Process method for synthesizing trans-3-hydroxycyclobutanecarboxylic acid

Abstract

The invention discloses a process method for synthesizing trans-3-hydroxy cyclobutane formic acid, which comprises the following steps: by taking 3-oxo-cyclobutane formate as a raw material, reducing carbonyl by adopting aluminum triisopropoxide under the catalysis of tri (pentafluorophenyl) borane to generate a cis-trans isomer with trans as a main component, and reacting with a solvent to obtain trans-3-hydroxy cyclobutane formic acid. The preparation method comprises the following steps: preparing a 3-hydroxycyclobutane formic acid cis-trans mixture, hydrolyzing in alkali to obtain the 3-hydroxycyclobutane formic acid cis-trans mixture, salifying and purifying the 3-hydroxycyclobutane formic acid cis-trans mixture and an alpha-methylbenzylamine compound to obtain trans-3-hydroxycyclobutane formic acid amine salt, and dissociating to obtain the trans-3-hydroxycyclobutane formic acid. According to the method, the selectivity of a trans-product during carbonyl reduction is improved, cis-trans isomers are separated in a salifying manner, single trans-3-hydroxycyclobutanecarboxylic acid is purified, the process conditions are mild, the operation is simple and convenient, and the method is suitable for process production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid. Background Art

[0002] Trans-3-Hydroxycyclobutanecarboxylic acid, English name trans-3-Hydroxycyclobutanecarboxylic acid, CAS: 1268521-85-2, due to its unique stereochemical structure, is used in various fine chemicals, drug synthesis and biomedicine fields, such as butorphanol metabolites and NTRK kinase inhibitors. The market demand for this product is increasing and the prospects are very good.

[0003] At present, this compound has shown more and more application value. However, there are few synthetic methods of trans-3-hydroxycyclobutanecarboxylic acid reported in the literature, and there are also few synthetic methods of its intermediate trans-3-hydroxycyclobutanecarboxylate, mainly the following two:

[0004] The first method is to use the polarity difference between cis and trans isomers to separate the trans product. The document European Journal of Organic Chemistry, 2024, 27, e202400493 (1 of 9) reported that 3-oxocyclobutanecarboxylate was reduced with sodium borohydride to obtain a cis-dominant cis-trans isomer mixture with a cis / trans ratio of 4 / 1. Patent US2009 / 118287 discloses that 3-hydroxycyclobutanecarboxylic acid methyl ester is used as a raw material, reacted with benzyl bromide under the action of NaH, and the corresponding trans product is obtained by column chromatography separation, with a yield of only 15.4%. The cis-trans isomer separation method in the existing literature has a low yield of the trans product, is difficult to purify, and is not easy to scale up production.

[0005] The second method is to use configuration inversion to convert the cis isomer into the trans isomer. Patent WO2015 / 66413 uses cis-3-hydroxycyclobutanecarboxylic acid methyl ester as raw material, reacts with methanesulfonyl chloride, and then reacts with potassium acetate at 120°C for 21 hours to obtain trans-3-acetoxycyclobutanecarboxylic acid methyl ester by configuration inversion, and then removes the acetyl group under the action of sodium methoxide to obtain trans-3-hydroxycyclobutanecarboxylic acid. This method requires a cis raw material with high purity, and during the reaction with potassium acetate at 120°C, an elimination reaction is easily generated to generate cyclobut-2-ene-1-carboxylic acid methyl ester, which is not easy to separate and purify from the product.

[0006] Patent CN108129288 uses 3-oxocyclobutanecarboxylate as a raw material, reduces it with a reducing agent to obtain a single cis-3-hydroxycyclobutanecarboxylate, and then undergoes a three-step reaction of Mitsunobu reaction and hydrolysis to obtain trans-3-hydroxycyclobutanecarboxylic acid. This method uses a reducing agent (lithium triethylborohydride, lithium tri-tert-butoxyaluminum hydride or lithium tri-sec-butylborohydride), which is expensive and flammable, and has a high raw material cost. A large amount of waste solid containing triphenylphosphine oxide is generated during the Mitsunobu reaction, which is not environmentally friendly and is not suitable for industrial production.

