CN107602399A - A kind of preparation method of enkephalinase inhibitor intermediate - Google Patents
A kind of preparation method of enkephalinase inhibitor intermediate Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of deltorphin delta enzyme inhibitor intermediate, this method reacts to obtain target compound Formulas I, compound of formula I can be used for preparing deltorphin delta enzyme inhibitor medicine Sacubtril using compound shown in formula IV as starting material by less step.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of deltorphin delta enzyme inhibitor intermediate.
Background technology
LCZ696 (Entresto, Scheme 1) is a kind of pioneering compound drug of Novartis Co., Ltd's exploitation.The medicine is by brain coffee
Peptide enzyme level Sacubitril and angiotensin receptor blocker Valasartan are with 1：1 ratio composition, in July, 2015
List in the U.S. through FDA approvals, lower for treating in having chronic heart failure (NYHA classification II-IV) patient to heart failure
Exhaust cardiovascular death and the risk being in hospital and reduce LVEF.The medicine security is good, evident in efficacy, is treatment heart failure disease
Weight pound medicine, and one of heart failure therapy field great breakthrough in 25 years in the past, have good market prospects.
Scheme1：Entresto structure
Sacubtril synthetic method main method has following several：
It is divided into method one：Document J.Med. Chem. 1995,38,1689-1700 report former by starting of D-Tyrosine
Material, react to obtain the synthetic line of target product by nearly ten steps such as Suzuki coupling reactions, Witting reactions, hydrogenations
（Scheme 2）.The shortcomings that the method is using originals such as expensive alpha-non-natural amino acid, trifluoromethanesulfanhydride anhydride and fragrant boric acid
Material, and circuit is long, and so the cost of product is high, product price is high.
Scheme 2：Sacubitril synthetic method one
Synthetic method two：Document WO2014/032627 is reported so that with 4- bromo biphenyls, S- epoxychloropropane is that raw material passes through grignard
Reaction, light prolong reaction, oxidation reaction, Witting reacts, and hydrogenation synthesizes Sacubitril new method（Scheme
3）, this line cost has obvious advantage compared with first circuit, but step is still longer.
Scheme 3：Sacubitril synthetic method two
Synthetic method three：Document WO2011/035569, WO2015/024991 report catalytic asymmetric hydrogenation synthesis
Sacubitril method, the circuit is using 4- bromo biphenyls as Material synthesis 4- biphenylcarboxaldehydes, then is reacted and closed by Erlenmeyer
Into dehydrogenation propylhomoserin（Scheme 4）, the latter again under the catalysis of chiral catalyst with hydrogen occur asymmetric hydrogenation closed
Key chiral intermediate.
Scheme 4：Sacubitril synthetic method three
This circuit has certain novelty, but step is also longer, and being synthesized to finished product also has more than ten to walk, and due to using
Expensive chiral rhodium catalyst, so comparatively speaking cost does not have clear superiority with Article 2 circuit.
The content of the invention
The invention discloses a kind of preparation method of deltorphin delta enzyme inhibitor intermediate, specifically there is provided a kind of new
Deltorphin delta enzyme inhibitor Sacubitril preparation method, this method is using compound shown in formula IV as starting material, by less step
Suddenly intermediate 2- methyl -4- carbonyls -5- is obtained（4 '-xenyl）Valeric acid or ester（Formula II compound）, Formula II compound passes through again：
1）The reduction amination and debenzylation reaction of chiral phenyl ethylamine induction, or 2）Split after ammonia generation reduction amination, then with chiral acid,
Or 3）The reductive amination process of chiral ruthenium catalyst catalysis, or 4）The modes such as Biocatalysis method obtain compound of formula I.
Wherein, R H, methyl, ethyl or other low alkyl groups.
The route reported compared to document before, circuit of the present invention reuse target from initiation material to target product
Product prepares deltorphin delta enzyme inhibitor medicine Sacubitril, and whole technique is more shorter than the circuit of document report before, and economy is more
Height, three waste discharge is less, and cost is low, with more market competition advantage, is advantageous to improve occupation rate of market, promotes this enterprise and doctor
The development of medicine industry.
Embodiment
Embodiment 1：The synthesis of 4- biphenyl acetyl chlorides
The synthesized reference document Bioorganic and Medicinal Chemistry of 4- biphenyl acetyl chlorides, 2006, vol.
