Preparation and purification method of 4-chloromethyl-5-methyl-1, 3-dioxole-2-ketone

Abstract

The invention provides a preparation method and a purification method of 4-chloromethyl-5-methyl-1, 3-dioxole-2-ketone, and particularly provides a preparation method and a purification method of 4-chloromethyl-5-methyl-1, 3-dioxole-2-ketone. Specifically, the present invention provides a DMDO-Cl crude product purification method, which comprises: (1) providing a DMDO-Cl crude product, an organic solvent and an organic alkali mixed system, and carrying out a reaction on the mixed system to obtain a reaction liquid; (2) washing the reaction liquid obtained in the step (1) with water, and separating to obtain an organic phase; and (3) removing the organic solvent in the organic phase obtained in the step (2) so as to obtain a DMDO-Cl purified product. According to the method disclosed by the invention, the organic alkali is added to destroy impurities, and the high-purity product can be obtained only by removing the solvent through reduced pressure distillation, so that the problems of high temperature, high vacuum degree, easy deterioration of the product and low purity of the product in the existing process are solved, and the method is an efficient, economic and feasible process for industrial amplification implementation.

Description

Technical Field

[0001] The present application belongs to the pharmaceutical field, and specifically relates to a method for purifying 4-chloromethyl-5-methyl-1,3-dioxole-2-one. Background Art

[0002] 4-Chloromethyl-5-methyl-1,3-dioxol-2-one, referred to as DMDO-Cl, is an important pharmaceutical intermediate that can be used to synthesize drugs such as lenampicillin and olmesartan. For the synthesis of DMDO-Cl, 4,5-dimethyl-1,3-dioxol-2-one (DMDO) is generally used to react with sulfonyl chloride to first generate 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one, and then a rearrangement reaction is performed to obtain a crude DMDO-Cl product, and finally a vacuum distillation is performed to obtain DMDO-Cl. For example, patents US4554358 and CN114437015 perform vacuum distillation at 91-93°C (2 mmHg) to obtain purified DMDO-Cl.

[0003]

[0004] For the purification of DMDO-Cl, currently most industrial production uses vacuum distillation. However, on the one hand, DMDO-Cl has poor stability at high temperatures and is prone to decomposition and polymerization reactions, which can deteriorate, affecting the yield and product purity. The purity of the product detected by GC is around 90% to 95%, which is difficult to achieve the high purity requirement of more than 98%; on the other hand, the vacuum degree of 2 mmHg is difficult to achieve in industry, and the requirements for equipment are very high. Further expansion of production scale is limited, which seriously affects the production capacity of DMDO-Cl.

[0005] In addition, during the reaction process, a portion of cis- and trans-dichloro impurities 4,5-dichloro-4,5-dimethyl-1,3-dioxolane-2-one are often generated. This impurity is difficult to remove and will cause the residues of these two impurities in the product.

[0006]

[0007] Li Peicheng, Zhang Xiaoyu, Min Qigang. Research on the industrial synthesis of 4-chloromethyl-5-methyl-1,3-dioxole-2-one [J]. Fine Chemical Intermediates, 2001(01):16-18. It was reported that after vacuum distillation to remove the front fraction and flash evaporation and other refining processes, only a product with a purity of 75% was finally obtained, of which the impurity content of the trans isomer was 8% and the impurity content of the cis isomer was 10%.

[0008] Patent CN102617542 uses a recrystallization method to purify DMDO-Cl: crystallization is performed at a low temperature of -20°C in a mixed solvent of one or more alkane solvents and ether solvents. However, the crystallization temperature of -20°C consumes a lot of energy and is difficult to achieve in industry; in addition, since DMDO-Cl is a liquid at room temperature, the subsequent filtration operation also needs to be carried out in a low temperature environment, but low-temperature filtration at -20°C is difficult to achieve in industry, and part of DMDO-Cl will melt into liquid during filtration, which seriously affects the filtration efficiency and yield; in addition, since DMDO-Cl is a liquid at room temperature, the product obtained by filtration cannot be dried to remove the solvent residue, thereby affecting the purity of the product. We have also tried to purify according to this method, but the crystallization was not successful.

[0009] In view of this, it is necessary to develop an efficient, industrially feasible and high-yield purification method for DMDO-Cl. Summary of the invention

[0010] The purpose of the present invention is to provide a method for purifying and preparing 4-chloromethyl-5-methyl-1,3-dioxole-2-one.

