A process for the preparation of (s)-oxetan-2-methylamine and its p-toluenesulfonic acid salt

Abstract

The application relates to a preparation method of (S)-oxetan-2-methylamine and a p-toluenesulfonic acid salt thereof. By adopting a specific preparation route, the problem of poisoning of a palladium-carbon catalyst caused by residual sulfur elements is solved, and the use of explosive and highly toxic sodium azide is avoided. The process is safe and reliable, raw materials are low in price, product quality is good, chiral purity is high, and the method is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation, and specifically relates to a method for preparing (S)-oxetane-2-methylamine and its p-toluenesulfonate. Background Technology

[0002] The key to preparing (S)-oxetane-2-methylamine p-toluenesulfonate is to first synthesize (S)-oxetane-2-methylamine.

[0003] (S)-Epoxycyclobutane-2-methylamine is a key intermediate for certain glucagon-like peptide-1 receptor agonists and is used in the synthesis of Danuglipron (PF-06882961), an oral small-molecule GLP-1 receptor agonist developed by Pfizer. This small-molecule drug (PF-06882961) differs from injectable and oral peptide GLP-1 receptor agonists, offering a differentiated and innovative therapy for patients with diabetes and obesity. Currently, the main synthetic routes for (S)-epoxycyclobutane-2-methylamine include the following:

[0004] Patent application WO2018109607A1 discloses the following route one:

[0005]

[0006] Route 1 begins with (S)-benzyloxymethyl ethylene oxide A1, which undergoes ring expansion with trimethyl sulfoxide under alkaline conditions to yield chiral benzyl ethylene oxide A2; further debenzylation yields chiral ethylene oxide methanol A3; then it reacts with methanesulfonyl chloride to generate methanesulfonate A4, which is then replaced with sodium azide to generate chiral butane azide A5, and finally hydrogenated to obtain the target compound A0.

[0007] The first step of this method is a ring-expansion reaction, which expands ethylene oxide into oxetane. In the fourth step, the use of azide compounds poses risks of instability, explosiveness, and high toxicity, resulting in high safe production costs and severely limiting large-scale production.

[0008] Patent CN114728923B discloses the following route two:

[0009]

[0010] Using dibenzylamine as a starting material, a ring-opening reaction is carried out with chiral epichlorohydrin to obtain C2, and then the ring is closed under basic conditions to obtain dibenzylamine chiral epichlorohydrin C3; similarly, compound C3 undergoes a ring-expansion reaction with trimethyl sulfoxide under basic conditions to obtain dibenzylamine chiral oxobutane C4, and finally hydrogenation and debenzylation are carried out to obtain the target compound A0.

[0011] This route has one less reaction step than route one, which avoids the use of explosive and highly toxic sodium azide. However, the ring-opening reaction between dibenzylamine and chiral epichlorohydrin produces side reactions, and the resulting impurities are difficult to separate, resulting in a low yield.

[0012] Patent application CN115991685A discloses the following route three:

[0013]

[0014] Route 3 uses chiral glycidol B1 as the starting material, and prepares compound B2 by protection with vinyl ethyl ether. Compound B3 is prepared by basic ring expansion with trimethyl sulfoxide. Compound B4 is prepared by deprotection. Compound B4 reacts with p-toluenesulfonyl chloride to generate p-toluenesulfonate B5. Then, it is substituted with potassium phthalimide to generate mixture B6. Finally, deprotection is performed to obtain the target compound A0.

[0015] The biggest change in Route 3 compared to Route 1 is that the benzyl protecting group has been replaced with a vinyl ether protecting group; in addition, the easily explosive reagent sodium azide has been replaced with potassium phthalimide.

[0016] This process still has the following problems: First, chiral glycidol is unstable; the 3-hydroxyl group can undergo a ring-opening reaction with the epoxy of another molecule, thus continuing the polymerization into a high molecular weight compound. Polymerization is slow at room temperature. However, during the formation distillation stage, due to the high temperature, it is prone to explosive polymerization, releasing a large amount of heat and causing an explosion. Therefore, chiral glycidol cannot be produced on a large scale, and raw materials are not easily guaranteed. Furthermore, the final step of the process uses easily explosive hydrazine hydrate for deprotection, posing certain safety risks.

