CN105085322B - The Preparation Method And Their Intermediate of the intermediates of AHU 377 and the preparation method of intermediate - Google Patents
The Preparation Method And Their Intermediate of the intermediates of AHU 377 and the preparation method of intermediate Download PDFInfo
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- 0 CC(C)(C)OC(NC(C1)(C[C@@](C(N([C@@](*)CO2)C2=O)=O)c2c3)C1c2ccc3-c1ccccc1)=O Chemical compound CC(C)(C)OC(NC(C1)(C[C@@](C(N([C@@](*)CO2)C2=O)=O)c2c3)C1c2ccc3-c1ccccc1)=O 0.000 description 2
- INMRDXLXYCEVNO-HGCBZUSOSA-N CC(C)(C)OC(NC(C1)(C[C@@H]2C(O)=O)C1c(cc1)c2cc1-c1ccccc1)=O Chemical compound CC(C)(C)OC(NC(C1)(C[C@@H]2C(O)=O)C1c(cc1)c2cc1-c1ccccc1)=O INMRDXLXYCEVNO-HGCBZUSOSA-N 0.000 description 1
Abstract
Field is synthesized the present invention relates to pharmaceutical chemistry, and in particular to a kind of Preparation Method And Their Intermediate of intermediates of AHU 377 and the preparation method of intermediate.The preparation method of the intermediates of AHU 377 shown in formula (I), described method is included the compound shown in formula (II) compound and formula (III) by the way that, again by the intermediate of the AHU 377 shown in hydrolysis formula (I), described hydrolysis is carried out in the presence of hydrogen peroxide and hydronium(ion) lithia after substitution reaction：It is a further object of the present invention to provide a kind of new compound, shown in structure such as formula (II)：
Description
Technical field
Field is synthesized the present invention relates to pharmaceutical chemistry, and in particular to the preparation method of a kind of AHU-377 intermediates and wherein
The preparation method of mesosome and intermediate.
Background technology
LCZ696 was a kind of economic benefits and social benefits angiotensin receptor enkephalinase inhibitor researched and developed by Novartis, July 7 in 2015
Obtain FDA approvals day, develop the treatment of heart failure (HFrEF) patient reduced for LVEF.LCZ696 be AHU-377 and
Hypertension drug Valsartan (Diovan, common name of Novartis：Valsartan) compound, with unique binding mode, be considered as
The strain of failure heart can be reduced, wherein AHU-377 can block threat to be responsible for the mechanism of action of 2 kinds of polypeptides reduced blood pressure,
Diovan can then improve vasodilation, stimulate body to drain sodium and water.
AHU-377 is a kind of pro-drug, and its chemical name is：4- (((2S, 4R) -1- ([1,1 '-diphenyl] -4-
Base) -5- ethyoxyl -4- methyl -5- oxo -2- amyl groups)-amino) -4- ketobutyric acids, concrete structure formula is as follows：
In AHU-377 building-up process, the compound shown in formula (I) is an important intermediate, and concrete structure is such as
Under：
N- (3- carboxyl -1- oxopropyls)-(4S)-(to phenylphenylmethyl) -4- ammonia is disclosed in patent US5217996
The preparation of base-(2R)-methylbutanoic acid ethyl ester (i.e. AHU-377).In the preparation of the compound, N- tert-butoxycarbonyls-
(4R)-(to phenylphenylmethyl) -4- amino-2-methyls -2- alkenyls-ethyl butyrate is hydrogenated the formula of obtaining in the presence of palladium carbon
(I) compound shown in.One major defect of methods described be the step of hydrogenation be not very have selectivity, target product with
The ratio of its diastereoisomer is 80:20, and the diastereoisomer is difficult removing, causes the reduction of yield and purity.
The content of the invention
To solve the above problems, a kind of selectivity of present invention offer is good, high income, AHU-377 shown in the formula being easily purified (I)
The preparation method of intermediate.
