CN108203396A - A kind of synthesis of enkephalinase inhibitor - Google Patents
A kind of synthesis of enkephalinase inhibitor Download PDFInfo
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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Abstract
The invention discloses a kind of enkephalinase inhibitors for a kind of synthesis of enkephalinase inhibitor（Sacubitril）New synthetic method; this method is using L pyroglutamic acids as raw material; by multistep reaction; then epimerization crystallizes to obtain and the chiral consistent compound of formula I of Sacubitril; Formula II compound is obtained by the reaction with biphenyl after compound of formula I acylation; hydrolysis obtains formula III compound again, after formula III compound is reacted with succinic anhydride, restores to obtain Sacubitril.Present invention employs new chiral control strategies, and new chiral centre is constructed in more simple and reliable method；The control of chiral key intermediate is placed on the leading portion of synthetic line, risk is advantageously reduced and reduces cost.
Description
Technical field
The invention belongs to field of medicine and chemical technology.
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
Peptase inhibits Sacubitril and angiotensin receptor blocker Valasartan with 1：1 ratio composition, in July, 2015
It lists in the U.S. through FDA approvals, lowers in having chronic heart failure (NYHA classification II-IV) patient to heart failure for treating
It exhausts cardiovascular death and the risk being hospitalized and reduces ejection fraction.The medicine safety is good, significant in efficacy, is treatment heart failure disease
Weight pound drug and one of heart failure therapy field great breakthrough in 25 years in the past, have good market prospects.
Document WO2008083967A2 reports the method that Sacubitril is synthesized using L-Glutimic acid as starting material
（Scheme 2）, this circuit needs condition of ultralow temperature when being reacted when methylating, severe reaction conditions, cumbersome, is unfavorable for
Large-scale production, and chiral control is undesirable, selectivity is not high.
Document WO2009090251A2 also reported to be synthesized using L-Glutimic acid as raw material by asymmetric catalytic hydrogenation
The new method of Sacubitril（Scheme 3）.The method employs completely new asymmetric catalytic hydrogenation plan to the introducing of methyl
Slightly, it is selectively significantly improved, effect is good.But as a result of expensive chiral catalyst and grignard reaction
It uses, causes cost higher, there is promotion and improved space.
Invention content
In view of the above-mentioned problems, the invention discloses a kind of new preparation process of enkephalinase inhibitor Sacubitril.It should
Method reacts synthesis Formula VII compound using L-Glutimic acid as starting material, by several steps, then passes through epimerization reaction
Crucial chiral intermediate Formulas I is obtained, product Sacubitril is obtained by the reaction using the number step such as friedel-crafts reaction, hydrolysis.Cause
To employ new chiral control strategy, new chiral centre is constructed in more simple and reliable method, it will be chiral crucial intermediate
The control of body is placed on the leading portion of synthetic line, advantageously reduces risk and control cost.
The preparation method of Sacubitril is as follows：
This method, by upper blocking group, obtains compound V using L-Glutimic acid as starting material, wherein, R1 independences are selected from
The amido protectings group such as H or t-butyl formate, acetyl group, benzyl formate, benzyl.Chemical combination is further prepared in V compounds
Compound VII is prepared by Pd/C reduction in object VI.Formula VII compound is prepared into the presence of DBU (diazabicylo)
To compound I.
Sacubitril is prepared by following steps again in compound I：
A：Compound of formula I is dissolved in organic solvent, and acylating agent is added dropwise, and such as oxalyl chloride after the reaction was complete, is reacted with biphenyl, obtained
To Formula II compound.
B：Formula II compound is in the case where acid acts on, and such as hydrochloric acid, hydrolysis obtains formula III compound, and wherein R2 is independently selected from H
Or the alkyl of C1-C4.
C：Formula IV compound is obtained by the reaction with succinic anhydride in formula III compound.
D：Formula IV compound obtains Sacubitril by reduction reaction again.
In stepb, the product after hydrolysis is isolated and purified through 732 type cation exchange resin columns, is concentrated to give formula III
Close object.
In stepb, sodium chloride is added in into the product after hydrolysis, cooling crystallization obtains formula III chemical combination after drying
Object.