[0017] Patent CN 118420569 B reports the fourth synthetic route, with the following reaction formula:

[0018]

[0019] This route is basically the same as route three. Both start with chiral glycidol B1 as the starting material, prepare compound B2 by protection with vinyl ethyl ether, prepare compound B3 by basic ring expansion with trimethyl sulfoxide, prepare compound B4 by deprotection, react compound B4 with methanesulfonyl chloride to generate methanesulfonate (formula IV), then replace it with sodium diformamide to generate compound V, and finally release it to obtain the target compound A0 (formula VI).

[0020] Similarly, this process also suffers from the drawback that chiral glycidol (glycidol) raw materials are not readily available, making industrial-scale production impossible.

[0021] CN 120058644 improved the above route by proceeding through three steps, represented by the following reaction equations:

[0022]

[0023] In the first step, levorotatory epichlorohydrin and bis(tert-butyloxycarbonyl)amine salt undergo a substitution reaction in an organic solvent to generate intermediate 1; in the second step, intermediate 1 and trimethyl sulfoxide undergo a ring-expansion reaction in an organic solvent under the action of a base to generate intermediate 2; in the third step, intermediate 2 is deprotected in an organic solvent under the action of an acid to generate the product.

[0024] The disadvantages of this route are: potassium bis(tert-butyloxycarbonyl)amine is difficult to obtain, and since it is an amide salt, it has low reactivity and the reaction is difficult. During the acidic deprotection reaction of intermediate 2, the oxa-four-membered ring is prone to ring-opening, making product purification difficult and quality hard to guarantee.

[0025] Patent CN117903088A reports a new route that avoids the use of trimethyl sulfoxide for ring expansion reactions, as follows:

[0026]

[0027] Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate (compound VI) reacts with sodium azide to form ethyl (R)-(+)-4-azido-3-hydroxybutyrate (compound VII), which is then reduced with sodium borohydride to give (R)-(+)-4-azido-1,3-dibutanol (compound II). Further reaction with p-toluenesulfonyl chloride yields (R)-(+)-1-azido-4-p-toluenesulfonyloxy-2-butanol (compound III). Substitution with potassium iodide or sodium iodide gives (R)-(+)-1-azido-4-iodo-2-butanol (compound IV), which undergoes cyclization with a base to form (S)-2-azidomethyloxetane (compound V). Finally, hydrogenation yields the target product (S)-oxetane-2-methylamine A0 (compound I).

[0028] Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate can be easily synthesized from ethyl chloroacetoacetate via enzymatic hydrolysis, making the raw materials inexpensive and readily available. However, this process still uses sodium azide, which is explosive and highly toxic, posing safety hazards in production. Furthermore, potassium iodide and sodium iodide are very expensive, resulting in high production costs and weak competitiveness. Therefore, this severely restricts the industrial-scale production of this process.

[0029] Patent CN2025111433279 also reports a new synthesis method, as follows:

[0030]

[0031] (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester (compound A) was cyclized under alkaline conditions to give (R)-(+)-3,4-epoxybutyrate ethyl ester (compound B); then reacted with dibenzylamine to give (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester (compound C); reduced with sodium borohydride to give (R)-(+)-4-dibenzylamino-1,3-dibutanol (compound D); further reacted with p-toluenesulfonyl chloride to give (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol (compound E), then cyclized with a base to give (S)-oxetane-2-dibenzylaminomethyl (compound F); finally hydrogenated under palladium on carbon catalyst to give (S)-oxetane-2-methylamine (compound A0).

[0032] While this route avoids the use of explosive and highly toxic sodium azide, the synthetic route is lengthy. The reduction reaction of sodium borohydride also poses certain safety risks.

[0033] Therefore, in view of the shortcomings of the above synthetic route, there is an urgent need for a safe and low-cost method for preparing (S)-oxetane-2-methylamine. Summary of the Invention

[0034] To address the shortcomings of existing technologies, the technical problem this invention aims to solve is to provide a method for preparing (S)-oxetane-2-methylamine and its p-toluenesulfonate. The method of this invention features a short synthetic route, a safe and reliable process, inexpensive raw materials, high-quality products with high chiral purity and yield, and is suitable for industrial-scale production.

