[go: up one dir, main page]

CN109206419B - Sakubi koji intermediate and preparation method and application thereof - Google Patents

Sakubi koji intermediate and preparation method and application thereof Download PDF

Info

Publication number
CN109206419B
CN109206419B CN201710517896.4A CN201710517896A CN109206419B CN 109206419 B CN109206419 B CN 109206419B CN 201710517896 A CN201710517896 A CN 201710517896A CN 109206419 B CN109206419 B CN 109206419B
Authority
CN
China
Prior art keywords
compound
reaction
sodium
formula
alkaline reagent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710517896.4A
Other languages
Chinese (zh)
Other versions
CN109206419A (en
Inventor
李金亮
赵楠
娄彦鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Puxin Pharmaceutical Co ltd
Shanghai Desano Pharmaceuticals Investment Co ltd
Yancheng Desano Pharmaceutical Co ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
Original Assignee
Jiangsu Puxin Pharmaceutical Co ltd
Shanghai Desano Pharmaceuticals Investment Co ltd
Yancheng Desano Pharmaceutical Co ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Puxin Pharmaceutical Co ltd, Shanghai Desano Pharmaceuticals Investment Co ltd, Yancheng Desano Pharmaceutical Co ltd, Shanghai Desano Chemical Pharmaceutical Co Ltd filed Critical Jiangsu Puxin Pharmaceutical Co ltd
Priority to CN201710517896.4A priority Critical patent/CN109206419B/en
Publication of CN109206419A publication Critical patent/CN109206419A/en
Application granted granted Critical
Publication of CN109206419B publication Critical patent/CN109206419B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a sabobiqu intermediate and a preparation method and application thereof. The sabobiqu intermediate has a chemical structure shown in chemical structures shown in the following formula III and/or formula IV. Wherein R is phenyl, benzyl or isopropyl; the intermediate of the invention is used for synthesizing the sabobiqu, and has the advantages of simple preparation process, mild reaction condition, environmental protection and the like. Has important significance and use value for realizing low cost, large scale and high-efficiency preparation of high-purity sakubi koji.

