CN106187808A - The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate - Google Patents
The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate Download PDFInfo
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- CN106187808A CN106187808A CN201510233583.7A CN201510233583A CN106187808A CN 106187808 A CN106187808 A CN 106187808A CN 201510233583 A CN201510233583 A CN 201510233583A CN 106187808 A CN106187808 A CN 106187808A
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- C07—ORGANIC CHEMISTRY
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- 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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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
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- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
Abstract
The invention provides the preparation method of a kind of AHU-377, the method is with chiral glycidol benzyl oxide as initiation material, by the additive reaction with xenyl Grignard reagent, Mitsunobu is occurred to react with succimide or phthalimide, the midbody compound (4) obtained after removing benzyl protection, midbody compound (4) is oxidized to aldehyde, react with phosphorus ylide again and obtain title intermediate compound (8), intermediate 9 is obtained under the conditions of selective catalytic hydrogenation, there is the hydrolysis of single amido link again in succimide, obtain target compound (10).The method obtains target compound AHU-377 by the seven i.e. high productivities of step reaction, it is to avoid amido protecting and deprotection process, has higher Atom economy and step economy, a following route of reaction scheme 1.Present invention also offers intermediate and the preparation method of midbody compound (6) preparing AHU-377, the following route of reaction scheme 2.
Description
Technical field
The present invention relates to small-molecule drug field, relate more specifically to a kind of AHU-377 preparation method,
AHU-377 intermediate and the preparation method of AHU-377 intermediate.
Background technology
Heart failure is the syndrome that a mortality rate is the highest, for heart failure patient, so far also
Do not have medicine can significantly improve mortality rate and sickness rate, thus a kind of novel medicine is the most necessary
's.AHU-377 (CAS 149709-62-6) is a kind of enkephalinase inhibitor, and it is a kind of precursor
Medicine, can lose ethyl ester group by hydrolysis, be transformed into the LBQ657 having pharmaceutically active, have and press down
The effect of endorphine enzyme processed (NEP), the principal biological effect of NEP be make natriuretic peptide, Kallidin I and its
The degraded such as his vasoactive peptide was lost efficacy.AHU-377 forms according to mol ratio 1:1 with angiotensin valsartan
LCZ696.LCZ696 is a kind of angiotensin receptor enkephalinase inhibitor, and it can reduce blood pressure,
It is likely to become a new medicine for the treatment of heart failure.Clinical data shows, LCZ696 is for treating high blood
It is more efficient that pressure ratio is used alone valsartan.
Patent US 5,217,996 and US 5,354,892 report the synthesis of AHU-377 the earliest, synthesize road
Line is as follows:
The reaction of above-mentioned route is with non-natural D type tyrosine derivative as substrate, and price is costly, same
Time synthesis second step will use Pd catalysis Suzuki coupling reaction, the most thus prepared by route
AHU-377 is relatively costly, and synthetic route is as follows:
Patent US 8,115,016 reports again by pyroglutamic acid, prepares AHU-377 through multistep reaction
Method, the method methylation reaction is relatively difficult, and yield is the highest.Patent US 8,580,974 is reported again
Road introduces N, N-dimethyl enamine at the alpha-position of carbonyl and is converted into methyl, but above-mentioned route is for methyl
All there are some problems in the structure of chiral centre, is not suitable for amplifying production, and synthetic route is as follows:
About the synthetic method of up-to-date AHU377 intermediate, patent WO2014032627A1 reports
Utilize Grignard reagent and epichlorohydrin reaction, obtain the weight of compound AHU377 synthesis more efficiently
Wanting intermediate, synthetic route is as follows:
But, the second step of this synthetic route utilizes succimide pass through Mitsunobu reaction and introduce
Nitrogen-atoms, removes succinic acid with hydrochloric acid hydrolysis, is subsequently converted to Boc protection, at AHU377
Again by Boc deprotection in rear building-up process, introduce in product structure with succinic anhydride reaction the most again
Succinic acid part, thus the Atom economy of this method and step economy are the most relatively low.
