CN104557600B - Sha Ku is than bent preparation method - Google Patents
Sha Ku is than bent preparation method Download PDFInfo
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- CN104557600B CN104557600B CN201510039610.7A CN201510039610A CN104557600B CN 104557600 B CN104557600 B CN 104557600B CN 201510039610 A CN201510039610 A CN 201510039610A CN 104557600 B CN104557600 B CN 104557600B
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- 0 *C(CC=CC=C(C=C)c1ccccc1)C=O Chemical compound *C(CC=CC=C(C=C)c1ccccc1)C=O 0.000 description 4
- TXHSIZTZLXYIES-UHFFFAOYSA-N CC(CC(Cc(cc1)ccc1C1=CCCC=C1)NC(OC(C)(C)C)=O)C(OC)=O Chemical compound CC(CC(Cc(cc1)ccc1C1=CCCC=C1)NC(OC(C)(C)C)=O)C(OC)=O TXHSIZTZLXYIES-UHFFFAOYSA-N 0.000 description 1
- VJQQQJKGMOMGKB-MOSHPQCFSA-N CCC/C=N\C(CC(CC1)CC=C1c1ccccc1)C=O Chemical compound CCC/C=N\C(CC(CC1)CC=C1c1ccccc1)C=O VJQQQJKGMOMGKB-MOSHPQCFSA-N 0.000 description 1
- RDXWFLUHYBUOBQ-UHFFFAOYSA-N CCNC(CC(C)C(OCC)[U])Cc(cc1)ccc1C1=CCCC=C1 Chemical compound CCNC(CC(C)C(OCC)[U])Cc(cc1)ccc1C1=CCCC=C1 RDXWFLUHYBUOBQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
Abstract
The husky storehouse that the present invention has disclosed one of a kind of Novel blood pressure-reducing medicine LCZ696 component is than bent (Sacubitril, AHU-377, I) preparation method, does its preparation process comprise: with chiral shift reagent (S)-1-(alpha-amido benzyl)-beta naphthal (S-betti? Base) make Sha Ku than bent (I) with 2R-methyl-4-oxo-butynic acid through reactions steps such as cyclization, addition, debenzylation, open loop, esterification and amidatioons. This preparation method's raw material is easy to get, and technique is succinct, and economic environmental protection is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and intermediate preparing technical field, particularlyThe husky storehouse of a kind of enkephalinase inhibitor is than the preparation method of bent (Sacubitril).
Background technology
LCZ696 is that this medicine combines Novartis by a kind of Novel blood pressure-reducing medicine of company of Novartis (Novartis) exploitationTwo kinds of components such as Valsartan (Diovan, common name: Valsartan) and experimental drug Sacubitril (AHU-377),Wherein Valsartan can improve vasodilation, stimulate body excretes sodium and water, and Sacubitri threat capable of blocking is fallenThe mechanism of action of hypotensive 2 peptide species, thereby LCZ696 is called as angiotensin-ii receptor and enkephalinsThe double inhibitor of enzyme. The unique effect pattern that clinical manifestation goes out, the hypotensive effect that is better than standard drug and minimizingEffect of heart failure, the express passway that makes this medicine obtain U.S. FDA and the EMEA of European Union is evaluated qualification.Industry generally believes that LCZ696 will bring the innovation of traditional heart failure therapeutic scheme. Due to Sacubitril(AHU-377) also do not there is the Chinese translation of standard, therefore the applicant is " Sha Ku is than bent " by its transliteration at this.
Sha Ku is more by name than bent chemistry: 4-(((2S, 4R)-1-(1,1 '-biphenyl-4-yl)-5-ethyoxyl-4-methyl-5-oxoPentane-2-yl) amino)-4-ketobutyric acid (I), its structural formula is:
The research report that Sha Ku is existing more more than bent preparation method, wherein US Patent No. 5217996 and the worldPatent WO2008031567, WO2010136474 and WO2012025501 etc. have reported a kind of following closingBecome route, taking chiral amino alcohol as raw material, through being oxidized to aldehyde, tie up terraced tin reaction, chiral hydrogenation and amidatioon contractingThe reaction such as close and make target product.