Description

Sakubi koji intermediate and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing sabobiqu, a novel intermediate compound related in the novel preparation method and a preparation method of the intermediate compound.
Background
Entrepto is a dual inhibitor of the angiotensin II receptor (AT II) and enkephalinase, consisting of the valsartan and NEP inhibitor drug sabobiqu (Sacubitril) in a 1:1 ratio. The chemical name is: [3- ((1S, 3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionic acid- (S) -3' -methyl-2 ' - (pentanoyl {2"- (tetrazol-5-ylate) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] trisodium hemi-pentahydrate. On 7 months 2015, entrestro was approved by the FDA for use in treating heart failure patients with reduced ejection fraction, reducing cardiovascular death and risk of heart failure hospitalization.
The sabobiqu is one of the important components, is an enkephalinase inhibitor and has the chemical name: (2R, 4S) -5-Biphenyl-4-yl-4- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester having the structural formula:
Figure BDA0001337028950000011
patent US5217996 originally reported a sabobiqu synthesis route which uses D-tyrosine as a starting material, uses expensive trifluoromethanesulfonic anhydride to activate phenolic hydroxyl groups, and requires the use of an expensive tetrakis triphenylphosphine palladium catalyst for Suzuki aryl coupling, resulting in higher processing costs.
Figure BDA0001337028950000021
Patent WO2014032627A1 reports the preparation of a sabobiqu intermediate by reaction of a grignard reagent with epichlorohydrin, then introducing a nitrogen atom by reaction with Misunobu of succinimide, hydrolyzing with hydrochloric acid to remove succinic acid, and then converting to Boc protection, while succinic anhydride is required to be introduced after the reaction, the reaction steps are cumbersome and the atom economy is low.
Figure BDA0001337028950000022
Therefore, the existing preparation method is limited by the aspects of raw materials, reaction reagents, cost and the like, and atomic economy cannot be well considered, so that the production cost of the sarcandra starter is high, the operation is complex, and industrialization is not easy to realize. Therefore, a novel route which is simple, economical and convenient for industrialization is designed and developed by using the pharmaceutical chemistry means, and the method has important significance for the industrialized popularization of the Shakubi koji.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a method for synthesizing the sabobiqu, which has low raw material cost, simple synthesis route and high yield, so as to meet the requirement of the sabobiqu industrialization.
The first aspect of the invention provides a sabobiqu intermediate, which has a chemical structure shown in the following formula III and/or formula IV:
Figure BDA0001337028950000031
wherein R is a group selected from the group consisting of: phenyl, benzyl, isopropyl.
In a second aspect, the present invention provides a process for the preparation of an intermediate according to the first aspect of the present invention, comprising the following reaction steps:
1) In the presence of an organic solvent and an alkaline reagent, carrying out Misunobu reaction on the compound I and succinimide to generate a compound II;
2) In the presence of an alkaline reagent, carrying out substitution reaction on the compound II and a 4-substituted 3-propionyl-2-oxazolidinone compound to obtain a compound III;
Figure BDA0001337028950000032
wherein X is Cl, br or I, R is phenyl, benzyl or isopropyl.
In another preferred embodiment, the preparation method further comprises the following steps:
3) Under the condition of hydrogen peroxide and an alkaline reagent, the compound of the formula III undergoes hydrolysis reaction, so that a compound of the formula IV is obtained;
Figure BDA0001337028950000033
r is phenyl, benzyl or isopropyl.
In another preferred embodiment, the organic solvent in step 1) is selected from toluene or methylene chloride; the alkaline reagent is selected from the group consisting of: diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or combinations thereof;
the alkaline agent described in step 2) is selected from the group consisting of: lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, n-butyllithium, t-butyllithium, or a combination thereof.
In another preferred embodiment, the substitution reaction temperature in step 2) is from-70℃to 0℃and preferably from-50℃to 0 ℃.
In another preferred embodiment, the alkaline agent described in step 3) is selected from the group consisting of: lithium hydroxide, sodium hydroxide, lithium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate, or a combination thereof.
In a third aspect the present invention provides a process for the preparation of sabobiqu using an intermediate according to the first aspect of the invention comprising the steps of:
c) Under the condition of hydrogen peroxide and an alkaline reagent, the compound of the formula III undergoes hydrolysis reaction, so that a compound of the formula IV is obtained;
d) Carrying out esterification reaction on the compound of the formula IV under the action of ethanol and thionyl chloride, thereby obtaining a compound of the formula V; and
e) The compound of formula V undergoes hydrolysis reaction in the presence of an alkaline reagent, thereby obtaining sarcandra;
Figure BDA0001337028950000041
wherein X is Cl, br or I, and R is phenyl, benzyl or isopropyl.
In another preferred embodiment, the base in step e) is an organic base or an inorganic base; the organic base is selected from the following group: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof; the inorganic base is selected from the following group: sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or a combination thereof.
In another preferred embodiment, the method for preparing the sarcandra comprises the following steps:
Figure BDA0001337028950000042