Summary of the invention
In order to overcome the problems referred to above of the prior art, the invention provides the preparation side of a kind of AHU-377
Method, AHU-377 intermediate and the preparation method of AHU-377 intermediate.The method of the present invention is easy to operate,
Safety is good and low cost, is suitable for industrialized production.
The technical solution used in the present invention is:
On the one hand, the invention provides the preparation method of a kind of AHU-377, comprise the following steps:
A () compound (1) S-(+)-2,3-Epoxy-1-propanol benzyl oxide and xenyl Grignard reagent occur instead in organic solvent
Should generate compound (2):
There is Mitsunobu in organic solvent in (b) compound (2) succimide or phthalimide
Reacting generating compound (3)；
C () compound (3) sloughs benzyl protection, generationization in organic solvent under the effect of catalyst
Compound (4)；
D () compound (4) with oxidant in organic solvent, occurs oxidation reaction to generate compound (7)；
(e) compound (7) and phosphorus ylide reagent reacting generating compound in organic solvent (8)；
F () compound (8) selective catalytic hydrogenation in organic solvent generates compound (9)；And
G () compound (9) occurs amide hydrolysis to generate in organic solvent under conditions of acid exists
Compound (10), i.e. AHU-377；
Reaction scheme is as follows:
Further, in step (a), reaction temperature is preferably-20～0 DEG C.
Preferably, in step (a), xenyl Grignard reagent and compound (1) S-(+)-2,3-Epoxy-1-propanol benzyl oxide
Mol ratio be 1:1～1:1.5, xenyl Grignard reagent is preferably xenyl magnesium bromide.
Preferably, in step (a), organic solvent is oxolane (THF), methyltetrahydrofuran
(Me-THF), one or more in ether, methyl tertiary butyl ether(MTBE).
Further, in step (b), reaction temperature is preferably-10～25 DEG C.
Preferably, in step (b), Mitsunobu reacts at triphenylphosphine or trimethyl-phosphine, and azo
Dioctyl phthalate diisopropyl ester or diethyl azodiformate or azoformic acid methyl ester are carried out under conditions of existing.
Preferably, in step (b), organic solvent selected from toluene, dichloromethane, Isosorbide-5-Nitrae-dioxane and
One or more in oxolane.
Further, in step (c), catalyst amount is 1%-50%, and catalyst is Pd/C, palladium black
Deng.
Preferably, in step (c), organic solvent is selected from methanol, ethanol, ethyl acetate, isopropyl acetate
One or more in ester.
It is highly preferred that in step (c), reaction is carried out at 30～80 DEG C, preferably 50～70 DEG C, enters one
Walk preferably 60 DEG C.
Further, in step (d), reaction temperature is preferably-10～25 DEG C.
Further, in step (d), oxidant is Dai Si-Martin's oxidant or sodium hypochlorite etc., but
It is not limited to this, other oxidants with suitable effect can be used.
Preferably, in step (d), organic solvent one in dichloromethane, chloroform, the acetonitrile or
Several.
Further, in step (e), reaction is at room temperature carried out, preferably 20～50 DEG C, more preferably 20～30
℃。
It is highly preferred that in step (e), organic solvent is selected from dichloromethane, isopropyl acetate, acetic acid second
One or more in ester, oxolane, 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), toluene.
Preferably, in step (f), the catalyst that catalytic hydrogenation is used is Pd/C, palladium black, platinum carbon etc.,
But being not limited to this, the similar catalyst that can play suitable catalytic effect all can use.
It is highly preferred that in step (f), catalytic hydrogenation is at room temperature carried out, preferably 20～50 DEG C, more preferably
20～30 DEG C.
It is highly preferred that in step (f), organic solvent is selected from ethanol, methanol, oxolane, 2-methyl four
One or several in hydrogen furan, toluene, dichloromethane, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE)
Kind.
Further, in step (g), acid is hydrochloric acid, acetic acid or its mixture.
Preferably, in step (g), hydrolysis is carried out at 70 DEG C～90 DEG C, preferably 75～85 DEG C,
Further preferred 80 DEG C.
On the other hand, present invention also offers a kind of intermediate preparing AHU-377, it is such as following formula (II)
Shown compound:
Wherein, X is hetero atom, and hetero atom is preferably N or O；
R1Represent H or succinyl or phthalimide-based；
R2Represent benzyl or substituted benzyl；
R3Represent and replace or unsubstituting aromatic yl group.
