CN120136801A - A preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazolyl-2-yl)ethyl carbamate - Google Patents
A preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazolyl-2-yl)ethyl carbamate Download PDFInfo
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Abstract
本发明提供一种氨基甲酸(R)‑1‑(2‑氯苯基)‑2‑(四唑‑2‑基)乙酯的制备方法，该方法采用四氮唑盐进行取代反应，然后通过钌催化剂进行手性还原，最终得到目标产物；该制备方法无需长时间高温条件下反应，安全系数高，反应后处理无需手性拆分，操作简单，产物化学及光学纯度高，适合工业化生产等优点。The invention provides a method for preparing (R)-1-(2-chlorophenyl)-2-(tetrazolyl-2-yl)ethyl carbamate. The method adopts a tetrazolium salt for substitution reaction, and then performs chiral reduction through a ruthenium catalyst to finally obtain a target product. The preparation method does not require a long-term reaction under high temperature conditions, has a high safety factor, does not require chiral separation in post-reaction treatment, is simple to operate, has high product chemical and optical purity, is suitable for industrial production, and has the advantages of being suitable for the same.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of an antiepileptic medicine carbamic acid (R) -1- (2-chlorophenyl) -2- (tetrazole-2-yl) ethyl ester.
Background
Benanate (English name: cenobamate), chemical name of which is carbamic acid (R) -1- (2-chlorphenyl) -2- (tetrazol-2-yl) ethyl ester, is a new generation antiepileptic drug developed by Korean SK company, and is used for treating treated epileptic secondary diseases, and the structural formula is shown as the following formula I:
The current synthesis method of the compound I is generally prepared by synthesizing a racemized compound and resolving the racemized compound. Patent CN101228138B discloses the following synthetic route 1, which uses 2-bromo-1- (2-chlorophenyl) ethane-1-one and tetrazole as raw materials, and the target product is prepared by reduction, resolution and further carbamation reaction. The method has the following defects that (1) tetrazole in the synthetic route participates in the reaction, the reaction is carried out for a long time at the reflux temperature of toluene (110-120 ℃), the reaction safety risk is high, the tetrazole is not high in stability at the temperature, and the scale production is not facilitated, and (2) the raceme intermediate is prepared by the reaction in the synthetic route, then the raceme intermediate is further obtained through resolution, the reaction operation is complex, the production cost is high, and the method is not suitable for industrial production.
Scheme 1
Patent CN101228138B also discloses the following synthetic route 2, which uses (R) -2-chlorostyrene and tetrazole as raw materials to prepare an (R) -configured alcohol compound, and then carries out a carbamation reaction to obtain a compound I. The method has the following defects that (1) the synthetic process route has high position isomer impurity, needs further column chromatography for separation and purification, is complex in operation and is not beneficial to industrial production, and (2) the initial raw material (R) -2-styrene oxychloride has no stable source, so that further mass production is limited.
