CN102875602B - Preparation method of Minodronic acid hydrate - Google Patents
Preparation method of Minodronic acid hydrate Download PDFInfo
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- CN102875602B CN102875602B CN201210414669.6A CN201210414669A CN102875602B CN 102875602 B CN102875602 B CN 102875602B CN 201210414669 A CN201210414669 A CN 201210414669A CN 102875602 B CN102875602 B CN 102875602B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229950011129 minodronic acid Drugs 0.000 title claims abstract description 21
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- 238000006212 diphosphorylation reaction Methods 0.000 claims abstract description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 27
- 125000000468 ketone group Chemical group 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- GPAPAOGRNKUFGH-UHFFFAOYSA-N (1-hydroxy-2-imidazo[1,2-a]pyridin-3-yl-1-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 GPAPAOGRNKUFGH-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003223 protective agent Substances 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 238000006366 phosphorylation reaction Methods 0.000 claims description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 2
- 229940035437 1,3-propanediol Drugs 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000002009 diols Chemical class 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000002576 ketones Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 description 18
- ZVBVKRNOISRONE-UHFFFAOYSA-N 2-imidazo[1,2-a]pyridin-3-ylacetic acid Chemical compound C1=CC=CN2C(CC(=O)O)=CN=C21 ZVBVKRNOISRONE-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- -1 imidazo [1,2-a ] pyridine-3-yl Chemical group 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- SFCNXCZZKZRJLZ-UHFFFAOYSA-N ethyl 2-imidazo[1,2-a]pyridin-3-ylacetate Chemical compound C1=CC=CN2C(CC(=O)OCC)=CN=C21 SFCNXCZZKZRJLZ-UHFFFAOYSA-N 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxylic acid Natural products OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 3
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ZOIRMVZWDRLJPI-OWOJBTEDSA-N (e)-4-oxobut-2-enoic acid Chemical compound OC(=O)\C=C\C=O ZOIRMVZWDRLJPI-OWOJBTEDSA-N 0.000 description 2
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 description 2
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 2
- APYSHMNJHJRIDR-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine Chemical compound C1=CC=CN2C(Br)=CN=C21 APYSHMNJHJRIDR-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- LOLKAJARZKDJTD-UHFFFAOYSA-N butanedioic acid monoethyl ester Natural products CCOC(=O)CCC(O)=O LOLKAJARZKDJTD-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 0 *C(*)(Cc1cnc2[n]1cccc2)O Chemical compound *C(*)(Cc1cnc2[n]1cccc2)O 0.000 description 1
- PJWDPOBWIWWXCP-UHFFFAOYSA-N 2-imidazo[1,2-a]pyridin-3-ylacetonitrile Chemical compound C1=CC=CN2C(CC#N)=CN=C21 PJWDPOBWIWWXCP-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- RLIRIVMEKVNVQX-UHFFFAOYSA-L disodium;(2-cycloheptyl-1-phosphonatoethyl)-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound [Na+].[Na+].OP([O-])(=O)C(P(O)([O-])=O)CC1CCCCCC1 RLIRIVMEKVNVQX-UHFFFAOYSA-L 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- BIMFXGRFHPQCIN-UHFFFAOYSA-N ethyl 2-[2-(chloromethyl)-1,3-dioxolan-2-yl]acetate Chemical compound CCOC(=O)CC1(CCl)OCCO1 BIMFXGRFHPQCIN-UHFFFAOYSA-N 0.000 description 1
- MGDWUTQKXCZNAJ-UHFFFAOYSA-N ethyl 4-bromo-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CBr MGDWUTQKXCZNAJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- KIMZVDLDHKECSU-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carbaldehyde Chemical compound C1=CC=CN2C(C=O)=CN=C21 KIMZVDLDHKECSU-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of Minodronic acid hydrate, which comprises the following steps: carrying out ketonic group protection on a compound (VII) to obtain a compound (VI), carrying out nucleophilic substitution reaction on the compound (VI) and 2-aminopyridine to obtain a compound (V), carrying out ketonic group deprotection on the compound (V), and carrying out cyclization reaction to obtain a compound (IV); and hydrolyzing the compound (IV) to obtain a compound (III), carrying out diphosphorylation on the compound (III) to obtain a compound (II), and recrystallizing the compound (II) to obtain the Minodronic acid hydrate (I). The synthetic route disclosed by the invention has the advantages of sufficient initial raw material sources, low cost, environment-friendly reagents used in the reaction process, safe industrial production, mild reaction conditions, fewer side reaction, simple after-treatment and no need of special or complex reaction equipment, is convenient to operate, and can easily implement industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of a minodronic acid hydrate [ 1-hydroxy-2- (imidazo [1,2-a ] pyridine-3-yl) ethylidene ]1, 1-diphosphonic acid monohydrate.
