CN114436877B - Synthesis process of heart failure resistant medicine Sha Kuba yeast - Google Patents
Synthesis process of heart failure resistant medicine Sha Kuba yeast Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 18
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 240000004808 Saccharomyces cerevisiae Species 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 16
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960002317 succinimide Drugs 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 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 description 17
- 238000002360 preparation method Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 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 description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 229940117803 phenethylamine Drugs 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- IYAMYECUTLASCU-UHFFFAOYSA-L disodium;ethanol;carbonate Chemical compound [Na+].[Na+].CCO.[O-]C([O-])=O IYAMYECUTLASCU-UHFFFAOYSA-L 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 10
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 12
- 238000004537 pulping Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 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
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960004699 valsartan Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis process of heart failure resistant medicine Sha Kuba yeast, which comprises the following specific steps: (1) Reacting the compound V with ethanol in the presence of concentrated sulfuric acid to generate a compound VI; (2) The compound VI and succinimide undergo Michael addition reaction in the presence of alkali to generate a compound VII; (3) hydrolyzing the compound VII to generate a compound I; i.e. said Sha Kuba curve. The synthesis process has the advantages of easily obtained starting materials, simple operation, small pollution in the whole synthesis process, easy separation and purification, convenient dosage amplification for realizing industrial production, higher yield of target products and lower synthesis cost.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a synthesis process of heart failure resistant medicine Sha Kuba yeast.
Background
Sha Kuba triptan (entrestro) is a salt complex of Sha Kuba and valsartan combined in a 1:1 molar ratio, month 7 of 2015, sha Kuba starter/valsartan sodium was FDA approved in the united states; for 5 months 2016, europe and the United states updated heart failure guidelines, respectively, sha Kuba Qu/valsartan was used as an analogy to heart failure I. Sha Kuba starter/valsartan sodium in 2017 is marketed in China, and an anti-heart failure guide in China is written in 2018.
Sha Kuba the one of the main components of Sha Kuba troxalatan (entrestro) is chemically named 4- (((2 s,4 r) -1- ([ 1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopropan-2-yl) amino) -4-oxobutanoic acid.
The preparation method of Sha Kuba koji has been reported in many researches, wherein U.S. Pat. No. 5217996 and International patent WO2008031567 report a synthetic route of sabobaqu, and target products are prepared by taking chiral amino alcohol as a raw material, oxidizing the chiral amino alcohol into aldehyde, wittig reaction, chiral hydrogenation, amidation and other reactions. The route is a main process route for synthesizing Sha Kuba yeast at present, the cost of the starting materials of the route is high, and high-risk reactions such as oxidation, hydrogenation and the like are needed, so that the route is not beneficial to industrial scale-up production.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis process of heart failure resistant medicine Sha Kuba yeast. The synthesis process has the advantages of easily obtained starting materials, simple operation, small pollution in the whole synthesis process, easy separation and purification, convenient dosage amplification for realizing industrial production, higher yield of target products and lower synthesis cost.
The technical scheme of the invention is as follows:
A synthesis process of heart failure resistant medicine Sha Kuba yeast is carried out according to the following route:
The method comprises the following specific steps:
(1) Reacting the compound V with ethanol in the presence of concentrated sulfuric acid to generate a compound VI;
preferably, the concentration of the concentrated sulfuric acid is 18mol/L;
Preferably, the molar ratio of the compound V to the concentrated sulfuric acid is 1:0.05-0.1; the reaction condition is that the reaction is carried out for 3-6 hours at 70-80 ℃.
(2) The compound VI and succinimide undergo Michael addition reaction in the presence of alkali to generate a compound VII;
Preferably, the molar ratio of the compound VI to the succinimide is 1:1-1.2; the alkali is one or more of potassium carbonate, sodium methoxide, sodium hydroxide and potassium hydroxide; the molar ratio of the compound VI to the alkali is 1:1-1.2.
Preferably, the solvent for the Michael addition reaction is one or more of tetrahydrofuran, dioxane, N-dimethylformamide; the reaction temperature is 60-80 ℃ and the reaction time is 3-6h.
(3) Hydrolyzing the compound VII to generate a compound I; i.e. said Sha Kuba curve.
Preferably, the hydrolysis reaction is carried out in aqueous sodium carbonate ethanol; the hydrolysis temperature is 20-50 ℃ and the hydrolysis time is 3-6h.
