CN105753741A - Method for preparing Sacubitril intermediate of anti-heart-failure medicine - Google Patents
Method for preparing Sacubitril intermediate of anti-heart-failure medicine Download PDFInfo
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- HNCUXLSIVYDGBW-GFCCVEGCSA-N CC(C)(C)OC(N[C@H](Cc(cc1)ccc1I)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@H](Cc(cc1)ccc1I)C(OC)=O)=O HNCUXLSIVYDGBW-GFCCVEGCSA-N 0.000 description 2
- 0 CC(C)(C)*C(N)=O Chemical compound CC(C)(C)*C(N)=O 0.000 description 1
- XJFJKCSCNLXBCY-GOSISDBHSA-N CC(C)(C)OC(N[C@H](Cc(cc1)ccc1-c1ccccc1)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@H](Cc(cc1)ccc1-c1ccccc1)C(OC)=O)=O XJFJKCSCNLXBCY-GOSISDBHSA-N 0.000 description 1
- PFQXZIKGYZOCFN-MRTLOADZSA-N CC(C)(C)OC(N[C@H](Cc(cc1)ccc1-c1ccccc1)C1OC1)=O Chemical compound CC(C)(C)OC(N[C@H](Cc(cc1)ccc1-c1ccccc1)C1OC1)=O PFQXZIKGYZOCFN-MRTLOADZSA-N 0.000 description 1
- FFJCJOBIONHKJL-SECBINFHSA-N COC([C@@H](Cc(cc1)ccc1I)N)=O Chemical compound COC([C@@H](Cc(cc1)ccc1I)N)=O FFJCJOBIONHKJL-SECBINFHSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- 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
- C07C227/16—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 not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a method for preparing a Sacubitril intermediate of anti-heart-failure medicine as indicated in the formula (VII).The method comprises the following steps of taking D-phenylalanine which is low in price and easy to obtain as the raw material, and conducting an iodination reaction, an esterification reaction, a Boc protection reaction, a negishi coupling reaction, a DIBAL-H reduction reaction and a wittig reaction, so that the Sacubitril intermediate is obtained through preparation.The method for preparing the Sacubitril intermediate is mild in reaction condition and environmentally friendly, compared with existing preparation methods, the yield is higher, and the method is economical, effective and suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of cardiotonic agents Sacubitril intermediate.
Background technology
In July, 2015, the most soul-stirring cardiotonic agents of FDA approval listing Novartis
Sacubitril/Valsartan (Sha Kubi song/Valsartan), trade name Entresto, will challenge
Successfully cardiovascular drugs.
Entresto is the ARNI inhibitor class medicine of first success of the test.ARNI inhibitor is a kind of blood
Angiotensin inhibitor, but it can strengthen the effect of endogenous natriuretic peptide (vasodilator) simultaneously.This medicine
It is a kind of economic benefits and social benefits angiotensin receptor enkephalinase inhibitor, there is the binding mode of uniqueness, be believed to
Reduce the strain of failure heart.Entresto combines the Valsartan (Diovan, common name: Valsartan) of Novartis
With experimental drug AHU-377 (Sacubitril).AHU377 (Sacubitril) can block threat and be responsible for reduction
The mechanism of action of 2 peptide species of blood pressure, Diovan then can improve vasodilation, stimulates health excretion sodium and water,
Both play pharmacological action the most jointly by reaction forming.
Patent WO2014032627 discloses the preparation method of a kind of Sacubitril intermediate, its synthetic route
As follows:
The method is to be raw material with 4-bromobiphenyl, reacts with chiral epichlorohydrin after making grignard reagent,
Open loop obtains compound (IIa), compound (IIa) and succimide generation nucleophilic substitution generationization
Compound (IIIa), uses the diethyl azodiformate acceptor as hydrogen in reaction.Compound (IIIa) exists
Hydrolysis occurring under conditions of hydrochloric acid reflux, generates compound (IVa), compound (IVa) carries out boc
Protection, generates compound (Va), and compound (Va) occurs TEMPO oxidation reaction to generate compound (VI),
There is Witting reacting generating compound (VII) in compound (VI).But the defect of said method is, ring
Oxygen chloropropane is that emphasis supervises hazardous chemical, and zoopery proves there is potential carcinogenesis, should avoid making for a long time
With；Diethyl azodiformate, to light, heat and vibrations sensitivity, can produce high-explosive during heating；Hydrolysis needs
By hydrochloric acid reflux, severe reaction conditions, bring danger to large-scale production.