Background
Minodronic Acid Hydrate (Minodronic Acid Hydrate), chemical name [ 1-hydroxy-2- (imidazo [1,2-a ] pyridin-3-yl) ethylene ]1, 1-bisphosphate monohydrate, structural formula shown below:
minodronic acid is a novel heterocyclic bisphosphate compound developed by pharmaceutical companies in japan mountains for treating osteoporosis and hypercalcemia caused by osteoporosis and malignant tumors, and pharmacological experiments show that the activity of inhibiting bone resorption is 2, 10 and 100 times that of disodium incadronate (sodium acadronate), sodium alendronate (sodium alendronate) and disodium pamidronate (sodium pamidrate), respectively, and the compound can antagonize osteolysis caused by myeloma and tumors. The product has obvious benefits in the aspect of the incidence rate of spine fracture and greatly reduces the side effects of intestines and stomach, and is determined to be a novel effective medicine for resisting osteoporosis and preventing fracture. The research and development of the medicine undoubtedly provide a safer, more effective and more convenient treatment medicine for clinical disease patients, and good social and economic benefits are certainly generated after the medicine is listed on the market.
The preparation of minodronate hydrate is reported in patent EP0354806, which discloses a preparation process of:
EP0354806 discloses only a method for preparing minodronic acid hydrate from compound (VIII), does not disclose a source and a preparation method of the starting compound (VIII), and has a low yield. Wherein compound (VIII) is the dihydrochloride of compound (III).
Document "journal of the chinese medical industry" 35 (4), 2004: 193-194 disodium minodronate; chem, 1969,12 (1): the preparation route disclosed in 122-126 is as follows:
the synthesis process takes imidazo [1,2-a ] pyridine as an initial raw material, and obtains a compound (III) 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid through Mannich reaction, cyanidation and hydrolysis, and the compound (II) is obtained through diphosphorylation. The method uses the virulent sodium cyanide, is dangerous to operate, has more side reactions, is difficult to purify products, has more reaction steps, is complicated to operate and has great environmental pollution.
The synthesis route disclosed in patent document (CN 101531681) is as follows:
the method comprises the steps of taking succinic acid monoethyl ester acyl chloride as an initial raw material, synthesizing a compound (IV) ethyl 2- (imidazo [1,2-a ] pyridine-3-yl) acetate with a 2-aminopyridine ring after reduction and bromination, hydrolyzing to obtain a compound (III) ethyl 2- (imidazo [1,2-a ] pyridine-3-yl) acetate, and carrying out phosphorylation to obtain a compound (II) minodronic acid. The route relates to ultralow temperature reaction, the synthesis of the starting material succinic acid monoethyl ester acyl chloride is expensive, and a large amount of bromine is used in the bromination in the reaction process, so that the method is not environment-friendly and is not suitable for industrial production.
The synthetic route disclosed in patent document CN102020676 is as follows:
the method comprises the steps of taking 2, 2-dimethoxyacetaldehyde and triethyl phosphonoacetate as initial raw materials, synthesizing a compound (IV) ethyl 2- (imidazo [1,2-a ] pyridine-3-yl) acetate with a 2-aminopyridine ring after condensation, obtaining a compound (III) ethyl 2- (imidazo [1,2-a ] pyridine-3-yl) acetate after hydrolysis, and then preparing a compound (I) minodronic acid hydrate. The starting material 2, 2-dimethoxyacetaldehyde in the route is low in market supply and expensive, so that the production cost is high, and the route is not suitable for industrial production.
