CN102858739A - A process for amidation of pyrrole carboxylate compounds - Google Patents
A process for amidation of pyrrole carboxylate compounds Download PDFInfo
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- CN102858739A CN102858739A CN2010800662651A CN201080066265A CN102858739A CN 102858739 A CN102858739 A CN 102858739A CN 2010800662651 A CN2010800662651 A CN 2010800662651A CN 201080066265 A CN201080066265 A CN 201080066265A CN 102858739 A CN102858739 A CN 102858739A
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- 238000000034 method Methods 0.000 title claims abstract description 50
- 230000009435 amidation Effects 0.000 title claims abstract description 17
- 238000007112 amidation reaction Methods 0.000 title claims abstract description 16
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 title abstract description 5
- 230000008569 process Effects 0.000 title abstract description 3
- -1 indolone-substituted pyrrole carboxylate compounds Chemical class 0.000 claims abstract description 34
- 239000007822 coupling agent Substances 0.000 claims abstract description 21
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 83
- 238000006243 chemical reaction Methods 0.000 claims description 36
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 claims description 36
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 26
- 229940034785 sutent Drugs 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000001408 amides Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 229940116298 l- malic acid Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000004149 thio group Chemical group *S* 0.000 claims description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract description 3
- 150000008064 anhydrides Chemical class 0.000 abstract 2
- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical class NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 230000009471 action Effects 0.000 description 15
- 229940059260 amidate Drugs 0.000 description 15
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000002585 base Substances 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 0 CC1(C(C2)C1C1)C3(C)C(C)(C4)*2C4(*)C2[C@@]1C32 Chemical compound CC1(C(C2)C1C1)C3(C)C(C)(C4)*2C4(*)C2[C@@]1C32 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BRZYBFNUINXZMJ-UHFFFAOYSA-N CCN(CC)CCNC(c1c(C)[nH]c(C=O)c1C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(C=O)c1C)=O BRZYBFNUINXZMJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a cyclic alkyltriphosphonate anhydride coupling agent of formula (4) wherein A is C1-C6 alkyl group, preferably n-propyl group and to the use of the cyclic alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
Description
Some pyrroyl aminated compounds is important medical compounds.For example Sutent (chemically be (Z)-N-[2-(diethylamino) ethyl of formula (I)]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indoles-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide)
Be developed for the preparation of the medicine that is used for the treatment of patients with gastrointestinal stromal tumors (GIST) and metastatic renal cell cancer.On it and the many structures similarly the pyrroyl aminated compounds be disclosed simultaneously among the WO 01/60814 (EP 1255752, and US 6573293).Other has on the structure of similar medicine activity similarly the pyrroyl aminated compounds and for example has been disclosed among WO2004/76410, WO 2006/127961, WO 2007/81560, the WO 2008/33562.
The Sutent molecule has an asymmetric pair of key between indole ring and pyrrole ring.This compound is with (Z) configuration form list marketing on the described pair of key.
This compound can form acid salt, Sutent L MALIC ACID salt for example, and it is the activeconstituents in the medicament production (for example being sold with trade(brand)name SUTENT by Pfizer).
Committed step on preparation Sutent and the structure in the currently known methods of relevant pyrroyl amine compound is included in corresponding amine in suitable stage of reaction sequence and the amidate action of suitable pyrroles's carboxylic acid, wherein can the optional activation carboxyl for amidate action.
Can in WO 01/60814, find the example of the method for this generation Sutent.With 5-formyl radical-2,4-dimethyl-1H-pyrroles-3-formic acid (III)
With N, N-diethylamino ethamine (II)
In dimethyl formamide, exist lower in alkali (triethylamine), react under the effect of the coupling agent of molar excess a little, described coupling agent is the mixture of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [EDCI] and I-hydroxybenzotriazole [HBT].Then with the product (IV) that obtains
With 5-fluoro-1,3-Indolin-2-one (V)
In inert solvent, reaction in the presence of alkali is to generate the Sutent of expectation.
