CN117447355B - 一种米洛巴林中间体的制备方法 - Google Patents
一种米洛巴林中间体的制备方法 Download PDFInfo
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- CN117447355B CN117447355B CN202311793078.9A CN202311793078A CN117447355B CN 117447355 B CN117447355 B CN 117447355B CN 202311793078 A CN202311793078 A CN 202311793078A CN 117447355 B CN117447355 B CN 117447355B
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- 238000002360 preparation method Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 claims description 6
- -1 n-propyl dimethoxyphosphonoacetate Chemical compound 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- IGBDTYLMORCVJN-UHFFFAOYSA-N C(C)(C)(C)OC(CP(=O)(OOC)OOC)=O Chemical compound C(C)(C)(C)OC(CP(=O)(OOC)OOC)=O IGBDTYLMORCVJN-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- ZHAWKUPJGIBSJJ-UHFFFAOYSA-N COOP(=O)(OOC)CC(=O)OCCCC Chemical compound COOP(=O)(OOC)CC(=O)OCCCC ZHAWKUPJGIBSJJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 2
- YLKFNRYOMXWJRZ-UHFFFAOYSA-N ethyl 2-bis(methylperoxy)phosphorylacetate Chemical compound CCOC(=O)CP(=O)(OOC)OOC YLKFNRYOMXWJRZ-UHFFFAOYSA-N 0.000 claims description 2
- QDGILFRPOFKDCL-UHFFFAOYSA-N methyl 2-bis(methylperoxy)phosphorylacetate Chemical group COOP(=O)(OOC)CC(=O)OC QDGILFRPOFKDCL-UHFFFAOYSA-N 0.000 claims description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- FNSIQWSTVYALBA-UHFFFAOYSA-N 2-bis(methylperoxy)phosphorylacetic acid Chemical compound COOP(=O)(CC(O)=O)OOC FNSIQWSTVYALBA-UHFFFAOYSA-N 0.000 claims 2
- 125000005907 alkyl ester group Chemical group 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 2
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- OKJXJRVWXYRSAN-TXULWXBWSA-N 2-[(1r,5s,6s)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid;benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1.C1C(CC)=C[C@H]2[C@](CC(O)=O)(CN)C[C@H]21 OKJXJRVWXYRSAN-TXULWXBWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical class OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 229940126523 co-drug Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009007 sensory signaling Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/26—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms
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Abstract
本发明公开一种米洛巴林中间体的制备方法，由式(A)所示结构经过五步反应生成式(F)所示结构。本发明方法是全新的技术路线，未见任何文献或专利报道。通过本发明所述方法，可大幅提升产品的收率，适合工业化生产。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种米洛巴林中间体的制备方法。
背景技术
2019年1月，由第一三共制药研发的Mirogabalin besilate(苯磺酸米洛巴林)获得日本医药品医疗器械综合机构(PMDA)批准上市，用于治疗外周神经性疼痛(PNP)，包括糖尿病性外周神经疼痛(DPNP)和带状疱疹后遗神经痛(PHN)。米洛巴林属于加巴喷丁类药物，加巴喷丁类药物可以作用于电压门钙通道(VGCC)亚基α2δ(CACNA2D)，通过与α2δ结合，抑制背角中钙离子介导的神经递质的释放，阻断神经元兴奋和感觉信号传导。
米洛巴林中间体结构如下：
。
发明专利CN111116345A公开了如下合成路线，如下：
。
该路线步骤2需要高温操作，产物大量降解，产物收率低。发明人重复该专利，并未得到终产物。
发明内容
本发明公开一种制备式(E)所示结构的方法，包括如下步骤：
，
其中：
R1选自C1-6烷基；
R2选自C1-6烷基；
步骤(4)：氮气环境下，式(D)化合物在碱和醚类溶剂中与对甲基苯磺酰甲基异腈反应，生成式(E)所示化合物。
在一个实施方式中，式(D)所示结构通过以下方法制备：
，
其中：
步骤(1)：式(A)化合物与二甲氧基膦酰基乙酸烷基酯在碱的作用下进行Wittig-Horner反应生成式(B)化合物；
步骤(2)：将式(B)化合物与硝基甲烷和碱反应生成式(C)化合物；
步骤(3)：投入碱和醇溶剂，溶清后投加式(C)化合物，缓慢滴加氧化剂的水溶液，反应生成式(D)化合物。
在一个实施方式中，步骤(4)所述碱选自叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠或碳酸钾；步骤(4)所述醚类溶剂选自四氢呋喃、1,4-二氧六环、二甲醚或2-甲基四氢呋喃。
在一个实施方式中，步骤(1)所述二甲氧基膦酰基乙酸烷基酯选自二甲氧基膦酰基乙酸甲酯、二甲氧基膦酰基乙酸乙酯、二甲氧基膦酰基乙酸正丙酯、二甲氧基膦酰基乙酸异丙酯、二甲氧基膦酰基乙酸叔丁酯或二甲氧基膦酰基乙酸正丁酯；步骤(1)所述碱选自氢化钠、乙醇钠、叔丁醇钾、叔丁醇钠或甲醇钠。
在一个实施方式中，步骤(2)所述碱选自DBN、DBU、TMG、TBD或TEA。
在一个实施方式中，步骤(3)所述碱选自氢氧化钾、氢氧化钠、叔丁醇钾、叔丁醇钠、甲醇钠、氢化钠或碳酸钾；步骤(3)所述醇溶剂选自甲醇、乙醇、异丙醇和叔丁醇；步骤(3)所述氧化剂选自高锰酸钾、过一硫酸氢钾或过氧化氢。
在一个实施方式中，一种制备式(F)所示结构的方法，包括如下步骤：
，
其中：
步骤(4)：氮气环境下，式(D)化合物在碱和醚类溶剂中与对甲基苯磺酰甲基异腈反应，生成式(E)所示化合物；
步骤(5)：将式(E)所示化合物与乙二醇和碱反应生成式(F)所示结构。
在一个实施方式中，步骤(4)所述碱选自叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠或碳酸钾；步骤(4)所述醚类溶剂选自四氢呋喃、1,4-二氧六环、二甲醚或2-甲基四氢呋喃；步骤(5)所述碱选自氢氧化钠和氢氧化钾。
本发明还公开一种式(D)的化合物，
，
其中：
R1选自C1-6烷基；优选为甲基或乙基；
R2选自C1-6烷基；优选为甲基、乙基、正丙基、异丙基或正丁基。
本发明还公开一种式(E)的化合物，
，
R1选自C1-6烷基；优选为甲基或乙基；
