CN107011203B - A kind of preparation method of LCZ696 intermediate A HU-377 - Google Patents
A kind of preparation method of LCZ696 intermediate A HU-377 Download PDFInfo
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- CN107011203B CN107011203B CN201710294596.4A CN201710294596A CN107011203B CN 107011203 B CN107011203 B CN 107011203B CN 201710294596 A CN201710294596 A CN 201710294596A CN 107011203 B CN107011203 B CN 107011203B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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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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Abstract
The invention discloses the preparation methods of LCZ696 intermediate A HU-377 a kind of, are the preparation method of compound of formula I: 2 compound of formula passes through amidation, oxidation, condensation and hydrogenation, obtains compound of formula I.The preparation method of LCZ696 intermediate (1 compound of formula) provided by the present invention has many advantages, such as that brief step, easy to operate, yield and purity is high, post-processing are simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of new preparation methods of LCZ696 intermediate A HU-377 (formula 1), belong to medication chemistry neck
Domain.
Background technique
LCZ696 is the therapeutic agent of heart failure (HFrEF) patient reduced for ejection fraction a kind of, as one
Kind economic benefits and social benefits angiotensin receptor enkephalinase inhibitor, has unique binding mode, is believed to reduce failure heart
Strain.LCZ696 combines the hypertension drug Valsartan (Diovan, common name: Valsartan) and experimental drug AHU- of Novartis
377 (1 compounds of formula).AHU377 can block threat to be responsible for the mechanism of action of reduce blood pressure 2 kinds of polypeptides, and Diovan can then improve
Vasodilation, stimulation body drain sodium and water.The safety threshold of cardiovascular drugs is high, and LCZ696 is even shown
Surmount the greater security of conventional medicine.Before this, the cardiovascular drugs serelaxin of Novartis's Devoting Major Efforts To Developing is exactly because of safety
Problem is kept outside of the door in pairs by FDA and European Union, is undoubtedly a heavy blow to Novartis.And the success of LCZ696, repayment is given
A big epoch of the Novartis in cardiovascular field.
Industry thinks, the outstanding performance of LCZ696, makes during the medicine becomes history 10 years, cardiological field obtains most heavy
One of progress wanted；Meanwhile over the next several years, cardiovascular field will can contend with without any drug with LCZ696.Some analysts
Prediction, LCZ696 sale peak value is up to 8,000,000,000 dollars, and Deutsche Bank analyst is, it is expected that reduce cardiovascular close in view of LCZ696
The sale peak value of the superior performance of key risk, the medicine is up to 6,000,000,000 dollars.Although each side's data slightly difference, unquestionably
, LCZ696 will become super heavy pound star, for Novartis bring billowing financial resources while, will also lead cardiovascular treatment greatly across
Stepping enters the new epoch.
Just because of the good action of LCZ696, everybody concern is increasingly received.Study on the synthesis as the product is outstanding
It is that the synthesis of its key intermediate AHU-377 (1 compound of formula) is also increasingly taken seriously
Patent WO2014032627 reports a kind of synthetic method of 1 compound of formula, and route is as follows:
The technique is de- by amido protecting, oxidation, condensation, hydrolysis, reduction, esterification, amino using 2 compound of formula as raw material
Protection, finally reacts 1 compound of the formula of being prepared with succinic anhydride.The technique main problem is that feed preparation process step is numerous
It is trivial, and part steps not easy purification, cause target product yield relatively low, cost is very high, is not suitable for industrialized production.
Summary of the invention
The purpose of the present invention is being directed to the deficiency of prior art, we have invented a kind of new by a large amount of experiment effort
LCZ696 intermediate (1 compound of formula) preparation method, this method step is brief, it is easy to operate, be suitble to industrialized production.
The purpose of the present invention can be achieved by the following measures:
The present invention relates to the preparation methods of 1 compound of formula:
The preparation method of compound of formula I of the invention includes the following steps: 2 compound of formula by amidation, oxidation, condensation
And hydrogenation, compound of formula I is obtained, reaction route is as follows:
In the present invention, it is related to the new preparation method of one kind of 3 compound of formula.That is 2 compound of formula and the chloro- 4- oxo of 4-
Benzyl butyrate carries out amidation process under alkaline condition, obtains 3 compound of formula.
In the present invention, formula 3 can be prepared under alkaline condition by 2 compound of formula and the chloro- 4- ketobutyric acid benzyl ester of 4-
It obtains, can usually operate as follows:
2 compound of formula Formula, solvent and alkali are mixed, the chloro- 4- ketobutyric acid benzyl ester of 4- is slowly added dropwise in control temperature
Solution, after reaction, be added water stirring after be layered, organic layer be concentrated to dryness after be added stirring solvent cooling be precipitated knot
Crystalline substance, suction filtration obtain 3 compound of formula.
In the present invention, alkali used in amidation process can be able to be three second with organic base and inorganic base, organic base
Amine, tri-n-butylamine, the tertiary amines such as diethyl isopropyl amine, inorganic base can be sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate etc..