[0011] In a first aspect of the present invention, a method for purifying a crude DMDO-Cl product is provided, comprising the steps of:

[0012] (1) providing a mixed system of a crude DMDO-Cl product, an organic solvent, and an organic base, and reacting the mixed system to obtain a reaction solution;

[0013] (2) washing the reaction solution obtained in step (1) with water and separating to obtain an organic phase; and

[0014] (3) removing the organic solvent in the organic phase obtained in step (2) to obtain a purified DMDO-Cl product;

[0015] Here, DMDO-Cl refers to 4-chloromethyl-5-methyl-1,3-dioxol-2-one.

[0016] In another preferred embodiment, the purity of the crude DMDO-Cl is less than 90%.

[0017] In another preferred embodiment, the crude DMDO-Cl contains cis-dichloro impurities;

[0018]

[0019] In another preferred embodiment, the content of cis-dichloro impurity in the crude DMDO-Cl is >0.5%; preferably, >1%; more preferably, >2%.

[0020] In another preferred embodiment, the crude DMDO-Cl contains trans-dichloro impurities;

[0021]

[0022] In another preferred embodiment, the content of trans-dichloro impurity in the crude DMDO-Cl is >0.5%; preferably, >1%; more preferably, >2%; and most preferably, >7%.

[0023] In another preferred embodiment, in the purified DMDO-Cl product, the GC purity of DMDO-Cl is >98.5%, more preferably, >99.0%.

[0024] In another preferred embodiment, in the purified DMDO-Cl product, the cis-dichloro impurity content is <0.05%; preferably, <0.03%; more preferably, <0.02%.

[0025] In another preferred embodiment, the content of trans-dichloro impurity in the DMDO-Cl purified product is less than 0.02%; preferably, less than 0.01%; more preferably, less than 0.0025%.

[0026] In another preferred embodiment, the organic base is an organic base containing a tertiary amine group (-N=).

[0027] In another preferred embodiment, the organic base is a cyclic organic base, and the tertiary amine-containing group (-N=) is a ring atom on the ring.

[0028] In another preferred embodiment, the organic base is selected from:

[0029] (a) a pyridine derivative organic base represented by formula A;

[0030]

[0031] Among them, R 1 and R 2 Each independently selected from the following group: H, C 1-6 Alkyl, optionally substituted C 2-3 Alkylene, or R 1 and R 2 and the nitrogen to which it is attached together form an optionally substituted 4- to 6-membered nitrogen-containing cycloalkyl, wherein the substitution refers to one or more hydrogen atoms in the group being replaced by a C1-4 alkyl group; and when R 1 and / or R 2 C 2-3 When alkylene is 2-3 The other end of the alkylene group (i.e., the end not connected to N) is connected to the 3-position and / or 5-position of pyridine to form a 5- or 6-membered heterocyclic ring;

[0032] (b) a nitrogen-containing cycloalkyl derivative organic base represented by formula B;

[0033]

[0034] Among them, R 3 C 1-6 Alkyl, n1 and n2 are each independently 1 or 2, and X is NH, N(C1-C6 alkyl), O or S;

[0035] (c) alkylamine organic bases;

[0036] (d) metal alkoxide organic bases;

[0037] (e) a 5- to 10-membered nitrogen-containing heterocyclic ring; and

[0038] (f) Combinations of the above organic bases.

[0039] In another preferred embodiment, the organic base is selected from: a pyridine derivative organic base represented by formula A and a nitrogen-containing cycloalkyl derivative organic base represented by formula B, or a combination thereof.

[0040] In another preferred embodiment, the organic base represented by formula A includes: 4-pyrrolidinylpyridine, 4-dimethylaminopyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, and 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ][1,6]naphthyridine.

[0041] In another preferred embodiment, the organic base represented by formula B includes: N-methylmorpholine.

[0042] In another preferred embodiment, N(C 1-6 alkyl) 3 (such as triethylamine, tributylamine, diisopropylethylamine), N,N,N',N'-tetramethylethylenediamine.

[0043] In another preferred embodiment, the alcohol metal salt organic base is a C1-6 alcohol metal salt base; preferably includes: sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide.

[0044] In another preferred embodiment, the nitrogen-containing 5- to 10-membered heterocycle is a nitrogen-containing 5- or 6-membered heterocycle; preferably, it includes: imidazole, pyridine, and piperazine.

