KR101961897B1 - Preparation method of sacylitol - Google Patents

Abstract

The present invention relates to a process for the production of Sacubitril (AHU-377, I), one of the components of the new blood pressure lowering drug, LCZ696, which comprises the asymmetric induction reagent (S) -1- ) Cyclic addition, debenzylation, cyclization, esterification and amidation of 2-methyl-2-naphthalenol and 2R-methyl-4-oxo-butanoic acid ). The above production method is easy to obtain the raw material, simple in process, economical and environment-friendly, and is very suitable for industrial production.

Description

Preparation method of sacylitol

Field of the Invention The present invention relates to the field of organic synthesis route design and the production of its raw materials and intermediates, and in particular to a process for the preparation of the neprilyl lysine inhibitor Sacubitril.

LCZ696 is a new type of hypotensive agent developed by Novartis. It consists of two components: Novovib (Diovan) and Vasutan (Saccharide) (AHU-377) LCZ696 is referred to as a dual inhibitor of angiotensin II receptor and neprilasin, because it inhibits the mechanism of action of two multi-peptides that enhance blood vessel dilation and stimulate the release of sodium and water in the body and Sacubitri, which threatens blood pressure lowering . The unique clinical mode of action of this drug demonstrates superiority over standard drug efficacy and relieving heart failure, and has earned the US FDA and European EMEA fast channel evaluation qualifications. The industry has universally acknowledged that the LCZ696 will revolutionize traditional heart disease treatment options. Since Sacubitril (AHU-377) does not have a standardized name translated into Chinese, the applicant named it "Sakyubitol" by pronouncing it.

The chemical name of sacylitol is 4 - (((2S, 4R) -1- (1,1'-biphenol-4-yl) -5-ethoxy- ) Amino) -4-oxo-butanoic acid (I), the structural formula of which is shown below,

The production method of the saccharide has already been reported, and the following synthetic routes are reported in US Pat. No. 5,217,996 and International Patents WO2008031567, WO2010136474 and WO2012025501. Asymmetric amino alcohols are used as starting materials, and the desired products are produced by reactions such as oxidation with aldehydes, Bietih reaction, asymmetric hydrogenation, and amidation condensation.

Other types of manufacturing methods are reported in International Patents WO2008083967, WO2011088797, WO2012025502 and WO2014198195. The target product is prepared by the reaction of 2-carbonylproline as a raw material with carbonyl activation, biphenyl substitution, carbonyl reduction, asymmetric methylation, cyclopentylation, and amidation condensation.

Although the synthesis routes described in the above two documents are somewhat different in the order of use of the starting raw materials, the asymmetric formation method and the unit reaction, all of them are difficult to obtain asymmetric raw materials, the reaction procedure is extensive, the asymmetric catalytic reduction catalyst is expensive, It has defects such as repeated use of amino protection and deprotection, which makes it difficult to realize industrialization of the synthetic route.

Thus, conventional manufacturing methods have not completely solved the problem of producing asymmetric amino groups of target compounds, and conventional processes are very difficult to industrialize due to various restrictions such as raw materials, cost, equipment, and environmental friendliness. It is therefore important to understand how to operate modern asymmetric synthesis techniques, how to effectively use asymmetric directing agents, and how to design and develop new synthetic routes that are simple, fast and economical, eco-friendly and easy to industrialize.

The object of the present invention is to prepare the target product saccharide with a readily available industrial raw material and an asymmetric directing agent " Betti base " for defects present in the prior art, It has advantages such as simple process, environment friendly and industrial production.