In step C, formula III compound is dissolved in absolute ethyl alcohol, is added dropwise chloroacetic chloride, after back flow reaction 12h, is cooled to room
50% sodium carbonate liquor is added dropwise in temperature, adjusts pH value to alkalescent, continues to be cooled to 5 degree or so, succinic anhydride is added portionwise, react
After completely, decompression boils off ethyl alcohol, and dilute hydrochloric acid adjusts pH value to 3-4, formula IV compound is obtained after extraction concentration.
In step C, formula III compound is dissolved in absolute ethyl alcohol, is added dropwise chloroacetic chloride, and after back flow reaction 12h, decompression distilled is removed
Ethyl alcohol is removed, then rejoins absolute ethyl alcohol, triethylamine and succinic anhydride, after complete reaction, removes solvent, residue ethyl alcohol
It is recrystallized with water, formula IV compound is obtained after drying.
In step D, the catalyst used in reduction reaction is selected from Pd/C HSiEt3/BF3 systems.
Meanwhile midbody compound II, III, IV in reaction process,
Wherein, R1 independences be selected from the amido protectings group such as H or t-butyl formate, acetyl group, benzyl formate, benzyl；R2 is independent
Selected from H or C1-C4 alkyl.
Specific embodiment
Embodiment 1：The synthesis of compound V (R1=Ac)
The synthesis reference literature of compound V (R1=Ac)（Journal of Organic Chemistry, 1986 ,vol. 51,
p. 3494–3498）Method.104g is added in into there-necked flask（0.80mol, 1eq）L-Glutimic acid and 300g
138g (2.2eq) chloroacetic chloride is added dropwise in (2.88wt.) methanol.After being added dropwise, being warming up to 55-65 DEG C, the reaction was complete to raw material.
Vacuum distillation obtains white solid after removing solvent, adds in 300g (2.88wt) toluene, 178g (2.2eq) triethylamine is added dropwise, so
69g (1.1eq) chloroacetic chloride is added dropwise again afterwards, after the completion of reaction, adds in 160g water, is layered after stirring, organic phase is successively with dilute salt
Acid, sodium bicarbonate solution, water washing obtain white solid 122g. after concentration
Embodiment 2：Compound VI (R1=Ac) synthesis
Compound VI (R1=Ac) synthesis reference literature（Synthesis, 1997,863-865）Method.By 50g
(0.27mol, 1.0eq) compound V（R1=Ac, the product in embodiment 1）, 70.6g (1.5eq) tert-butoxy it is double（Dimethyl
Amido）Methane（Bredereck reagents）, 200mL glycol dimethyl ethers be added in reaction bulb, be heated to 68-70 DEG C reaction
10h.Cooling crystallization, filtering, filter cake are washed with a small amount of solvent, compound VI (R after drying1=Ac), weight 46.3g.
Embodiment 3：Compound VII (R1=Ac) synthesis
Compound VII (R1=Ac) synthesis reference literature（Synthesis, 1997, 863-865）Method obtains.
Embodiment 3.1：By 24g (0.1mol, 1.0eq) compounds VI（R1=Ac, the product in embodiment 2）、 2.4g
10% palladium carbon, 260mL isopropanols are added in reaction bulb, are passed through hydrogen reaction, until the reaction is complete until.It filters and concentrates
Product VII (R is obtained afterwards1=Ac, HPLC analysis result show that VII is the mixture of VII-1 and VII-2, and its ratio be VII-1/
VII-2=83/17)。
Embodiment 3.2：By 12g (0.05mol, 1.0eq) compounds VI（R1=Ac, the product in embodiment 2）、 1.2g
10% palladium carbon, 80mL isopropanols are added in reaction kettle, and air in hydrogen displacement kettle is flushed with hydrogen gas to 2.0MPa, is warming up to 40-
50 DEG C of reactions keep temperature and pressure until the reaction was complete.Product VII (R is obtained after filtering and concentrating1=Ac, HPLC analysis knot
Fruit shows that VII is the mixture of VII-1 and VII-2, and its ratio be VII-1/VII-2=68/32).
Embodiment 4：Compound I (R1=Ac) synthesis
Embodiment 4.1：The synthesis reference literature of compound I（Tetrahedron, 2004,60,10277-10284）Method.It will
12g（0.06mol, 1.0eq）Compound VII (R1=Ac, dr=68/32, the product in embodiment 3.2), 100mL dichloromethanes
Alkane is added in flask, is cooled to 0-5 DEG C, and 17g (4.0eq) DBU is added dropwise.It is warming up to 20-30 DEG C to react 48 hours, add in dilute
Salt acid for adjusting pH value is to 5-6, and layering, organic layer concentration, the addition 2M LiOH aqueous solutions into residue, stirring is to the reaction was complete.