In the present invention, the molar ratio example of 2 compound of formula and the chloro- 4- ketobutyric acid benzyl ester of 4- can for 1:0.5~
5.0, it is preferably in a proportion of 1:0.8~1.5, the ingredient proportion of the chloro- 4- ketobutyric acid benzyl ester of 4- is too low, and to will lead to substrate reactions endless
Entirely, ratio is excessively high may generate impurity.
In the present invention, solvent used in amidation process can be methylene chloride, THF, ethyl acetate, toluene etc..
For amidation process temperature general control between -10~25 degree, temperature is too low to will lead to reaction not in the present invention
Completely, temperature is excessively high is easy to produce impurity.
In the present invention, also relate to a kind of preparation method of formula 4: 3 compound of formula is under the action of potassium bromide and TEMPO
Oxidation reaction is carried out with sodium hypochlorite or DMSO- oxalyl chloride.
In the present invention, formula 4 can be prepared by 3 compound sodium hypochlorite of formula, can usually be operated as follows: by formula
3 compounds and organic solvent mixing, are added the TEMPO (tetramethyl piperidine nitrogen oxides) of potassium bromide and suitable quantity of water and catalytic amount,
Liquor natrii hypochloritis is added dropwise in cooling, and drop finishes, insulation reaction, reacts stratification after terminating to be added sodium thiosulfate stirring, organic
It is concentrated to dryness to obtain 4 compound of formula after layer washing.
In the present invention, necessary low temperature, general control sodium hypochlorite formula 3 between -10~20 DEG C when sodium hypochlorite is added dropwise
The molar ratio of compound can be 1:0.5~2.0, and preferential ratio is 1:0.8~1.1.
Formula 4 can also be aoxidized at low temperature with DMSO- oxalyl chloride by 3 compound of formula and is prepared in the present invention.
In the present invention, be related to the new preparation method of one kind of Formula 5: 4 compound of formula and ethoxycarbonyl are sub-
Ethyl triphenyl phosphine carries out condensation reaction.
5 compound of formula can be prepared by 4 compound of formula and ethoxycarbonyl ethylidene triphenylphosphine condensation reaction, usually
It operates as follows: 4 compound of formula is dissolved in organic solvent, it is anti-that the stirring of ethoxycarbonyl ethylidene triphenylphosphine is added at room temperature
It answers, water stirring layering is added after reaction, organic layer is concentrated to dryness to obtain 5 compound of formula.
The solvent of condensation reaction can be the esters solvents such as ethyl acetate, isopropyl acetate.
In the present invention, be related to the new preparation method of one kind of Formula 1: 5 compound of formula is in noble metal catalyst
In the presence of hydrogenation prepare.
Formula compound can hydrogenation be prepared in the presence of noble metal catalyst by 5 compound of formula, usually operates
It is as follows: 5 compound of formula being dissolved in organic solvent, is transferred to hydriding reactor, noble metal catalyst is added, uses hydrogen again after nitrogen displacement
Then displacement controls certain pressure and carries out hydrogenation, nitrogen is replaced after reaction, and after filters pressing, filtrate is concentrated to dryness to obtain
1 compound of formula.
In the present invention, hydrogenation solvent can be the alcohols solvents such as methanol, ethyl alcohol, or ethyl acetate isopropyl acetate
The esters solvents such as ester, preferred solvent are methanol, ethyl alcohol.
In the present invention, hydrogenation noble metal catalyst can be for palladium carbon, palladium dydroxide or ruthenium charcoal etc., and hydrogenation pressure can be with
For normal pressure to 50atm, preferred pressure range is 2~10atm.
The preparation method of LCZ696 intermediate (1 compound of formula) provided by the present invention, operation letter brief with step
Single, yield and purity is high, post-processing is simple, is suitble to the advantages that industrialized production.
Specific embodiment
The present invention will be described in detail referring to following non-limiting examples, this is not necessarily to be construed as the range of limitation invention.
The preparation of 1 formula of embodiment, 3 compound
2 compound of formula compound 22.7g formula is dissolved in 150ml methylene chloride, 15g triethylamine is added, stirs lower ice-water bath
To -5 degree, the chloro- 4- ketobutyric acid benzyl ester of 24g 4- is slowly added dropwise for 5 degree of temperature of control or less and the mixing of 50ml methylene chloride is molten
Liquid, drop Bi Ziran are warming up to 15~20 degree of insulation reactions 4~5 hours, and TLC after reaction, divides after the stirring of 100ml water is added
Layer, organic layer are concentrated to dryness, and stirring cooling after 80ml ethyl acetate dissolves by heating are added, crystallization is precipitated, suction filtration is obtained
3 compound 32.5g, HPLC purity 97.1% of formula.
