Synthesis method of flomoxef axetil

Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of flomoxef axetil, which comprises the following steps: carrying out substitution reaction on a compound II tert-butyl alcohol and sodium hypochlorite in an organic solvent to generate a compound III tert-butyl hypochlorite; the compound I and a compound III tert-butyl hypochlorite are subjected to a methoxylation reaction to generate a compound IV; removing an amino protecting group from the compound IV under the action of amino acylase to obtain a compound V; reacting the compound VI potassium difluoromethyl mercaptoacetate under the action of hydrochloric acid to generate a compound VII; the compound V reacts with a compound VII (difluoromethyl mercaptoacetic acid) to obtain a target compound VIII; the method is simple and reliable in reaction operation, short in reaction route, green and environment-friendly, high in yield and easy in post-treatment, and high-purity flomoxef axetil is obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a method for synthesizing fluoxetine. Background Art

[0002] Sodium fluoxetine, chemical name is (6R,7R)-7-[2-(difluoromethylthio)acetamido]-7-methoxy-3-{[1-(2-hydroxyethyl)1H-tetrazol-5-yl]thiomethyl}-8-oxo-5-oxa-1-azabicyclo[4,2,0]oct-2-ene-carboxylate sodium, developed by Shionogi Pharmaceutical Co., Ltd. of Japan, and has the advantages of being stable to β-lactamase, low in nephrotoxicity, and having a broad antibacterial spectrum; Publication No. CN10295 2149A reports a route for synthesizing fluoxetine using 7α-methoxy-7β-amido-3-chloromethyl-oxycephem as a starting material. The intermediate after deprotection with phosphorus pentachloride is not stable enough, and the reaction steps are many, resulting in a low yield. WO2007105253 reports a route for synthesizing fluoxetine using 7-amino-3-chloromethyl-oxycephem ester compounds as a starting material. The route has the disadvantages of low yield, use and generation of toxic substances, and unstable intermediates. Summary of the invention

[0003] The invention aims to provide a method for synthesizing fluoxetine which is green, environmentally friendly, has few side reactions, is easy to operate and has a high yield.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is:

[0005] A method for synthesizing fluoxetine comprises the following steps:

[0006] S1. Compound II tert-butyl alcohol is placed in an organic solvent and reacted with sodium hypochlorite to generate compound III tert-butyl hypochlorite, and compound I is dissolved in an organic solvent of dichloromethane, and reacted with compound III tert-butyl hypochlorite to generate compound IV under the action of lithium methoxide;

[0007] S2. removing the amino protecting group of compound IV dissolved in an organic solvent in the reaction solvent under the action of aminoacylase to obtain compound V, and removing the potassium ion of compound VI difluoromethylthioglycolate potassium salt under the action of hydrochloric acid to generate compound VII;

[0008] S3. Compound V and compound VII difluoromethylthioglycolic acid are subjected to a condensation reaction to obtain the target compound VIII; the synthetic route of the reaction is as follows:

[0009]

[0010] In the formula, R1 is an acyl residue and R2 is a carboxyl protecting group.

[0011] Furthermore, the reaction temperature of the substitution reaction in step S1 is -40 to 0°C, the amount of sodium hypochlorite used is 3 to 10 molar equivalents relative to tert-butyl alcohol, and the reaction time is 1 to 10 hours; the temperature of the methoxylation reaction is -100 to -20°C, the amount of tert-butyl hypochlorite used is 0.2 to 2.5 molar equivalents relative to compound I; the amount of lithium methoxide used is 1 to 2 molar equivalents relative to compound I, and the reaction is 1 to 6 hours.

[0012] Furthermore, in the reaction of removing the amino protecting group in step S2, the organic solvent is dichloromethane or DMSO that is miscible with water, the amount of the organic solvent used is 1.2 to 100 molar equivalents relative to compound IV, the reaction solvent is one of water, borate buffered saline solution, and phosphate buffered saline solution, the amount used is 2.3 to 16 parts by weight relative to compound IV, the reaction temperature is 25 to 35° C., and the amount of the enzyme used is 0.5 to 1.5 parts by weight relative to compound IV; the amount of hydrochloric acid used in the potassium ion removal reaction is 1 to 3 molar equivalents relative to compound VI, the reaction temperature is -40 to 10° C., and the reaction time is 1 to 8 hours.

[0013] Furthermore, in the condensation reaction of step S3, the molar equivalent of compound VI difluoromethylthioglycolic acid is 0.5 to 3 relative to compound V, the reaction temperature is -60 to -20°C, and the reaction time is 1 to 5 hours.