in another preferred embodiment, the compound I is synthesized by the following steps: preparing 4-bromodiphenyl into a Grignard reagent, and reacting the prepared Grignard reagent with epoxy halopropane to obtain a compound I, wherein the epoxy halopropane comprises a compound selected from the group consisting of: 3-chloro-1, 2-epoxypropane, 3-bromo-1, 2-epoxypropane, or 3-iodo-1, 2-epoxypropane;
Figure BDA0001337028950000051
wherein X is Cl, br or I.
In a fourth aspect, the invention provides a pharmaceutical composition comprising sabcomeline prepared from an intermediate according to the first aspect of the invention and a pharmaceutically acceptable carrier.
In a fifth aspect the present invention provides the use of an intermediate according to the first aspect of the invention for the preparation of sabobiqu.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor designs a class of intermediates for preparing the sakubi koji through long-term and intensive researches, the process for preparing the sakubi koji by using the intermediates is simple, environment-friendly and strong in operability, and the purity and the yield of the prepared sakubi koji are far higher than those of the prior art. Based on the above findings, the inventors have completed the present invention.
Intermediate and synthesis method thereof
The sabobiqu intermediate has a chemical structural formula shown in the following formula III and formula IV:
Figure BDA0001337028950000052
wherein R is phenyl, benzyl or isopropyl.
A preferred intermediate synthesis route of the present invention is shown below:
1) Preparing 4-bromodiphenyl into a Grignard reagent, and reacting the prepared Grignard reagent with 3-chloro-1, 2-epoxypropane (or 3-bromo-1, 2-epoxypropane or 3-iodo-1, 2-epoxypropane) to obtain a compound I;
Figure BDA0001337028950000061
2) The compound I and succinimide react in an organic solvent to generate a compound II;
3) The compound II and the 4-substituted 3-propionyl-2-oxazolidinone compound undergo substitution reaction under the alkaline condition to obtain a compound III;
Figure BDA0001337028950000062
wherein X is Cl, br or I, and R is phenyl, benzyl or isopropyl.
Wherein the organic solvent used in step 2) includes (but is not limited to): toluene, methylene dichloride, wherein the alkaline reagent used in the Misunobu reaction is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or a combination thereof; the alkaline reagent in step (3) includes (but is not limited to): lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, n-butyllithium, t-butyllithium, or a combination thereof; the substitution reaction temperature is-70 to 0 ℃, preferably-50 to 0 ℃.
3) Carrying out hydrolysis reaction on the compound III under hydrogen peroxide and alkaline conditions to obtain a compound IV;
Figure BDA0001337028950000063
the base includes (but is not limited to): one or more of lithium hydroxide, sodium hydroxide, lithium carbonate, sodium carbonate, lithium bicarbonate and sodium bicarbonate.
Preparation method of sarcandra
The sarcandra of the present invention is synthesized using the above intermediates. The specific synthetic route is as follows:
d) The intermediate compound IV prepared by the method is subjected to esterification reaction in an ethanol solvent under the action of thionyl chloride to obtain a compound V;
e) Hydrolyzing the compound V under alkaline conditions to obtain sarcandra;
Figure BDA0001337028950000071
wherein X is Cl, br or I, R is phenyl, benzyl or isopropyl;
the base used in step e) is an organic base or an inorganic base; the organic base includes (but is not limited to): sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, including (but not limited to): one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
Compared with the prior art, the invention has the main advantages that:
(1) The method for preparing the Shakubi koji has the advantages of low price of the raw materials, wide sources, contribution to reducing the production cost and contribution to industrial production popularization.
(2) The intermediate of the invention is used for synthesizing the saprolegnian, and has the advantages of simple and controllable preparation process, mild reaction condition, environmental protection and the like.
(2) The purity of the saprolegniasis synthesized by using the intermediate of the invention is up to 99.3 percent, and the yield is up to 90.2 percent, which is superior to the prior art.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
Figure BDA0001337028950000081
50g (0.2 mol) (S) -1- ([ 1,1' -biphenyl ] -4-yl) -3-chloropropan-2-ol and 600ml toluene solvent are added into a 1L reaction bottle, the mixture is stirred at room temperature, the temperature of the reaction system is reduced to 0-5 ℃, 63.8g triphenylphosphine (0.24 mol,1.2 eq) and 23.76g (0.24 mol,1.2 eq) succinimide are added, 48.5g (0.3 mol,1.5 eq) diisopropyl azodicarboxylate is added, the mixture is heated to 20-30 ℃ after the addition, 150ml water is added, the mixture is stirred at room temperature for 5-10 minutes, the mixture is separated, the organic layer is washed with saturated saline (100 ml multiplied by 2), dried with anhydrous MgSO4 and concentrated to obtain 54.68g of white solid compound IIa, and the yield is 82.3%.
Example 2
Figure BDA0001337028950000082
50g (0.17 mol) (S) -1- ([ 1,1' -biphenyl ] -4-yl) -3-bromopropan-2-ol and 600ml of dichloromethane solvent are added into a 1L reaction bottle, the mixture is stirred at room temperature, the temperature of the reaction system is reduced to 0-5 ℃, 53.5g triphenylphosphine (0.204 mol,1.2 eq) and 20.2g (0.204 mol,1.2 eq) succinimide are added, 38.4g (0.22 mol,1.3 eq) diethyl azodicarboxylate is added, the mixture is heated to 20-30 ℃ after the addition, 150ml of water is added, the mixture is stirred at room temperature for 5-10 minutes, the mixture is separated, the organic layer is washed with saturated saline (100 ml multiplied by 2), anhydrous 4 is dried and concentrated, and the solid compound IIb is obtained in 56.7g with the yield of 93.4% MgSO.
Example 3
Figure BDA0001337028950000083
