CN109206419B - Sakubi koji intermediate and preparation method and application thereof - Google Patents
Sakubi koji intermediate and preparation method and application thereof Download PDFInfo
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
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- C07—ORGANIC CHEMISTRY
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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
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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
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:
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.
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.
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:
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;
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;
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;
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:
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;
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:
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;
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;
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;
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;
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
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
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
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
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
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
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
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
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
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
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:
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;
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;
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;
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;
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.
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| 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 * |
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