In order to achieve the object of the present invention, the present invention adopts the following main technical solution, which is a method for producing the neprilysin inhibitor Sacubitri (I)

(7aR, 9R) by the cyclization reaction of (S) -1- (alpha -aminobenzyl) -2-naphthalenol (II) with 2R-methyl-4-oxo-butanoic acid , 12S) -9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydro-12H-naphtho [ 3] oxazine (IV), and reacting the (7aR, 9R, 12S) -9-methyl-10-oxo-12- Biphenyl-4-methyl) magnesium chloride or (1,1'-biphenyl-4-methyl) -Methyl) -5-bromo-5-methyl-5-methyl-5- (1,1'-biphenyl- (3-methyl-5- (1,1'-biphenyl-4-yl) (3R, 5S) -3-methyl-5- (1,1'-biphenol (3R, 5S) -3-methyl-5- (1,1'-biphenol-4-yl-methyl) -2 - pyrrolidone (VI) (1,1'-biphenol-4-yl) -valerate ((2R, 4S) -2-methyl-4-amino- (VII) and succinic anhydride are reacted with an alkaline promoting agent (VIII), and the (2R, 4S) -2-methyl- , An amidation reaction is carried out to obtain the cubitol (I).

The present invention also provides the following technical means.

The starting molar ratio of the cyclization of (S) -1- (α-aminobenzyl) -2-naphthalenol (II) and 2R-methyl-4-oxo-butanoic acid (III) Preferably 1: 1.0 to 1.3, and the solvent of the cyclization reaction is toluene, 1,2-dichloroethane, N, N-dimethylformamide, acetonitrile or dimethylsulfoxide, preferably toluene And the cyclization reaction temperature is 25 to 100 ° C, preferably 55 to 70 ° C.

(7aR, 9R, 12S) -9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydro- 12H-naphtho [ (1, 1'-biphenyl-4-methyl) magnesium chloride or (1,1'-biphenyl-4-methyl) The raw material dosing molar ratio of the reaction is 1: 1-2, preferably 1: 1.2-1.6, and the solvent for the addition reaction is ethyl ether, isopropyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, Is ethyl ether or tetrahydrofuran, and the addition reaction temperature is -100 to 0 占 폚, preferably -78 占 폚.

The reaction system of the debenzene reaction is a Pd / C catalytic hydrogenation reduction system or a cerium containing ammonium nitrate oxidation system. The solvent of the Pd / C catalytic hydrogenation reduction system is methanol, ethanol, isopropanol, dichloromethane, ethyl acetate or isopropyl acetate, preferably methanol. The solvent of the cerium containing ammonium nitrate system is acetonitrile / water, dichloromethane / water or tetrahydrofuran / water, preferably acetonitrile / water, the volume ratio is 1-5: 1, preferably 2 : 1.

The acidic catalyst for the ring opening and esterification reaction is hydrochloric acid, sulfuric acid, trifluoroacetic acid, perchloric acid or p-sulfonic acid toluene, preferably hydrochloric acid or sulfuric acid, the solvent for the cyclic thermal and esterification reaction is ethanol, The temperature of the cyclization and esterification reaction is 0 to 100 캜, preferably 70 to 90 캜.

The alkali promoter for the amidation reaction is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, tert-butyl alcohol, pyridine or triethylamine, preferably pyridine or triethylamine. The amidation reaction temperature is preferably 0 to 90 ° C. The amidation reaction may be carried out in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, N, N-dimethylformamide or dioxane, preferably dichloromethane or tetrahydrofuran, Deg.] C, preferably 30 to 50 [deg.] C.

Compared with the prior art, the production method of the saccharide (I) according to the present invention is advantageous in industrial production of the raw material drug because it has the advantages of easy obtaining of raw material, simple process, environment-friendly and economical And promote the development of economic technology.

In the following, in combination with various comparatively preferred embodiments, further description of the non-limiting aspects of the present technical means will be given. The production of (S) -1- (α-aminobenzyl) -2-naphthalenol (Ⅱ) as a starting material was carried out in accordance with "Asymmetric compound (S) - (+) and (R)" under the theme of Chinese invention patent No. CN1348952A - (-) - 1- (α-aminobenzylen) -2-naphthalenol "(publication date: May 15, 2002), the raw material 2R- Methyl-4-oxo-butanoic acid (III) is described in Journal of the American Chemical Society, 107 (2), 443-8; 1985 ", " Journal of the American Chemical Society, 126 (45), 14740-14745; 2004 " and " Tetrahedron, 63 (26), 5754-5767; 2007 " and the like.

Example 1

(4S, 1'R) -4,5-dihydro-2- (1-methyl-3-butylene) -4- (1-methylethyl) oxazine (16.7 g , 0.1 mol) was added to hydrochloric acid (10% w / w, 250 mL), the temperature was raised until the water was boiled, the reaction was carried out for 3 hours with stirring, cooled to room temperature, extracted three times with dichloromethane, Is recovered and the pressure is reduced and distilled to obtain yellow liquid 2R-methyl-4-pentenoic acid. The yellow oily substance is placed in 250 mL of dichlorobetane, the temperature is lowered to -78 DEG C, the ozone is passed through, the color of the solution gradually changes to the heart-green color, and the reaction is terminated after about 15 minutes. The excess ozone was removed with nitrogen and the temperature was raised to room temperature. The solution was washed successively with 5% aqueous sodium thiosulfate solution and pure water, dried over anhydrous sodium sulfate, and the solvent was recovered to obtain a pale yellow oily substance 2R- 7.9 g of oxo-butanoic acid (III) was obtained, and the yield was 68.1%. FAB-MS m / z: 117 [M + H] < ⁺ >.

Example 2

(7.5 g, 30 mmol) and 2R-methyl-4-oxo-butanoic acid (III) (3.7 g, 31.5 mmol ) And 100 mL of toluene were charged, and the temperature was raised to 40 to 50 DEG C, and the reaction was carried out for 36 hours with stirring, and the completion of the reaction was checked by TLC. The temperature was lowered to remove insoluble material by filtration and vacuum drying gave a white solid (7aR, 9R, 12S) -9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydro- 7.2 g of 12H-naphtho [1,2-e] pyrrole [2,1-b] [1,3] oxazine (IV) was obtained. The yield was 72.9%. _{1H NMR (CDCl 3) δ 7.72-765} (m, 2H), 7.35-7.28 (m, 1H), 7.24-7.13 (m, 7H), 7.10 (d, 1H), 5.84 (s, 1H), 5.65- FAB-MS m / z: 330 [M + H] < ⁺ >.

Example 3

A small amount of bromoethane (inducing agent), magnesium powder (1.0 g, 40 mmol), and dried tetrahydrofuran (10 mL) were placed in a dry reaction bottle at room temperature and under a nitrogen atmosphere, and 4-bromomethyl- '-Biphenol (4.92 g, 20 mmol) in tetrahydrofuran was dropped and then reacted for 3 to 4 hours with continued stirring to obtain a Grignard reagent (1,1'-biphenol-4-yl -Methyl) < / RTI > magnesium bromide. The temperature was lowered to -78 < 0 > C and a solution of (7aR, 9R, 12S) -9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydro-12H-naphtho [ (100 ml) of tetrahydrofuran [2,1-b] [1,3] oxazine (IV) (4.9 g, 15 mmol) was dropped and reacted for 2 to 3 hours at that temperature. Completion is checked. The reaction was turned off with 50 mL of saturated ammonium chloride, the temperature was raised to room temperature, extracted three times with dichloromethane, the organic phase was combined and dried over anhydrous magnesium sulfate. After concentration, the residue was recrystallized from ethyl acetate and normal hexane (volume ratio 1: 1) to obtain a white solid (1S, 3R, 5S) -1 - [[3-methyl-5- (1,1'- Yl) methyl) -2-pyrrolidone] benzyl] -2-naphthalenol (V) was obtained in a yield of 85.8%. mp 215 [deg.] C (decomposition), FAB-MS m / z: 498 [M + H] < ⁺ >.

Example 4

The reaction was carried out by adding (1S, 3R, 5S) -1 - [[3-methyl-5- (1,1'-biphenyl-4-ylmethyl) -2- pyrrolidol] benzyl] Hydrogen was passed until hydrogen was not absorbed at room temperature and atmospheric pressure, and hydrogen passage was stopped. The reaction solution was cooled to room temperature and atmospheric pressure, . The catalyst was filtered off and the pressure was reduced to recover the solvent and the residue was recrystallized from ethyl acetate and normal hexane (volume ratio 1: 1) to give (3R, 5S) 1'-biphenol-4-yl-methyl) -2-pyrrolidone (VI) was obtained in a yield of 88.0%. _{1H NMR (CDCl 3) δ 7.54-7.58} (m, 4H), 7.44 (d, 2H), 7.33 (m, 1H), 7.25 (d, 2H), 7.13 (s, 1H), 3.86 (m, 1H) , 2.82 (dd, 2H), 2.42 (m, 1H), 1.83-2.13 (m, 2H), 1.09 (d, 3H); FAB-MS m / z: 266 [M + H] ⁺ .

Example 5

The reaction was carried out by adding (1S, 3R, 5S) -1 - [[3-methyl-5- (1,1'-biphenyl-4-ylmethyl) -2- pyrrolidol] benzyl] 55 mL of a mixed solvent of acetonitrile and water (volume ratio 2: 1) was added to the mixture, and the mixture was stirred for 5 to 7 hours at room temperature. To complete the reaction. Filter, add sodium bicarbonate solution to the filtrate, extract 3 times with dichloroethane, combine the organic phase and dry with anhydrous sodium carbonate. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate and normal hexane (volume ratio 1: 1) to give white solid (3R, 5S) -3-methyl-5- (1,1'- Yl-methyl) -2-pyrrolidone (VI) was obtained in a yield of 81.8%. _{1H NMR (CDCl 3) δ 7.54-7.58} (m, 4H), 7.44 (d, 2H), 7.33 (m, 1H), 7.25 (d, 2H), 7.13 (s, 1H), 3.86 (m, 1H) , 2.82 (dd, 2H), 2.42 (m, 1H), 1.83-2.13 (m, 2H), 1.09 (d, 3H); FAB-MS m / z: 266 [M + H] ⁺ .

Example 6

(1.33 g, 5 mmol), 36.5% concentrated hydrochloric acid (1 ml) was added to the reaction bottle, to which was added a solution of (3R, 5S) -3-methyl- And 25 mL of ethanol are added and dissolved by stirring. The temperature is raised to 75 to 85 캜, and the mixture is stirred for 24 hours, and the completion of the reaction is checked by TLC. The filtrate was concentrated under reduced pressure and the residue was recrystallized from di-toluene to give white solid (2R, 4S) -2-methyl-4-amino-5- (1,1'-biphenol- 1.4 g of ethyl (VII) (salt salt) was obtained, and the yield was 80.5%. _{1H NMR (DMSO- d 6) δ} 8.30 (brs, 3H), 7.62 (m, 4H), 7.43 (m, 2H), 7.35 (m, 2H), 7.31 (m, 1H), 3.95 (q, 2H) 1H), 1.08 (t, 3H), 1.05 (d, 3H), 3.65 (m, ); FAB-MS m / z: 312 [M + H] < ⁺ >.

Example 7

The reaction mixture was charged with (3R, 5S) -3-methyl-5- (1,1'-biphenol-4-ylmethyl) -2- pyrrolidone (VI) And 25 mL of ethanol are added and dissolved by stirring, and then the temperature is raised to 75 to 85 DEG C and stirred for 16 hours, and the completion of the reaction is checked by TLC. The filtrate was concentrated under reduced pressure and the residue was recrystallized from di-toluene to give white solid (2R, 4S) -2-methyl-4-amino-5- (1,1'-biphenol- 1.8 g of ethyl (VII) (hydrogencarbonate) was obtained, and the yield was 88.2%. _{1H NMR (DMSO- d 6) δ} 8.57 (brs, 3H), 7.64 (m, 4H), 7.46 (m, 2H), 7.34 (m, 2H), 7.33 (m, 1H), 3.75 (m, 2H) , 2.78 (m, 1H), 2.86 (m, 1H), 1.86 (m, 1H) + H] ⁺ .

Example 8

The reaction mixture was added with ethyl (VII) (1.55 g, 5 mmol), pyridine (1.2 g, 5 mmol), (2R, 4S) , Succinic anhydride (1.0 g, 10 mmol) was added, and the temperature was raised to 40 to 45 ° C. The mixture was reacted for 6 hours with stirring, and succinic anhydride (0.5 g, 5 mmol ), The reaction was continued for 4 hours, and the completion of the reaction was checked by TLC. The pressure was lowered and concentrated, and the residue was recrystallized from ethyl acetate and normal hexane to obtain 1.6 g of white solid cubicolide (I). The yield was 77.9%. _{1H NMR (CDCl 3) δ 7.51} (d, 2H), 7.46 (d, 2H), 7.36 (m, 2H), 7.27 (m, 1H), 7.17 (d, 2H), 5.72 (d, 1H), 4.19 (brs, IH), 4.06 (q, 2H), 2.87-2.72 (m, 2H), 2.62-2.54 (M, 1H), 1.54-1.43 (m, 1H), 1.18 (t, 3H), 1.10 (d, 3H); FAB-MS m / z: 412 [M + H] ⁺ .

It should be noted that the above embodiments are merely intended to illustrate the technical concept and features of the present invention and are intended to enable the skilled artisan skilled in the art to understand and to practice the present invention, The scope of protection of the invention shall not be limited. All equivalent changes or modifications based on the spirit and contents of the present invention are within the scope of the present invention.

Claims (6)

(7aR, 9R, 12S) -9-methyl-10-naphthalenol was obtained by cyclization of (S) -1- 12-phenyl-7a, 8,9,10-tetrahydro-12H-naphtho [1,2-e] pyrrole [2,1- b] [1,3] 1,2-e] pyrrolo [2,1-b] pyridin-2-ylmethoxy) -7a, 8,9,10-tetrahydro- [1, 3] oxazine was synthesized by the reaction of (1S, 3R (3,3'-biphenyl-4-methyl) , 5S) -1- [[3-methyl-5- (1,1'-biphenyl-4-yl-methyl) -2- pyrrolidone] benzyl] -2- naphthalenol, 2-pyrrolidone] benzyl] -2-naphthalenol was prepared from benzyl 2- (3-methyl-5- (3R, 5S) -3-methyl-5- (1,1'-biphenol-4-yl-methyl) -2- pyrrolidone, Methyl-5- (1,1'-biphenol-4-yl-methyl) -2-pyrrolidone is hydrolyzed and esterified in ethanol under the action of an acidic catalyst (2R, 4S) -2-methyl-4-amino-5- (1,1'-biphenol-4-yl) -4-amino-5- (1,1'-biphenol-4-yl) -valerate and succinic anhydride undergo the action of an amidation reaction under the action of an alkaline promoter to obtain sacubitril By weight. The method according to claim 1,
The starting molar ratio of the (S) -1- (α-aminobenzyl) -2-naphthalenol to the 2R-methyl-4-oxo-butanoic acid in the cyclization reaction is 1: 1 to 2, Wherein the solvent is toluene, 1,2-dichloroethane, N, N-dimethylformamide, acetonitrile or dimethylsulfoxide, and the cyclization temperature is 25 to 100 占 폚. The method according to claim 1,
(7aR, 9R, 12S) -9-methyl-10-oxo-12-phenyl-7a, 8,9,10-tetrahydro- 12H-naphtho [ (1, 1'-biphenyl-4-methyl) magnesium chloride or (1,1'-biphenyl-4-methyl) 1: 1 to 2, and the solvent for the addition reaction is ethyl ether, isopropyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, and the temperature for the addition reaction is -100 to 0 ° C . The method according to claim 1,
Wherein the reaction system of the debenzene reaction is a Pd / C catalytic hydrogenation reduction system or a cerium ammonium nitrate oxidation system, and the solvent of the Pd / C catalytic hydrogenation reduction system is methanol, ethanol, isopropanol, dichloromethane, Wherein the solvent of the cerium containing ammonium nitrate oxidation system is acetonitrile / water, dichloromethane / water or tetrahydrofuran / water, and the volume ratio is 1 to 5: 1. The method according to claim 1,
Wherein the acidic catalyst of the cyclization and esterification reaction is hydrochloric acid, sulfuric acid, trifluoroacetic acid, perchloric acid or p-sulfonic acid toluene, and the temperature of the cyclic thermal and esterification reaction is 0 to 100 ° C. The method according to claim 1,
The solvent for the amidation reaction may be dichloromethane, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, Dimethylformamide or dioxane, and the amidation reaction temperature is 0 to 90 ° C.