Process for preparation of 4-substituted 2-oxazolidinones

Abstract

The invention relates to a method for preparing a compound of formula (II), in which M is selected from Na, K and Li, by reacting a compound of formula (I), in which R1 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. # imgabs0 #

Description

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

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

[0003] Therefore, there remains a need to improve the chemical yields for preparing 4-substituted 2-oxazolidinones while ensuring easier isolation, especially for large-scale production.

[0004] The object of the present invention is to overcome the problems of the prior art by proposing a process for the preparation of 4-substituted 2-oxazolidinones which presents an optimized yield and / or an optimized purity while ensuring an easier separation, being fully scalable to a manufacturing scale.

[0005] To this end, the object of the present invention is to provide a process for preparing a compound of formula II:

[0006]

[0007] wherein M is selected from Na, K and Li,

[0008] The method comprises reacting a compound having formula I with a base, a reagent and optionally an organic solvent:

[0009]

[0010] Where R 1 is selected from hydrogen, Na, K and Li,

[0011] The process is characterized in that the base is a metal salt of an alkoxide.

[0012] The compound having formula II is a metal salt of 2-oxooxazolidine-4-carboxylic acid, and more preferably is a potassium salt of 2-oxooxazolidine-4-carboxylic acid.

[0013] In a preferred embodiment, the compound having Formula II may have the following structure:

[0014]

[0015] In a preferred embodiment, the compound having Formula I may have the following structure:

[0016]

[0017] In the present invention, the metal salt of alkoxide is more specifically a strong base. The metal salt of alkoxide can be an alkali metal salt of C1-C5 alkoxide, which can be selected from potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, sodium tert-amylate, sodium tert-butoxide, potassium tert-butoxide and any mixture thereof.

[0018] More preferably, the metal salt of the 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, for example, it does not include an aqueous hydroxide base.

[0019] In the process according to the invention, the amount of the base may 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. The expression "molar equivalent" in relation to the base is based on the number of moles (mol) of the compound of formula I.

[0020] The reagent according to the present invention may include any suitable reagent well known in the art. For example, the reagent may be selected from organic carbonates, halogenated carbonates and any mixture thereof.

[0021] The organic carbonate can be selected from aryl carbonate, alkyl carbonate, aryl alkyl carbonate and any mixture thereof. For example:

[0022] - the aryl carbonate may be diphenyl carbonate;

[0023] - the alkyl carbonate may be selected from dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate and trimethylene carbonate;

[0024] The aryl alkyl carbonate may be methyl phenyl carbonate.

[0025] The halogenated carbonate may preferably be a chlorocarbonate. For example, the halogenated carbonate may be selected from phosgene or a derivative thereof. The phosgene derivative may be, for example, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate or benzyl chloroformate.

[0026] In the process according to the invention it is preferred to use organic carbonates in order to limit the toxicity of the reagents, and more preferably dimethyl carbonate.

[0027] In the method according to the invention, the amount of the 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. The expression "molar equivalent" related to the reagent is based on the mole number (mol) of the compound of formula I.

[0028] Organic solvent according to the present invention can comprise any suitable organic solvent well known in the art, and more preferably alcohol.For example, organic solvent can be selected from methanol, ethanol, propyl alcohol, isopropanol, butanol, the tert-butyl alcohol, tert-amyl alcohol, toluene, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (THF) and any mixture thereof.Reagent according to the present invention can be used as solvent, or can be used in the form of a mixture with the organic solvent.

[0029] In the method 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. The expression "molar equivalent" related to the organic solvent is based on the moles (mol) of the compound of formula I.

[0030] The process according to the invention may further comprise a crystallization step and optionally a subsequent isolation step. More specifically, once the compound of formula II is obtained, said compound of formula II may be crystallized and then isolated.

[0031] The separation step is intended to remove the alkali and reagent used in excess and the optional solvent. This separation step can be carried out by techniques well known in the art, such as, for example, by distillation, decantation, centrifugation or filtration (e.g. using a centrifuge, suction filter, candle filter or bag filter), or a combination of these techniques, and more preferably by filtration.

[0032] 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 can be induced to crystallize by adding seeds 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 completely insoluble, such as methyl isobutyl ketone or toluene. Crystallization can also be induced by distilling and concentrating the reaction mixture. The separated compound of formula II can be dried by techniques well known in the art. Typically, the drying step can be carried out at an elevated temperature and under vacuum, such as at a temperature ranging from 30° C. to 100° C. and a pressure ranging from 500 mbar to 1 mbar, in a dryer (such as a paddle dryer, a conical dryer or a filter dryer).

[0033] Another object of the present invention relates to a process for preparing a compound of formula III:

[0034]

[0035] The method comprises reacting a compound having formula II with an acid in the presence of a solvent.

[0036] In a preferred embodiment, the compound having formula III may have the following structure:

[0037]

[0038] More specifically, this further object relates to a process for preparing a compound of formula II according to the present invention, wherein the process may further comprise a step of reacting the compound of formula II with an acid in the presence of a solvent to prepare a compound of formula III.

[0039] In a particular embodiment, after the 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 exchanged by distillation, which is a technique well known in the art.

[0040] In another specific embodiment, after the compound of formula II is crystallized, the compound of formula III can be obtained by filtering out 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, and then continuing to prepare the compound of formula III. The suitable solvent can be an organic solvent described hereinafter.

[0041] In the preparation of the compound of formula III, the acid can be more specifically a strong acid, which can be selected from hydrochloric acid (HCl), sulfuric acid (H2SO4), hydrobromic acid (HBr), trifluoroacetic acid, methanesulfonic acid, perchloric acid and any mixture thereof. Preferably, the acid can be selected from hydrochloric acid, sulfuric acid and any mixture thereof.

[0042] The acid can be an anhydrous acid, such as HCl gas, 98% H2SO4; an aqueous acid, such as hydrochloric acid, and preferably concentrated hydrochloric acid with a concentration between 30% and 35%, or a solution in an organic solvent, such as HCl in methanol, HCl in dioxane, HBr in acetic acid. If an aqueous acid is used, the water can be removed by azeotropic distillation.

[0043] The amount of acid may 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. The expression "molar equivalent" in relation to the acid is based on the number of moles (mol) of the compound having formula II.

[0044] In the preparation of the compound of formula III, the solvent may 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 to prepare the compound of formula III) is insoluble.

[0045] For example, the solvent may 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 any mixture thereof.

[0046] In a preferred embodiment, the solvent used to obtain the compound having 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.

[0047] A small amount of water (typically 2%-5% by weight) may be added to the solvent to increase the solubility of the compound of formula III. In addition, elevated temperatures, such as ranging from 50°C to 100°C, are preferred for better dissolution of the compound of formula III.

[0048] In another embodiment, a solvent 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, may be used. In this case, a suitable solvent (such as an organic solvent as described above) in which the compound of formula III is soluble and the salt of the acid (used to prepare the compound of formula III) is insoluble may be used to dissolve the compound of formula III at a later stage (such as during filtration).

[0049] In the preparation of the compound of formula III, the amount of solvent may be from 1 to 200 molar equivalents, and preferably from 5 to 100 molar equivalents. The expression "molar equivalent" in relation to the solvent is based on the number of moles (mol) of the compound of formula II.

[0050] The method for preparing a compound of formula III may further comprise a separation step and a subsequent optional crystallization step, and optionally another separation step. More specifically, once a compound of formula III is obtained, the compound of formula III may be separated and then crystallized. If an aqueous acid is used, water may be removed by azeotropic distillation, preferably before and / or during the separation step.

[0051] The separation step is intended to remove the salt of the acid used to prepare the compound of formula III. This separation step can be carried out by techniques well known in the art, such as, for example, by decantation, centrifugation or filtration (for example using a centrifuge, a suction filter, a candle filter or a bag filter).

[0052] 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 ranging from 100°C to -10°C, and preferably from 80°C to 0°C; and / or evaporating the solvent under vacuum or non-vacuum, typically at a temperature ranging from 30°C to 80°C.