The people such as Sun disclose alternative reaction scheme at J.Med.Chem. among 2003,46, the 1116-1119.In this article, with described 5-formyl radical-2,4-dimethyl-1H-pyrroles-3-formic acid (III) at first with 5-fluoro-1,3-Indolin-2-one (V) reacts in ethanol and in the presence of piperidines alkali, to generate acid (VI)
Then by amine (II) under the effect of EDCI and HBT coupling agent with acid (VI) amidation.
As apparent from the alternative embodiment 80 of WO 01/60814, the yield of described amidate action very low (43%).
Disclose through improved amidation method among the WO 03/070725 and among the WO 05/023765, wherein for amidate action, by the heterocyclic group of covalent bonding, for example by the carbonyl on 1H-imidazoles-1-base activation pyrrole ring.With activated intermediate, compound (IIIa) for example
May in a step, react with amine (II) and indolone (V), to generate the Sutent (embodiment 1 of WO ' 725) of expectation.
The activation of pyrrolylcarbonyl needs extra reactions steps (for example, compound (IIIa) is by corresponding acid (III) and carbonyl dimidazoles preparation), comprises the separation activated intermediate that produces and the remnants that remove disadvantageous reagent.In addition, the formyl radical of compound (IV) can react with activating reagent and/or with amine (II) in side reaction, and this also is undesirable.
Desirable is to have a kind of alternative for preparing the relevant oxindole compounds that replaces through the pyrroles on Sutent and other structure, and described compound has amide substituents in pyrrole ring, and wherein said method does not show above-mentioned shortcoming.
The invention summary
The present invention relates to the method for a kind of amidation minaline ester cpds (comprise indolone replace minaline ester cpds), it is characterized in that adopting cheapness, nontoxic and effectively be used for the specific coupling agent of amidate action.
In first aspect, the invention provides a kind of method for preparing general formula (1) compound
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the wherein said chain optional position can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group (thiono-), halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom,
Described method comprises the steps: formula (2) compound
Amine with formula (3)
NH
2-R (3)
Reaction in the presence of the cyclic alkyl triphosphine acid anhydrides coupling agent of formula (4)
Wherein A is the C1-C6 alkyl, is preferably n-propyl.
Aspect specific, the Z group represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group, and R
1, R
2It is methyl.Therefore, preferred formula (2) compound is formula (2a) or formula (2b) compound
Again one specific aspect, radicals R is N, N-diethylamino ethyl, and the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
Correspondingly, preferred formula (1) compound is formula (1a) or (1b) compound
Obviously, compound (1b) is equivalent to Sutent.
Again one specific aspect, the reaction of formula (2) compound and formula (3) amine is in the presence of the coupling agent of formula (4), in inert solvent or in the amine (3) as solvent, typically in envrionment temperature or near carrying out under the envrionment temperature.Randomly, reaction product is separated also purifying from reaction mixture.
If the part of the X in the Z group of formula as hereinbefore defined (1) or (2) compound is not equivalent to inferior indoles ketone group
Wherein, Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group, and the fluoro group (is hydrogen at W for example typically, and C=X is in the situation of C=O group), aforesaid method can comprise that the C=X Partial Conversion with the Z group is the next step of described inferior indoles ketone group so.In the example of this conversion, formula (1a) compound can be converted into Sutent (1b).
In second aspect, the invention provides the first method of the Sutent of preparation formula (1b), it may further comprise the steps order:
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a) with the N of formula (3), N-diethylamino ethamine is the amidation of formula (2a) compound, and
-the acid amides (1a) that will so obtain and the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
In addition, the invention provides the second method of the Sutent of preparation formula (1b), it may further comprise the steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reaction is with production (2b) compound
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), use the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
In the third aspect, the invention provides formula (4) compound, particularly formula (4a) compound for the preparation of general formula (1) compound, typically preparation formula (1a) and/or (1b) the new purposes in the method for compound
In fourth aspect, the present invention relates to the purposes of cyclic alkyl triphosphine acid anhydrides coupling agent in preparation pyrroyl aminated compounds of formula (4).
Detailed Description Of The Invention
The present invention relates to the improved amidation method for the preparation of the pyrroyl amine compound of general formula (1)
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the wherein said chain optional position can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group, halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom.
