CN113135836A - Preparation method of Sacubitril calcium salt - Google Patents
Preparation method of Sacubitril calcium salt Download PDFInfo
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Abstract
The invention provides a preparation method of Sacubitril calcium salt. In the preparation method, the compound III can be subjected to hydrogenation reduction reaction without alkaline hydrolysis, so that the reaction steps can be reduced; meanwhile, the selection of the protecting group can effectively avoid the formation of self-condensation impurities during the esterification reaction; the deprotection of the protecting group can be completed in the amidation reaction, so that the reaction steps are reduced, and the reaction yield is improved.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of Sacubitril calcium salt.
Background
LCZ696 is a new antihypertensive drug developed by noval corporation, which contains two components, valsartan, which improves vasodilation, stimulates the body to excrete sodium and water, and AHU-377 (sabotarol), which blocks the action of 2 polypeptides that threaten lowering blood pressure, and thus LCZ696 is called a dual inhibitor of angiotensin ii receptor and enkephalinase. The structural formula is as follows:
LCZ696 has antihypertensive effect and reduced heart failure efficacy over standard drugs, which qualify the drug for rapid access approval by FDA and EMEA in the united states, and it is generally accepted in the industry that LCZ696 will bring innovation to traditional treatment regimens for heart failure.
Sacubitril is a prodrug with the chemical name: 4- ((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid, the structural formula of which is shown below:
at present, the existing literature reports a plurality of methods for synthesizing the Sacubitril, and compared with the classical route (for example, the literature reports: the synthesis of related substances of the Sacubitril, Baiwenuki, Mufanbo, Tangzhebo, etc., China journal of medical industry, 2018) uses (2R) -1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl-tert-butyl carbamate as a starting material, uses the classical Anelli method to oxidize hydroxyl into aldehyde, uses the aldehyde and ethoxycarbonylethylidene triphenyl phosphine to carry out wittig reaction and alkaline hydrolysis to obtain an olefine acid compound, the olefine acid compound is reduced into a carboxylic acid compound with a single configuration through hydrogenation reaction under the action of a chiral catalyst and a ligand, uses ethanol as a solvent, and uses the carboxylic acid compound in SOCl2And (3) performing ethyl esterification under the action of the catalyst, and removing tert-butyl formate to obtain an amino hydrochloride compound. Reacting the amino hydrochloride compound with succinic anhydride under an alkaline condition, and salifying with calcium chloride to prepare the Shakubatrox calcium salt.
The calcium salt of Sacubitril reacts with hydrochloric acid to displace Sacubitril, and then LCZ696 is further prepared.
The calcium salt of shakubatrox prepared in this route is advantageous for purification and storage, but the route has many steps and low yield, and particularly, self-condensed impurities (3R,5S) -5- ([1,1' -biphenyl ] -4-ethylmethyl) -4-methylpiperidin-2-one (537-06) are easily formed when thionyl chloride catalyzes the ethyl esterification of a carboxylic acid compound with ethanol, as shown below:
the synthesis of related substances of Shakubai (Baiwenzun, Menfanbo, Tang Zhebo, etc., J of Chinese medical industry, 2018) reported the condensation impurities of related reactants of Shakubai and the mechanism of the generation thereof, and pointed out that the existing route can not avoid the generation of the impurities all the time. In the prior art, the treatment for removing the self-condensation impurities of the reactants is not reported, and the impurities can be brought into a final product, so that the yield and the purity of the product are influenced, the quality of the product is influenced finally, and the potential safety hazard of medication exists.
Disclosure of Invention
Aiming at the problems of low conversion rate and more generated impurities in the existing preparation process of the Sacubitril, the invention aims to provide a technical method which is simple to operate, mild in reaction conditions, high in product yield, high in purity and less in pollution and is suitable for industrial production of Sacubitril calcium salt.
The invention provides a preparation method of Sacubitril calcium salt, which comprises the following steps:
step a: taking (2R) -1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl-aminofluorenylmethoxycarbonyl ester (compound II) as an initial raw material, carrying out oxidation reaction in an organic solvent A to obtain a compound II-1, and carrying out Wittig reaction on the compound II-1 and tert-butyloxycarbonyl ethylidene triphenylphosphine to obtain a compound III.