[0045] In another preferred embodiment, in step (1), the organic base is selected from the following group: N-methylmorpholine, 4-pyrrolidinylpyridine, 4-dimethylaminopyridine, imidazole, triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, piperazine, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ][1,6]naphthyridine, sodium methoxide, sodium ethoxide, N,N,N',N'-tetramethylethylenediamine.

[0046] In another preferred embodiment, the organic base is selected from the following group: 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, 4-pyrrolidinylpyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ][1,6]naphthyridine.

[0047] In another preferred embodiment, in step (1), the reaction temperature of the reaction is 0 to 40°C; preferably, 20 to 30°C.

[0048] In another preferred embodiment, in step (1), the organic solvent is selected from the following group: C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, aromatic solvents, C1-C6 ester solvents, C2-C6 ether solvents, or a combination thereof.

[0049] In another preferred example, the C1-C6 halogenated alkane solvent includes: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or a combination thereof.

[0050] In another preferred example, the aromatic hydrocarbon solvent includes toluene, chlorobenzene, or a combination thereof.

[0051] In another preferred embodiment, in step (1), the organic solvent is a C1-C6 halogenated alkane solvent; preferably, it is dichloromethane.

[0052] In another preferred embodiment, in step (1), the ratio of the organic solvent to the crude DMDO-Cl product is 1-5 mL:1 g, preferably 2±1 mL:1 g.

[0053] In another preferred embodiment, in step (1), the molar ratio of the organic base to the crude DMDO-Cl is 0.1-0.5:1, preferably 0.3±0.1:1.

[0054] In another preferred embodiment, in step (2), the water for washing is provided in the form of pure water or an aqueous solution; preferably, it is provided in the form of an aqueous solution.

[0055] In another preferred embodiment, in step (2), the aqueous solution is an aqueous solution of an acid.

[0056] In another preferred embodiment, in step (2), the acid is selected from the following group: hydrochloric acid, sulfuric acid, acetic acid or a combination thereof.

[0057] In another preferred embodiment, in step (2), the washing water is provided in the form of an aqueous acid solution, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid or a combination thereof, preferably hydrochloric acid.

[0058] In another preferred embodiment, the concentration of the acid in the aqueous solution of the acid is 0.5 wt % to 10 wt %; preferably, 1 wt % to 5 wt %.

[0059] In another preferred embodiment, an aqueous acid solution is used to wash the remaining organic base.

[0060] In another preferred embodiment, in step (3), the organic solvent in the organic phase is removed by distillation under reduced pressure.

[0061] In another preferred embodiment, in step (3), distillation under reduced pressure is performed at a temperature of ≤50°C (preferably, ≤40°C).

[0062] In a second aspect of the present invention, a method for preparing DMDO-Cl is provided, the method comprising the steps of:

[0063] (A) Preparation steps of crude DMDO-Cl; and

[0064] (B) Purification steps of crude DMDO-Cl;

[0065] in,

[0066] The preparation steps of the DMDO-Cl crude product include:

[0067] (A1) subjecting DMDO to a chlorine substitution reaction to obtain a chlorine substitution product, 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one; wherein DMDO refers to 4,5-dimethyl-1,3-dioxol-2-one; and

[0068] (A2) subjecting 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one to a rearrangement reaction to obtain a crude DMDO-Cl product;

[0069] The purification step of the crude DMDO-Cl product comprises:

[0070] (1) providing a mixed system of a crude DMDO-Cl product, an organic solvent, and an organic base, and reacting the mixed system to obtain a reaction solution;

[0071] (2) washing the reaction solution obtained in step (1) with water and separating to obtain an organic phase; and

[0072] (3) removing the organic solvent in the organic phase obtained in step (2) to obtain a purified DMDO-Cl product;

[0073] Here, DMDO-Cl refers to 4-chloromethyl-5-methyl-1,3-dioxol-2-one.

[0074] In another preferred embodiment, the chlorine substitution reaction can be carried out according to conventional methods in the art.

[0075] In another preferred embodiment, the chlorination reagent used in the chlorine substitution reaction is selected from the following group: sulfonyl chloride, chlorine gas, N-chlorosuccinimide, thionyl chloride, phosphorus oxychloride, triphosgene, or a combination thereof.

[0076] In another preferred embodiment, the molar ratio of the chlorination reagent and DMDO used in the chlorine substitution reaction is 0.5-2:1; preferably 0.9-1.5:1; more preferably, 1-1.2:1; most preferably, 1-1.1:1.

