CN105061263B - A kind of preparation method of nep inhibitor intermediate - Google Patents
A kind of preparation method of nep inhibitor intermediate Download PDFInfo
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- CN105061263B CN105061263B CN201510489129.8A CN201510489129A CN105061263B CN 105061263 B CN105061263 B CN 105061263B CN 201510489129 A CN201510489129 A CN 201510489129A CN 105061263 B CN105061263 B CN 105061263B
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Abstract
The invention discloses a kind of preparation method of nep inhibitor intermediate, discloses neutral endopeptidase（NEP）The optionally reducing preparation method in the presence of chiral ligand of 5 ([1,1 ' xenyl] 4 bases) 4 ((tertbutyloxycarbonyl) amino) 2 methylvaleric acids of inhibitor intermediate (2R, 4S).Specifically include a kind of being used in the case where there is transition-metal catalyst and chiral ligand with hydrogen diastereoselectivity ground hydrogenation synthesis method.Metallic catalyst used by the present invention is cheap, and chiral ligand is easy to get, and with generation has highly purified product in high yield and preferably, it is higher than 90 preferably to produce diastereoisomer ratio：10 product.
Description
Technical field
The present invention relates to a kind of preparation method of nep inhibitor intermediate, and in particular to one kind is used for the presence of transition gold
With hydrogen diastereoselectivity ground hydrogenation synthesis (2R, 4S) -5- ([1,1 '-biphenyl in the case of metal catalyst and chiral ligand
Base] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid industrialized production preparation method.
Background technology
With the quickening of modern life rhythm, the increase of life stress, the incidence of disease of cardiovascular disease increase year by year, high
Blood pressure is one of modal angiocardiopathy, is to cause congestive heart failure, brain finally dead, coronary heart disease, kidney failure, sustainer
The Major Risk Factors of the incidence of disease of knurl, its seriously threaten human health.The whole world is close to 20,000,000 people every year and dies from because of high blood
Cardiovascular and cerebrovascular disease caused by pressure, the wherein patient of more than half die from acute myocardial infarction or cerebral vessels embolism disease.At present I
State hyperpietic there are about people more than 200,000,000, will also increase hyperpietic 10,000,000 every year newly, and the illness of China's adult's heart failure
Rate increases year by year, and the demand of the medicine of the anti-heart failure of new class is extremely urgent.
Research finds, the endogenous ANP factor (ANF) has diuresis in the mammal body, promote natruresis and
Arterial dilation.It is to be metabolized inactivation by the digestive enzyme of neutral endopeptidase (NEP) that natural ANF peptides are metabolized inactivation
, while NEP also is responsible for the metabolic inactivation of such as enkephalins.Research demonstrates the inhibitor of NEP, can be used as mammal ANF
The inhibitor of digestive enzyme, extends and strengthens ANF in mammalian body by suppressing ANF to be degraded to the relatively low metabolite of activity
Interior diuresis, natruresis and vasodilation characteristic.Therefore nep inhibitor can be used to treat cardiovascular disorder such as：Hypertension, kidney
Insufficiency, including oedema, pulmonary edema and congestive heart failure etc..
The weight pound medicine LCZ696 of the anti-heart failure that Novartis puts on market is first continuous acquisition European Union and FDA
The cardiovascular drugs of Accelerated evaluation qualification.LCZ696 is a kind of economic benefits and social benefits nep inhibitor, with very high inhibitory activity, can subtract
The strain of few heart failure heart.LCZ696 combines the hypertension drug Valsartan and experimental drug AHU-377 of Novartis.
AHU377 can suppress NEP, Valsartan improve vasodilation, stimulate body excretion and water.The security door of cardiovascular drugs
Sill are high, and LCZ696 even shows the greater security for surmounting conventional medicine.Its appearance, is that a history is dashed forward
Broken, Gospel is brought to such Disease.
The inhibitor AHU377 of NEP is the 4- amino-butyric acid derivatives of a class biaryl substituted.(2R,4S)-5-([1,
1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid (II) be synthesize AHU377 key intermediate,
It includes two chiral centres, and the key for synthesizing the intermediate is to control the synthesis of two chiral centres.
Preparation (2R, 4S) -5- ([1,1 '-xenyl] -4- the bases) -4- ((tertbutyloxycarbonyl) amino) for having reported at present -
The method of 2 methyl valeric acid (formula (II)) is mainly the method by catalytic hydrogenation, such as：US5217996 is disclosed as preferential reality
(2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) the amino) -2 methyl valeric acid of scheme is applied, affiliated
In the preparation of compound, N- tertbutyloxycarbonyls-(4R)-(p- phenylphenylmethyl) -4- amino-2-methyl -2- butenoic acids are existed
Hydrogenate in the case of palladium carbon, so as to obtain 80：20 diastereoisomer (II)：(III) form of mixture, by being refining to obtain
Compound (II) is arrived, selective not high, chiral yield is low, the more difficult separation of isomer impurities, and loss is big, so as to cause yield to drop
Low, cost increases, and is not suitable for industrialized production.