Further preferably, in step (1), the preparation method of the compound V is:
s1, reacting a compound II with thionyl chloride to generate a compound III;
The molar ratio of the compound II to the thionyl chloride is 1:1.1-1.2; the solvent for the reaction is one or a mixture of two of dichloromethane and dichloroethane; the reaction temperature is 40-60 ℃ and the reaction time is 2-6h.
S2, condensing the compound III with R-phenethylamine to generate a compound IV;
The mol ratio of the compound III to the R-phenethylamine is 1:1-1.2; the solvent for the reaction is one or a mixture of two of dichloromethane and dichloroethane; the reaction temperature is 20-40 ℃ and the reaction time is 2-6h;
The reaction system also comprises a triethylamine acid binding agent, and the mol ratio of the compound III to the triethylamine is 1:1-1.2.
S3, hydrolyzing the compound IV under a sulfuric acid system to generate a compound V.
The molar ratio of the compound IV to sulfuric acid is 1:2-10; the concentration of sulfuric acid is 3mol/L to 6mol/L; the solvent for hydrolysis reaction is one or two of tetrahydrofuran and dioxane; the temperature of the hydrolysis reaction is 60-80 ℃ and the time is 3-6h.
Further preferred, the key starting material compound II is synthesized by the following route:
The p-phenyl benzaldehyde is used as a starting material, and the target compound is generated through Wittig reaction, reduction, chlorination, substitution and decarboxylation, so that the starting material has low cost and high reaction yield.
The beneficial technical effects of the invention are as follows:
The method avoids high-risk reactions such as Grignard reaction, oxidation and the like in the synthetic route process, effectively avoids potential risks brought by genotoxic impurities such as epichlorohydrin and the like in a finished product, ensures that the yield of the compound IV through making epimers, racemization and recrystallization can reach more than 76%, does not use expensive chiral prosthetic groups to construct a second chiral center, and has low cost; meanwhile, the chiral reagent R-phenethylamine is low in price and can be recycled. The compound VII is prepared into epimers through Michael addition, the operation is simple, and the method is ingenious.
The method has the advantages of easily obtained starting materials, simple operation, small pollution in the whole synthesis process, easy separation and purification, higher yield and diastereoselectivity, convenience for amplifying the dosage to realize industrial production, and higher chiral purity of the obtained sakur than the starter intermediate. In the process of further preparing the sarcandra-base koji, complicated steps such as separation and the like are omitted, and the production efficiency is improved.
Drawings
FIG. 1 is a schematic illustration of the synthesis process of the present invention;
FIG. 2 is a 1 H-NMR spectrum of Sha Kuba% of the curve obtained in example 1;
FIG. 3 is an HPLC chromatogram of Sha Kuba% of the curve obtained in example 1.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples.
Example 1
A synthesis process of heart failure resistant medicine Sha Kuba yeast comprises the following specific steps:
(1) Preparation of Compound V
S1, 266g (1 mol) of compound II,1000ml of dichloromethane and 143g (1.2 mol) of thionyl chloride are added into a reaction bottle, the mixture is heated to 40 ℃ and stirred for 4 hours under reflux, and the reaction is tracked by HPLC until the compound II is completely reacted; the reaction mixture was concentrated to obtain 298g of compound III in molar yield: 105%.
S2, adding 1000ml of dichloromethane, 298g (1 mol) of compound III,121g (1.2 mol) of triethylamine, dropwise adding 121g of R-phenethylamine (1 mol) at 20 ℃, stirring for 2 hours, and tracking the reaction by HPLC until the reaction of the compound III is complete; washing the organic layer with 1M dilute hydrochloric acid, washing with saturated sodium chloride, concentrating, pulping with 1000ml toluene to obtain 147g of compound IV, racemizing the mother liquor with sodium hydroxide aqueous solution, extracting with dichloromethane, concentrating, pulping with 1000ml toluene to obtain 135g of compound IV, and purifying twice to obtain 282g of compound IV with molar yield: 76.4%.
S3, adding 1000ml of dioxane, 184.5g (0.5 mol) of compound IV,3mol/L sulfuric acid 1666ml (5 mol) of 80 ℃ and stirring for 4 hours, and tracking the reaction by HPLC until the reaction of the compound IV is complete; concentrating, pulping by adding water, filtering and drying to obtain 130g of compound V, and molar yield: 97.7%.