[0007] Therefore, it is necessary to develop a suitable process method to solve the problem of effectively generating more trans products or how to separate cis and trans isomers to facilitate industrial production. Summary of the invention

[0008] In order to overcome the above problems, the present invention discloses a process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid. The method uses 3-oxocyclobutanecarboxylic acid ester as a raw material, uses aluminum triisopropoxide to reduce the carbonyl under the catalysis of tri(pentafluorophenyl)borane, generates trans-based cis-trans isomers, and then hydrolyzes in an alkali to obtain a cis-trans mixture of 3-hydroxycyclobutanecarboxylic acid, and then purifies it by salting with α-methylbenzylamine compounds to obtain trans-3-hydroxycyclobutanecarboxylic acid amine salt, and then dissociates to obtain trans-3-hydroxycyclobutanecarboxylic acid. The method improves the selectivity of the trans product during carbonyl reduction, separates cis-trans isomers by salting, purifies single trans-3-hydroxycyclobutanecarboxylic acid, has mild process conditions, is easy to operate, and is suitable for process production.

[0009] The present invention provides a process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid, which is expressed by the following equation:

[0010]

[0011] The steps include:

[0012] In the first step, 3-oxocyclobutanecarboxylate and aluminum triisopropoxide are subjected to carbonyl reduction under the catalysis of tri(pentafluorophenyl)borane to obtain trans-based 3-hydroxycyclobutanecarboxylate (compound 1);

[0013] In the second step, the trans-form-based 3-hydroxycyclobutanecarboxylic acid ester (compound 1) is hydrolyzed with an alkaline aqueous solution to obtain the trans-form-based 3-hydroxycyclobutanecarboxylic acid (compound 2);

[0014] In the third step, the trans-form-based 3-hydroxycyclobutanecarboxylic acid (compound 2) is salified with an α-methylbenzylamine compound in an organic solvent, and trans-3-hydroxycyclobutanecarboxylic acid amine salt (compound 3) is obtained by filtration; then dilute hydrochloric acid is added to water to adjust the pH value to acidic, and trans-3-hydroxycyclobutanecarboxylic acid is obtained by treatment.

[0015] Furthermore, in the first step, the molar ratio of 3-oxocyclobutanecarboxylate, aluminum triisopropoxide and tris(pentafluorophenyl)borane is 1.0:0.4-0.5:0.03-0.05.

[0016] Furthermore, in the first step, the reaction temperature is 0-25°C; and the reaction solvent is selected from isopropanol.

[0017] Furthermore, in the second step, the alkaline aqueous solution is selected from KOH or NaOH aqueous solution; and the reaction temperature is 20-30°C.

[0018] Furthermore, in the third step, the α-methylbenzylamine compound is selected from D-α-methylbenzylamine, L-α-methylbenzylamine or DL-α-methylbenzylamine, preferably L-α-methylbenzylamine.

[0019] Furthermore, in the third step, the molar ratio of the trans-mainly 3-hydroxycyclobutanecarboxylic acid (compound 2) and the α-methylbenzylamine compound is 1.0:1.0.

[0020] Furthermore, in the third step, the organic solvent is selected from acetone; and the reaction temperature is 20-80°C.

[0021] Furthermore, in the third step, the pH is adjusted to 1-2 with dilute hydrochloric acid, extracted with dichloromethane, concentrated, and slurried with n-heptane to obtain trans-3-hydroxycyclobutanecarboxylic acid (compound 4).

[0022] The present invention has the following advantages:

[0023] 1. Using 3-oxocyclobutanecarboxylate as raw material, under the action of aluminum isopropoxide and tri(pentafluorophenyl)borane, the trans selectivity is improved, and the trans-based reduction product is obtained, which greatly improves the yield of preparing trans-3-hydroxycyclobutanecarboxylate.

[0024] 2. A method for purifying the cis-trans mixture by salt formation with α-methylbenzylamine compounds is used to obtain a single trans salt, which is then dissociated to obtain trans-3-hydroxycyclobutanecarboxylic acid with a GC purity of >98%. No column chromatography is required, thus solving the problem of difficulty in separating and purifying cis-trans isomers.

[0025] 3. The raw materials of this method are cheap and easy to obtain, the operation is simple, the yield is high, it is safe and environmentally friendly, and it is suitable for process production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 For the product trans-3-hydroxycyclobutanecarboxylic acid in Example 4 1 HNMR spectrum; Specific embodiments

[0027] Example 1

[0028] Under nitrogen protection, aluminum triisopropoxide (40.8 g, 0.2 mol), tri(pentafluorophenyl)borane (10.2 g, 0.02 mol) and 150 mL of isopropanol were added to the reaction bottle, and 3-oxocyclobutanecarboxylic acid methyl ester (51.2 g, 0.4 mol) / 100 mL of isopropanol solution was added dropwise at 0-5 ° C. After the addition was completed, the mixture was stirred at room temperature for 16 hours. The raw material 3-oxocyclobutanecarboxylic acid methyl ester was controlled to be <1% in GC, and the cis-trans isomers of compound 1, 3-hydroxycyclobutanecarboxylic acid methyl ester, were 96.9% (trans / cis=74.4 / 25.6), and the reaction mixture was stirred at 20-30 ° C. 80 mL of 30% NaOH solution was added dropwise at 400 ° C. After the addition was completed, the mixture was kept warm and stirred for 5 hours. The compound 1 was controlled to be less than 1% in GC. The isopropanol was concentrated under reduced pressure, 200 mL of dichloromethane was added, and 10% hydrochloric acid was added dropwise at 0-10 ° C. to adjust the pH to 4-5. The layers were separated, and the aqueous layer was extracted with dichloromethane twice, 200 mL each time. The organic layers were combined and washed with saturated brine. After the organic layer was concentrated under reduced pressure, it was slurried with 100 mL of n-heptane, filtered and dried to obtain 41.8 g of off-white solid compound 2, GC: 97.3% (trans / cis=74.2 / 25.8), and the yield was 90.2%.

[0029] Example 2

[0030] Under nitrogen protection, aluminum triisopropoxide (32.7 g, 0.16 mol), tri(pentafluorophenyl)borane (6.2 g, 0.012 mol) and 150 mL of isopropanol were added to the reaction bottle, and ethyl 3-oxocyclobutanecarboxylate (56.8 g, 0.4 mol) / 100 mL of isopropanol solution was added dropwise at 0-5 ° C. After the addition was completed, the mixture was stirred at room temperature for 16 hours. The raw material 3-oxocyclobutanecarboxylic acid methyl ester was controlled to be <1% in GC, and the cis-trans isomers of compound 1, 3-hydroxycyclobutanecarboxylic acid methyl ester, were 96.4% (trans / cis=73.7 / 26.3), 20-30 ° C. 80 mL of 30% NaOH solution was added dropwise at 400 ° C. After the addition was completed, the mixture was kept warm and stirred for 5 hours. The compound 1 was controlled to be <1% in GC. The isopropanol was concentrated under reduced pressure, 200 mL of dichloromethane was added, and 10% hydrochloric acid was added dropwise at 0-10 ° C. to adjust the pH to 4-5. The layers were separated, and the aqueous layer was extracted with dichloromethane twice, 200 mL each time. The organic layers were combined and washed with saturated brine. After the organic layer was concentrated under reduced pressure, 100 mL of n-heptane was used for slurrying, and the mixture was filtered and dried to obtain 41.1 g of off-white solid compound 2, GC: 97.0% (trans / cis=73.4 / 26.6), and the yield was 88.6%.

[0031] Example 3

[0032] Compound 2 (GC 97.3% (trans / cis = 74.2 / 25.8) (41.8 g, 0.36 mol) and 400 mL of acetone were added to the reaction bottle, stirred until completely dissolved, L-α-methylbenzylamine (43.6 g, 0.36 mol) / 230 mL of acetone solution was added dropwise, and a white solid was gradually precipitated. The mixture was heated to 70-80° C. and stirred for 1 hour, the solid was completely dissolved, and the system was clear. The temperature was slowly cooled to room temperature to precipitate a white solid, which was filtered to obtain 47.2 g of white solid compound 3 trans-3-hydroxycyclobutanecarboxylic acid L-α-methylbenzylamine salt. 1 HNMR purity: 98.9% (trans / cis=72 / 1), yield 55.3%.

[0033] Compound 2 (1 eq) and α-methylbenzylamine (1 eq) obtained by the method of Example 1 were salted in different solvents. The experimental results are as follows:

[0034]

[0035] Example 4

[0036] 70 mL of water and compound 3 (47.2 g, 0.20 mol, trans / cis = 72 / 1) were added to the reaction flask, stirred, 10-20 ° C, 45 mL of 20% HCl solution was added dropwise, pH = 1-2, dichloromethane extraction (100 mL × 3), the organic layers were combined, washed with saturated brine, the organic layer was concentrated under reduced pressure, 40 mL of n-heptane was added and beaten for 1 hour, filtered, and white solid trans-3-hydroxycyclobutanecarboxylic acid 20.3 g was obtained, GC: 98.8%, yield 87.3%; 1 H-NMR characterization spectrum Figure 1 shown.

[0037] Comparative Example 1

[0038] Under nitrogen protection, aluminum triisopropoxide (40.8 g, 0.2 mol) and 150 mL of isopropanol were added to the reaction bottle, and 3-oxocyclobutanecarboxylic acid methyl ester (51.2 g, 0.4 mol) / 100 mL of isopropanol solution was added dropwise at 0-5 ° C. After the addition was completed, the mixture was stirred at room temperature for 16 hours. The raw material 3-oxocyclobutanecarboxylic acid methyl ester was controlled to be <1% in GC, and the cis-trans isomers of compound 1, 3-hydroxycyclobutanecarboxylic acid methyl ester, were 97.6% (trans / cis=55.3 / 44.7). 80 mL of the mixture was added dropwise at 20-30 ° C. The mixture was added with 30% NaOH solution, and after the addition was completed, the mixture was kept warm and stirred for 5 hours. The compound 1 was controlled to be <1% in GC. The isopropanol was concentrated under reduced pressure, 200 mL of dichloromethane was added, and 10% hydrochloric acid was added dropwise at 0-10°C to adjust the pH to 4-5. The layers were separated, and the aqueous layer was extracted with dichloromethane twice, 200 mL each time. The organic layers were combined and washed with saturated brine. After the organic layer was concentrated under reduced pressure, it was slurried with 100 mL of n-heptane and filtered to obtain 42.5 g of off-white solid compound 2, GC: 98.2% (trans / cis=54.8 / 45.2), and the yield was 91.6%.

[0039] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid, characterized in that: The steps include: In the first step, 3-oxocyclobutanecarboxylate and aluminum triisopropoxide are subjected to carbonyl reduction under the catalysis of tri(pentafluorophenyl)borane to obtain 3-hydroxycyclobutanecarboxylate which is mainly trans-form; In the second step, the trans-form-based 3-hydroxycyclobutanecarboxylic acid ester is hydrolyzed with an alkaline aqueous solution to obtain the trans-form-based 3-hydroxycyclobutanecarboxylic acid; In the third step, the trans-based 3-hydroxycyclobutanecarboxylic acid and α-methylbenzylamine compounds are salted in an organic solvent, and trans-3-hydroxycyclobutanecarboxylic acid amine salt is obtained by filtration; then dilute hydrochloric acid is added to water to adjust the pH value to acidic, and trans-3-hydroxycyclobutanecarboxylic acid is obtained by treatment.

2. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the first step, the molar ratio of 3-oxocyclobutanecarboxylate, aluminum triisopropoxide and tri(pentafluorophenyl)borane is 1.0:0.4-0.5:0.03-0.

05.

3. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the first step, the reaction solvent is selected from isopropanol; and the reaction temperature is 0-25°C.

4. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the second step, the alkaline aqueous solution is selected from KOH or NaOH aqueous solution.

5. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the second step, the reaction temperature is 20-30°C.

6. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the third step, the α-methylbenzylamine compound is selected from D-α-methylbenzylamine, L-α-methylbenzylamine or DL-α-methylbenzylamine.

7. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the third step, the molar ratio of the trans-based 3-hydroxycyclobutanecarboxylic acid and the α-methylbenzylamine compound is 1.0:1.

0.

8. The process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid according to claim 1, characterized in that: In the third step, the organic solvent is selected from acetone; and the reaction temperature is 20-80°C.

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