CN114805135A - Synthetic method of key intermediate of Sacubitril - Google Patents
Synthetic method of key intermediate of Sacubitril Download PDFInfo
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- CN114805135A CN114805135A CN202210348058.XA CN202210348058A CN114805135A CN 114805135 A CN114805135 A CN 114805135A CN 202210348058 A CN202210348058 A CN 202210348058A CN 114805135 A CN114805135 A CN 114805135A
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- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 title claims abstract description 16
- 229960003953 sacubitril Drugs 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims abstract description 12
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 10
- 239000011592 zinc chloride Substances 0.000 claims abstract description 10
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 10
- 239000012044 organic layer Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910001868 water Inorganic materials 0.000 claims abstract description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims abstract description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims abstract description 5
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000009413 insulation Methods 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- JXTNUXJSXXIIFE-VISDOYDDSA-N (e,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pent-2-enoic acid Chemical compound C1=CC(C[C@H](\C=C(/C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 JXTNUXJSXXIIFE-VISDOYDDSA-N 0.000 claims description 5
- -1 N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate Chemical group 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- NQRAWXHLZGWKRS-FTBISJDPSA-N [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 Chemical compound [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 NQRAWXHLZGWKRS-FTBISJDPSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- TYQICOFAZDVKMK-GOSISDBHSA-N tert-butyl n-[(2r)-1-hydroxy-3-(4-phenylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(C[C@H](CO)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 TYQICOFAZDVKMK-GOSISDBHSA-N 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- ANSSRUHZDLNVIJ-UHFFFAOYSA-N CCOC(=O)C(C)P(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CCOC(=O)C(C)P(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ANSSRUHZDLNVIJ-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- WKGDNXBDNLZSKC-UHFFFAOYSA-N oxido(phenyl)phosphanium Chemical compound O=[PH2]c1ccccc1 WKGDNXBDNLZSKC-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种沙库巴曲关键中间体的合成方法，包括以下步骤：室温下水、溴化钠、碳酸氢钠、醋酸异丙酯、N‑[(1R)‑2‑[1,1'‑联苯]‑4‑基‑1‑(羟基甲基)乙基]氨基甲酸叔丁酯混合；低温加入2,2,6,6‑四甲基哌啶氧化物、次氯酸钠溶液保温反应；加入硫代硫酸钠溶液淬灭反应，取有机层；向有机层中加入2‑(三苯基膦亚基)丙酸乙酯，室温下反应；反应完毕后，加入氯化锌，保温搅拌，过滤，收集滤液，减压蒸馏，所得固体进行下一步反应；所得固体加入乙醇中溶解，升温，加入氢氧化钠溶液，保温反应；反应完毕后过滤，滤液用醋酸溶液调pH至弱酸性，降温析晶，过滤，洗涤干燥得到目前产物，即(R,E)‑5‑([1,1'‑联苯]‑4‑基)‑4‑((叔丁氧羰基)氨基)‑2‑甲基‑2‑戊烯酸。
The invention relates to a method for synthesizing a key intermediate of sacubitril, comprising the following steps: water at room temperature, sodium bromide, sodium bicarbonate, isopropyl acetate, N-[(1R)-2-[1,1' -biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate mixing; adding 2,2,6,6-tetramethylpiperidine oxide, sodium hypochlorite solution at low temperature for insulation reaction; adding Sodium thiosulfate solution was used to quench the reaction, and the organic layer was taken; 2-(triphenylphosphineidene) ethyl propionate was added to the organic layer, and the reaction was carried out at room temperature; after the reaction was completed, zinc chloride was added, kept stirring, and filtered. , the filtrate was collected, distilled under reduced pressure, and the obtained solid was subjected to the next step of reaction; the obtained solid was dissolved in ethanol, the temperature was increased, sodium hydroxide solution was added, and the reaction was kept warm; after the reaction was completed, the filtrate was filtered, and the pH of the filtrate was adjusted to weakly acidic with acetic acid solution, and the temperature was cooled and analyzed. crystallized, filtered, washed and dried to obtain the current product, namely (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl base-2-pentenoic acid.
Description
技术领域technical field
本发明涉及化合物合成技术领域，具体指一种沙库巴曲关键中间体的合成方法。The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing a key intermediate of sacubitril.
背景技术Background technique
沙库巴曲缬沙坦钠片，又名诺欣妥，由诺华开发，用于治疗射血分数降低的慢性心力衰竭成人患者，能降低心血管死亡和心力衰竭住院的风险。沙库巴曲缬沙坦钠由沙库巴曲和缬沙坦组合而成，其中沙库巴曲的结构式如式1所示，其化学名为4-(((2S,4R)-1-([1,1’-二苯基]-4-基)-5-乙氧基-4-甲基-5-氧代-2-戊基)-氨基)-4-氧代丁酸。Sacubitril and Valsartan Sodium Tablets, also known as Nuoxintuo, were developed by Novartis for the treatment of adults with chronic heart failure and reduced ejection fraction, which can reduce the risk of cardiovascular death and heart failure hospitalization. Sacubitril and valsartan sodium is composed of sacubitril and valsartan, wherein the structural formula of sacubitril is shown in
在沙库巴曲合成过程中，(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基-2-戊烯酸是关键的中间体之一，结构式如式Ⅳ所示。During the synthesis of sacubitril, (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl- 2-Pentenoic acid is one of the key intermediates, and its structural formula is shown in formula IV.
现有专利CN106431993B公开了化合物式Ⅳ的合成路线，如图1所示，醋酸异丙酯、化合物式Ⅰ溴化钠依次加入到反应釜中，20-35℃下搅拌20-40min，加入2,2,6,6-四甲基哌啶氧化物(以下称为TEMPO)，向其中快速滴加NaHCO3-NaClO水溶液，恒温在10-35℃反应1-5h得到化合物式Ⅱ，滴加硫代硫酸钠终止反应，用NaHCO3水溶液和NaCl水溶液洗涤得到化合物式Ⅱ的醋酸异丙酯溶液；向其中加入磷叶立德，30-35℃反应1h，加入一水柠檬酸终止反应，得到化合物式Ⅲ的有机溶液；加入氢氧化锂，78-82℃保温反应1h，降温析晶，抽滤得到化合物式Ⅳ。Existing patent CN106431993B discloses the synthetic route of compound formula IV, as shown in Figure 1, isopropyl acetate and compound formula I sodium bromide are successively added to the reactor, stirred at 20-35 ° C for 20-40min, add 2, 2,6,6-Tetramethylpiperidine oxide (hereinafter referred to as TEMPO), to which NaHCO 3 -NaClO aqueous solution was rapidly added dropwise, and the reaction was performed at a constant temperature of 10-35 ° C for 1-5 h to obtain compound formula II, and thiocyanate was added dropwise. The reaction was terminated with sodium sulfate, washed with NaHCO 3 aqueous solution and NaCl aqueous solution to obtain the isopropyl acetate solution of compound formula II; phosphorus ylide was added thereto, reacted at 30-35 ° C for 1 h, and citric acid monohydrate was added to terminate the reaction to obtain compound formula III Organic solution; Lithium hydroxide is added, the reaction is kept at 78-82° C. for 1 h, the temperature is lowered for crystallization, and the compound formula IV is obtained by suction filtration.
在上述工艺中，得到的化合物式Ⅳ的纯度较低，且在分离过程中抽滤困难，这是由于体系存在大量的副产物三苯基氧膦(即化合物式Ⅱ到化合物式Ⅲ的wittig反应的副产物)，与化合物式Ⅳ共同析出，造成滤饼粘稠，不利于生产操作，直接影响了产物的纯度。In the above-mentioned process, the purity of the compound formula IV obtained is relatively low, and suction filtration is difficult in the separation process, because a large amount of by-product triphenylphosphine oxide (that is, the wittig reaction of compound formula II to compound formula III) exists in the system. The by-product), co-precipitated with the compound formula IV, resulting in a viscous filter cake, which is not conducive to production operations, and directly affects the purity of the product.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是针对现有技术的现状，提供一种通过控制反应过程中三苯基氧膦的量从而提高产物纯度的沙库巴曲关键中间体的合成方法。The technical problem to be solved by the present invention is to provide a synthesis method of the key intermediate of sacubitril which improves the purity of the product by controlling the amount of triphenylphosphine oxide in the reaction process.