In addition, international monopoly WO2008083967, WO2011088797, WO2012025502 and WOThe reports such as 2014198195 be the preparation method of another type. This route is to be former by 2-carbonyl prolineMaterial, through activated carboxylic, biphenyl replacement, carbonyl reduction, chirality methyl, ring-opening reaction and amidatioon condensationMake target product Deng reaction.
The synthetic route of above-mentioned two sections of documents, although at method and the list of the formation of the use of initiation material, chiralityIn the order of elementary reaction, there is certain difference, but all have that chiral raw material is difficult to obtain, reactions steps is various,The shortcomings such as chiral catalysis reducing catalyst costliness and Reusability carboxyl or the protection of amino fourth and deprotection, makeSaid synthesis route is difficult to successfully realize its industrialization.
Find out thus, existing preparation scheme does not solve the chiral amino of target compound on the one hand wellPreparation, existing technique is subject to all many-sided restrictions such as raw material, cost, equipment and environmental protection on the other hand, noBe easy to industrialization. So, how to use modern chirality synthetic technology, adopt effective chiral shift reagent, establishCount and develop simple and easy quick, economic environmental protection and be convenient to industrialized new synthesis route, for the economy of this medicineTechnical development is significant.
Summary of the invention
The object of the invention is to for defect of the prior art, by the raw material of industry and the chiral induction that are easy to getReagent " BETTY BOOP alkali " (Bettibase) is prepared the husky storehouse of target product than bent, and the method has that raw material is easy to get, workThe advantages such as succinct, the economic environmental protection of skill and applicable suitability for industrialized production.
For achieving the above object, the present invention has adopted following main technical schemes: a kind of enkephalinase suppressesThe preparation method of agent husky storehouse ratio bent (Sacubitril, I),
Its preparation process comprises: (S)-1-(alpha-amido benzyl)-beta naphthal (II) and 2R-methyl-4-oxo-butynic acid (III)There is ring-closure reaction and generate (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphthaleneAnd also [2,1-b] [1,3] oxazine (IV) of [1,2-e] pyrrole ring; Described (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrrole ring is [2,1-b] [1,3] oxazine (IV) and RMgBr (1,1 '-Lian alsoBenzene-4-base-methyl) magnesium chloride or (1,1 '-biphenyl-4-base-methyl) magnesium bromide generation addition reaction generation(1S, 3R, 5S)-1-[[3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone] benzyl]-beta naphthal (V); Described(1S, 3R, 5S)-1-[[3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone] benzyl] the de-benzyl of-beta naphthal (V) warpRadical reaction generates (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone (VI); Described(3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone (VI) is under acidic catalyst effect and secondIn alcohol, there is open loop and esterification and obtain (2R, 4S)-2-methyl-4-amino-5-(1,1 '-biphenyl-4-yl)-ethyl valerate(VII); Described (2R, 4S)-2-methyl-4-amino-5-(1,1 '-biphenyl-4-yl)-ethyl valerate (VII) exists with succinic anhydrideThe lower amidation process that occurs of alkali promoter effect makes Sha Ku than bent (I).
In addition, the present invention also proposes following attached technical scheme:
There is ring-closure reaction with 2R-methyl-4-oxo-butynic acid (III) in described (S)-1-(alpha-amido benzyl)-beta naphthal (II)Molar ratio be 1: 1-2, preferably 1: 1.0-1.3; And the solvent of described ring-closure reaction is toluene, 1,2-Dichloroethanes, DMF, acetonitrile or methyl-sulfoxide, preferably toluene; And described ring-closure reactionTemperature be 25-100 DEG C, preferably 55-70 DEG C.
Described (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrroleCough up also [2,1-b] [1,3] oxazine (IV) and RMgBr (1,1 '-biphenyl-4-base-methyl) magnesium chloride or (1,1 '-biphenyl-4-of ringBase-methyl) molar ratio of magnesium bromide generation addition reaction is 1: 1-2, preferably 1: 1.2-1.6; And described in addBecoming the solvent of reaction is ether, isopropyl ether, oxolane or 2-methyltetrahydrofuran, preferably ether or tetrahydrochysene furanMutter; And the temperature of described addition reaction is-100-0 DEG C, preferably-78 DEG C.