(2) Preparation of Compound VI
1000Ml of ethanol, 100g (0.376 mol) of compound V,1.84g of concentrated sulfuric acid (18.8 mmol) at 80℃were added to the flask and stirred for 4 hours, and the reaction was followed by HPLC until the reaction of compound V was complete; concentrating, pulping by adding water, filtering and drying to obtain 109g of compound V, and molar yield: 98.6%.
(3) Preparation of Compound VII
To the reaction flask was added 500ml of tetrahydrofuran, 58.8g (0.2 mol) of compound VI,19.8g (0.2 mol) of succinimide, 21.2g of sodium carbonate (0.2 mol), stirred at 80℃for 6 hours, and the reaction was followed by HPLC until the reaction of compound VI was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing with ethyl acetate to obtain 31.4g of compound V with molar yield: 40%.
(4) Preparation of Compound I
200Ml of ethanol, 100ml of water, 20g (51 mmol) of compound VI,5.4g (51 mmol) of sodium carbonate and stirring at 20℃for 6 hours were added to the reaction flask, and the reaction was followed by HPLC until the reaction of compound VII was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing ethyl acetate to obtain 16.7g of compound I, namely Sha Kuba g of the compound I, wherein the molar yield is as follows: 80%.
FIG. 2 shows the hydrogen spectrum of the compound I prepared in this example ,1H-NMR(400MHz,CDCl3)δ:7.56(dq,J=2.6、1.7Hz,2H),7.51(d,J=8.2Hz,2H),7.46-7.39(m,2H),7.35-7.28(m,1H),7.23(d,J=8.2Hz,2H),5.90(d,J=8.6Hz,1H),4.24(d,J=3.2Hz,1H),4.12(q,J=7.1Hz,2H),2.93-2.76(m,2H),2.69-2.60(m,2H),2.59-2.50(m,1H),2.42(t,J=6.5Hz,2H),1.93(ddd,J=13.8、9.4、4.2Hz,1H),1.59-1.48(m,1H),1.27-1.20(m,3H),1.15(d,J=7.1Hz,3H).
FIG. 3 is a liquid chromatogram of compound I obtained in this example, showing that the relative retention time of compound I is 10.433min, and the purity of the main content is 98.93%.
Example 2
A synthesis process of heart failure resistant medicine Sha Kuba yeast comprises the following specific steps:
(1) Preparation of Compound V
S1, 266g (1 mol) of compound II,1000ml of dichloromethane and 131g (1.1 mol) of thionyl chloride are added into a reaction bottle, the mixture is heated, refluxed and stirred for 6 hours, and the reaction is tracked by HPLC until the compound II is completely reacted; the reaction mixture was concentrated to give 297.8g of Compound III in molar yield: 105%.
S2, 1000ml of dichloromethane, 297.8g (1 mol) of compound III,101g (1.0 mol) of triethylamine, 121g R-phenethylamine (1 mol) dropwise at 30 ℃ and stirring for 6 hours are added into a reaction bottle, and the reaction is tracked by HPLC until the reaction of the compound III is complete; washing an organic layer by using 1M dilute hydrochloric acid, washing by using saturated sodium chloride, concentrating, adding 1000ml of toluene, pulping to obtain 146.5g of a compound IV, racemizing a mother solution by using a sodium hydroxide aqueous solution, extracting by using methylene dichloride, concentrating, pulping by using 1000ml of toluene to obtain 134g of the compound IV, purifying twice to obtain 280.5g of the compound IV, and obtaining the molar yield: 76%.
S3, adding 1000ml of dioxane, 184.5g (0.5 mol) of compound IV, 166ml (1 mol) of 6mol/L sulfuric acid and stirring at 80 ℃ for 3 hours, and tracking the reaction by HPLC until the reaction of the compound IV is complete; concentrating, pulping by adding water, filtering and drying to obtain 128g of compound V, and molar yield: 96.2%.
(2) Preparation of Compound VI
1000Ml of ethanol, 100g (0.376 mol) of compound V,1.84g of concentrated sulfuric acid (18.8 mmol) at 70℃were added to the flask and stirred for 6 hours, and the reaction was followed by HPLC until the reaction of compound V was complete; concentrating, pulping by adding water, filtering and drying to obtain 107g of compound V, and molar yield: 96.8%.
