CN112390823B - Synthesis method of minodronic acid - Google Patents
Synthesis method of minodronic acid Download PDFInfo
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- CN112390823B CN112390823B CN201910763344.0A CN201910763344A CN112390823B CN 112390823 B CN112390823 B CN 112390823B CN 201910763344 A CN201910763344 A CN 201910763344A CN 112390823 B CN112390823 B CN 112390823B
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- 229950011129 minodronic acid Drugs 0.000 title claims abstract description 40
- 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 claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 39
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 22
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 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 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 28
- 238000010992 reflux Methods 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000006136 alcoholysis reaction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- 238000000967 suction filtration Methods 0.000 description 21
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 20
- 238000009776 industrial production Methods 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 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 9
- -1 imidazo [1,2-a ] pyridin-3-yl Chemical group 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 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 3
- 230000036632 reaction speed Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-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
- LOLKAJARZKDJTD-UHFFFAOYSA-N butanedioic acid monoethyl ester Natural products CCOC(=O)CCC(O)=O LOLKAJARZKDJTD-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 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 description 1
- GAYVRFSEJYRVCM-UHFFFAOYSA-N 1-imidazo[1,2-a]pyridin-3-yl-n,n-dimethylmethanamine Chemical compound C1=CC=CN2C(CN(C)C)=CN=C21 GAYVRFSEJYRVCM-UHFFFAOYSA-N 0.000 description 1
- XBQWTFBQHNSGPP-UHFFFAOYSA-N 3-imidazo[1,2-a]pyridin-3-ylpropanenitrile Chemical compound C1=CC2=NC=C(N2C=C1)CCC#N XBQWTFBQHNSGPP-UHFFFAOYSA-N 0.000 description 1
- PLMCCOPFYJURPS-UHFFFAOYSA-N 4-bromo-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CBr PLMCCOPFYJURPS-UHFFFAOYSA-N 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000005672 Willgerodt-Kindler rearrangement reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 208000027697 autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- SDGAEBKMHIPSAC-ONEGZZNKSA-N ethyl (e)-4-oxobut-2-enoate Chemical compound CCOC(=O)\C=C\C=O SDGAEBKMHIPSAC-ONEGZZNKSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 238000010534 nucleophilic substitution 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
- 229940046231 pamidronate Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 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 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention belongs to the technical field of medicine synthesis, and provides a synthesis method of minodronic acid, which comprises the steps of adding a ROH solution of a compound III imidazo [1,2-a ] pyridine-3-acetonitrile and hydrogen chloride into a corresponding ROH solvent, and performing temperature control reaction to obtain a compound II; reacting the compound II with water and phosphorus trichloride to obtain minodronate; the method has the advantages of mild reaction conditions, simple operation process and low production cost, and the prepared minodronate has higher purity and yield.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of minodronic acid.
Background
Minodronic acid (Minodronic acid), chemical name 1-hydroxy-2- (imidazo [1,2-a ] pyridin-3-yl) ethylene-1, 1-bisphosphonic acid monohydrate, which is a third generation nitrogen-containing heteroaryl bisphosphonate derivative developed by Nippon mountain pharmaceutical Co-Ltd. The compound has high anti-bone resorption activity, which is 10 times and 100 times that of alendronic acid and pamidronate respectively, and has an osteolysis antagonizing effect caused by myeloma and tumor, so that the compound has a broad market prospect. The chemical structure is as follows:
the synthesis processes reported at present for minodronic acid mainly comprise the following steps:
1) Scheme 1Luidi almiranate in j.med.chem,1969, 12 (1): 122-126 and Pi Shiqing in journal 2004, 35 (4) of the chinese medical industry: 193-194 is as follows:
the method takes 2-imidazo [1,2-a ] pyridine as a raw material, carries out Mannich reaction with paraformaldehyde and dimethylamine hydrochloride to obtain 3- [ (N, N-dimethylamino) methyl ] imidazo [1,2-a ] pyridine, reacts with bromoethane to form quaternary ammonium salt, then reacts with sodium cyanide to obtain 3-cyanoethylimidazo [1,2-a ] pyridine, and hydrolyzes under alkaline conditions to obtain 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid. The method uses the extremely toxic sodium cyanide, is dangerous to operate, is not easy to control and environment-friendly, has more side reactions, and the generated product is difficult to purify, has more reaction steps and complex operation, and is not suitable for industrial production.
2) Scheme 2 patent CN101531681a (2009-09-16): a high-purity minodronic acid and a preparation method thereof are reported as follows:
the method comprises the steps of taking succinic acid monoethyl ester acyl chloride as an initial raw material, reducing with lithium aluminum hydride with tri-tert-butoxy, then carrying out bromination, reacting with 2-aminopyridine to generate a compound 2- (3-imidazo [1,2-a ] pyridine) ethyl acetate, carrying out hydrolysis to obtain a compound 2- [ imidazo (1, 2-a) pyridine-3-yl ] acetic acid, and finally carrying out phosphorylation in toluene to obtain a final product. Although the method has a short route, the starting material of the succinic acid monoethyl ester acyl chloride is not easy to purchase, a large amount of liquid bromine and trimethyl chlorosilane which are high in corrosiveness, strong in irritation and easy to volatilize are required in the bromination process, the method causes great harm to the environment, operators and equipment, the required reducing agent of the tri-tert-butoxy aluminum lithium hydride has high price, and the cost is high in large-scale industrial production, so that the method is unfavorable for industrial production.
3) Literature (chem. Pharm. Bull,1998,46 (11), 1703) reports a process for the preparation of minodronic acid, the synthetic route being as follows:
the synthetic route is that 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid is obtained by hydrolysis after cyclization of 2-aminopyridine and 4-bromoacetoacetate, and minodronic acid is obtained after double phosphorylation. In the preparation process of the method, the cyclic reaction has a plurality of byproducts (mainly 2- (imidazo [1,2-a ] pyridine-2-yl) ethyl acetate), the reaction yield is low, the byproducts are not easy to remove, and the method is not suitable for industrial mass production. In addition, 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid is synthesized in a similar manner as in patent CN101973993A, CN102153585A, CN102093352A, CN105111238A, CN105837635 a.
4) Synthetic route 4 patent CN102875602a discloses a preparation method of minodronic acid hydrate, which comprises the steps of protecting ketone group, carrying out nucleophilic substitution reaction with 2-aminopyridine, carrying out ring closure reaction after removing ketone group protection, and finally carrying out hydrolysis, double phosphorylation and other steps to obtain the target product minodronic acid. The specific process route is as follows:
the method has mild reaction conditions and solves the problem of more byproducts, but has the problems of slow reaction speed, low yield and the like.
5) Synthetic route 5 patent document CN102020676a discloses the following synthetic route:
the method takes 2, 2-dimethoxy acetaldehyde and triethyl phosphonoacetate as initial raw materials, and the initial raw materials are condensed and then cyclized with 2-aminopyridine to synthesize a compound of 2- (imidazo [1,2-a ] pyridine-3-yl) ethyl acetate, and the compound of 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid is obtained after hydrolysis, and then the compound minodronic acid hydrate is prepared. The starting material 2, 2-dimethoxy acetaldehyde of the route has low market supply and high price, so that the production cost is high, and the method is not suitable for industrial production.
6) Synthetic route 6 patent document CN102250090a discloses the following synthetic route:
the route is to take 3-bromoimidazo [1,2-a ] pyridine as a starting material, condense with malonic diester and hydrolyze to obtain a compound 2- (imidazo [1,2-a ] pyridin-3-yl) acetic acid. The 3-bromoimidazo [1,2-a ] pyridine starting material for this route is essentially not available in the market, requires customization, and requires anhydrous handling during the reaction, which is not suitable for commercial production.
7) Scheme 7 is Tian Jian et al (Tian Jian, zhong Jianfeng, guo; university of shanxi journal (natural science edition) 34 (s 2): 55-56, 2011), a new reaction route is disclosed, ethyl formate and o-aminopyridine are used as raw materials, and target compounds are obtained through condensation, bromination, ring closure and Willgerodt-kindler reaction. The synthesis is as follows:
the bromine is used in the route, which is inconvenient to produce, has long route and difficult purification, and is not suitable for industrial production.
8) Scheme 8 (2013, chai Huifang, zhao Chunshen; instructions on Shenyang university of medical science, 2013,30 (6), 439-441); the method is characterized in that 2-aminopyridine and maleic anhydride are used as raw materials, and ester groups are subjected to cyclization, esterification, chlorination, reduction and hydrolysis to obtain a compound 2- [ imidazo (1, 2-a) pyridine-3-yl ] acetic acid, and the compound reacts with phosphorous acid to obtain minodronic acid monohydrate. The synthetic route is as follows:
the process route is long, wherein phosphorus oxychloride or phosphorus trichloride is used for chlorination in two steps, one-step hydrogenation is carried out, and the steps are long; the cost is high, and the process is not suitable for industrial production.
9) Synthetic route the synthetic route disclosed in patent document 9CN102344448A is as follows:
in the route, high-temperature decarboxylation is needed to be carried out at 190-220 ℃ when 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid is synthesized, impurities are easy to generate at high temperature, and the method is not beneficial to industrial production.
10 Synthetic route 10 the synthetic route disclosed in patent document CN102344463a is as follows:
the method uses trans-4-oxo-2-butenoic acid ethyl ester as a raw material, performs cyclization, and then performs hydrolysis to obtain 2- (imidazo [1,2-a ] pyridine-3-yl) acetic acid, and performs double phosphorylation to obtain minodronic acid. The yield in the cyclization step was 50%.
In summary, in the technical processes for preparing minodronic acid that have been reported, the following problems are mainly present:
(1) The reaction uses highly toxic sodium cyanide or highly corrosive, strongly irritating and volatile liquid bromine, trimethylchlorosilane and the like, which causes great harm to the environment, operators and equipment and operational danger.
(2) The side reaction is more, the produced product is difficult to purify, the reaction steps are more, the operation is complex, and the method is not suitable for industrial production.
(3) The market supply of the initial raw materials is less, the raw materials are not easy to purchase, the price is high, and the cost is high in large-scale industrial production.
(4) The reaction speed is slow and the yield is not high.
(5) In the reaction process, anhydrous operation and the like are required, so that the method is not suitable for industrial production.
In view of the problems of the prior art, the research and search of a preparation method which has the advantages of mild reaction conditions, simple operation process, high product yield, high purity and low production cost and is suitable for industrial production of minodronic acid still needs to be solved at present.
Disclosure of Invention
Aiming at the problems existing in the existing minodronic acid synthesis technology, the invention provides a synthesis method of minodronic acid. The method has the advantages of mild reaction conditions, simple operation process and low production cost, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
the synthesis process of minodronic acid includes alcoholysis of compound III imidazo [1,2-a ] pyridine-3-acetonitrile with hydrochloric acid to obtain compound II; the compound II is phosphorylated with purified water and phosphorus trichloride to obtain a compound I minodronic acid, and the reaction formula is as follows:
the synthesis method of minodronic acid specifically comprises the following steps:
step 1, adding a ROH solution of a compound III imidazo [1,2-a ] pyridine-3-acetonitrile and hydrogen chloride into a corresponding ROH solvent, performing temperature control reaction, performing reduced pressure distillation after the reaction is finished, cooling, stirring, crystallizing and filtering residues to obtain a compound II; wherein R is one of methyl, ethyl and n-propyl;
and 2, adding the compound II and water into a reaction solvent, heating, adding phosphorus trichloride, continuing to perform a temperature-controlled reaction, discharging an organic phase after the reaction is finished, adding a hydrochloric acid solution for temperature-controlled hydrolysis, performing reduced pressure concentration after the reaction is finished, obtaining brown oily matter, adding methanol for crystallization, performing suction filtration, and drying to obtain the compound I minodronic acid.