The synthetic route disclosed in patent document (CN 101812062) is as follows:
the route takes trans-4-oxo-2-butenoate as a starting material, synthesizes a compound (IV) ethyl 2- (imidazo [1,2-a ] pyridine-3-yl) acetate with 2-aminopyridine ring, and obtains the compound (III) 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid after hydrolysis. The starting material trans-4-oxo-2-butenoate in the route has low market supply and high price, so that the production cost is high and the route is not suitable for industrial production.
The synthetic route disclosed in patent document CN102250090 is as follows:
the route takes 3-bromoimidazo [1,2-a ] pyridine as a starting material, and the starting material is condensed with malonic diester and then hydrolyzed to obtain a compound (III), namely 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid. The 3-bromoimidazo [1,2-a ] pyridine serving as a starting material of the route is basically unavailable in the market, needs to be customized, needs to be operated without water in the reaction process and is not suitable for industrial production.
The synthetic routes disclosed in patent documents US5464843 and CN10234448 are as follows:
the route takes alpha-oxoglutaric acid as a starting material, and the compound (III) 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid is obtained by esterification, bromination, condensation with 2-aminopyridine, hydrolysis and decarboxylation. In the route, saturated hydrogen chloride gas needs to be introduced in the esterification reaction, and bromination needs to be carried out, so that the method is not environment-friendly during production and is not suitable for industrial production.
The synthetic route disclosed in patent document CN 102030752 is as follows:
the route takes 3-imidazo [1,2-a ] pyridine carboxaldehyde and p-methyl benzenesulfonyl methyl isonitrile as starting materials, obtains 2- (imidazo [1,2-a ] pyridine-3-yl) acetonitrile under the catalysis of potassium tert-butoxide, and the obtained product can be used for preparing a compound (III), namely 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid. However, the reaction of the route not only needs ultralow temperature reaction, but also needs nitrogen charging protection, and the production operation is extremely inconvenient and is not suitable for industrial production.
The synthetic route disclosed in patent document CN 102093352 is as follows:
the route takes imidazo [1,2-a ] pyridine and glyoxylic acid ester or glyoxylic acid as starting materials to react to obtain 2- (3-imidazo [1,2-a ] pyridine), 2-hydroxyacetic acid, and the product obtained by the process can be used for preparing a compound (III), namely 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid. However, the reaction of the route needs to be protected by filling inert gas, the production operation is inconvenient, the number of byproducts is large, the reaction yield is low, and the route is not suitable for industrial production.
The synthetic route disclosed in patent document CN 1020101860 is as follows:
the route takes 1, 4-butyrolactone as an initial raw material, and the compound (III) 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid is obtained by ring opening, oxidation, bromination, cyclization with 2-aminopyridine and hydrolysis. However, the route requires ultralow temperature reaction, is inconvenient to produce and operate, uses a large amount of bromine, is not environment-friendly and is not suitable for industrial production.
In patent documents CN 102153585 and Chem Pharm Bull 1988, 46 (11): 1703 the reported process route is:
in the synthetic route, 2-aminopyridine and 4-bromoacetoacetic acid ethyl ester are cyclized and hydrolyzed to obtain 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid, and the minodronic acid is obtained after diphosphorylation. The preparation method has the advantages of more byproducts (mainly 2- (imidazo [1,2-a ] pyridine-2-yl) ethyl acetate) in the cyclization reaction in the preparation process, low reaction yield, difficult removal of the byproducts and unsuitability for industrial large-scale production.
Disclosure of Invention
The invention aims to provide a synthetic method of minodronate hydrate, which has low requirement on equipment, is simple, convenient and easy to control, has mild reaction conditions, is environment-friendly, has high yield and is suitable for industrial mass production.
The invention also aims to provide a synthesis method of minodronic acid.
