CN111943862A - Preparation method of heart failure resistant drug Entresto key component Shakuba koji - Google Patents
Preparation method of heart failure resistant drug Entresto key component Shakuba koji Download PDFInfo
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- CN111943862A CN111943862A CN201910408348.7A CN201910408348A CN111943862A CN 111943862 A CN111943862 A CN 111943862A CN 201910408348 A CN201910408348 A CN 201910408348A CN 111943862 A CN111943862 A CN 111943862A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/64—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by simultaneous introduction of -OH groups and halogens
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- 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
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- 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
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a heart failure resistant drug Entresto, which comprises key components of Sacubibara-chemical name: the preparation method of 4- (((2S, 4R) -1- (1, 1' -biphenyl-4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutyric acid is characterized in that 4-bromobiphenyl is used as a starting material, the process route is simple, the cost is low, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a heart failure resistant drug Entresto key component Shakuba koji.
Background
Entresto is an Angiotensin Receptor (ARB) -enkephalinase (NEP) double-effect inhibitor, is a novel anti-heart-failure medicament developed by Nowa company, is approved by FDA to be marketed 7.7.2015, and is combined by two molecules 1:1 of valsartan and Sacubitril, wherein the former can block angiotensin II receptors in RAAS, and the metabolite of the latter can inhibit NEP, and plays roles in relaxing blood vessels, preventing and reversing cardiovascular remodeling, natriuresis and the like. Clinically, unique mode of action, hypotensive effect superior to that of standard drugs and efficacy in reducing heart failure are shown, so that the drug is qualified for rapid access evaluation by FDA and EMEA in the united states. It is widely accepted in the industry that Entresto will bring innovation to traditional treatment regimens for heart failure.
The Shakuba koji is one of the main components of Entresto, and has the chemical name: 4- (((2S, 4R) -1- (1, 1' -biphenyl-4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid, having the formula:
the preparation method of the Sacubibara yeast has more research reports, wherein, U.S. Pat. No. 5,5217996 and international patents WO2008031567, WO2010136474, WO2012025501 and the like report a following synthetic route, chiral amino alcohol is used as a raw material, and a target product is prepared by the reactions of oxidation to aldehyde, vinylon reaction, chiral hydrogenation, amidation condensation and the like.
The route is the main process route for synthesizing the Shakubaqu at present, but the route steps are still too many; the starting materials need to be synthesized in multiple steps, and the starting materials are expensive and the process cost is high, so that the synthesis method with lower cost and high efficiency needs to be developed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthetic method of the Sacubitril, which has simple process route and low cost and is suitable for industrial production.
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows:
a preparation method of a key component of Entresto, a novel anti-heart failure drug, Shakubaqu, is a compound shown in formula 10, and is characterized by comprising the following steps c-g or steps a-g in a synthetic route:
the step a is to obtain a Grignard reagent 1-a by reacting 4-bromobiphenyl with metal magnesium in tetrahydrofuran; and the step b is a Grignard reaction, namely, the Grignard reagent 1-a reacts with the compound of the formula 2 in the presence of a catalyst to obtain the compound of the formula 3, wherein the catalyst is cuprous halide, preferably cuprous iodide.
The step c is as follows: reacting the compound of formula 3 with the compound of formula 4 in the presence of triphenylphosphine, toluene and isopropyl azodicarboxylate to obtain the compound of formula 5.
The step c is specifically as follows: b, adding the compound of the formula 3 obtained in the step b, triphenylphosphine, toluene and succinimide into a reactor, stirring, dropwise adding a mixed solution of diisopropyl azodicarboxylate and toluene, keeping the temperature at 0-5 ℃ for 1-2 hours after dropwise adding, removing toluene, adding hydrochloric acid and water to perform hydrolysis reaction at the temperature of 100-106 ℃ for 10-15 hours, heating and separating liquid after hydrolysis, putting the organic phase into a kettle added with toluene and stirring, keeping the temperature and stirring for 1 hour at 15-25 ℃, filtering, washing with toluene to obtain crude product of the compound shown in formula 5, cooling the upper water phase to 15-25 deg.C, stirring for 1 hr, then filtering to obtain a crude product of the compound shown in the formula 5, combining the crude products, pulping by using dichloromethane, cooling to 10-35 ℃, stirring for 1 hour, filtering, washing by using dichloromethane, and drying to obtain a refined product of the compound shown in the formula 5.