The reaction system of described debenzylation is palladium charcoal catalytic hydrogenating reduction system or ammonium ceric nitrate oxidation system.The solvent of described palladium charcoal catalytic hydrogenating reduction system is methyl alcohol, ethanol, isopropyl alcohol, carrene, ethyl acetateOr isopropyl acetate, particular methanol. And the solvent of described ammonium ceric nitrate oxidation system is acetonitrile/water, dichloroMethane/water or oxolane/water, preferably acetonitrile/water; Its volume ratio is 1-5: 1, and preferably 2: 1.
The acidic catalyst of described open loop and esterification is hydrochloric acid, sulfuric acid, trifluoracetic acid, perchloric acid or to firstBenzene sulfonic acid, preferably hydrochloric acid or sulfuric acid; And the solvent of described open loop and esterification is ethanol; And described in openThe temperature of ring and esterification is 0-100 DEG C, preferably 70-90 DEG C.
The alkali promoter of described amidation process is NaOH, potash, sodium carbonate, potassium tert-butoxide, pyridineOr triethylamine, preferably pyridine or triethylamine; And the solvent of described amidation process is carrene, tetrahydrochysene furanMutter, acetonitrile, DMF or dioxane, preferably carrene or oxolane; And described inAmidation process temperature is 0-90 DEG C, preferably 30-50 DEG C.
Than prior art, husky storehouse involved in the present invention is than the preparation method of bent (I), have raw material be easy to get,The features such as the succinct and environmental protection and economy of technique, so be beneficial to the suitability for industrialized production of this bulk drug, promote its economic technologyDevelopment.
Detailed description of the invention
Below in conjunction with several preferred embodiments, technical solution of the present invention is further non-limitingly described in detail.The preparation of its Raw (S)-1-(alpha-amido benzyl)-beta naphthal (II) can be with reference to Chinese invention patentBe entitled as " the preparation of chipal compounds (S)-(+) and (R)-(-)-1-(alpha-amido benzyl)-beta naphthal for No. CN1348952AMethod " description (open day: on May 15th, 2002) prepared about this compound; Raw material 2R-methyl-4-Oxo-butynic acid (III) can be with reference to " JournaloftheAmericanChemicalSociety, 107 (2), 443-8;1985”、“JournaloftheAmericanChemicalSociety，126(45)，14740-14745；2004”" Tetrahedron, 63 (26), 5754-5767; The preparation method of document to same compound such as 2007 ".
Embodiment mono-:
Under 0-5 DEG C and blanket of nitrogen, by (4S, 1 ' R)-4,5-dihydro-2-(1-methyl-3-cyclobutenyl)-4-(1-Methylethyl)Oxazole (16.7g, 0.1mol) joins in hydrochloric acid (10%w/w, 250mL), is warming up to water boiling, stirring reaction 3Hour, be cooled to room temperature, use dichloromethane extraction three times, normal pressure reclaims solvent, and decompression distillation obtains yellow liquidBody 2R-methyl-4-alkene-valeric acid. Gained yellow oil is dissolved in 250mL carrene, is cooled to-78 DEG C,Pass into ozone, solution colour becomes bottle green gradually, and after approximately 15 minutes, reaction finishes. It is unnecessary to remove with nitrogenOzone, rises to room temperature, washs with 5% sodium thiosulfate solution and pure water successively, and anhydrous sodium sulfate drying,Reclaim solvent and obtain faint yellow grease 2R-methyl-4-oxo-butynic acid (III) 7.9g, yield 68.1%; FAB-MSm/z：117[M+H]+。
Embodiment bis-:
In reaction bulb, add (S)-1-(alpha-amido benzyl)-beta naphthal (II) (7.5g, 30mmol), 2R-methyl-4-oxygenGeneration-butyric acid (III) (3.7g, 31.5mmol) and toluene 100mL, be warming up to 40-50 DEG C, stirring reaction 36 hours,TLC detection reaction completes. Cooling, removes by filter insoluble matter. Concentration and recovery toluene, gained grease isopropylEther recrystallization, vacuum drying obtains white solid (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-Tetrahydrochysene-12H-naphtho-[1,2-e] pyrrole ring is [2,1-b] [1,3] oxazine (IV) 7.2g, yield 72.9% also; 1HNMR(CDCl3)δ7.72-765(m，2H)，7.35-7.28(m，1H)，7.24-7.13(m，7H)，7.10(d，1H)，5.84(s，1H)，5.65-5.54(m，1H)，2，43-2.67(m，1H)，2.24-2.57(m，2H)，1.16(d，3H)；FAB-MSm/z：330[M+H]+。
Embodiment tri-:
Under room temperature and blanket of nitrogen, in dry reaction bottle, add a small amount of bromoethane (initator), magnesium powder (1.0g,40mmol) with dry tetrahydrofuran 10mL, after question response causes, drip 4-bromomethyl-1,1 '-biphenyl (4.92g,100mL dry tetrahydrofuran solution 20mmol), is added dropwise to complete rear continuation stirring reaction 3-4 hour, is prepared intoTo RMgBr (1,1 '-biphenyl-4-base-methyl) magnesium bromide. Be cooled to-78 DEG C, drip (7aR, 9R, 12S)-9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrrole ring is [2,1-b] [1,3] oxazine (IV) alsoThe 100mL dry tetrahydrofuran solution of (4.9g, 15mmol), keeps this thermotonus 2-3 hour, and TLC detectsReaction completes. With saturated ammonium chloride 50mL cancellation reaction, rise to room temperature, use dichloromethane extraction three times, closeAnd organic phase, anhydrous magnesium sulfate drying. Concentrated, residue is heavily tied with ethyl acetate and n-hexane (volume ratio 1: 1)Crystalline substance, obtains white solid (1S, 3R, 5S)-1-[[3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone] benzylBase]-beta naphthal (V) 6.4g, yield 85.8%; M.p.215 DEG C (decomposition), FAB-MSm/z:498[M+H]+。
Embodiment tetra-:
In hydrogenation bottle, add (1S, 3R, 5S)-1-[[3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-pyrrolidinesKetone] benzyl]-beta naphthal (V) (1.5g, 3mmol), 10% palladium charcoal (Pd/C) (0.32g, 0.3mmol) and methyl alcohol 25mL,Under room temperature and normal pressure, pass into hydrogen, be no longer absorbed to hydrogen, stop logical hydrogen. Filtering recovering catalyst, subtractsPush back receipts solvent, ethyl acetate and n-hexane (volume ratio 1: 1) recrystallization for residue, obtain off-white color solid(3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone (VI) 0.7g, yield 88.0%; 1HNMR(CDCl3)δ7.54-7.58(m，4H)，7.44(d，2H)，7.33(m，1H)，7.25(d，2H)，7.13(s，1H)，3.86(m，1H)，2.82(dd，2H)，2.42(m，1H)，1.83-2.13(m，2H)，1.09(d，3H)；FAB-MSm/z：266[M+H]+。
Embodiment five:
In reaction bulb, add (1S, 3R, 5S)-1-[[3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone] benzylBase]-beta naphthal (V) (1.5g, 3mmol), ammonium ceric nitrate (4.1g, 7.5mmol) and acetonitrile and water (volume ratio 2: 1)Mixed solvent 55mL, stirring at room temperature 5-7 hour, TLC detection reaction finishes. Filter, in filtrate, add carbonAcid hydrogen sodium solution, and with dichloromethane extraction three times, merging organic phase, anhydrous sodium sulfate drying. Reduced pressure concentration,Ethyl acetate and n-hexane (volume ratio 1: 1) recrystallization for residue, obtain off-white color solid (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone (VI) 0.65g, yield 81.8%; 1HNMR (CDCl3)δ7.54-7.58(m，4H)，7.44(d，2H)，7.33(m，1H)，7.25(d，2H)，7.13(s，1H)，3.86(m，1H)，2.82(dd，2H)，2.42(m，1H)，1.83-2.13(m，2H)，1.09(d，3H)；FAB-MSm/z：266[M+H]+。
Embodiment six:
Add in reaction bulb (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone(VI) (1.33g, 5mmol), 36.5% concentrated hydrochloric acid 2mL and ethanol 25mL, after stirring and dissolving, be warming up to75-85 DEG C, stirs 24 hours, and TLC detection reaction finishes. Reduced pressure concentration, residue is recrystallized with dimethylbenzene,Obtain white solid (2R, 4S)-2-methyl-4-amino-5-(1,1 '-biphenyl-4-yl)-ethyl valerate (VII) (hydrochloric acidSalt) 1.4g, yield 80.5%; 1HNMR (DMSO-d6)δ8.30(brs，3H)，7.62(m，4H)，7.43(m，2H)，7.35(m，2H)，7.31(m，1H)，3.95(q，2H)，3.36(m，1H)，2.81-3.08(dd，2H)，2.74(m，1H)，1.85(m，1H)，1.61(m，1H)，1.08(t，3H)，1.05(d，3H)；FAB-MSm/z：312[M+H]+。
Embodiment seven:
Add in reaction bulb (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone(VI) (1.33g, 5mmol), 98% concentrated sulfuric acid 1mL and ethanol 25mL, after stirring and dissolving, be warming up to 75-85 DEG C,Stir 16 hours, TLC detection reaction finishes. Reduced pressure concentration, residue is recrystallized with dimethylbenzene, obtains whiteLook solid (2R, 4S)-2-methyl-4-amino-5-(1,1 '-biphenyl-4-yl)-ethyl valerate (VII) (disulfate) 1.8g,Yield 88.2%; 1HNMR (DMSO-d6)δ8.57(brs，3H)，7.64(m，4H)，7.46(m，2H)，7.34(m，2H)，7.33(m，1H)，3.75(m，2H)，2.78-2.98(dd，2H)，2.66(m，1H)，1.86(m，1H)，1.58(m，1H)，1.10-1.15(m，6H)；FAB-MSm/z：312[M+H]+。
Embodiment eight:
Add in reaction bulb (2R, 4S)-2-methyl-4-amino-5-(1,1 '-biphenyl-4-yl)-ethyl valerate (VII)(1.55g, 5mmol), pyridine (1.2g, 15mmol) and carrene 25mL, after stirring and dissolving, add fourth twoAcid anhydrides (1.0g, 10mmol), is warming up to 40-45 DEG C, stirring reaction 6 hours. Add succinic anhydride (0.5g,5mmol), continue reaction 4 hours, TLC detection reaction finishes. Reduced pressure concentration, residue ethyl acetateWith n-hexane recrystallization, obtain the husky storehouse of off-white color solid than bent (I) 1.6g, yield 77.9%; 1HNMR (CDCl3)δ7.51(d，2H)，7.46(d，2H)，7.36(m，2H)，7.27(m，1H)，7.17(d，2H)，5.72(d，1H)，4.19(brs，1H)，4.06(q，2H)，2.87-2.72(m，2H)，2.62-2.54(m，2H)，2.49(brs，1H)，2.43-2.33(m，2H)，1.88(m.1H)，1.54-1.43(m，1H)，1.18(t，3H)，1.10(d，3H)；FAB-MSm/z：412[M+H]+。
It is pointed out that above-described embodiment is only explanation technical conceive of the present invention and feature, its object isPerson skilled in the art can be understood content of the present invention and implement according to this, can not limit this with thisBright protection domain. All equivalences that Spirit Essence is done according to the present invention change or modify, and all should be encompassed in thisWithin bright protection domain.
Claims (6)
1. husky storehouse is than a bent preparation method,
Its preparation process comprises: (S)-1-(alpha-amido benzyl)-beta naphthal and 2R-methyl-4-oxo-butynic acid generation cyclizationReaction generates (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrroleCough up also [2,1-b] [1,3] oxazine of ring; Described (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxo-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrrole ring is [2,1-b] [1,3] oxazine and (1,1'-biphenyl-4-base-methyl) magnesium chloride or (1,1'-connection alsoBenzene-4-base-methyl) magnesium bromide generation addition reaction generation (1S, 3R, 5S)-1-[[3-methyl-5-(1,1'-biphenyl-4-base-firstBase)-2-Pyrrolidone] benzyl]-beta naphthal; Described (1S, 3R, 5S)-1-[[3-methyl-5-(1,1'-biphenyl-4-base-methyl)-2-Pyrrolidones] benzyl]-beta naphthal generates (3R, 5S)-3-methyl-5-(1,1'-biphenyl-4-base-methyl)-2-through debenzylationPyrrolidones; Described (3R, 5S)-3-methyl-5-(1,1'-biphenyl-4-base-methyl)-2-Pyrrolidone is done at acidic catalystWith lower and open loop occurs in ethanol and esterification obtains (2R, 4S)-2-methyl-4-amino-5-(1,1'-biphenyl-4-Base)-ethyl valerate; Described (2R, 4S)-2-methyl-4-amino-5-(1,1'-biphenyl-4-yl)-ethyl valerate and succinic anhydrideUnder the effect of alkali promoter, there is amidation process and make Sha Ku than bent.