In the compounds of the invention, R is one of methyl, ethyl and n-propyl; among them, n-propyl is particularly preferred.
Preferably, in the process of preparing the compound II, the concentration of the hydrogen chloride organic solution is 5-10%; of these, 8% is particularly preferable.
Preferably, in the process of preparing the compound II in the step 1, TLC detects the reaction progress, and the reaction time is 8-14 h.
Preferably, in the process of preparing the compound II in the step 1, the temperature control temperature is 60 ℃ to the temperature at which the reaction liquid reaches a reflux state.
Preferably, in the process of preparing the compound II in the step 1, the crystallization time is 2-5 h.
Preferably, in the process of preparing the compound II in the step 1, the crystallization temperature is-5-15 ℃; of these, 0 to 5℃is particularly preferred.
Preferably, in the process of preparing the compound I in the step 2, the mass volume ratio of the compound II to water is 1: 0.08-0.12 g/ml.
Preferably, in the process of preparing the compound I in the step 2, the reaction solvent is one or a combination of toluene, chlorobenzene, 1, 4-dioxane and xylene; among them, toluene is particularly preferable.
Preferably, in the process of preparing the compound I in the step 2, the temperature is raised to 55-65 ℃ before the phosphorus trichloride is dropwise added.
Preferably, in the process of preparing the compound I in the step 2, the feeding mole ratio of the compound II to the phosphorus trichloride is 1.0:2.5 to 4.0; of these, 1.0 is particularly preferred: 3.0.
preferably, in the process of preparing the compound I in the step 2, the reaction temperature after dropwise adding phosphorus trichloride is 75-85 ℃.
Preferably, in the process of preparing the compound I in the step 2, TLC detects the reaction progress, and the reaction time is 6-8 h.
Preferably, in the process of preparing the compound I in the step 2, the concentration of the hydrochloric acid is 4mol/L and 6mol/L; of these, 6mol/L is particularly preferred.
Preferably, in the process of preparing the compound I in the step 2, the hydrolysis temperature is 70-80 ℃.
Preferably, in the process of preparing the compound I in the step 2, the crystallization temperature is 0-30 ℃; of these, 10 to 20℃is particularly preferred.
Preferably, in the process of preparing the compound I in the step 2, the crystallization time is 4-7 h.
Compared with the prior art, the invention has the technical effects that:
(1) The method has the advantages of easily obtained starting materials, avoiding the use of extremely toxic and highly corrosive substances in the reaction, along with fewer reaction steps, simple operation and suitability for industrial production.
(2) The reaction speed is faster, the impurity is less, the reaction yield and purity are improved, and the cost is reduced.
Drawings
FIG. 1 shows a diagram of the substances related to the HPLC of minodronate obtained in example 1 of the present invention.
FIG. 2 shows a diagram of the substances related to the HPLC of minodronate obtained in example 7 of the present invention.
FIG. 3 is a chart showing the HPLC related substances of minodronate obtained in example 10 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: the compound imidazo [1,2-a ] pyridine-3-acetonitrile is commercially available, and can also be prepared by reference to the techniques disclosed herein; the materials used in the other experiments were not of the indicated source and specification, either commercially available analytically pure or chemically pure.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 1
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 8% hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, the three-neck flask is heated to 70 ℃ for reaction for 12h, TLC detection reaction is finished, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, and 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl) is obtained through suction filtration, the yield is 97.2%, and the HPLC purity is 97.52%.
