A process for the preparation of a sodium fosinopril intermediate

Abstract

The present application provides a method for preparing a fosinopril sodium intermediate, comprising using propionic acid-1-bromoisobutyl ester instead of propionic acid-1-chloroisobutyl ester disclosed in the prior art and reacting with [hydroxy(4-phenylbutyl)oxyphosphinyl]benzyl acetate, the method has higher non-corresponding selectivity, the yield of the target product levosimendan is significantly improved, and the product is easier to refine.

Description

Technical Field

[0001] This invention relates to a method for preparing a sodium fosinopril intermediate, belonging to the field of organic chemical synthesis. Technical Background

[0002] Fosinopril sodium is a potent, long-acting ACE inhibitor developed by Bristol-Myers Squibb in the United States, used to treat various types of hypertension and heart failure.

[0003] Fosinopril sodium has the chemical name 4-cyclohexyl-1-[(2-methyl-1-(propionyloxy)propoxy)(4-phenylbutyl)phosphonoacetyl]-L-proline sodium, and its structural formula is shown in Formula I:

[0004]

[0005] Currently, there are many reported methods for synthesizing fosinopril sodium, and the fosinopril sodium intermediate levo-5 is a key intermediate in its synthesis. It is a mixture of two isomers shown in formula II-1 and formula II-2:

[0006]

[0007] The synthesis of levosinopril 5 mainly consists of two steps: First, propionyl chloride (Formula VII) and isobutyraldehyde (Formula VI) are reacted in dichloromethane under zinc chloride catalysis to yield 1-chloroisobutyl propionate (Formula IV); second, 1-chloroisobutyl propionate (Formula IV) reacts with benzyl acetate (Formula V) to yield the intermediate (Formula III). The intermediate (Formula III) is then reacted directly under palladium-carbon catalytic hydrogenation without separation to generate fosinopril sodium levosinopril 5. The synthetic route is shown below:

[0008]

[0009]

[0010] Formula III has four chiral isomers, which are mixtures of the four isomers shown in Formula III-1, Formula III-2, Formula III-3, and Formula III-4.

[0011]

[0012] The III-1 / III-2 configuration is the dominant configuration and is present in a larger proportion in intermediate formula III, while the III-3 / III-4 configuration is present in a smaller proportion. The ratio of the contents of (III-1 / III-2) and (III-3 / III-4) is called the dr value. The intermediate of formula III is hydrogenated and then recrystallized to remove unwanted isomers, yielding fosinopril sodium lev-5 as described above.

[0013] Chinese patent CN1026791C discloses a method for preparing fosinopril sodium levo-5. 1-chloroisobutyl propionate (Formula IV) and benzyl hydroxy(4-phenylbutyl)oxyphosphino]acetate (Formula V) are reacted in toluene at 95°C for 18-19 hours under N-methylmorpholine as a base, yielding an intermediate containing formula III. The selectivity dr ≈ 1.5. This reaction solution is acid-washed and then hydrogenated. The hydrogenated solution is extracted with methyl isobutyl ketone (MOH) as a base, and then recrystallized twice with MOH to obtain levo-5, with an overall yield of 44%. This process has low selectivity, requires two recrystallizations to obtain qualified levo-5, is cumbersome, and has a low overall yield.

[0014] Indian patent IN754CHE2005 also reports a similar method for preparing levo-5. 1-Chloroisobutyl propionate (Formula IV) and benzyl hydroxy(4-phenylbutyl)oxyphosphonyl]acetate (Formula V) are reacted in toluene at 95–100°C for 10 hours under N-methylmorpholine as a base, yielding a reaction solution containing the intermediate of Formula III. This reaction solution is then acid-washed and hydrogenated. The hydrogenated solution is extracted with methyl tert-butyl ether using sodium bicarbonate as an alkali, and the methyl tert-butyl ether is recrystallized twice to obtain levo-5, with an overall yield of 45%. This process requires two recrystallizations to obtain levo-5 of acceptable quality, is cumbersome, and has a low overall yield.

[0015] In summary, the currently reported methods for preparing fosinopril sodium lev-5 have drawbacks such as low diastereoselectivity, cumbersome operation, low atom economy, and low yield. Therefore, it is essential to develop a simple, environmentally friendly, safe, and high-yield method suitable for industrial production of fosinopril sodium lev-5. Summary of the Invention

[0016] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a method for preparing the fosinopril sodium intermediate Levo-5. This method has the advantages of high diastereoselectivity, simple post-processing, high atom economy, and high yield, and is suitable for industrial production. Levo-5 is a mixture of isomers represented by Formula II-1 and Formula II-2.

[0017]

[0018] The method includes the following steps:

[0019] a) In an organic solvent and in the presence of a base, benzyl hydroxy(4-phenylbutyl)oxyphosphino]acetate of formula V is reacted with 1-bromoisobutyl propionate of formula VIII to obtain a reaction mixture containing four isomers of formula III-1, formula III-2, formula III-3 and formula III-4.

[0020]

[0021] b) Under positive pressure and in the presence of palladium on carbon, hydrogen gas is passed into the above reaction mixture to hydrogenate the mixture of the four isomers and remove the benzyl ester.

[0022] c) The desired levo-5 is separated from the hydrogenation reaction solution of b).

[0023] According to the method provided by the present invention, the base in step a) is selected from N-methylmorpholine, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, with N-methylmorpholine being the most preferred.

[0024] When N-methylmorpholine is selected, more preferably, the mass ratio of [hydroxy(4-phenylbutyl)oxyphosphino]benzyl acetate (V) to N-methylmorpholine in step a) is 1:0.5 to 1:1, with the optimal ratio being 1:0.54.

[0025] The reaction solvent added in step a) is preferably toluene, ethyl acetate, n-hexane, or dichloromethane, with toluene being the most preferred.

[0026] In step a), the mass ratio of benzyl hydroxy(4-phenylbutyl)oxyphosphono]acetate (shown in formula V) to 1-bromoisobutyl propionate (shown in formula VIII) is 1:1.0 to 1:1.5, with the optimal ratio being 1:1.05.

[0027] Step a) is preferably carried out at room temperature.

[0028] After the reaction in step a) is completed and before the hydrogenation reaction, the reaction solution is preferably washed with dilute hydrochloric acid.

[0029] Step b) The hydrogenation pressure is preferably 0.40 ± 0.05 MPa.

[0030] Step c) Preferred separation includes the following process: filtration of the reaction solution from step b), washing the resulting hydrogenated solution with an inorganic alkaline aqueous solution, discarding the organic layer and retaining the aqueous solution; adding hydrochloric acid to the aqueous solution to adjust the pH to 1-4, adding an organic solvent for extraction, and cooling to crystallize to obtain the desired L-5 intermediate.

[0031] More preferably, the inorganic alkali used for washing in step c) is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide, with sodium bicarbonate being the most preferred.

[0032] More preferably, the organic solvent used for extraction in step c) is ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, methyl tert-butyl ether, methyl isobutyl ketone, or toluene, with ethyl acetate being the most preferred.

[0033] The synthesis method of 1-bromoisobutyl propionate (VIII) used in step a) is as follows: propionyl bromide (IX) and isobutyraldehyde (VI) are reacted in dichloromethane under the catalysis of zinc chloride. After the reaction is completed, the reaction solution is washed with alkali, washed with water, dried and concentrated by distillation to obtain 1-bromoisobutyl propionate (VIII).

[0034] Compared with the prior art, the positive technical effects achieved by the present invention are as follows:

[0035] 1. Replacing 1-chloroisobutyl propionate (IV) with 1-bromoisobutyl propionate and reacting with [hydroxy(4-phenylbutyl)oxyphosphonyl]benzyl acetate (V) results in high non-corresponding selectivity, which significantly improves the yield of the target product levo-5, for example, up to 56%, which is a substantial improvement over the 44% reported in previous patents.

[0036] 2. The reaction has good non-corresponding selectivity, and the post-processing only requires recrystallization once to obtain a qualified intermediate, reducing the generation of waste solvent. Detailed Implementation

[0037] The present invention will be further described in conjunction with embodiments. The following embodiments are merely illustrative of the invention and are not intended to limit the invention in any way. The dr values ​​in the following embodiments refer to the content ratio of (III-1 / III-2) and (III-3 / III-4).

[0038] Example 1 (Screening of Reaction Base):

[0039] Add 300 mL of toluene to a 1 L three-necked flask, then add 54 g of the alkali shown in Table 1, 100 g of [hydroxy(4-phenylbutyl)oxyphosphono]benzyl acetate (V), and 105 g of 1-bromoisobutyl propionate (VIII). Stir until dissolved and react at 25 °C for 20–24 h. HPLC analysis of the reaction solution is performed, and the dr value of the reaction solution is calculated. The results are shown in Table 1.