14, p. 6640-6658 methods.By 106g (0.5mol) biphenylacetic acid, 1.8g (0.025mol) N, N- dimethyl formyl
Amine, 400mL dichloromethane, it is added in 1L there-necked flasks, ice-water bath is cooled to 0 ~ 10 DEG C, and 78g (0.65mol) chlorine is added dropwise
Change sulfoxide, after being added dropwise, remove ice-water bath, be warming up to back flow reaction 16h.Solvent is removed under reduced pressure, to the remaining oil after distillation
Add 150mL normal heptanes in shape thing, be heated to 55 ± 5 DEG C of dissolvings, be subsequently cooled to 5 DEG C of crystallizations, filtering, 40 DEG C are dried under reduced pressure
Off-white powder 103.8g, yield 90%.
Embodiment 2：3- carbonyls -4-（4 '-xenyl）The synthesis of ethyl butyrate
3- carbonyls -4-（4 '-xenyl）Synthesized reference document J., Am, Chem., the Soc. 2006,6893- of ethyl butyrate
6902 methods.46g (0.2mol) 4- biphenyl acetyl chlorides are added into 500mL there-necked flasks, 250mL dichloromethane is added, stirs
Mix and dissolve to obtain settled solution.29g is added into reaction bulb（0.2mol）Michaelis acid and 52g (0.4mol) diisopropylethylamine.
25 ± 5 DEG C of insulation reaction 2h.Reaction solution 0.1M hydrochloric acid, salt solution wash successively, anhydrous sodium sulfate drying, filtering, after concentration
Yellow solid.Yellow solid is transferred in 250mL there-necked flasks, adds 150mL absolute ethyl alcohols, back flow reaction 4h.Reaction is complete
Afterwards, reaction solution is cooled to 0 DEG C, yellow solid is collected by filtration, solid is washed with cold ethanol, yellow solid 48g is obtained after drying,
Yield 85%.
Embodiment 3：(2R) -2- methyl -3- Ethyl formate -4- carbonyls -5-（4 '-xenyl）The synthesis of ethyl valerate
(2R) -2- methyl -3- Ethyl formate -4- carbonyls -5-（4 '-xenyl）The synthesized reference document of ethyl valerate
Synthesis, 1991, p162-164 methods.
Embodiment 3.1：Obtained compound 3- carbonyl is added in 14g (0.05mol) embodiment 2 into 250mL there-necked flasks
Base -4-（4 '-xenyl）Ethyl butyrate, 150mL tetrahydrofurans, stirring and dissolving, ice-water bath are cooled to 0 DEG C, add 6.7g
(0.06mol) potassium tert-butoxide, after stirring reaction 2h, 20.4g (0.075mol) is added dropwise（R）- 2- tolysulfonyl epoxide propionic acid
The 50mL tetrahydrofuran solutions of ethyl ester, after being added dropwise, it is complete to reaction to continue stirring.Add glacial acetic acid regulation reacting liquid pH value
To 4-5, filtering, yellow oily liquid is obtained after filtrate decompression distillation, residue isolates and purifies, and is directly used in and reacts in next step.
Embodiment 3.2：100mL tetrahydrofurans are added into 250mL there-necked flasks, add the hydrogen of 2.5g (0.06mol) 60%
Change sodium, ice-water bath is cooled to 0 ± 5 DEG C.The compound 3- carbonyls -4- obtained in 14g (0.05mol) embodiment 2 is added dropwise（4’-
Xenyl）Ethyl butyrate and 20.4g (0.075mol)（R）The 100mL tetrahydrofurans of -2- tolysulfonyl epoxide ethyl propionates
Mixed solution, after being added dropwise, it is complete to reaction to continue stirring.Reaction mixed liquor is transferred in frozen water in batches and is quenched, so
4-5 is arrived with acetic acid regulation reacting liquid pH value afterwards, is layered after standing, aqueous phase is extracted with 100mL methyl tertiary butyl ether(MTBE)s, and merging is organic
Phase, yellow oily liquid is obtained after vacuum distillation and is directly used in and is reacted in next step.
Embodiment 3.3：Obtained compound 3- carbonyl is added in 14g (0.05mol) embodiment 2 into 250mL there-necked flasks
Base -4-（4 '-xenyl）Ethyl butyrate, 150mL tetrahydrofurans, stirring and dissolving, ice-water bath are cooled to 0 ± 5 DEG C, add 3.3g
(0.06mol) sodium methoxide, after stirring reaction 2h, 20.4g (0.075mol) is added dropwise（R）- 2- tolysulfonyl epoxide ethyl propionates
50mL tetrahydrofuran solutions, after being added dropwise, continue stirring to reacting complete.Add glacial acetic acid and adjust reacting liquid pH value to 4-
5, filtering, yellow oily liquid 3 is obtained after filtrate decompression distillation, residue isolates and purifies, and is directly used in and reacts in next step.