[0014] The advantages of the present invention are: the method of the present invention is reasonably designed, the reaction operation is simple and reliable, the reaction route is short, it is green and environmentally friendly, the yield is high, the post-processing is easy, and high-purity fluoxetine is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is the gas chromatogram of compound III tert-butyl hypochlorite prepared in Example 1.

[0016] Figure 2 This is the liquid chromatogram of the methoxide of compound IV prepared in Example 1.

[0017] Figure 3 This is the liquid chromatogram of the methoxide deprotected product of Compound V prepared in Example 1.

[0018] Figure 4 It is the liquid chromatogram of compound VIII fluoxetine F3 prepared in Example 1. DETAILED DESCRIPTION

[0019] Example 1

[0020] A method for synthesizing fluoxetine comprises the following steps:

[0021] The first step: Synthesis of compound Ⅲ tert-butyl hypochlorite

[0022] 0.62 g (1.15 mol) of sodium hypochlorite and 17 g (0.23 mol) of tert-butyl alcohol were added to a flask, and the atmosphere was replaced with nitrogen. 1.18 g of glacial acetic acid was added, and the mixture was stirred at -20 °C for 6 h. The mixture was extracted, dried, filtered, and concentrated to obtain 15.6 g of a slightly yellow viscous liquid with a yield of 92%. The purity of tert-butyl hypochlorite was 98% and the residual content of tert-butyl alcohol was determined by GC ( Figure 1 shown).

[0023] In order to compare the synthesis of tert-butyl hypochlorite under different reaction conditions, the reaction conditions such as temperature, amount of sodium hypochlorite, reaction time, etc. in the first step of Example 1 were adjusted and changed. The reaction results are shown in Table 1.

[0024] Table 1: Comparison of yields under different reaction conditions

[0025] Serial number Temperature(℃) Sodium hypochlorite dosage Time (h) Yield (%) First step reaction -20 5 molar equivalent 6 92 Comparison 1 -20 5 molar equivalent 1 19 Comparison 2 0 5 molar equivalent 6 80 Contrast 3 -20 3 molar equivalent 6 75 Contrast 4 -20 10 molar equivalent 6 93 Contrast 5 -40 5 molar equivalent 6 84 Contrast 6 -20 5 molar equivalent 10 89

[0026] Step 2 Synthesis of Compound IV

[0027] 18.0 g (0.03 mol) of compound I was added to a flask, and the atmosphere was replaced with nitrogen. 6.5 g (0.06 mol) of tert-butyl hypochlorite and 2.3 g (0.06 mol) of lithium methoxide were added. After stirring at -80 °C for 5 h, the pH was adjusted to 6-8 with glacial acetic acid, and then saturated sodium chloride was added for extraction, drying, filtering, and concentration to obtain 17.1 g of a white solid with a yield of 95%. The purity of compound IV was 97% and the residual content of the parent nucleus of compound I ( Figure 2 shown).

[0028] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of tert-butyl hypochlorite, amount of lithium methoxide, reaction time, etc. in the second step reaction of Example 1 were changed. The reaction results are shown in Table 2.

[0029] Table 2: Comparison of product yields under different reaction conditions

[0030]

[0031] Step 3 Synthesis of Compound Ⅴ

[0032] 80 ml of water was added to a flask, and then one weight portion of aminoacylase was added, and the pH was adjusted to 7.0 with sodium bicarbonate solution. 16.8 g (0.03 mol) of compound IV dissolved in 26 ml of dichloromethane was slowly added to the reaction solution, and the pH was controlled at about 7.0. After reacting at 25°C for 3 hours, the mixture was filtered, and ethyl acetate was added for extraction. Hydrochloric acid was added dropwise to adjust the pH to 6-8, and the mixture was extracted, filtered, and dried to obtain 15.3 g of compound V with a yield of 91%. The residual content of compound IV in compound V was monitored by HPLC ( Figure 3 shown).

[0033] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, enzyme dosage, organic solvent dosage, reaction solvent dosage, reaction time, etc. in the third step reaction of Example 1 were changed. The reaction results are shown in Table 3.

[0034] Table 3: Comparison of product yields under different reaction conditions

[0035]

[0036] Step 4 Synthesis of Compound VII

[0037] Add 18.0 g (0.1 mol) of compound VI potassium difluoromethylthioglycolate into a flask, add 20 ml of water, and after dissolving, add 62.4 g (0.8 mol) of sodium chloride and about 16.7 ml (0.2 mol) of hydrochloric acid. Control the temperature to -10°C. After reacting for 5 hours, add ethyl acetate to the reaction solution for extraction. Concentrate and dry to obtain 16.9 g of compound VII with a yield of 94%.

