Synthesis method of sacubitril intermediate
Through condensation, Mitsunobu reaction and ester combination ring methods, the sacubaqu intermediate is efficiently synthesized, which solves the problems of lengthy routes and high costs in the prior art, and achieves the sacubaqu with higher economicality and reduced waste. intermediate production.
Patent Information
- Application Number
- CN202411354794.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-27
- Publication Date
- 2025-01-03
AI Technical Summary
The existing synthesis route of sakubalivalsartan sodium is long, costly and produces a large amount of hazardous waste. The asymmetric hydrogenation and enzyme catalytic methods have problems with wastewater treatment and catalyst waste in large-scale commercial production.
Compound SM1 and ethyl 2-cyanopropionate were used to condense and decarboxylate under alkaline conditions, followed by Mitsunobu reaction with succinimide and hydrochloric acid hydrolysis, and then the sakubaqual intermediate was prepared by esterification and combined ring reaction. Use mild reaction conditions and conventional easily available materials to avoid precious metal catalysts and expensive chiral supplements.
It has achieved a shorter synthesis route, reduced production costs, reduced waste, is suitable for industrial production, and has mild reaction conditions, and has market competitive advantages.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical chemicals and relates to a method for preparing a sacubitril intermediate. Background Art
[0002] Sacubitril-valsartan sodium is a dual-acting angiotensin receptor neprilysin inhibitor developed by Novartis. It was approved by the FDA in July 2015 for use in adult patients with chronic heart failure with reduced ejection fraction (NYHA class II-IV, LVEF ≤ 40%) to reduce the risk of cardiovascular death and heart failure hospitalization. In addition, sacubitril-valsartan sodium tablets can replace angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARB) and be used in combination with other heart failure treatment drugs, and have huge market prospects. Sacubitril-valsartan sodium is a co-crystal product of sacubitril sodium and valsartan sodium, which is a semi-pentahydrate with the following structural formula:
[0003]
[0004] Among them, sacubitril sodium is the sodium carboxylate salt of sacubitril, which contains two chiral centers located at carbon positions 2 and 4 respectively. It is difficult to synthesize. How to construct two chiral centers is the key to synthesizing sacubitril. The methods reported to introduce the chiral center of sacubitril are mainly as follows:
[0005] Patents WO2014 / 032627 and WO2008031567B1 reported the synthesis of sacubitril using 4-bromobiphenyl and S-epichlorohydrin as raw materials through Grignard reaction, Mitsunobu reaction, hydrolysis reaction and other reactions, wherein the chiral center at position 4 is introduced by S-epichlorohydrin, and the chiral center at position 2 is generated by asymmetric hydrogenation in the presence of a ruthenium catalyst and a chiral ligand. The reaction route is as follows:
[0006]
[0007] This is the main synthesis route at present, but its main disadvantages are lengthy synthesis steps and high total cost. In addition, multi-step synthesis will inevitably produce a large amount of hazardous waste, which will bring great pressure to environmental protection. On the other hand, asymmetric hydrogenation will use expensive precious metal catalysts and chiral ligands, and requires high-pressure hydrogenation equipment. After the asymmetric hydrogenation is completed, the catalyst and ligand cannot be recovered and reused, resulting in waste.
[0008] Jiangsu Ocean University's patent CN118516422A reports a method for enzymatic asymmetric reduction of olefins, using enolate reductase, NADP coenzyme, glucose and glucose dehydrogenase to construct the chiral center at position 2, and the process is as follows:
[0009]
[0010] Similarly, patent US2018 / 362439 also discloses a method for constructing a chiral center at position 4 by catalyzing the reduction of a carbonyl group to a chiral amine using ω transaminase.
[0011] The steps before enzyme catalysis also have the problem of a long route. Although the conversion rate of enzyme catalysis can reach 90%, the chirality (ee) value can reach 99.5%, and the catalytic efficiency is relatively high, the construction and extraction methods of the enzyme are relatively complicated, which is not conducive to large-scale commercial production. In addition, the enzyme reaction concentration is relatively dilute, which will inevitably produce a large amount of active wastewater, which brings great pressure to wastewater treatment.
[0012] Patent WO2008083967A2 reports the synthesis of sacubitril using L-pyroglutamic acid as raw material through multiple steps of carboxyl activation, 4-bromobiphenyl substitution, carbonyl hydrogenation reduction, etc. The chiral center at position 4 is introduced by L-pyroglutamic acid, and the chiral center at position 2 is generated by methylation. The methylation reaction has a certain selectivity, and the product is mainly the target configuration trans. When the protecting group R1 is pivaloyl and KHMDS is used as the base, the ratio of trans to cis can be as high as 92:8. The reaction route is as follows:
[0013]
[0014] CN109456212A discloses a method for isomerizing compound C-1 to increase the trans ratio by treating with an organic metal base. The isomerization reaction formula is as follows:
[0015]
[0016] This method first constructs a five-membered ring lactam (B-4), and then selectively methylates or first methylates and then isomerizes to a thermodynamically stable trans configuration to obtain a product with the target configuration as the main component. Although the method for constructing the chiral center is relatively clever and does not require precious metal catalytic hydrogenation or enzyme catalytic reaction, the front-end synthesis of the five-membered ring lactam is long, harsh reaction conditions are used, and precious metal catalysts are also used, which limits the commercial application of this method.
[0017] Therefore, compared with asymmetric hydrogenation and enzyme catalysis, the method of diastereoisomerization of five-membered ring lactams has mild conditions, uses readily available materials, produces less waste, and is more in line with the needs of industrial production. How to efficiently synthesize five-membered ring lactams is the key to this method. Summary of the invention
[0018] The object of the present invention is to provide a method for efficiently synthesizing a sacubitril intermediate (D), and the specific reaction route is as follows:
[0019]
[0020] The method comprises the following steps:
[0021] In the first step, compound SM1 is used as the starting material, and condensed and decarboxylated with ethyl 2-cyanopropionate under alkaline conditions to obtain compound D-1;
[0022] The solvent 1 used in the first step of condensation and decarboxylation reaction is isopropanol, tert-butanol or ethanol, preferably tert-butanol; the base used is potassium tert-butoxide, lithium tert-butoxide or sodium hydrogen hydride, preferably potassium tert-butoxide.
[0023] In the second step, compound D-3 is prepared by a one-pot method using compound D-1 and succinimide through mitsunobu reaction and hydrochloric acid hydrolysis;
[0024] The solvent 2 used in the second step Mitsunobu reaction is tetrahydrofuran or dichloromethane, preferably dichloromethane;
[0025] The azo reagent used in the second step Mitsunobu reaction is diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD);
[0026] The intermediate of the second step Mitsunobu reaction is directly hydrolyzed with concentrated hydrochloric acid without isolation.
[0027] The third step is to prepare compound D by esterification and cyclization of compound D-3;
[0028] The third step of esterification reaction uses ethanol as solvent and sulfuric acid as catalyst; after esterification, the reaction solution is directly alkalized with sodium hydroxide aqueous solution to close the ring.
[0029] The present invention provides a method for efficiently synthesizing a sacubitril intermediate (D), which is shorter than the existing route, does not use expensive chiral auxiliary groups, precious metal catalysts and ligands, has mild reaction conditions, is more economical, and has greater market competitiveness. DETAILED DESCRIPTION
[0030] The present invention can be more specifically understood through the following examples, which are intended to illustrate rather than limit the scope of the present invention.
[0031] Example 1: Preparation of Compound D-1
[0032] Add tert-butanol (400 mL), ethyl 2-cyanopropionate (36.3 g, 0.285 mol), potassium tert-butoxide (32.0 g, 0.285 mol) to the reaction flask, heat to 60 ° C and react for 20 min, add the starting material SM1 (40.0 g, 0.19 mol), keep warm at 60 ° C for 4 h, monitor the reaction completion by TLC, cool to 20 ° C, add water (40 mL), potassium carbonate (26.3 g, 0.19 mol), heat to 80 ° C for 6 h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45 ° C, add water (400 mL), ethyl acetate (400 mL), stir to dissolve, separate the aqueous phase, wash the organic phase with water (400 mL) once, and concentrate the organic phase under reduced pressure at 45 ° C to obtain a light brown oil (48.3 g, yield 95.6%).
[0033] Example 2: Preparation of Compound D-1
[0034] Add isopropanol (100 mL), ethyl 2-cyanopropionate (9.1 g, 0.071 mol), potassium tert-butoxide (8.0 g, 0.071 mol) to the reaction flask, heat to 60 ° C and react for 20 min, add the starting material SM1 (10.0 g, 0.048 mol), keep warm at 60 ° C for 4 h, monitor the reaction completion by TLC, cool to 20 ° C, add water (10 mL), potassium carbonate (6.6 g, 0.048 mol), heat to 80 ° C for 6 h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45 ° C, add water (100 mL), ethyl acetate (100 mL), stir to dissolve, separate the aqueous phase, wash the organic phase with water (100 mL) once, and concentrate the organic phase under reduced pressure at 45 ° C to obtain a light brown oil (10.9 g, yield 86.0%).
[0035] Example 3: Preparation of Compound D-1
[0036] Add ethanol (100 mL), ethyl 2-cyanopropionate (9.1 g, 0.071 mol), potassium tert-butoxide (8.0 g, 0.071 mol) to the reaction flask, heat to 60 ° C and react for 20 min, add the starting material SM1 (10.0 g, 0.048 mol), keep warm at 60 ° C for 4 h, monitor the reaction completion by TLC, cool to 20 ° C, add water (10 mL), potassium carbonate (6.6 g, 0.048 mol), heat to 80 ° C for 6 h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45 ° C, add water (100 mL), ethyl acetate (100 mL), stir to dissolve, separate the aqueous phase, wash the organic phase with water (100 mL) once, and concentrate the organic phase under reduced pressure at 45 ° C to obtain a light brown oil (8.5 g, yield 67.5%).
[0037] Example 4: Preparation of Compound D-1
[0038] Add tert-butanol (100 mL), ethyl 2-cyanopropionate (9.1 g, 0.071 mol), and lithium tert-butoxide (5.7 g, 0.071 mol) to the reaction flask, heat to 60°C and react for 20 min, add the starting material SM1 (10.0 g, 0.048 mol), heat to 60°C and react for 4 h, monitor the reaction completion by TLC, cool to 20°C, add water (10 mL) and potassium carbonate (6.6 g, 0.048 mol), heat to 80°C and react for 6 h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45°C, add water (100 mL) and ethyl acetate (100 mL), stir to dissolve, separate the aqueous phase, wash the organic phase once with water (100 mL), and concentrate the organic phase under reduced pressure at 45°C to obtain a light brown oil (11.3 g, yield 89.5%).
[0039] Example 5: Preparation of Compound D-1
[0040] Add tert-butanol (100 mL), ethyl 2-cyanopropionate (9.1 g, 0.071 mol), and sodium hydrogen (1.71 g, 0.071 mol) to the reaction flask, heat to 60°C and react for 20 min, add the starting material SM1 (10.0 g, 0.048 mol), heat to 60°C and react for 4 h, monitor the reaction completion by TLC, cool to 20°C, add water (10 mL) and potassium carbonate (6.6 g, 0.048 mol), heat to 80°C and react for 6 h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45°C, add water (100 mL) and ethyl acetate (100 mL), stir to dissolve, separate the aqueous phase, wash the organic phase once with water (100 mL), and concentrate the organic phase under reduced pressure at 45°C to obtain a light brown oil (10.0 g, yield 79.3%).
[0041] Example 6: Preparation of Compound D-3
[0042] Dichloromethane (100 mL), intermediate D-1 (20.0 g, 0.075 mol), and succinimide (11.2 g, 0.113 mol) were added to the reaction flask. After nitrogen substitution, triphenylphosphine (29.7 g, 0.113 mol) was added. After nitrogen substitution three times, DIAD (22.9 g, 0.113 mol) was added dropwise at 10 °C. After the addition was completed, the reaction was kept warm for 2 h. The reaction was completed under TLC monitoring. The mixture was concentrated to dryness under reduced pressure. Concentrated hydrochloric acid (100 mL) was added, the temperature was raised to 100 °C and the reaction was kept warm for 24 h. The reaction was completed under TLC monitoring. The temperature was lowered to 10 °C, dichloromethane (50 mL) was added, and the mixture was stirred for 30 min. After filtration, it was dried to obtain an off-white solid (20.5 g, yield 85.1%).
[0043] Example 7: Preparation of Compound D-3
[0044] Dichloromethane (100 mL), intermediate D-1 (20.0 g, 0.075 mol), and succinimide (11.2 g, 0.113 mol) were added to the reaction flask. After nitrogen substitution, triphenylphosphine (29.7 g, 0.113 mol) was added. After nitrogen substitution three times, DIAD (24.1 g, 0.113 mol) was added dropwise at 10 °C. After the addition was completed, the reaction was kept warm for 2 h. The reaction was completed under TLC monitoring. The mixture was concentrated under reduced pressure to dryness. Concentrated hydrochloric acid (100 mL) was added, the temperature was raised to 100 °C and the reaction was kept warm for 24 h. The reaction was completed under TLC monitoring. The temperature was lowered to 10 °C, dichloromethane (50 mL) was added, and the mixture was stirred for 30 min. After filtration, it was dried to obtain an off-white solid (19.9 g, yield 82.5%).
[0045] Example 8: Preparation of Compound D-3
[0046] Tetrahydrofuran (100 mL), intermediate D-1 (20.0 g, 0.075 mol), succinimide (11.2 g, 0.113 mol) were added to the reaction flask. After nitrogen substitution, triphenylphosphine (29.7 g, 0.113 mol) was added. After nitrogen substitution three times, DIAD (22.9 g, 0.113 mol) was added dropwise at 10 °C. After the addition was completed, the mixture was kept warm for 2 h. The reaction was completed under TLC monitoring. The mixture was concentrated under reduced pressure to dryness. Concentrated hydrochloric acid (100 mL) was added, the temperature was raised to 100 °C and the reaction was kept warm for 24 h. The reaction was completed under TLC monitoring. The temperature was lowered to 10 °C, dichloromethane (50 mL) was added, and the mixture was stirred for 30 min. After filtration, it was dried to obtain an off-white solid (19.4 g, yield 80.4%).
[0047] Example 9: Preparation of Sacubitril Intermediate D:
[0048]
[0049] Add ethanol (150mL), intermediate D-3 (25.0g, 0.078mol) to the reaction bottle, add concentrated sulfuric acid (1mL) dropwise, raise the temperature to 78°C, reflux with stirring for 8h, monitor the reaction completion by TLC, cool to 25°C, add sodium hydroxide (4.1g, 0.102mol), water (50mL), react at 40°C for 2h, monitor the reaction completion by TLC, concentrate under reduced pressure at 45°C to remove ethanol, precipitate solid, filter and dry to obtain a white solid (19.7g, yield 94.8%).
Claims
1. A method for synthesizing a sacubitril intermediate (D), wherein the reaction formula is as follows:
2. The method according to claim 1, wherein the solvent 1 used in the condensation and decarboxylation reactions is isopropanol, the tert-butyl alcohol or ethanol, preferably the tert-butyl alcohol; and the base used is potassium tert-butylate, lithium tert-butylate or sodium hydrogen, preferably potassium tert-butylate.
3. The method according to claim 1, wherein the solvent 2 used in the Mitsunobu reaction is tetrahydrofuran or dichloromethane, preferably dichloromethane; and the azo reagent used is diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD).
4. The method according to claim 1, wherein the Mitsunobu reaction intermediate is directly hydrolyzed with concentrated hydrochloric acid to form compound D-3 without isolation.
5. The method according to claim 1, wherein the esterification reaction uses ethanol as solvent and sulfuric acid as catalyst; after esterification, the reaction solution is directly alkalized with sodium hydroxide aqueous solution for ring closure.
6. The method according to claim 1, wherein the chiral center at the carbonyl ortho position of the obtained compound D is a mixture of R configuration and S configuration in a ratio of about 1:1.