Embodiment 4：(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）The synthesis of valeric acid or ester
Embodiment 4.1：(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）The synthesis of valeric acid
10g compounds (the 2R) -2- methyl -3- Ethyl formate -4- carbonyls -5- obtained into embodiment 3（4 '-xenyl）Valeric acid
The 6mL tert-butyl alcohols are added in ethyl ester, 35mL 4M hydrochloric acid, said mixture are heated to back flow reaction.After the completion of reaction, 5 are cooled to
± 5 DEG C of crystallizations, filter (2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）The crude product of valeric acid, then with after re crystallization from toluene
Obtain the target product that purity is more than 98%.
Embodiment 4.2：(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）The synthesis of valerate
10g compounds (the 2R) -2- methyl -3- Ethyl formate -4- carbonyls -5- obtained into embodiment 3（4 '-xenyl）Valeric acid
The 6mL tert-butyl alcohols are added in ethyl ester, 35mL 4M hydrochloric acid, said mixture are heated to back flow reaction.After the completion of reaction, 5 are cooled to
± 5 DEG C of crystallizations, filter (2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）The crude product of valeric acid, then with after re crystallization from toluene
Obtain the product that purity is more than 98%.
By above-mentioned product and methanol or ethanol or low alkyl group alcohol esterification, (2R) -2- methyl -4- carbonyls -5- is obtained（4’-
Xenyl）Methyl valerate obtains (2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Ethyl valerate obtains (2R) -2- first
Base -4- carbonyls -5-（4 '-xenyl）Valeric acid lower alkyl ester.
Embodiment 5：The synthesis of (2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid
Embodiment 5.1：Obtained compound (2R) -2- methyl -4- carbonyl -5- is added in 10g embodiments 4 into autoclave pressure
（4 '-xenyl）Valeric acid compound, then add 100mL saturation methanolic ammonia solutions, 1g 10% palladium carbon.It is warming up to 45 ± 5
DEG C reaction, after the completion of reaction, carefully discharges gas reactor, takes out reaction solution, filtering, the water-soluble of D- Tartaric acids is added dropwise into filtrate
Liquid, stirring reaction 2h, filtering, filter cake are washed with methanol, and filter cake is recrystallized 2 times with first alcohol and water, obtain optical purity more than 98%
(2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid.
Embodiment 5.2：Using the method for embodiment 5.2, obtained compound is added in embodiment 4 into autoclave pressure
(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Valerate, can obtain optical purity more than 98% (2R, 4S) -2- methyl -
4- amino -5- (4 '-xenyl) valerate compound.
Embodiment 5.3：Compound (the 2R)-2- methyl-4- carbonyls obtained into reaction bulb in addition 15g embodiments 4-
5-（4 '-xenyl）Valeric acid, 7.0g (R)-phenyl ethylamine, 100mL dichloromethane, 22.4g NaBH are then added in batches
(OAc)3, the reaction 24 hours of 25 ± 5 DEG C of control temperature.30mL water is added into reaction solution, stratification after stirring, collects lower floor
Organic phase, it is evaporated under reduced pressure and removes solvent, residue adds methanol dissolving, and then methanol solution is transferred in reactor, adds
The palladium carbons of 1.5g 10%, gas is flushed with hydrogen to 1.0 ± 0.5MPa, 25 ± 5 DEG C of reaction 8h of temperature control.Filtering, concentration filtrate obtain (2R, 4S) -2-
The crude product of methyl -4- amino -5- (4 '-xenyl) valeric acid, crude product with first alcohol and water recrystallize optical purity 97% target produce
Thing.
Embodiment 5.4：Using the method for embodiment 5.3, obtained compound is added in embodiment 4 into autoclave pressure
(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Valerate, can obtain optical purity more than 98% (2R, 4S) -2- methyl -
4- amino -5- (4 '-xenyl) valerate compound.
Embodiment 5.5：Compound (the 2R) -2- methyl -4- carbonyls -5- that will be obtained in 20g embodiments 4（4 '-xenyl）
Valeric acid, 20g ammonium acetates, 120mL methanol are added in autoclave pressure, after stirring and dissolving, with air in nitrogen displacement kettle, are then added
0.59g Ru[(S)-BINAP(OAc)2], with gas in hydrogen replacement reaction kettle, gas is flushed with hydrogen to 2 ± 0.5MPa, is warming up to 55
± 5 DEG C of reaction more than 36h.20 DEG C are cooled to, carefully releases gas reactor, reaction solution is transferred in flask, is removed under reduced pressure molten
Agent, methyl tertiary butyl ether(MTBE) is added in residue, be heated to 40 DEG C, stir 2 hours, cooled and filtered, filter cake is washed with the tertiary ether of first,
Obtain off-white powder (2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid, optical purity 81%.