With dilute hydrochloric acid pH value is adjusted to 2-3, then be extracted with ethyl acetate.Vacuum distillation remove ethyl acetate, residue with isopropanol/
Water recrystallizes, and obtains compound I (R1=Ac), weight 4.6g (de>99%).
Embodiment 4.2：By 12g（0.06mol, 1.0eq）Compound VII (R1=Ac, dr=68/32, in embodiment 3.2
Product), 100mL methanol be added in flask, add in 20.7g (2.5eq) potassium carbonate.It is small to be warming up to 20-30 DEG C of reaction 72
When, it filters, dilute hydrochloric acid is added in filtrate and adjusts pH value to 2-3.Concentration adds in methanol distillation band water into residue, to remnants
Absolute methanol is added in object, is filtered after stirring, concentrates filtrate, residue is recrystallized with isopropanol/water, obtains compound I (R1=
), Ac weight 5.1g (de>99%).
Embodiment 5：Compound II (R1=Ac) synthesis
By 5g (0.027mol, 1.0eq) compound I (R1=Ac, the product in embodiment 4), 100mL dichloromethane, 0.2g
(0.1eq) DMF is added in there-necked flask, and the 10mL dichloromethane solutions of 4.2g (1.2eq) oxalyl chloride are then added dropwise, drip
Bi Hou reacts at room temperature 2h.- 5-0 DEG C are cooled to, adds in 7.9g (2.5eq) aluminum trichloride (anhydrous), 4.2g (1.0eq) is added in and joins
Benzene, stirring is to the reaction was complete.It adding in 2N dilute hydrochloric acid and reaction is quenched, organic phase is dried with anhydrous sodium sulfate, filtering, after concentration
6.5g compound II (R1=Ac), product is not purified, is directly used in and reacts in next step.
Embodiment 6：Compound III (R1=H, R2=H) synthesis
Embodiment 6.1：By 5.5g compounds II（R1=Ac, the product in embodiment 5）, 30mL 4M hydrochloric acid is added in flask,
It is heated to back flow reaction for 24 hours.Reaction solution is concentrated into 10mL or so, is isolated and purified through 732 type cation exchange resin columns, is received
Collect (the R of III containing compound1=Ac, R2=H) eluent, after concentration compound III (R1=H, R2=H), weight 4.15g.
Embodiment 6.2：By 5.2g compounds II（R1=Ac, the product in embodiment 5）, 35mL 4M hydrochloric acid is added to burning
In bottle, it is heated to back flow reaction for 24 hours.6g sodium chloride is added in into reaction solution, is cooled to 0-5 DEG C of crystallization, is filtered, after drying
Compound III (R1=H, R2=H), weight 4.7g.
Embodiment 7：Compound IV (R2=Et) synthesis
Embodiment 7.1：By 15g (0.05mol, 1.0eq) compounds III（R1=H, R2=H, the product in embodiment 6）、60mL
Absolute ethyl alcohol is added in there-necked flask, and 8.8g (2.2eq) chloroacetic chloride, back flow reaction 12h is added dropwise.Room temperature is cooled to, is added dropwise about
The sodium carbonate liquor of 15mL 50% adjusts pH value of solution to 8-9.Solution is cooled to 5 DEG C or so, adds in 5g (1.0eq) in batches
Succinic anhydride, stirring is to the reaction was complete, and after the completion of reaction, decompression boils off ethyl alcohol, then adjusts solution ph to 3- with dilute hydrochloric acid
4, first tertiary ether extraction obtains compound IV (R after concentration2=Et), weight 18.7g.
Embodiment 7.2：By 15g (0.05mol, 1.0eq) compounds III（R1=H, R2=H, the product in embodiment 6）、
60mL absolute ethyl alcohols, are added in there-necked flask, and 8.8g (2.2eq) chloroacetic chloride, back flow reaction 12h is added dropwise.Vacuum distillation removes second
Alcohol adds 60mL absolute ethyl alcohols, 11.0g is then added dropwise（2.1eq）Triethylamine adds 5g (1.0eq) succinic anhydride, stirring
Until the reaction was complete, solvent is distilled off, residue is recrystallized with second alcohol and water, and filtering obtains product I V (R after drying2=
), Et weight 15.3g.