本发明解决上述技术问题所采用的技术方案为：The technical scheme adopted by the present invention to solve the above-mentioned technical problems is:
一种沙库巴曲关键中间体的合成方法，包括以下步骤：A synthetic method of a key intermediate of Sacubitril, comprising the following steps:
(1)在室温下，将水、溴化钠、碳酸氢钠加入反应器中，搅拌溶解；(1) at room temperature, add water, sodium bromide, sodium bicarbonate into the reactor, stir and dissolve;
在室温下，向上述溶液中加入醋酸异丙酯、N-[(1R)-2-[1,1'-联苯]-4-基-1-(羟基甲基)乙基]氨基甲酸叔丁酯，搅拌；To the above solution was added isopropyl acetate, tertiary N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate at room temperature Butyl ester, stirring;
在低温下，向上述溶液中2,2,6,6-四甲基哌啶氧化物、次氯酸钠溶液，保温反应；At low temperature, 2,2,6,6-tetramethylpiperidine oxide and sodium hypochlorite solution are added to the above solution, and the reaction is incubated;
(2)反应完毕后，加入硫代硫酸钠溶液淬灭反应，降至室温下，分层，取有机层进行下一步反应；(2) after the completion of the reaction, add sodium thiosulfate solution to quench the reaction, drop to room temperature, layer by layer, take the organic layer and carry out the next step reaction;
(3)在室温下，向有机层中加入2-(三苯基膦亚基)丙酸乙酯，在室温下反应；(3) at room temperature, add 2-(triphenylphosphinoidene) ethyl propionate to the organic layer, and react at room temperature;
反应完毕后，加入氯化锌，保温搅拌，过滤，收集滤液，减压蒸馏，所得固体进行下一步反应；After the completion of the reaction, zinc chloride was added, kept stirring, filtered, the filtrate was collected, distilled under reduced pressure, and the obtained solid was subjected to the next step reaction;
(4)所得固体加入乙醇中溶解，升温，加入氢氧化钠溶液，保温反应；(4) gained solid is added in ethanol to dissolve, heat up, add sodium hydroxide solution, insulation reaction;
反应完毕后过滤，滤液用醋酸溶液调pH至弱酸性，降温析晶，过滤，洗涤干燥得到目前产物，即(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基-2-戊烯酸。After the reaction is completed, filter, adjust the pH of the filtrate to weak acidity with acetic acid solution, cool down and crystallize, filter, wash and dry to obtain the current product, namely (R,E)-5-([1,1'-biphenyl]-4-yl )-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid.
步骤(4)中，保温反应的反应温度为30～50℃，反应完毕后过滤，滤液用醋酸溶液调pH至5～7，降温析晶，用水洗涤干燥得到化合物式Ⅳ。In step (4), the reaction temperature of the insulation reaction is 30-50° C., after the reaction is completed, filter the filtrate, adjust the pH of the filtrate to 5-7 with an acetic acid solution, cool down for crystallization, wash and dry with water to obtain compound formula IV.
优选地，步骤(1)中所述的低温为-10～10℃。Preferably, the low temperature in step (1) is -10-10°C.
优选地，步骤(3)中，2-(三苯基膦亚基)丙酸乙酯与氯化锌的当量比为1:(0.3～1.0)进一步优选为1:0.4。Preferably, in step (3), the equivalent ratio of ethyl 2-(triphenylphosphino)propionate to zinc chloride is 1:(0.3-1.0), more preferably 1:0.4.
本发明将碳酸氢钠与次氯酸钠分开添加，且碳酸氢钠是在室温下添加，次氯酸钠是在低温下添加，一方面可以防止产业化过程中热量积累而温度飙升的风险，另一方面也可以抑制过氧化副产物的生成。In the present invention, sodium bicarbonate and sodium hypochlorite are added separately, and sodium bicarbonate is added at room temperature, and sodium hypochlorite is added at low temperature. On the one hand, it can prevent the risk of heat accumulation and temperature soaring in the industrialization process, and on the other hand, it can also inhibit the Formation of peroxide by-products.
与现有技术相比，本发明的优点在于：本发明使用一锅三步法，大大节省了反应时间，简化了操作工艺；步骤(3)中反应完毕后加入氯化锌，将大部分三苯基氧膦络合成盐，通过简单的过滤可以有效除去三苯基氧膦杂质，使得合成反应可操作性强，易于产业化，且产物为类白色粉末，无需精制，有效提高了产物纯度。Compared with the prior art, the advantages of the present invention are: the present invention uses a one-pot three-step method, which greatly saves the reaction time and simplifies the operation process; in step (3), after the reaction is completed, zinc chloride is added, and most of the three Phenylphosphine oxide complex salts can effectively remove triphenylphosphine oxide impurities through simple filtration, which makes the synthesis reaction strong and easy to industrialize, and the product is off-white powder without refining, which effectively improves the purity of the product .
附图说明Description of drawings
图1为本发明背景技术的合成路线图；Fig. 1 is the synthetic route diagram of the background technology of the present invention;
图2为本发明实施例1所得产物的HPLC图谱；Fig. 2 is the HPLC collection of illustrative plates of the product obtained in Example 1 of the present invention;
图3为本发明实施例2所得产物的HPLC图谱。Figure 3 is the HPLC spectrum of the product obtained in Example 2 of the present invention.
具体实施方式Detailed ways
以下结合附图实施例对本发明作进一步详细描述。The present invention will be further described in detail below with reference to the embodiments of the accompanying drawings.
实施例1：Example 1:
本实施例中沙库巴曲关键中间体的合成方法，包括以下步骤：The synthetic method of Sacubitril key intermediate in the present embodiment, comprises the following steps:
室温下向反应瓶中加入10g水、2.35g溴化钠、1.54g碳酸氢钠，搅拌10min；Add 10g water, 2.35g sodium bromide, 1.54g sodium bicarbonate to the reaction flask at room temperature, and stir for 10min;
加入54.4g醋酸异丙酯、5g N-[(1R)-2-[1,1'-联苯]-4-基-1-(羟基甲基)乙基]氨基甲酸叔丁酯，搅拌10min；Add 54.4g isopropyl acetate, 5g N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid tert-butyl ester, stir for 10min ;
降温至-5～5℃，滴加次氯酸钠溶液(浓度为3.8％，65g)，反应1h；Cool down to -5～5℃, add sodium hypochlorite solution (concentration: 3.8%, 65g) dropwise, and react for 1h;
反应完毕后，加入硫代硫酸钠溶液(浓度为33％，9g)淬灭反应；静置分层，取有机层进行下一步反应；After the completion of the reaction, sodium thiosulfate solution (concentration of 33%, 9 g) was added to quench the reaction;
室温下向有机层中加入5.8g 2-(三苯基膦亚基)丙酸乙酯，反应3h；5.8g of ethyl 2-(triphenylphosphinoidene)propionate was added to the organic layer at room temperature, and the reaction was carried out for 3h;
反应完毕后，加入1g氯化锌搅拌1h，过滤后的滤液减压蒸馏，得到固体用于下一步反应；After the completion of the reaction, 1 g of zinc chloride was added and stirred for 1 h, and the filtered filtrate was distilled under reduced pressure to obtain a solid for the next reaction;
所得固体加入乙醇溶解，加热至45℃，滴加氢氧化钠溶液(浓度为17.6％，24g)反应3h；The obtained solid was dissolved in ethanol, heated to 45°C, and sodium hydroxide solution (concentration: 17.6%, 24g) was added dropwise to react for 3h;
反应完毕后过滤，用乙醇洗涤，45℃下滴加冰醋酸(浓度为12％)调pH至5～7；降温至0℃搅拌1h过滤，水洗，滤饼真空干燥得到目标产物(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基-2-戊烯酸，收率82.7％；如图2所示，色谱纯度98.92％。After the reaction is completed, filter, wash with ethanol, add glacial acetic acid (concentration 12%) dropwise at 45 ° C to adjust pH to 5-7; cool to 0 ° C, stir for 1 h, filter, wash with water, and vacuum dry the filter cake to obtain the target product (R, E )-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid, yield 82.7%; as shown in the figure 2, the chromatographic purity was 98.92%.
实施例2：Example 2:
本实施例中沙库巴曲关键中间体的合成方法，包括以下步骤：The synthetic method of Sacubitril key intermediate in the present embodiment, comprises the following steps:
室温下向反应瓶中加入10g水、2.35g溴化钠、1.54g碳酸氢钠，搅拌10min；Add 10g water, 2.35g sodium bromide, 1.54g sodium bicarbonate to the reaction flask at room temperature, and stir for 10min;
加入54.4g醋酸异丙酯、5g N-[(1R)-2-[1,1'-联苯]-4-基-1-(羟基甲基)乙基]氨基甲酸叔丁酯，搅拌10min；Add 54.4g isopropyl acetate, 5g N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid tert-butyl ester, stir for 10min ;
降温至-5～5℃，滴加次氯酸钠溶液(浓度为3.8％，65g，反应1h；Cool to -5～5℃, add dropwise sodium hypochlorite solution (concentration is 3.8%, 65g, react for 1h;
反应完毕后，加入硫代硫酸钠溶液(浓度为33％，9g)淬灭反应；静置分层，取有机层进行下一步反应；After the completion of the reaction, sodium thiosulfate solution (concentration of 33%, 9 g) was added to quench the reaction;
室温下向有机层中加入5.8g 2-(三苯基膦亚基)丙酸乙酯，反应3h；5.8g of ethyl 2-(triphenylphosphinoidene)propionate was added to the organic layer at room temperature, and the reaction was carried out for 3h;
反应完毕后，加入2g氯化锌搅拌1h，过滤后的滤液减压蒸馏，得到固体用于下一步反应；After the completion of the reaction, 2 g of zinc chloride was added and stirred for 1 h, and the filtered filtrate was distilled under reduced pressure to obtain a solid for the next reaction;
所得固体加入乙醇溶解，加热至45℃，滴加氢氧化钠溶液(浓度为17.6％，24g)反应3h；The obtained solid was dissolved in ethanol, heated to 45°C, and sodium hydroxide solution (concentration: 17.6%, 24g) was added dropwise to react for 3h;
反应完毕后过滤，用乙醇洗涤，45℃下滴加冰醋酸(浓度为12％)调pH至5～7；降温至0℃搅拌1h过滤，水洗，滤饼真空干燥得到目标产物(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基-2-戊烯酸，收率82.7％；如图3所示，色谱纯度99.05％。After the reaction is completed, filter, wash with ethanol, add glacial acetic acid (concentration 12%) dropwise at 45 ° C to adjust pH to 5-7; cool to 0 ° C, stir for 1 h, filter, wash with water, and vacuum dry the filter cake to obtain the target product (R, E )-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid, yield 82.7%; as shown in the figure 3, the chromatographic purity was 99.05%.
对比本发明的实施例1与实施例2，可以看出，氯化锌的添加量对于目标产物纯度的提高来说非常关键，当2-(三苯基膦亚基)丙酸乙酯与氯化锌的当量比为1:0.4时，可获得非常理想的纯度，高达99.05％。Comparing Example 1 and Example 2 of the present invention, it can be seen that the addition amount of zinc chloride is very critical for the improvement of the purity of the target product. When the equivalence ratio of zinc oxide is 1:0.4, a very ideal purity can be obtained, up to 99.05%.
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| CN106431993A (en) * | 2016-09-14 | 2017-02-22 | 重庆市碚圣医药科技股份有限公司 | Method for preparing LCZ-696 key intermediate |
| CN106946742A (en) * | 2017-03-28 | 2017-07-14 | 常州沃腾化工科技有限公司 | A kind of preparation method of the bent intermediates of the low Sha Kubi of triphenylphosphinc oxide content |
| AU2018305416A1 (en) * | 2017-07-27 | 2019-05-30 | Jiangsu Zhongbang Pharmaceutical Co.,Ltd. | Method for preparing sacubitril intermediate |
| CN112158977A (en) * | 2020-09-07 | 2021-01-01 | 湖北凌晟药业有限公司 | Treatment method of triphenylphosphine oxide-containing wastewater |
| CN112409409A (en) * | 2020-11-25 | 2021-02-26 | 湖北凌晟药业有限公司 | Recovery method of triphenylphosphine oxide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106431993A (en) * | 2016-09-14 | 2017-02-22 | 重庆市碚圣医药科技股份有限公司 | Method for preparing LCZ-696 key intermediate |
| CN106946742A (en) * | 2017-03-28 | 2017-07-14 | 常州沃腾化工科技有限公司 | A kind of preparation method of the bent intermediates of the low Sha Kubi of triphenylphosphinc oxide content |
| AU2018305416A1 (en) * | 2017-07-27 | 2019-05-30 | Jiangsu Zhongbang Pharmaceutical Co.,Ltd. | Method for preparing sacubitril intermediate |
| CN112158977A (en) * | 2020-09-07 | 2021-01-01 | 湖北凌晟药业有限公司 | Treatment method of triphenylphosphine oxide-containing wastewater |
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