It is highly preferred that X is O, R1For H, R2For benzyl, R3It is specially such as following formula (2) institute for phenyl, i.e. intermediate
The compound shown:
It is highly preferred that X is N, R1For phthalimide-based, R2For benzyl, R3It is specially for phenyl, i.e. intermediate
Compound as shown in following formula (3):
It yet still another aspect, the invention provides a kind of intermediate preparing AHU-377, it is such as following formula (III)
Shown compound:
Wherein, R4Represent C1-C6Alkyl；
R5Represent and replace or unsubstituting aromatic yl group.
Preferably, R4For ethyl, R5For phenyl, intermediate is specially the chemical combination as shown in following formula (8) or formula (9)
Thing:
On the other hand, present invention also offers the preparation of a kind of AHU-377 intermediate such as following formula (6)
Method, comprises the following steps: compound (4) is occurring hydrolysis generationization under acid or alkaline conditions
Compound (5), the upper Boc protection group of compound (5) obtains compound (6),
Preferably, above-mentioned acid condition is by using other formation of hydrochloric acid or hydrochloric acid, and alkalescence condition is by making
Formed by one or more in sodium hydroxide, potassium hydroxide, Feldalat NM, sodium tert-butoxide, potassium tert-butoxide.
It is highly preferred that the hydrolysis of above-claimed cpd (4) is carried out in a heated condition, preferably at 50 DEG C
Carry out to reflux temperature.
Wherein, the solvent used in the above steps of the present invention can use other with identical functions
Solvent replaces, and is not limited to described solvent, and those skilled in the art can use by selectivity according to actual needs.
Raw material and reagent that in the present invention, each step is used all can be bought by commercial sources, it is possible to according to often
Rule chemical means synthesis, such as compound (3) can directly be bought, it is possible to is synthesized by said method.
Compared with prior art, the invention have the advantages that and the invention provides a kind of AHU-377's
Preparation method, prepare the midbody compound of AHU-377 and the intermediate of AHU-377.The side of the present invention
Method is avoided using expensive non-natural amino acid starting material tyrosine, and easy to operate, and safety is good.The present invention
Reaction scheme use low in raw material price be easy to get, be not related to environmentally harmful solvent, intermediate and product
Thing is isolated and purified easily, and route is shorter, decreases loaded down with trivial details protection deprotection process, is suitable for large-scale production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, in order to those skilled in the art can
It is more fully understood that the present invention, thus protection scope of the present invention is made apparent clear and definite defining.
Embodiment 1
Synthesis compound 2
Under inert gas shielding, add in 500mL there-necked flask under room temperature compound 1 (10g, 1
Eq), after 90mL THF dissolves, add CuI (4.814g, 0.1eq), system is moved to low temperature bath
In when being cooled to-20 DEG C, start to drip xenyl magnesium bromide, temperature not higher than-10 DEG C in controlling.Drip to finish and close
Refrigeration, recovers to room temperature reaction overnight.Reactant liquor completely, is poured into saturated NH by reaction4Cl (10vol,
0.5h is stirred under room temperature in 100mL).Sucking filtration, filter cake is with a small amount of EA drip washing, and filtrate is transferred to separatory
Separatory in funnel, aqueous phase EA (10vol × 2,100mL × 2) extracts, and merges organic facies, saturated
NaHCO3、NH4Cl, Brine each 150mL (15vol) wash once, anhydrous MgSO4It is dried, takes out
Filter, is concentrated to give white solid.Cross column purification and obtain product 15.2g, yield 78%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 7.57 (d, J=7.6Hz, 2H), 7.52 (d, J=8.1Hz,
2H), 7.42 (t, J=7.6Hz, 2H), 7.38 7.25 (m, 8H), 4.62 4.47 (m, 2H), 4.09 (dd,
J=6.7,3.5Hz, 1H), 3.54 (dd, J=9.5,3.5Hz, 1H), 3.43 (dd, J=9.4,6.9Hz,
1H), 2.84 (d, J=6.6Hz, 2H), 2.38 (s, 1H).