The object of the invention can be achieved by the following measures:
a preparation method of minodronate hydrate comprises the following steps: performing ketone group protection on the compound (VII) to obtain a compound (VI), performing nucleophilic substitution reaction on the compound (VI) and 2-aminopyridine to obtain a compound (V), and performing ring-closure reaction on the compound (V) after the ketone group protection is removed to obtain a compound (IV); hydrolyzing the compound (IV) to obtain a compound (III), carrying out diphosphorylation on the compound (III) to obtain a compound (II), and recrystallizing the compound (II) to obtain minodronic acid hydrate (I);
wherein,
x is halogen;
r is C1-4 alkyl;
R1or R2Are each independently C1～4Alkyl, or R1And R2Are connected to form C2～4An alkylene group.
The invention also comprises a preparation method of the minodronic acid, which comprises the following steps: performing ketone group protection on the compound (VII) to obtain a compound (VI), performing nucleophilic substitution reaction on the compound (VI) and 2-aminopyridine to obtain a compound (V), and performing ring-closure reaction on the compound (V) after the ketone group protection is removed to obtain a compound (IV); hydrolyzing the compound (IV) to obtain a compound (III), and carrying out diphosphorylation on the compound (III) to obtain a compound (II). The reaction routes are shown in formulas VII to II.
In the compounds of the formulae of the present invention, X is preferably I, Br or a Cl atom, most preferably a Cl atom; r is preferably methyl, ethyl, propyl or isopropyl, most preferably ethyl; r1Or R2Preferably each independently methyl or ethyl, or R1And R2Linked to form an ethylene or propylene group. Therefore, the compound (VII) preferably has a structure of ethyl 4-chloroacetoacetate.
In the protection of the compound (VII) with a ketone group, the ketone group protecting agent used is C1～4Alkyl alcohol or C2～4An alkyl diol, which is preferably methanol, ethanol, ethylene glycol or 1, 3-propanediol, most preferably ethylene glycol; the catalyst for protecting the ketone group is activated carbon loaded phosphotungstic acid.
In the ketone group protection reaction, the dosage of the catalyst is 0.1-5%, preferably 0.5-1%, of the total mass of the reaction materials, the preferred ketone group protection reaction solvent is cyclohexane, and the preferred ketone group protection reaction temperature is 50-85 ℃.
Adding an acid-binding agent in the nucleophilic substitution reaction process of the compound (VI) and 2-aminopyridine; the acid-binding agent is selected from one or more of triethylamine, diethylamine, pyridine, sodium acetate, sodium carbonate and potassium carbonate; the molar weight of the acid-binding agent is 1-3 times of that of the 2-aminopyridine. Tetrahydrofuran is preferably selected as a solvent in the reaction, and the reaction temperature is 50-70 ℃.
When the compound (V) is subjected to deprotection, the pH value of the reaction system is 1-6, and the preferable pH value is 3-4; the catalyst used in the de-keto protection reaction is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, acetic acid or formic acid, preferably hydrochloric acid. The preferred solvent for the de-keto protection reaction is water; the preferable temperature of the ketonization protection reaction is 20-30 ℃; the preferable cyclization reaction temperature is 90-105 ℃; the cyclization reaction solvent is preferably water.
In the hydrolysis reaction of the compound (IV), the solvent is selected from one or more of acetonitrile-water, methanol-water and ethanol-water mixed solvents; the hydrolysis reaction process comprises the following steps: dissolving the compound (IV), adding sodium hydroxide or potassium hydroxide for hydrolysis, then concentrating under reduced pressure to dryness, dissolving the remainder with water, washing with ethyl acetate, finally adjusting the pH of the water phase to 6.0-7.0 with hydrochloric acid, standing for crystallization, and filtering to obtain the compound (III).
In the course of the bisphosphorylation reaction of compound (III), the bisphosphorylation reagents are phosphorous acid and phosphorus oxychloride, the reaction solvent preferably being toluene. The process of the double phosphorylation reaction is as follows: adding the compound (III) into a reaction solvent, heating to 80-90 ℃, adding phosphorous acid and phosphorus oxychloride, heating to 95-115 ℃ for reaction, pouring out the reaction solvent, adding hydrochloric acid, and reacting at 90-105 ℃ to obtain a compound (II).