Step b: and carrying out asymmetric reduction reaction on the compound III in ethanol to obtain a compound III-1, and continuously adding thionyl chloride to obtain a compound IV.
Step c: and (3) carrying out acylation reaction on the compound IV and succinic anhydride under the action of triethylamine to generate a compound IV-1, adjusting the compound IV to be alkaline by using a sodium hydroxide aqueous solution, and then salifying the compound IV and calcium chloride to obtain the compound I.
The specific reaction steps are as follows:
step a: adding a compound II, sodium bicarbonate, sodium bromide and TEMPO (2,2,6, 6-tetramethylpiperidine oxide) into an organic solvent A, cooling to 0-10 ℃, adding an oxidant under stirring, stirring for reaction for 1h, adding a quenching agent to treat excess oxidant, continuing stirring for reaction for 1h, standing for layering, and separating out an organic phase; and adding the obtained organic phase into a reaction bottle, heating, adding tert-butyloxy formyl ethylidene triphenylphosphine, stirring for reacting for 2 hours, and recrystallizing, filtering and drying after the reaction is finished to obtain a compound III.
Step b: adding ethanol, a compound III and a catalyst into a closed pressure-resistant reaction kettle, adjusting the temperature of the system, adding a reducing agent, maintaining the pressure for reaction for 4 hours, filtering the reaction solution to remove the catalyst, transferring the reaction solution into a reaction bottle, dropwise adding thionyl chloride while stirring, keeping the temperature for reaction for 2 hours, and after the reaction is finished, recrystallizing, filtering and drying to obtain a compound IV.
Step c: adding an organic solvent B, a compound IV and succinic anhydride into a reaction bottle, stirring and adding triethylamine, continuously stirring and reacting for 2-3 h, after TLC detection reaction is finished, washing reaction liquid by using a HCl solution (0.1mol/L) with a mass-volume ratio (m/v, calculated by the compound IV) of 10 times, collecting an organic layer, adding a NaOH aqueous solution (0.5mol/L) with a mass-volume ratio (m/v, calculated by the compound IV) of 10 times, continuously stirring and reacting for 1-2 h, separating liquid, collecting a water layer, dropwise adding a calcium chloride solution (a certain amount of calcium chloride is prepared to be 1.8mol/L), stirring and crystallizing for 3-5 h after dropping, filtering and drying to obtain a compound I.
Preferably, the mass ratio of the compound II, the sodium bicarbonate, the sodium bromide and the TEMPO in the step a is 1:1.5:1.8: 0.03;
preferably, the oxidant in step a is sodium hypochlorite solution with effective chlorine content of 10-15%, preferably 15%; wherein the mass volume ratio of the reactant to the sodium hypochlorite is 1:2.3, g/mL;
preferably, the mole ratio of the compound II to the tert-butyloxyformyl ethylidene triphenylphosphine in the step a is 1: 1-1.2, preferably 1: 1.1;
preferably, the organic solvent A in step a is one or a combination of ethyl acetate, isopropyl acetate, acetonitrile and dichloromethane, preferably isopropyl acetate;
preferably, the mass-to-volume ratio (g/mL) of the compound II to the organic solvent A in the step a is 1: 15-25, preferably 1: 20;
preferably, the heating temperature in the step a is 10-30 ℃;
preferably, the quenching agent in the step a is a 9% by mass aqueous solution of sodium thiosulfate, and the added volume amount of the quenching agent is the same as that of the organic solvent A;
preferably, the recrystallization process in step a is as follows: dissolving the concentrated reaction solution in isopropyl acetate with the mass volume ratio (m/v, calculated as a compound II) of 3 times, adding n-heptane with the mass volume ratio (m/v, calculated as the compound II) of 6 times, and stirring for crystallization for 6 h;