[0038] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of sodium chloride, amount of hydrochloric acid, reaction time, etc. in the fourth step of Example 1 were changed. The reaction results are shown in Table 4.

[0039] Table 4: Comparison of product yields under different reaction conditions

[0040] Serial number Temperature(℃) Sodium chloride dosage Hydrochloric acid dosage Time (h) Yield (%) The fourth step reaction -10 8 molar equivalent 2 molar equivalent 5 94 Comparison 1 -10 3 molar equivalent 2 molar equivalent 5 36 Comparison 2 -10 12 molar equivalent 2 molar equivalent 5 95 Contrast 3 -40 8 molar equivalent 2 molar equivalent 5 45 Contrast 4 10 8 molar equivalent 2 molar equivalent 5 48 Contrast 5 -10 8 molar equivalent 1 molar equivalent 5 76 Contrast 6 -10 8 molar equivalent 3 molar equivalent 5 96 Contrast 7 -10 8 molar equivalent 2 molar equivalent 1 28 Contrast 7 -10 8 molar equivalent 2 molar equivalent 8 95

[0041] Step 5 Synthesis of Compound Ⅷ

[0042] 8.56 g (0.02 mol) of compound V and 4.26 g (0.03 mol) of compound VII were added to a flask respectively, the temperature was controlled at -40°C, 6.0 ml (0.04 mol) of phenyl dichlorophosphate and 8.78 ml (0.08 mol) of N-methylmorpholine were added, and the reaction was continued for 3 hours. Hydrochloric acid was added dropwise to adjust the pH to 6-8, ethyl acetate was added to the reaction solution for extraction, and the mixture was concentrated and dried to obtain 6.9 g of compound VIII with a yield of 81%. The purity of compound VIII was 98% (98%) as determined by HPLC. Figure 4 shown).

[0043] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of phenyl dichloride phosphate, amount of N-methylmorpholine, reaction time, etc. in the fifth step of Example 1 were changed. The reaction results are shown in Table 5.

[0044] Table 5: Comparison of product yields under different reaction conditions

[0045]

Claims

1. A method for synthesizing fluoxetine, characterized in that: The following steps are involved: S1. Compound II tert-butyl alcohol is placed in an organic solvent and reacted with sodium hypochlorite to generate compound III tert-butyl hypochlorite, and compound I is dissolved in an organic solvent of dichloromethane, and reacted with compound III tert-butyl hypochlorite to generate compound IV under the action of lithium methoxide; S2. removing the amino protecting group of compound IV dissolved in an organic solvent in the reaction solvent under the action of aminoacylase to obtain compound V, and removing the potassium ion of compound VI difluoromethylthioglycolate potassium salt under the action of hydrochloric acid to generate compound VII; S3. Compound V and compound VII difluoromethylthioglycolic acid are subjected to a condensation reaction to obtain the target compound VIII; the synthetic route of the reaction is as follows: In the formula, R1 is an acyl residue and R2 is a carboxyl protecting group.

2. The method for synthesizing fluoxetine as claimed in claim 1, characterized in that: The reaction temperature of the substitution reaction in step S1 is -40 to 0°C, the amount of sodium hypochlorite used is 3 to 10 molar equivalents relative to tert-butyl alcohol, and the reaction time is 1 to 10 hours; the temperature of the methoxylation reaction is -100 to -20°C, the amount of tert-butyl hypochlorite used is 0.2 to 2.5 molar equivalents relative to compound I; the amount of lithium methoxide used is 1 to 2 molar equivalents relative to compound I, and the reaction is 1 to 6 hours.

3. The method for synthesizing fluoxetine as claimed in claim 1, characterized in that: In the deamino protecting group reaction in step S2, the organic solvent is dichloromethane or DMSO miscible with water, the amount of the organic solvent used is 1.2 to 100 molar equivalents relative to compound IV, the reaction solvent is one of water, borate buffered saline solution, and phosphate buffered saline solution, the amount used is 2.3 to 16 parts by weight relative to compound IV, the reaction temperature is 25 to 35° C., and the amount of the enzyme used is 0.5 to 1.5 parts by weight relative to compound IV; the amount of hydrochloric acid used in the potassium ion removal reaction is 1 to 3 molar equivalents relative to compound VI, the reaction temperature is -40 to 10° C., and the reaction time is 1 to 8 hours.

4. The method for synthesizing fluoxetine as claimed in claim 3, characterized in that: In the condensation reaction of step S3, the molar equivalent of compound VI difluoromethylthioacetic acid is 0.5 to 3 relative to compound V, the reaction temperature is -60 to -20°C, and the reaction time is 1 to 5 hours.

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