[0053] The solid of the compound of formula III obtained 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, by distillation, decantation, centrifugation or filtration (for example using a centrifuge, a suction filter, a candle filter or a bag filter), or a combination of these techniques.

[0054] The isolated compound of formula III may be dried by techniques well known in the art. Typically, the drying step may be carried out at elevated temperature and under vacuum, such as, for example, at a temperature ranging from 30° C. to 100° C. and a pressure ranging from 500 mbar to 1 mbar, in a dryer such as a paddle dryer, a cone dryer or a filter dryer.

[0055] Another object of the present invention relates to a compound having formula Ia:

[0056]

[0057] Where R 2 Selected from C 1-4 alkyl, phenyl, benzyl, C2H4OH, C3H6OH, CHCH3CH2OH and CH2CHCH3OH; and M is selected from Na, K and Li. 2 Preferably C 1-4 An alkyl group, and more preferably a methyl group.

[0058] In a preferred embodiment, the compound having Formula Ia may have the following structure:

[0059]

[0060] During the process for preparing the compound of formula II, the compound of formula Ia may be formed as an intermediate.

[0061] Another object of the present invention relates to a process for preparing a compound of formula VI:

[0062]

[0063] The method comprises a method according to the invention for preparing a compound of formula II and / or comprises a method according to the invention for preparing a compound of formula III. More specifically, this further object relates to a method according to the invention for preparing a compound of formula II and / or a method according to the invention for preparing a compound of formula III, wherein the method may further comprise preparing a compound of formula VI.

[0064] Compounds of formula VI can be prepared, for example, as shown in Scheme 2 on page 27 of WO 2015 / 166094 (incorporated herein by reference).

[0065] More specifically, the compound of formula VI can be prepared by reacting the compound of formula III obtained by the process according to the invention with a compound of formula V:

[0066]

[0067] Preferably, the reaction comprises preparing the corresponding acid halide (preferably the acid chloride) of the compound of formula III to facilitate the conversion to the compound of formula VI, wherein R 10 A compound of formula IV is halogen

[0068]

[0069] Where R 10 Acid halides that are halogens (ie, 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.

[0070] Alternatively, where R 10 Compounds of formula IV that are halogens can be prepared from alkali metal (Li, Na, K) salts of compounds of formula III that are compounds of formula II 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, 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 method according to the present invention.

[0071] In a particular embodiment, after crystallization of the compound having formula III, the compound having formula IV can be obtained without any isolation step of the compound having formula III.

[0072] In another particular embodiment, after crystallization of the compound of formula II, the compound of formula IV can be obtained by the process according to the invention in the form of a dry solid without further isolation of the compound of formula II and / or the compound of formula III.

[0073] Another object of the present invention relates to a process for preparing a compound of formula VIII:

[0074]

[0075] The method comprises a method according to the invention for preparing a compound of formula II and / or using a method according to the invention for preparing a compound of formula III. More specifically, this further object relates to a method according to the invention for preparing a compound of formula II and / or a method according to the invention for preparing a compound of formula III, wherein the method may further comprise preparing a compound of formula VIII, in particular after preparing a compound of formula VI.

[0076] In a preferred embodiment, the compound having formula VIII may have the following structure:

[0077]

[0078] Compounds of formula VIII can be prepared, for example, according to WO 2015 / 166094 (incorporated herein by reference).

[0079] More specifically, the compound of formula VIII can be prepared by converting the compound of formula VI to the compound of formula VII using a base, and more preferably an aqueous base solution.

[0080]

[0081] For example, the base may be an aqueous solution of sodium bicarbonate, sodium carbonate and / or sodium hydroxide.

[0082] In a preferred embodiment, the compound having formula VII may have the following structure:

[0083]

[0084] The method may then include reacting a compound having formula VII with a second compound, wherein the second compound includes a carboxylic acid, acyl halide, ester, or thioester functional group, and the reaction includes reacting an amine functional group of the compound having formula VII with a carboxylic acid, acyl halide, ester, or thioester functional group of the second compound so that the compound having formula VII is coupled to the second compound via an amide functional group, or wherein the second compound includes a dicarbonate group, and the reaction includes reacting an amine functional group of the compound having formula VII with a dicarbonate group of the second compound so that the compound having formula VII is coupled to the second compound via a carbamate functional group.

