CN109053495B - Synthesis method of LCZ696 intermediate - Google Patents
Synthesis method of LCZ696 intermediate Download PDFInfo
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- CN109053495B CN109053495B CN201810809611.9A CN201810809611A CN109053495B CN 109053495 B CN109053495 B CN 109053495B CN 201810809611 A CN201810809611 A CN 201810809611A CN 109053495 B CN109053495 B CN 109053495B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/10—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfur dioxide and halogen or by reaction with sulfuryl halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract
The invention discloses an LCZ696 intermediate: a method for synthesizing (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropan-2-yl) carbamate, which comprises the following steps: 1) reacting a raw material BOC-D-tyrosine I with substituent sulfonyl chloride to obtain an intermediate II; 2) coupling the intermediate II with a phenyl Grignard reagent to obtain an intermediate III; 3) reducing the intermediate III by potassium borohydride to obtain (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate IV; the method of the invention uses cheap p-toluenesulfonyl to replace expensive and virulent trifluoromethanesulfonic anhydride, avoids using expensive metal catalyst Pd, has simple experimental operation and high yield, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical chemicals, in particular to a method for preparing a key intermediate (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate of Sacubitril.
Background
A new heavy pound blood pressure reducing and heart failure resisting drug LCZ696 (trade name Entresto) developed by Nowa is a double-effect angiotensin receptor enkephalinase inhibitor, combines the high blood pressure drugs of Nowa, namely Valsartan (Valsartan) and Sacubitril (Sacubitril), is used for treating heart failure patients with reduced ejection fraction, has obvious curative effect and low side effect, and has wide market prospect. LCZ696 is a valsartan and Sacubitril sodium salt hydrate eutectic, the synthesis process is basically that a product is obtained in a hydrated eutectic mode by acidifying and dissociating a Sacubitril calcium salt and valsartan in a sodium hydroxide solution, and the synthesis process of the valsartan is relatively mature, so that the synthesis focus falls on a Sacubitril fragment. The chemical name of sabatier is 4- { [ (2S,4R) -1- (1, 1' -biphenyl-4-yl) -5-ethoxy-4-methyl-5-oxo-2-pentyl ] amino } -4-oxoacetic acid, which has the following structure:
there are many synthetic reports before the preparation of the Sacubitril program, among which J.Med.chem.1995, 38 vol 1689-1700 page reports the synthetic method of the Sacubitril:
the initial raw material of the route is BOC-D-tyrosine methyl ester, expensive and virulent trifluoromethanesulfonic anhydride is needed to be used when a biphenyl structure is synthesized through a coupling reaction, large equivalent amount of tetrakis (triphenylphosphine) palladium is also needed to be used as a catalyst, EDCI, lithium aluminum hydride, palladium carbon and the like are used in subsequent reactions, the reagents are expensive, part of process steps are dangerous to operate, and in addition, the step route is too long, so that the method is not suitable for large-scale production.
PCT patents WO2008031567, WO2010136474, WO2012025501 and the like report that 4-bromobiphenyl is used as an initial raw material, chiral epichlorohydrin is subjected to ring opening through grignard reaction, then chiral amino alcohol (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate is obtained through mitsunobu reaction, hydrolysis reaction and Boc protection reaction, then aldehyde is formed through oxidation, and finally sabotabeth is obtained through series of reactions.
The route is the main process route for synthesizing the Saccharum sinensis Roxb, but the steps of the route are still too many; the starting materials need to be synthesized in multiple steps, large equivalent amount of strong acid is used in the production process, a large amount of waste liquid is generated, and the environmental protection pressure is large; in addition, a noble metal catalyst is needed in the chiral reduction step, the reaction is difficult to control, and the process cost is high. At present, the synthetic routes of the Saccharum sinensis Roxb have certain limitations and higher process amplification cost, so a lower-cost and high-efficiency synthetic method needs to be developed, and the key point is to find a low-cost and high-efficiency synthetic key intermediate (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-
Radical) -3-hydroxypropan-2-yl) carbamate.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a key intermediate of Sacubitril, which has simple process route and low cost and is suitable for industrial production: a method for synthesizing (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: an LCZ696 intermediate: a method for synthesizing (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate;
1) reacting a raw material BOC-D-tyrosine I with substituent sulfonyl chloride to obtain an intermediate II;
wherein, RSO2Cl is a substituent sulfonyl chloride, base is a base, R is methyl, ethyl, phenyl or p-tolyl; the substituent sulfonyl chloride is one of methyl sulfonyl chloride, ethyl sulfonyl chloride, phenyl sulfonyl chloride or p-tolyl sulfonyl chloride.
2) Coupling the intermediate II with a phenyl Grignard reagent to obtain an intermediate III;
wherein the catalyst is catalyst, MX is magnesium chloride, magnesium bromide or magnesium iodide; the phenyl Grignard reagent is one of phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide.
3) Reducing the intermediate III by potassium borohydride to obtain (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl)
And (3) carbamate IV.
In the step 1), the selected base is organic base, specifically one of triethylamine, diisopropylethylamine, DBU or pyridine; the reaction solvent is one or a mixture of more of dichloromethane, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene or acetone; the reaction temperature is-10 to 110 ℃.
In the step 2), the selected catalyst is one of bis (triphenylphosphine) nickel dichloride or nickel dichloride; the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane; in the reaction process of the step 3), no ligand or ligand triphenylphosphine can be added; the reaction temperature is-15 to 50 ℃.
In the step 3), the reaction solvent is a mixed solvent of methanol and tetrahydrofuran; the reaction temperature is-10 to 80 ℃.
The invention has the advantages that: the method of the invention is a key intermediate of the Biqu of Saccharum sinensis Roxb: the improvement of the synthetic route of (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate not only selects cheap sulfonyl chloride as a substituent to replace expensive and virulent trifluoromethanesulfonic anhydride, but also selects a nickel catalyst with low price, and avoids the use of expensive metal catalyst Pd. Meanwhile, the invention is applicable to experimental conditions in a process route such as: the selection of reactants, reaction conditions, solvent, catalyst and the like are optimized, the experimental operation is simple, the yield is high, and the method is suitable for large-scale production.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1: preparing (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropan-2-yl) carbamate;
1) adding BOC-D-tyrosine methyl ester Ia (29.53g,100mmol), diisopropylethylamine (19.39g,150 mmol) and dichloromethane (148mL) into a three-neck flask, stirring uniformly, cooling to 0-5 ℃, slowly dropwise adding a dichloromethane (50mL) solution of p-toluenesulfonyl chloride (22.88g,120 mmol), and slowly heating to room temperature for reaction after dropwise adding. After the reaction, water (148mL) was added for separation, the aqueous phase was extracted with dichloromethane (74mL) 2 times, the combined organic phases were washed with brine 1 time (148mL), dried over sodium sulfate, filtered, concentrated, slurried with petroleum ether, filtered, and dried to give intermediate IIa (41.59g, 96.2% purity, 89% yield).
2) Adding an intermediate IIa (44.95g,100mmol) and tetrahydrofuran (225mL) into a three-neck flask, stirring and dissolving, cooling in a ice salt bath, switching nitrogen gas for 3 times in vacuum, adding bis (triphenylphosphine) nickel dichloride (654mg,1.0mmol) and triphenylphosphine (525mg,2.0mmol), dropwise adding a tetrahydrofuran solution (105mmol, 105mL) of 1.0M phenylmagnesium bromide, stirring at 10-0 ℃ for 30 minutes, slowly heating to room temperature for reaction, adding dilute hydrochloric acid (2mol/L,112mL) to quench the reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (112mL) for 3 times, combining organic phases, washing with water for 2 times (112mL), drying with sodium sulfate, filtering, concentrating, adding a mixed solvent of ethyl acetate and petroleum ether, and pulping to obtain an intermediate III (30.53g, the purity is 97.8%, and the yield: 84%).
3) Adding the intermediate III (35.54g,100mmol) and tetrahydrofuran (178mL) into a three-neck flask, stirring uniformly, adding potassium borohydride (5.39g,100mmol), heating to 45-50 ℃, slowly dropping methanol (36mL), and preserving heat for reacting overnight after dropping. After the reaction is finished, cooling to 10-15 ℃, adding 0.5mol/L dilute hydrochloric acid (178mL) to quench the reaction, adding ethyl acetate (178mL) into a water phase to extract for 2 times, combining organic phases, washing with saturated salt water for 2 times (178mL), drying with sodium sulfate, concentrating, pulping with an ethanol petroleum ether mixed solvent, filtering, and drying to obtain (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate IV (30.03g, the purity is 99.2%, and the yield is 91%).
Example 2: preparation of (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropan-2-yl) carbamate
1) Adding BOC-D-tyrosine methyl ester Ia (29.53g,100mmol), triethylamine (15.18g,150mmol) and tetrahydrofuran (148mL) into a three-neck flask, uniformly stirring, cooling to 0-5 ℃, slowly dropwise adding a tetrahydrofuran (50mL) solution of methylsulfonyl chloride (13.75g,120mmol), and slowly heating to room temperature for reaction after dropwise adding. After the reaction, water (148mL) was added and a part of the solvent was removed by rotation, the aqueous phase was extracted 3 times with dichloromethane (148mL), the combined organic phases were washed with brine 1 time (148mL), dried over sodium sulfate, filtered, concentrated, slurried with petroleum ether, filtered, and dried to give intermediate IIb (33.91g, purity 95.8%, yield 87%).
2) Adding an intermediate IIb (37.34g,100mmol) and 2-methyltetrahydrofuran (187mL) into a three-neck flask, stirring and dissolving, cooling in a ice salt bath, switching nitrogen gas for 3 times under vacuum, adding bis (triphenylphosphine) nickel dichloride (654mg,1.0mmol) and triphenylphosphine (525mg,2.0mmol), dropwise adding a tetrahydrofuran solution (105mmol, 105mL) of 1.0M phenylmagnesium chloride, stirring at 10-0 ℃ for 30 minutes, slowly heating to room temperature for reaction, adding dilute hydrochloric acid (2mol/L,112mL) to quench the reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (93mL) for 3 times, combining organic phases, washing with water for 2 times (93mL), drying with sodium sulfate, filtering, concentrating, adding a mixed solvent of ethyl acetate and petroleum ether, and pulping to obtain an intermediate III (28.89g, 97.2%, yield: 79%).
3) Adding the intermediate III (35.54g,100mmol) and tetrahydrofuran (178mL) into a three-neck flask, stirring uniformly, adding potassium borohydride (5.39g,100mmol), heating to 50-55 ℃, slowly dropping methanol (36mL), and reacting for 4-6 hours after dropping. After the reaction is finished, cooling to 10-15 ℃, adding 0.5mol/L dilute hydrochloric acid (178mL) to quench the reaction, adding ethyl acetate (178mL) into a water phase to extract for 2 times, combining organic phases, washing with saturated salt water for 2 times (178mL), drying with sodium sulfate, concentrating, pulping with an ethanol petroleum ether mixed solvent, filtering, and drying to obtain (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate IV (29.46g, the purity is 98.9%, and the yield is 89%).
Example 3: comparative example: the technical solution of the present invention was subjected to comparative tests according to the operating method of example 1, with the other conditions being unchanged, and the results obtained are shown in the following table:
from the above table, the first step reactants selected in example 1: p-toluenesulfonyl chloride, second step reactant: phenyl magnesium bromide, third step reactant: potassium borohydride is the best embodiment; when other substituent groups and phenyl Grignard reagent are adopted, the reaction and yield of each part are changed to a certain extent, because the stability of the compound after synthesis is reduced to a certain extent due to different substituent groups, and finally the purity and yield of the final product (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate IV are reduced, and the cost of the whole synthesis route is increased.
Example 4: comparative example: the technical solution of the present invention was subjected to comparative tests according to the operating method of example 1, with the other conditions being unchanged, and the results obtained are shown in the following table:
from the above table, the organic base of the first step selected in example 1: diisopropylethylamine, second-step catalyst: the reaction temperature of the three steps is 0-5 ℃, 10-0 ℃ and 45-50 ℃, which is the best embodiment; it follows that when the reaction temperature, organic base and catalyst of the present invention are changed, the yield and purity of the final product are also directly affected.
It should be noted that the above-mentioned embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any combination or equivalent changes made on the basis of the above-mentioned embodiments are also within the scope of the present invention.
Claims (2)
1. A synthetic method of LCZ696 intermediate is characterized in that,
1) reacting a raw material BOC-D-tyrosine I with substituent sulfonyl chloride to obtain an intermediate II;
Ⅰ Ⅱ
the selected base is organic base, specifically one of triethylamine, diisopropylethylamine, DBU or pyridine; the reaction solvent is one or a mixture of more of dichloromethane, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene or acetone; the reaction temperature is-10 to 110 ℃;
2) coupling the intermediate II with a phenyl Grignard reagent to obtain an intermediate III;
Ⅱ Ⅲ
the selected catalyst is one of bis (triphenylphosphine) nickel dichloride or nickel dichloride; the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane; selecting triphenylphosphine as a ligand, and controlling the reaction temperature to be-15-50 ℃;
3) reducing the intermediate III by potassium borohydride to obtain (R) -tert-butyl (1- ([1,1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate IV,
Ⅲ Ⅳ
2. the method for synthesizing the intermediate of LCZ696 of claim 1, wherein in step 3), the reaction solvent is a mixed solvent of methanol and tetrahydrofuran; the reaction temperature is-10 to 80 ℃.
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| CN111253425B (en) * | 2020-02-21 | 2022-04-29 | 常州南京大学高新技术研究院 | Synthesis method of 1, 3-bis [2- (3, 4-epoxycyclohexyl) ethyl ] tetramethyldisiloxane |
| CN112661671B (en) * | 2020-12-22 | 2022-04-22 | 江苏阿尔法药业股份有限公司 | Preparation method of Sacubitril intermediate |
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| EP2161254B1 (en) * | 2002-03-05 | 2014-08-13 | Sumitomo Chemical Company, Limited | Intermediate for preparing a biaryl compound |
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| CN104011013A (en) * | 2011-10-17 | 2014-08-27 | 拜欧赛里克斯公司 | Substituted biaryl alkyl amides |
| CN105198775A (en) * | 2015-10-10 | 2015-12-30 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of chiral N-Boc biphenyl alaninol |
| CN107540574A (en) * | 2017-09-19 | 2018-01-05 | 成都西岭源药业有限公司 | The preparation method of R biphenyl Propanolamines |
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