R2选自C1-6烷基；优选为甲基、乙基、正丙基、异丙基或正丁基。
发明详述
术语“C1-6烷基”，包括C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基、C1-3烷基或C1-4烷基，实例包括但不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
TosMIC是指对甲基苯磺酰甲基异腈；THF是指四氢呋喃；DME是指乙二醇二甲醚；2-MeTHF是指2-甲基四氢呋喃；DBN是指1,5-二氮杂双环[4.3.0]-5-壬烯；DBU是指1,8-二氮杂二环十一碳-7-烯；TMG是指四甲基胍；TBD是指三氮杂二环；TEA是指三乙醇胺。
本发明有益技术效果：现有技术CN111116345A公开的路线收率低，发明人重复该专利，并未得到终产物。本发明路线是全新的，未见任何文献/专利报道，本发明路线具有非常高的收率。
附图说明
图1：化合物(D-1)的核磁氢谱谱图。
图2：化合物(E-1)的核磁氢谱谱图。
具体实施方式
实施例1：化合物(F-1)的合成
将化合物(A-1)(200 g，1.0 eq)，THF和二甲氧基膦酰基乙酸叔丁酯(1.2 eq)投入反应瓶，室温搅拌，分批加入60%NaH(1.2 eq)，加毕，室温搅拌3 h，TLC监控反应结束。0℃~10℃缓慢加水淬灭，加入EA搅拌，静置分液，水相用EA提取两次，合并有机相，减压浓缩，得化合物(B-1)，淡黄色液体，收率按100%计算(理论：344g)。
将化合物(B-1)(344 g，1.0 eq)、硝基甲烷(5.0 eq)和DBU(3.0 eq)投入反应瓶中，55±5℃保温搅拌6 h，TLC监控反应结束。降温至15±5℃，滴加磷酸二氢钾的水溶液，静置分液，水相用MTBE提取两次，合并有机相，减压浓缩，石油醚溶解后湿法上样柱层析纯化(PE/EA=100/1)，除去色素和部分杂质，得化合物(C-1)(350 g)，淡黄色液体，收率：80.70%。
向四口瓶中加入氢氧化钾(1.2 eq)和甲醇，室温搅拌溶清，加入化合物(C-1)(320g，1.0 eq)，缓慢滴加高锰酸钾(1.0 eq)的水溶液，放热明显，控制内温低于30 ℃，滴毕，室温反应2 h，TLC监控原料不再减少即为反应终点。向反应体系中加入EA，搅拌后抽滤(硅藻土)，分液；水相用EA提取两次，合并有机相，饱和食盐水洗涤，有机相减压浓缩，得化合物(D-1)(171.4 g)，黄色液体，收率：59.85%，粗品直接用于下一步。MS+=287.1(M+Na)。HNMR(400 MHz, DMSO-d6)δ 9.75 (1H, s), 5.23 (1H, s), 3.03 (1H, s), 2.82-2.72 (1H,m), 2.59-2.53 (2H, m), 2.47-2.40 (2H, m), 2.15-2.03 (3H, m), 1.50-1.40 (1H,m) , 1.34 (9H, s) , 1.04 (3H, t)。其谱图见附图1。
氮气流保护下，向四口瓶中依次加入叔丁醇钾(2.6 eq)和THF，机械搅拌，干冰-乙醇浴降温至-50℃，缓慢滴加TosMIC(1.7 eq)的THF溶液，放热明显，控制内温-50±5℃，加毕，保温搅拌15 min；滴加化合物(D-1)(171.4 g，1.0 eq)的THF溶液；加毕，保温搅拌1 h；控温滴加甲醇，加毕，加热内温至65±5℃，保温反应2 h，LCMS监控反应结束。降温至室温，加入水，搅拌10 min，加入EA，搅拌20 min，静止分液，水相用EA提取一次，合并有机相，减压浓缩(45℃)得粗品化合物(E-1)，深棕色液体，柱层析(PE/EA=100/1)纯化，得化合物(E-1)(40.40 g)，淡黄色液体，收率22.63%。MS+=276.2(M+H)。HNMR(400 MHz, DMSO-d6)δ 5.30(1H, s), 3.00 (1H, s), 2.92-2.81 (3H, m), 2.47-2.40 (1H, m), 2.36-2.25 (2H,m), 2.11-2.10 (2H, m), 2.09-1.99 (2H, m) , 1.52-1.40 (1H, m) , 1.39 (9H, s) ,1.05 (3H, t)。其谱图见附图2。