[0085] This method is well known in the art and is described, for example, in WO 2015166094 (incorporated herein by reference).

[0086] Another object of the present invention relates to the preparation of compounds having formula XI:

[0087]

[0088] It comprises a method according to the invention for preparing a compound of formula II and / or comprises a method according to the invention for preparing a compound of formula III. More specifically, this further object relates to a method according to the invention for preparing a compound of formula II and / or a method according to the invention for preparing a compound of formula III, wherein the method may further comprise preparing a compound of formula XI, in particular after preparing a compound of formula VIII.

[0089] In a preferred embodiment, the compound having formula XI may have the following structure:

[0090]

[0091] The preparation of compounds of formula XI is based on a dehydration reaction, which is well known in the art. For example, compounds of formula XI can be prepared according to WO 2011 / 067272, specifically as shown in Scheme 3 on pages 18-19. More specifically, compounds of formula XI can be prepared by: reacting a compound of formula X with a precipitate of 1:1% NH 2 ...

[0092]

[0093] In an organic solvent (such as hexane, heptane, methylcyclohexane, toluene, xylene, chlorobenzene, o-dichlorobenzene, dichloromethane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylethyl ether, anisole, acetonitrile, propionitrile, butyronitrile, benzonitrile or any combination thereof), with a base (such as triethylamine, tri-n-butylamine, pyridine or any combination thereof), 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 a catalyst (such as an aminopyridine catalyst, which may be, for example, 4-dimethylaminopyridine or 4-pyrrolidinopyridine). The mixture may be stirred in a reactor generally at 0° C. to 150° C., preferably 0° C. to 20° C., and more preferably 0° C. to 10° C. for about 10 minutes to 96 hours, and preferably about 1 to 20 hours.

[0094] In a preferred embodiment, the compound having formula X may have the following structure:

[0095]

[0096] The compound of formula XI can be isolated by separating the base, dehydrating agent, catalyst or their respective reaction products from the compound of formula XI using work-up conditions well known in the art.

[0097] In a first embodiment, the compound of formula XI according to the present invention may comprise an E-configuration compound of formula XI and an optional Z-configuration compound of formula XI. More specifically, the compound of formula XI may comprise an E / Z ratio of from 90:10 to 100:0, preferably from 95:5 to 100:0, and more preferably from 99:1 to 100:0.

[0098] In a second embodiment, the compound of formula XI according to the present invention may comprise an R / S ratio from 50:50 to 100:0, preferably from 90:10 to 100:0, and more preferably from 95:5 to 100:0.

[0099] In a third embodiment, the compound having Formula XI according to the present invention may include the first embodiment and the second embodiment.

[0100] As previously described, the preparation of compounds of formula X is based on an aldol condensation reaction, which is well known in the art. More specifically, compounds of formula X can be prepared by reacting an aromatic ketone compound of formula IX with

[0101]

[0102] and reacting with a compound of formula VIII in the presence of a base with or without a solvent.

[0103] The base can be, for example, triethylamine, trimethylamine, diethylamine, tert-butylamine, pyridine, 1,8-diaza(5,4,0)-7-bicycloundecene, potassium carbonate, or any combination thereof.

[0104] The solvent may, for example, be selected from toluene, xylene, chlorobenzene, dichlorobenzene, anisole, dimethoxybenzene, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, ethyl acetate, methoxyethyl acetate, and any combination thereof.

[0105] By adjusting the amount of solvent, the equilibrium of the reaction can be shifted toward the compound of formula X so that the reaction is run as concentrated as possible under adequate mixing. The mixture can be a homogeneous solution or can be a slurry. The mixture can be stirred in a reactor typically at 0°C to 150°C, preferably 20°C to 60°C, and more preferably 30°C to 50°C for about 1 to 150 hours, and preferably about 1 to 96 hours.