preferably, the catalyst in step b is one of tetrakis (triphenylphosphine) palladium on carbon, bis (triphenylphosphine) palladium on carbon dichloride, [1, 1-bis (diphenylphosphine) (ferrocene) ] palladium on carbon dichloride, triphenylphosphine palladium on carbon acetate, preferably tetrakis (triphenylphosphine) palladium on carbon;
preferably, the mole ratio of the compound III to the catalyst in the step b is 1: 0.03-0.1, preferably 1: 0.07;
preferably, the system temperature in the step b is 10-30 ℃; the reducing agent is hydrogen; the pressure of the pressure maintaining reaction is 4-6 Mpa, preferably 5 Mpa;
preferably, the molar ratio of the compound III to the thionyl chloride in the step b is 1: 1-1.5, preferably 1: 1.3;
preferably, the temperature of the heat preservation reaction in the step b is 20-50 ℃, and preferably 30 ℃;
preferably, the recrystallization process in step b is: dissolving the concentrated reaction solution in isopropyl acetate with the mass volume ratio (m/v, calculated by the compound III) of 2 times, adding n-heptane with the mass volume ratio (m/v, calculated by the compound III) of 6 times, and stirring for crystallization for 6 h;
preferably, the solvent B used in the acylation reaction in the step c is ethyl acetate, isopropyl acetate, dichloromethane or trichloromethane;
preferably, the mole ratio of the compound IV, triethylamine and succinic anhydride in the step c is 1: 2-31-1.2, preferably 1:2.5: 1.1;
preferably, the molar ratio of the compound IV to the calcium chloride in the step c is 1: 0.4-0.5, preferably 1: 0.45;
preferably, the temperature of the reaction in the step c is 10-30 ℃, and preferably 20 ℃;
compared with the prior art, the invention has the following technical effects:
1. the tert-butyloxyformyl ethylidene triphenyl phosphine is used as wittig reagent, so that the compound III can be subjected to hydrogenation reduction reaction without alkali hydrolysis, one-step reaction can be reduced, and SOCl is not influenced2Catalyzing the ethyl esterification of III-1.
2. The protection of the fluorenylmethoxycarbonyl (Fmoc) group on amino and the stability of the fluorenylmethoxycarbonyl (Fmoc) group in an acid environment can effectively avoid the formation of self-condensed impurities (3R,5S) -5- ([1,1' -biphenyl ] -4-ethylmethyl) -4-methylpiperidine-2-one during the esterification reaction in the step b; meanwhile, triethylamine can remove Fmoc protecting groups and can be used as a catalyst for succinic anhydride amidation.
3. The preparation process of the Sacubibara calcium salt provided by the invention has the advantages of short route, low cost, easily available raw materials, high yield and high purity, and is suitable for industrial mass production.
Drawings
FIG. 1 HPLC chromatogram of Sacubitril calcium salt; the relative retention time of the calcium salt of Sacubitril was 16.222 min.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
EXAMPLE 1 preparation of Compound III
Adding compound II (100g), sodium bicarbonate (25.2g,1.5eq), sodium bromide (37.04g,1.8eq) and TEMPO (0.94g,0.03eq) into a reaction flask, adding isopropyl acetate (2L,20v/m) into the reaction flask, cooling to 0-10 ℃, dropwise adding sodium hypochlorite solution (99.25g, 15% of available chlorine, 1eq) under stirring, continuing stirring for reaction for 1h after dropwise adding, TLC [ developing agent: petroleum ether: detecting the reaction completion by ethyl acetate ═ 2:1], adding 2L of 9% sodium thiosulfate solution into the reaction solution, continuing to stir the reaction for 1h, and standing for layering. The organic layer was transferred to a reaction flask, the temperature was adjusted to 20 ℃, t-butyloxycarbonylethylenetriphenylphosphine (85.84g,1.1eq) was added, and the reaction was stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml,3v/m), stirred and added with n-heptane (600ml,6v/m) dropwise, stirred and crystallized for 6h, filtered and dried to give white solid III (yield 89.55%, HPLC: 98.49%).