In the recrystallization of the compound (II), the selected solvent is hydrochloric acid, nitric acid or sulfuric acid solution, preferably hydrochloric acid; the concentration of the hydrochloric acid is 0.1-3N, preferably 0.5-1N, and the weight ratio of the dosage of the recrystallization solvent to the compound (II) is 20-60: 1; the recrystallization process comprises the following steps: heating and dissolving the compound (II) in a solvent, adding water into the solution, and finally crystallizing, wherein the weight ratio of the water to the compound (II) is (20-100): 1.
the following further illustrates a more specific method for synthesizing minodronate hydrate by taking ethylene glycol as a ketone group protecting agent as an example, which comprises the following steps:
(1) uniformly stirring and mixing the compound (VII) and a ketone group protective agent, adding a proper amount of activated carbon-loaded phosphotungstic acid, adding a proper amount of cyclohexane, heating to reflux, reacting for 2 hours, filtering, and evaporating the solvent under reduced pressure to obtain an oily substance, namely a compound (VI);
(2) dissolving a compound (VI) and 2-aminopyridine in a proper amount of organic solvent, uniformly stirring, slowly dropwise adding a proper amount of triethylamine, heating for reflux reaction, detecting by TLC (ethyl acetate: methanol = 70: 30) until spots of the compound (VI) disappear, adding a proper amount of water, then adjusting the pH value of the reaction solution to 3.0-4.0 by using 1N hydrochloric acid, stirring for reaction at room temperature for 1 hour, heating to reflux reaction for 3 hours, then concentrating the reaction solution under reduced pressure to dryness, adding a proper amount of ethyl acetate into the concentrate for dissolution, then washing the organic phase by using a proper amount of water, concentrating the organic phase, refluxing and dissolving the concentrate by using acetonitrile, filtering, and crystallizing at 0 ℃ to obtain a light yellow needle-shaped crystal, namely a compound (IV);
(3) dissolving the compound (IV) in methanol, adding a proper amount of sodium hydroxide solution, reacting at room temperature for 1 hour, concentrating the reaction solution to dryness, adding water for dissolving, washing the water phase with ethyl acetate, adjusting the pH of the water phase to 6.0-7.0 with 3N hydrochloric acid, standing for crystallization, and performing suction filtration to obtain a light yellow solid, namely the compound (III).
(4) Adding the compound (III) into a proper amount of toluene, heating to 80-90 ℃, adding a proper amount of phosphorous acid, stirring uniformly, then dropwise adding phosphorus oxychloride, heating to reflux for 6 hours, pouring out the toluene, adding a proper amount of 6N hydrochloric acid, heating and refluxing for 4 hours, separating liquid, taking a water layer, concentrating to dryness, adding methanol, standing for crystallization, and performing suction filtration to obtain a white solid, namely a compound (II).
(5) Adding the compound (II) into a proper amount of hydrochloric acid solution, heating to a clear solution, filtering, dropwise adding a proper amount of pure water into the filtrate, after dropwise adding, crystallizing at room temperature for 6 hours, and performing suction filtration to obtain white or slightly reddish white crystals, namely the compound (I) minodronic acid hydrate.
The synthesis method of the minodronate hydrate has the following characteristics:
1. the initial raw materials for the reaction have sufficient sources, the cost is low, the reagent used in the reaction process is environment-friendly, and the industrial production is safe.
2. Mild reaction conditions, convenient operation, less side reaction, simple post-treatment, no need of special or complex reaction equipment and easy industrial production.
Detailed Description
The following examples further illustrate the invention but do not limit it.
Example 1:
1. preparation of Compound (VI)
Adding 165.0g (1.0 mol) of 4-chloroacetoacetic acid ethyl ester into 112ml of ethylene glycol (2.0 mol), uniformly stirring and mixing, adding 1.375g (0.5%) of activated carbon loaded phosphotungstic acid, adding 1000ml of cyclohexane, heating to reflux, reacting for 2 hours, filtering, and evaporating the solvent under reduced pressure to obtain 181.4g of oily matter, wherein the yield is 86.8 percent, and the compound is the compound (VI) (2-chloromethyl- [1,3] -dioxolan-2-yl) acetic acid ethyl ester.
