CN105001173A - Preparation method of LZ969 - Google Patents
Preparation method of LZ969 Download PDFInfo
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- CN105001173A CN105001173A CN201510384430.2A CN201510384430A CN105001173A CN 105001173 A CN105001173 A CN 105001173A CN 201510384430 A CN201510384430 A CN 201510384430A CN 105001173 A CN105001173 A CN 105001173A
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- biphenyl
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- valsartan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
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Abstract
The invention provides a preparation method of LZ969. According to the preparation method, LZ969 is used for representing a compound of valsartan and 4-(((2S, 4R)-1-(1, 1'-biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxo pentane-2-yl) amino)-4-oxo butyric acid at a molar ratio of 1:1. A preparation method of valsartan comprises following steps: L-valine methyl ester hydrochloride is synthesized; nucleophilic substitution is carried out so as to obtain N-[2'-cyano-(biphenyl-4-yl)-methyl]-L-valine methyl ester hydrochloride; valeryl chloride is added, sodium carbonate is taken as an acid-binding agent, acetone is taken as a solvent, and N-[2'-cyano-(biphenyl-4-yl)-methyl]-N-valeryl is obtained via reaction; and N-[2'-cyano-(biphenyl-4-yl)-methyl]-N-valeryl, sodium azide, and chloro-substituted tributyltin are subjected to heating reaction by taking pyridine as a solvent so as to obtain valsartan. Technical route reaction of the preparation method is mild; operation is simple; and yield is high.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the preparation method of a kind of LZ969.
Background technology
Heart failure is that a kind of Progressive symmetric erythrokeratodermia causes the disease that declines, and the heart of patient can not pump enough blood to supply whole body, and the symptoms such as expiratory dyspnea, weak and fluid retention can slowly occur, and increase the weight of gradually, obviously affect quality of life.Heart failure is also an important and increasingly serious public health problem, and the whole world fund spent in every year on heart failure is 1,080 hundred million dollar 15, and wherein hospitalization cost accounts for the 60%-70% of medical expense.
LCZ696 is a kind of angiotensin receptor enkephalinase inhibitor (ARNI), for valsartan and sacubitril(AHU377) a kind of mixture, comprise the ratio of the valsartan of half molecule and the AHU377(1:1 of half molecule) LCZ696 is valsartan and sacubitril(AHU377) a kind of mixture, comprise the ratio of the valsartan of half molecule and the AHU377(1:1 of half molecule).
LCZ696 comprises angiotensin receptor blocker (ARB) valsartan part and enkephalinase inhibitor sacubitril part, and both play pharmacological action by reaction forming together jointly, has two target spot restraining effect.
All there is various problem in the operational path of two kinds of components of current LZ696, operational path is loaded down with trivial details, and yield is not high.
Summary of the invention
The object of this invention is to provide a kind of operational path simple, after condition optimizing, reaction temperature and, material cost is low, and the preparation method of the preparation method, particularly valsartan of the LZ696 that yield is high, to overcome the deficiencies in the prior art.
For achieving the above object, the present invention takes following technical proposals to realize:
The preparation method of a kind of LZ969, described LZ969 is valsartan and the 4-(((2S of mol ratio 1:1,4R)-1-(1,1 '-biphenyl-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino)-4-ketobutyric acid mixture, wherein the preparation method of valsartan comprises the following steps:
Step a, the synthesis of Valine methyl esters, react under thionyl chloride and anhydrous methanol low temperature and generate protochloride sulfuric ester, in Valine, then add protochloride sulfuric ester carry out esterification, add re-crystallizing in ethyl acetate after reaction and obtain Valine methyl ester hydrochloride;
Step b, in Valine methyl ester hydrochloride, add 2 '-cyano group-4-brooethyl-biphenyl take tetrahydrofuran (THF) as solvent, and nucleophilic substitution reaction under sodium carbonate exists, obtains N-[2 '-cyano group-(biphenyl-4-base)-methyl]-Valine methyl ester hydrochloride;
Step c, to N-[2 '-cyano group-(biphenyl-4-base)-methyl] add valeryl chloride in-Valine methyl ester hydrochloride, take sodium carbonate as acid binding agent, acetone is solvent, is obtained by reacting N-[2 '-cyano group-(biphenyl-4-base)-methyl]-N-valeryl;
Steps d, adds N-[2 '-cyano group-(biphenyl-4-base)-methyl in reaction vessel]-N-valeryl, sodiumazide, chloro tributyl tin, be solvent with pyridine, reacting by heating obtains valsartan.
Further, valsartan after refining and 4-(((2S, 4R)-1-(1,1 '-biphenyl-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino) the obtained LZ969 of-4-ketobutyric acid 1:1 mixing in molar ratio.