50g (0.15 mol) (S) -1- ([ 1,1' -biphenyl ] -4-yl) -3-iodopropan-2-ol and 600ml dichloromethane solvent were added to a 1L reaction flask, stirred at room temperature, the system was dissolved, the temperature of the reaction system was lowered to 0 to 5 ℃, 47.2g triphenylphosphine (0.18 mol,1.2 eq) and 17.8g (0.18 mol,1.2 eq) succinimide were added, 33.9g diethyl azodicarboxylate (0.195 mol,1.3 eq) was added, the reaction was carried out for 3 to 5 hours at 20 to 30℃after the addition was completed, 150ml water was added, stirred at room temperature for 5 to 10 minutes, the separated solution was washed with saturated brine (100 ml. Times.2), dried with anhydrous MgSO4, and concentrated to obtain 56.1g of solid compound IIc in a yield of 90.5%.
Example 4
Figure BDA0001337028950000091
To the reaction flask was added 150mL of a 1M solution of NaHMDS (sodium bis (trimethylsilyl) amide) in tetrahydrofuran and cooled to-70 ℃. A solution of 34.3g (0.15 mol,1.1 eq) of (S) -4-benzyl-3-propionyloxazolidinone in tetrahydrofuran (60 mL) was slowly added dropwise, and the addition was continued at-70℃for 80 minutes with stirring. 43.8g (0.134 mol,1.0 eq) of anhydrous tetrahydrofuran containing compound IIa are added dropwise(100 mL) solution, and after the dripping, the temperature is kept constant and stirring is continued for 30 minutes. Slowly warm to room temperature and stir until the substrate is completely converted. The organic layer was washed with saturated ammonium chloride solution (100 ml), water (100 ml), saturated brine (100 ml), and separated, and the organic layer was dried over anhydrous MgSO 4 Drying and concentration gave 63.6g of crude compound IIIa in 90.2% yield.
Example 5
Figure BDA0001337028950000092
To the reaction flask was added 150mL of a 1M solution of LiHMDS (lithium bis (trimethylsilyl) amide) in tetrahydrofuran and cooled to-50 ℃. A solution of 32.8g (0.15 mol,1.1 eq) of (S) -4-phenyl-3-propionyl oxazolidinone in tetrahydrofuran (60 mL) was slowly added dropwise, and the addition was continued at-50℃for 80 minutes with stirring. A solution of compound IIb 50g (0.134 mol,1.0 eq) in anhydrous tetrahydrofuran (100 mL) was added dropwise, and the stirring was continued for 30 minutes after the addition. Slowly warm to room temperature and stir until the substrate is completely converted. The organic layer was washed with saturated ammonium chloride solution (100 ml), water (100 ml), saturated brine (100 ml), and separated, and the organic layer was dried over anhydrous MgSO 4 Drying and concentration gave 53.2g of crude compound IIIb in 87.3% yield.
Example 6
Figure BDA0001337028950000101
To the reaction flask was added 150mL of 1M LDA (lithium diisopropylamide) in tetrahydrofuran, and the mixture was cooled to-30 ℃. A solution of 27.7g (0.15 mol,1.1 eq) of (S) -4-isopropyl-3-propionyloxazolidinone in tetrahydrofuran (60 mL) was slowly added dropwise, and the addition was continued at-30℃for 80 minutes with stirring. A solution of compound IIc 56.2g (0.134 mol,1.0 eq) in anhydrous tetrahydrofuran (100 mL) was added dropwise, and stirring was continued for 30 minutes with continued incubation. Slowly warm to room temperature and stir until the substrate is completely converted. The organic layer was washed with saturated ammonium chloride solution (100 ml), water (100 ml), saturated brine (100 ml), and separated, and the organic layer was dried over anhydrous MgSO 4 Drying and concentrating to obtain 48.1g crude compound IIIc,the yield thereof was found to be 84.7%.
Example 7
Figure BDA0001337028950000102
35g (0.067 mol,1.0 eq) of compound IIIa is dissolved in 300ml tetrahydrofuran, cooled to 0-5 ℃, 3.2g of lithium hydroxide (0.13 mol,2.0 eq) is added, then 26.6g (0.24 mol,3.5 eq) of 30% hydrogen peroxide is gradually added dropwise into the system, and the reaction is carried out for 3-5 hours at room temperature after the dropwise addition is completed, so that the substrate is completely converted. And (3) treating residual hydrogen peroxide in the reaction system by using an excessive saturated sodium bisulphite solution. Adjusting pH of the system to about 3-4, extracting aqueous layer with ethyl acetate (150 ml. Times.3), mixing organic phases with anhydrous Na 2 SO 4 The organic phase was dried and concentrated to give 22.4g of crude compound IV in 92.2% yield.
Example 8
Figure BDA0001337028950000111
35g (0.073 mol,1.0 eq) of compound IIIc is dissolved in 300ml tetrahydrofuran, cooled to 0-5 ℃,3.5 g of lithium hydroxide (0.15 mol,2.0 eq) is added, then 28.8g (0.26 mol,3.5 eq) of 30% hydrogen peroxide is gradually added dropwise into the system, and the reaction is carried out at room temperature for 3-5 hours after the dropwise addition is completed, so that the substrate conversion is complete. And (3) treating residual hydrogen peroxide in the reaction system by using an excessive saturated sodium bisulphite solution. Adjusting pH of the system to about 3-4, extracting aqueous layer with ethyl acetate (150 ml. Times.3), mixing organic phases with anhydrous Na 2 SO 4 The organic phase was dried and concentrated to give 24.6g of crude compound IV in 91.7% yield.
Example 9
Figure BDA0001337028950000112
Dissolving 50g (0.14 mol,1.0 eq) of compound IV in 350ml of absolute ethanol, adding 25g (0.21 mol,1.5 eq) of thionyl chloride, heating the system to 50-60 ℃, preserving heat for 3-5 hours, reacting the substrate basically completely, cooling to room temperature and concentrating the reaction system to obtain a crude product of the compound V
Example 10
Figure BDA0001337028950000113
Dissolving the crude compound V in 450ml of absolute ethyl alcohol, adding 38.6g (0.28 mol,2.0 eq) of potassium carbonate, heating the system to 50-60 ℃, preserving heat for reaction for 5-7 hours, allowing the substrate to react basically completely, adding dilute acetic acid solution to adjust pH to 6-7, cooling to room temperature, concentrating the reaction system, adding ethyl acetate and water, extracting and separating liquid, and evaporating to dryness to obtain 44.6g of sarcandra, wherein the purity is 99.3%, and the yield is 90.2%.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (9)