Journal of Medicinal Chemistry, reports one in 1995, Vol.38, No.10 1691
The preparation method of Sacubitril intermediate, its synthetic route is as follows:
The method is as initiation material with compound (Ib), higher with TFMS anhydride reactant generation activity
Compound (IIb), under the catalysis of tetra-triphenylphosphine palladium, there is Suzuki in compound (IIb) and phenyl boric acid
Reaction, generates compound (IIIb), and compound (IIIb) generates compound (IVb), compound through hydrolysis
(IVb) and N, O-dimethyl hydroxylamine generation condensation reaction generate compound (Vb), compound (Vb) warp
Lithium Aluminium Hydride reduction generates compound (VI), and compound (VI) occurs Witting reacting generating compound (VII).
But the defect of said method is, raw material (Ib) price is costly, the most honest and the cleanest at market row at present
The industrial goods of valency can be bought；The palladium catalyst that Suzuki reaction is used is relatively costly, and reclaims difficulty；Lithium Aluminium Hydride
Meet water and explosive decomposition easily occurs, bring danger to large-scale production.Before good medicinal of Sacubitril
Scape, it is therefore desirable to develop the preparation method of the Sacubitril intermediate of a kind of economy, safety.
Summary of the invention
The invention aims to overcome deficiency of the prior art to provide a kind of cardiotonic agents
The preparation method of Sacubitril intermediate, uses the method for the present invention to prepare Sacubitril intermediate, reaction
Mild condition, environmental protection, and yield are higher than existing preparation method, economical and effective, are suitable to large-scale work
Industry metaplasia is produced.
The preparation method of a kind of cardiotonic agents Sacubitril intermediate that the present invention proposes, synthetic route includes:
The preparation method of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) that the present invention proposes,
It is characterized in that, described preparation method includes:
Step one: formula (I) compound obtains formula (II) compound through iodide reaction
Step 2: formula (II) compound obtains formula (III) compound through esterification
Step 3: the amino of formula (III) compound obtains formula (IV) compound through Boc protection reaction
Step 4: formula (IV) compound and halogeno-benzene obtain formula (V) compound through negishi coupling reaction
Step 5: formula (V) compound obtains formula (VI) compound through DIBAL-H reduction reaction
Step 6: formula (VI) compound obtains formula (VII) compound through witig reaction
The preparation method of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) that the present invention proposes
Further preferred scheme be:
Solvent used by iodide reaction described in step one is acetic acid；Oxidant used by described iodide reaction is acid iodide
Sodium.
Solvent used by esterification described in step 2 is methyl alcohol；Activator used by described esterification is chlorination
Sulfoxide.
Described in step 3, the solvent used by Boc protection reaction includes oxolane and water, acetonitrile and water, dichloromethane
Alkane, or dioxane；Alkali used by described Boc protection reaction includes sodium carbonate, potassium carbonate, NaOH
Or triethylamine.
The catalyst used by negishi coupling reaction described in step 4 is Raney nickel or palladium catalyst；Step
Halogeno-benzene described in four is bromobenzene or iodobenzene；Solvent used in described negishi coupling reaction be ether or
Oxolane；Zincon used in described negishi coupling reaction is that grignard reagent prepares with zinc chloride displacement.
Wherein, described Raney nickel is 1,2-double (diphenylphosphine) ethane chlorination nickel, nickel acetylacetonate, double (triphenyl
Phosphorus) nickel chloride or double-1,5-cyclo-octadiene nickel；Described palladium catalyst is four triphenyl phosphorus palladiums, double (triphenylphosphines)
Palladium bichloride or double (two subunit acetone) palladium.
Described in step 5 through the solvent used by DIBAL-H reduction reaction be toluene or dichloromethane；Step 6 institute
State the solvent used by witig reaction and include ethyl acetate, dichloromethane, oxolane or DMF.
Wherein, described in step 3, the concrete steps of Boc protection reaction include: compound (III) is dissolved in four
In hydrogen furans, add water and sodium carbonate, be cooled to-5-10 DEG C, drip Boc acid anhydrides, warm naturally to room temperature,
Stirring 3-14h, after reaction terminates, steams oxolane, and through extracting, wash, being dried, crystallization prepares
Compound (IV).