化合物(E-1)(40.40 g，1.0 eq)、乙二醇和氢氧化钾(10.0 eq)投入反应瓶，搅拌下升温至155±5℃反应4 h，120±5℃反应16 h，LCMS监控反应结束。降温至室温，加入水，滴加6M盐酸溶液，调节pH 1~2，大量固体析出，搅拌后抽滤；滤饼用甲醇溶解，加入活性炭搅拌脱色，抽滤；滤液在机械搅拌下分批加入水，大量固体析出，抽滤；滤饼用石油醚打浆，抽滤；滤饼减压烘干(60℃)，得化合物(F-1)(29.71 g)，土黄色固体，收率：85.00%，HPLC纯度：99.50%。HNMR(400 MHz, DMSO-d6)δ 12.00 (2H, s), 5.30 (1H, s), 3.03 (1H, s),2.81-2.73 (1H, m), 2.65 (1H, s), 2.35-2.44 (3H, m), 2.15-2.05 (3H, m), 1.97(2H, d, J = 16.44 Hz) , 1.42-1.37 (1H, m) , 1.04 (3H, t)。MS+=221.1(M-H2O+H)，MS-=236.9(M-H)。
对比例1：重复专利CN111116345A
将化合物H分批加入到预热至80℃的80%硫酸水溶液中，体系变黑，LCMS监控显示体系有杂质生成；升温至110℃，LCMS显示原料剩余很少，体系复杂；升温至150℃保温2 h，LCMS显示无原料、无产物、无明显中间体，体系黑色粘稠(碳化)。
对比例2：重复专利CN111116345A
将化合物(H)分批加入到预热至60℃的浓盐酸中，LCMS监控显示体系有少量杂质生成；升温至90℃保温3 h，LCMS显示体系略微变杂，无产物；升温至110℃保温3 h，LCMS显示无原料、无产物、无明显中间体。
Claims (10)
1.一种制备式(E)所示结构的方法，包括如下步骤：
其中：
R1选自C1-6烷基；
R2选自C1-6烷基；
步骤(4)：氮气环境下，式(D)化合物在碱和醚类溶剂中与对甲基苯磺酰甲基异腈反应，生成式(E)所示化合物。
2.根据权利要求1所述的制备式(E)所示结构的方法，其特征在于式(D)所示结构通过以下方法制备：
其中：
步骤(1)：式(A)化合物与二甲氧基膦酰基乙酸C1-6烷基酯在碱的作用下进行Wittig-Horner反应生成式(B)化合物；
步骤(2)：将式(B)化合物与硝基甲烷和碱反应生成式(C)化合物；
步骤(3)：投入碱和醇溶剂，溶清后投加式(C)化合物，滴加氧化剂的水溶液，反应生成式(D)化合物。
3.根据权利要求1所述的制备式(E)所示结构的方法，其特征在于：
步骤(4)所述碱选自叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠或碳酸钾；
步骤(4)所述醚类溶剂选自四氢呋喃、1,4-二氧六环、二甲醚或2-甲基四氢呋喃。
4.根据权利要求2所述的制备式(E)所示结构的方法，其特征在于：
步骤(1)所述二甲氧基膦酰基乙酸C1-6烷基酯选自二甲氧基膦酰基乙酸甲酯、二甲氧基膦酰基乙酸乙酯、二甲氧基膦酰基乙酸正丙酯、二甲氧基膦酰基乙酸异丙酯、二甲氧基膦酰基乙酸叔丁酯或二甲氧基膦酰基乙酸正丁酯；
步骤(1)所述碱选自氢化钠、乙醇钠、叔丁醇钾、叔丁醇钠或甲醇钠。
5.根据权利要求4所述的制备式(E)所示结构的方法，其特征在于：
步骤(2)所述碱选自DBN、DBU、TMG、TBD或TEA。
6.根据权利要求5所述的制备式(E)所示结构的方法，其特征在于：
步骤(3)所述碱选自氢氧化钾、氢氧化钠、叔丁醇钾、叔丁醇钠、甲醇钠、氢化钠或碳酸钾；步骤(3)所述醇溶剂选自甲醇、乙醇、异丙醇或叔丁醇；
步骤(3)所述氧化剂选自高锰酸钾、过一硫酸氢钾或过氧化氢。
7.一种制备式(F)所示结构的方法，包括如下步骤：
其中：
步骤(4)：氮气环境下，式(D)化合物在碱和醚类溶剂中与对甲基苯磺酰甲基异腈反应，生成式(E)所示化合物；
步骤(5)：将式(E)所示化合物与乙二醇和碱反应生成式(F)所示结构。
8.根据权利要求7所述的制备式(F)所示结构的方法，其特征在于：
步骤(4)所述碱选自叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠或碳酸钾；
步骤(4)所述醚类溶剂选自四氢呋喃、1,4-二氧六环、二甲醚或2-甲基四氢呋喃；
步骤(5)所述碱选自氢氧化钠或氢氧化钾。
9.一种式(D)的化合物，
其中：
R1选自C1-6烷基；
R2选自C1-6烷基。
10.一种式(E)的化合物，
R1选自C1-6烷基；
R2选自C1-6烷基。
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