Patent WO2008031567A1 and CN101516831A report high with obtaining in the presence of transition metal and part
Diastereoisomer (II):(III), ratio is higher than 88：12.What catalyst was selected is two iodos (cymol) ruthenium (II) two
Polymers), part selects SL-M004-2, and the ratio for obtaining diastereoisomer can reach 90：10.Although the method improves non-
The ratio of enantiomter, but the synthesis difficulty of part is larger, reagent costly, unfavorable use industrial amplification production.
Two iodos (cymol) ruthenium (II) dimer):
Part SL-M004-2：
In order that the easy industrialized production of chipal compounds, reduces cost, we are entered to catalyst and part
The research of one step, have found a route for being applied to industrialized production.
Content of the invention
Purpose：In order to overcome the deficiencies in the prior art, the present invention to provide a kind of preparation of nep inhibitor intermediate
Method.It is an object of the invention to provide a kind of selective preparation (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((uncles
Butoxy carbonyl) amino) -2 methyl valeric acid (II) compound method, the compound can be in the preparation of nep inhibitor AHU377
It is used as intermediate.
Another purpose is to provide one kind in the method for preparing the intermediate (formula (II)) of nep inhibitor AHU377 for choosing
The step of hydrogenation that selects, wherein described step of hydrogenation preferably have in high yield and preferably produce with highly purified product,
It is preferred that it is higher than 90 to produce diastereoisomer ratio：10 product.
The purpose of the present invention can pass through in (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl)
Amino) -2 methyl valeric acid (formula (II)) preparation in specific catalyst and specific chiral ligand used in step of hydrogenation
To realize.
Specific catalyst choice transition-metal catalyst includes the metal-organic complex of rhodium, iridium, ruthenium, preferred transition
Metallic catalyst includes that rhodium or ruthenium, metal-organic complex include norbornadiene (nbd), cyclo-octadiene (cod), cymene.
Particularly a preferred catalyst is：Double (dicyclopentadiene) tetrafluoro boric acid rhodiums.
Chiral ligand, what the present invention was selected is phosphorous part, and below in several parts, experiment finds CK-01, CK-
The selectivity that 02, CK-03, CK-04 chiral ligand is obtained preferably, is particularly preferred that CK-04, and the selectivity of diastereoisomer can
To reach 90：10, so in the present invention, part prioritizing selection part CK-04.
Technical scheme：For solving above-mentioned technical problem, the technical solution used in the present invention is：
A kind of preparation method of nep inhibitor intermediate, nep inhibitor intermediate be (2R, 4S) -5- ([1,1 '-biphenyl
Base] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid, its chiral molecules structural formula is as follows：
Preparation method is as follows：(R, E) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2- first
Base -2- penetenoic acids are catalyzed by catalyst and Phosphine ligands, and asymmetric reduction occurs with hydrogen, the configuration required for selectively obtaining
Product (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid；
Synthetic route is as follows：
Preferably, the preparation method of described nep inhibitor intermediate, it is characterised in that：Reaction dissolvent is selected from
Methyl alcohol, ethanol or methyl alcohol and the mixed solvent of ethanol, reaction temperature are 25-50 DEG C, and the reaction time is 8-12 hours.
The preparation method of described nep inhibitor intermediate, it is characterised in that：The catalyst is transition metal-catalyzed
Agent, including rhodium, iridium, ruthenium or rhodium, iridium, ruthenium metal-organic complex.
Preferably, metal-organic complex include norbornadiene (nbd), cyclo-octadiene (cod), cymene and rhodium, iridium,
The complex compound of ruthenium.
As it is further preferred that the catalyst is double (dicyclopentadiene) tetrafluoro boric acid rhodiums.
The preparation method of described nep inhibitor intermediate, it is characterised in that：The Phosphine ligands, selected from CK-01, CK-
02,CK-03,CK-04.
Preferably, the Phosphine ligands select CK-04.
Beneficial effect：The preparation method of the nep inhibitor intermediate that the present invention is provided,.
Specific embodiment
The present invention is further described with reference to specific embodiment.
The preparation method of (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid,
It is characterized in that：
Embodiment one：(R, E) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertiary butyloxycarbonyls are sequentially added in autoclave
Base) amino) -2- methyl -2- penetenoic acid 381g, ethanol 3.5kg, double (dicyclopentadiene) tetrafluoro boric acid rhodium 99mg and Phosphine ligands
CK-01 221mg, replacing hydrogen, 15 kilograms of pressure, 40 DEG C of temperature, control reaction in stirring to LC completely, are filtered, and filtrate is spin-dried for
Crude product, two isomers II of chiral analysis：III=82：18.Crude product ethyl acetate and petroleum ether, are then tied again with ethanol
Crystalline substance, obtains product (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid
307g.
