Synthetic method of 3-aminooxetane-3-formic acid

Abstract

The invention belongs to the field of medicine synthesis, and relates to a synthesis method of a medicine intermediate 3-aminooxetane-3-formic acid. The method has the advantages of cheap and easily available raw materials, non-toxic intermediate products and high yield of final products, and has industrial production prospects.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing 3-aminooxetane-3-carboxylic acid. Background Art

[0002] 3-Aminooxetane-3-carboxylic acid is an important biopharmaceutical intermediate and can be widely used in the synthesis of various drugs. It has a small molecular weight and unique structure, and can be derived into a variety of downstream products, so it has a wide range of uses.

[0003] There are few literatures reporting the synthesis of this compound. One of them is reported by Kozikowski et al. in 1991. They used oxocyclobutanone as the starting material to make aminonitrile under the action of sodium cyanide, and then hydrolyzed and hydrogenated to obtain the product. This method uses highly toxic sodium cyanide, which limits its application. The specific synthesis route is as follows:

[0004]

[0005] In addition, CN103408511A adopts the same route, which replaces sodium cyanide with cuprous cyanide. Although the toxicity is reduced, cyanide ions are still released during the reaction, which is also extremely dangerous.

[0006] In addition, the price of the starting material oxocyclobutanone is relatively expensive, and the overall production cost is high. Therefore, more research on the synthesis of 3-aminooxetane-3-carboxylic acid is needed to meet market demand. Summary of the invention

[0007] The synthetic route of 3-aminooxetane-3-carboxylic acid provided by the present invention is the first to be discovered by the present invention. Compared with the currently reported literature, our advantages are extremely obvious. First, the starting material Tris used by us is cheap and easily available, the synthetic route is novel, the reagents used in the entire synthetic process are all cheap and easily available reagents, and the post-treatment is relatively simple.

[0008] The present invention provides a method for synthesizing 3-aminooxetane-3-carboxylic acid, comprising the following synthesis steps:

[0009]

[0010] S1: Using 2-amino-2-(hydroxymethyl)propane-1,3-diol as a starting material, under the action of an amino protecting group, performing double protecting group protection on the amino group to obtain 2-double protected amino-2-(hydroxymethyl)propane-1,3-diol;

[0011] S2: Under alkaline conditions, in a certain solvent, the 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol obtained in S1 is cyclized to (3-(diprotected amino)oxetan-3-yl)methanol under the action of an activator;

[0012] S3: (3-(diprotected amino)oxetane-3-yl)methanol obtained in S2 is reacted in the presence of an oxidizing agent to obtain (3-(diprotected amino)oxetane-3-carboxylic acid;

[0013] S4: The 3-(diprotected amino)oxetane-3-carboxylic acid obtained in S3 is subjected to a deprotection method to obtain the product 3-aminooxetane-3-carboxylic acid.

[0014] In some embodiments, the amino protecting group in S1 is Bn, Cbz, Fmoc, PMB or Alloc.

[0015] In some embodiments, the amino protecting group in S1 is Bn.

[0016] Bn is benzyl; Cbz is benzyloxycarbonyl; Fmoc is fluorenylmethoxycarbonyl; PMB is p-methoxybenzyl; Alloc is allyloxycarbonyl.

[0017] In some embodiments, in S1, the molar ratio of 2-amino-2-(hydroxymethyl)propane-1,3-diol to the amino protecting group is 1:(2.1-5).

[0018] In some embodiments, in S1, the molar ratio of 2-amino-2-(hydroxymethyl)propane-1,3-diol to the amino protecting group is 1:(2.1-3).

[0019] In some embodiments, the base in S2 is an inorganic base.

[0020] In some embodiments, the inorganic base is one or more of an alkali metal hydroxide salt or an alkali metal carbonate salt.

[0021] In some embodiments, the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

[0022] In some embodiments, the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0023] In some embodiments, in S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the base is 1:(1-4).

[0024] In some embodiments, in S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the base is 1:(1.5-2).

[0025] In some embodiments, the activating agent in S2 is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, benzenesulfonyl chloride or trifluoroacetic anhydride.

[0026] In some embodiments, the activating agent is p-toluenesulfonyl chloride, benzenesulfonyl chloride, or trifluoroacetic anhydride.

[0027] In some embodiments, in S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the activator is 1:(0.6-1.2).

[0028] In some embodiments, in S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the activator is 1:(0.8-1).

[0029] In some embodiments, the solvent in S2 is an organic solvent containing water.

[0030] In some embodiments, the solvent in S2 contains water by volume in a percentage of 20v% to 80v%.

[0031] In some embodiments, the solvent in S2 contains water in a volume percentage of 40v% to 60v%

[0032] In some embodiments, the solvent in S2 contains 50 v% water.

[0033] In some embodiments, the solvent in S2 is a mixed system of an alcohol solvent and water, a mixed system of THF and water, or a system of dioxane and water; preferably, the solvent in S2 is a mixed system of THF and water.

[0034] In some embodiments, the oxidant in S3 is selected from Jones oxidant, potassium permanganate, IBX, DMP, Oxone.

[0035] IBX is 2-iodobenzoic acid; DMP is Dess-Martin periodinane; Oxone is potassium peroxydisulfate complex salt.

[0036] In some embodiments, in S3, the molar ratio of (3-(diprotected amino)oxetan-3-yl)methanol to the oxidant is 1:(2-5).

[0037] In some embodiments, in S3, the molar ratio of (3-(diprotected amino)oxetan-3-yl)methanol to the oxidant is 1:(3-4).

[0038] Beneficial Effects

[0039] 1. The raw materials of the method of the present invention are cheap and easily available, the intermediate products are non-toxic, and there is no need to introduce amino groups by using toxic raw materials such as cyanide.

[0040] 2. In the present invention, during the cyclization, the amino group is double-protected, so that the yield of the final cyclization product is high and has the prospect of industrial production.

[0041] Terminology

[0042] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0043] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0044] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0045] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0046] In the following, all numbers disclosed herein are approximate, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% is explicitly disclosed, where "+ / -" means plus or minus.

[0047] v% is volume percentage. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is the LC-MS diagram of the Boc-protected intermediate cyclization. DETAILED DESCRIPTION

[0049] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0050] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0051] Route design:

[0052] The initial design route of the present invention is as follows:

[0053]

[0054] The inventors designed a process of using 2-amino-2-(hydroxymethyl)propane-1,3-diol as a starting material to obtain the product 3-aminooxetane-3-carboxylic acid by cyclization, which not only avoids the use of cyanide, but also makes the raw materials cheap and easily available, and the entire route has the potential for industrialization.

[0055] Research experiment 1: Selection of Boc as the amino protecting group

[0056]

[0057] Boc is tert-butyloxycarbonyl.

[0058] S1: Weigh Tris (tris(hydroxymethylaminomethane, 50.00 g, 412.76 mmol) and add it to acetonitrile (100 mL), then add saturated sodium bicarbonate solution (50 mL), stir at room temperature, then slowly drop Boc anhydride (117.11 g, 536.59 mmol), stir and react at room temperature overnight; post-treatment: concentrate under reduced pressure, extract with dichloromethane (100 mL), wash twice with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 83.12 g of the product, with a yield of 91.02%.

[0059] S2: Weigh (Boc)Tris (83.12 g, 375.68 mmol) and add it to acetonitrile (100 mL), then add a solution of sodium hydroxide (30.05 g, 751.36 mmol) in water (50 mL), slowly dropwise add a solution of TsCl (64.46 g, 338.11 mmol) in acetonitrile (100 mL), and continue stirring at room temperature overnight. Post-treatment: concentrate under reduced pressure, extract with dichloromethane (100 mL), wash twice with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 29.00 g of the product with a yield of 37.98%.

[0060] S3: Weigh tert-butyl (3-(hydroxymethyl)oxetane-3-yl)carbamate (29.00 g, 142.69 mmol) and add it to water, then add saturated sodium bicarbonate solution (100 mL), and finally add potassium permanganate (180.04 g, 1.14 mol) in batches, and react at room temperature overnight. Post-treatment: 2M hydrochloric acid adjusts pH to 4-6, extracts with dichloromethane (100 mL), washes twice with saturated brine (50 mL), dries over anhydrous sodium sulfate, and concentrates under reduced pressure to obtain 13.07 g of the product, with a yield of 42.17%.

[0061] S4: Weigh 3-((tert-butyloxycarbonyl)amino)oxetane-3-carboxylic acid (1.00 g, 4.60 mmol) and add it to dichloromethane (5 mL), then add trifluoroacetic acid, stir overnight at room temperature, take a sample and LCMS control, it is found that there is no product peak in the reaction solution, mainly the ring-opening byproduct. LCMS Figure 1 .

[0062] Research Experiment 2: Selection of Bn as the amino protecting group

[0063]

[0064] S1: Weigh Tris (10.00 g, 82.55 mmol), benzaldehyde (9.64 g, 90.81 mmol), and acetic acid (7.44 g, 123.83 mmol) respectively, add them to tetrahydrofuran (50 mL), stir at room temperature, and finally add sodium cyanoborohydride (7.78 g, 123.83 mmol). After the addition, stir at room temperature for about 24 hours. Stop stirring, concentrate the reaction solution under reduced pressure, add saturated sodium bicarbonate solution to adjust the pH to alkaline, extract with dichloromethane (50 mL), wash once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (13.78 g, 79.01%).

[0065] S2: Weigh 2-(benzylamino)-2-(hydroxymethyl)propane-1,3-diol (2.50 g, 11.83 mmol) and add it to tetrahydrofuran (15 mL) and water (15 mL), then add sodium hydroxide (520.64 mg, 13.02 mmol), stir at room temperature, and finally add TsCl (2.03 g, 10.65 mmol) in batches, stir overnight at room temperature. DCM extraction, washing with brine, drying with sodium sulfate, concentrating under reduced pressure, and silica gel column chromatography to obtain about 0.61 g of the target compound and another impurity of 1.21 g.

[0066] In the above route, S2 can obtain the target product, but the yield is low, and the impurities obtained by the reaction are difficult to separate and purify, which is not suitable for industrial production. Therefore, the entire route is not suitable for industrialization.

[0067] New design ideas:

[0068]

[0069] S1: Using 2-amino-2-(hydroxymethyl)propane-1,3-diol as a starting material, under the action of an amino protecting group, performing double protecting group protection on the amino group to obtain 2-double protected amino-2-(hydroxymethyl)propane-1,3-diol;

[0070] S2: Under alkaline conditions, in a certain solvent, the 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol obtained in S1 is cyclized to (3-(diprotected amino)oxetan-3-yl)methanol under the action of an activator;

[0071] S3: (3-(diprotected amino)oxetane-3-yl)methanol obtained in S2 is reacted in the presence of an oxidizing agent to obtain (3-(diprotected amino)oxetane-3-carboxylic acid;

[0072] S4: The 3-(diprotected amino)oxetane-3-carboxylic acid obtained in S3 is subjected to a deprotection method to obtain the product 3-aminooxetane-3-carboxylic acid.

[0073] Preparation method of the present invention:

[0074] Example 1

[0075]

[0076] S1: Weigh Tris (100.00 g, 825.52 mmol) and add it to DMF (300 mL), then add potassium carbonate (342.27 g, 2.48 mol), and finally slowly add benzyl chloride (229.89 g, 1.82 mol) dropwise. After the addition is complete, react at room temperature for about 24 hours.

[0077] Post-treatment: add water (1 L), stir at room temperature overnight, filter with suction, add ethyl acetate to the filter cake to slurry, and the product can be obtained as a white solid (231 g), with a yield of 92.85%.

[0078] S2: Weigh 2-(dibenzylamino)-2-(hydroxymethyl)propane-1,3-diol (231.00 g, 766.46 mmol) and add it to a solution of THF (1.2 L) and sodium hydroxide (45.98 g) in water (1.2 L), place it in an ice bath and stir, then add p-toluenesulfonyl chloride (138.81 g, 728.14 mmol) in batches and stir at 0°C overnight.

[0079] Post-treatment: add water (8V), extract with ethyl acetate (3V x 2), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound as a colorless oily liquid (196 g), with a yield of 90.24%.

[0080] S3: Weigh (3-(dibenzylamino)oxetane-3-yl) (196 g, 691.7 mmol) and add it to acetone (1.1 L), add Jones periodic agent (3 eq), and stir at room temperature overnight.

[0081] Post-treatment: concentrate to dryness under reduced pressure, then adjust the reaction pH to 6-7 with sodium bicarbonate, a large amount of white solid precipitates, filter, and wash the filter cake with ice water to obtain the title compound as a white solid 139 g, yield 67.6%.

[0082] S4: 3-(Dibenzylamino)oxetane-3-carboxylic acid (139 g, 467.5 mmol) was dissolved in water (5 V) and anhydrous methanol (5 V), and then 10% palladium carbon (6.80 g) was added. The mixture was stirred under a hydrogen balloon atmosphere and reacted overnight.

[0083] Post-treatment: filtration, the filter cake was rinsed with anhydrous methanol / water, the filtrate was concentrated under reduced pressure and then recrystallized with acetonitrile to obtain the title compound as a white solid (49.60 g), with a yield of 90.6%.

[0084] Research on the preparation method of the present invention:

[0085] 1. Study on the influence of different activators on the reaction of the present invention:

[0086] The activating agent p-toluenesulfonyl chloride in step S2 of Example 1 was replaced by: methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride and trifluoroacetic anhydride (TFAA). Results: Different activating agents have an effect on the final yield. The yield of the product obtained by p-toluenesulfonyl chloride, benzenesulfonyl chloride and trifluoroacetic anhydride (TFAA) is more than 3 times the yield of the product obtained by methanesulfonic acid chloride and methanesulfonic anhydride.

[0087] 2. Study on the effects of different bases and solvents on the reaction:

[0088] The sodium hydroxide and water in step S2 of Example 1 were replaced by triethylamine / DCM, triethylamine / THF, DIEA / DCM, DBU / THF, potassium hydroxide / THF / H2O, and DBU / THF / H2O, respectively. Results: The reaction effect of using an inorganic base, such as sodium hydroxide and potassium hydroxide, in combination with an aqueous solvent system, such as tetrahydrofuran / water, was better than that of an organic base with a non-aqueous organic solvent system, and the product yield of the sodium hydroxide / potassium hydroxide and tetrahydrofuran / water system was more than 7 times that of DBU / THF.

[0089] 3. Study on the effect of different base equivalents and different temperatures on the reaction:

[0090] The amount of sodium hydroxide and p-toluenesulfonyl chloride in step S2 of Example 1 was changed, and the reaction was studied at different temperatures. The results are shown in Table 1.

[0091] Table 1

[0092]

[0093]

[0094] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for synthesizing 3-aminooxetane-3-carboxylic acid, characterized in that: The synthesis steps include: S1: Using 2-amino-2-(hydroxymethyl)propane-1,3-diol as a starting material, under the action of an amino protecting group, performing double protecting group protection on the amino group to obtain 2-double protected amino-2-(hydroxymethyl)propane-1,3-diol; S2: Under alkaline conditions, in a certain solvent, the 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol obtained in S1 is cyclized to (3-(diprotected amino)oxetan-3-yl)methanol under the action of an activator; S3: (3-(diprotected amino)oxetane-3-yl)methanol obtained in S2 is reacted in the presence of an oxidizing agent to obtain (3-(diprotected amino)oxetane-3-carboxylic acid; S4: The 3-(diprotected amino)oxetane-3-carboxylic acid obtained in S3 is subjected to a deprotection method to obtain the product 3-aminooxetane-3-carboxylic acid.

2. The synthesis method according to claim 1, characterized in that The amino protecting group in S1 is Bn, Cbz, Fmoc, PMB or Alloc; preferably, the amino protecting group in S1 is Bn.

3. The synthesis method according to claim 1 or 2, characterized in that In S1, the molar ratio of 2-amino-2-(hydroxymethyl)propane-1,3-diol to the amino protecting group is 1:(2.1-5); preferably 1:(2.1-3).

4. The synthesis method according to claim 1, characterized in that The base in S2 is an inorganic base; preferably, the inorganic base is one or more of an alkali metal hydroxide salt or an alkali metal carbonate salt; preferably, the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; preferably, the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

5. The synthesis method according to claim 1 or 4, characterized in that: In S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the base is 1:(1-4); preferably 1:(1.5-2).

6. The synthesis method according to claim 1, characterized in that The activating agent in S2 is methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, benzenesulfonyl chloride or trifluoroacetic anhydride; preferably, the activating agent is p-toluenesulfonyl chloride, benzenesulfonyl chloride or trifluoroacetic anhydride.

7. The synthesis method according to claim 1 or 6, characterized in that: In S2, the molar ratio of 2-diprotected amino-2-(hydroxymethyl)propane-1,3-diol to the activator is 1:(0.6-1.2); preferably 1:(0.8-1).

8. The synthesis method according to claim 1, characterized in that The solvent in S2 is an organic solvent containing water; preferably, the volume percentage of water in the solvent in S2 is 20v% to 80v%; preferably 40v% to 60v%; preferably 50v%; preferably, the solvent in S2 is a mixed system of alcohol solvent and water, a mixed system of THF and water, or a system of dioxane and water; preferably, the solvent in S2 is a mixed system of THF and water.

9. The synthesis method according to claim 1, characterized in that The oxidant in S3 is selected from Jones oxidant, potassium permanganate, IBX, DMP or Oxone.

10. The synthesis method according to claim 1 or 7, characterized in that: In S3, the molar ratio of (3-(diprotected amino)oxetan-3-yl)methanol to the oxidant is 1:(2-5); preferably 1:(3-4).

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