[0106] Compounds of formula X may be isolated or may be used without such further work-up to yield compounds of XI.

[0107] Another object according to the present invention relates to a method for preparing a compound having formula XII or an enrichment composition comprising a compound having formula XII:

[0108]

[0109] The method comprises a method according to the invention for preparing a compound of formula II and / or comprises a method according to the invention for preparing a compound of formula III. More specifically, this further object relates to a method according to the invention for preparing a compound of formula II and / or a method according to the invention for preparing a compound of formula III, wherein the method may further comprise preparing a compound of formula XII, in particular after preparing a compound of formula XI.

[0110] In a preferred embodiment, the compound having Formula XII may have the following structure:

[0111]

[0112] It is the (5S, 4R) isomer of 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). The preparation of the enrichment composition may contain the compound of formula XII (5S, 4R) and at least one of the isomers of the compound of formula XII selected from the group consisting of isomer (5S, 4S), isomer (5R, 4R), isomer (5R, 4S) and any combination thereof. 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; Isomer (5R, 4R) is 4-[(5R)-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; and 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-isoxazolidin-4-yl]-2-methyl-benzamide. The enriched composition may contain a molar proportion of the isomer (5S,4R) greater than 50%, for example at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, relative to the total amount of isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S).

[0113] Compounds of formula XII can be prepared, for example, according to WO 2011 / 067272 or WO 2016 / 023787 (incorporated herein by reference).

[0114] More specifically, the process for preparing the compound having formula XII is carried out by reacting the compound having formula XI as described in the present invention with hydroxylamine or a salt thereof, a base, a chiral catalyst and an organic solvent.

[0115] The term "hydroxylamine" means free hydroxylamine having the formula H2NOH, and the hydroxylamine salt may be, for example, hydroxylamine chloride.

[0116] The chiral catalyst may more specifically be a catalyst comprising at least one chiral moiety, and preferably at least two chiral moieties.The chiral catalyst may include any suitable chiral catalyst well known in the art. In a first example, the chiral catalyst can be a compound of formula III described on page 2 of WO 2016 / 023787 (incorporated by reference), preferably a dimerization chiral catalyst of formula III described on page 4 of WO 2016 / 023787, and more preferably a compound R-(6-methoxy-4-quinolyl)-[(2S)-1-[[2,3,5,6-tetrafluoro-4-[[(2S)-2-[(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidine-1-ium-1-yl]methyl]phenyl]methyl]-5-vinyl-quinuclidine-1-ium-2-yl]methanol dibromide (TFBBQ) having the following CAS number: 1879067-61-4. On pages 7-8 of WO 2016 / 023787, the compound having formula XVII can be prepared by reacting a compound having formula XV with a suitable halogenating agent (such as SOBr2, POBr3, PBr3, HBr, NaBr / H2SO4, or 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) to produce a compound having formula XVI. Then, the compound of formula XVI can be reacted with the compound of formula X described on page 7 of WO 2016 / 023787 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 produce a compound of formula XVII. In a second example, the chiral catalyst can be a compound of formula 2 to formula 12 as a chiral phase transfer catalyst described in US2014350261A1 (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).

[0117] The organic solvent used in the reaction of 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, isopropanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, 2-methylpropionitrile, butyronitrile, preferably 1,2-dichloroethane, 2-methyltetrahydrofuran, acetonitrile or dichloromethane, at a temperature between -78°C and 60°C, preferably between -20°C and +20°C and a dilution of, for example, 0.1M to 1M. The reaction time is generally between 30 minutes and 48 hours, preferably between 1 and 4 hours. The amount of catalyst can generally be from 0.01 to 0.4 molar equivalents, preferably from 0.02 to 0.2 molar equivalents. The amount of hydroxylamine can be from 1 to 10 equivalents, preferably from 1.0 to 1.2 equivalents.

