitate and separate from rare HCl.K-281 4 is converted into thick LBH589 free alkali 5 via reacting in water/methyl alcohol with azanol and sodium hydroxide under being lower than 0 ℃.Need, then the thick LBH589 free alkali 5 of purifying by recrystallize from hot ethanol/water.Moisture racemic lactic acid and water with 85% are handled LBH589 free alkali 5 at ambient temperature.After adding kind of crystalline substance, mixture heating up to about 65 ℃, is stirred under this temperature and slowly cools to 45-50 ℃.With the gained slurries filtration and wash with water, drying obtains LBH589 lactic acid salt (6).
Need, can recrystallize be once from water in the presence of the 30mol% racemic lactic acid with LBH589 lactic acid salt 6.At last, the LBH589 lactic acid salt is gone piece (delump) obtain drug substance.Reprocess LBH589 lactic acid salt drug substance 6 if desired, then in ethanol/water, use sodium-hydroxide treatment LBH589 lactic acid salt, form lactic acid salt subsequently as mentioned above and remove piece to discharge LBH589 free alkali 5.
Be used for synthetic Lactated all raw materials of LBH589, reagent and solvent according to the internal rules test or available from the supplier who determines in order to avoid analysis authentication.
Claims (23)
1. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the crystal salt of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is dissolved or suspended in the solvent of appropriate amount; With
(b) under suitable temperature, handle N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl with salt forming agent] amino] methyl] phenyl]-2E-2-acrylamide free alkali, wherein said salt forming agent is selected from the source of supply of hydrochloride, lactic acid salt, maleate, mesylate, tartrate, acetate, benzoate, Citrate trianion, fumarate, gentisate, malate, malonate, oxalate, phosphoric acid salt, propionic salt, vitriol, succinate, sodium, potassium, calcium or zine ion.
2. according to the process of claim 1 wherein that described solvent is selected from ethanol, Virahol, acetone, ethyl acetate, ethanol/water mixture, iso-propanol/water mixture, acetone, acetonitrile, tetrahydrofuran (THF), 2-propyl alcohol and composition thereof.
3. according to the process of claim 1 wherein that the temperature range in the step (b) is that envrionment temperature is to about 60 ℃.
4. according to the process of claim 1 wherein that described salt forming agent is selected from hydrochloric acid, lactic acid, toxilic acid, methylsulfonic acid, tartrate, acetate, phenylformic acid, citric acid, fumaric acid, gentisinic acid, oxysuccinic acid, propanedioic acid, oxalic acid, phosphoric acid, propionic acid, sulfuric acid, succsinic acid, NaOH, KOH, CaCl
2And ZnCl
2
5. according to the process of claim 1 wherein N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mol ratio of 2E-2-acrylamide and salt forming agent is the about 1:2 of about 1:1-.
6. according to the process of claim 1 wherein N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl that uses equimolar amount] amino] methyl] phenyl]-2E-2-acrylamide and salt forming agent.
7. according to the method for claim 1, it comprises the steps: that further (c) reduces N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mixture temperature of 2E-2-acrylamide and salt forming agent.
8. according to the method for claim 1, it comprises the steps: that further (d) separates described salt.
9. according to the method for claim 1, it further comprises the steps: (d) dry described salt.
10. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the hydrochloride of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethanol;
(b) be added dropwise to hydrochloric acid in envrionment temperature with under stirring, wherein hydrochloric acid exists with the amount of 50% molar excess;
(c) the reaction mixture stirring is enough to make the sedimentary time of hydrochloride; With
(d) reaction mixture.
11. according to the method for claim 10, it further comprises the steps:
(e) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide hydrochloride;
(f) with the described salt of cold washing with alcohol; With
(g) dry described salt.
12. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the L-tartrate of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the ethanol;
(b) 60 ℃ and stir under be added dropwise to L-tartrate, wherein L-tartrate exists with the amount of 10% molar excess;
(c) reaction mixture is stirred the time that is enough to make the L-tartrate precipitation; With
(d) reaction mixture.
13. according to the method for claim 12, it further comprises the steps:
(e) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide L-tartrate;
(f) with the described salt of cold washing with alcohol; With
(g) dry described salt.
14. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated method of single hydration of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone;
(b) be added dropwise to lactic acid in envrionment temperature with under stirring, wherein lactic acid exists with equimolar amount;
(c) the reaction mixture stirring is enough to make single sedimentary time of hydration lactic acid salt; With
(d) reaction mixture.
15. according to the method for claim 14, it further comprises the steps:
(e) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide list hydration lactic acid salt;
(f) wash described salt with cold acetone; With
(g) dry described salt.
16. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated method of 2E-2-acrylamide, it comprises the steps:
(a) provide lactic acid solution;
(b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in the water;
(c) suspension is heated to suitable temp;
(d) add lactic acid solution to form solution;
(e) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution;
(f) with the solution stirring certain hour;
(g) solution is heated to second suitable temp;
(h) with the solution stirring certain hour;
(i) cooling solution; With
(j) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide.
17. according to the method for claim 16, it further comprises the steps:
(k) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate;
(l) wash described salt with water; With
(m) dry described salt.
18. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated method of 2E-2-acrylamide, it comprises the steps:
(a) provide lactic acid solution;
(b) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali is suspended in 1: 1 mixture of second alcohol and water;
(c) suspension is heated to suitable temp;
(d) add lactic acid solution to form solution;
(e) cooling solution;
(f) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous Lactated suspension of 2E-2-acrylamide adds kind of a crystalline substance to solution;
(g) with the solution stirring certain hour;
(h) cooling solution; With
(i) solution stirring is enough to make N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-sedimentary time of anhydrous lactitol hydrochlorate of 2E-2-acrylamide.
19. according to the method for claim 18, it further comprises the steps:
(j) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide anhydrous lactitol hydrochlorate;
(k) wash described salt with water; With
(l) dry described salt.
20. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the mesylate of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the ethyl acetate;
(b) be added dropwise to methylsulfonic acid in envrionment temperature with under stirring, wherein methylsulfonic acid exists with equimolar amount, to produce precipitation;
(c) reaction mixture is heated to about 50 ℃ through about 4 hours of about 2-from about 40 ℃; With
(d) reaction mixture is with precipitation N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide mesylate.
21. according to the method for claim 20, it further comprises the steps:
(e) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide mesylate;
(f) wash described salt with cold ethyl acetate; With
(g) dry described salt.
22. one kind prepares N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of the maleate of 2E-2-acrylamide, it comprises the steps:
(a) with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the acetone;
(b) 45 ℃ and stir under be added dropwise to toxilic acid, wherein toxilic acid exists with equimolar amount;
(c) the reaction mixture stirring is enough to make the sedimentary time of maleate; With
(d) reaction mixture.
23. according to the method for claim 22, it further comprises the steps:
(e) the N-hydroxyl-3-[4-[[[2-of precipitation separation (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide maleate;
(f) wash described salt with cold acetone; With
(g) dry described salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80452906P | 2006-06-12 | 2006-06-12 | |
| US60/804,529 | 2006-06-12 | ||
| US60/853,259 | 2006-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101466673A true CN101466673A (en) | 2009-06-24 |
Family
ID=40806589
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800220599A Pending CN101466673A (en) | 2006-06-12 | 2007-06-07 | Process for making salts of n-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101466673A (en) |
| ZA (1) | ZA200809651B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017032281A1 (en) * | 2015-08-21 | 2017-03-02 | 苏州晶云药物科技有限公司 | Novel crystal forms of panobinostat lactate |
| CN106866492A (en) * | 2015-12-10 | 2017-06-20 | 江苏豪森药业集团有限公司 | LBH589 lactate crystal formation II and its production and use |
| CN106866491A (en) * | 2015-12-10 | 2017-06-20 | 江苏豪森药业集团有限公司 | LBH589 lactate crystal formation I and its production and use |
| CN111116451A (en) * | 2020-01-16 | 2020-05-08 | 宁波大学 | A kind of polysubstituted tryptamine benzamide compound and its preparation method and use |
-
2007
- 2007-06-07 CN CNA2007800220599A patent/CN101466673A/en active Pending
-
2008
- 2008-11-12 ZA ZA200809651A patent/ZA200809651B/en unknown
Cited By (6)
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| WO2017032281A1 (en) * | 2015-08-21 | 2017-03-02 | 苏州晶云药物科技有限公司 | Novel crystal forms of panobinostat lactate |
| CN106866492A (en) * | 2015-12-10 | 2017-06-20 | 江苏豪森药业集团有限公司 | LBH589 lactate crystal formation II and its production and use |
| CN106866491A (en) * | 2015-12-10 | 2017-06-20 | 江苏豪森药业集团有限公司 | LBH589 lactate crystal formation I and its production and use |
| CN106866492B (en) * | 2015-12-10 | 2021-11-26 | 江苏豪森药业集团有限公司 | Panobinostat lactate crystal form II and preparation method and application thereof |
| CN106866491B (en) * | 2015-12-10 | 2021-12-10 | 江苏豪森药业集团有限公司 | Panobinostat lactate crystal form I and preparation method and application thereof |
| CN111116451A (en) * | 2020-01-16 | 2020-05-08 | 宁波大学 | A kind of polysubstituted tryptamine benzamide compound and its preparation method and use |
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| Publication number | Publication date |
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| ZA200809651B (en) | 2009-11-25 |
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Application publication date: 20090624 |