1 H NMR(400MHz,DMSO-d6)8.39(d,J＝7Hz,1H),7.78(d,J＝8Hz,1H),7.49(s,1H),7.21(m,1H),6.91(dd,J＝7,7Hz,1H),4.20(s,2H),4.12(m,2H),1.17(m,2H)，0.95(m,3H)。
3- (2, 2-tripropoxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (8.0 ml) and toluene (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 7h after finishing TLC detection, the temperature is reduced, a toluene layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3h, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, thus obtaining brown oily matter. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 87.5 percent, and the HPLC purity is 99.942 percent.
Example 2
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 5% hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, the temperature is heated to 80 ℃ for reaction for 12h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, suction filtration is carried out, and 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl) is obtained, the yield is 95.7%, and the HPLC purity is 97.12%.
3- (2, 2-tripropoxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (6.4 ml) and 1.4-dioxane (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 80 ℃ after the addition is finished, reflux reaction is carried out for 7 hours, the temperature is reduced after the reaction is finished, a 1.4-dioxane layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3 hours, the reaction is finished, the mixture is transferred into a 1000ml single-port bottle, and the mixture is decompressed and concentrated until no liquid flows out, so that brown oily matter is obtained. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 85.5%, and the HPLC purity is 99.901%.
Example 3
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 10 percent hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, heated to 70 ℃ for reaction for 12h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, and suction filtration is carried out, thus obtaining 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl), the yield is 96.1 percent, and the HPLC purity is 97.35 percent.
3- (2, 2-tripropoxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (9.6 ml) and xylene (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 7h after the addition is completed, the reaction is completed, a xylene layer is cooled down, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3h, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, so that brown oily matter is obtained. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 86.1 percent, and the HPLC purity is 99.912 percent.
Example 4
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 8% hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, the mixture is heated to reflux reaction for 8h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, suction filtration is carried out, and 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl) is obtained, the yield is 96.5%, and the HPLC purity is 96.53%.
3- (2, 2-tripropoxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (8.0 ml) and toluene (350 ml) are added into a 1000ml three-port bottle, the temperature is raised to 55 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 75 ℃ for reflux reaction for 8 hours after the addition is completed, the temperature is reduced, a toluene layer is discharged, 4mol/L hydrochloric acid (350 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 4 hours, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, so that brown oily matter is obtained. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 87.1 percent, and the HPLC purity is 99.905 percent.
Example 5
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 8% hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, the temperature is heated to 85 ℃ for reaction for 10h, the reaction is finished, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, suction filtration is carried out, and 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl) is obtained, the yield is 95.9%, and the HPLC purity is 97.01%.
3- (2, 2-tripropoxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (8.0 ml) and toluene (350 ml) are added into a 1000ml three-port bottle, the temperature is raised to 65 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 85 ℃ for reflux reaction for 6 hours after the addition is completed, the temperature is reduced, a toluene layer is discharged, 4mol/L hydrochloric acid (350 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3 hours, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, so that brown oily matter is obtained. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 87.1 percent, and the HPLC purity is 99.915 percent.
Example 6
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol), normal propyl alcohol (200 mL) and 8% hydrogen chloride normal propyl alcohol solution (5 mL) are added into a 500mL three-neck flask, the temperature is heated to 70 ℃ for reaction for 12h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 10-15 ℃, stirred and crystallized for 5h, and suction filtration is carried out, thus obtaining 3- (2, 2-tripropyloxy ethyl) imidazo [1,2-a ] pyridine (R is normal propyl), the yield is 95.5%, and the HPLC purity is 97.25%.
3- (2, 2-tripropyloxyethyl) imidazo [1,2-a ] pyridine (80.1 g,0.25 mol), water (8.0 ml) and toluene (440 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (137.3 g,1.0 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 7h after the completion of the addition, the temperature is reduced, a toluene layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3h, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, thus obtaining brown oily matter. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 86.8%, and the HPLC purity is 99.896%.
Example 7
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol) and ethanol (200 mL) are added into a 500mL three-neck flask, 8% hydrogen chloride ethanol solution (5 mL) is heated to reflux reaction for 12h, reaction is finished, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, suction filtration is carried out, and 3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (R is ethyl) is obtained, the yield is 93.1%, and the HPLC purity is 97.23%.
1 H NMR (400 mhz, dmso-d 6) 8.39 (d, j=7 hz, 1H), 7.80 (d, j=8 hz, 1H), 7.47 (s, 1H), 7.21 (m, 1H), 6.91 (dd, j=7, 7hz, 1H), 4.20 (s, 2H), 4.08 (q, j=7 hz, 2H), 1.15 (t, j=7 hz, 3H) (ethyl).
3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (69.5 g,0.25 mol), water (8.0 ml) and toluene (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (85.8 g,0.625 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 7h after the completion of the addition, the temperature is reduced, a toluene layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 80 ℃ for reflux reaction for 3h, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, thus obtaining brown oily matter. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 84.5%, and the HPLC purity is 99.941%.
Example 8
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol) and ethanol (200 mL) are added into a 500mL three-neck flask, the mixture is heated to 60 ℃ for reaction for 14h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 5-10 ℃, stirred and crystallized for 4h, and suction filtration is carried out, thus obtaining 3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (R is ethyl), the yield is 91.8%, and the HPLC purity is 96.79%.
3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (69.5 g,0.25 mol), water (8.0 ml) and chlorobenzene (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 7h after the completion of the addition, the temperature is reduced, a chlorobenzene layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 70 ℃ for reflux reaction for 3h, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, thus obtaining brown oily matter. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 85.7%, and the HPLC purity is 99.918%.
Example 9
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol) and ethanol (200 mL) are added into a 500mL three-neck flask, the mixture is heated to 70 ℃ for reaction for 12h, the reaction is completed, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, and suction filtration is carried out, thus obtaining 3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (R is ethyl), the yield is 92.1 percent, and the HPLC purity is 99.68 percent.
3- (2, 2-triethoxyethyl) imidazo [1,2-a ] pyridine (69.5 g,0.25 mol), water (7.0 ml) and toluene (400 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (120.2 g,0.875 mol) is dropwise added, the temperature is continuously raised to 80 ℃ for reflux reaction for 8 hours after the completion of the addition, the temperature is reduced, a toluene layer is discharged, 4mol/L hydrochloric acid (350 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3 hours, the reaction is completed, the mixture is transferred into a 1000ml single-port bottle, and the mixture is concentrated under reduced pressure until no liquid flows out, thus obtaining brown oily matter. Methanol (400 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 87.2 percent, and the HPLC purity is 99.894 percent.
Example 10
Imidazo [1,2-a ] pyridine-3-acetonitrile (157.2 g,1.0 mol) and methanol (200 mL) are added into a 500mL three-neck flask, 8% hydrogen chloride methanol solution (5 mL) is heated to reflux reaction for 12h, reaction is finished, the temperature is reduced to 30-50 ℃, about 150mL of solvent is distilled off under reduced pressure, the residue is cooled to 0-5 ℃, stirred and crystallized for 3h, suction filtration is carried out, and 3- (2, 2-trimethoxyethyl) imidazo [1,2-a ] pyridine (R is methyl) is obtained, the yield is 95.2%, and the HPLC purity is 96.75%.