[0118] The base used in the reaction of the compound with formula XI to the compound with formula XII can include an alkali metal hydroxide (such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide), and its amount is usually between 0.05 and 2 equivalents. Preferably, the amount of the base used is from 0.05 to 1.0 equivalent. The reaction can be carried out in the presence of water. The expression "molar equivalent" for obtaining a compound with formula XII is based on the mole number (mol) of the compound with formula XI.

[0119] The invention will now be described by way of non-limiting examples.

[0120] Examples

[0121] Example 1: Preparation of potassium (4R)-2-oxooxazolidine-4-carboxylate using potassium methoxide in methanol

[0122] Under nitrogen atmosphere, a solution of potassium methoxide in methanol (390.9 g, 1.80 mol, 32%) was charged in a double-jacketed reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser. D-serine (160.0 g, 1.50 mol, 98%) was added in 2 portions at 5-minute intervals while stirring. The resulting suspension was heated to 50° C., and then dimethyl carbonate (150.0 g, 1.70 mol, 99%) was added within 1 h while maintaining the temperature at 50° C. The reaction mixture was stirred at 50° C. for 2 h to obtain a conversion of ≥ 98% (based on a reaction mixture in DMSO-d6 doped with a few drops of methanol). 1H NMR analysis). The suspension was cooled to 0°C within 1 h and then left at 0°C overnight while stirring. The next day, the reaction mixture was filtered, the filter cake was washed with cold methanol (94 g) and dried in a drying oven at 50°C overnight to give (4R)-2-oxooxazolidine-4-carboxylate as a white, well-flowing, non-hygroscopic crystalline powder (252.5 g). The chemical purity was 96% (based on quantitative analysis in D2O). 1 H NMR with maleic acid as standard) and the isolated yield was 96%.

[0123] 1 H NMR (400 MHz, D2O) δ ppm: 4.63-4.69 (m, 1H), 4.48-4.55 (m, 2H), NH is not visible due to exchange with deuterium.

[0124] 1 H NMR (400 MHz, CD3OD) δppm: 4.56-4.60 (m, 1H), 4.35-4.39 (m, 1H), 4.18-4.22 (m, 1H). NH is not visible due to exchange with deuterium.

[0125] 13 C NMR (100.6MHz, D2O) δppm: 177.9, 161.9, 69.2, 55.9.

[0126] Example 2: Preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate using sodium methoxide in methanol

[0127] Under nitrogen atmosphere, D-serine (1.05 g, 10.0 mmol) and methanol (2.0 mL) were charged in a screw cap septum vial. To the resulting suspension was added a solution of sodium methoxide in methanol (2.17 g, 12.0 mol, 30%) at room temperature over 1 min. The mixture was stirred for 10 min to produce 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 another 2 h. 1 H NMR analysis (400 MHz, DMSO-d6 with a few drops of MeOH added) indicated 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.

[0128] Example 3: Preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate using sodium ethoxide in ethanol

[0129] Under nitrogen atmosphere, D-serine (1.06 g, 10.0 mmol) and ethanol (2.0 mL) were charged into a screw cap septum vial. A solution of sodium ethoxide in ethanol (4.5 mL, 3.89 g, 12.0 mol, 21%) was added to the resulting suspension at room temperature. The mixture was stirred for 10 min, 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) indicated 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.

[0130] Example 4: Preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from D-serine without isolating potassium (4R)-2-oxooxazolidine-4-carboxylate