[0035] This invention provides a method for preparing (S)-oxetane-2-methylamine, comprising:

[0036] (1) Reaction of (R)-epoxychloropropane D1, ammonia and benzaldehyde to open the ring yields (R)-1-benzyloxime-3-chloro-2-propanol D2;

[0037] (2) The (R)-1-benzyloxime-3-chloro-2-propanol was cyclized under basic conditions to give (S)-3-benzyloxime-1,2-epoxypropane D3;

[0038] (3) (S)-3-benzyloxime-1,2-epoxypropane and trimethyl sulfoxide were ring expanded under alkaline conditions to obtain (S)-2-benzyloxime methyloxetane D4;

[0039] (4) Under catalytic conditions, (S)-2-benzyloxime methyloxetane was reacted with hydrogen to obtain (S)-oxetane-2-methylamine D5.

[0040] Preferably, the ammonia in step (1) includes one or more of ammonia water and liquid ammonia alcohol solutions; wherein the liquid ammonia alcohol solutions include one or more of ammonia methanol solution, ammonia ethanol solution, and ammonia isopropanol solution.

[0041] Preferably, in step (1), the molar ratio of (R)-epoxychloropropane, ammonia, and benzaldehyde is 1.0:(0.8-1.5):(0.8-1.5). Preferably, in step (1), the reaction is carried out at 35-40℃ for 4-6 hours.

[0042] After the reaction in step (1) is completed, the solvent and water generated in the reaction are distilled under reduced pressure until dry to obtain crude (R)-1-benzyloxime-3-chloro-2-propanol product. Without purification, it is directly added to the next reaction step.

[0043] Preferably, the alkaline condition used in step (2) includes one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0044] Preferably, in step (2), the molar ratio of (R)-1-benzyloxime-3-chloro-2-propanol to the base is (0.8-1.5):1.

[0045] Preferably, the ring-closing reaction temperature in step (2) is 0-50℃, more preferably 10-25℃.

[0046] The reaction time in step (2) is 0.5-2h.

[0047] In steps (1) and (2), the reaction raw materials are mixed at a temperature below 10-20℃.

[0048] Preferably, the alkaline condition used in step (3) includes one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxide.

[0049] The solvent used in step (3) includes tert-butanol.

[0050] Preferably, in step (3), the molar ratio of (S)-3-benzyloxime-1,2-epoxypropane to trimethyl sulfoxide is 1:(1-5), more preferably 1:(1.5-3.5), and even more preferably 1:(2.0-3.0).

[0051] Preferably, the reaction temperature in step (3) is 50-90℃, and more preferably 70-85℃.

[0052] The reaction time in step (3) is 2-8 hours.

[0053] Preferably, the catalyst in step (4) is a palladium-on-carbon catalyst; the solvent used in step (4) includes one or more of methanol, ethanol, isopropanol, and ethyl acetate.

[0054] Preferably, the reaction temperature in step (4) is 0-100℃, more preferably 30-80℃, and the pressure is 0.1-3MPa, more preferably 0.5-1.5 MPa.

[0055] The reaction time in step (4) is 10-25 hours.

[0056] This invention provides a method for preparing (S)-oxetane-2-methylamine p-toluenesulfonate, comprising dissolving (S)-oxetane-2-methylamine prepared by the method in an organic solvent, and forming a salt with p-toluenesulfonic acid to obtain (S)-oxetane-2-methylamine p-toluenesulfonate DO.

[0057] Preferably, the organic solvent includes one or more of methanol, ethanol, and isopropanol; isopropanol is more preferred.

[0058] Preferably, the molar ratio of (S)-oxetane-2-methylamine to p-toluenesulfonic acid is 1:(0.8-1.2), more preferably 1:(0.9-1.0).

[0059] Preferably, the salt formation reaction temperature is 0-60℃, and more preferably 0-20℃.

[0060] The salt formation reaction takes 4-10 hours.

[0061] The reaction formulas for (S)-oxetane-2-methylamine and its p-toluenesulfonate of the present invention are shown below:

[0062] .

[0063] The present invention provides a method for preparing (S)-oxacyclobutane-2-methylamine and its p-toluenesulfonate. By adopting a specific preparation route, it solves the problem of palladium carbon catalyst poisoning caused by residual sulfur, and also avoids the use of easily explosive and highly toxic sodium azide. The process is safe and reliable, and the raw materials are inexpensive, the product quality is good, the chiral purity is high, and it is suitable for industrial-scale production.

[0064] Advantages

[0065] This invention provides a method for preparing (S)-oxetane-2-methylamine and its p-toluenesulfonate. The synthetic route is short, the reaction yield is high, the process is safe and reliable, the raw materials are inexpensive, the product quality is good, the chiral purity is high, and it is suitable for industrial-scale production. Attached Figure Description

[0066] Figure 1 This is the 1H NMR spectrum of (S)-oxetane-2-methylamine obtained in Example 1.

[0067] Figure 2 This is the 1H NMR spectrum of (S)-oxetane-2-methylamine p-toluenesulfonate obtained in Example 1. Detailed Implementation

[0068] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0069] Example 1

[0070] This embodiment provides a method for preparing (S)-oxetane-2-methylamine, the specific steps of which are as follows:

[0071]

[0072] Step 1: Preparation of compound D2. In a 1000 mL reaction flask, add 250 mL of methanol, 111.5 g of benzaldehyde (1.05 mol), and 250 mL of 4M ammonia-methanol solution (1.0 mol). After thorough mixing, cool to 10-15 °C and add 92.5 g of (R)-epimylochloropropane (ee value: 99.8%) dropwise. Control the dropping rate to ensure the reaction solution temperature does not exceed 20 °C. After the addition is complete, maintain the reaction at 35-40 °C for 6 hours. Sample to check if the reaction of raw material D1 is complete. Distill the solvent methanol and the water produced in the reaction under reduced pressure until dry to obtain crude product D2. Without purification, directly add to the next reaction step.

[0073] The second step is the preparation of compound D3. 500 g of dichloromethane was added to the reaction solution from the previous step at room temperature. The mixture was cooled to 12-15°C, and 40 g of sodium hydroxide (1.0 mol) was added in portions. The addition rate was controlled to ensure the reaction solution temperature did not exceed 20°C. After the addition was complete, the mixture was kept at 20-25°C for 1 hour. A sample was taken to confirm the complete conversion of raw material D2 to D3. The reaction was stopped, and the inorganic salts were removed by filtration. The filtrate was washed with 100 mL of water and dried over anhydrous sodium sulfate. The filtrate was filtered again, collected, and concentrated by atmospheric distillation to recover the solvent dichloromethane. The product was then distilled under high vacuum to obtain 150.3 g (0.93 mol) of a pale yellow oil. The combined yield of the two steps was 93.33%. ee value: 99.7%, chemical purity: 99.1%.

[0074] Step 3: Preparation of compound D4. In a 3000 mL reaction flask, 1200 mL of tert-butanol, 253 g of trimethyl sulfoxide (1.15 mol), and 224.5 g of potassium tert-butoxide (2.0 mol) were added. Under nitrogen protection, the temperature was raised to 70 °C, and 80.6 g of compound D3 (0.5 mol) and 250 mL of tert-butanol solution were added dropwise. After the addition was complete, the reaction was maintained at 75-80 °C for 6 hours. The mixture was cooled to room temperature, and 1200 mL of water was added to concentrate and remove the tert-butanol. The residue was extracted with methyl tert-butyl ether (500 mL × 2). The organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, and the methyl tert-butyl ether solvent was recovered by atmospheric distillation. High-vacuum distillation of the product yielded compound D4, a colorless oil, 53.86 g (0.31 mol), yield 61.6%, ee value: 99.6%, chemical purity 98.7%.

[0075] Step 4: Preparation of compound D5. 53.86 g (0.31 mol) of compound D4 was dissolved in 1000 mL of methanol, 3 g of 10% palladium on carbon catalyst was added, hydrogen gas was introduced, the mixture was heated to 65-75 °C, pressurized to 1.0 MPa, and maintained at this temperature and pressure for 20 hours. HPLC analysis was performed until the starting material D4 was completely eliminated. The catalyst was removed by filtration, methanol was removed by atmospheric distillation to dryness, and the product was distilled under reduced pressure to obtain 25.67 g (0.295 mol) of a colorless oily liquid, with a yield of 95.2%.

[0076] The characterization data are as follows:

[0077] 1 H-NMR (CDCl3; 400 MHz): δ 4.76-4.82 (m, 1H), 4.64-4.69 (m, 1H), 4.47-4.52 (m, 1H), 4.87-4.89 (m, 2H), 2.58-2.66 (m, 1H), 2.39-2.47(m, 1H), 1.67(r, 2H).

[0078] Step 5: Preparation of compound D0. Dissolve 53.3 g of monohydrate and 0.28 mol of p-toluenesulfonic acid in 150 mL of isopropanol. Cool to 5-10 °C, and stir while adding 25.67 g of compound D5 (0.295 mol) to 50 mL of isopropanol. Control the dropping rate so that the reaction mixture does not exceed 10 °C. After the addition is complete, maintain the reaction temperature at 0-5 °C for 8 hours. Filter, and wash the filter cake with a small amount of acetone. Dry under vacuum at 50 °C to obtain 66.12 g (0.255 mol) of product D0. Yield: 86.4%, ee value: 99.9%, chemical purity: 99.6%.

[0079] The characterization data are as follows: 1H-NMR (DMSO; 400 MHz): δ 7.91 (br, 3H), 7.48-7.51 (m,2H), 7.12-7.14 (m, 2H), 4.86-4.89 (m, 1H), 4,44-4.58 (m, 2H), 3.01-3.14 (m,2H), 2.66-2.67 (m, 1H), 2.44-2.51 (m, 1H), 2.29 (s, 3H);

[0080] The applicant declares that the preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0081] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing (S)-oxetane-2-methylamine, comprising: (1) Reaction of (R)-epoxychloropropane, ammonia and benzaldehyde to open the ring yields (R)-1-benzyloxime-3-chloro-2-propanol; (2) The (R)-1-benzyloxime-3-chloro-2-propanol was subjected to a cyclization reaction under basic conditions to obtain (S)-3-benzyloxime-1,2-epoxypropane; (3) (S)-3-benzyloxime-1,2-epoxypropane and trimethyl sulfoxide are ring-expanded under alkaline conditions to obtain (S)-2-benzyloxime methyloxetane; (4) Under catalytic conditions, (S)-2-benzyloxime methyloxetane was reacted with hydrogen to obtain (S)-oxetane-2-methylamine.

2. The preparation method according to claim 1, characterized in that, The ammonia in step (1) includes one or more of ammonia water and liquid ammonia alcohol solutions; wherein the liquid ammonia alcohol solutions include one or more of ammonia methanol solution, ammonia ethanol solution, and ammonia isopropanol solution. In step (1), the molar ratio of (R)-epoxychloropropane, ammonia, and benzaldehyde is 1.0:(0.8-1.5):(0.8-1.5). The reaction in step (1) is carried out at 35-40℃ for 4-6 hours.

3. The preparation method according to claim 1, characterized in that, The alkaline conditions used in step (2) include one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. In step (2), the molar ratio of (R)-1-benzyloxime-3-chloro-2-propanol to the base is (0.8-1.5):1; The ring-closing reaction temperature in step (2) is 0-50℃.

4. The preparation method according to claim 1, characterized in that, The alkaline conditions used in step (3) include one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxide. In step (3), the molar ratio of (S)-3-benzyloxime-1,2-epoxypropane to trimethyl sulfoxide is 1:(1-5).

5. The preparation method according to claim 1, characterized in that, The reaction temperature in step (3) is 50-90℃.

6. The preparation method according to claim 1, characterized in that, The catalyst in step (4) is a palladium-on-carbon catalyst; the solvent used in step (4) includes one or more of methanol, ethanol, isopropanol, and ethyl acetate.

7. The preparation method according to claim 1, characterized in that, In step (4), the reaction temperature is 0-100℃ and the pressure is 0.1-3 MPa.

8. A method for preparing (S)-oxetane-2-methylamine p-toluenesulfonate, comprising dissolving (S)-oxetane-2-methylamine prepared by the method of claim 1 in an organic solvent, and forming a salt with p-toluenesulfonic acid to obtain (S)-oxetane-2-methylamine p-toluenesulfonate.

9. The preparation method according to claim 8, characterized in that, The organic solvent includes one or more of methanol, ethanol, and isopropanol; the molar ratio of (S)-oxetane-2-methylamine and p-toluenesulfonic acid is 1:(0.8-1.2).

10. The preparation method according to claim 8, characterized in that, The salt formation reaction temperature is 0-60℃.

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