(3) Preparation of Compound VII
To the reaction flask was added 500ml of tetrahydrofuran, 58.8g (0.2 mol) of compound VI,19.8g (0.2 mol) of succinimide, 27.6g of potassium carbonate (0.2 mol), stirred at 70℃for 4 hours, and the reaction was followed by HPLC until the reaction of compound VI was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing ethyl acetate to obtain 32.3g of compound V with molar yield: 41%.
(4) Preparation of Compound I
200Ml of ethanol, 100ml of water, 20g (51 mmol) of compound VI,5.4g (51 mmol) of sodium carbonate, and stirring at 30℃for 4 hours were added to the reaction flask, and the reaction was followed by HPLC until the reaction of compound VII was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing ethyl acetate to obtain 14.6g of compound I, namely Sha Kuba g of the compound I, wherein the molar yield is as follows: 70%.
Example 3
A synthesis process of heart failure resistant medicine Sha Kuba yeast comprises the following specific steps:
(1) Preparation of Compound V
S1, 266g (1 mol) of compound II,1000ml of dichloromethane and 131g (1.1 mol) of thionyl chloride are added into a reaction bottle, the mixture is heated, refluxed and stirred for 2 hours, and the reaction is tracked by HPLC until the compound II is completely reacted; the reaction mixture was concentrated to obtain 298g of compound III in molar yield: 105%.
S2, adding 1000ml of dichloromethane, 298g (1 mol) of compound III,111g (1.1 mol) of triethylamine, dropwise adding 121g R-phenethylamine (1 mol) at 40 ℃, stirring for 4 hours, and tracking the reaction by HPLC until the reaction of the compound III is complete; washing the organic layer with 1M dilute hydrochloric acid, washing with saturated sodium chloride, concentrating, pulping with 1000ml toluene to obtain 147g of compound IV, racemizing the mother liquor with sodium hydroxide aqueous solution, extracting with dichloromethane, concentrating, pulping with 1000ml toluene to obtain 133.5g of compound IV, purifying twice to obtain 280.5g of compound IV, and obtaining the molar yield: 76.7%.
S3, adding 1000ml of dioxane, 184.5g (0.5 mol) of compound IV, and 750ml (3 mol) of 4mol/L sulfuric acid at 60 ℃ to a reaction bottle, stirring for 6 hours, and tracking the reaction by HPLC until the reaction of the compound IV is complete; concentrating, pulping by adding water, filtering and drying to obtain 125g of compound V, and molar yield: 93.9%.
(2) Preparation of Compound VI
1000Ml of ethanol, 100g (0.376 mol) of Compound V,3.68g of concentrated sulfuric acid (37.6 mmol) at 70℃were added to the flask and stirred for 3 hours, followed by HPLC until the reaction of Compound V was complete; concentrating, pulping by adding water, filtering and drying to obtain 110g of compound V, and molar yield: 99.5%.
(3) Preparation of Compound VII
To the reaction flask was added 500ml of tetrahydrofuran, 58.8g (0.2 mol) of Compound VI,19.8g (0.2 mol) of succinimide, 8g of sodium hydroxide (0.2 mol), stirred at 60℃for 3 hours, and the reaction was followed by HPLC until the reaction of Compound VI was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing with ethyl acetate to obtain 26g of compound V with molar yield: 33%.
(4) Preparation of Compound I
200Ml of ethanol, 100ml of water, 20g (51 mmol) of compound VI,5.4g (51 mmol) of sodium carbonate and stirring at 50℃for 3 hours were added to the reaction flask, and the reaction was followed by HPLC until the reaction of compound VII was complete; quenching into dilute hydrochloric acid, filtering, and recrystallizing ethyl acetate to obtain 12.9g of compound I, namely Sha Kuba g of the compound I, wherein the molar yield is as follows: 62%.
Claims (8)
1. The synthesis process of the heart failure resistant medicine Sha Kuba is characterized by comprising the following steps of:
The method comprises the following specific steps:
(1) Reacting the compound V with ethanol in the presence of concentrated sulfuric acid to generate a compound VI;
(2) The compound VI and succinimide undergo Michael addition reaction in the presence of alkali,
Generating a compound VII;
(3) Hydrolyzing the compound VII to generate a compound I; i.e. said Sha Kuba curve;
in the step (1), the preparation method of the compound V comprises the following steps:
s1, reacting a compound II with thionyl chloride to generate a compound III;
S2, condensing the compound III with R-phenethylamine to generate a compound IV;
S3, hydrolyzing the compound IV under a sulfuric acid system to generate a compound V.