1 H NMR(400MHz,DMSO-d6)8.40(d,J＝7Hz,1H),7.80(d,J＝8Hz,1H),7.47(s,1H),7.22(m,1H),6.91(dd,J＝7,7Hz,1H),4.20(s,2H),4.08(s,3H)。
3- (2, 2-trimethoxyethyl) imidazo [1,2-a ] pyridine (59.1 g,0.25 mol), water (7.0 ml) and 1.4-dioxane (350 ml) are added into a 1000ml three-port bottle, the temperature is raised to 60 ℃, phosphorus trichloride (103.0 g,0.75 mol) is dropwise added, the temperature is continuously raised to 80 ℃ after the addition is finished, reflux reaction is carried out for 6 hours, the reaction is finished, the temperature is reduced, a 1.4-dioxane layer is discharged, 6mol/L hydrochloric acid (240 g) is added, the temperature is continuously raised to 75 ℃ for reflux reaction for 3 hours, the reaction is finished, the mixture is transferred into a 1000ml single-port bottle, and the mixture is decompressed and concentrated until no liquid flows out, so that brown oily matter is obtained. Methanol (350 ml) is added, stirred and crystallized for 5 hours at the temperature of 10-20 ℃, and then the pale yellow solid minodronic acid is obtained after suction filtration and drying, the yield is 84.3%, and the HPLC purity is 99.922%.
Claims (9)
1. The synthesis method of minodronic acid shown in formula I is characterized by comprising the following steps: alcoholysis of imidazo [1,2-a ] pyridine-3-acetonitrile of compound III with hydrogen chloride to obtain compound II; the compound II is phosphorylated with purified water and phosphorus trichloride to obtain a compound I minodronic acid, and the reaction formula is as follows:
，
wherein R is one of methyl, ethyl and n-propyl.
2. The synthesis method according to claim 1, comprising the specific steps of: step 1, adding a ROH solution of a compound III imidazo [1,2-a ] pyridine-3-acetonitrile and hydrogen chloride into a corresponding ROH solvent, performing temperature control reaction, performing reduced pressure distillation after the reaction is finished, cooling, stirring, crystallizing and filtering residues to obtain a compound II; wherein R is one of methyl, ethyl and n-propyl;
and 2, adding the compound II and water into a reaction solvent, heating, dropwise adding phosphorus trichloride, continuously controlling the temperature, reacting, discharging an organic phase after the reaction is finished, adding a hydrochloric acid solution for controlling the temperature for hydrolysis, concentrating under reduced pressure to obtain brown oily matter, adding methanol for crystallization, filtering, and drying to obtain the compound I minodronic acid.
3. The synthesis method according to claim 1 or 2, wherein the temperature control in step 1 is 60 ℃ to a temperature at which the reaction solution reaches a reflux state.
4. The synthetic method according to claim 2, wherein the reaction solvent in step 2 is one of toluene, chlorobenzene, 1, 4-dioxane, xylene or a combination thereof.
5. The synthesis method according to claim 2, wherein the mass-to-volume ratio of the compound ii to water in step 2 is 1: 0.08-0.12 g/ml.
6. The method according to claim 2, wherein the molar ratio of the compound ii to phosphorus trichloride in step 2 is 1.0:2.5 to 4.0.
7. The synthesis method according to claim 2, wherein the temperature rise temperature before dropping the phosphorus trichloride in step 2 is 55-65 ℃.
8. The synthesis method according to claim 2, wherein the reaction temperature after dropping phosphorus trichloride in step 2 is 75-85 ℃.
9. The synthetic method according to claim 2, wherein the hydrolysis temperature in step 2 is 70-80 ℃.
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| EP1891081A1 (en) * | 2005-06-13 | 2008-02-27 | Jubilant Organosys Limited | Process for producing bisphosphonic acids and forms thereof |
| CN102286024A (en) * | 2011-08-30 | 2011-12-21 | 江苏正大清江制药有限公司 | Synthesis method of risedronate sodium |
| CN104725422A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Minodronic acid preparation method |
| CN105111238A (en) * | 2015-07-01 | 2015-12-02 | 中山海泓药业有限公司 | Method for producing minodronic acid monohydrate by using water as solvent |
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| EP1891081A1 (en) * | 2005-06-13 | 2008-02-27 | Jubilant Organosys Limited | Process for producing bisphosphonic acids and forms thereof |
| CN102286024A (en) * | 2011-08-30 | 2011-12-21 | 江苏正大清江制药有限公司 | Synthesis method of risedronate sodium |
| CN104725422A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Minodronic acid preparation method |
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