1. A sabobiqu intermediate, characterized in that the intermediate has a chemical structure as shown in the following formula III:
Figure FDA0004194163830000011
wherein R is a group selected from the group consisting of: phenyl, benzyl, isopropyl.
2. A process for the preparation of an intermediate as claimed in claim 1, comprising the following reaction steps:
1) In the presence of an organic solvent and an alkaline reagent, the compound I and the succinimide are subjected to Misunobu reaction,
generating a compound II; and
2) In the presence of an alkaline reagent, carrying out substitution reaction on the compound II and a 4-substituted 3-propionyl-2-oxazolidinone compound to obtain a compound III;
Figure FDA0004194163830000012
wherein X is Cl, br or I, R is phenyl, benzyl or isopropyl.
3. A process for the preparation of a compound of formula IV comprising the steps of:
1) In the presence of an organic solvent and an alkaline reagent, the compound I and the succinimide are subjected to Misunobu reaction,
generating a compound II; and
2) In the presence of an alkaline reagent, carrying out substitution reaction on the compound II and a 4-substituted 3-propionyl-2-oxazolidinone compound to obtain a compound III;
Figure FDA0004194163830000021
3) Under the condition of hydrogen peroxide and an alkaline reagent, the compound of the formula III undergoes hydrolysis reaction, so that a compound of the formula IV is obtained;
Figure FDA0004194163830000022
r is phenyl, benzyl or isopropyl, X is Cl, br or I.
4. A process according to claim 2 or 3, wherein the organic solvent in step 1) is selected from toluene or methylene chloride; the alkaline reagent is selected from the group consisting of: diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or combinations thereof;
the alkaline agent described in step 2) is selected from the group consisting of: lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, n-butyllithium, t-butyllithium, or a combination thereof.
5. A process according to claim 2 or 3, wherein the substitution reaction temperature in step 2) is-70 to 0 ℃.
6. A process according to claim 3, wherein the alkaline agent in step 3) is selected from the group consisting of: lithium hydroxide, sodium hydroxide, lithium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate, or a combination thereof.
7. A process for preparing sabobiqu using the intermediate of claim 1 comprising the steps of:
c) Under the condition of hydrogen peroxide and an alkaline reagent, the compound of the formula III undergoes hydrolysis reaction, so that a compound of the formula IV is obtained;
d) Carrying out esterification reaction on the compound of the formula IV under the action of ethanol and thionyl chloride, thereby obtaining a compound of the formula V; and
e) The compound of formula V undergoes hydrolysis reaction in the presence of an alkaline reagent, thereby obtaining sarcandra;
Figure FDA0004194163830000031
wherein X is Cl, br or I, and R is phenyl, benzyl or isopropyl.
8. The method for preparing sacubiqu as claimed in claim 7, wherein the base in step e) is an organic base or an inorganic base; the organic base is selected from the following group: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof; the inorganic base is selected from the following group: sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or a combination thereof.
9. Use of an intermediate as claimed in claim 1 for the preparation of sabobiqu.
CN201710517896.4A 2017-06-29 2017-06-29 Sakubi koji intermediate and preparation method and application thereof Active CN109206419B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710517896.4A CN109206419B (en) 2017-06-29 2017-06-29 Sakubi koji intermediate and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710517896.4A CN109206419B (en) 2017-06-29 2017-06-29 Sakubi koji intermediate and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN109206419A CN109206419A (en) 2019-01-15
CN109206419B true CN109206419B (en) 2023-07-14