Further, in step a, esterification reaction temperature is 15-20 DEG C.
Further, in step a, the reaction times is 30h.
Further, in step b, temperature of reaction is 70 DEG C, and the reaction times is 2h.
Further, in step b, after reaction terminates, add toluene extracting and separating.
Further, in step c, temperature of reaction is 50 DEG C, and the reaction times is 8h.
Further, in steps d, temperature of reaction is 150 DEG C, and the reaction times is 52h.
Compared with prior art, the present invention has the following advantages:
The present invention is by the synthesis of Valine methyl esters, react under thionyl chloride and anhydrous methanol low temperature and generate protochloride sulfuric ester, then in Valine, add protochloride sulfuric ester carry out esterification, add re-crystallizing in ethyl acetate after reaction and obtain Valine methyl ester hydrochloride; In Valine methyl ester hydrochloride, add 2 '-cyano group-4-brooethyl-biphenyl take tetrahydrofuran (THF) as solvent, and nucleophilic substitution reaction under sodium carbonate exists, obtains N-[2 '-cyano group-(biphenyl-4-base)-methyl]-Valine methyl ester hydrochloride; To N-[2 '-cyano group-(biphenyl-4-base)-methyl] add valeryl chloride in-Valine methyl ester hydrochloride, take sodium carbonate as acid binding agent, acetone is solvent, is obtained by reacting N-[2 '-cyano group-(biphenyl-4-base)-methyl]-N-valeryl; N-[2 '-cyano group-(biphenyl-4-base)-methyl is added in reaction vessel]-N-valeryl, sodiumazide, chloro tributyl tin, be solvent with pyridine, reacting by heating obtains valsartan.
The present invention is verified repeatedly by great many of experiments, optimized process flow and reaction conditions, and reaction conditions is relatively gentle, simple to operate, and yield is high.
Embodiment
Below in conjunction with specific embodiment, the present invention will be described in detail.
Embodiment 1
The synthesis of Valine methyl esters.
Thionyl chloride is added in reaction vessel, esterification is carried out in anhydrous methanol and Valine, the mol ratio of thionyl chloride and Valine is 1-1.5:1, the volume of anhydrous methanol and the mass ratio of Valine are 10-15L/kg, esterification reaction temperature is 15-20 DEG C, reaction times is 30h, adds re-crystallizing in ethyl acetate and obtain Valine methyl ester hydrochloride after reaction.
Embodiment 2
2 '-cyano group-4-brooethyl-biphenyl are added in Valine methyl ester hydrochloride, ' mol ratio of-cyano group-4-brooethyl-biphenyl is 1-1.5:1 to Valine methyl ester hydrochloride and 2, add acid binding agent sodium carbonate, ' mol ratio of-cyano group-4-brooethyl-biphenyl is 2-2.5:1 to sodium carbonate and 2, take tetrahydrofuran (THF) as solvent, temperature of reaction is 70 DEG C, reaction times is 2h, after reaction terminates, add toluene extracting and separating, obtain N-[2 '-cyano group-(biphenyl-4-base)-methyl]-Valine methyl ester hydrochloride.
Embodiment 3:
To N-[2 '-cyano group-(biphenyl-4-base)-methyl] add valeryl chloride in-Valine methyl ester hydrochloride, take sodium carbonate as acid binding agent, N-[2 '-cyano group-(biphenyl-4-base)-methyl] mol ratio of-Valine methyl ester hydrochloride and valeryl chloride is 1:1.6-2, N-[2 '-cyano group-(biphenyl-4-base)-methyl] mol ratio of-Valine methyl ester hydrochloride and sodium carbonate is 1:2.5-3, acetone is solvent, temperature of reaction is 50 DEG C, reaction times is 8h, is obtained by reacting N-[2 '-cyano group-(biphenyl-4-base)-methyl]-N-valeryl.
Embodiment 4
N-[2 '-cyano group-(biphenyl-4-base)-methyl is added in reaction vessel]-N-valeryl, sodiumazide, chloro tributyl tin, the mol ratio of sodiumazide and chloro tributyl tin is 1:1, N-[2 '-cyano group-(biphenyl-4-base)-methyl] mol ratio of-N-valeryl and sodiumazide is 1:2-2.5, take pyridine as solvent, temperature of reaction is 150 DEG C, reaction times is 52h, is obtained by reacting valsartan.
Embodiment 5
Valsartan after refining and 4-(((2S, 4R)-1-(1,1 '-biphenyl-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino) the obtained LZ969 of trisodium half pentahydrate 1:1 mixing in molar ratio of-4-ketobutyric acid.
Although the present invention with preferred embodiment openly as above; but it is not for limiting the present invention; any those skilled in the art without departing from the spirit and scope of the present invention; the Method and Technology content of above-mentioned announcement can be utilized to make possible variation and amendment to technical solution of the present invention; therefore; every content not departing from technical solution of the present invention; according to technical spirit of the present invention to any simple modification made for any of the above embodiments, equivalent variations and modification, all belong to the protection domain of technical solution of the present invention.
Claims (8)
1. the preparation method of a LZ969, it is characterized in that, described LZ969 is valsartan and the 4-(((2S of mol ratio 1:1,4R)-1-(1,1 '-biphenyl-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino)-4-ketobutyric acid mixture, wherein the preparation method of valsartan comprises the following steps:
Step a, the synthesis of Valine methyl esters, react under thionyl chloride and anhydrous methanol low temperature and generate protochloride sulfuric ester, in Valine, then add protochloride sulfuric ester carry out esterification, add re-crystallizing in ethyl acetate after reaction and obtain Valine methyl ester hydrochloride;
Step b, in Valine methyl ester hydrochloride, add 2 '-cyano group-4-brooethyl-biphenyl take tetrahydrofuran (THF) as solvent, and nucleophilic substitution reaction under sodium carbonate exists, obtains N-[2 '-cyano group-(biphenyl-4-base)-methyl]-Valine methyl ester hydrochloride;
Step c, to N-[2 '-cyano group-(biphenyl-4-base)-methyl] add valeryl chloride in-Valine methyl ester hydrochloride, take sodium carbonate as acid binding agent, acetone is solvent, is obtained by reacting N-[2 '-cyano group-(biphenyl-4-base)-methyl]-N-valeryl;
Steps d, adds N-[2 '-cyano group-(biphenyl-4-base)-methyl in reaction vessel]-N-valeryl, sodiumazide, chloro tributyl tin, be solvent with pyridine, reacting by heating obtains valsartan.
2. method according to claim 1, it is characterized in that, valsartan after refining and 4-(((2S, 4R)-1-(1,1 '-biphenyl-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino) the obtained LZ969 of-4-ketobutyric acid 1:1 mixing in molar ratio.
3. method according to claim 1, is characterized in that, in step a, esterification reaction temperature is 15-20 DEG C.
4. method according to claim 1, is characterized in that, in step a, the reaction times is 30h.
5. method according to claim 1, is characterized in that, in step b, temperature of reaction is 70 DEG C, and the reaction times is 2h.
6. method according to claim 1, is characterized in that, in step b, after reaction terminates, adds toluene extracting and separating.
7. method according to claim 1, is characterized in that, in step c, temperature of reaction is 50 DEG C, and the reaction times is 8h.
8. method according to claim 1, is characterized in that, in steps d, temperature of reaction is 150 DEG C, and the reaction times is 52h.
Priority Applications (1)
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| CN201510384430.2A CN105001173A (en) | 2015-06-30 | 2015-06-30 | Preparation method of LZ969 |
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| CN201510384430.2A CN105001173A (en) | 2015-06-30 | 2015-06-30 | Preparation method of LZ969 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
| CN105929031A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound |
| CN107033094A (en) * | 2016-02-04 | 2017-08-11 | 南京卡文迪许生物工程技术有限公司 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362728A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan synthesis method |
| EP1926705B1 (en) * | 2005-08-22 | 2009-09-02 | Alembic Limited | Process for preparing valsartan |
| CN101558758A (en) * | 2009-05-26 | 2009-10-21 | 上海师范大学 | L-alpha-amino acid ester contained Z-configuration anabasine pesticide and preparation method thereof |
-
2015
- 2015-06-30 CN CN201510384430.2A patent/CN105001173A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1926705B1 (en) * | 2005-08-22 | 2009-09-02 | Alembic Limited | Process for preparing valsartan |
| US7923567B2 (en) * | 2005-08-22 | 2011-04-12 | Alembic Limited | Process for preparing valsartan |
| CN101362728A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan synthesis method |
| CN101558758A (en) * | 2009-05-26 | 2009-10-21 | 上海师范大学 | L-alpha-amino acid ester contained Z-configuration anabasine pesticide and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 徐梦林: "LCZ696治疗心力衰竭的研究进展", 《现代医药卫生》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330609A (en) * | 2015-12-07 | 2016-02-17 | 南京正大天晴制药有限公司 | Method for preparing LCZ696 |
| CN105929031A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound |
| CN105929031B (en) * | 2015-12-18 | 2018-08-21 | 重庆两江药物研发中心有限公司 | The separation method of impurity in the compound of a kind of angiotensin receptor antagonist and nep inhibitor |
| CN107033094A (en) * | 2016-02-04 | 2017-08-11 | 南京卡文迪许生物工程技术有限公司 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
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Application publication date: 20151028 |