It is an object of the present invention to provide the preparation method of AHU-377 intermediates shown in a kind of formula (I),
Described method is included formula (II) compound with the compound shown in formula (III) by passing through again after substitution reaction
Hydrolyze the intermediate of the AHU-377 shown in formula (I), described hydrolysis is depositing in hydrogen peroxide and hydronium(ion) lithia
Carried out lower：
Wherein, R is phenyl, benzyl or isopropyl, preferably benzyl；
X is leaving group, preferably halogen or substituted sulfonyl, more preferably halogen；Wherein, the preferred bromine of described halogen
Or iodine.Described substituted sulphonyl includes but is not limited to：Mesyl, p-toluenesulfonyl, benzenesulfonyl or trifluoromethyl sulphur
Acyl group；It is preferred that mesyl or p-toluenesulfonyl.
The substitution reaction can be in the presence in titanium tetrachloride and tertiary amine, when reaction temperature is -20 DEG C~10 DEG C
Carry out；Or in the presence of the highly basic such as lithium diisopropyl amido (LDA), lithium hexamethyldisilazide (HMDSLi), reaction temperature
Spend for -70 DEG C~-50 DEG C when carry out；The substitution reaction preferably in the presence of titanium tetrachloride and tertiary amine, reaction temperature for-
Carried out at 20 DEG C~0 DEG C；
The preferred equal proportion input reaction of titanium tetrachloride and tertiary amine；Titanium tetrachloride and formula (II) compound mole are worked as
Measure ratio preferably 1.1:1.
The tertiary amine used in the substitution reaction is preferably diisopropylethylamine (DIPEA) or triethylamine (TEA), more excellent
Elect diisopropylethylamine as；
The substitution reaction is carried out in organic solvent, is carried out preferably in tetrahydrofuran or halogenated hydrocarbon solvent, more excellent
It is selected in tetrahydrofuran or dichloromethane and carries out；
Hydrogen peroxide preferred mass percentage is 30% hydrogen peroxide in the hydrolysis；
The hydrolysis is carried out at 15 DEG C~30 DEG C；
The molar equivalent ratio of compound shown in formula (II) compound and formula (III) is 1.0:1.0~1.0:1.5, it is excellent
Select 1.0:1.1.
It is a further object of the present invention to provide a kind of new compound, shown in structure such as formula (II)：
Wherein, X is leaving group, is halogen or substituted sulfonyl, preferably halogen；Described substituted sulphonyl include but
It is not limited to：Mesyl, p-toluenesulfonyl, benzenesulfonyl, trifluoromethyl sulfonyl, preferably mesyl or tolysulfonyl
Base.
It is a further object of the present invention to provide the preparation method of compound shown in a kind of formula (II), compound (II) is by chemical combination
Thing (V) is obtained with halogenating agent or the reaction of substituted sulfonic acid chloride：
Wherein, X is leaving group, is halogen or substituted sulfonyl, preferably halogen.Described substituted sulphonyl include but
It is not limited to：Mesyl, p-toluenesulfonyl, benzenesulfonyl or trifluoromethyl sulfonyl；It is preferred that mesyl or to toluene sulphur
Acyl group.
Described halogenating agent is selected from iodine, bromine, alkaline metal iodide, alkali metal bromide, N- bromo-succinimides
(NBS), one kind in the conventional halogenating agent such as N- chlorosuccinimides (NCS)；It is preferably selected from sodium iodide, iodine, lithium bromide, N-
One kind in bromo-succinimide；
The substituted sulfonic acid chloride is preferably mesyl chloride or paratoluensulfonyl chloride；More preferably mesyl chloride；
In the course of reaction, the consumption of halogenating agent or substituted sulfonic acid chloride is the excess of compound shown in formula (V)；
The reaction is carried out at 10 DEG C~35 DEG C, and preferable reaction temperature is 20 DEG C~25 DEG C；
The solvent used that reacts can be selected from halogenated hydrocarbon solvent, esters solvent, tetrahydrofuran, acetonitrile, acetone etc.
One kind in common solvent；The solvent is preferably dichloromethane, tetrahydrofuran, acetonitrile, acetone
When X is halogen, the reaction is carried out in the presence of triphenylphosphine, according to this area conventional technical means, institute
The consumption for stating triphenylphosphine is the excess of compound shown in formula (V)；
When X is the sulfonyl of substitution, the reaction is carried out in the presence of sulfonic acid chloride and alkali；The alkali is preferably organic
Alkali, more preferably triethylamine.