Embodiment 5.6：Using the method for embodiment 5.5, obtained compound is added in embodiment 4 into autoclave pressure
(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Valerate, it can obtain (2R, 4S) -2- first that optical purity is more than 98%
Base -4- amino -5- (4 '-xenyl) valerate compound.
Embodiment 5.7：Compound (the 2R) -2- methyl -4- carbonyls -5- that will be obtained in 15g embodiments 4（4 '-xenyl）
Valeric acid, 20g ammonium acetates, 120mL methanol are added in autoclave pressure, after stirring and dissolving, with air in nitrogen displacement kettle, are then added
0.59g Ru[(S)-BINAP(OAc)2], with gas in hydrogen replacement reaction kettle, gas is flushed with hydrogen to 6 ± 0.5MPa, is warming up to 80
± 5 DEG C of reaction 24h.20 DEG C are cooled to, carefully releases gas reactor, reaction solution is transferred in flask, removes solvent under reduced pressure, it is residual
Methyl tertiary butyl ether(MTBE) is added in excess, is heated to 40 DEG C, is stirred 2 hours, cooled and filtered, filter cake is washed with the tertiary ether of first, obtains class
White solid (2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid, optical purity 80%.
Embodiment 5.8：Compound (the 2R) -2- methyl -4- carbonyls -5- that will be obtained in 15g embodiments 4（4 '-xenyl）
Valeric acid, 20g ammonium acetates, 120mL methanol are added in autoclave pressure, after stirring and dissolving, with air in nitrogen conversion kettle, are then added
0.5g Ru(OAc)2[(S)-MeO-BIPHEP], with gas in hydrogen replacement reaction kettle, gas is flushed with hydrogen to 2 ± 0.5MPa, heating
It is small to 60 ± 5 DEG C of reactions 48.20 DEG C are cooled to, carefully releases gas reactor, reaction solution is transferred in flask, is removed under reduced pressure molten
Agent, methyl tertiary butyl ether(MTBE) is added in residue, be heated to 40 DEG C, stir 2 hours, cooled and filtered, filter cake is washed with the tertiary ether of first,
Obtain off-white powder (2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid, optical purity 92%.
Embodiment 5.9：Using the method for embodiment 5.8, obtained compound is added in embodiment 4 into autoclave pressure
(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Valerate, can obtain optical purity more than 98% (2R, 4S) -2- methyl -
4- amino -5- (4 '-xenyl) valerate compound.
Embodiment 5.10：1L 0.1mol/L Tris/HCl buffer solutions, 1L isooctane are added into 3L three-necked flasks, then
Sequentially add compound (the 2R) -2- methyl -4- carbonyls -5- obtained in 282.3g embodiments 4（4 '-xenyl）Valeric acid,
242.4g (S)-α-phenylethylamine, 24.7g phosphopyridoxal pyridoxal phosphates, 0.5g transaminases I（From Polaromonas sp.）.35-38℃
Filtered after stirring reaction 48hrs, filter cake is washed with a small amount of isooctane, after filter cake recrystallizing methanol (2R, 4S) -2- methyl -
4- amino -5- (4 '-xenyl) valeric acid, yield 85%, e.e% ﹥ 99%.
Embodiment 5.11：Using the method for embodiment 5.10, obtained compound is added in embodiment 4 into beaker
(2R) -2- methyl -4- carbonyls -5-（4 '-xenyl）Valerate, can obtain optical purity more than 98% (2R, 4S) -2- methyl -
4- amino -5- (4 '-xenyl) valerate compound.
Embodiment 5.12：1L 0.1mol/L Tris/HCl buffer solutions, 1L isooctane are added into 3L three-necked flasks, then
Sequentially add compound (the 2R) -2- methyl -4- carbonyls -5- obtained in 282.3g embodiments 4（4 '-xenyl）Valeric acid,
242.4g (S)-α-phenylethylamine, 24.7g phosphopyridoxal pyridoxal phosphates, 1.5g transaminases II（From Burkholderia graminis）.