EXAMPLE 2 preparation of Compound III
Adding compound II (100g), sodium bicarbonate (25.2g,1.5eq), sodium bromide (37.04g,1.8eq) and TEMPO (0.94g,0.03eq) into a reaction bottle, adding ethyl acetate (1.5L,15v/m) into the reaction bottle, cooling to 0-10 ℃, dropwise adding sodium hypochlorite solution (99.25g, 10% of available chlorine) while stirring, continuing stirring for reaction for 1h, and performing TLC [ developing agent: petroleum ether: after the reaction was detected to be completed with ethyl acetate ═ 2:1], 1.5L of a 9% sodium thiosulfate solution was added to the reaction solution, and the reaction was continued for 1 hour with stirring and then allowed to stand for separation. The organic layer was transferred to a reaction flask, the temperature was adjusted to 10 ℃, t-butyloxycarbonylethylenetriphenylphosphine (78.04g,1eq) was added, and the reaction was stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml,3v/m), stirred and added with n-heptane (600ml,6v/m) dropwise, stirred and crystallized for 6h, filtered and dried to give white solid III (yield 88.21%, HPLC: 98.45%).
EXAMPLE 3 preparation of Compound III
Adding compound II (100g), sodium bicarbonate (25.2g,1.5eq), sodium bromide (37.04g,1.8eq) and TEMPO (0.94g,0.03eq) into a reaction bottle, adding acetonitrile (2.5L,25v/m) into the reaction bottle, cooling to 0-10 ℃, dropwise adding sodium hypochlorite solution (99.25g, 15% of available chlorine) while stirring, continuing to stir for 1h, and TLC [ developing agent: petroleum ether: after the reaction was detected to be completed with ethyl acetate ═ 2:1], 2.5L of a 9% sodium thiosulfate solution was added to the reaction solution, and the reaction was continued for 1 hour with stirring and then allowed to stand for separation. The organic layer was transferred to a reaction flask, the temperature was adjusted to 30 ℃, tert-butyloxycarbonylethylenetriphenylphosphine (93.65g,1.2eq) was added, and the reaction was stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml,3v/m), stirred and added with n-heptane (600ml,6v/m) dropwise, stirred and crystallized for 6h, filtered and dried to give white solid III (yield 88.53%, HPLC: 98.46%).
EXAMPLE 4 preparation of Compound III
Adding compound II (100g), sodium bicarbonate (20.2g,1.2eq), sodium bromide (41.16g,2eq) and TEMPO (1.57g,0.05eq) into a reaction bottle, adding dichloromethane (3L,30v/m) into the reaction bottle, cooling to 0-10 ℃, dropwise adding sodium hypochlorite solution (99.25g, 15% of available chlorine and 1eq) while stirring, continuing to stir for 1h, and performing TLC [ developing agent: petroleum ether: detecting the reaction completion by ethyl acetate ═ 2:1], adding 3L of 9% sodium thiosulfate solution into the reaction solution, continuing to stir the reaction for 1h, and standing for layering. The organic layer was transferred to a reaction flask, the temperature was adjusted to 20 ℃, t-butyloxycarbonylethylenetriphenylphosphine (117.05g,1.5eq) was added, and the reaction was stirred for 1 h. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml,3v/m), stirred and added with n-heptane (600ml,6v/m) dropwise, stirred and crystallized for 6h, filtered and dried to give white solid III (yield 78.53%, HPLC: 96.36%).
Detection of compound III (HPLC normalization): chromatography column Agilent Eclipse XDB-C18 (4.6X 150mm,5 μm); mobile phase a phase: 0.1% phosphoric acid aqueous solution, phase B: acetonitrile, gradient elution (0 → 20min: A70% → 40%; 20 → 30min: A5%; 30 → 40min A80%); detection wavelength: 200 nm; the column temperature is 25 ℃; the flow rate was 1 mL/min.