Further, the preparation method of compound also includes the preparation of compound (V), compound shown in above-mentioned formula (II)
(VI) compound (V) is obtained through reduction
Wherein, R1It is alkyl；It is preferred that, R1It is C1-C6 alkyl；It is furthermore preferred that R1It is methyl, ethyl；
The reduction reaction is the conventional technical means, the reduction such as alkali metal borohydride reduction or catalytic hydrogen reduction
Preferably alkali metal borohydride is reduced, more preferably sodium borohydride or lithium borohydride reduction；
The reduction reaction is carried out in the conventional organic solvent such as alcohols solvent, ether solvent under normal temperature, described organic molten
The preferred alcohols solvent of agent, the organic solvent is more preferably methanol, ethanol or isopropanol.
The preparation of the compound (VI) can be with bibliography US5217996.
It is a further object of the present invention to provide a kind of new compound, the compound is the pass needed for prepare compound (I)
Key intermediate, shown in structure such as formula (IV)：
Wherein, R is phenyl, benzyl or isopropyl, preferably benzyl.
It is a further object of the present invention to provide the preparation method of compound shown in a kind of formula (IV), comprise the following steps：Institute
State formula (IV) formula (II) compound and carry out substitution reaction with the compound shown in formula (III),
Wherein, R is phenyl, benzyl or isopropyl, preferably benzyl；X is leaving group, preferably halogen or substituted sulphonyl
Base, more preferably halogen；
The preferred bromine or iodine of described halogen；Described substituted sulphonyl includes but is not limited to：Mesyl, tolysulfonyl
Base, benzenesulfonyl, trifluoromethyl sulfonyl, preferably mesyl or p-toluenesulfonyl.
Enter when the substitution reaction is preferably in the presence of titanium tetrachloride and tertiary amine, reaction temperature is -20 DEG C~10 DEG C
OK, or in the presence of the highly basic such as lithium diisopropyl amido (LDA), lithium hexamethyldisilazide (HMDSLi), reaction temperature
For -70 DEG C~-50 DEG C when carry out；The substitution reaction is more preferably in the presence of titanium tetrachloride and tertiary amine, reaction temperature for-
Carried out at 20 DEG C~0 DEG C；
The preferred equal proportion input reaction of titanium tetrachloride and tertiary amine；Titanium tetrachloride and formula (II) compound mole are worked as
Measure ratio preferably 1.1:1.
The tertiary amine used in the substitution reaction is preferably diisopropylethylamine (DIPEA) or triethylamine (TEA), more excellent
Elect diisopropylethylamine as；
The substitution reaction is carried out in organic solvent, is carried out preferably in tetrahydrofuran or halogenated hydrocarbon solvent, more excellent
It is selected in tetrahydrofuran or dichloromethane and carries out；
The molar equivalent ratio of compound shown in formula (II) compound and formula (III) is 1.0:1.0~1.0:1.5, preferably
1.0:1.1。
In the present invention, formula (III) compound can be prepared by following methods, and compound (III) is by propionyl chloride and formula (VII)
Shown compound carries out amidation process and obtained：
The amidation process is in the presence of organic base, and reaction temperature is progress at -5 DEG C~5 DEG C, and the organic base is excellent
Select triethylamine or pyridine.
Or, formula (III) compound can be obtained with commercially available.
Further, above-mentioned formula (IV) compound can be used for formula (I) compound, including formula (IV) compound is existed
Reaction is hydrolyzed in the presence of hydrogen peroxide and hydronium(ion) lithia and obtains formula (I) compound, specific reaction equation is as follows：
Wherein, R is phenyl, benzyl or isopropyl, preferably benzyl.
Hydrogen peroxide preferred mass percentage is 30% hydrogen peroxide in the hydrolysis；
The hydrolysis is carried out at 15 DEG C~30 DEG C；
Applicant has found in research process, in variation route of the invention, due to using formula (II) compound and formula (III)
Shown compound reaction prepares compound shown in new formula (IV), and selectivity is very good, and what is generated in course of reaction is non-
Seldom, these very small amount diastereoisomers also need to can only be removed the amount of enantiomter by simple post processing.Especially
It is that reaction is generated even without diastereoisomer when R replaces for benzyl, and X is halogen, product chiral purity is up to 100%,
And reaction yield is attained by more than 95%.Largely solve reaction selectivity in the prior art bad, diastereomeric
The problem of isomers is difficult to remove.