Filtered after 35-38 DEG C of stirring reaction 96hrs, filter cake is washed with a small amount of isooctane, after filter cake recrystallizing methanol (2R, 4S)-
2- methyl -4- amino -5- (4 '-xenyl) valeric acid, yield 40%, e.e% ﹥ 99%.
Embodiment 5.13：Using the method for embodiment 5.12, obtained compound (2R) -2- is added in embodiment 4 into beaker
Methyl -4- carbonyls -5-（4 '-xenyl）Valerate, can obtain optical purity more than 98% (2R, 4S) -2- methyl -4- amino -
5- (4 '-xenyl) valerate compound.
Embodiment 6：Sacubitril synthesis
Embodiment 6.1：By compound (2R, the 4S) -2- methyl -4- amino -5- obtained in 11g (0.04mol) embodiment 5 (4 ' -
Xenyl) valeric acid, 200mL ethanol is added in there-necked flask, is cooled to 5 DEG C ± 5,9.5g (0.08mol) thionyl chloride is added dropwise,
After being added dropwise, 60 DEG C ± 5 reaction 24h are warming up to.Reaction solution is cooled to 20 DEG C, added in saturated sodium carbonate solution and anti-
Answer liquid；Add 4.4g (0.044mol) succinic anhydride in batches again, 25 DEG C of insulation reaction 8h, after the completion of reaction, be evaporated under reduced pressure,
Concentration removes solvent, and 2M HCl to pH=3-4, ethyl acetate extraction are added into residue, and organic phase is done with anhydrous magnesium sulfate
Dry, filtering, concentration filtrate obtains Sacubitril 12.1g, yield 73%.
Embodiment 6.2：By compound (2R, the 4S) -2- methyl -4- amino -5- obtained in 0.04mol embodiments 5 (4 ' -
Xenyl) valerate hydrolyzes (2R, 4S) -2- methyl -4- amino -5- (4 '-xenyl) valeric acid in 10ml aqueous hydrochloric acid solutions,
Sacubitril 11.5g, yield 69% is prepared using the method for embodiment 6.1.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this
Among the right of invention.
Claims (10)
1. a kind of synthetic method of enkephalinase inhibitor intermediate (Formulas I), it is characterised in that Formula II compound passes through asymmetry
Reduction amination, compound of formula I is obtained,
Wherein, R H, methyl, ethyl or other low alkyl groups.
2. method according to claim 1, it is characterised in that Formula II compound is under methanol ammonia and Pd/C effects, reduction amination,
Then split to obtain compound of formula I by D- tartaric acid.
3. method according to claim 1, it is characterised in that Formula II compound is in chiral phenyl ethylamine, NaBH (OAc)3Effect issues
Raw reduction amination, then obtains compound of formula I with Pd/C debenzylations.
4. method according to claim 1, it is characterised in that Formula II compound chiral ruthenium catalyst effect under, with Ammonium Acetate,
Asymmetric reduction aminating reaction occurs for hydrogen, obtains compound of formula I.
5. method according to claim 1, it is characterised in that Formula II compound obtains compound of formula I under transaminase effect.
6. method according to claim 5, it is characterised in that described transaminase be Polaromonas sp. or
Burkholderia graminis。
7. according to the method shown in claim 2,3,4 or 5, it is characterised in that Formula II compound can as shown in formula III compound
It is prepared：
Wherein, R H, methyl, ethyl or other low alkyl groups；R1 is H, methyl, ethyl or other low alkyl groups.
8. method according to claim 7, it is characterised in that formula III compound compound can be prepared as shown in formula IV：
Wherein, R H, methyl, ethyl or other low alkyl groups；R1 is H, methyl, ethyl or other low alkyl groups.
9. Formula II compound
Wherein, R H, ethyl or other low alkyl groups.
10. formula III compound
Wherein, R H, methyl, ethyl or other low alkyl groups；R1 is H, methyl, ethyl or other low alkyl groups.
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Cited By (3)
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| US10479753B2 (en) | 2016-02-29 | 2019-11-19 | Sunshine Lake Pharma Co., Ltd | Sacubitril intermediate and preparation method thereof |
| 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 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108602785A (en) * | 2015-12-10 | 2018-09-28 | 诺华股份有限公司 | New technique and intermediate |
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| US11370739B2 (en) | 2016-02-29 | 2022-06-28 | Sunshine Lake Pharma Co., Ltd. | Sacubitril intermediate and preparation method thereof |
| 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 |
| CN112174798B (en) * | 2019-07-03 | 2023-08-08 | 山东科巢生物制药有限公司 | Synthesis method of Sakuba/valsartan sodium LCZ696 |
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