According to claim 1 husky storehouse than bent preparation method, described (S)-1-(alpha-amido benzyl)-beta naphthalWith the molar ratio of 2R-methyl-4-oxo-butynic acid generation ring-closure reaction be 1:1-2; And described ring-closure reactionSolvent is toluene, 1,2-dichloroethanes, DMF, acetonitrile or methyl-sulfoxide; And described cyclizationThe temperature of reaction is 25-100 DEG C.
According to claim 1 husky storehouse than bent preparation method, described (7aR, 9R, 12S)-9-methyl isophthalic acid 0-oxygenGeneration-12-phenyl-7a, 8,9,10-tetrahydrochysene-12H-naphtho-[1,2-e] pyrrole ring is [2,1-b] [1,3] oxazine and (1,1'-biphenyl-4-alsoBase-methyl) molar ratio of magnesium chloride or (1,1'-biphenyl-4-base-methyl) magnesium bromide generation addition reaction is 1:1-2;And the solvent of described addition reaction is ether, isopropyl ether, oxolane or 2-methyltetrahydrofuran; And instituteThe temperature of stating addition reaction is-100-0 DEG C.
4. husky storehouse is than bent preparation method according to claim 1, and the reaction system of described debenzylation isPalladium charcoal catalytic hydrogenating reduction system or ammonium ceric nitrate oxidation system; The solvent of described palladium charcoal catalytic hydrogenating reduction systemFor methyl alcohol, ethanol, isopropyl alcohol, carrene, ethyl acetate or isopropyl acetate; And described ammonium ceric nitrateThe solvent of oxidation system is acetonitrile/water, carrene/water or oxolane/water, and its volume ratio is 1-5:1.
5. husky storehouse is than bent preparation method according to claim 1, and the acidity of described open loop and esterification is urgedAgent is hydrochloric acid, sulfuric acid, trifluoracetic acid, perchloric acid or p-methyl benzenesulfonic acid; And described open loop and esterificationTemperature be 0-100 DEG C.
6. husky storehouse is than bent preparation method according to claim 1, and the alkali promoter of described amidation process isNaOH, potash, sodium carbonate, potassium tert-butoxide, pyridine or triethylamine, and described amidation processSolvent is carrene, oxolane, acetonitrile, DMF or dioxane; And described acylAminating reaction temperature is 0-90 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510039610.7A CN104557600B (en) | 2015-01-26 | 2015-01-26 | Sha Ku is than bent preparation method |
| PCT/CN2016/070020 WO2016119574A1 (en) | 2015-01-26 | 2016-01-04 | Method for preparing sacubitril |
| KR1020177023388A KR101961897B1 (en) | 2015-01-26 | 2016-01-04 | Preparation method of sacylitol |
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| CN201510039610.7A CN104557600B (en) | 2015-01-26 | 2015-01-26 | Sha Ku is than bent preparation method |
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| CN104557600A CN104557600A (en) | 2015-04-29 |
| CN104557600B true CN104557600B (en) | 2016-05-04 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104557600B (en) * | 2015-01-26 | 2016-05-04 | 苏州明锐医药科技有限公司 | Sha Ku is than bent preparation method |
| WO2016150337A1 (en) * | 2015-03-20 | 2016-09-29 | 苏州晶云药物科技有限公司 | Ahu377 crystal form, preparation method and use thereof |
| 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 |
| CN104860894B (en) * | 2015-06-10 | 2017-05-17 | 北京博全健医药科技有限公司 | Method for preparing cardiotonic drug LCZ696 |
| CN106309388A (en) * | 2015-06-30 | 2017-01-11 | 深圳信立泰药业股份有限公司 | Medicine composition for treating congestive heart failure and preparation method thereof |
| CN105085322B (en) * | 2015-08-15 | 2017-10-03 | 浙江永宁药业股份有限公司 | The Preparation Method And Their Intermediate of the intermediates of AHU 377 and the preparation method of intermediate |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
| CN105237560B (en) * | 2015-10-15 | 2018-07-06 | 上海博氏医药科技有限公司 | A kind of LZC696 intermediates and its synthetic method |
| CN106854187B (en) * | 2015-12-08 | 2020-04-14 | 苏州晶云药物科技股份有限公司 | Preparation method of AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II |
| JP7001597B2 (en) | 2015-12-10 | 2022-01-19 | ノバルティス アーゲー | New processes and intermediates |
| CN106977415B (en) * | 2016-01-15 | 2021-03-26 | 广东东阳光药业有限公司 | Intermediate of shakubiqu and preparation method thereof |
| WO2017148357A1 (en) * | 2016-02-29 | 2017-09-08 | 广东东阳光药业有限公司 | Sacubitril intermediate and preparation method thereof |
| CN105753733B (en) * | 2016-04-15 | 2019-06-18 | 苏州晶云药物科技股份有限公司 | Crystal form of AHU377 and preparation method thereof and purposes |
| JP6944473B2 (en) | 2016-07-05 | 2021-10-06 | ノバルティス アーゲー | A new method for early sacubitril intermediates |
| CN107602399B (en) * | 2016-07-11 | 2020-09-25 | 江西东邦药业有限公司 | Preparation method of enkephalinase inhibitor intermediate |
| US10851059B2 (en) | 2016-08-17 | 2020-12-01 | Novartis Ag | Processes and intermediates for NEP inhibitor synthesis |
| CN106380421B (en) * | 2016-08-26 | 2017-12-08 | 中国科学院上海有机化学研究所 | Synthetic method bent Sha Kubi |
| CN108203396B (en) * | 2016-12-19 | 2020-12-08 | 江西东邦药业有限公司 | Synthesis of enkephalinase inhibitor |
| ES2883363T3 (en) | 2016-12-23 | 2021-12-07 | Novartis Ag | New process for initial sacubitril intermediates |
| CN108238981A (en) * | 2016-12-23 | 2018-07-03 | 宁波爱诺医药科技有限公司 | A kind of preparation method of LCZ-696 key intermediates |
| CN106699604B (en) * | 2017-01-09 | 2019-01-01 | 四川同晟生物医药有限公司 | One seed sand library is than bent and its intermediate preparation method |
| CN106966926B (en) * | 2017-04-01 | 2018-10-19 | 沧州那瑞化学科技有限公司 | A kind of preparation method of LCZ696 intermediates |
| CN110878039A (en) * | 2019-12-18 | 2020-03-13 | 株洲千金药业股份有限公司 | Preparation method of Sacubitril valsartan sodium impurity |
| CN113121342B (en) * | 2019-12-31 | 2022-05-31 | 浙江医药股份有限公司新昌制药厂 | Preparation method and application of shakubiqu intermediate |
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| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| EP1903027A1 (en) | 2006-09-13 | 2008-03-26 | Novartis AG | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| MX2009007474A (en) * | 2007-01-12 | 2009-10-08 | Novartis Ag | New process. |
| EA201101672A1 (en) | 2009-05-28 | 2012-06-29 | Новартис Аг | SUBSTITUTED DERIVATIVES OF AMINOISAL ACID AS NEPRILISIN INHIBITORS |
| DK2435409T3 (en) * | 2009-05-28 | 2014-10-27 | Novartis Ag | Substituted aminopropionic acid derivatives as neprilysin inhibitors |
| US8673974B2 (en) * | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
| US8993631B2 (en) * | 2010-11-16 | 2015-03-31 | Novartis Ag | Method of treating contrast-induced nephropathy |
| CN104230865B (en) * | 2013-06-13 | 2018-01-09 | 上海翰森生物医药科技有限公司 | 4 amino butyric acid derivatives of biaryl substituted and its production and use |
| CN104557600B (en) * | 2015-01-26 | 2016-05-04 | 苏州明锐医药科技有限公司 | Sha Ku is than bent preparation method |
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