[0040] Table 1

[0041]

[0042]

[0043] Example 2 (Screening of reaction solvents):

[0044] Add 300 mL of the organic solvent shown in Table 2 to a 1 L three-necked flask, then add 54 g of N-methylmorpholine, 100 g of [hydroxy(4-phenylbutyl)oxyphosphono]benzyl acetate (V), and 105 g of 1-bromoisobutyl propionate (VIII). Stir until dissolved and react at 25 °C for 20–24 h. Take the reaction solution for HPLC analysis and calculate the dr value of the reaction solution. The results are shown in Table 2.

[0045] Table 2

[0046] Serial Number solvent dr value of reaction solution 1 Toluene 2.5:1 2 Ethyl acetate 2.3:1 3 n-Hexane 2.4:1 4 dichloromethane 2.2:1

[0047] Example 3 (Screening of Feeding Ratio):

[0048] Add 300 mL of toluene to a 1 L three-necked flask, then add 100 g of N-methylmorpholine, 100 g of [hydroxy(4-phenylbutyl)oxyphosphino]acetate benzyl acetate (V), and 1-bromoisobutyl propionate (VIII). Stir until dissolved. The mass ratio of compound (V):compound (VIII):N-methylmorpholine is as shown in Table 3. React at 25 °C for 20–24 h. Analyze the reaction solution using HPLC. The data are shown in Table 3.

[0049] Table 3

[0050] Serial Number The mass ratio of compound (V): compound (VIII): N-methylmorpholine dr value of reaction solution 1 1:1.05:0.54 2.5:1 2 1:1.10:0.54 2.3:1 3 1:1.50:0.54 2.3:1 4 1:1.05:0.50 2.2:1 5 1:1.05:1.00 2.2:1

[0051] Example 4 (Screening of alkali in alkaline washing):

[0052] Add 300 mL of toluene to a 1 L three-necked flask, then add 54 g of N-methylmorpholine, 100 g of [hydroxy(4-phenylbutyl)oxyphosphono]benzyl acetate (V), and 105 g of 1-bromoisobutyl propionate (VIII). Stir until dissolved and allow to settle. React at 25 °C for 20–24 h. After the reaction is complete, wash with 400 mL of dilute hydrochloric acid, allowing the layers to separate; discard the aqueous layer. Add 2.5 g of palladium on carbon to the toluene layer, controlling the hydrogenation pressure at 0.2–0.5 MPa and the temperature at 10–50 °C until no hydrogen absorption occurs. Filter the palladium on carbon to obtain the hydrogenated liquid. Add 400 mL of drinking water and 40 g of the solution shown in Table 4 to the hydrogenated liquid. alkali Stir and wash, separate the layers, discard the toluene layer. Add 300 mL of ethyl acetate to the aqueous layer, adjust the pH of the aqueous layer to 1-4 using hydrochloric acid, separate the layers, discard the aqueous layer. Slowly cool the ethyl acetate solution to -10℃ to -5℃, crystallize for 1 hour, filter, and obtain [(2-methyl-1-propanoyloxypropoxy)(4-phenylbutyl)oxyphosphine]acetic acid (II), with a purity greater than 99%.

[0053] Table 4

[0054] Serial Number alkali yield 1 Sodium carbonate 53％ 2 Potassium carbonate 55％ 3 Sodium bicarbonate 56％ 4 Potassium bicarbonate 52％ 5 Sodium hydroxide 51％ 6 potassium hydroxide 50％

[0055] Example 5 (Screening of organic solvents for extraction):

[0056] Add 300 mL of toluene to a 1 L three-necked flask, then add 54 g of N-methylmorpholine, 100 g of [hydroxy(4-phenylbutyl)oxyphosphono]benzyl acetate (V), and 105 g of 1-bromoisobutyl propionate (VIII). Stir until dissolved and allow to settle. React at 25 °C for 20–24 h. After the reaction is complete, wash with 400 mL of dilute hydrochloric acid, allowing the layers to separate; discard the aqueous layer. Add 2.5 g of palladium on carbon to the toluene layer, controlling the hydrogenation pressure at 0.2–0.5 MPa and the temperature at 10–50 °C until no hydrogen absorption occurs. Filter the palladium on carbon to obtain the hydrogenated liquid. Add 400 mL of drinking water and 40 g of sodium bicarbonate to the hydrogenated liquid, stir and wash, allowing the layers to separate; discard the toluene layer. Add 300 mL of the organic solvent shown in Table 5 to the aqueous layer, adjust the pH of the aqueous layer to 1–4 using hydrochloric acid, allow the layers to separate, and discard the aqueous layer. The liquid was slowly cooled to -10℃ to -5℃, crystallized for 1 hour, and then filtered to obtain [(2-methyl-1-propanoyloxypropoxy)(4-phenylbutyl)oxyphosphino]acetic acid (II), with a purity greater than 99%.

[0057] Table 5

[0058] Serial Number solvent yield 1 Ethyl acetate 56％ 2 Isopropyl acetate 51％ 3 Ethylene glycol dimethyl ether 50％ 4 Methyl tert-butyl ether 53％ 5 Methyl isobutyl ketone 55％ 6 Toluene 50％

[0059] Example 6 (Synthesis of 1-bromoisobutyl propionate):

[0060] Add 890 g of propionyl bromide, 1250 mL of dichloromethane, and a small amount of zinc chloride to a 3 L three-necked flask, and cool to 5–10 °C. Maintain the temperature at 5–10 °C and slowly add 480 g of isobutyraldehyde dropwise. After the isobutyraldehyde addition is complete, raise the temperature to 20–30 °C and maintain the reaction for 3–5 hours. After the reaction is complete, add 800 mL of drinking water and 40 g of sodium bicarbonate, stir and wash, separating the layers; discard the upper aqueous layer. Add 800 mL of drinking water to the dichloromethane solution, stir and wash once, separating the layers; discard the aqueous layer, and dry the dichloromethane layer with 30 g of anhydrous magnesium sulfate. Filter, evaporate the dichloromethane to dryness, and obtain 1-bromoisobutyl propionate in 80% yield.

Claims

1. A method for preparing fosinopril sodium intermediate Levo-5, wherein Levo-5 is a mixture of isomers shown in Formula II-1 and Formula II-2: The method includes the following steps: a) In an organic solvent and in the presence of a base, benzyl hydroxy(4-phenylbutyl)oxyphosphono]acetate of formula V reacts with 1-bromoisobutyl propionate of formula VIII to obtain a reaction mixture containing four isomers of formula III-1, formula III-2, formula III-3 and formula III-4; the base is selected from N-methylmorpholine, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; the organic solvent is toluene, ethyl acetate, n-hexane, or dichloromethane. b) Under positive pressure and in the presence of palladium on carbon, hydrogen gas is passed into the above reaction mixture to hydrogenate the mixture of the four isomers and remove the benzyl ester. c) Separate the desired mixture of isomers represented by formulas II-1 and II-2 from the hydrogenation reaction solution of b).

2. The method according to claim 1, wherein the base in step a) is N-methylmorpholine.

3. The method according to claim 1, wherein the base in step a) is N-methylmorpholine, and the mass ratio of [hydroxy(4-phenylbutyl)oxyphosphine]benzyl acetate (V) to N-methylmorpholine in step a) is 1:0.5 to 1:

1.

4. The method according to claim 3, wherein the base in step a) is N-methylmorpholine, and the mass ratio of [hydroxy(4-phenylbutyl)oxyphosphono]benzyl acetate (V) to N-methylmorpholine in step a) is 1:0.

54.

5. The method according to claim 1, wherein the reaction solvent added in step a) is toluene.

6. According to the method of claim 1, in step a), the mass ratio of benzyl hydroxy(4-phenylbutyl)oxyphosphono]acetate as shown in formula V and 1-bromoisobutyl propionate as shown in formula VIII is 1:1.0 to 1:1.

5.

7. The method according to claim 6, wherein in step a), the mass ratio of benzyl hydroxy(4-phenylbutyl)oxyphosphino]acetate as shown in formula V and 1-bromoisobutyl propionate as shown in formula VIII is 1:1.

05.

8. The method according to claim 1, wherein step a) is carried out at room temperature.

9. According to the method of claim 1, after step a) the reaction is completed and before step b) the hydrogenation reaction, the reaction solution is washed with dilute hydrochloric acid.

10. The method according to claim 1, wherein the hydrogenation pressure in step b) is 0.40 ± 0.05 MPa.

11. The method according to claim 1, wherein the separation in step c) comprises the following steps: filtering the hydrogenation reaction solution from step b), washing the filtered hydrogenation solution with an inorganic alkaline aqueous solution, discarding the organic layer and retaining the aqueous solution; adjusting the pH to 1-4 with hydrochloric acid in the aqueous solution, extracting with an organic solvent, and cooling to crystallize to obtain the desired diastereomers shown in formula II-1 and II-2.

12. The method according to claim 11, wherein the inorganic alkali used for washing in step c) is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.

13. The method according to claim 12, wherein the inorganic alkali used for washing in step c) is sodium bicarbonate.

14. The method according to claim 11, wherein the organic solvent used for extraction in step c) is ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, methyl tert-butyl ether, methyl isobutyl ketone, or toluene.

15. The method according to claim 14, wherein the organic solvent used for extraction in step c) is ethyl acetate.

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