Embodiment 2
Synthesis compound 3
In inert gas shielding, in 500mL there-necked flask, at room temperature add Ph3P (18.54g, 2eq),
240mL DCM dissolves, and adds succimide (6.44g), compound 2 (15g), and ice-water bath drops
Temperature is to about 0 DEG C, and dropping DIAD (14mL) drips complete, and reaction is gone to room temperature reaction.Raw material
Reaction completely, adds water (100mL) cancellation reaction in system, stirs 10min；Separatory, aqueous phase is used
DCM (100mL × 2) extracts, and merges organic facies, saturated Brine 100mL × 2) wash, anhydrous MgSO4
It is dried, sucking filtration, is spin-dried for obtaining white solid；Cross column purification and obtain product 15.4g, yield 82%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 7.56 (d, J=7.4Hz, 2H), 7.49 (d, J=8.0Hz,
2H), 7.42 (t, J=7.6Hz, 2H), 7.37 7.30 (m, 3H), 7.27 (d, J=6.7Hz, 3H), 7.22
(d, J=8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J=12.0Hz, 1H), 4.45 (d, J=12.0Hz,
1H), 4.06 (t, J=9.6Hz, 1H), 3.70 (dd, J=10.0,5.2Hz, 1H), 3.23 (dd, J=13.8,
10.3Hz, 1H), 3.14 3.00 (m, 1H), 2.48 (d, J=4.0Hz, 4H).
Embodiment 3
Synthesis compound 4
Inert gas shielding, adds compound 3 (18.81g), 470mL in 1L there-necked flask under room temperature
EtOH dissolves, and adds Pd/C, replaces H2Three times, move to heat in oil bath 60 DEG C of reactions.Raw material reaction
Completely, system is removed oil bath, reactant liquor suction filtered through kieselguhr, is concentrated to give crude product.Cross column purification and obtain sterling
11.8g, yield 81.2%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 7.57 (d, J=7.8Hz, 2H), 7.51 (d, J=7.8Hz,
2H), 7.42 (t, J=7.5Hz, 2H), 7.33 (t, J=7.2Hz, 1H), 7.26 (d, J=7.2Hz, 2H),
4.55 (d, J=5.2Hz, 1H), 4.06 3.97 (m, 1H), 3.86 (dd, J=12.0,3.1Hz, 1H),
3.16 (dd, J=8.1,2.9Hz, 2H), 2.58 (t, J=7.0Hz, 4H), 1.26 (s, 2H).
Embodiment 4
Synthesis compound 7
Inert gas shielding, adds Dess-Martin oxidant (767.7 in 25mL there-necked flask under room temperature
Mg), 10mL DCM dissolves, and system is cooled to-10 DEG C, adds 4 (500mg).Raw material reaction is complete,
Adding each 5mL of saturated NaHCO3 and Na2S2O3 in system, cancellation is reacted, and stirs 10min；
Aqueous phase DCM (10mL × 3) extracts, and merges organic facies, each 30mL of saturated NaHCO3, Brine
Washing, anhydrous MgSO4 is dried, sucking filtration, is spin-dried for obtaining crude product, is directly used in and casts single step reaction.
Embodiment 5
Synthesis compound 8
Inert gas shielding, adds 7 (497.5mg), 10mL DCM in 500mL there-necked flask under room temperature
Dissolving ice-water bath is lowered the temperature, and adds phosphorus ylide reagent (880.6mg), system removes ice-water bath, room temperature
Lower reaction.The complete stopped reaction of raw material reaction, adds water (5mL) cancellation reaction in system.Separatory,
Aqueous phase DCM (10mL × 2) extracts, and merges organic facies, and saturated Brine 20mL × 2 are washed, anhydrous
MgSO4 is dried, sucking filtration, is spin-dried for obtaining crude product.Cross column purification and obtain product 563mg, productivity 90%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 7.60 7.53 (m, 2H), 7.51 (d, J=8.1Hz, 2H),
7.42 (t, J=7.6Hz, 2H), 7.33 (d, J=7.3Hz, 1H), 7.23 (d, J=8.1Hz, 2H), 7.13
(dd, J=9.2,1.5Hz, 1H), 5.26 (td, J=9.5,6.9Hz, 1H), 4.25 4.05 (m, 2H),
3.40 (dd, J=13.7,9.7Hz, 1H), 3.13 (dd, J=13.8,6.7Hz, 1H), 2.53 (d, J=2.2
Hz, 4H), 1.85 (d, J=1.4Hz, 3H), 1.30 (t, J=7.1Hz, 3H).