[0131] Under nitrogen atmosphere, a double-jacketed reactor equipped with a mechanical stirrer, a thermometer and a Dean-Stark apparatus was charged with a solution of potassium methoxide in methanol (126.0 g, 0.575 mol, 32%). 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%) over 0.5 h while maintaining the temperature at 50° C. The reaction mixture was stirred at 50° C. for 2 h to obtain a conversion of ≥ 98% (based on quantitative analysis in DMSO-d6 spiked with a few drops of methanol). 1 H NMR analysis). The reaction mixture was neutralized to pH 7-8 (wetted pH paper) with concentrated sulfuric acid (3.8 g, 0.0375 mol, 98%). Methanol was replaced by methyl isobutyl ketone by first distilling off a portion of the methanol (53 g, about 1 / 3 of the total amount), and then methyl isobutyl ketone was continuously added while continuing to distill off the methanol (temperature T in the reactor). r The temperature was from 65°C to 80°C; the vacuum was from 1000 to 300 mbar). A total of 224 g of methyl isobutyl ketone were introduced. The residual amount of methanol in the reaction mixture accounted for 1 w% ( 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 dehydrated by azeotropic removal of water (temperature T in the reactor). rFrom 55 ℃ to 63 ℃; vacuum degree is 300 mbar). After releasing the vacuum, acetone (121g) is added, and the mixture is heated to 64 ℃. The suspension of salts is filtered (hot filtration), the filter cake is washed with hot acetone (43g), and the combined mother liquor is returned to the reactor. Acetone is distilled from the mixture, first at ambient pressure, and then under vacuum (from 1000 to 300 mbar) to crystallize the product. The resulting suspension is cooled to room temperature and filtered. The filter cake is washed with methyl isobutyl ketone (42g) and dried overnight at 50 ℃ in a drying oven to obtain (4R)-2-oxooxazolidine-4-carboxylic acid as a white crystalline solid (61.6g). The chemical purity is 93.4% (according to quantitative in D2O 1 H NMR with maleic acid as standard) and the isolated yield was 88%.

[0132] 1 H NMR (400 MHz, D2O) δ ppm: 4.60-4.64 (m, 1H), 4.44-4.53 (m, 2H), NH and COOH are not visible due to exchange with deuterium.

[0133] 1 H NMR (400MHz, DMSO-d6) δppm: 13.21 (br s, 1H), 8.12 (s, 1H), 4.44-4.51 (m, 2H), 4.27-4.36 (m, 2H).

[0134] 13 C NMR (100.6MHz, D2O) δppm: 174.3, 161.5, 67.8, 53.9.

[0135] Example 5: Preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from potassium (4R)-2-oxooxazolidine-4-carboxylate using gaseous HCl.

[0136] In a double-jacketed reactor equipped with a mechanical stirrer, a thermometer, a distillation apparatus and a gas introduction tube, (4R)-2-oxoxazolidine-4-formate potassium (75.1 g, 0.431 mol, 97%) was suspended in methyl isobutyl ketone (92 g). A stream of hydrogen chloride (25.0 g, 0.517 mol) was introduced below the liquid surface within 15 min while the temperature was maintained at 20 ° C. The reaction mixture was stirred for 20 min at 20 ° C. In order to remove excess HCl, a nitrogen stream was passed through the reaction mixture during 30 min. Acetone (115 g) and water (4 g) were added, and the mixture was then heated to 62 ° C. The suspension of the salt was filtered (hot filtration), the filter cake was washed with hot acetone (28 g), and the combined filtrate was returned to the reactor. Acetone was distilled from the mixture, first at ambient pressure, and then under vacuum (from 1000 to 300 mbar) to crystallize the product. The resulting suspension was cooled to room temperature and filtered. The filter cake was washed with methyl isobutyl ketone (51 g) and dried in a drying oven at 50° C. overnight to give (4R)-2-oxooxazolidine-4-carboxylic acid as a white crystalline solid (49.3 g). The chemical purity was 93.7% (based on quantitative analysis in D2O). 1 H NMR with maleic acid as standard) and the isolated yield was 82%.

[0137] NMR data: 1 H NMR (400 MHz, D2O) δ ppm: 4.62-4.67 (m, 1H), 4.47-4.55 (m, 2H), NH and COOH are not visible due to exchange with deuterium.

[0138] Example 6: Preparation of (4R)-2-oxooxazolidine-4-carboxylic acid from potassium (4R)-2-oxooxazolidine-4-carboxylate using concentrated H2SO4 and 2-pentanone as solvents.

