Preparation process of 4-substituted 2-oxazolidinone

Abstract

The present invention relates to a compound of formula (II) [Formula 1] JPEG2025517548000032.jpg38161, wherein M is selected from Na, K and Li, comprising the steps of: [chemical 2] JPEG2025517548000033.jpg36161 (in the formula, R 1 is selected from hydrogen, Na, K and Li) with a base, a reagent and, optionally, an organic solvent, characterized in that the base is a metal salt of an alkoxide.

Description

[Technical field]

[0001] The present invention relates to a novel process for the preparation of 4-substituted 2-oxazolidinones, which are useful intermediates in the preparation of 2-substituted cycloserines. [Background technology]

[0002] 2-Substituted cycloserines are useful in the preparation of certain insecticidally active compounds, such as those described in WO 2011 / 067272 and WO 2012 / 163959. Furthermore, the preparation of 4-substituted 2-oxazolidinones described in WO 2015 / 166094 does not provide optimal yields and they are not easy to isolate.

[0003] Thus, there remains a need to improve the chemical yield of the preparation of 4-substituted 2-oxazolidinones while ensuring easier separation, especially for large-scale production. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention aims to overcome the problems associated with the prior art by proposing a process for the preparation of 4-substituted 2-oxazolidinones, which is fully scalable to manufacturing scale, resulting in optimal yields and / or optimal purity while ensuring easier isolation. [Means for solving the problem]

[0005] For this purpose, the present invention provides a compound of formula II [ka] wherein M is selected from Na, K and Li. A process for the preparation of a compound of formula I [ka] (In the formula, R 1is selected from hydrogen, Na, K and Li with a base, a reagent and, optionally, an organic solvent, wherein the base is a metal salt of an alkoxide.

[0006] The compound of formula II is a metal salt of 2-oxooxazolidine-4-carboxylic acid, more preferably the potassium salt of 2-oxazolidine-4-carboxylic acid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] In a preferred embodiment, the compound of formula II has the following structure: [ka] It is possible that the

[0008] In a preferred embodiment, the compound of formula I has the following structure: [ka] It is possible that the

[0009] In the present invention, the metal salt of an alkoxide is more specifically a strong base. 1 ~C 5 It can be an alkali metal salt of an alkoxide, which can be selected from, for example, potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium tert-butoxide, potassium tert-butoxide, and any mixture thereof.

[0010] More preferably, the metal salt of an alkoxide is a non-aqueous base. In certain embodiments, the process for preparing the compound of formula II does not include any aqueous base, such as does not include an aqueous hydroxide base.

[0011] In the process according to the invention, the amount of base can be from 0.01 to 10 molar equivalents, preferably from 0.01 to 5 molar equivalents, preferably from 0.05 to 3.0 molar equivalents, and more preferably from 0.1 to 2 molar equivalents. In relation to the base, the designation "molar equivalent" is based on the number of moles (mol) of the compound of formula I.

[0012] The reagent of the present invention can include any suitable reagent known in the art, for example, the reagent can be selected from organic carbonates, halocarbonates, and any mixtures thereof.

[0013] The organic carbonate can be selected from aryl-carbonates, alkyl-carbonates, aryl-alkyl-carbonates, and mixtures of any of these. For example: - the aryl-carbonate can be diphenyl carbonate; - the alkyl carbonate may be selected from dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate and trimethylene carbonate; The -aryl-alkyl-carbonate can be methyl phenyl carbonate.

[0014] The halocarbonate can preferably be a chloro-carbonate. For example, the halocarbonate can be selected from phosgene or its derivatives. The phosgene derivative can be, for example, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, or benzyl chloroformate.

[0015] The use of an organic carbonate is preferred in the process according to the invention to limit the toxicity of the reagents, more preferably dimethyl carbonate.

[0016] In the process according to the invention, the amount of reagent can be from 0.1 to 10 molar equivalents, preferably from 0.5 to 5 molar equivalents, preferably from 0.5 to 2.0 molar equivalents, and more preferably from 0.5 to 1.5 molar equivalents. With respect to reagents, the designation "molar equivalent" is based on the number of moles (mol) of the compound of formula I.

[0017] The organic solvent of the present invention can include any suitable organic solvent known in the art, and is more preferably an alcohol. For example, the organic solvent can be selected from methanol, ethanol, propanol, isopropanol, butanol, t-butanol, t-amyl alcohol, toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, and any mixture thereof. The reagent of the present invention can be used as a solvent or in a mixture with said organic solvent.

[0018] In the process according to the invention, the amount of organic solvent can be from 1 to 200 molar equivalents, preferably from 1 to 100 molar equivalents, and more preferably from 1 to 20 molar equivalents. With respect to the organic solvent, the designation "molar equivalent" is based on the number of moles (mol) of the compound of formula I.