Family

ID=64976870

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710517896.4A Active CN109206419B (en) 2017-06-29 2017-06-29 Sakubi koji intermediate and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN109206419B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727213B (en) * 2018-06-29 2021-06-08 中国科学院上海有机化学研究所 A kind of preparation method of sacubitril
CN113387829B (en) * 2020-03-13 2023-04-07 凯特立斯（深圳）科技有限公司 Preparation method of shakubiqu
CN114436877B (en) * 2021-12-24 2024-04-30 无锡双启科技有限公司 Synthesis process of heart failure resistant medicine Sha Kuba yeast

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104230865A (en) * 2013-06-13 2014-12-24 上海翰森生物医药科技有限公司 Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof
CN106187808A (en) * 2015-05-08 2016-12-07 苏州鹏旭医药科技有限公司 The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate
WO2017033128A1 (en) * 2015-08-25 2017-03-02 Novartis Ag Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104230865A (en) * 2013-06-13 2014-12-24 上海翰森生物医药科技有限公司 Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof
CN106187808A (en) * 2015-05-08 2016-12-07 苏州鹏旭医药科技有限公司 The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate
WO2017033128A1 (en) * 2015-08-25 2017-03-02 Novartis Ag Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
吕训磊，等.沙库必曲合成路线图解.《中国医药工业杂志》.2016,第47卷(第11期),第1470-1473页. *
沙库必曲合成路线图解;吕训磊，等;《中国医药工业杂志》;20161231;第47卷(第11期);第1470-1473页 *

Also Published As

Publication number Publication date
CN109206419A (en) 2019-01-15

Similar Documents

Publication Publication Date Title
CN109206419B (en) Sakubi koji intermediate and preparation method and application thereof
JP5628427B2 (en) Method for preparing rosuvastatin calcium intermediate
CA2636256C (en) Carbonyl asymmetric alkylation
CN105017082A (en) Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate
CN113912509B (en) Preparation method of amide compound
US9000205B2 (en) Process for the preparation of 2-cyanophenylboronic acid and esters thereof
CN103649081A (en) Novel method for synthesizing rivaroxaban intermediate, 4-{4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazoligdin-3-yl]phenyl}morpholin-3-one
CN108623455B (en) Intermediate of anti-heart failure medicine
CN101967075B (en) Method for synthesizing terminal alkyne compound by using 3-aryl-2,3-dibromopropionic acid
CN107513056B (en) A kind of synthetic method of quinoline compound containing tetrahydrofuran group
CN102477007A (en) Novel method for preparing S-N-protecting group-azetidine-2-carboxylic acid
EP3560934A1 (en) Process for the preparation of pure 2-cyanophenylboronic acid and esters thereof, intermediates of perampanel or of e2040
CN107698533B (en) Method for preparing linezolid
CN115677585B (en) Synthesis process of formaldehyde pyrazole derivative
CN110330509B (en) Synthesis process of eucalyptus thioether
CN102093168B (en) Novel isomerization method of 4-(trans-4'-normal alkylcyclohexyl) cyclohexanol
CN114213291B (en) Synthesis method of thiodiethylene bis [3- (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ]
JP5250693B2 (en) Method for producing carboxylic acid compound
CN115074404B (en) A method for synthesizing (2S, 4R)-2-amino-4-methylnonanoic acid
CN103319461A (en) Preparation method of olmesartan medoxomil intermediate and synthesis method of olmesartan medoxomil
WO2015163446A1 (en) Method for producing imidazole compound
CN109867619B (en) OLED intermediate 11-chloro-7H-benzo [ c ] carbazole and synthetic method thereof
JP4172200B2 (en) Ether compound and process for producing the same
KR20240069893A (en) Novel method for preparing high purity 9-phenylcarbazole
CN119350211A (en) Preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant