CN111205204A - Sacubitril intermediate and synthetic method and application thereof - Google Patents
Sacubitril intermediate and synthetic method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a shakubiqu intermediate, a synthetic method and application thereof, wherein the synthetic method comprises the following steps: a plurality of reactions which are successively carried out by using D-biphenylalanine as an initial raw material; crystallizing and filtering to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol; the Sacubitril intermediate and the synthesis method and application thereof select D-biphenylalanine as an initial raw material, and finally synthesize the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol by combining with subsequently added reactants to perform multiple reactions in succession, so that the method has the advantages of simple reaction steps, environmental protection, contribution to industrial production and the like, particularly has the chemical purity of a product of over 96 percent and the yield of over 85 percent, and has better industrial prospect.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a shakubiqu intermediate, and a synthesis method and application thereof.
Background
Heart failure (heart failure for short) is a complex clinical syndrome of ventricular filling or impaired ability to eject blood due to any abnormal cardiac structure or function, and is the terminal stage of various heart diseases, and has high morbidity and high fatality rate. With the aggravation of aging of population, the incidence of common heart failure diseases such as coronary heart disease, hypertension, diabetes, myocardial infarction and the like is increased year by year, the prevalence rate of heart failure is obviously increased, the health and economic burden of human beings caused by heart failure is more and more serious, and the cardiovascular disease treating medicine is the most important battlefield for cardiovascular doctors in the future.
7 months 2015, Basel-Nowa company announced that the U.S. Food and Drug Administration (FDA) approved the Entresto previously called LCZ696TMThe (sartori/valsartan) tablets are used for treating heart failure with reduced ejection fraction and can reduce the risk of cardiovascular death and heart failure hospitalization. LCZ696 is a co-crystal of sabotazole and valsartan. LCZ696 overturns the invariable heart failure treatment principle for over ten years, and the treatment effect is far higher than that of the current first-line treatment drug 'enalapril'.
(R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is one of important intermediates of Sacubitril which is one of LCZ696 components, and with good curative effect of LCZ696 medicines in the field of medicine, the demand of the intermediates is greatly increased, so that the method for preparing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol in a large scale with low cost and high yield is found, and the method has strong practical application value.
The structural formula of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is as follows:
at present, various research reports on the method for synthesizing (R) -2- (N-tert-butoxycarbonylamino) diphenylpropanol:
1) in the patent W02014032627, 4-bromobiphenyl is reported to be used as a raw material, and the target product (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is obtained by Grignard reaction, then reaction with chiral propylene oxide, ammoniation and amino protection, and is shown as follows:
the method adopts the Grignard reaction, has high activity and harsh reaction conditions, needs strict anhydrous and anaerobic conditions, and uses a triphenylphosphine reagent in the reaction process, and the reagent has great environmental pollution, so the synthesis method is not suitable for mass production.
2) In patent CN105237560A, D-serine methyl ester hydrochloride is used as a starting material, and a target product is prepared by trityl protection, esterification, ring closing, deprotection, Boc loading, reduction, tert-butyldimethylsilyl chloride protection, grignard reaction, and deprotection, as follows:
the method frequently adopts a protection deprotection mode, has low atom utilization rate and causes cost increase. And the process also adopts the Grignard reaction, which is not suitable for the amplification reaction.
3) In patent CN201510578877, (R) -N-acetylbiphenylalanine ethyl ester is first reduced to (R) -2-acetamidobiphenyl propanol with sodium borohydride, and then acid hydrolysis and amino protection are performed to obtain the product:
although the method has fewer reaction steps and a simple synthetic route, the total yield of the small experiment from (R) -N-acetyl biphenylalanine ethyl ester to (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is more than 50 percent, and the yield is low, so the method is not suitable for industrial production.
From the existing methods for preparing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, the method which has low cost, high yield, short synthesis steps and suitability for industrial production is significant.
Disclosure of Invention
The invention aims to provide a shakubiqu intermediate, a synthetic method and application thereof.
In order to solve the technical problem, the invention provides a method for synthesizing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, which comprises the following steps: a plurality of reactions which are successively carried out by using D-biphenylalanine as an initial raw material; and crystallizing and filtering to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
Further, the reaction formula of the first reaction is as follows:
further, the first reaction comprises:
adding D-biphenylalanine into water, and adding sodium carbonate to maintain the pH value at 8-9;
then adding BOC-anhydride to react for 7.5-8.5h at normal temperature;
regulating pH to 1-2 with pH regulator; and
crystallizing and filtering to obtain BOC-D-biphenylalanine for later use.
Further, the molar ratio of the D-biphenylalanine to the BOC-anhydride is 1: 1.1-1.2.
Further, the reaction formula of the second reaction is:
further, the second reaction comprises:
dissolving BOC-D-biphenylalanine in water, and adding H2SO4 to maintain pH at 1-3;
then adding a metal catalyst, introducing hydrogen, heating to 90-110 ℃ after ensuring a pure hydrogen environment, and reacting for 7.5-8.5h under the condition of keeping the pressure of 6-8 MPa;
after the reaction is finished, recovering the filtered metal catalyst and concentrating to obtain a small-volume filtrate; and
and after the concentration is finished, adding an alkaline alcohol mixed solution, stirring and crystallizing to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
Further, the alkali alcohol mixed solution includes: saturated NaOH solution and methanol solution; the molar ratio of the saturated NaOH solution to the methanol solution is 3: 1.
further, the amount of the metal catalyst is 2% of the amount of BOC-D-biphenylalanine.
Further, the synthesis method further comprises:
adding BOC-D-biphenylalanine into the concentrated filtrate recovered in the second reaction, adding the recovered metal catalyst, and repeating the step of the second reaction to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
In still another aspect, the present invention also provides (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol having the structural formula:
in a third aspect, the present invention also provides a first reactant for synthesizing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, the first reactant having a structural formula:
in a fourth aspect, the invention also provides application of the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol as an intermediate for synthesizing the Sacubitril.
The invention has the beneficial effects that the Sacubitril intermediate and the synthesis method and application thereof select D-biphenylalanine as an initial raw material, and the subsequent added reactants are combined to carry out a plurality of reactions in sequence to finally synthesize the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, so that the invention has the advantages of simple reaction steps, environmental protection, contribution to industrial production and the like, particularly the chemical purity of the product can reach more than 96%, the yield can reach more than 85%, and the invention has better industrial prospect.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a process flow diagram of the synthesis method of (R) -2- (N-t-butoxycarbonylamino) diphenylpropanol of the present invention.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
As shown in fig. 1, this example 1 provides a method for synthesizing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, which includes: step S1, a plurality of reactions are carried out successively with D-biphenylalanine as an initial raw material; and step S2, crystallizing and filtering to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
Specifically, the synthesis method of embodiment 1 selects D-biphenylalanine as the initial raw material, and the reaction steps are simple and environment-friendly, thereby facilitating industrial production. The chemical purity of the product can reach more than 96 percent, the yield can reach more than 85 percent, and the method has better industrial prospect.
The reaction formula of the first reaction is as follows:
as an alternative to the first reaction.
The first reaction comprises the following steps: adding D-biphenylalanine into water, and adding sodium carbonate to maintain the pH value at 8-9; then adding BOC-anhydride to react for 7.5-8.5h at normal temperature; regulating pH to 1-2 with pH regulator; crystallizing and filtering to obtain BOC-D-biphenylalanine for later use.
Alternatively, the PH adjuster is, for example and without limitation, dilute hydrochloric acid.
Preferably, the molar ratio of the D-biphenylalanine to the BOC-anhydride is 1: 1.1-1.2.
The reaction formula of the second reaction is as follows:
as an alternative embodiment of the second reaction.
The second reaction comprises the following steps: dissolving BOC-D-biphenylalanine in water, and adding H2SO4 to maintain pH at 1-3; then adding a metal catalyst, introducing hydrogen, heating to 90-110 ℃ after ensuring a pure hydrogen environment, and reacting for 7.5-8.5h under the condition of keeping the pressure of 6-8 MPa; after the reaction is finished, recovering the filtered metal catalyst and concentrating to obtain a small-volume filtrate; and after the concentration is finished, adding an alkaline alcohol mixed solution, stirring and crystallizing to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
Alternatively, the metal catalyst is, for example, but not limited to, ruthenium carbon (Ru/C) as a metal catalyst.
In this embodiment, the alkali alcohol mixed solution includes: saturated NaOH solution and methanol solution; the molar ratio of the saturated NaOH solution to the methanol solution is 3: 1.
preferably, the metal catalyst is used in an amount of 2% of the amount of BOC-D-biphenylalanine.
Further, the synthesis method further comprises: adding BOC-D-biphenylalanine into the concentrated filtrate recovered in the second reaction, adding the recovered metal catalyst, and repeating the step of the second reaction to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
Specifically, the synthesis method of the embodiment can recycle the recovered metal catalyst and the concentrated filtrate, so that the synthesis cost of the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is low, and the method is more beneficial to industrial production.
Example 2
Based on example 1, this example 2 provides (R) -2- (N-tert-butoxycarbonylamino) diphenylpropanol, which has the following structural formula:
for the component content and the specific implementation process of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, refer to the relevant discussion of example 1, and the details are not repeated here.
Example 3
Based on example 1, this example 3 provides a first reactant for synthesizing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, the first reactant having a formula:
specifically, the first reactant is BOC-D-biphenylalanine.
For the component content and specific implementation process of BOC-D-biphenylalanine, refer to the relevant discussion of example 1, and are not repeated here.
Example 4
Based on example 1, this example 4 provides an application of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol as an intermediate for synthesizing sabotabifonazole.
For the component content and the specific implementation process of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, refer to the relevant discussion of example 1, and the details are not repeated here.
Example 5
Example 5 illustrates three experiments, and the influence factors of the purity and yield of the product (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol synthesized by the three experiments were investigated, as shown in Table 1.
TABLE 1 component content and product yield
Group 1
(1) 200g of D-biphenylalanine was added to 1000ml of water, pH 8-9 was adjusted with sodium carbonate, 199g of BOC-anhydride was added, reaction was carried out at 20-30 ℃ for 8 hours, pH 1-2 was adjusted with HCl, crystallization was carried out for 1 hour, and 266g of BOC-D-biphenylalanine was obtained by filtration.
(2) Adding 133g of BOC-D-biphenylalanine obtained in the step (1) into 650ml of water, acidifying with H2SO4 until the pH value is 1-3, adding 2.7g of metal catalyst (Ru/C), introducing hydrogen for 0.5H, heating to 90 ℃, keeping the pressure at 8MPa for reaction for 8H, filtering out the metal catalyst after the reaction is finished, concentrating the filtrate to a small volume, distilling and recovering the metal catalyst and the filtrate, adding 100ml of alkaline alcohol mixed solution after the concentration, stirring for crystallization, and filtering to obtain 116.2g of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol with the purity of 96.6% and the yield of 85.6%.
(3) 133g of BOC-D-biphenylalanine obtained in the step (1) was added to the distillation filtrate recovered in the step (2), a small amount of H2SO4 was added to maintain the pH at 1-3, and the recovered metal catalyst (Ru/C) was added to repeat the step (2), thereby obtaining 117.1g of (R) -2- (N-t-butoxycarbonylamino) biphenylpropanol with a purity of 96.5% and a yield of 86.3%.
Group 2
(1) 200g of D-biphenylalanine was added to 1000ml of water, the pH was adjusted to 8-9 with sodium carbonate, 208g of BOC-anhydride was added, the reaction was carried out at 20-30 ℃ for 8 hours, the pH was adjusted to 1-2 with HCl, crystallization was carried out for 1 hour, and 268.9g of BOC-D-biphenylalanine was obtained by filtration.
(2) Adding 134.4g of BOC-D-biphenylalanine obtained in the step (1) into 650ml of water, acidifying with H2SO4 until the pH value is 1-3, adding 2.7g of metal catalyst (Ru/C), introducing hydrogen for 0.5H, heating to 90 ℃, keeping the pressure at 8Mpa for reaction for 8H, filtering out the metal catalyst after the reaction is finished, concentrating the filtrate to a small volume, distilling and recovering the metal catalyst and the filtrate, adding 100ml of alkali alcohol mixed solution after the concentration, stirring for crystallization, and filtering to obtain 122.4g of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol with the purity of 98.7% and the yield of 90.2%.
(3) 134.4g of BOC-D-biphenylalanine obtained in step (1) was added to the distillation filtrate recovered in step (2), a small amount of H2SO4 was added to maintain a pH of 1-3, and the recovered metal catalyst (Ru/C) was added to repeat step (2), to obtain 122.2g of (R) -2- (N-t-butoxycarbonylamino) biphenylpropanol with a purity of 98.5% and a yield of 90.1%.