Research finds that when new route prepares formula (I) intermediate, compound (IV) is deposited in hydrogen peroxide and hydronium(ion) lithia
When reaction is hydrolyzed under, the configuration reversal of compound (IV) is not resulted in yet, whole piece route is due to introducing new compound
(IV) configuration of compound shown in important intermediate formula (I), is controlled well, overcomes prior art defect.
Specific embodiment
With reference to embodiment, the invention will be further described, but the protection content of the present invention is not limited only to these realities
Apply example.
Method therefor is conventional method unless otherwise instructed in the following example.Material required in following examples
Material or reagent, are that market is bought unless otherwise specified.
Embodiment 1
The synthesis of compound (III-a)
(R) -4- phenyl -2- oxazolidones (16.3g, 1 equivalent) are dissolved in 180ml dichloromethane, under 0 DEG C of ice bath stirring
Triethylamine (15.2g, 1.5 equivalents) is added, DMAP (DMAP) (366mg, 0.03 equivalent) is then added dropwise third
Acyl chlorides (9.2g, 1 equivalent), maintains 0 DEG C to stir 1 hour, adds dchloromethane, and washing, saturated sodium bicarbonate washing is organic
Through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography, obtains target chemical combination
Thing (III-a) (20.1g, yield 92%).
Embodiment 2
The synthesis of compound (III-b)
(R) -4- benzyl -2- oxazolidones (20g, 1 equivalent) are dissolved in 200ml dichloromethane, 0 DEG C of ice bath stirring is lower to be added
Enter triethylamine (17.1g, 1.5 equivalents), propionyl chloride is then added dropwise in DMAP (414mg, 0.03 equivalent)
(10.4g, 1 equivalent), maintains 0 DEG C to stir 1 hour, adds dchloromethane, washing, saturated sodium bicarbonate washing, organic phase
Through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography, obtains target compound
(III-b) (24.3g, yield 93%).
Embodiment 3
The synthesis of compound (III-c)
(R) -4- isopropyl -2- oxazolidones (14.3g, 1 equivalent) are dissolved in 150ml dichloromethane, 0 DEG C of ice bath stirring
Propionyl chloride is then added dropwise in lower addition triethylamine (15.2g, 1.5 equivalents), DMAP (366mg, 0.03 equivalent)
(9.2g, 1 equivalent), maintains 0 DEG C to stir 1 hour, adds dchloromethane, washing, saturated sodium bicarbonate washing, organic phase warp
Anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography, obtains target compound
(III-c) (18.3g, yield 92%).
Embodiment 4
The synthesis of compound (V)
Compound (VI-a) (100g, 1 equivalent) is dissolved in 300ml ethanol, under 0 DEG C of stirring, hydroboration is added in batches
Sodium (12.8g, 1.2 equivalents), moves to 20-25 DEG C and stirs 2.5 hours after finishing.PH value is adjusted to acidity with 2N hydrochloric acid, then
Extracted with ethyl acetate/water, obtained organic phase saturated common salt water washing, through anhydrous sodium sulfate drying.It is evaporated under reduced pressure and removes
Solvent, obtains crude product.Crude product is purified by column chromatography, obtains target compound (V) (81g, yield 88%).
Embodiment 5
The synthesis of compound (II-a)
Compound (V) (50g, 1 equivalent) is dissolved in 150ml dichloromethane, triethylamine (17g, 1.1 equivalents), 0 is added
DEG C stirring under, be added dropwise methylsufonyl chloride (19.2g, 1.1 equivalents) drop finish after move to 20-25 DEG C stir 3 hours.System adds water
Dilution, dichloromethane is extracted after hydrochloric acid acidifying, and obtained organic phase is through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, is obtained
To crude product.Crude product is purified by column chromatography, obtains target compound (II-a) (56.9g, yield 92%).
1H NMR(400MHz,DMSO):δ 7.65 (d, J=7.4Hz, 2H), 7.60 (d, J=8.1Hz, 2H), 7.47 (t, J
=7.6Hz, 2H), 7.35 (t, J=7.4,1H), 7.33 (d, J=8.1Hz, 2H), 4.08-3.94 (m, 1H), 3.83 (s, 3H),
3.78 (dd, J=10.1,3.8Hz, 1H), 3.52 (dd, J=10.1,3.7Hz, 1H), 2.92 (dd, J=13.7,7.6Hz,
1H), 2.76 (dd, J=13.7,7.7Hz, 1H), 1.33 (s, 9H)
Embodiment 6
The synthesis of compound (II-b)
By triphenylphosphine (56g, 1.4 equivalents), imidazoles (18.7g, 1.8 equivalents) is added in dichloromethane, under 0 DEG C of stirring,
The dichloromethane solution of iodine (58g, 1.5 equivalents) is added dropwise, drop maintains 0 DEG C of stirring 30min after finishing.Compound is added dropwise
(V) dichloromethane solution of (50g, 1 equivalent), drop moves to 20-25 DEG C and stirred 6 hours after finishing.90ml is added into reaction system
1N sodium sulfite solutions, stir 0.5 hour, then extracted with dichloromethane, obtained organic phase is through anhydrous sodium sulfate drying.
Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography, obtains target compound (II-b) (59g, yield
90%).
1H NMR(400MHz,DMSO):δ 7.64 (d, J=7.4Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.46 (t, J
=7.6Hz, 2H), 7.35 (t, J=7.4Hz, 1H), 7.31 (d, J=8.1Hz, 2H), 3.71-3.61 (m, 1H), 3.35 (dd, J
=9.9,4.8Hz, 1H), 3.24 (dd, J=9.9,7.0Hz, 1H), 2.88 (dd, J=13.5,6.4Hz, 1H), 2.73 (dd, J
=13.5,6.5Hz, 1H), 1.34 (s, 9H)
Embodiment 7
The synthesis of compound (II-b)
Take compound (II-a) (40g, 1 equivalent) to add the dissolving of 100ml acetonitriles, and sodium iodide is added into the solution
(55g, 3 equivalents), finish rear system and are stirred 3 hours in 30 DEG C.Solvent removed by evaporation at reduced pressure, is extracted with ethyl acetate/water, obtained
Organic phase saturated common salt water washing, through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product passes through
Column chromatography is purified, and obtains target compound (II-b) (35g, yield 82%).
Embodiment 8
The synthesis of compound (II-c)
Compound (V) (50g, 1 equivalent) is dissolved in 150ml dichloromethane, 0 DEG C of ice bath stirring is lower to add triphenyl
Phosphine (56g, 1.4 equivalents), maintains 0 DEG C of stirring 30min, NBS (37g, 1.36 equivalents) is added in batches, 20-25 is moved to after finishing
DEG C stirring 2 hours.Dchloromethane is added into reaction system, massive laundering is subsequently added, obtained organic phase is through anhydrous
Sodium sulphate is dried.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is beaten with ethyl acetate and purified, and obtains target compound
(II-c) (57.6g, yield 97%).
1H NMR(400MHz,DMSO):δ 7.64 (d, J=7.4Hz, 2H), 7.59 (d, J=8.1Hz, 2H), 7.46 (t, J
=7.6Hz, 2H), 7.34 (t, J=7.4,1H), 7.32 (d, J=8.1Hz, 2H), 3.92-3.79 (m, 1H), 3.58 (dd, J=
9.9,5.1Hz, 1H), 3.48 (dd, J=9.9,5.2Hz, 1H), 2.91 (dd, J=13.7,7.7Hz, 1H), 2.75 (dd, J=
13.7,7.8Hz,1H),1.33(s,9H).
Embodiment 9
The synthesis of compound (II-c)
Take compound (II-a) (40g, 1 equivalent) add 98ml acetone solutions, and into the solution add lithium bromide (26g,
3 equivalents), finish rear system and stirred 3 hours in 30 DEG C.Solvent removed by evaporation at reduced pressure, is extracted, what is obtained has with ethyl acetate/water
Machine mutually uses saturated common salt water washing, through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is by post layer
Analysis purifying, obtains target compound (II-c) (31g, yield 80%).