The step d is as follows: the compound of formula 5 is reacted with a compound of formula 6 in the presence of titanium tetrachloride, N-diisopropylethylamine, and dichloromethane to give a compound of formula 7.
The step d is specifically as follows: and d, dissolving the compound of the formula 5 obtained in the step c in dichloromethane, cooling to 0 ℃, dropwise adding a dichloromethane solution of titanium tetrachloride, and keeping stirring at the temperature of below 0 ℃ for 10 minutes after dropwise adding. Diisopropylethylamine was added dropwise, and after completion of the addition, stirring was maintained at 0 ℃ or lower for 30 minutes. Dissolving the compound shown in the formula 6 in dichloromethane, dropwise adding the solution into a reaction system, and moving the reaction system to 20-25 ℃ after the dropwise adding is finished, and stirring the solution for 10 hours. The reaction system was added with an aqueous solution of saturated ammonium chloride, extracted with dichloromethane, and the resulting organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the crude compound of formula 7. And purifying the crude product by column chromatography to obtain a refined product of the compound shown in the formula 7.
The step e is as follows: dissolving the compound shown in the formula 7 in tetrahydrofuran, adding hydrogen peroxide, and then dropwise adding hydrated lithium hydroxide to react to obtain the compound shown in the formula 8.
The step e is specifically as follows: and d, dissolving the compound of the formula 7 obtained in the step d in tetrahydrofuran, cooling to 0 ℃, adding hydrogen peroxide while stirring, and stirring for 30 minutes after the hydrogen peroxide is added. Maintaining the temperature, dropwise adding lithium hydroxide hydrate, moving to 20-25 ℃ after dropwise adding, stirring for 3 hours, stopping stirring, removing the water phase, removing the excessive peroxide from the organic phase by using a saturated sodium bisulfite solution, removing the water phase, and removing the solvent by pressure evaporation of the organic phase to obtain a crude product containing the compound of the formula 8. Adding water to the crude product, adjusting the pH value to 12-13 with sodium hydroxide solution, washing the water phase with tert-butyl methyl ether for 3 times, adjusting the pH value to 3-4 with concentrated hydrochloric acid, extracting the product with ethyl acetate, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and evaporating the mother liquor under reduced pressure to remove the solvent to obtain a refined product of the compound of the formula 8.
The hydrogen peroxide is preferably 30 percent.
The step f is as follows: the compound of the formula 8 and thionyl chloride are subjected to esterification reaction in ethanol to obtain the compound of the formula 9.
The step f is specifically as follows: and e, dissolving the compound of the formula 8 obtained in the step e in ethanol, slowly dripping thionyl chloride at room temperature, stirring at room temperature for 6-8 hours, finishing the reaction, adding saturated sodium carbonate to quench the reaction, evaporating the reaction liquid under reduced pressure to remove ethanol, extracting with ethyl acetate, combining organic phases, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain the compound of the formula 9.
The step g is as follows: and (3) carrying out a ring-opening reaction on the compound of the formula 9 under the action of a ring-opening reagent sodium hydroxide to obtain the compound of the formula 10, namely the Shakubaqu.
The step g is specifically as follows: and f, dissolving the compound of the formula 9 obtained in the step f in a mixed solvent, adding lithium hydroxide, reacting at room temperature for 1.5 hours, adding water, quenching the reaction, extracting the reaction liquid with ethyl acetate, acidifying the water phase with 5% diluted HCl, extracting with ethyl acetate, combining organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain the compound of the formula 10, namely the Shakuba koji.
The technical scheme of the invention has simple process route and low cost and is suitable for industrial production.
Detailed Description
The technical scheme of the invention is further detailed and completely explained by combining the embodiment.