Embodiment 6
Synthesis compound 9
Inert gas shielding, adds 8 (365mg, 1eq), 9mL second in 50mL there-necked flask under room temperature
Alcohol stirring and dissolving, by system hydrogen exchange three times, adds and reacts under Pd/C (25%w/w) room temperature.Former
Material reacts complete stopped reaction, adds water (5mL) cancellation reaction in system.Reactant liquor kieselguhr
Sucking filtration, is concentrated to give crude product.Cross column purification and obtain product, yield 80.2%, purity 97.2%.
Embodiment 7
Synthesis compound 10
Acetic acid (9mL), hydrochloric acid (1mL) is added in the reaction bulb equipped with compound 9 (100mg).
Oil bath 80 DEG C of reactions of heating.The complete stopped reaction of raw material reaction, adds water (5mL) in system and quenches
Go out reaction.Saturated NaHCO3 extracts be concentrated to give crude product with rear EA.Cross column purification and obtain product 90mg,
Yield 84%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3)δ7.61–7.54(m,2H),7.53–7.48(m,2H),
7.41 (dd, J=10.5,4.9Hz, 2H), 7.31 (dd, J=8.3,6.4Hz, 1H), 7.22 (d, J=8.2
Hz, 2H), 5.93 (t, J=9.7Hz, 1H), 4.34 4.00 (m, 3H), 2.91 2.71 (m, 2H), 2.68
2.57 (m, 2H), 2.55 (ddd, J=9.4,7.0,4.3Hz, 1H), 2.42 (dt, J=13.3,6.8Hz,
2H), 1.97 1.74 (m, 1H), 1.64 1.46 (m, 1H), 1.23 (td, J=7.1,3.3Hz, 3H),
1.14 (dd, J=7.1,3.9Hz, 3H).
Embodiment 8
Synthesis compound 5
Example 8-1: addition compound 4 (1eq) addition water (2Vol) in reaction bulb, concentrated hydrochloric acid (2Vol),
Oil bath heats 110 DEG C of reactions overnight, and raw material converts completely, HPLC peak area 97%.Add 10%
NaOH solution regulation pH to about 10, filters to obtain product.Yield 85%.
Example 8-2: add compound 4 (1eq) in reaction bulb and add ethanol (5Vol), water (5Vol), hydrogen
Potassium oxide (8eq), overnight, raw material converts completely 110 DEG C of reactions of oil bath heating, HPLC peak area 99%.
Add water (5Vol), filter to obtain product.Yield 95%.Product is dissolved in toluene, adds acidic alcohol, analysis
Go out the hydrochlorate of compound 5.
The nuclear magnetic data of product is as follows:
1H NMR (400MHz, DMSO) δ 8.31 (s, 3H), 7.70-7.61 (m, 4H), 7.47 (t, J=
7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (dq, J=42.6,7.1Hz, 1H), 3.62-3.51 (m,
1H),3.50-3.41(m,1H),3.11-3.00(m,1H),2.95-2.84(m,1H),1.30-1.10(m,
1H)。
Above only certain embodiments of the present invention is illustrated, but the protection content of the present invention not only limits
In above example, in the art of the present invention, the usual knowledge of a GPRS, it is possible at it
Diversified change is carried out in the range of technology main idea.