Embodiment 10
The synthesis of compound (IV-a)
Take (S) -4- benzyl -3- propionos oxazolidone (16.5g, 1.1 equivalents) to be dissolved in 40ml dichloromethane, cool down
To at 0 DEG C, the dichloromethane solution of titanium tetrachloride (14g, 1.1 equivalents) is added dropwise, 0 DEG C of maintenance is stirred below after drop finishes
10min.Diisopropylethylamine (9.7g, 1.1 equivalents) is added dropwise, drop maintains 0 DEG C of 30min stirred below after finishing.By compound
(II-b) (30g, 1 equivalent) is dissolved in dichloromethane, is added to dropwise in reaction system, and drop moves to 20-25 DEG C of stirring 10 after finishing
Hour.The aqueous solution of saturated ammonium chloride is added into reaction system, is extracted with dichloromethane, obtained organic phase respectively with water and
Saturated common salt water washing, through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography,
Obtain target compound (IV-a) (33.9g, yield 91%).HPLC detects that no diastereoisomer is detected, i.e. chiral purity
100%.
1H NMR(400MHz,DMSO):δ 7.65 (d, J=7.4Hz, 2H), 7.60 (d, J=8.1Hz, 2H), 7.47 (t, J
=7.6Hz, 2H), 7.35 (t, J=7.4,1H), 7.33 (d, J=8.1Hz, 2H), 7.26-7.12 (m, 5H), 4.86-4.71
(m, 1H), 4.39 (dd, J=22.7,14.8Hz, 1H), 4.01 (dd, J=22.6,15.9Hz, 1H), 3.90-3.76 (m, 1H),
3.35-3.16 (m, 1H), 2.92 (dd, J=13.7,7.6Hz, 2H), 2.76 (dd, J=13.7,7.7Hz, 2H), 1.56 (dd, J
=13.2,2.6Hz, 1H), 1.51 (dd, J=13.1,2.5Hz, 1H), 1.33 (s, 9H), 1.12 (d, J=13.0Hz, 3H)
Embodiment 11
The synthesis of compound (IV-a)
Take (S) -4- benzyl -3- propionos oxazolidone (22.5g, 1.5 equivalents) to be dissolved in 55ml dichloromethane, cool down
To at 0 DEG C, the dichloromethane solution of titanium tetrachloride (14g, 1.1 equivalents) is added dropwise, 0 DEG C of maintenance is stirred below after drop finishes
10min.(9.7g, 1.1 equivalents) diisopropylethylamine is added dropwise, drop maintains 0 DEG C of 30min stirred below after finishing.By compound
(II-b) (30g, 1 equivalent) is dissolved in dichloromethane, is added to dropwise in reaction system, and drop moves to 20-25 DEG C of stirring 10 after finishing
Hour.The aqueous solution of saturated ammonium chloride is added into reaction system, is extracted with dichloromethane, obtained organic phase respectively with water and
Saturated common salt water washing, through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product is purified by column chromatography,
Obtain target compound (IV-a) (32.4g, yield 87%).HPLC detects that no diastereoisomer is detected, i.e. chiral purity
100%.
Embodiment 12
The synthesis of compound (I)
Compound (IV-a) (30g, 1 equivalent) is dissolved in 77ml tetrahydrofurans, 0 DEG C is cooled to, stirring is lower to be added
30% hydrogen peroxide (25g, 4 equivalents), 30min is stirred after adding.Maintain the temperature that hydronium(ion) lithia (4.6g, 2 is added dropwise
Equivalent), drop moves to 20-25 DEG C and stirred 3 hours after finishing.Aqueous phase is removed after stopping stirring, organic phase is molten with saturation sodium hydrogensulfite
Liquid removes unnecessary peroxide, then removes aqueous phase, and organic phase solvent removed by evaporation at reduced pressure obtains crude product.Crude product adds water, and uses hydrogen
Sodium hydroxide solution adjusts pH value to 12-13, and aqueous phase is washed 3 times with t-butyl methyl ether, then adjusts pH value to 3-4 with concentrated hydrochloric acid,
Ethyl acetate extracts product, and anhydrous sodium sulfate drying is filtered to remove drier, and mother liquor solvent removed by evaporation at reduced pressure obtains target
Compound (I) (18.9g, yield 90%, chiral purity 100%).
Embodiment 13
According to the method prepare compound (IV) of embodiment 10, different substrates feeds intake by same usage ratio to be produced
The yield and chiral purity of thing are as shown in the table：
Claims (6)
1. the preparation method of AHU-377 intermediates shown in formula (I), formula (II) compound is passed through with the compound shown in formula (III)
It is prepared by substitution reaction and the step of hydrolysis two, wherein the substitution reaction is carried out in the presence of titanium tetrachloride and tertiary amine, institute
The hydrolysis stated is carried out in the presence of hydrogen peroxide and hydronium(ion) lithia
Wherein, R is phenyl, benzyl or isopropyl, and X is leaving group.
2. according to the method described in claim 1, it is characterised in that compound is by compound (V) and halogen shown in the formula (II)
Obtained for reagent or the reaction of substituted sulfonic acid chloride：
Wherein,
Described halogenating agent be selected from iodine, bromine, alkaline metal iodide, alkali metal bromide, N- bromo-succinimides (NBS),
One kind in N- chlorosuccinimides (NCS)；
The substituted sulfonic acid chloride is mesyl chloride or paratoluensulfonyl chloride.
3. method according to claim 2, it is characterised in that in the course of reaction, halogenating agent or substituted sulphonyl
The consumption of chlorine is the excess of compound shown in formula (V)；The reaction is carried out at 10 DEG C~35 DEG C.
4. method according to claim 3, it is characterised in that：The compound (V) is that compound (VI) is obtained through reduction
Wherein, R1It is alkyl,
The reduction reaction is that alkali metal borohydride is reduced or catalytic hydrogen reduction；
The reduction reaction is carried out in alcohols solvent or ether solvent under normal temperature.
5. the method according to claim 1 or 2 or 3, it is characterised in that：Described leaving group is bromine or iodine.
6. compound shown in a kind of formula (IV)
Wherein, R is phenyl, benzyl or isopropyl.
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| CN105859615B (en) * | 2016-05-11 | 2019-05-03 | 安徽恒星制药有限公司 | A kind of preparation method and intermediate of Dequalinium Chloride |
| JP6944473B2 (en) | 2016-07-05 | 2021-10-06 | ノバルティス アーゲー | A new method for early sacubitril intermediates |
| EP3500549B1 (en) | 2016-08-17 | 2020-12-16 | Novartis AG | New processes and intermediates for nep inhibitor synthesis |
| CN106478437A (en) * | 2016-09-27 | 2017-03-08 | 南通常佑药业科技有限公司 | A kind of preparation method of γ aminovaleric acid ester derivant |
| CN106608845A (en) * | 2016-10-08 | 2017-05-03 | 天津津泰生物医药技术有限公司 | Novel preparation method of aplysiatoxin 10 intermediate tert-butoxycarbonyl pyroglutamic acid-derived propionic acid |
| CN108238981A (en) * | 2016-12-23 | 2018-07-03 | 宁波爱诺医药科技有限公司 | A kind of preparation method of LCZ-696 key intermediates |
| WO2018116203A1 (en) | 2016-12-23 | 2018-06-28 | Novartis Ag | New process for early sacubitril intermediates |
| CN106699604B (en) * | 2017-01-09 | 2019-01-01 | 四川同晟生物医药有限公司 | One seed sand library is than bent and its intermediate preparation method |
| CN106966926B (en) * | 2017-04-01 | 2018-10-19 | 沧州那瑞化学科技有限公司 | A kind of preparation method of LCZ696 intermediates |
| CN116987012A (en) * | 2022-04-29 | 2023-11-03 | 凯特立斯（深圳）科技有限公司 | Sabobiqu intermediate, preparation method and application thereof |
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| EP1903027A1 (en) * | 2006-09-13 | 2008-03-26 | Novartis AG | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN101774941A (en) * | 2009-01-13 | 2010-07-14 | 浙江九洲药业股份有限公司 | Method for preparing and splitting 2-acyl amino-3-biphenylyl propionic acid |
| WO2013026773A1 (en) * | 2011-08-19 | 2013-02-28 | Dsm Ip Assets B.V. | Synthesis of r-biphenylalaninol |
| AR092278A1 (en) * | 2012-08-31 | 2015-04-08 | Novartis Ag | PROCESS FOR OBTAINING N-ACILIC DERIVATIVES OF BIFENYL-ALANINE AND RELATED INTERMEDIARIES |
| CN104557600B (en) * | 2015-01-26 | 2016-05-04 | 苏州明锐医药科技有限公司 | Sha Ku is than bent preparation method |
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