2. Preparation of Compound (IV)
Dissolving 180.0g of compound (VI) 2-chloromethyl- [1,3] -dioxolan-2-yl and 120.0g of 2-aminopyridine in 1000ml of tetrahydrofuran, stirring uniformly, slowly dropwise adding 150.0g of triethylamine, heating and refluxing for reaction, detecting by TLC (ethyl acetate: methanol = 70: 30) the reaction solution until the spot of compound (VI) disappears, adding 1000ml of water, then adjusting the pH value of the reaction solution to 3.0 with 1N hydrochloric acid, stirring for reaction at room temperature for 1 hour, then heating to reflux for reaction for 3 hours, then concentrating the reaction solution under reduced pressure to dryness, adding 500ml of ethyl acetate to the concentrate for dissolution, then washing the organic phase with 500ml of X3 water, concentrating the organic phase, refluxing and dissolving the concentrate with 500ml of acetonitrile, then filtering, crystallizing at 0 ℃ to obtain 145.8g of light yellow needle-like crystals, namely compound (IV) ethyl 2- (imidazo [1,2-a ] pyridin-3-yl) acetate, yield 83.0%, melting point: 75.5 to 78.0 ℃.
3. Preparation of Compound (III)
Dissolving 145.0g of compound (IV) ethyl 2- (imidazo [1,2-a ] pyridin-3-yl) acetate in 180ml of methanol, adding 150ml of 30% sodium hydroxide solution, stirring at room temperature for reaction for 1 hour, concentrating the reaction solution to dryness, adding 500ml of water for dissolution, washing the water phase with 300ml of X3 ethyl acetate, adjusting the pH of the water phase to 6.0 with 3N hydrochloric acid, standing for crystallization, and performing suction filtration to obtain 100.9g of a light yellow solid, namely compound (III) 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid, wherein the yield is 80.6%, and the melting point is as follows: 258.5-260.5 ℃.
4. Preparation of Compound (II)
Adding 100.0g of compound (III) 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid into 1000ml of toluene, heating to 85 ℃, adding 116.6g of phosphorous acid, stirring uniformly, then adding 261.2g of phosphorus oxychloride dropwise, heating to reflux for 6 hours, pouring out the toluene, adding a proper amount of 2000ml of 6N hydrochloric acid, heating to reflux for 4 hours, separating to obtain a water layer, concentrating to dryness, adding 3500ml of methanol, standing for crystallization for 6 hours, and performing suction filtration to obtain 103.4g of white solid, namely compound (II) [ 1-hydroxy-2- (imidazo [1,2-a ] pyridin-3-yl) ethylidene ]1, 1-diphosphonic acid (minophosphonic acid), wherein the yield is 56.3%, and the melting point: 242.5-245.5 ℃.
5. Preparation of minodronate hydrate of Compound (I)
Adding 100.0g of compound (II) minodronic acid into 3000ml of 1N hydrochloric acid solution, heating to clear, filtering, dropwise adding 3000ml of pure water into the filtrate, after dropwise adding, crystallizing at room temperature for 6 hours, and performing suction filtration to obtain 91.3g of reddish white crystals, namely compound (I) minodronic acid hydrate, wherein the yield is 86.5%, and the melting point is as follows: 249.0-250.0 ℃.
Example 2:
1. preparation of Compound (VI)
Adding 165.0g (1.0 mol) of 4-chloroacetoacetic acid ethyl ester into 160ml (2.0 mol) of methanol, stirring and mixing uniformly, adding 1.465g (0.5%) of activated carbon supported phosphotungstic acid, adding 1000ml of cyclohexane, heating to reflux, reacting for 2 hours, filtering, and evaporating under reduced pressure to remove the solvent to obtain 173.7g of oily matter, wherein the yield is 82.3%, namely the compound (VI) 4-chloro-3, 3-dimethoxy-ethyl butyrate.