EXAMPLE 5 preparation of Compound IV
Adding a compound III (80g), tetrakis (triphenylphosphine) palladium carbon (5.6g,0.07m/m) and ethanol (1.2L,15v/m) into a closed pressure-resistant reaction kettle, adjusting the temperature to 20 ℃, replacing air in the reaction kettle with hydrogen, introducing hydrogen, maintaining the pressure for 5Mp, stirring for reaction for 6 hours, filtering the reaction liquid, transferring the filtrate into a reaction bottle with mechanical stirring, dropwise adding thionyl chloride (22.17g,1.3eq), continuously stirring for reaction for 2 hours at the constant temperature of 30 ℃, and TLC [ developing agent: petroleum ether: the reaction was checked for completion with ethyl acetate 2: 1. The reaction mixture was evaporated to dryness under reduced pressure, and isopropyl acetate (160mL, m/v, based on Compound III) was added and dissolved, n-heptane (480mL, m/v, based on Compound III) was added dropwise with stirring, and crystallization was performed for 6 hours with stirring, and filtration and drying were performed to obtain a white solid IV (yield 92.69%, HPLC: 98.86%).
EXAMPLE 6 preparation of Compound IV
Adding a compound III (80g), tetrakis (triphenylphosphine) palladium carbon (2.4g,0.03m/m) and ethanol (1.2L,15v/m) into a closed pressure-resistant reaction kettle, adjusting the temperature to 10 ℃, replacing air in the reaction kettle with hydrogen, introducing hydrogen, maintaining the pressure for 4Mp, stirring for reaction for 6 hours, filtering the reaction liquid, transferring the filtrate into a reaction bottle with mechanical stirring, dropwise adding thionyl chloride (17.05g,1.0eq), continuously stirring for reaction for 2 hours at a constant temperature of 20 ℃, and TLC [ developing agent: petroleum ether: the reaction was checked for completion with ethyl acetate 2: 1. The reaction mixture was evaporated to dryness under reduced pressure, and isopropyl acetate (160mL, m/v, based on Compound III) was added and dissolved, n-heptane (480mL, m/v, based on Compound III) was added dropwise with stirring, and crystallization was performed for 6 hours with stirring, and filtration and drying were performed to obtain white solid IV (yield 91.26%, HPLC: 98.84%).
EXAMPLE 7 preparation of Compound IV
Adding a compound III (80g), bis (triphenylphosphine) palladium dichloride carbon (5.3g,0.1m/m) and ethanol (1.2L,15v/m) into a closed pressure-resistant reaction kettle, adjusting the temperature to 30 ℃, replacing air in the reaction kettle with hydrogen, introducing hydrogen, maintaining the pressure for 6Mp, stirring for reaction for 6 hours, filtering the reaction liquid, transferring the filtrate into a reaction bottle with mechanical stirring, dropwise adding thionyl chloride (25.58g,1.5eq), continuously stirring for reaction for 2 hours at a constant temperature of 50 ℃, and TLC (developing agent: petroleum ether: the reaction was checked for completion with ethyl acetate 2: 1. The reaction mixture was evaporated to dryness under reduced pressure, and isopropyl acetate (160mL, m/v, based on Compound III) was added and dissolved, n-heptane (480mL, m/v, based on Compound III) was added dropwise with stirring, and crystallization was performed for 6 hours with stirring, and filtration and drying were performed to obtain white solid IV (yield 91.56%, HPLC: 98.85%).
EXAMPLE 8 preparation of Compound IV
Adding a compound III (80g), palladium carbon triphenylphosphine acetate (6.2g,0.12m/m) and ethanol (1.2L,15v/m) into a sealed pressure-resistant reaction kettle, adjusting the temperature to 40 ℃, replacing air in the reaction kettle with hydrogen, introducing hydrogen, maintaining the pressure for 3Mp, stirring for reaction for 6 hours, filtering the reaction liquid, transferring the filtrate into a reaction bottle with mechanical stirring, dropwise adding thionyl chloride (27.29g,1.6eq), continuously stirring for reaction for 2 hours at the constant temperature of 30 ℃, and TLC (developing agent: petroleum ether: the reaction was checked for completion with ethyl acetate 2: 1. The reaction mixture was evaporated to dryness under reduced pressure, and isopropyl acetate (160mL, m/v, based on Compound III) was added and dissolved, n-heptane (480mL, m/v, based on Compound III) was added dropwise with stirring, and crystallization was performed for 6 hours with stirring, and filtration and drying were performed to obtain white solid IV (yield 82.52%, HPLC: 96.82%).
Detection of compound IV (HPLC normalization): chromatography column Agilent Eclipse XDB-C18 (4.6X 150mm,5 μm); mobile phase a phase: 0.03mol/L potassium dihydrogen phosphate (containing 0.1% triethylamine, pH 3 adjusted by phosphoric acid), phase B: acetonitrile, gradient elution (0 → 20min: A85% → 35%; 20 → 30min: A35%; 30 → 40min A85%); the detection wavelength is 201 nm; the column temperature is 25 ℃; the flow rate was 1 mL/min.
EXAMPLE 9 preparation of Compound I
Compound IV (80g), succinic anhydride (16.51g,1.1eq), isopropyl acetate (800mL,10v/m) were added dropwise with stirring triethylamine (37.95g,2.5eq), and after completion of addition, the reaction was continued for 2h with stirring, TLC [ developing agent: dichloromethane: detecting that the reaction is finished with methanol (12: 1), adding 0.1mol/LHCl solution (800mL,10v/m), continuing stirring for 5min, separating, collecting an organic layer, adding 0.5mol/L aqueous solution of NaOH (800mL,10v/m), stirring for reaction for 1h, separating, collecting an aqueous layer, dropwise adding 1.8mol/L calcium chloride solution (7.49g,0.45eq) while stirring, stirring for crystallization for 3h, filtering and drying to obtain a white solid I, namely the Shakubatrox calcium salt (yield 85.65%, HPLC: 99.93%).
EXAMPLE 10 preparation of Compound I
Compound IV (80g), succinic anhydride (15.00g,1eq), and ethyl acetate (800mL,10v/m) were added dropwise with stirring triethylamine (30.36g,2eq), and after completion of the addition, the reaction was continued for 2h with stirring, TLC [ developing agent: dichloromethane: detecting that the reaction is finished with methanol (12: 1), adding 0.1mol/LHCl solution (800mL,10v/m), continuing stirring for 5min, separating, collecting an organic layer, adding 0.5mol/L aqueous solution of NaOH (800mL,10v/m), stirring for reaction for 1h, separating, collecting an aqueous layer, dropwise adding 1.8mol/L calcium chloride solution (6.66g,0.4eq) while stirring, stirring for crystallization for 3h, filtering and drying to obtain a white solid I, namely the Shakubatrox calcium salt (yield is 85.28%, HPLC: 99.90%).
EXAMPLE 11 preparation of Compound I
Compound IV (80g), succinic anhydride (18.00g,1.2eq), and dichloromethane (800mL,10v/m) were added dropwise with stirring, triethylamine (45.54g,3eq) was added dropwise, and stirring was continued for 2h, TLC [ developing agent: dichloromethane: detecting that the reaction is finished with methanol (12: 1), adding 0.1mol/LHCl solution (800mL,10v/m), continuing stirring for 5min, separating, collecting an organic layer, adding 0.5mol/L aqueous solution of NaOH (800mL,10v/m), stirring for reaction for 1h, separating, collecting an aqueous layer, dropwise adding 1.8mol/L calcium chloride solution (8.33g,0.5eq) while stirring, stirring for crystallization for 3h, filtering and drying to obtain a white solid I, namely the Shakubatrox calcium salt (yield 85.76%, HPLC: 99.89%).
EXAMPLE 12 preparation of Compound I
Compound I (80g), succinic anhydride (22.51g,1.5eq), and chloroform (800mL,10v/m) were added dropwise with stirring to triethylamine (22.77g,2.5eq), and stirring was continued for 2h, TLC [ developing agent: dichloromethane: detecting that the reaction is finished with methanol (12: 1), adding 0.1mol/LHCl solution (800mL,10v/m), continuing stirring for 5min, separating, collecting an organic layer, adding 0.5mol/L aqueous solution of NaOH (800mL,10v/m), stirring for reaction for 1h, separating, collecting an aqueous layer, dropwise adding 1.8mol/L calcium chloride solution (9.99g,0.6eq) while stirring, stirring for crystallization for 3h, filtering and drying to obtain a white solid I (yield 78.96%, HPLC: 96.82%).
Detection of compound III (HPLC normalization): chromatography column Agilent Eclipse XDB-C18 (4.6X 150mm,5 μm); mobile phase a phase: 0.02mol/L ammonium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid) as a mobile phase, and B phase: acetonitrile, gradient elution (0 → 30min: A70% → 55%; 30 → 35min: A55%; 35 → 55min A50% → 25%); the detection wavelength is 201 nm; the column temperature is 25 ℃; the flow rate was 1 mL/min.
Claims (10)
1. The preparation method of the Sacubitril calcium salt is characterized by comprising the following steps:
step a: a compound II, namely (2R) -1- ((1, 1' -biphenyl) -4-yl) -3-hydroxypropane-2-yl-aminofluorenylmethoxycarbonyl ester, is taken as a starting material and subjected to oxidation reaction in an organic solvent A to obtain a compound II-1, and the compound II-1 and tert-butyloxycarbonyl ethylidene triphenylphosphine are subjected to Wittig reaction to obtain a compound III.
Step b: and carrying out asymmetric reduction reaction on the compound III in ethanol to obtain a compound III-1, and continuously adding thionyl chloride for heat preservation reaction to obtain a compound IV.
Step c: and (3) carrying out acylation reaction on the compound IV and succinic anhydride under the action of triethylamine to generate a compound IV-1, adjusting the compound IV to be alkaline by using a sodium hydroxide aqueous solution, and then salifying the compound IV and calcium chloride to obtain the compound I.
2. The preparation method of claim 1, wherein the catalyst for the oxidation reaction in step a is a combination of sodium bicarbonate, sodium bromide and TEMPO, wherein the mass ratio of the compound II, the sodium bicarbonate, the sodium bromide and the TEMPO is 1:1.5:1.8: 0.03; the oxidant of the oxidation reaction is sodium hypochlorite solution with 10-15% of available chlorine.
3. The preparation method according to claim 1, wherein the organic solvent A in step a is one or a combination of ethyl acetate, isopropyl acetate, acetonitrile and dichloromethane; the temperature of the oxidation reaction is 0-10 ℃.
4. The preparation method according to claim 1, wherein the molar ratio of the compound II in the step a to the tert-butyloxycarbonylethylenetriphenylphosphine is 1:1 to 1.2; the temperature of the Wittig reaction is 10-30 ℃.
5. The method according to claim 1, wherein the reducing agent for the asymmetric reduction reaction in step b is hydrogen gas; the reaction temperature is 10-30 ℃; the reaction pressure is 4-6 Mpa.
6. The preparation method of claim 1, wherein the catalyst for the asymmetric reduction reaction in step b is one or a combination of tetrakis (triphenylphosphine) palladium on carbon, bis (triphenylphosphine) palladium on carbon, [1, 1-bis (diphenylphosphine) (ferrocene) ] palladium on carbon dichloride, and triphenylphosphine palladium on carbon acetate, wherein the molar ratio of the compound III to the catalyst is 1: 0.03-0.1.
7. The preparation method according to claim 1, wherein the molar ratio of the compound III to the thionyl chloride in the step b is 1:1 to 1.5; and c, the temperature of the heat preservation reaction in the step b is 20-50 ℃.
8. The process according to claim 1, wherein the solvent B used in the acylation reaction in step c is ethyl acetate, isopropyl acetate, dichloromethane or chloroform.
9. The preparation method according to claim 1, wherein the molar ratio of the compound IV, triethylamine and succinic anhydride in the step c is 1: 2-3: 1-1.2, preferably 1:2.5: 1.1.
10. The method according to claim 1, wherein the molar ratio of the compound IV to the calcium chloride in the step c is 1:0.4 to 0.5.
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|---|---|---|---|---|
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| US5250522A (en) * | 1992-10-09 | 1993-10-05 | Ciba-Geigy Corporation | Phosphono/biaryl substituted amino acid derivatives |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| US5250522A (en) * | 1992-10-09 | 1993-10-05 | Ciba-Geigy Corporation | Phosphono/biaryl substituted amino acid derivatives |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
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| Title |
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| 刘鹰翔: "《药物合成反应》", vol. 2, 北京：中国中医药出版社, pages: 146 - 148 * |
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