Embodiment two：(R, E) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertiary butyloxycarbonyls are sequentially added in autoclave
Base) amino) -2- methyl -2- penetenoic acid 381g, ethanol 3.5kg, double (dicyclopentadiene) tetrafluoro boric acid rhodium 99mg and Phosphine ligands
CK-02 230mg, replacing hydrogen, 15 kilograms of pressure, 40 DEG C of temperature, control reaction in stirring to LC completely, are filtered, and filtrate is spin-dried for
Crude product, two isomers II of chiral analysis：III=85：15.Crude product ethyl acetate and petroleum ether beating, are then tied again with ethanol
Crystalline substance, crude product ethyl acetate and petroleum ether beating, obtain product (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertiary fourths
Oxygen carbonyl) amino) -2 methyl valeric acid 280g.
Embodiment three：(R, E) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertiary butyloxycarbonyls are sequentially added in autoclave
Base) amino) -2- methyl -2- penetenoic acid 381g, ethanol 3.5kg, double (dicyclopentadiene) tetrafluoro boric acid rhodium 99mg and Phosphine ligands
CK-04 279mg, replacing hydrogen, 15 kilograms of pressure, 40 DEG C of temperature, control reaction in stirring to LC completely, are filtered, and filtrate is spin-dried for
Crude product, two isomers II of chiral analysis：III=90：10.Crude product ethyl acetate and petroleum ether beating, are then tied again with ethanol
Crystalline substance, crude product ethyl acetate and petroleum ether beating, obtain product (2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertiary fourths
Oxygen carbonyl) amino) -2 methyl valeric acid 340g.
The above is only the preferred embodiment of the present invention, it should be pointed out that：Ordinary skill people for the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (2)
1. a kind of preparation method of nep inhibitor intermediate, it is characterised in that the nep inhibitor intermediate be (2R, 4S)-
5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid, its chiral molecules structural formula are as follows：
Preparation method is as follows：(R, E) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2-
Penetenoic acid is catalyzed by catalyst and Phosphine ligands, and asymmetric reduction occurs with hydrogen, the anomeric product required for selectively obtaining
(2R, 4S) -5- ([1,1 '-xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2 methyl valeric acid；The catalyst is double
(dicyclopentadiene) tetrafluoro boric acid rhodium, the Phosphine ligands select CK-04, and chemical structural formula is as follows；
Synthetic route is as follows：
2. the preparation method of nep inhibitor intermediate according to claim 1, it is characterised in that：Reaction dissolvent is selected from first
Alcohol, ethanol or methyl alcohol and the mixed solvent of ethanol, reaction temperature are 25-50 DEG C, and the reaction time is 8-12 hours.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523964B (en) * | 2015-12-09 | 2017-05-24 | 苏州楚凯药业有限公司 | Preparation method of anti-heart-failure drug intermediate |
| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| CN109563019A (en) | 2016-08-17 | 2019-04-02 | 诺华股份有限公司 | The new method and intermediate of nep inhibitor synthesis |
| JP7138106B2 (en) | 2016-12-23 | 2022-09-15 | ノバルティス アーゲー | A novel method for the initial sacubitril intermediate |
| CN108084058A (en) * | 2017-12-15 | 2018-05-29 | 江苏中邦制药有限公司 | A kind of preparation method of LCZ696 intermediates |
| UY38072A (en) | 2018-02-07 | 2019-10-01 | Novartis Ag | COMPOSITIONS DERIVED FROM BUTANOIC ESTER SUBSTITUTED WITH BISPHENYL AS INHIBITORS OF NEP, COMPOSITIONS AND COMBINATIONS OF THE SAME |
| CN113321600B (en) * | 2020-02-28 | 2024-06-14 | 四川科伦药物研究院有限公司 | Process for preparing chiral biaryl-substituted 4-amino-butanoic acid and derivatives thereof |
| CN111269148B (en) * | 2020-04-08 | 2022-02-08 | 台州职业技术学院 | Preparation method of Sacubitril intermediate |
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| WO2009058314A1 (en) * | 2007-10-30 | 2009-05-07 | Janssen Pharmaceutica, N.V. | Enantioselective process for preparing a substituted alkanoic acid |
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| US8993631B2 (en) * | 2010-11-16 | 2015-03-31 | Novartis Ag | Method of treating contrast-induced nephropathy |
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| JP2005247715A (en) * | 2004-03-02 | 2005-09-15 | Univ Of Tokyo | Method for synthesizing ligand |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN101631765A (en) * | 2007-01-12 | 2010-01-20 | 诺瓦提斯公司 | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| WO2009058314A1 (en) * | 2007-10-30 | 2009-05-07 | Janssen Pharmaceutica, N.V. | Enantioselective process for preparing a substituted alkanoic acid |
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