Group 3
(1) 200g of D-biphenylalanine was added to 1000ml of water, pH 8-9 was adjusted with sodium carbonate, 208g of BOC-anhydride was added, the reaction was carried out at 20-30 ℃ for 8 hours, pH 1-2 was adjusted with HCl, crystallization was carried out for 1 hour, and 270g of BOC-D-biphenylalanine was obtained by filtration.
(2) Adding 135g of BOC-D-biphenylalanine obtained in the step (1) into 650ml of water, acidifying with H2SO4 until the PH value is 1-3, adding 2.7g of metal catalyst (Ru/C), introducing hydrogen for 0.5H, heating to 90 ℃, keeping the pressure at 8Mpa for reaction for 8H, filtering out the metal catalyst after the reaction is finished, concentrating the filtrate to a small volume, distilling and recovering the metal catalyst and the filtrate, adding 100ml of alkaline alcohol mixed solution after the concentration, stirring for crystallization, and filtering to obtain 129.1g of (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol with the purity of 99.5% and the yield of 95.1%.
(3) 135g of BOC-D-biphenylalanine obtained in step (1) was added to the distillation filtrate recovered in step (2), a small amount of H2SO4 was added to maintain a pH of 1-3, and the recovered metal catalyst (Ru/C) was added thereto, and step (2) was repeated to obtain 129.1g of (R) -2- (N-t-butoxycarbonylamino) biphenylpropanol with a purity of 99.6% and a yield of 95.1%.
In conclusion, the Sacubitril intermediate, the synthesis method and the application thereof select D-biphenylalanine as an initial raw material, sequentially carry out a plurality of reactions in combination with subsequently added reactants, finally synthesize the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol, and can effectively improve the reaction rate and shorten the reaction time by controlling the reaction conditions (such as reaction conditions, reactant adding time, reaction temperature and the like) of each reaction; by reasonably setting the component content proportion of each raw material, the purity and yield of the product can be effectively improved. Therefore, the synthesis method has the advantages of simple reaction steps, environmental protection, contribution to industrial production and the like, and particularly has the advantages that the chemical purity of the product can reach more than 96 percent, the yield can reach more than 85 percent, and the synthesis method has better industrial prospect. In addition, the synthesis method of the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol can recycle the recovered metal catalyst and concentrated filtrate, so that the synthesis cost of the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is low, and the industrial production is facilitated.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (12)
1. A method for synthesizing (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol is characterized by comprising the following steps: a plurality of reactions which are successively carried out by using D-biphenylalanine as an initial raw material; and
crystallizing and filtering to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
3. the method of synthesis according to claim 1,
the first reaction comprises the following steps:
adding D-biphenylalanine into water, and adding sodium carbonate to maintain the pH value at 8-9;
then adding BOC-anhydride to react for 7.5-8.5h at normal temperature;
regulating pH to 1-2 with pH regulator; and
crystallizing and filtering to obtain BOC-D-biphenylalanine for later use.
4. The method of synthesis according to claim 3,
the molar ratio of the D-biphenylalanine to the BOC-anhydride is 1: 1.1-1.2.
6. the method of synthesis according to claim 3,
the second reaction comprises the following steps:
dissolving BOC-D-biphenylalanine in water, and adding H2SO4 to maintain pH at 1-3;
then adding a metal catalyst, introducing hydrogen, heating to 90-110 ℃ after ensuring a pure hydrogen environment, and reacting for 7.5-8.5h under the condition of keeping the pressure of 6-8 MPa;
after the reaction is finished, recovering the filtered metal catalyst and concentrating to obtain a small-volume filtrate; and
and after the concentration is finished, adding an alkaline alcohol mixed solution, stirring and crystallizing to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
7. The method of synthesis according to claim 6,
the alkali alcohol mixed solution comprises: saturated NaOH solution and methanol solution;
the molar ratio of the saturated NaOH solution to the methanol solution is 3: 1.
8. the method of synthesis according to claim 6,
the dosage of the metal catalyst is 2% of the dosage of the BOC-D-biphenylalanine.
9. The method of synthesis according to claim 6,
the synthesis method further comprises the following steps:
adding BOC-D-biphenylalanine into the concentrated filtrate recovered in the second reaction, adding the recovered metal catalyst, and repeating the step of the second reaction to obtain the (R) -2- (N-tert-butoxycarbonylamino) biphenylpropanol.
12. an application of (R) -2- (N-tert-butyloxycarbonylamino) biphenylpropanol as an intermediate for synthesizing Sacubitril.
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