Example 1: preparation of the Compound of formula 3
Adding 4-bromobiphenyl 22.4g, magnesium 49.06g and tetrahydrofuran 90g into a reactor, adding elementary iodine particles 0.224g for initiation, adding tetrahydrofuran 360g, controlling the temperature to be 40-50 ℃, dropwise adding mixed solution of 4-bromobiphenyl 425.6g and tetrahydrofuran 630g, cooling to 0-5 ℃ after reacting for 2h, adding cuprous iodide 3.6g, continuously cooling to-15 ℃, dropwise adding mixture of (S) -epichlorohydrin 195g and tetrahydrofuran, and stirring for reacting for 2.0 h;
dripping acid solution into the reactor, heating to 30 ℃ after dripping, fully stirring for 0.5h, standing for layering, collecting tetrahydrofuran phase, evaporating solid, extracting water phase with dissolving solvent, combining organic phases, dissolving solid, performing heat filtration, and distilling the organic phases under reduced pressure;
adding absolute ethyl alcohol into a reactor, uniformly mixing, heating to 60 ℃, stopping heating, dropwise adding primary water into the reactor, cooling the mother liquor to 20 ℃ after 1h of addition, and stirring for 1h under heat preservation; filtering, washing the filter cake with primary water to obtain a wet crude product, pulping the wet crude product with cyclohexane at 45 ℃, cooling to 5 ℃, filtering, washing with cyclohexane and drying to obtain the compound of formula 3 (yield 95%).
Example 2: preparation of Compounds of formula 5
Taking 180g of the compound of the formula 3 obtained in the example 1, 531.8g of toluene, 220g of triphenylphosphine and 79.2g of succinimide, stirring in a reactor, dropwise adding a mixed solution of 177g of diisopropyl azodicarboxylate and 177g of toluene, keeping the temperature at 0 ℃ for 2h after dropwise adding, removing the toluene by rotary evaporation, adding 366g of hydrochloric acid and 366g of water, heating to 100 ℃ for hydrolysis reaction for 20h, heating for liquid separation after hydrolysis, putting an organic phase into a kettle added with 366g of toluene, stirring, cooling to 15 ℃, keeping the temperature and stirring for 1h, filtering, washing a filter cake with toluene to obtain a crude product, cooling an upper aqueous phase to 15 ℃, stirring for 1h, filtering to obtain the crude product, combining the crude products, pulping with dichloromethane, cooling to 20 ℃, stirring for 1h, filtering, washing with 120g of dichloromethane, and drying to obtain a fine product of the compound of the formula 5 (yield 93%).
Example 3 preparation of the Compound of formula 7
82.5g of the compound of formula 6 was dissolved in 200ml of methylene chloride, cooled to 0 ℃ or lower, and 70g of a methylene chloride solution of titanium tetrachloride was added dropwise thereto, and the mixture was stirred at 0 ℃ or lower for 30 minutes. 150g of the compound of formula 5 obtained in example 2 was dissolved in methylene chloride, added dropwise to the reaction system, and after completion of the addition, the reaction system was stirred at 20 to 25 ℃ for 10 hours. The reaction system was added with an aqueous solution of saturated ammonium chloride, extracted with dichloromethane, and the resulting organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the crude compound of formula 7. The crude product was purified by column chromatography to give a crude product of the compound of formula 7 (218.49g, 91% yield). No diastereoisomer was detected by HPLC, i.e. 100% chiral purity.
Example 4: preparation of the Compound of formula 8
120g of the compound of formula 7 obtained in example 3 was dissolved in 77ml of tetrahydrofuran, cooled to 0 ℃, and then 30% hydrogen peroxide solution (100 g) was added thereto with stirring, and then stirred for 30 min. 18.4g of hydrated lithium hydroxide is added dropwise while maintaining the temperature, and the mixture is stirred for 3 hours after the addition of the hydrated lithium hydroxide is completed and the temperature is raised to 20-25 ℃. After the stirring is stopped, the aqueous phase is removed, the organic phase is freed of excess peroxide with saturated sodium bisulfite solution and the aqueous phase is removed again, and the organic phase is freed of the solvent by evaporation under reduced pressure to give the crude compound of formula 8. The crude product was taken up in water, the pH adjusted to 12-13 with sodium hydroxide solution, the aqueous phase was washed 3 times with tert-butyl methyl ether, then the pH adjusted to 3-4 with concentrated hydrochloric acid, the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the drying agent and the mother liquor was evaporated under reduced pressure to remove the solvent to give the compound of formula 8 (76.95g, 92% yield, 100% chiral purity).
Example 5: preparation of Compounds of formula 10
Dissolving 70g of the compound of the formula 8 prepared in the example 4 in ethanol, slowly dripping 45.59g of thionyl chloride at room temperature, stirring at room temperature for about 7 hours to finish the reaction, adding saturated sodium carbonate to quench the reaction, evaporating the reaction liquid under reduced pressure to remove ethanol, extracting with ethyl acetate, combining organic phases, washing the organic phases with water and saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain the compound of the formula 9 with the yield of 91%.
68.59g of the compound of formula 9 is dissolved in a mixed solvent (THF: H)2O3: 1, volume ratio), adding 5g of lithium hydroxide, reacting at room temperature for 1.5 hours, adding water to quench the reaction, and using ethyl to react the reaction solutionExtracting with ethyl acetate, acidifying the water phase with 5% diluted HCl, extracting with ethyl acetate, mixing the organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, and performing column chromatography to obtain Sacubitril with yield of 85%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (7)
1. A preparation method of a key component of Entresto, a novel anti-heart failure drug, Shakubaqu, is a compound shown in formula 10, and is characterized by comprising the following steps c-g or steps a-g in a synthetic route:
2. the preparation method according to claim 1, wherein the step a is to obtain a Grignard reagent 1-a by reacting 4-bromobiphenyl with metal magnesium in tetrahydrofuran; the step b is a Grignard reaction, namely, the Grignard reagent 1-a reacts with the compound shown in the formula 2 in the presence of a catalyst to obtain the compound shown in the formula 3, wherein the catalyst is cuprous halide.
3. The method according to claim 1, wherein the step c is: reacting the compound of formula 3 with the compound of formula 4 in the presence of triphenylphosphine, toluene and diisopropyl azodicarboxylate to give the compound of formula 5.
4. The method according to claim 1, wherein the step d is: the compound of formula 5 is reacted with a compound of formula 6 in the presence of titanium tetrachloride, N-diisopropylethylamine, and dichloromethane to give a compound of formula 7.
5. The method according to claim 1, wherein the step e is: dissolving the compound shown in the formula 7 in tetrahydrofuran, adding hydrogen peroxide, and then dropwise adding hydrated lithium hydroxide to react to obtain the compound shown in the formula 8.
6. The method according to claim 1, wherein the step f is: the compound of the formula 8 and thionyl chloride are subjected to esterification reaction in ethanol to obtain the compound of the formula 9.
7. The method according to claim 1, wherein the step g is: and (3) carrying out a ring-opening reaction on the compound of the formula 9 under the action of a ring-opening reagent sodium hydroxide to obtain the compound of the formula 10, namely the Shakubaqu.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114436877A (en) * | 2021-12-24 | 2022-05-06 | 无锡双启科技有限公司 | Synthesis process of heart failure resistant drug Shakuba koji |
| CN115745841A (en) * | 2021-09-03 | 2023-03-07 | 凯特立斯（深圳）科技有限公司 | Preparation method of shakubiqu intermediate |
| 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 |
-
2019
- 2019-05-16 CN CN201910408348.7A patent/CN111943862A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115745841A (en) * | 2021-09-03 | 2023-03-07 | 凯特立斯（深圳）科技有限公司 | Preparation method of shakubiqu intermediate |
| WO2023029235A1 (en) * | 2021-09-03 | 2023-03-09 | 凯特立斯（深圳）科技有限公司 | Method for preparing sacubitril intermediate |
| CN115745841B (en) * | 2021-09-03 | 2024-04-16 | 凯特立斯（深圳）科技有限公司 | Preparation method of sakubi-qu intermediate |
| CN114436877A (en) * | 2021-12-24 | 2022-05-06 | 无锡双启科技有限公司 | Synthesis process of heart failure resistant drug Shakuba koji |
| 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 |
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