2. Preparation of Compound (IV)
Dissolving 170.0g of compound (VI) 4-chloro-3, 3-dimethoxy-ethyl butyrate and 113.0g of 2-aminopyridine in 1000ml of tetrahydrofuran, uniformly stirring, slowly dropwise adding 142.0g of triethylamine, heating and refluxing for reaction, detecting a reaction solution (ethyl acetate: methanol = 70: 30) by TLC (detection of ethyl acetate: methanol = 70: 30) until spots of the compound (VI) disappear, adding 1000ml of water, then adjusting the pH value of the reaction solution to 3.0 by using 1N hydrochloric acid, stirring for reaction at room temperature for 1 hour, then heating to reflux for reaction for 3 hours, then concentrating the reaction solution under reduced pressure to dryness, adding 500ml of ethyl acetate into a concentrate to dissolve, then washing an organic phase by using 500ml of X3 water, concentrating the organic phase, refluxing and dissolving the concentrate by using 500ml of acetonitrile, then filtering, crystallizing at 0 ℃ to obtain 128.3g of light yellow needle-like crystals, namely compound (IV) ethyl 2- (imidazo [1,2-a ] pyridin-3-yl) acetate, yield 77.3%, melting point: 76.5-78.5 ℃.
3. Preparation of Compound (III)
125.0g of compound (IV) ethyl 2- (imidazo [1,2-a ] pyridin-3-yl) acetate is dissolved in 150ml of methanol, 130ml of 30% sodium hydroxide solution is added, the mixture is stirred at room temperature for reaction for 1 hour, the reaction solution is concentrated to dryness, 450ml of water is added for dissolution, the water phase is washed by 250ml of X3 ethyl acetate, the pH of the water phase is adjusted to 7.0 by 3N hydrochloric acid, the mixture is kept stand for crystallization, and 100.983.9g of light yellow solid, namely compound (III) 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid, is obtained by suction filtration, the yield is 77.7%, and the melting point: 257.5 to 260.0 ℃.
4. Preparation of Compound (II)
Adding 80.0g of compound (III) 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid into 800ml of toluene, heating to 85 ℃, adding 93.3g of phosphorous acid, stirring uniformly, then adding 209.0g of phosphorus oxychloride dropwise, heating to reflux for 6 hours, pouring out the toluene, adding an appropriate amount of 1600ml of 6N hydrochloric acid, heating to reflux for 4 hours, separating to obtain a water layer, concentrating to dryness, adding 2800ml of methanol, standing for crystallization for 6 hours, and performing suction filtration to obtain 82.5g of white solid, namely compound (II) [ 1-hydroxy-2- (imidazo [1,2-a ] pyridin-3-yl) ethylidene ]1, 1-diphosphonic acid (minophosphonic acid), wherein the yield is 56.1%, and the melting point: 242.0-245.5 ℃.
5. Preparation of minodronate hydrate of Compound (I)
Adding 80.0g of compound (II) minodronic acid into 3200ml of 1N hydrochloric acid solution, heating to clear, filtering, dropwise adding 3200ml of pure water into the filtrate, after dropwise adding, crystallizing at room temperature for 6 hours, and performing suction filtration to obtain 72.5g of reddish white crystals, namely compound (I) minodronic acid hydrate, wherein the yield is 85.9%, and the melting point is as follows: 249.5-250.5 ℃.
Claims (12)
1. A preparation method of minodronate hydrate is characterized in that a compound (VII) is firstly subjected to ketone group protection to obtain a compound (VI), then the compound (VI) and 2-aminopyridine are subjected to nucleophilic substitution reaction to obtain a compound (V), and the compound (V) is subjected to ring closure reaction after ketone group removal protection to obtain a compound (IV); hydrolyzing the compound (IV) to obtain a compound (III), carrying out diphosphorylation on the compound (III) to obtain a compound (II), and recrystallizing the compound (II) to obtain minodronic acid hydrate (I); wherein the keto protecting agent used for the keto protection of the compound (VII) is C1～4Alkyl alcohol or C2～4Alkyl diol, wherein the catalyst for protecting the ketone group is activated carbon loaded phosphotungstic acid, and the solvent for protecting the ketone group is cyclohexane; the solvent selected in the recrystallization of the compound (II) is hydrochloric acid, nitric acid or sulfuric acid solution, and the weight ratio of the amount of the recrystallization solvent to the compound (II) is 20-60: 1; the recrystallization process comprises the following steps: heating and dissolving the compound (II) in a solvent, adding water into the solution, and finally crystallizing, wherein the weight ratio of the water to the compound (II) is 20-100: 1;
wherein,
x is halogen;
r is C1～4An alkyl group;
R1or R2Are each independently C1～4Alkyl, or R1And R2Are connected to form C2～4An alkylene group.