The preparation of 2 formula of embodiment, 4 ester
Will 3 compound 41.7g and 300ml methylene chloride of formula put into bottle in, sequentially add water 50ml, potassium bromide 13.1g and
0.1g TEMPO opens stirring, and ice-water bath controls 0~5 degree of temperature, 10% sodium hypochlorite 75g is slowly added dropwise, drips off within about 1 hour, drips
Finish, insulation reaction 2 hours, sodium thiosulfate 10g is added after reaction and stirs 30 minutes for TLC monitoring, stratification, organic layer
It is concentrated to dryness to obtain 4 crude compound of formula after washing.Crude product is added in ethyl alcohol 110ml and is heated to 70 degree or so dissolved clarifications,
It being slow cooling to 0 degree or so crystallization 5 hours, filters, 50 degree of lower vacuum drying obtain 4 compound fine work 30.8g of formula in 8 hours,
HPLC purity 98.5%.
The preparation of 3 formula of embodiment, 5 compound
By in 4 compound 20g and 120ml isopropyl acetate of formula and investment reaction flask, 50g ethoxycarbonyl is added dropwise at room temperature
Ethylidene triphenylphosphine and 50ml isopropyl acetate mixed solution drip Bi Jixu insulated and stirred 5 hours, and TLC display reaction terminates
Afterwards, water 200ml is added into bottle, is layered after stirring, water layer 100ml isopropyl acetate extracts primary, merging organic layer,
100ml saturated brine is concentrated to dryness to obtain 5 compound 23g of formula after washed once, and direct plunges into next step without purifying.
The preparation of 4 formula of embodiment, 1 compound
By in 5 compound of 20g formula and 300ml ethyl alcohol investment hydriding reactor, 10% palladium carbon 0.8g is added, opens stirring, nitrogen is set
It changes and is replaced three times with hydrogen afterwards three times, be slowly warming up to 35~40 degree or so, Hydrogen Vapor Pressure control is kept the temperature in 7~9atm or so
Reaction, until not inhaling hydrogen.Slow cooling is to room temperature after reaction, filters pressing after nitrogen is replaced 3 times, and filtrate decompression is concentrated into
It is dry to obtain 1 crude compound of formula.Acetonitrile 120ml is added into crude product, slow cooling to 10 degree or less analysis are tied after being heated to dissolved clarification
It is 4 hours brilliant, it filters, obtains 1 compound 12.2g, HPLC purity 99.2% of formula.
Claims (5)
1. a kind of preparation method of 1 compound of formula, it is characterised in that 2 compound of formula and the chloro- 4- ketobutyric acid benzyl ester of 4- are in alkalinity
Under the conditions of carry out amidation process, obtain 3 compound of formula；3 compound of formula under the action of potassium bromide and TEMPO with sodium hypochlorite
Or DMSO- oxalyl chloride carries out oxidation reaction, obtains 4 compound of formula；4 compound of formula and ethoxycarbonyl ethylidene triphenylphosphine into
5 compound of formula is prepared in row condensation reaction；5 compound of formula, 1 chemical combination of hydrogenation preparation formula in the presence of noble metal catalyst
Object；Its reaction route is as follows:
2. according to the method described in claim 1, it is characterized in that alkali used in amidation process be selected from triethylamine, tri-n-butylamine,
One or more of diethyl isopropyl amine, sodium bicarbonate, sodium carbonate, saleratus or potassium carbonate.
3. according to the method described in claim 1, it is characterized in that mole of 2 compound of formula and the chloro- 4- ketobutyric acid benzyl ester of 4-
Than for 1:0.5~5.0, reaction dissolvent is methylene chloride, THF, ethyl acetate or toluene；Reaction temperature is -10 DEG C~25 DEG C.
4. according to the method described in claim 1, it is characterized in that the temperature of oxidation reaction be -10~20 DEG C, sodium hypochlorite with
The molar ratio of 3 compound of formula is 1:0.5~2.0.
5. according to the method described in claim 1, it is characterized in that the noble metal catalyst is palladium carbon, palladium dydroxide or ruthenium
Charcoal, hydrogenation pressure are normal pressure to 50atm, and hydrogenation solvent is methanol, ethyl alcohol, ethyl acetate or isopropyl acetate.
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| CN112592294B (en) * | 2020-12-22 | 2022-05-13 | 江苏阿尔法药业股份有限公司 | Synthetic method of shakubatu drug intermediate |
| CN115974634B (en) * | 2023-02-15 | 2023-11-28 | 瑞博(苏州)制药有限公司 | Method for preparing Sha Kuba curved compound by asymmetric catalytic hydrogenation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5962660A (en) * | 1995-03-21 | 1999-10-05 | The Scripps Research Institute | Sialyl Lewis X mimetics incorporating fucopeptides |
| 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 |
| CN105026361A (en) * | 2012-08-31 | 2015-11-04 | 浙江九洲药业股份有限公司 | New process |
-
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- 2017-04-28 CN CN201710294596.4A patent/CN107011203B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5962660A (en) * | 1995-03-21 | 1999-10-05 | The Scripps Research Institute | Sialyl Lewis X mimetics incorporating fucopeptides |
| 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 |
| CN105026361A (en) * | 2012-08-31 | 2015-11-04 | 浙江九洲药业股份有限公司 | New process |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.9 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |