Synthesis method of a sacubitril pharmaceutical intermediate

Abstract

The present invention belongs to the field of organic synthesis, particularly relates to the field of organic drug synthesis technology, and more specifically relates to a method for synthesizing a sacubitril drug intermediate. Using compound V and compound VI as raw materials, compound IV is obtained by reacting compound V and compound VI in the presence of a base and a phase transfer catalyst. Then, in the presence of a catalyst, compound IV is oxidized with an oxidant to obtain compound III. Finally, in the presence of a base, compound II and compound III are reacted at low temperature to obtain the target product compound I. This method not only has mild reaction conditions, high safety, and simple preparation process, but also has a high yield and high purity of the target compound, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, particularly relates to the field of organic drug synthesis, and more specifically relates to a method for synthesizing a sacubitril drug intermediate. Background Art

[0002] Heart failure has become a global public health problem seriously endangering human health. It is the terminal stage of the occurrence and development of cardiovascular diseases, and its incidence, re-hospitalization rate and mortality are all increasing year by year. This makes it urgent to further develop more effective new drugs for the treatment of heart failure. The listing of sacubitril / valsartan with a dual mechanism of action of angiotensin receptor-neprilysin inhibitor has brought new changes to the treatment of heart failure patients.

[0003] Sacubitril / valsartan (Entresto) is a dual-acting angiotensin receptor-neprilysin inhibitor developed by Novartis and can be clinically used for the treatment of hypertension and heart failure. This drug consists of sacubitril acting on neprilysin and valsartan acting on the renin-angiotensin-aldosterone system, and can effectively improve the symptoms of heart failure, lower blood pressure and actively improve renal function. It is an ideal drug for the treatment of heart failure.

[0004] Since the synthesis process of valsartan is relatively mature, the research focus of those skilled in the art is concentrated on the synthesis optimization of the sacubitril part.

[0005] Sacubitril, chemically named 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, has the following structure:

[0006]

[0007] Compound I is an important intermediate for the preparation of sacubitril drugs.

[0008]

[0009] Currently, the preparation method of sacubitril disclosed in the original research patent US5217996 is adopted in the prior art, and its synthesis route is as follows:

[0010]

[0011] It can be seen that in this synthesis route, Compound I is prepared by the Witting reaction of Compound II with a phosphonium ylide reagent, and the structure of the phosphonium ylide reagent is as shown in Formula a.

[0012]

[0013] However, the yield of Compound I under this method is only 78%. The low reaction yield not only causes waste of chiral alcohol raw materials, but also makes the industrial synthesis cost of sacubitril remain high.

[0014] Therefore, developing a preparation method for sacubitril intermediate (Compound I) with high yield, low synthesis cost and more suitable for industrial production has become a hot issue for those skilled in the art to study. Summary of the Invention

[0015] The problem to be solved by the present invention is to provide a new synthesis method for sacubitril intermediate (Compound I), with the expectation that after adopting the new synthesis method, the product yield can be increased and the synthesis cost can be reduced, thereby further reducing the industrial synthesis cost of sacubitril.

[0016] To solve the above technical problems, the present invention discloses a synthesis method for a sacubitril drug intermediate. This method is that under low-temperature conditions and in the presence of a base, Compound II reacts with Compound III to obtain Compound I. The specific synthesis route is as follows:

[0017]

[0018] Among them, R is selected from any one of

[0019] Preferably, the base is one of sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyllithium, potassium tert-butoxide, sodium tert-butoxide or LDA.

[0020] Preferably, the solvent is any one or several of tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, ethyl acetate, acetone or methyl isopropyl ketone.

[0021] Preferably, the reaction temperature is -90 to -60 °C, which can be but is not limited to -90 °C, -85 °C, -80 °C, -75 °C, -70 °C, -65 °C or -60 °C. To obtain better results, the reaction temperature is preferably -70 °C.

[0022] Specifically, the synthesis method is as follows: Under nitrogen protection, add Compound II, Compound III and the reaction solvent to the reaction vessel. After dissolution, cool the reaction mixture to reach the low-temperature reaction conditions; then add the base and continue to stir and react under this low-temperature condition to obtain Compound I;

[0023] Further preferably, the molar ratio of Compound II to Compound III and the base is 1:(1 - 1.5):(1 - 1.5).

[0024] Further, a method for synthesizing Compound III is disclosed in the present invention, and Compound III is obtained by oxidizing Compound IV with an oxidizing agent;

[0025]

[0026] wherein, R is selected from any one of

[0027] Furthermore, Compound IV is obtained by reacting Compound V and Compound VI in the presence of a base and a phase transfer catalyst, and its synthetic route is as follows:

[0028]

[0029] In a specific preferred embodiment, the preparation of Compound III includes the following steps:

[0030] (1) React Compound V and Compound VI in the presence of a base and a phase transfer catalyst to obtain Compound IV;

[0031] (2) In the presence of a catalyst, oxidize Compound IV with an oxidizing agent to obtain Compound III,

[0032] The specific synthetic route is as follows:

[0033]

[0034] wherein, R is selected from any one of

[0035] Preferably, in step (1), the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride or 18-crown-6 ether.

[0036] Preferably, in step (1), the base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

[0037] Preferably, in step (1), the reaction temperature is 80-140 °C, which can be but is not limited to 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C or 140 °C. For better results, the reaction temperature is preferably 125 °C.

[0038] Preferably, in step (1), the solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropanol or N-methylpyrrolidone.

[0039] Preferably, in step (2), the catalyst is one of ammonium heptamolybdate tetrahydrate, phosphomolybdic acid or tungsten trioxide.

[0040] Preferably, in step (2), the oxidizing agent is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate or m-chloroperbenzoic acid.

[0041] Preferably, in step (2), the solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methylpyrrolidone.

[0042] Preferably, in step (2), the reaction temperature is -10 to 40 °C, which can be but is not limited to -10 °C, -5 °C, 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C or 40 °C. For better results, the reaction temperature is preferably 5 °C.

[0043] The present invention discloses a method for synthesizing a sacubitril drug intermediate. Using compound V and compound VI as raw materials, compound IV is obtained by reacting compound V and compound VI in the presence of a base and a phase transfer catalyst. Then, in the presence of a catalyst, compound IV is oxidized with an oxidizing agent to obtain compound III. Finally, in the presence of a base, compound II and compound III are reacted at low temperature to obtain the target product compound I. This method not only has mild reaction conditions, high safety, and simple preparation process, but also has a high yield and high purity of the target compound, and is suitable for large-scale industrial production. Detailed implementation manners

[0044] To better understand the present invention, the present invention will be further elaborated below in combination with specific examples.

[0045] Unless otherwise specified, the reagents used in the embodiments of the present invention are all ordinary commercially available products.

[0046] Example 1

[0047]

[0048] (1) Synthesis of compound IV-1

[0049] Under nitrogen protection, compound V (10 g, 73 mmol), compound VI-1 (14.3 g, 80.3 mmol) and 100 ml of dimethyl sulfoxide were added to the reaction vessel and stirred until dissolved. Then tetrabutylammonium bromide (1.2 g, 3.7 mmol) and sodium bicarbonate (12.3 g, 146 mmol) were added, and the reaction mixture was reacted at 125 °C. After the reaction was completed, the reaction mixture was cooled to 20 °C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was washed with 100 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, and then concentrated to obtain compound IV-1 with a yield of 96.5% and a purity of 99.4%.

[0050] (2) Synthesis of compound III-1

[0051] Compound IV-1 (10 g, 36 mmol) and 100 mL of dimethyl sulfoxide were added to the reaction vessel and stirred until dissolved. The reaction solution was cooled to 5 °C, then ammonium molybdate tetrahydrate (0.9 g, 0.72 mmol) and 30% hydrogen peroxide (16.3 g, 144 mmol) were added, and the reaction mixture was reacted at 5 °C. After the reaction was completed, the reaction mixture was warmed to 20 °C, 50 mL of dimethyl sulfoxide and 100 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, washed with 50 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, concentrated, and then recrystallized from isopropanol to obtain compound III-1 with a yield of 92.7% and a purity of 99.1%.

[0052] Example 2

[0053]

[0054] (1) Synthesis of compound IV-2

[0055] Under nitrogen protection, compound V (10 g, 73 mmol), compound VI-2 (13.4 g, 80.3 mmol) and 100 ml of N,N-dimethylformamide were added to the reaction vessel and stirred until dissolved. Then tetrabutylammonium chloride (1 g, 3.7 mmol) and sodium carbonate (15.5 g, 146 mmol) were added, and the reaction mixture was reacted at 140 °C. After the reaction was completed, the reaction mixture was cooled to 20 °C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was washed with 100 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, and then concentrated to obtain compound IV-2 with a yield of 94.1% and a purity of 99.2%.

[0056] (2) Synthesis of Compound III-2

[0057] Compound IV-2 (9.6 g, 36 mmol) and 100 mL of acetonitrile were added to a reaction vessel and stirred until dissolved. The reaction solution was cooled to -10°C, and then phosphomolybdic acid (1.3 g, 0.72 mmol) and 30% hydrogen peroxide (16.3 g, 144 mmol) were added. The reaction mixture was reacted at -10°C. After the reaction was completed, the reaction mixture was warmed to 20°C, 50 mL of acetonitrile and 100 mL of saturated aqueous NaHCO3 were added. The organic phase was separated, washed with 50 mL of saturated aqueous NaHCO3, dried over Na2SO4, concentrated, and then recrystallized from isopropanol to obtain Compound III-2 with a yield of 89.6% and a purity of 99.2%.

[0058] Example 3

[0059]

[0060] (1) Synthesis of Compound IV-3

[0061] Under nitrogen protection, Compound V (10 g, 73 mmol), Compound VI-3 (10.6 g, 80.3 mmol) and 100 ml of methanol were added to a reaction vessel and stirred until dissolved. Benzyltriethylammonium chloride (0.84 g, 3.7 mmol) and sodium hydroxide (5.8 g, 146 mmol) were added, and the reaction mixture was reacted at 80°C. After the reaction was completed, the reaction mixture was cooled to 20°C, 200 mL of methyl tert-butyl ether and 200 mL of saturated aqueous NaHCO3 were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was washed with 100 mL of saturated aqueous NaHCO3, dried over Na2SO4, and concentrated to obtain Compound IV-3 with a yield of 91.8% and a purity of 99.3%.

[0062] (2) Synthesis of Compound III-3

[0063] Compound IV-3 (8.4 g, 36 mmol) and 100 mL of N,N-dimethylformamide were added to a reaction vessel and stirred until dissolved. The reaction solution was cooled to 40 °C, and then ammonium heptamolybdate tetrahydrate (0.9 g, 0.72 mmol) and m-chloroperoxybenzoic acid (24.8 g, 144 mmol) were added. The reaction mixture was reacted at 40 °C. After the reaction was completed, the reaction mixture was heated to 20 °C, 50 mL of N,N-dimethylformamide and 100 mL of saturated aqueous NaHCO3 solution were added. The organic phase was separated, washed with 50 mL of saturated aqueous NaHCO3 solution, dried over Na2SO4, concentrated, and then recrystallized from isopropanol to obtain Compound III-3 with a yield of 87.9% and a purity of 99.1%.

[0064] Example 4

[0065]

[0066] Under nitrogen protection, Compound II (30 g, 92 mmol), Compound III-1 (32.6 g, 105 mmol) and 200 ml of tetrahydrofuran were added to a reaction vessel and stirred until dissolved. The reaction mixture was cooled to -70 °C with stirring. Then LiHMDS (20.2 g, 120 mmol) was slowly added, and the reaction was stirred at -70 °C. After the reaction was completed, the reaction mixture was heated to -10 °C, and the reaction was quenched with 100 mL of 10% aqueous NaHCO3 solution. The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous Na2CO3 solution, and concentrated in vacuo. After concentration was completed, methanol was added for recrystallization to obtain Compound I with a yield of 93.6% and a purity of 99.5%.

[0067] Example 5

[0068]

[0069] Under nitrogen protection, Compound II (30 g, 92 mmol), Compound III-2 (41.3 g, 138 mmol) and 200 ml of toluene were added to a reaction vessel and stirred until dissolved. The reaction mixture was cooled to -90 °C with stirring. Then sodium hydride (2.3 g, 95.8 mmol) was slowly added, and the reaction was stirred at -90 °C. After the reaction was completed, the reaction mixture was heated to -10 °C, and the reaction was quenched with 100 mL of 10% aqueous NaHCO3 solution. The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous Na2CO3 solution, and concentrated in vacuo. After concentration was completed, methanol was added for recrystallization to obtain Compound I with a yield of 90.8% and a purity of 99.3%.

[0070] Example 6

[0071]

[0072] Under nitrogen protection, compound II (30 g, 92 mmol), compound III-3 (24.4 g, 92.3 mmol) and 200 ml of dioxane were added to the reaction vessel and stirred until dissolved. The reaction mixture was cooled to -60 °C with stirring. Then NaHMDS (25.3 g, 138 mmol) was slowly added, and the reaction was stirred at -60 °C. After the reaction was completed, the reaction mixture was warmed to -10 °C, and the reaction was quenched with 100 mL of 10% aqueous NaHCO3 solution. The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous Na2CO3 solution, and concentrated in vacuo. After concentration was completed, recrystallization from methanol gave compound I in a yield of 89.2% and a purity of 99.2%.

[0073] The above are the specific embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements are also regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing a sacubitril drug intermediate, characterized in that, This method involves the reaction of compound II with compound III under low-temperature conditions in the presence of a base to obtain compound I, and its synthetic route is as follows: ； Among them, R is selected from any one of; The reaction solvent is any one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, ethyl acetate, acetone, and methyl isopropyl ketone.

2. The synthesis method of the sacubitril drug intermediate according to claim 1, wherein, The base is any one of sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyllithium, potassium tert-butoxide, sodium tert-butoxide, or LDA.

3. The synthesis method of the sacubitril drug intermediate according to claim 1, characterized in that, The low-temperature conditions are -90~-60°C.

4. The synthesis method of the sacubitril drug intermediate according to claim 1, characterized in that, The specific synthesis method is as follows: Under nitrogen protection, add compound II, compound III, and the reaction solvent to the reaction vessel. After dissolution, cool the reaction mixture to reach the low-temperature reaction conditions; then add the base and continue to stir and react under this low-temperature condition to obtain compound I.

5. The synthesis method of the sacubitril drug intermediate according to claim 1, characterized in that, The molar ratio of compound II to compound III and the base is 1:(1~1.5):(1~1.5).

6. The synthesis method of the sacubitril pharmaceutical intermediate according to claim 1, characterized in that, Compound III is obtained by oxidizing compound IV with an oxidizing agent; ; wherein, R is selected from any one of 7. The synthesis method according to claim 6, characterized in that: Compound IV is obtained by reacting compound V and compound VI in the presence of a base and a phase transfer catalyst, and its synthetic route is as follows: 。 8. The synthesis method according to claim 7, wherein The phase transfer catalyst in the synthesis of compound IV is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride, or 18-crown-6 ether.

9. The synthesis method according to claim 7, wherein The base in the synthesis of compound IV is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.

10. The synthesis method according to claim 7, characterized in that, The temperature of the reaction system in the synthesis of compound IV is 80~140°C.

11. The synthesis method according to claim 7, characterized in that, The reaction solvent in the synthesis of compound IV is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropanol, or N-methylpyrrolidone.

12. The synthesis method according to claim 6, wherein, A catalyst is also added to the reaction in the synthesis of compound III, and the catalyst is one of ammonium heptamolybdate tetrahydrate, phosphomolybdic acid, or tungsten trioxide.

13. The synthesis method according to claim 6, characterized in that, The oxidizing agent in the synthesis of compound III is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate, or m-chloroperoxybenzoic acid.

14. The synthesis method according to claim 6, wherein The temperature of the reaction system in the synthesis of compound III is -10~40°C.

15. The synthesis method according to claim 6, characterized in that, The reaction solvent in the synthesis of compound III is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, or N-methylpyrrolidone.

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