Wherein, described in step 4, negishi coupling reaction concrete steps include: be dissolved in oxolane by bromobenzene,
It is made into bromobenzene tetrahydrofuran solution stand-by；In the container filling magnesium powder and iodine, bromobenzene is added under the protection of nitrogen
Tetrahydrofuran solution, treats that the color of iodine is decorporated, and continues dropping bromobenzene tetrahydrofuran solution, and heat release is obvious, dropping
Completing, continue stirring 30-120min, solution is grey black, adds anhydrous zinc chloride, continues stirring 1-3h；
Add 1, double (diphenylphosphine) the ethane chlorination nickel of 2-and compound (IV), 3-6h is stirred at room temperature；After having reacted
Add the hydrochloric acid reaction of 1N, steam oxolane, then by extracting, wash, being dried, preparation of decolouring
Obtain compound (V).
Wherein, described in step 5, the concrete steps of DIBAL-H reduction reaction include: by molten for compound (V)
In dichloromethane, it is cooled to-78 DEG C under nitrogen protection, the hexane solution of dropping DIBAL-H, wherein
The concentration of the hexane solution of described DIBAL-H is 1-2M, is incubated 1-2h at-78--70 DEG C, prepares
Compound (VI)；Wherein compound (VI) is unstable, is not isolated and directly carries out next step reaction；
The concrete steps of witig reaction described in step 6 include: the compound (VI) prepared to step (5)
The middle dichloromethane solution adding tin reagent of loving and respect one's elder brother Wei, is incubated 1-2h at-78--70 DEG C, then warms naturally to
20-25 DEG C, stir 3-14h, after reaction terminates, reactant liquor is added in saturated potassium sodium tartrate solution, stirring
30-120min, through extracting, washing, be dried prepare compound (VII)；Love and respect one's elder brother wherein said Wei tin reagent
Dichloromethane solution be Wei is loved and respect one's elder brother formulated in the dichloromethane solution that tin reagent joins.
The preparation method of a kind of anti-heart failure medicine Sacubitril intermediate that the present invention provides, compared with prior art
Have the beneficial effect that:
(1) raw material (I) compound more of the prior art (Ib) that step one of the present invention uses is cheap and easy to get；Should
Reaction is at European Journal of Organic Chemistry:nb.5:(2006): existing in p.1216-1221
Report, reaction yield is high, and easy purification is suitable for industrialized production.
(2) step 2 of the present invention reaction is used reagent methyl alcohol and thionyl chloride are cheap and easy to get；Reaction condition is gentle；
Yield is the highest；Post processing is simple, and solvent evaporated i.e. can get compound (II), is suitable for industrialized production.
(3) step 3 of the present invention, this reaction is the reaction that the art is highly developed；Reaction yield is high；Reaction
Mild condition, is suitable for industrialized production.
(4) reaction of the negishi in step 4 of the present invention is the reaction that the art is highly developed, reaction condition
Gentle；Reaction yield is high；There is obvious advantage relative to other coupling reaction, be possible not only to avoid using
Relatively costly phenyl boric acid and the serious organo-chromium reagent of environmental pollution, and just can be efficient with Raney nickel
Mediate this reaction, with low cost, it is suitable for industrialized production.
(5) reduction of the DIBAL-H in step 5 of the present invention ester group is the witig reaction in aldehyde radical and step 6
Being all the most classical reaction of the art, reaction yield is higher, and reaction stability is good, is suitable for industry metaplasia
Produce.
In sum, the preparation method of a kind of Sacubitril intermediate disclosed by the invention, use the present invention's
Method prepares Sacubitril intermediate, and reaction condition is gentle, environmental protection, and yield is than existing preparation
Method is high, and economical and effective is suitable to large-scale industrial production.
Accompanying drawing explanation
The nucleus magnetic hydrogen spectrum figure of Fig. 1: formula (II) compound.
The nucleus magnetic hydrogen spectrum figure of Fig. 2: formula (III) compound.
The nucleus magnetic hydrogen spectrum figure of Fig. 3: formula (IV) compound.
The nucleus magnetic hydrogen spectrum figure of Fig. 4: formula (V) compound.
The nucleus magnetic hydrogen spectrum figure of Fig. 5: formula (VII) compound.
Detailed description of the invention
Below by way of specific embodiment, technical scheme is described, but protection scope of the present invention is not limited to
This.
Embodiment 1
Step one: formula (I) compound obtains formula (II) compound through iodide reaction
85.2g compound (I) is dissolved in 470mL acetic acid and the 62mL concentrated sulfuric acid, under stirring, adds 52.4g
Iodine and 20.4g sodium iodate, with exothermic phenomenon.Finish, be heated to 70 DEG C, be incubated 20 hours, solution in
Claret.Add 4g sodium metaperiodate, continue stirring at 70 DEG C, until reactant liquor becomes crocus.Steam vinegar
Acid, adds 800ml water, extracts impurity with 500mL ether and 500mL dichloromethane.Aqueous phase 11g lives
Property carbon decoloring, filter, filtrate with NaOH regulate PH to 5, a large amount of white solids separate out, suction filtration.With
1700mL water and 650mL ethanol rinse filter cake, dry cake, obtain 118g white solid, i.e. compound
(II), yield 87%.The nmr analysis data of compound (II) are as follows: ' H NMR (DMSO) δ 7.61 (d,
2H),7.05(d,2H),3.33(t,lH),3.01(dd,lH),2.48(dd,1H).See Fig. 1.
Step 2: formula (II) compound obtains formula (III) compound through esterification
20g compound (II) is added in 100mL methyl alcohol and breaks up, it is impossible to molten clearly, be cooled to 0 DEG C, slowly
Dropping 20mL thionyl chloride, reactant liquor gradually becomes clarification, after stirring a period of time, has again a large amount of white solid
Separate out.Dripping and finish, warm naturally to room temperature, stirring reaction is overnight.Reacting complete, solvent evaporated, solid is used
100mL ethyl acetate is pulled an oar, and suction filtration obtains 22.5g white solid, i.e. compound (III), yield 99%.
The nmr analysis data of compound (III) are as follows: ' H NMR (CDCl3) δ 8.66 (s, 3H), 7.64 (d, 2H),
7.10(d,2H),4.26(t,lH),3.66(s,3H),3.03(m,2H).See Fig. 2.
Step 3: the amino of formula (III) compound obtains formula (IV) compound through Boc protection reaction
50g compound (III) is dissolved in 500mL oxolane, adds 250mL water and 38.8g carbonic acid
Sodium, select sodium carbonate is preferred version herein, and in Boc of the present invention protection reaction, alkali used is not limited only to carbon
Acid sodium, it is also possible to select potassium carbonate, NaOH or triethylamine；It is cooled to 0 DEG C, drips Boc acid anhydrides, add
Finishing and warm naturally to room temperature, reaction stirring 14h is overnight.React complete, steam oxolane, use 750mL
Ethyl acetate extracts, and merges organic layer, and organic layer saturated nacl aqueous solution washs, then does with anhydrous sodium sulfate
Dry except water, steam ethyl acetate, add the making beating of 150mL n-hexane, at 0 DEG C to 5 DEG C, crystallization is overnight, obtains
49g white solid, i.e. compound (IV), yield 83%.The nmr analysis data of compound (IV) are such as
Under: ' H NMR (CDCl3) δ 7.61 (d, 2H), 6.86 (d, 2H), 4.98-4.96 (m, lH), 4.59-4.55
(m,lH),3.72(s,3H),3.08(q,lH),2.98(q,lH),1.41(s,9H).See Fig. 3.
Step 4: formula (IV) compound and halogeno-benzene obtain formula (V) compound through negishi coupling reaction
Being added by the iodine of 1.38g magnesium powder and trace in 250mL there-necked flask, nitrogen is protected, by molten for 8.5g bromobenzene
In 85mL oxolane, wiring solution-forming is stand-by.The tetrahydrofuran solution of a small amount of bromobenzene is added in there-necked flask,
Treating that the color of iodine is decorporated, continue the tetrahydrofuran solution of dropping bromobenzene, heat release is obvious, drips and finishes, and continues stirring
30 minutes, magnesium powder almost disappeared, and solution is grey black.Adding anhydrous zinc chloride, a large amount of white solids separate out,
Continue stirring 1 hour.Add double (diphenylphosphine) the ethane chlorination nickel of 1.3g1,2-and 20g compound (IV),
It is stirred at room temperature 3 hours.React complete, add the reaction of 1N hydrochloric acid, steam THF, use 255mL second
Acetoacetic ester extracts, and merges organic layer, and organic layer saturated sodium-chloride washs, and anhydrous slufuric acid ammonium is dried, and has been dried
Bi Hou, with activated carbon decolorizing, suction filtration goes out activated carbon, is evaporated filtrate, and residue n-hexane is pulled an oar, and obtains
14.5g white solid, i.e. compound (V), yield 83%.The nmr analysis data of compound (V) are such as
Under: ' H NMR (CDC13) δ 7.56 (d, 2H), 7.51 (d, 2H), 7.44 (t, 2H), 7.32 (t, lH), 7.18
(d,2H),5.01(d,lH),4.62(q,lH),3.72(s,3H),3.15(m,2H),1.39(s,9H).See Fig. 4.
Wherein, the halogeno-benzene that step 4 is selected is bromobenzene, and catalyst selects 1, double (diphenylphosphine) ethane chlorination of 2-
Nickel is preferred version, the invention is not restricted to this, and the halogeno-benzene of the present invention can also select iodobenzene, catalyst
Nickel acetylacetonate, double (triphenyl phosphorus) nickel chloride, double-1,5-cyclo-octadiene nickel, four triphenyls can also be selected
Phosphorus palladium, double (triphenylphosphine) palladium bichloride or double (two subunit acetone) palladium.
Step 5: formula (V) compound obtains formula (VI) compound through DIBAL-H reduction reaction
Being dissolved in 200mL dichloromethane by 35g compound (V), nitrogen is protected, and is cooled to-78 DEG C, slow
The slow hexane solution (1M) dripping 200mlDIBAL-H, drips and finishes, and is incubated 1 hour at-78 DEG C, preparation
Obtain formula (VI) compound.Compound (VI) is unstable, does not separate and directly carries out next step reaction.
Step 6: formula (VI) compound obtains formula (VII) compound through witig reaction
Add, in formula (VI) compound that step (5) prepares, tin reagent of loving and respect one's elder brother the Wei prepared in advance
Dichloromethane solution, and it is incubated 1 hour at-78 DEG C, then warm naturally to 25 DEG C, stirring reaction 14h mistake
Night.React complete, reactant liquor is poured in the saturated potassium sodium tartrate solution of 1500mL, be stirred vigorously 30
Minute, aqueous layer with ethyl acetate extracts three times, merges organic layer, and organic layer saturated nacl aqueous solution washs,
Anhydrous sodium sulfate is dried.Steam solvent, crude product through being refining to obtain 38g white solid, i.e. compound (VII),
Yield 80%.The nmr analysis data of compound (VII) are as follows: ' H NMR (CDC13) δ 7.52 (d, 2H),
7.48(d,lH),7.44(t,2H),7.35(t,lH),7.25(d,2H),6.54(d,lH),4.70(s,lH),4.61(s,
lH),4.18(q,2H),2.94(dd,lH),2.83(dd,lH),1.74(s,3H),1.40(s,9H),1.28(t,3H)。
See Fig. 5.
The explanation being not directed in the detailed description of the invention of the present invention belongs to techniques well known, refers to known skill
Art is carried out.
The present invention, through validation trial, achieves satisfied trial effect.
Embodiments of the present invention are not limited to above-described embodiment, and that makes on the premise of without departing from present inventive concept is various
Within change belongs to protection scope of the present invention.
Claims (10)
1. the preparation method of the cardiotonic agents Sacubitril intermediate shown in a formula (VII), it is characterised in that
Described preparation method includes:
Step one: formula (I) compound obtains formula (II) compound through iodide reaction
Step 2: formula (II) compound obtains formula (III) compound through esterification
Step 3: the amino of formula (III) compound obtains formula (IV) compound through Boc protection reaction
Step 4: formula (IV) compound and halogeno-benzene obtain formula (V) compound through negishi coupling reaction
Step 5: formula (V) compound obtains formula (VI) compound through DIBAL-H reduction reaction
Step 6: formula (VI) compound obtains formula (VII) compound through witig reaction
2. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 1
Method, it is characterised in that: the solvent used by iodide reaction described in step one is acetic acid；Used by described iodide reaction
Oxidant be sodium iodate.
3. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 1
Method, it is characterised in that: the solvent used by esterification described in step 2 is methyl alcohol；Used by described esterification
Activator be thionyl chloride.
4. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 1
Method, it is characterised in that: described in step 3, the solvent used by Boc protection reaction includes oxolane and water,
Acetonitrile and water, dichloromethane or dioxane；Alkali used by described Boc protection reaction includes sodium carbonate, carbon
Acid potassium, NaOH or triethylamine.
5. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 1
Method, it is characterised in that: described in step 4, the catalyst used by negishi coupling reaction is Raney nickel or palladium
Catalyst；Halogeno-benzene described in step 4 is bromobenzene or iodobenzene；Molten used by described negishi coupling reaction
Agent is ether or oxolane；Zincon used by described negishi coupling reaction is grignard reagent and zinc chloride
Displacement prepares.
6. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 5
Method, it is characterised in that: described Raney nickel is 1, double (diphenylphosphine) the ethane chlorination nickel of 2-, nickel acetylacetonate,
Double (triphenyl phosphorus) nickel chlorides or double-1,5-cyclo-octadiene nickel；Described palladium catalyst is four triphenyl phosphorus palladiums, double
(triphenylphosphine) palladium bichloride or double (two subunit acetone) palladium.
7. the preparation of the cardiotonic agents Sacubitril intermediate shown in a kind of formula (VII) as claimed in claim 1
Method, it is characterised in that: described in step 5, the solvent used by DIBAL-H reduction reaction is toluene or dichloromethane
Alkane；Solvent used by witig reaction described in step 6 include ethyl acetate, dichloromethane, oxolane or
DMF。
8. in the cardiotonic agents Sacubitril shown in a kind of formula (VII) as described in claim 1 to 7 is arbitrary
The preparation method of mesosome, it is characterised in that the concrete steps of step (3) described Boc protection reaction include:
Compound (III) is dissolved in oxolane, adds water and sodium carbonate, be cooled to-5-10 DEG C, drip Boc
Acid anhydrides, warms naturally to room temperature, stirs 3-14h, after reaction terminates, steams oxolane, through extraction, washes
Wash, be dried, crystallization prepares compound (IV).
9. in the middle of the cardiotonic agents Sacubitril shown in a kind of formula (VII) as described in claim 1 to 7 is arbitrary
The preparation method of body, it is characterised in that described in step 4, negishi coupling reaction concrete steps include: by bromine
Benzene is dissolved in oxolane, is made into bromobenzene tetrahydrofuran solution stand-by；Under the protection of nitrogen to fill magnesium powder and
The container of iodine adds bromobenzene tetrahydrofuran solution, treats that the color of iodine is decorporated, continue dropping bromobenzene oxolane molten
Liquid, heat release is obvious, is added dropwise to complete, and continues stirring 30-120min, and solution is grey black, adds anhydrous chlorination
Zinc, continues stirring 1-3h；Adding 1, double (diphenylphosphine) the ethane chlorination nickel of 2-and compound (IV), room temperature is stirred
Mix 3-6h；Add the hydrochloric acid reaction of 1N after having reacted, steam oxolane, then by extracting, washing
Wash, be dried, decolouring prepares compound (V).
10. in the cardiotonic agents Sacubitril shown in a kind of formula (VII) as described in claim 1 to 7 is arbitrary
The preparation method of mesosome, it is characterised in that described in step 5, the concrete steps of DIBAL-H reduction reaction include:
Compound (V) is dissolved in dichloromethane, is cooled to-78 DEG C under nitrogen protection, dropping DIBAL-H's
Hexane solution, the concentration of the hexane solution of wherein said DIBAL-H is 1-2M ,-78--70 DEG C of guarantor
Temperature 1-2h, prepares compound (VI)；The concrete steps of witig reaction described in step 6 include: will
Compound (VI) adds the dichloromethane solution of tin reagent of loving and respect one's elder brother Wei, at-78--70 DEG C of insulation 1-2h, then from
So it is warming up to 20-25 DEG C, stirs 3-14h, after reaction terminates, reactant liquor is added to saturated sodium potassium tartrate tetrahydrate molten
In liquid, stir 30-120min, through extract, washing, dry prepare compound (VII).
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| CN201610266698.0A CN105753741A (en) | 2016-04-26 | 2016-04-26 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
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| CN107382785A (en) * | 2017-08-09 | 2017-11-24 | 常州制药厂有限公司 | One planting sand storehouse must bent key intermediate preparation method |
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