Claims (10)
1. the preparation method of an AHU-377, it is characterised in that comprise the following steps:
A () compound (1) S-(+)-2,3-Epoxy-1-propanol benzyl oxide and xenyl Grignard reagent react life in organic solvent
Become compound (2)；
There is Mitsunobu in organic solvent in (b) compound (2) succimide or phthalimide
Reacting generating compound (3)；
C () compound (3) is sloughed benzyl protection in organic solvent under the effect of catalyst and is generated compound
(4)；
D () compound (4) and oxidant occur oxidation reaction to generate compound (7) in organic solvent；
(e) compound (7) and phosphorus ylide reagent reacting generating compound in organic solvent (8)；
F () compound (8) selective catalytic hydrogenation in organic solvent generates compound (9)；And
G () compound (9) occurs amide hydrolysis to generate chemical combination in organic solvent under conditions of acid exists
Thing (10), i.e. AHU-377；
2. according to the preparation method of claim AHU-377, it is characterised in that: in step (a), reaction temperature
For-20～0 DEG C；And/or in step (b), reaction temperature is-10～25 DEG C；And/or in step (d), instead
Answering temperature is-10～25 DEG C；And/or in step (b), described Mitsunobu reacts at triphenylphosphine or three
Methylphosphine, and diisopropyl azodiformate or diethyl azodiformate or azoformic acid methyl ester exist
Under the conditions of carry out.
3. according to the preparation method of claim AHU-377, it is characterised in that: in step (d), described oxygen
Agent is Dai Si-Martin's oxidant or sodium hypochlorite.
4. according to the preparation method of claim AHU-377, it is characterised in that: in step (g), described acid
For hydrochloric acid, acetic acid or its mixture.
5. preparing an intermediate of AHU-377, it is the compound as shown in following formula (II):
Wherein, X is hetero atom, and described hetero atom is N or O；
R1Represent H or succinyl or phthalimide-based；
R2Represent benzyl or substituted benzyl；
R3Represent and replace or unsubstituting aromatic yl group.
The intermediate preparing AHU-377 the most according to claim 5, it is characterised in that: X is O, R1For
H, R2For benzyl, R3For phenyl, described intermediate is specially the compound as shown in following formula (2):
The intermediate preparing AHU-377 the most according to claim 5, it is characterised in that: X is N, R1For
Phthalimide-based, R2For benzyl, R3For phenyl, described intermediate is specially the chemical combination as shown in following formula (3)
Thing:
8. preparing an intermediate of AHU-377, it is the compound as shown in following formula (III):
Wherein, R4Represent C1-C6Alkyl；
R5Represent and replace or unsubstituting aromatic yl group.
The intermediate preparing AHU-377 the most according to claim 8, it is characterised in that: R4For ethyl,
R5For phenyl, described intermediate is specially the compound as shown in following formula (8) or formula (9):
10. the preparation method of the AHU-377 intermediate of a kind such as following formula (6), it is characterised in that include following
Step: compound (4) is occurring hydrolysis to generate compound (5), chemical combination under acid or alkaline conditions
The upper Boc protection group of thing (5) obtains compound (6),
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| PCT/CN2016/081244 WO2016180275A1 (en) | 2015-05-08 | 2016-05-06 | Ahu-377 intermediates and method for preparing ahu-377 and ahu-377 intermediates |
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| CN106318988A (en) * | 2016-08-23 | 2017-01-11 | 威海迪素制药有限公司 | Preparation method of LCZ696 key intermediate |
| CN106966926A (en) * | 2017-04-01 | 2017-07-21 | 沧州那瑞化学科技有限公司 | A kind of preparation method of LCZ696 intermediates |
| CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
| CN109206419A (en) * | 2017-06-29 | 2019-01-15 | 上海迪赛诺化学制药有限公司 | Sha Ku is than bent intermediate and its preparation method and application |
| CN114075129A (en) * | 2020-08-12 | 2022-02-22 | 凯特立斯（深圳）科技有限公司 | Sacubitril intermediate and synthetic method and application thereof |
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| CN107382779B (en) * | 2017-07-27 | 2020-04-17 | 江苏中邦制药有限公司 | Preparation method of shakubiqu intermediate |
| 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 |
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| 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 |
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| CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
| CN108727213B (en) * | 2018-06-29 | 2021-06-08 | 中国科学院上海有机化学研究所 | Preparation method of shakubiqu |
| CN114075129A (en) * | 2020-08-12 | 2022-02-22 | 凯特立斯（深圳）科技有限公司 | Sacubitril intermediate and synthetic method and application thereof |
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