Embodiment 8：The synthesis of Sacubtril
Embodiment 8.1：By 10.3g (0.025mol) compound IV (R2=Et, the product in embodiment 7), 0 .5g ice second
Acid, 50mL ethyl alcohol are added in anti-bottle, the lower palladium carbon for adding in 0.1g 10% of N2 protections.With air in hydrogen conversion bottle, it is heated to
40-50 DEG C of reaction 12h.Filtering, concentration, obtains crude product 10g, crude product can obtain purity with recrystallisation from isopropanol>99.5% product.
Embodiment 8.2：Nitrogen is protected, by 4.2g (0.01mol) compound IV (R2=Et, the product in embodiment 7),
30mL dichloromethane, 10mL acetonitriles, 3.0g（2.5eq）Triethylsilane is added in reaction bulb, is cooled to 0-5 DEG C.It is added dropwise
3.7mL (3.0eq) boron trifluoride/diethyl ether solution after being added dropwise, is warming up to 30-40 DEG C of reaction to compound IV disappearances.Reaction
After, reaction solution is transferred in the 60g saturated aqueous sodium carbonates of cooling, is layered after stirring, water layer 50mL dichloromethanes
Alkane extracts, and merges organic phase, is washed with water, is layered after standing, and product, weight 3.5g are obtained after organic phase concentration.
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 in good embodiment, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the right of invention.
Claims (10)
1. a kind of preparation method of enkephalinase inhibitor Sacubitril, it is characterised in that include the following steps：
A：Compound of formula I is reacted with biphenyl, and Formula II compound is prepared；
B：The open loop in the case where acid acts on of Formula II compound obtains formula III compound；
C：Formula IV compound is obtained by the reaction with succinic anhydride in formula III compound；
D：Formula IV compound obtains Sacubitril by reduction reaction again；
Wherein, R1Independent is selected from the amido protectings group such as H or t-butyl formate, acetyl group, benzyl formate, benzyl；R2Independent choosing
From H or C1-C4Alkyl.
2. the method as described in claim 1, in step, acylating agent used are selected from oxalyl chloride.
3. the method as described in claim 1, in stepb, the product after hydrolysis is through 732 type cation exchange resin columns
It isolates and purifies, is concentrated to give formula III compound.
4. the method as described in claim 1 in stepb, sodium chloride, cooling analysis is added in into the product after hydrolysis
Crystalline substance obtains formula III compound after drying.
5. the method as described in claim 1, in step C, formula III compound is dissolved in absolute ethyl alcohol, chloroacetic chloride, reflux is added dropwise
After reacting 12h, room temperature is cooled to, 50% sodium carbonate liquor is added dropwise, pH value is adjusted to alkalescent, continues to be cooled to 5 degree or so, divide
It criticizes and adds in succinic anhydride, after the reaction was complete, decompression boils off ethyl alcohol, and dilute hydrochloric acid adjusts pH value to 3-4, and extraction obtains formula IV after concentrating
Compound.
6. method as claimed in claim 1, in step C, formula III compound is dissolved in absolute ethyl alcohol, and chloroacetic chloride, back flow reaction is added dropwise
After 12h, decompression distilled removes ethyl alcohol, then rejoin absolute ethyl alcohol, triethylamine and succinic anhydride, after complete reaction, removes
Solvent, residue are recrystallized with second alcohol and water, and formula IV compound is obtained after drying.
7. the method as described in claim 1, in step D, the catalyst used in reduction reaction are selected from Pd/C or HSiEt3/
BF3System.
8. method as claimed in claim 1, the preparation method of compound of formula I is as follows：
Wherein, R1Independent is selected from the amido protectings group such as H or t-butyl formate, acetyl group, benzyl formate, benzyl.
9. compound II, III, IV,
Wherein, R1Independent is selected from the amido protectings group such as H or t-butyl formate, acetyl group, benzyl formate, benzyl；R2Independent choosing
From H or C1-C4Alkyl.
10. compound as claimed in claim 9, R1For H or acetyl group；R2For H or ethyl.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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