[0139] A double-jacketed reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser was charged with (4R)-2-oxoxazolidine-4-formate potassium (50.0 g, 0.288 mol, 97.3%). Wet 2-pentanone (120 g, 3 w% water) prepared from 2-pentanone (116.4 g) and water (3.6 g) was added. The resulting suspension was heated to 80 ° C, and concentrated sulfuric acid (28.8 g, 0.288 mol, 98%) was subsequently added dropwise while the temperature was maintained in the range of 80 ° C-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. About 1 / 3 of the total amount of 2-pentanone (120 g) was distilled off in vacuum (from 340 to 240 mbar). The solution was cooled from 73 ° C to 25 ° C in 2 h to crystallize the product. The resulting suspension was stirred at 25°C overnight and filtered. The filter cake was washed with 2-pentanone (16 g) and dried in a drying oven at 60°C overnight to give the title compound as a pale yellow crystalline solid (20.9 g). The chemical purity was 90.4% (based on quantitative analysis in D2O). 1 H NMR with maleic acid as standard) 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.

[0140] 1 H NMR (400 MHz, D2O) δ ppm: 4.62-4.67 (m, 1H), 4.47-4.56 (m, 2H), NH and COOH are not visible due to exchange with deuterium.

Claims

1. A method for preparing a compound of formula II: wherein M is selected from Na, K and Li, The method comprises reacting a compound having formula I with a base, a reagent and optionally an organic solvent: Where R 1 is selected from hydrogen, Na, K and Li, The process is characterized in that the base is a metal salt of an alkoxide.

2. The method according to claim 1, characterized in that The metal salt of the alkoxide is an alkali metal salt of a C1-C5 alkoxide.

3. The method according to any one of the preceding claims, characterized in that The reagent is selected from the group consisting of organic carbonates, halogenated carbonates, and any mixtures thereof.

4. The method according to any one of the preceding claims, characterized in that The agent is selected from the group consisting of aryl carbonates, alkyl carbonates, aryl alkyl carbonates, and any mixtures thereof.

5. The method according to any one of the preceding claims, characterized in that The reagent is a chlorocarbonate.

6. The method according to any one of the preceding claims, characterized in that The organic solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, tert-amyl alcohol, toluene, tetrahydrofuran and any mixture thereof.

7. The method according to any one of the preceding claims, characterized in that The amount of the base is from 0.01 to 10 molar equivalents, preferably from 0.05 to 5 molar equivalents, preferably from 0.1 to 2.0 molar equivalents, and more preferably from 0.1 to 1.5 molar equivalents.

8. The method according to any one of the preceding claims, characterized in that The amount of the reagent is 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.

9. The method according to any one of the preceding claims, characterized in that The amount of the organic solvent is from 1 to 200 molar equivalents, preferably from 1 to 100 molar equivalents, and more preferably from 1 to 20 molar equivalents.

10. The method according to any one of the preceding claims, characterized in that The process further comprises a crystallization step and optionally a subsequent separation step.

11. A method for preparing a compound of formula III: The method comprises reacting a compound having formula II with an acid in the presence of a solvent.

12. The method according to claim 11, characterized in that The process further comprises a crystallization step and optionally a subsequent separation step.

13. The method 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 any mixture thereof.

14. The method according to any one of claims 11 to 13, 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 any mixture thereof.

15. A compound having formula Ia Where R 2 Selected from C 1-4 alkyl, phenyl, benzyl, C2H4OH, C3H6OH, CHCH3CH2OH and CH2CHCH3OH; and M is selected from Na, K and Li.

16. A method for preparing a compound of formula VI: The method comprises the method for preparing a compound having formula II according to claim 1 and / or comprises the method for preparing a compound having formula III according to claim 11.

17. A method for preparing a compound of formula VIII: The method comprises the method for preparing a compound having formula II according to claim 1 and / or comprises the method for preparing a compound having formula III according to claim 11.

18. A method for preparing a compound of formula XI: The method comprises the method for preparing a compound having formula II according to claim 1 and / or comprises the method for preparing a compound having formula III according to claim 11.

19. A method for preparing a compound of formula XII or an enrichment composition comprising a compound of formula XII: The method comprises the method for preparing a compound having formula II according to claim 1 and / or comprises the method for preparing a compound having formula III according to claim 11.

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