[0077] In another preferred embodiment, the chlorine substitution reaction is carried out in a reaction solvent.

[0078] In another preferred embodiment, the chlorine substitution reaction is carried out at reflux temperature.

[0079] In another preferred embodiment, the reaction time of the chlorine substitution reaction is 1 to 4 hours.

[0080] In another preferred embodiment, the rearrangement reaction is carried out under solvent-free conditions.

[0081] In another preferred embodiment, the reaction temperature of the rearrangement reaction is 40-100°C, preferably 50-60°C.

[0082] In another preferred embodiment, the reaction time of the rearrangement reaction is 1 to 8 hours.

[0083] In another preferred embodiment, step (A1) comprises the steps of:

[0084] (A1.1) providing a chlorination reaction system of 4,5-dimethyl-1,3-dioxol-2-one (DMDO) and a chlorination agent in a reaction solvent;

[0085] (A1.2) 4,5-dimethyl-1,3-dioxol-2-one (DMDO) in the chlorination reaction system is subjected to a chlorine substitution reaction to obtain a system containing 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolan-2-one.

[0086] In another preferred embodiment, the reaction solvent is selected from the following group: C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, aromatic hydrocarbon solvents, C2-C6 ether solvents, or a combination thereof; preferably, the reaction solvent is a C1-C6 halogenated alkane solvent; more preferably, the reaction solvent is dichloromethane.

[0087] In another preferred embodiment, the chlorine substitution reaction is carried out under reflux.

[0088] In another preferred embodiment, step (A2) comprises the steps of:

[0089] (A2.1) removing the reaction solvent in the system containing 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one obtained in step (1.2); and

[0090] (A2.2) Rearrange 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one to obtain a system containing DMDO-Cl.

[0091] In another preferred embodiment, in step (A2.1), the reaction solvent is removed by distillation under reduced pressure.

[0092] In another preferred embodiment, in step (A2.1), the reaction solvent is removed by distillation under reduced pressure at an external temperature of ≤40°C.

[0093] In another preferred embodiment, steps (1), (2) and (3) are as defined in the first aspect.

[0094] In another preferred embodiment, the total yield of the preparation method is ≥70% (preferably, ≥75%; optimally, ≥80%), calculated on the basis of DMDO.

[0095] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 The gas chromatogram (GC) of DMDO-Cl prepared in Example 1 is shown.

[0097] Figure 2The gas chromatogram (GC) of DMDO-Cl prepared in Example 2 is shown.

[0098] Figure 3 The gas chromatogram (GC) of the crude DMDO-Cl prepared in Example 1 is shown.

[0099] Figure 4 The gas chromatogram (GC) of the crude DMDO-Cl prepared in Example 2 is shown.

[0100] Figure 5 A gas chromatogram of the crude product before purification in Comparative Example 1 is shown.

[0101] Figure 6 The gas chromatogram of the product after purification by adding NaOH solution with a pH value of 9 to 9.5 in Comparative Example 1 is shown.

[0102] Figure 7 The gas chromatogram of the product after purification by adding NaOH solution with a pH value of 8 to 9 in Comparative Example 1 is shown.

[0103] Figure 8 The gas chromatogram (GC) of the crude DMDO-Cl prepared in Example 3 is shown.

[0104] Fig. 9 The gas chromatogram (GC) of DMDO-Cl prepared in Example 3 is shown. DETAILED DESCRIPTION

[0105] After extensive and in-depth research, the inventor unexpectedly found that the use of organic bases (especially nitrogen-containing cycloalkyl derivative organic bases and nitrogen-containing cycloalkyl derivative organic bases shown in formula B) in the treatment of crude DMDO-Cl can effectively destroy impurities that are difficult to separate without affecting DMDO-Cl, thereby obtaining high-purity DMDO-Cl with high yield by only using reduced pressure distillation to remove the solvent. Based on this, the inventor completed the present invention.

[0106] the term

[0107] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0108] As used herein, the terms "DMDO-Cl" and "4-chloromethyl-5-methyl-1,3-dioxol-2-one" are used interchangeably.

[0109] As used herein, the terms "DMDO" and "4,5-dimethyl-1,3-dioxol-2-one" are used interchangeably.

[0110] As used herein, when a numerical value is expressed as "A±a", it means Aa≤specified value≤A+a, for example, 0.3±0.1 means 0.2≤specified value≤0.4.

[0111] As used herein, the term "alkylamine organic base" refers to an amine organic base having a structure such as NH2R, NHR2 or NR3, wherein R is an alkyl group (such as C 1-6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, etc.), and each R may be the same or different.

[0112] As used herein, the term "alkyl" refers to a straight or branched chain or cyclic hydrocarbon group (e.g., C 1-6 Indicates 1-6 carbons, C 2-10 represents 2-10 carbons). Alkyl (such as C 1-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, n-pentyl, n-hexyl, cyclopropyl and the like.

[0113] As used herein, the term "alkylene" refers to a divalent group derived from an alkane, for example, -CH 2 CH 2 -、-CH 2 CH 2 CH 2 -. In this context, optionally substituted alkylene refers to an alkylene group that is unsubstituted or substituted by one or more (e.g., 1, 2, or 3) C1-4 alkyl groups (e.g., methyl). 2-3 Examples of alkyl groups include, for example, -CH 2 CH 2 -、-CH 2 CH(CH 3 )-、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 C(CH 3 ) 2 -wait.

[0114] As used herein, unless otherwise defined, the term "nitrogen-containing cycloalkyl" is a saturated or unsaturated (preferably saturated) non-aromatic heterocyclic ring having at least one nitrogen heteroatom as a ring atom, and the heterocyclic ring may optionally contain 1 or 2 heteroatoms selected from O or S as ring atoms. Preferably, the ring atoms of the nitrogen-containing cycloalkyl are composed of nitrogen heteroatoms and carbon atoms; more preferably, only one ring atom of the nitrogen-containing cycloalkyl is a nitrogen heteroatom, and the remaining ring atoms are carbon atoms.

[0115] As used herein, the term "5- to 10-membered nitrogen-containing heterocycle" refers to a saturated or unsaturated, aromatic or non-aromatic, monocyclic or bicyclic heterocycle having 5 to 10 ring atoms, and the ring atoms consist of at least one nitrogen heteroatom, an optional oxygen or sulfur heteroatom, and the remainder of carbon atoms. Preferably, the 5- to 10-membered nitrogen-containing heterocycle is aromatic. Examples of 5- to 10-membered nitrogen-containing heterocycles include imidazole, pyridine, piperazine, and the like.

[0116] Purification method of 4-chloromethyl-5-methyl-1,3-dioxole-2-one (DMDO-Cl)

[0117] In order to solve the shortcomings of the prior art, namely, the technical shortcomings of low production capacity, low purity, high energy consumption and the like in the industrial production of DMDO-Cl, the present invention provides an industrially feasible DMDO-Cl purification method.

[0118] In a specific embodiment, a method for purifying a crude DMDO-Cl product is provided, wherein the purification method is as described in the first aspect.

[0119] In another specific embodiment, a method for purifying 4-chloromethyl-5-methyl-1,3-dioxole-2-one (ie, DMDO-Cl) is provided, comprising the following steps:

[0120] (S1) adding an organic solvent and an organic base to the crude DMDO-Cl product and stirring the reaction;

[0121] (S2) adding water to the reaction solution obtained in (S1) for washing, and separating the organic phase;

[0122] (S3) The solvent is removed from the organic phase obtained in (S2) to obtain DMDO-Cl.

[0123] Optionally, the organic solvent described in step (S1) is selected from: C1-C6 alkane solvents, C1-C6 ester solvents, C2-C6 ether solvents, or a combination thereof, preferably dichloromethane.

[0124] Optionally, the organic base described in step (S1) is selected from: triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, piperazine, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, IJ] [1,6] naphthyridine, imidazole, sodium methoxide, sodium ethoxide, N,N,N',N'-tetramethylethylenediamine, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, 4-pyrrolidinylpyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ] [1,6] naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ] [1,6] naphthyridine.

[0125] Optionally, in step (S1), the ratio of the organic solvent to the crude DMDO-Cl product is 1-5 mL:1 g, preferably 2 mL:1 g.

[0126] Optionally, in step (S1), the molar ratio of the organic base to the crude DMDO-Cl product is 0.1 to 0.5:1, preferably 0.3:1.

[0127] Optionally, step (S2) further comprises washing the remaining organic base with an acid, wherein the acid may be hydrochloric acid, sulfuric acid, acetic acid or a combination thereof, preferably hydrochloric acid;

[0128] Optionally, in step (S3), the solvent is removed by distillation under reduced pressure.

[0129] Preparation method of 4-chloromethyl-5-methyl-1,3-dioxole-2-one (DMDO-Cl)

[0130] In a specific embodiment, a method for preparing DMDO-Cl is provided, wherein the preparation method is as described in the second aspect.

[0131] In another specific embodiment, a method for preparing 4-chloromethyl-5-methyl-1,3-dioxole-2-one (ie, DMDO-Cl) is provided, comprising the following steps:

[0132] (Z1): 4,5-dimethyl-1,3-dioxol-2-one undergoes chlorine substitution to give 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxol-2-one;

[0133] (Z2) 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one is rearranged to generate crude DMDO-Cl;

[0134] (Z3) adding an organic solvent and an organic base to the crude DMDO-Cl product and stirring the reaction;

[0135] (Z4) adding water to the reaction solution obtained in (Z3), washing, and separating the organic phase;

[0136] (Z5) The solvent is removed from the organic phase obtained in (Z4) to obtain DMDO-Cl.

[0137] According to the present invention, the reaction conditions of the chlorine substitution and rearrangement reaction in steps (Z1) and (Z2) can be selected with reference to conventional methods in the art, such as the reaction conditions in US4554358.

[0138] Optionally, the organic solvent in step (Z3) is selected from: C1-C6 alkane solvents, C1-C6 ester solvents, C2-C6 ether solvents, or a combination thereof, preferably dichloromethane.

[0139] Optionally, the organic base in step (Z3) is selected from: triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, piperazine, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, IJ] [1,6] naphthyridine, imidazole, sodium methoxide, sodium ethoxide, N,N,N',N'-tetramethylethylenediamine, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, 4-pyrrolidinylpyridine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ] [1,6] naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ] [1,6] naphthyridine.

[0140] Optionally, in step (Z3), the ratio of the organic solvent to the crude DMDO-Cl product is 1-5 mL:1 g, preferably 2 mL:1 g.

[0141] Optionally, in step (Z3), the molar ratio of the organic base to the crude DMDO-Cl is 0.1 to 0.5:1, preferably 0.3:1.

[0142] Optionally, step (Z4) further comprises washing the remaining organic base with an acid, wherein the acid may be hydrochloric acid, sulfuric acid, acetic acid or a combination thereof, preferably hydrochloric acid;

[0143] Optionally, in step (Z4), the solvent is removed by distillation under reduced pressure.

[0144] The main advantages of the present invention include

[0145] 1. By adding organic base to destroy the impurities that are difficult to remove, high-purity DMDO-Cl can be obtained by simply removing the solvent by distillation under reduced pressure, thus avoiding the high vacuum and high temperature conditions that limit the production capacity in the current process. The entire purification process is simple to operate, has low equipment requirements, and low energy consumption, and can be applied to large-scale industrial production.

[0146] 2. Good yield and high-purity products: The process of the present invention avoids the decomposition of the product under high-temperature and reduced-pressure distillation conditions, and the yield exceeds 80% (based on DMDO). The purity of the obtained DMDO-Cl is higher than 99%, wherein the cis-dichloro impurity content is less than 0.02%, and the trans-dichloro impurity content is ND, ensuring that the product can meet the quality requirements of various pharmaceutical intermediates.

[0147] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0148] Example 1

[0149] Preparation of crude DMDO-Cl

[0150] The raw material DMDO (7.50 g, 0.066 mol) was added to 1,2-dichloroethane (30 mL), the reaction solution was heated to reflux, and then a solution of sulfonyl chloride (9.32 g, 0.069 mol) in 1,2-dichloroethane (30 mL) was added dropwise under reflux conditions. After the addition was completed, the reaction was continued under reflux conditions for 4 hours. After the reaction was completed, 1,2-dichloroethane was distilled off under reduced pressure; after the distillation was completed, the reaction solution was heated to 50-60°C for rearrangement reaction for 7 hours to obtain a crude DMDO-Cl product (purity 83.25%, cis-dichloro impurity content 4.01%, trans-dichloro impurity content 11.2%, see Figure 3 ).

[0151] Purification of DMDO-Cl

[0152] Dichloromethane (15 mL) and 4-dimethylaminopyridine (2.44 g, 0.020 mol) were added to the above DMDO-Cl crude product. The pH after addition was 8-8.5. The reaction was carried out at 20-30°C for 1 hour. After the reaction was completed, 3.6 wt% dilute hydrochloric acid aqueous solution (3.75 mL) was added for washing. The organic phase after washing was distilled under reduced pressure at no more than 40°C until no solvent was distilled out, and 7.83 g of colorless to light yellow liquid was obtained, with a molar yield of 80.14% (two steps, based on DMDO). The purity was 99.10%, the cis-dichloro impurity content was 0.02%, and the trans-dichloro impurity content was ND. The gas chromatogram is shown in the figure below. Figure 1 shown.

[0153] Example 2

[0154] Preparation of crude DMDO-Cl

[0155] The raw material DMDO (7.50 g, 0.066 mol) was added to dichloromethane (30 mL), the reaction solution was heated to reflux, and then a dichloromethane (30 mL) solution of sulfonyl chloride (9.32 g, 0.069 mol) was added dropwise under reflux conditions. After the addition was completed, the reaction was continued under reflux conditions for 4 hours. After the reaction was completed, the dichloromethane was distilled off under reduced pressure at an external temperature not exceeding 40°C; after the distillation was completed, the reaction solution was heated to 50-60°C for rearrangement reaction for 7 hours to obtain a crude DMDO-Cl product (purity 86.69%, cis-dichloro impurity content 2.44%, trans-dichloro impurity content 9.03%, see Figure 4 ).

[0156] Purification of DMDO-Cl

[0157] Add dichloromethane (15mL) and 4-pyrrolidinylpyridine (2.96g, 0.020mol) to the above DMDO-Cl crude product, and react at 20-30°C for 1h. After the reaction, add 3.6wt% dilute hydrochloric acid aqueous solution (3.75mL) for washing. The washed organic phase is distilled under reduced pressure at no more than 40°C until no solvent is distilled out, and 7.84g of colorless to light yellow liquid is obtained, with a molar yield of 80.20% (two steps, based on DMDO). According to gas phase detection, the purity is 99.04%, the cis-dichloro impurity content is 0.02%, and the trans-dichloro impurity content is ND. Its gas chromatogram is as follows Figure 2 shown.

[0158] Example 3

[0159] Preparation of crude DMDO-Cl

[0160] The raw material DMDO (7.50 g, 0.066 mol) was added to dichloromethane (30 mL), the reaction solution was heated to reflux, and then a dichloromethane (30 mL) solution of sulfonyl chloride (9.32 g, 0.069 mol) was added dropwise under reflux conditions. After the addition was completed, the reaction was continued under reflux conditions for 4 hours. After the reaction was completed, the dichloromethane was distilled off under reduced pressure at an external temperature not exceeding 40°C; after the distillation was completed, the reaction solution was heated to 50-60°C for rearrangement reaction for 7 hours to obtain a crude DMDO-Cl product (purity 87.28%, cis-dichloro impurity content 2.61%, trans-dichloro impurity content 8.15%, see Figure 8 ).

[0161] Purification of DMDO-Cl

[0162] Add dichloromethane (15mL) and N-methylmorpholine (2.00g, 0.020mol) to the above DMDO-Cl crude product, and react at 20-30°C for 1h. After the reaction, add 3.6wt% dilute hydrochloric acid aqueous solution (3.75mL) for washing. The washed organic phase is distilled under reduced pressure at no more than 40°C until no solvent is distilled out, and 7.86g of colorless to light yellow liquid is obtained, with a molar yield of 80.5% (two steps, based on DMDO). According to gas phase detection, the purity is 98.34%, the cis-dichloro impurity content is 0.17%, and the trans-dichloro impurity content is ND. Its gas chromatogram is as follows Fig. 9 shown.

[0163] Comparative Example 1

[0164] Take 1 g of DMDO-Cl crude product, add dichloromethane (5 mL), add 2 mL of NaOH solution with different pH values ​​at room temperature, react for 1 h, let stand, take the organic layer for gas chromatography detection, the results are as follows:

[0165]

[0166] It can be seen from the above experiments that when using sodium hydroxide for purification, at a higher pH, although some dichloro impurities can be destroyed, the stability of the product DMDO-Cl is worse, resulting in a decrease in product purity; at a lower pH similar to that of using an organic base, although the product DMDO-Cl has better stability, it has no effect on removing dichloro impurities.

[0167] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for purifying crude DMDO-Cl, It is characterized in that Includes steps: (1) providing a mixed system of a crude DMDO-Cl product, an organic solvent, and an organic base, and reacting the mixed system to obtain a reaction solution; (2) washing the reaction solution obtained in step (1) with water and separating to obtain an organic phase; and (3) removing the organic solvent in the organic phase obtained in step (2) to obtain a purified DMDO-Cl product; Here, DMDO-Cl refers to 4-chloromethyl-5-methyl-1,3-dioxol-2-one.

2. The purification method according to claim 1, It is characterized in that The organic base is selected from: (a) a pyridine derivative organic base represented by formula A; Among them, R 1 and R 2 Each independently selected from the following group: H, C 1-6 Alkyl, optionally substituted C 2-3 Alkylene, or R 1 and R 2 and the nitrogen to which it is attached together form an optionally substituted 4- to 6-membered nitrogen-containing cycloalkyl, wherein the substitution refers to one or more hydrogen atoms in the group being replaced by a C1-4 alkyl group; and when R 1 and / or R 2 C 2-3 When alkylene is 2-3 The other end of the alkylene group is connected to the 3-position and / or 5-position of pyridine to form a 5- or 6-membered heterocyclic ring; (b) a nitrogen-containing cycloalkyl derivative organic base represented by formula B; Among them, R 3 C 1-6 Alkyl, n1 and n2 are each independently 1 or 2, and X is NH, N(C1-C6 alkyl), O or S; (c) alkylamine organic bases; (d) metal alkoxide organic bases; (e) a 5- to 10-membered nitrogen-containing heterocyclic ring; and (f) a combination of the above organic bases; Preferably, the organic base is selected from: a pyridine derivative organic base represented by formula A and a nitrogen-containing cycloalkyl derivative organic base represented by formula B, or a combination thereof.

3. The purification method according to claim 1, It is characterized in that In step (1), the organic base is selected from the following group: N-methylmorpholine, 4-pyrrolidinylpyridine, 4-dimethylaminopyridine, imidazole, triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, piperazine, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine, 4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ][1,6]naphthyridine, sodium methoxide, sodium ethoxide, N,N,N',N'-tetramethylethylenediamine.

4. The purification method according to claim 1, It is characterized in that In step (1), the reaction temperature is 0 to 40°C; preferably, 20 to 30°C.

5. The purification method according to claim 1, It is characterized in that In step (1), the organic solvent is selected from the following group: C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, aromatic hydrocarbon solvents, C1-C6 ester solvents, C2-C6 ether solvents, or a combination thereof; preferably, the organic solvent is a C1-C6 halogenated alkane solvent; more preferably, it is dichloromethane.

6. The purification method according to claim 1, It is characterized in that In step (1), the ratio of the organic solvent to the crude DMDO-Cl product is 1-5 mL:1 g, preferably 2±1 mL:1 g.

7. The method according to claim 1, It is characterized in that In step (1), the molar ratio of the organic base to the crude DMDO-Cl is 0.1-0.5:1, preferably 0.3±0.1:

1.

8. The purification method according to claim 1, It is characterized in that In step (2), the washing water is provided in the form of an aqueous acid solution, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid or a combination thereof, preferably hydrochloric acid.

9. The purification method according to claim 1, It is characterized in that In step (3), the organic solvent in the organic phase is removed by distillation under reduced pressure.

10. A method for preparing DMDO-Cl, It is characterized in that The preparation method comprises the steps of: (A) Preparation steps of crude DMDO-Cl; and (B) Purification steps of crude DMDO-Cl; in, The preparation steps of the DMDO-Cl crude product include: (A1) subjecting DMDO to a chlorine substitution reaction to obtain a chlorine substitution product, 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one; wherein DMDO refers to 4,5-dimethyl-1,3-dioxol-2-one; and (A2) subjecting 4-chloro-4-methyl-5-methylene-5-methylene-1,3-dioxolane-2-one to a rearrangement reaction to obtain a crude DMDO-Cl product; The purification step of the DMDO-Cl crude product comprises: (1) providing a mixed system of a crude DMDO-Cl product, an organic solvent, and an organic base, and reacting the mixed system to obtain a reaction solution; (2) washing the reaction solution obtained in step (1) with water and separating to obtain an organic phase; and (3) removing the organic solvent in the organic phase obtained in step (2) to obtain a purified DMDO-Cl product; Here, DMDO-Cl refers to 4-chloromethyl-5-methyl-1,3-dioxol-2-one.

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