[0019] The process according to the invention can further comprise a crystallization step and, optionally, then a separation step. More specifically, once the compound of formula II is obtained, said compound of formula II can be crystallized and then separated.

[0020] The separation step aims to remove the base and the reagents used in excess, and optionally the solvent, and can be carried out by techniques well known in the art, such as, for example, distillation, decantation, centrifugation or filtration (for example using a centrifuge, a Nutsche filter, a candle filter or a pocket filter), or by a combination of these techniques, and more preferably by filtration.

[0021] The crystallization step can be carried out by techniques well known in the art. The compound of formula II can be crystallized during the reaction or crystallization can be induced by adding seed crystals of the compound of formula II during or after the reaction and / or by adding an anti-solvent. The anti-solvent is typically a solvent in which the compound of formula II is not at all soluble, such as methyl isobutyl ketone or toluene. Crystallization can also be initiated by concentrating the reaction mixture by distillation. The isolated compound of formula II can be dried by techniques well known in the art. Typically, the drying step can be carried out in a dryer such as a paddle dryer, a conical dryer or a filter dryer at high temperature and reduced pressure, such as at a temperature in the range of 30-100° C. and at a pressure in the range of 500-1 mbar.

[0022] Another object of the present invention is to provide a method for the preparation of a compound of formula III by reacting a compound of formula II with an acid in the presence of a solvent. [ka] The present invention relates to a process for the preparation of

[0023] In a preferred embodiment, the compound of formula III has the following structure: [ka] It is possible that the

[0024] More specifically, another object relates to a process for the preparation of a compound of formula II according to the present invention, which may further comprise the step of reacting a compound of formula II with an acid in the presence of a solvent to prepare a compound of formula III.

[0025] In certain embodiments, after crystallization of the compound of formula II, the compound of formula III can be obtained without any separation step of the compound of formula II. More specifically, the solvent can be replaced by distillation, a technique well known in the art.

[0026] In another particular embodiment, after crystallization of the compound of formula II, the compound of formula III can be obtained by filtering the compound of formula II, washing the separated compound of formula II with a suitable solvent, and resuspending the compound of formula II in a suitable solvent before continuing with the preparation of the compound of formula III. The suitable solvent can be an organic solvent as described below.

[0027] In the preparation of the compound of formula III, the acid can be, more specifically, a strong acid, such as hydrochloric acid (HCl), sulfuric acid (H 2 SO 4 ), hydrobromic acid (HBr), trifluoroacetic acid, methanesulfonic acid, perchloric acid, and any mixtures thereof. Preferably, the acid is selected from hydrochloric acid, sulfuric acid, and any mixtures thereof.

[0028] Acid is HCl gas, 98% H 2 SO 4 The acid can be anhydrous acid such as HCl, aqueous acid such as hydrochloric acid and preferably concentrated hydrochloric acid at a concentration of 30-35%; or a solution in an organic solvent such as HCl in methanol, HCl in dioxane, HBr in acetic acid, etc. If an aqueous acid is used, the water can be removed by azeotropic distillation.

[0029] The amount of acid can be from 0.05 to 5 molar equivalents, preferably from 0.1 to 2.0 molar equivalents, and more preferably from 0.5 to 1.5 molar equivalents. With respect to the acid, the designation "molar equivalent" is based on the number of moles (mol) of the compound of formula II.

[0030] In preparing the compound of formula III, the solvent can include any suitable solvent known in the art, and in particular any solvent in which the compound of formula III is soluble and in which the salt of the acid (used in preparing the compound of formula III) is not soluble.

[0031] For example, the solvent can be an organic solvent, more preferably selected from methyl isobutyl ketone, methyl ethyl ketone, acetone, 2-pentanone, propionic acid, acetic acid, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl acetate, ethyl acetate, butyl acetate, dimethyl carbonate, ethylene carbonate, and mixtures of any of these.

[0032] In a preferred embodiment, the solvent used to obtain the compound of formula III can be methyl isobutyl ketone, acetone, a mixture of methyl isobutyl ketone and acetone, 2-pentanone, a mixture of 2-pentanone and acetone, methyl ethyl ketone, a mixture of 2-pentanone and methyl ethyl ketone, propionic acid, or acetic acid.

[0033] A small amount of water (typically 2-5% by weight) can be added to the solvent to increase the solubility of the compound of formula III. Also, higher temperatures, such as in the range of 50-100° C., are preferred for better solubility of the compound of formula III.

[0034] In other embodiments, solvents can be used in which the compound of formula III is only partially soluble or insoluble at elevated temperatures (at least 50° C.), such as xylene or chlorobenzene. In this case, the compound of formula III can be dissolved at a later stage, such as during filtration, using a suitable solvent, such as the organic solvents mentioned above, in which the compound of formula III is soluble and in which the salt of the acid (used to prepare the compound of formula III) is not soluble.

[0035] In the preparation of the compound of formula III, the amount of solvent can be from 1 to 200 molar equivalents, and preferably from 5 to 100 molar equivalents. With respect to the solvent, the designation "molar equivalent" is based on the number of moles (mol) of the compound of formula II.

[0036] The preparation process of the compound of formula III can further include a separation step, then optionally a crystallization step, and optionally another separation step. More specifically, after the compound of formula III is obtained, said compound of formula III can be separated and then crystallized. When an aqueous acid is used, water can be removed by azeotropic distillation, preferably before and / or during the separation step.

[0037] The separation step is aimed at removing the salt of the acid used in the preparation of the compound of formula III and can be carried out by techniques well known in the art, such as for example by decantation, centrifugation or filtration (using for example a centrifuge, a Nutsche filter, a candle filter or a pocket filter).

[0038] The crystallization step can be carried out by techniques well known in the art. For example, the compound of formula III can be crystallized by cooling the solution, typically at a temperature in the range of 100 to -10°C, preferably 80 to 0°C; and / or by evaporating the solvent, typically at a temperature in the range of 30 to 80°C, with or without reduced pressure.

[0039] The resulting solid of the compound of formula III can be separated from the solvent used during crystallization. This separation step can be carried out by techniques well known in the art, such as, for example, distillation, decantation, centrifugation or filtration (e.g., using a centrifuge, Nutsche filter, candle filter or pocket filter), or by a combination of these techniques.

[0040] The isolated compound of formula III can be dried by techniques well known in the art. Typically, the drying step can be carried out in a dryer such as a paddle dryer, a conical dryer or a filter dryer at elevated temperature and reduced pressure, for example at a temperature in the range of 30-100° C. and a pressure in the range of 500-1 mbar.

[0041] Another object of the invention is the compound of formula Ia [ka] (In the formula, R 2 is C 1-4 Alkyl, phenyl, benzyl, C 2 H 4 O.H., C. 3 H 6 OHHHHH 3 CH 2 OH and CH 2 CHCH 3 OH; and M is selected from Na, K and Li. 2 is preferably C 1-4 It can be alkyl, and more preferably methyl.

[0042] In a preferred embodiment, the compound of formula Ia has the following structure: [ka] It is possible that the

[0043] Compounds of formula Ia can be formed as intermediates in the process of preparing compounds of formula II.

[0044] Another object of the present invention is to provide a compound of formula VI, including a process for the preparation of a compound of formula II according to the present invention and / or a process for the preparation of a compound of formula III according to the present invention. [ka] More specifically, another object relates to a process for the preparation of a compound of formula II according to the invention and / or a process for the preparation of a compound of formula III according to the invention, which may further comprise the preparation of a compound of formula VI.

[0045] Compounds of formula VI can be prepared, for example, according to WO 2015 / 166094 (as shown in Scheme 2, page 27), which is incorporated herein by reference.

[0046] More specifically, the compound of formula VI can be prepared by reacting the compound of formula III obtained by the process according to the present invention with the compound of formula V [ka] It can be prepared by reacting with

[0047] Preferably, this reaction is carried out with a compound of formula IV [ka] (In the formula, R 10 The method includes preparing the corresponding acid halide (preferably the acid chloride) of a compound of formula III, where R is a halogen, to facilitate conversion to a compound of formula VI.

[0048] R 10 Acid halides where is a halogen (i.e., compounds of formula IV) can be prepared from compounds of formula III under conditions well known to those skilled in the art, such as by treatment with thionyl chloride, oxalyl chloride, phosgene, diphosgene, or triphosgene.

[0049] Alternatively, a compound of formula IV, 10is a halogen), can be prepared from the alkali metal (Li, Na, K) salt of the compound of formula II, the compound of formula III, by treatment with oxalyl chloride, thionyl chloride, phosgene, diphosgene or triphosgene in the absence or presence of a catalyst and / or a phase transfer catalyst. Suitable catalysts include, but are not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone. Suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium chloride, Aliquat® 336 and (1-hexadecyl)trimethylammonium bromide. More specifically, the compound of formula VI can be prepared by reacting the compound of formula II obtained by the process according to the invention.

[0050] In certain embodiments, after crystallization of the compound of formula III, the compound of formula IV can be obtained without any separation step of the compound of formula III.

[0051] In another particular embodiment, after crystallization of the compound of formula II, the compound of formula IV can be obtained in a dry solid form by the process according to the invention without further isolation of the compound of formula II and / or the compound of formula III.

[0052] Another object of the present invention is to provide a compound of formula VIII, which comprises a process for the preparation of a compound of formula II according to the invention and / or which uses a process for the preparation of a compound of formula III according to the invention. [ka] More specifically, another object relates to a process for the preparation of a compound of formula II according to the invention and / or a process for the preparation of a compound of formula III according to the invention, which may further comprise, in particular after the preparation of a compound of formula VI, the preparation of a compound of formula VIII.

[0053] In a preferred embodiment, the compound of formula VIII has the following structure: [ka] It is possible that the

[0054] Compounds of formula VIII can be prepared, for example, according to WO 2015 / 166094, which is incorporated herein by reference.

[0055] More specifically, the compound of formula VIII can be prepared by converting the compound of formula VI to the compound of formula VII with a base, and more preferably an aqueous solution of a base. [ka] For example, the base can be an aqueous solution of sodium bicarbonate, sodium carbonate, and / or sodium hydroxide.

[0056] In a preferred embodiment, the compound of formula VII has the following structure: [ka] It is possible that the

[0057] The process may then comprise reacting the compound of formula VII with a second compound, where the second compound comprises a carboxylic acid, acid halide, ester or thioester functional group, and the reaction comprises reacting an amine functional group of the compound of formula VII with a carboxylic acid, acid halide, ester or thioester functional group of the second compound, such that the compound of formula VII is coupled to the second compound via an amide functional group, or where the second compound comprises a dicarbonate group, and the reaction comprises reacting an amine functional group of the compound of formula VII with a dicarbonate group of the second compound, such that the compound of formula VII is coupled to the second compound via a carbamate functional group.

[0058] This process is well known in the art and is described, for example, in WO2015166094, which is incorporated herein by reference.

[0059] Another object of the present invention is to provide a compound of formula XI, including a process for the preparation of a compound of formula II according to the invention and / or a process for the preparation of a compound of formula III according to the invention. [ka] More specifically, another object relates to a process for the preparation of a compound of formula II according to the invention and / or a process for the preparation of a compound of formula III according to the invention, which may further comprise the preparation of a compound of formula XI, in particular after the preparation of a compound of formula VIII.

[0060] In a preferred embodiment, the compound of formula XI has the following structure: [ka] It is possible that the

[0061] The preparation of the compound of formula XI is based on a dehydration reaction, which is well known in the art. The compound of formula XI can be prepared, for example, according to WO 2011 / 067272 (particularly as shown in Scheme 3, pages 18-19). More specifically, the compound of formula XI can be prepared by reacting the compound of formula X with the compound of formula [ka] in an organic solvent such as hexane, heptane, methylcyclohexane, toluene, xylene, chlorobenzene, o-dichlorobenzene, dichloromethane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl ethyl ether, anisole, acetonitrile, propionitrile, butyronitrile, benzonitrile, or any combination thereof; with a base such as triethylamine, tri-n-butylamine, pyridine, or any combination thereof; with a dehydrating agent such as phosgene, thionyl chloride, acetic anhydride, acetyl chloride, methanesulfonyl chloride, oxalyl chloride, methyl chloroformate, ethyl chloroformate, or any combination thereof; and with a catalyst such as an aminopyridine catalyst, which can be, for example, 4-dimethylaminopyridine or 4-pyrrolidinopyridine. The mixture can be stirred in a reactor for about 10 minutes to 96 hours, and preferably for about 1 to 20 hours, typically at 0 to 150°C, preferably 0 to 20°C, and more preferably 0 to 10°C.

[0062] In a preferred embodiment, the compound of formula X has the following structure: [ka] It is possible that the

[0063] The compound of formula XI can be isolated using bases, dehydrating agents, catalysts, or work-up conditions well known in the art for separating the compound of formula XI from its respective reaction product.

[0064] In a first embodiment, the compound of formula XI according to the present invention can include an E-configuration compound of formula XI and, optionally, a Z-configuration compound of formula XI. More specifically, the compound of formula XI can include an E / Z ratio of 90:10 to 100:0, preferably 95:5 to 100:0, and more preferably 99:1 to 100:0.

[0065] In a second embodiment, the compound of formula XI according to the present invention can have an R / S ratio of 50:50 to 100:0, preferably 90:10 to 100:0, and more preferably 95:5 to 100:0.

[0066] In a third aspect, the compounds of formula XI according to the invention can include the first and second embodiments.

[0067] As mentioned above, the preparation of the compound of formula X is based on the aldol reaction, which is well known in the art. More specifically, the compound of formula X can be prepared by reacting an aromatic ketone compound of formula IX with an aromatic ketone compound of formula IX. [ka] with a compound of formula VIII in the presence of a base with or without a solvent.

[0068] The base can be, for example, triethylamine, trimethylamine, diethylamine, tertbutylamine, pyridine, 1,8-diaza(5,4,0)-7-bicycloundecene, potassium carbonate, or any combination thereof.

[0069] The solvent may be selected from, for example, toluene, xylene, chlorobenzene, dichlorobenzene, anisole, dimethoxybenzene, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, ethyl acetate, methoxyethyl acetate, and any combination thereof.

[0070] The equilibrium of the reaction can be shifted towards the compound of formula X by adjusting the amount of solvent so that the reaction is carried out in as concentrated a form as possible that allows sufficient mixing. The mixture can be a homogeneous solution or a slurry. The mixture can be stirred in a reactor for about 1-150 hours, preferably about 1-96 hours, usually at 0-150°C, preferably 20-60°C, and more preferably 30-50°C.

[0071] The compound of formula X can be isolated or used directly without further workup to produce a compound of formula XI.

[0072] Another object of the present invention is to provide a compound of formula XII, including a process for the preparation of a compound of formula II according to the present invention and / or a process for the preparation of a compound of formula III according to the present invention. [ka] or a process for the preparation of an enriched composition comprising a compound of formula XII. More specifically, another object relates to a process for the preparation of a compound of formula II according to the invention and / or a process for the preparation of a compound of formula III according to the invention, which may further comprise the preparation of a compound of formula XII, in particular after the preparation of a compound of formula XI.

[0073] In a preferred embodiment, the compound of formula XII has the following structure: [ka] The enriched composition may include at least one isomer of the compound of formula XII selected from the compound of formula XII (4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide) (5S,4R). The enriched composition may include at least one isomer of the compound of formula XII selected from the compound of formula XII (5S,4R) and the compound of formula XII (5S,4S), the compound of formula XII (5R,4R), the compound of formula XII (5R,4S), and any combination thereof). The isomer (5S,4S) is 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide; the isomer (5R,4R) is 4-[(5R)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide; and the isomer (5R,4S) is 4-[(5R)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidine-4-yl]-2-methyl-benzamide. The enriched composition can contain a molar proportion of the (5S,4R) isomer of greater than 50%, such as at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, based on the total amount of the (5S,4R), (5S,4S), (5R,4R) and (5R,4S) isomers.

[0074] Compounds of formula XII can be prepared, for example, according to WO 2011 / 067272 or WO 2016 / 023787, which are incorporated herein by reference.

[0075] More specifically, the process for preparing the compound of formula XII is carried out by reacting the compound of formula XI according to the present invention with hydroxylamine or its salt, a base, a chiral catalyst, and an organic solvent.

[0076] The term "hydroxylamine" has the formula H 2 NOH means the free hydroxylamine, and the hydroxylamine salt can be, for example, hydroxylammonium chloride.

[0077] The chiral catalyst can be more specifically a catalyst comprising at least one chiral moiety, and preferably at least two chiral moieties. The chiral catalyst can include any suitable chiral catalyst known in the art. In a first example, the chiral catalyst is a compound of formula III as described in WO 2016 / 023787 (page 2) (incorporated by reference), preferably a dimeric chiral catalyst of formula III as described in WO 2016 / 023787 (page 4), and more preferably a compound R-(6-methoxy-4-quinolinyl)-1,2-diphenyl-1,3-diphenyl-2,4 ... In WO 2016 / 023787 (pages 7-8), the compound of formula XVII can be prepared by the reaction of a compound of formula XV with SOBr. 2 , POBr 3 , PBr 3 , HBr, NaBr / H 2 SO 4or any combination thereof; in a suitable solvent such as acetic acid, toluene, xylene, chlorobenzene, dichlorobenzene, heptane, ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, water, or any combination thereof. The compound of formula XVI can then be reacted with a compound of formula X as described in WO 2016 / 023787 (page 7) in the presence of a suitable organic solvent such as toluene, acetonitrile, acetone, methanol, ethanol, 1-pentanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, anisole, water, or any combination thereof to obtain a compound of formula XVII. In a second example, the chiral catalyst can be a compound of formula 2-12 as a chiral phase transfer catalyst described in U.S. Patent Publication No. 2014350261 (incorporated by reference). In a third example, the chiral catalyst can be a compound of formula III described in WO 2020 / 094434 (incorporated by reference) or WO 2021 / 197880 (incorporated by reference).

[0078] The organic solvent used in the reaction from the compound of formula XI to the compound of formula XII can be, for example, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, chloroform, tert-butyl methyl ether, iso-propanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, 2-methylpropionitrile, butyronitrile, preferably 1,2-dichloroethane, 2-methyltetrahydrofuran, acetonitrile or dichloromethane, at a temperature of -78°C to 60°C, preferably -20°C to +20°C, and at a dilution ratio of, for example, 0.1M to 1M. The reaction time can usually be 30 minutes to 48 hours, preferably 1 to 4 hours. The amount of catalyst can usually be 0.01 to 0.4 molar equivalents, preferably 0.02 to 0.2 molar equivalents. The amount of hydroxylamine can be 1 to 10 equivalents, preferably 1.0 to 1.2 equivalents.

[0079] The base used in the reaction of the compound of formula XI to the compound of formula XII can include an alkali hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, in a typical amount of 0.05 to 2 equivalents. Preferably, the amount of base used is 0.05 to 1.0 equivalent. The reaction can be carried out in the presence of water. The expression "molar equivalent" to obtain the compound of formula XII is based on the number of moles (mol) of the compound of formula XI.

[0080] The invention will now be illustrated by non-limiting examples. EXAMPLES

[0081] Example 1: Preparation of potassium (4R)-2-oxooxazolidine-4-carboxylate using potassium methoxide in methanol A double-jacketed reactor equipped with a mechanical stirrer, thermometer and reflux condenser was charged with a solution of potassium methoxide in methanol (390.9 g, 1.80 mol, 32%) under nitrogen atmosphere. D-Serine (160.0 g, 1.50 mol, 98%) was added in two portions with an interval of 5 min under stirring. The resulting suspension was heated to 50° C., followed by the addition of dimethyl carbonate (150.0 g, 1.70 mol, 99%) within 1 h while maintaining the temperature at 50° C. The reaction mixture was stirred at 50° C. for 2 h to achieve a conversion of ≧98% (in DMSO-d6 with the addition of a few drops of methanol). 1 H NMR-analysis). The suspension was cooled to 0° C. within 1 h and then left overnight at 0° C. with stirring. The next day the reaction mixture was filtered and the filter cake was washed with cold methanol (94 g) and dried overnight at 50° C. in a drying oven to give (4R)-2-oxooxazolidine-4-carboxylate as a white, free-flowing, non-hygroscopic crystalline powder (252.5 g). Chemical purity was 96% (D using maleic acid as standard). 2 Quantitative in O 1 1 H NMR) and the isolated yield was 96%. 1 H NMR (400MHz, D 2 O) δ ppm: 4.63-4.69 (m, 1H), 4.48-4.55 (m, 2H), NH not visible due to substitution with deuterium. 1 H NMR (400MHz, CD 3 OD) δ ppm: 4.56-4.60 (m, 1H), 4.35-4.39 (m, 1H), 4.18-4.22 (m, 1H). NH is not visible due to substitution with deuterium. 13 C NMR (100.6MHz, D 2 O)δ ppm:177.9,161.9,69.2,55.9.

[0082] Example 2: Preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate using sodium methoxide in methanol A screw-cap septum vial was charged with D-serine (1.05 g, 10.0 mmol) and methanol (2.0 mL) under nitrogen atmosphere. To the resulting suspension, a solution of sodium methoxide in methanol (2.17 g, 12.0 mol, 30%) was added at room temperature within 1 min. The mixture was stirred for 10 min to obtain a clear solution to which dimethyl carbonate (1.3 mL, 1.36 g, 15.0 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2 h and then at 50° C. for an additional 2 h. 1 H NMR analysis (400 MHz, DMSO-d6 with a few drops of MeOH) showed complete consumption of D-serine (sodium salt) and 75% conversion of the intermediate carbamate (compound of formula Ia) to sodium (4R)-2-oxooxazolidine-4-carboxylate.

[0083] Example 3: Preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate using sodium ethoxide in ethanol A screw-cap septum vial was charged with D-serine (1.06 g, 10.0 mmol) and ethanol (2.0 mL) under nitrogen atmosphere. To the resulting suspension was added a solution of sodium ethoxide in ethanol (4.5 mL, 3.89 g, 12.0 mol, 21%) at room temperature. The mixture was stirred for 10 minutes, followed by the addition of dimethyl carbonate (1.3 mL, 1.36 g, 15.0 mmol). The reaction mixture was stirred at room temperature overnight. 1 H NMR analysis (400 MHz, DMSO-d6 with a few drops of MeOH) showed complete consumption of D-serine (sodium salt) and 48% conversion of the intermediate carbamate (compound of formula Ia) to sodium (4R)-2-oxooxazolidine-4-carboxylate.

[0084] Example 4: Preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from D-serine without isolation of potassium (4R)-2-oxooxazolidine-4-carboxylate A double-jacketed reactor equipped with a mechanical stirrer, thermometer, and Dean-Stark apparatus was charged with a solution of potassium methoxide (126.0 g, 0.575 mol, 32%) in methanol under nitrogen atmosphere. D-Serine (53.7 g, 0.50 mol, 98%) was added and the resulting suspension was heated to 50° C., followed by the addition of dimethyl carbonate (47.8 g, 0.525 mol, 99%) within 0.5 h while maintaining the temperature at 50° C. The reaction mixture was stirred at 50° C. for 2 h to achieve a conversion of ≧98% (quantitative in DMSO-d6 with the addition of a few drops of methanol). 1 The reaction mixture was neutralized with concentrated sulfuric acid (3.8 g, 0.0375 mol, 98%) to pH=7-8 (wet pH indicator paper). First, a part of the methanol (53 g, about 1 / 3 of the total amount) was distilled off, followed by evaporating the methanol (temperature T in the reactor at 65-80 °C). r (1000-300 mbar vacuum) and the methanol was replaced by methyl isobutyl ketone by continuously adding methyl isobutyl ketone. A total of 224 g of methyl isobutyl ketone was introduced. The residual amount of methanol in the reaction mixture was 1% by weight ( 1 H NMR analysis). The mixture was cooled to 50 °C and aqueous HCl (69.1 g, 0.588 mol, 31%) was added within 10 min. The resulting mixture was subjected to azeotropic water removal (temperature T in the reactor of 55-63 °C). r The mixture was dehydrated by vacuum (300 mbar). After releasing the vacuum, acetone (121 g) was added and the mixture was heated to 64° C. The salt suspension was filtered (hot filtration), the filter cake was washed with hot acetone (43 g) and the combined mother liquors were returned to the reactor. The product was crystallized by distilling off the acetone from the mixture, first at ambient pressure and then under reduced pressure (1000-300 mbar). The resulting suspension was cooled to room temperature and filtered. The cake was washed with methyl isobutyl ketone (42 g) and dried overnight at 50° C. in a drying oven to give (4R)-2-oxooxazolidine-4-carboxylic acid as a white crystalline solid (61.6 g). The chemical purity was 93.4% (D using maleic acid as standard). 2 Quantitative in O 11 H NMR) and the isolated yield was 88%. 1 H NMR (400MHz, D 2 O) δ ppm: 4.60-4.64 (m, 1H), 4.44-4.53 (m, 2H), NH and COOH not visible due to substitution with deuterium. 1 H NMR(400MHz,DMSO-d6)δ ppm:13.21(br s,1H),8.12(s,1H),4.44-4.51(m,2H),4.27-4.36(m,2H). 13 C NMR (100.6MHz, D 2 O)δ ppm:174.3,161.5,67.8,53.9.

[0085] Example 5: Preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from potassium (4R)-2-oxooxazolidine-4-carboxylate using substrate HCl. In a double-jacketed reactor equipped with mechanical stirrer, thermometer, distillation apparatus and a pipe for gas introduction, potassium (4R)-2-oxooxazolidine-4-carboxylate (75.1 g, 0.431 mol, 97%) was suspended in methyl isobutyl ketone (92 g). Below the liquid surface, a stream of hydrogen chloride (25.0 g, 0.517 mol) was introduced for 15 min while maintaining the temperature at 20° C. The reaction mixture was stirred for 20 min at 20° C. A stream of nitrogen was passed through the reaction mixture for 30 min to remove excess HCl. Acetone (115 g) and water (4 g) were added and the mixture was then heated to 62° C. The salt suspension was filtered (hot filtration), the filter cake was washed with hot acetone (28 g) and the combined filtrates were returned to the reactor. Acetone was distilled off from the mixture, first at atmospheric pressure and then under reduced pressure (1000-300 mbar), to crystallize the product. The resulting suspension was cooled to room temperature and filtered. The cake was washed with methyl isobutyl ketone (51 g) and dried overnight in a drying oven at 50° C. to give (4R)-2-oxooxazolidine-4-carboxylic acid as a white crystalline solid (49.3 g). The chemical purity was 93.7% (D using maleic acid as standard). 2 Quantitative in O 1 1 H NMR) and the isolated yield was 82%. NMR data: 1 H NMR (400MHz, D 2 O) δ ppm: 4.62-4.67 (m, 1H), 4.47-4.55 (m, 2H), NH and COOH not visible due to substitution with deuterium.

[0086] Example 6: Strong H 2 SO 4 and preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from potassium (4R)-2-oxooxazolidine-4-carboxylate using 2-pentanone as solvent. A double-jacketed reactor equipped with a mechanical stirrer, thermometer and reflux condenser was charged with potassium (4R)-2-oxooxazolidine-4-carboxylate (50.0 g, 0.288 mol, 97.3%). Aqueous 2-pentanone (120 g, 3 wt.% water) prepared from 2-pentanone (116.4 g) and water (3.6 g) was added. The resulting suspension was heated to 80°C, followed by dropwise addition of concentrated sulfuric acid (28.8 g, 0.288 mol, 98%) while maintaining the temperature in the range of 80-85°C. The salt suspension was filtered (hot filtration), the filter cake was washed with hot 2-pentanone (63 g) and the combined filtrate was returned to the reactor. Approximately 1 / 3 of the total amount of 2-pentanone (120 g) was distilled off under reduced pressure (340-240 mbar). The solution was cooled from 73°C to 25°C over 2 hours to allow the product to crystallize. The resulting suspension was stirred overnight at 25°C and filtered. The cake was washed with 2-pentanone (16g) and dried overnight at 60°C in a drying oven to give the title compound as a slightly yellow crystalline solid (20.9g). The chemical purity was 90.4% (D using maleic acid as standard). 2 Quantitative in O 1 H NMR) and the isolated yield was 50%. 37% of the theoretical amount of (4R)-2-oxooxazolidine-4-carboxylic acid was found in the salt and mother liquor. 1 H NMR (400MHz, D 2 O) δ ppm: 4.62-4.67 (m, 1H), 4.47-4.56 (m, 2H), NH and COOH not visible due to substitution with deuterium.

Claims

1. Compound of formula II 【Chemistry 1】 (In the formula, M is selected from Na, K, and Li) A preparation process for a compound of formula I. 【Chemistry 2】 (In the formula, R 1 (Selected from hydrogen, Na, K, and Li) A preparation process comprising reacting with a base, a reagent, and optionally an organic solvent, wherein the base is a metal salt of an alkoxide.

2. The metal salt of the alkoxide is C 1 ~C 5 The process according to claim 1, characterized in that it is an alkali metal salt of an alkoxide.

3. The process according to claim 1 or 2, characterized in that the reagent is selected from an organic carbonate, a halocarbonate, and a mixture thereof.

4. The process according to claim 1 or 2, characterized in that the reagent is selected from aryl carbonates, alkyl carbonates, aryl-alkyl carbonates, and mixtures thereof.

5. The process according to claim 1 or 2, characterized in that the reagent is a chlorocarbonate.

6. The process according to claim 1 or 2, characterized in that the organic solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, t-butanol, t-amyl alcohol, toluene, tetrahydrofuran, and mixtures thereof.

7. The process according to claim 1 or 2, characterized in that the amount of the base is 0.01 to 10 molar equivalents, preferably 0.05 to 5 molar equivalents, preferably 0.1 to 2.0 molar equivalents, and more preferably 0.1 to 1.5 molar equivalents.

8. The process according to claim 1 or 2, characterized in that the amount of the reagent is 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents, preferably 0.5 to 2.0 molar equivalents, and more preferably 0.5 to 1.5 molar equivalents.

9. The process according to claim 1 or 2, characterized in that the amount of the organic solvent is 1 to 200 molar equivalents, preferably 1 to 100 molar equivalents, and more preferably 1 to 20 molar equivalents.

10. A process according to claim 1 or 2, characterized by further comprising a crystallization step and optionally, a separation step.

11. Compound III is obtained by reacting the compound of formula II in the presence of an acid and a solvent. 【Transformation 3】 The preparation process.

12. A process according to claim 11, characterized in that it further comprises a crystallization step and, optionally, a separation step.

13. The process according to claim 11 or 12, characterized in that the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, and mixtures thereof.

14. The process according to claim 11 or 12, characterized in that the solvent is selected from methyl isobutyl ketone, methyl ethyl ketone, acetone, 2-pentanone, propionic acid, acetic acid, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl acetate, ethyl acetate, butyl acetate, dimethyl carbonate, ethylene carbonate, and mixtures thereof.

15. Compound of formula Ia 【Chemistry 4】 (wherein, R 2 is C 1-4 alkyl, phenyl, benzyl, C 2 H 4 OH, C 3 H 6 OH, CHCH 3 CH 2 OH, and CH 2 CHCH 3 OH is selected from; and M is selected from Na, K and Li).

16. A compound of formula VI comprising the preparation process of a compound of formula II according to claim 1, and / or the preparation process of a compound of formula III according to claim 11. 【Transformation 5】 The preparation process.

17. A compound of formula VIII comprising the preparation process of the compound of formula II according to claim 1, and / or the preparation process of the compound of formula III according to claim 11. 【Transformation 6】 The preparation process.

18. A compound of formula XI comprising the preparation process of the compound of formula II according to claim 1, and / or the preparation process of the compound of formula III according to claim 11. 【Transformation 7】 The preparation process.

19. A compound of formula XII comprising the preparation process of the compound of formula II according to claim 1, and / or the preparation process of the compound of formula III according to claim 11. 【Transformation 8】 Or a process for preparing an enriched composition containing a compound of formula XII.

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