2. The synthetic process of claim 1 wherein in step (1), the concentration of concentrated sulfuric acid is 18mol/L; the molar ratio of the compound V to the concentrated sulfuric acid is 1:0.05-0.1; the reaction condition is that the reaction is carried out for 3-6 hours at 70-80 ℃.
3. The synthetic process according to claim 1, wherein in step S1, the molar ratio of compound II to thionyl chloride is 1:1.1-1.2; the solvent for the reaction is one or a mixture of two of dichloromethane and dichloroethane; the reaction temperature is 40-60 ℃ and the reaction time is 2-6h.
4. The synthetic process according to claim 1, wherein in step S2, the molar ratio of compound III to R-phenethylamine is 1:1-1.2; the solvent for the reaction is one or a mixture of two of dichloromethane and dichloroethane; the reaction temperature is 20-40 ℃ and the reaction time is 2-6h; the reaction system also comprises a triethylamine acid binding agent, and the mol ratio of the compound III to the triethylamine is 1:1-1.2.
5. The synthetic process of claim 1 wherein in step S3, the molar ratio of compound IV to sulfuric acid is 1:2-10; the concentration of sulfuric acid is 3mol/L-6mol/L; the solvent for hydrolysis reaction is one or two of tetrahydrofuran and dioxane; the temperature of the hydrolysis reaction is 60-80 ℃ and the time is 3-6h.
6. The synthetic process of claim 1 wherein in step (2), the molar ratio of compound VI to succinimide is 1:1-1.2; the alkali is one or more of potassium carbonate, sodium methoxide, sodium hydroxide and potassium hydroxide; the molar ratio of the compound VI to the alkali is 1:1-1.2.
7. The synthetic process of claim 1 wherein in step (2), the solvent for the michael addition reaction is one or more of tetrahydrofuran, dioxane, N-dimethylformamide; the reaction temperature is 60-80 ℃ and the reaction time is 3-6h.
8. The synthetic process of claim 1 wherein in step (3), the conditions of hydrolysis are: the hydrolysis reaction is carried out in sodium carbonate ethanol water solution; the hydrolysis temperature is 20-50 ℃ and the hydrolysis time is 3-6h.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187808A (en) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate |
CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
CN109206419A (en) * | 2017-06-29 | 2019-01-15 | 上海迪赛诺化学制药有限公司 | Sha Ku is than bent intermediate and its preparation method and application |
CN111943862A (en) * | 2019-05-16 | 2020-11-17 | 上海迪赛诺药业股份有限公司 | Preparation method of heart failure resistant drug Entresto key component Shakuba koji |
CN112174798A (en) * | 2019-07-03 | 2021-01-05 | 杭州科巢生物科技有限公司 | Synthesis method of Sacubitril valsartan sodium LCZ696 |
CN113387829A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯(深圳)科技有限公司 | Preparation method of shakubiqu |
-
2021
- 2021-12-24 CN CN202111600310.3A patent/CN114436877B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187808A (en) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate |
CN109206419A (en) * | 2017-06-29 | 2019-01-15 | 上海迪赛诺化学制药有限公司 | Sha Ku is than bent intermediate and its preparation method and application |
CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
CN111943862A (en) * | 2019-05-16 | 2020-11-17 | 上海迪赛诺药业股份有限公司 | Preparation method of heart failure resistant drug Entresto key component Shakuba koji |
CN112174798A (en) * | 2019-07-03 | 2021-01-05 | 杭州科巢生物科技有限公司 | Synthesis method of Sacubitril valsartan sodium LCZ696 |
CN113387829A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯(深圳)科技有限公司 | Preparation method of shakubiqu |
Non-Patent Citations (2)
Title |
---|
Chemo- and regioselective nucleophilic hydrofunctionalization of unactivated aliphatic alkenes under transition-metal-free catalysts;Ying Zhan, et al.,;《Green Chemistry》;3250–3255 * |
Hao Jiang, et al.,.Organocatalysed Asymmetric b-Amination and Multicomponent syn- Selective Diamination of a,b-Unsaturated Aldehydes.《Chem. Eur. J.》.2007,9068-9075. * |
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