Aspect specific, the Z group represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group, and R
1, R
2It is methyl.
Preferred formula (1) compound is formula (1a) or compound (1b)
Obviously, compound (1b) is equivalent to Sutent.
General formula (1) compound useful as drug active compound, for example Sutent and analogue thereof perhaps can be used as their intermediate of preparation.Its industrial usability can obtain from the instruction of WO01/60814, WO 03/070725, WO 05/023765, U. S. application 2006/0009510 etc.
In general, formula (1) compound is known, and can prepare them by various programs.Crucial synthetic route comprises a reactions steps, and this reactions steps comprises with the amine of formula (3) carries out amidate action to the carboxylic acid of formula (2).In typical example, the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
Because known amidation program has number of drawbacks in the method for preparation formula (1) compound, especially low yield the objective of the invention is the improvement of this aspect.
With amine the carboxylic acyloxy amination is needed coupling agent usually, this coupling agent is the reagent in conjunction with water, and described water produces by following amidate action:
-COOH+NH
2-R→-CONH-R+H-OH。
In conjunction with water molecular balance is changed to the direction that forms acid amides.
The currently known methods of the Sutent that usually has formula (1) from the acid of general formula (2) preparation and analogue and/or intermediate, usually with the carbodiimide coupling agent, be used for being connected to the amidate action on the carboxyl of pyrrole ring such as EDCI.Carbodiimide compound is poisonous compound, and it only provides the amidation of medium yield, and is difficult to remove from reaction mixture after finishing amidate action.As mentioned, in preparing the method for Sutent, the yield of the amidate action of carbodiimide-mediated only is 43%.Multiple other coupling agent can be used for amidate action in theory, but neither one is after deliberation for the preparation of Sutent and analogue thereof in them, except the benzotriazole of mentioning among the embodiment 129 of WO 01/60814 and the WO 2007/034272-1-base oxygen base three (dimethylaminos)-
Hexafluorophosphate (BOP) in addition.This coupling agent provides good amidation yield, but the by product of BOP itself and generation thereof is highly toxic compound, needs extra processing cost and security measures, especially on technical scale.
The invention provides the coupling agent by employing formula (4), the amidate action between general formula (2) and (3) compound, wherein A is the C1-C6 alkyl, is preferably n-propyl.This compound is cyclic phosphonic acid anhydrides, and the water reaction that discharges during itself and the amidate action forms linear triguaiacyl phosphate:
The ring-type of above scheme and linear triguaiacyl phosphate all in the soluble in water and multiple organic solvent, therefore can easily be removed from reaction product.They are nontoxic compounds, can process by standard approach.Amidate action carries out usually at ambient temperature, has almost quantitative conversion.
Formula (4) compound for example is disclosed among the WO 2005/014604.
The three n-propyl ring-type triphosphine acid anhydrides that preferred general formula (4) compound is formula (4a) (2,4,6-, 3 third-1-base-1,3,5-trioxa-2,4,6-triphosphine-2,4,6-trioxide),
It can obtain by commercial sources, and is referred to as T3P in this article.In favourable mode, it at suitable solvent, for example in the solution in ethyl acetate or the DMF, is used for method of the present invention.
Now explain without limitation the present invention with two kinds of methods that prepare Sutent (1b), these two kinds of methods are summarized in the following scheme.Described method comprises that the coupling agent of use formula (4a) is as the preferred member of general formula (4) compound.
The starting raw material 5-formyl radical-2 of formula (2a), 4-dimethyl-1H-pyrroles-3-formic acid has been disclosed among the WO 01/060814.
First method of the present invention may further comprise the steps order:
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is the amidation of formula (2a) compound, and
-formula (1a) compound that will so obtain and the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
In the first step, compound (2a) and amine (3a) are reacted in inert solvent in the presence of T3P coupling agent (4a).Because amine (3a) is liquid, also can be used as the solvent of this reaction.This amidate action can carry out in room temperature or under near room temperature (for example 10-40 ℃ scope, preferred approximately 25 ℃), and usually finishes in several hours.Reaction process can for example be monitored by TLC or HPLC by conventional analytical technology, and this reaction can stop after the degree of conversion that obtains expectation.The aftertreatment of reaction mixture represents described mixture basically in the distribution of (for example water and hydrocarbon or between the hydrocarbon of chlorination) between water and the organic phase, and from organic phase separated product.If necessary, can randomly after the resistates of the resistates that extracts employed amine or T3P reagent, further crude product be passed through recrystallization or redeposition purifying.The product (1a) of expectation can be used as solid obtaining above 90% yield.
Compound (1a) can be separated from reaction mixture or separates with purification solvent as free alkali or with the form of acid salt (for example hydrochloride).
Alternately, the reaction mixture of inclusion compound (1a) or through the reaction mixture (for example compound (1a) is at amine (3a) or the solution in organic solvent) of aftertreatment can in the situation that not separating compound (1a) be used for next reactions steps.Then two steps of first method all can be carried out in " one pot " device.
In second step, by conventional procedure, for example by disclosed method E among the WO 01/060814 formula (1a) compound is converted into Sutent (1b).Usually, with compound (1a) and the 5-fluoro-1 of equimolar amount, 3-Indolin-2-one (5) in inert solvent, for example in the fatty alcohol, preferably reacts in the presence of alkali at elevated temperatures.Can product be separated from reaction mixture by the program of routine, and carry out purifying if necessary.
Second method of the present invention consists essentially of the counter-rotating order of described amidation and condensation step, especially following steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reacts with production (2b) compound
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
In the first step, formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) in inert solvent, for example in fatty alcohol, react in the presence of organic or inorganic alkali at elevated temperatures.By conventional procedure, for example by precipitation, product is separated from reaction mixture, and carry out purifying if necessary.Can for example monitor reaction process by TLC or HPLC by conventional analytical technology, and this reaction can stop after the degree of conversion that obtains expectation.The details of this synthesis program can find in WO 2004/76410, WO 2006/127961 or in WO 2007/81560.
Typically, formula (2b) compound especially separates with the crystalline state that is conducive to store with further processing with solid form.Can be randomly with its with the salt of alkali, for example separate with sodium, potassium, magnesium, calcium or lithium salts.
In second step, compound (2b) and amine (3a) in the presence of T3P coupling agent (4a), are reacted in inert solvent.Described inert solvent is organic solvent, polar organic solvent typically, and most preferably be dipolar aprotic solvent, for example DMF, acetonitrile or methyl-sulphoxide.Temperature of reaction is essentially room temperature or near room temperature (10-40 ℃).Can by conventional analytical technology, for example monitor reaction process by TLC or HPLC.After the conversion that reaches expectation, product is separated from reaction mixture.Typically, can after water is with its dilution, it be precipitated from reaction mixture.Coupling agent rests in the aqueous mother liquor fully.With separated product washing and dry.If necessary, can for example pass through recrystallization (for example from ethanol) with its purifying.
The Sutent (1b) of expectation can be used as solid obtaining above 90% yield.
As in the method before, described two steps can all be carried out in the one kettle way device.
Randomly can be with compound (1b) from the reaction mixture of any aforesaid method, to separate (or being converted into subsequently described salt) with various forms inorganic or the organic acid acid salt; These sour examples are hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, toxilic acid, fumaric acid, oxalic acid, citric acid, oxysuccinic acid or succsinic acid without limitation.
Formula (1b) compound and/or its acid salt be its separated form usefully preferably, is more preferably solid-state form, such as any crystal or amorphous form; Described solid-state form is also contained solvate and hydrate.Because the industrial application of expection preferably has and is higher than 95% chemical purity, especially has the compound (1b) and the salt thereof that are higher than 99% chemical purity.
Especially the suitable acid salt of compound (1b) is Sutent-L MALIC ACID salt.
Other general formula (1) compound can prepare in substantially similar mode.For example, method of the present invention can be for the preparation of formula (1c) compound and the pharmacy acceptable salt thereof that are disclosed among WO 2004/76410 and the WO 2007/34272
Further illustrate the present invention by following examples.These embodiment are nonrestrictive and do not limit the scope of the invention.
Embodiment
Embodiment 1-(2a) is to the conversion of (1a)
Under stirring at room, to acid derivative
(2a)(835mg, ~ 5mmol) drip propane phosphoric anhydride (T3P) (10ml, 50%EtOAc solution) in the solution in N-diethyl ethylenediamine (10ml), and in 1.5 hours, finish.With the further stirred overnight of reaction mixture that produces.Add water (25ml) and methylene dichloride (25ml), and mixture was stirred 25 minutes.Dichloromethane layer is separated also concentrated so that oily mater to be provided in a vacuum.With this oily matter and ethyl acetate (50ml) and sodium carbonate solution (4%, 25ml) mix, and stirred 30 minutes at 70 ℃.After cooling, ethyl acetate layer is separated and water (10ml) washing dry (Na
2SO
4) and concentrated so that yellow solid to be provided
(1a)(1.35g).
Embodiment 2-(2a) is to the conversion of (1a)
Under stirring at room, to acid derivative
(2a)(835mg, ~ 5mmol) at N, drip (utilizing adding set) propane phosphoric anhydride (T3P) (6ml, 50%EtOAc solution) in the solution in the N-diethylamino ethamine (10ml), and in 1.5 hours, finish.Add water (25ml) and methylene dichloride (50ml), and the mixture that produces was stirred 20 minutes.Dichloromethane layer is separated, water (20ml) washing, and concentrated so that oily mater to be provided in a vacuum.This oily matter and ethyl acetate (50ml) and HCl solution (1M, 12ml) are mixed, and stirring at room 30 minutes.Then, mixture is alkalized to pH ~ 10.Ethyl acetate layer is separated, water (10ml) washing, and concentrated so that yellow solid to be provided in a vacuum
(1a)(1.3g).
Embodiment 3-(1a) is to the conversion of (1b)
To the 5-fluoro-1 of 150mg formula (5), interpolation ~ 0.5ml tetramethyleneimine (10) in 3-Indolin-2-one and the mixture of 450mg aldehyde derivatives (1a) in 10ml ethanol.With mixture heating up to refluxing 3 hours.After being cooled to room temperature, leach formed solid Sutent (1b).Concentrated filtrate also is dissolved in resistates in the 2ml ethanol.With clear solution at room temperature overnight storage to generate 2 batches of solid Sutents.
In vacuum, after the dried overnight, amount to the solid Sutent that obtains the 310mg expectation, (yield: 77%) at 40 ℃.
Embodiment 4-(2a) is to the conversion of (2b)
Interpolation ~ 0.5ml the piperidines (10) in the mixture in 6ml ethanol to 200mg 5-fluorine oxindole (5) and 266mg aldehyde (2a), and mixture heating up to 60 ℃ spent the night.After being cooled to room temperature, leaching solid and use twice of 5ml1M HCL solution washing.With solid in 40 ℃ of dried overnight under vacuum.Obtain the product (2b) of 390mg expectation.
Embodiment 5-(2b) is to the conversion of Sutent (1b)
Add 1.5ml N in the 150mg in 3ml DMF (2b), N-diethylamino ethamine is to form solution.Then utilize syringe pump in 50% solution of propane phosphonic acid cyclic acid anhydride in DMF that in 1.5 hours, adds 0.6ml under the envrionment temperature.At room temperature continue to stir to spend the night.Then the propane phosphonic acid acid anhydride that adds 0.1ml in DMF 50% solution and continue to stir 2 hours in room temperature.Add 50ml water and filter formed suspension.Solid is washed with water twice.At 40 ℃, under vacuum, after dry 3 hours, obtain about 150mg solid Sutent.Obtain analytic sample by recrystallization in ethanol.
Through describing the present invention, it is evident that to those skilled in the art, in this article in the actual enforcement of described concept and embodiment, can easily make maybe and can change and change to further by practice knowledge of the present invention, and not break away from by the spirit and scope of the present invention defined by the following claims.
Claims (17)
1. the method for preparing general formula (1) compound
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the optional position of wherein said chain can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group, halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom,
Described method comprises the steps: formula (2) compound
Amine with formula (3)
NH
2-R (3)
Reaction in the presence of the cyclic alkyl triphosphine acid anhydrides coupling agent of formula (4)
Wherein A is the C1-C6 alkyl.
2. according to claim 1 method, the A in its Chinese style (4) is n-propyl.
3. according to claim 1 and 2 method, wherein,
Group Z represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group,
And R
1, R
2It is methyl.
4. method according to claim 1-3, wherein said formula (2) compound are formula (2a) or formula (2b) compound
5. method according to claim 1-4, wherein radicals R is N, N-diethylamino ethyl, and the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
6. method according to claim 1-5, its Chinese style (1) compound are formula (1a) or (1b) compound
7. method according to claim 1-6, the reaction of the amine of its Chinese style (2) compound and formula (3) is carried out in inert solvent or in the amine (3) as solvent in the presence of the coupling agent of formula (4).
8. according to claim 7 method, wherein said reaction is in envrionment temperature or near carrying out under the envrionment temperature.
9. method according to claim 1-8 is wherein separated the reaction product of formula (1) from reaction mixture, and purifying randomly.
10. method according to claim 1-9, the Z group of its Chinese style (1) or (2) compound is not equivalent to inferior indoles ketone group
Wherein, Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
Described method comprises that further the C=X Partial Conversion with the Z group is the step of described inferior indoles ketone group.
11. method according to claim 10, wherein W is hydrogen, and C=X is the C=O group, and R is hydrogen or N, N-diethylamino ethyl, R
1And R
2Be methyl, and Y is fluorin radical.
12. the method for preparation formula (1b) compound
It may further comprise the steps order:
-with formula (2a) compound
With the N of formula (3a), N-diethylamino ethamine
Amidation in the presence of the ring-type n-propyl triphosphine acid anhydrides of formula (4a), and
-the acid amides (1a) that will so obtain
With the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
13. the method for preparation formula (1b) compound, it may further comprise the steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reacts with production (2b) compound,
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
14. according to claim 12 or 13 method, wherein compound (1b) is separated from reaction mixture.
15. method according to claim 14 wherein obtains compound (1b) or be translated into acid salt with acid salt, and preferably, described acid salt is Sutent L MALIC ACID salt.
16. the purposes of formula (4) compound in the method for preparing general formula (1) compound,
Wherein A is the C1-C6 alkyl, is preferably n-propyl.
17. purposes according to claim 16, its formula of (1) compound are formula (1a) and/or (1b) compound.
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1823079A (en) * | 2003-07-21 | 2006-08-23 | 科莱恩产品（德国）有限公司 | The preparation method of cyclic phosphonic anhydride |
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| JP2005528344A (en) | 2002-02-15 | 2005-09-22 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Method for producing indolinone derivatives |
| US7452913B2 (en) | 2003-02-24 | 2008-11-18 | Pharmacia & Upjohn Company | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2005023765A1 (en) | 2003-09-11 | 2005-03-17 | Pharmacia & Upjohn Company Llc | Method for catalyzing amidation reactions by the presence of co2 |
| US20060009510A1 (en) | 2004-07-09 | 2006-01-12 | Pharmacia & Upjohn Company Llc | Method of synthesizing indolinone compounds |
| AU2006249790A1 (en) | 2005-05-26 | 2006-11-30 | The Scripps Research Institute | Enhanced indolinone based protein kinase inhibitors |
| US20080275101A1 (en) | 2005-09-19 | 2008-11-06 | Pfizer Inc. | Solid Salt Forms Of A Pyrrole Substituted 2-Indolinone |
| US20090068718A1 (en) | 2005-12-29 | 2009-03-12 | Congxin Liang | Amino acid derivatives of indolinone based protein kinase inhibitors |
| EP2079727B1 (en) | 2006-09-15 | 2016-02-17 | Xcovery, INC. | Kinase inhibitor compounds |
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1823079A (en) * | 2003-07-21 | 2006-08-23 | 科莱恩产品（德国）有限公司 | The preparation method of cyclic phosphonic anhydride |
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| CN109485639A (en) * | 2018-12-20 | 2019-03-19 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Sutent preparation method |
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Application publication date: 20130102 |