2. The process according to claim 1, characterized in that said X is I, Br or a Cl atom; r is methyl, ethyl, propyl or isopropyl; r1Or R2Each independently being methyl or ethyl, or R1And R2Linked to form an ethylene or propylene group.
3. The process according to claim 2, characterized in that said X is a Cl atom; r is ethyl; r1Or R2Each independently being methyl or ethyl, or R1And R2Linked to form an ethylene or propylene group.
4. The process according to claim 1, wherein the compound (VII) is protected from ketone groups by a ketone group protecting agent selected from the group consisting of methanol, ethanol, ethylene glycol and 1, 3-propanediol; the dosage of the catalyst for protecting the ketone group is 0.1-5% of the total mass of the reaction materials, and the reaction temperature for protecting the ketone group is 50-85 ℃.
5. The process according to claim 4, wherein the amount of the ketone group-protecting catalyst is 0.5 to 1% by mass based on the total mass of the reaction materials.
6. The process according to claim 1, characterized in that an acid-binding agent is added during the nucleophilic substitution reaction of the compound (VI) with 2-aminopyridine; the acid-binding agent is selected from one or more of triethylamine, diethylamine, pyridine, sodium acetate, sodium carbonate and potassium carbonate; the molar weight of the acid-binding agent is 1-3 times of that of the 2-aminopyridine.
7. The method according to claim 1, wherein the pH value of the reaction system is 1 to 6 when the compound (V) is deprotected; the catalyst used in the de-keto protection reaction is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, acetic acid or formic acid.
8. The method according to claim 7, wherein the pH value of the reaction system is 3 to 4 when the compound (V) is deprotected; the catalyst used in the de-keto protection reaction is hydrochloric acid; the solvent for the ketone group removing protection reaction is water; the reaction temperature of the ketone group removing protection is 20-30 ℃; the cyclization reaction temperature is 90-105 ℃; the cyclization reaction solvent is water.
9. The method according to claim 1, wherein the compound (IV) hydrolysis reaction solvent is one or more selected from acetonitrile-water, methanol-water, ethanol-water mixed solvent; the hydrolysis reaction process comprises the following steps: dissolving the compound (IV), adding sodium hydroxide or potassium hydroxide for hydrolysis, then concentrating under reduced pressure to dryness, dissolving the remainder with water, washing with ethyl acetate, finally adjusting the pH of the water phase to 6.0-7.0 with hydrochloric acid, standing for crystallization, and filtering to obtain the compound (III).
10. The method of claim 1, wherein: in the process of the diphosphorylation reaction of the compound (III), reagents for diphosphorylation are phosphorous acid and phosphorus oxychloride, and a reaction solvent is toluene; the process of the double phosphorylation reaction is as follows: adding the compound (III) into a reaction solvent, heating to 80-90 ℃, adding phosphorous acid and phosphorus oxychloride, heating to 95-115 ℃ for reaction, pouring out the reaction solvent, adding hydrochloric acid, and reacting at 90-105 ℃ to obtain a compound (II).
11. The process according to claim 1, characterized in that the solvent chosen for the recrystallization of compound (ii) is hydrochloric acid; the concentration of the hydrochloric acid is 0.1-3N.
12. The process according to claim 11, characterized in that the solvent chosen for the recrystallization of compound (ii) is hydrochloric acid; the concentration of the hydrochloric acid is 0.5-1N.
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| Studies on Novel Bone Resorption Inhibitors.II.Synthesis and Pharmacological Activities of Fused Aza-heteroarylbisphosphonate Derivatives;Makoto Takeuchi et al.;《Chem. Pharm. Bull.》;19981130;第46卷(第11期);1703-1709 * |
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