Scheme 2
Patent CN102574821B discloses a method for obtaining R-configuration compound I by enantioselective enzymatic reduction of protected aryl ketone, which has high requirements on production equipment and has a large environmental impact, and is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the preparation method of the (R) -1- (2-chlorophenyl) -2- (tetrazole-2-yl) ethyl carbamate, which has the advantages of high safety coefficient, simple reaction operation, no need of chiral resolution after reaction, high chemical purity and optical purity of the product, suitability for industrial production and the like. Specifically, the invention adopts the following technical scheme:
The preparation method of the intermediate shown in the formula 1 comprises the steps of preparing the intermediate shown in the formula 1, namely 2-bromo-2-chloroacetophenone, from a compound o-chloroacetophenone through bromination reaction;
A process for the preparation of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate comprising:
(a) The intermediate of the formula 1 and tetrazole salt are subjected to substitution reaction to prepare an intermediate of the formula 2, namely 1- (2-chlorophenyl) -2- (1, 2,3, 4-tetrazole-2-yl) ethane-1-ketone;
(b) The intermediate of the formula 2 is subjected to catalytic reduction to prepare an intermediate (R) -1- (2-chlorophenyl) -2- (2H-tetrazol-2-yl) ethane-1-ol of the formula 3;
A preparation method of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate comprises the steps of obtaining a crude product of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate through carbamation reaction of an intermediate shown in a formula 3;
in some embodiments, the bromination reaction is performed under the action of a catalyst;
In some embodiments, the catalyst in the bromination reaction is one or both of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate;
in some embodiments, the bromination reaction is performed under the action of an organic solvent;
In some specific embodiments, the organic solvent in the bromination reaction is one or more of acetonitrile, ethyl acetate, isopropyl acetate and tetrahydrofuran;
In some embodiments, the bromination reaction is carried out at a reaction temperature of 60-80 ℃, preferably 60-70 ℃;
In some embodiments, the tetrazolium salt in the step (a) is one or more of tetrazolium sodium salt, tetrazolium potassium salt and tetrazolium lithium salt, preferably, the tetrazolium salt is tetrazolium sodium salt;
in some embodiments, the tetrazolium salt of step (a) is prepared by reacting tetrazolium with a base;
In some embodiments, the reaction temperature in the preparation of tetrazolium salt in step (a) is 20 to 50 ℃, preferably 40 to 50 ℃;
in some specific embodiments, the reaction solvent in the preparation of tetrazolium salt in the step (a) is an organic solvent, and the organic solvent is one or more of methanol, ethanol, methyl tert-butyl ether and n-heptane;
in some embodiments, the base in the preparation of tetrazolium salt in the step (a) is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, and lithium bicarbonate, preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide;
In some embodiments, the substitution reaction solvent in the step (a) is one or two of an organic solvent or an inorganic solvent, wherein the organic solvent is one or more of isopropyl acetate, ethyl acetate, methyl tertiary butyl ether and isopropanol;
in some embodiments, the substitution reaction temperature in step (a) is 50-100 ℃, preferably 70-90 ℃;
In some embodiments, the step (a) is performed with a recrystallization operation, wherein the step (a) is performed with dissolution and filtration of a small-polarity solvent to remove main impurities, the small-polarity solvent is one or more of methyl tertiary butyl ether, n-heptane and diethyl ether, the dissolution temperature is 15-40 ℃, preferably 20-30 ℃, the step (a) is performed with a large-polarity solvent to perform the purification of the intermediate 2 on the filtrate, the large-polarity solvent is one or more of isopropanol, methanol, tertiary butanol and water, and the recrystallization temperature is 10-30 ℃, preferably 10-15 ℃;
In some embodiments, the catalytic reduction reaction system in the step (b) is a triethylamine and formic acid system, and the catalyst is (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride;
in some embodiments, the catalytic reduction reaction solvent in the step (b) is an organic solvent, and the organic solvent is one or more of toluene, dichloromethane and isopropyl acetate;
In some embodiments, the catalytic reduction reaction temperature in step (b) is 20-30 ℃;
In some embodiments, the carbamylation reaction temperature is 0-25 ℃, preferably 0-15 ℃;
In some embodiments, the carbamylation reaction solvent is one or both of DMF, water.
In some embodiments, the crude (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate is further crystallized and purified to provide (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate;
In some specific embodiments, the crude product of (R) -1- (2-chlorophenyl) -2- (tetrazole-2-yl) ethyl carbamate is further crystallized and purified to obtain (R) -1- (2-chlorophenyl) -2- (tetrazole-2-yl) ethyl carbamate, the crystallization solvent of crystallization and purification is one or two of ethyl acetate and n-heptane, and the crystallization temperature of crystallization and purification is 0-10 ℃;
the time of all reactions of the present invention is generally based on the completion of the starting material reactions, and is monitored by HPLC and TLC methods. The preparation method has the advantages that the preparation method is free from long-time high-temperature operation, high in reaction safety coefficient, free from chiral resolution in post-reaction treatment, simple to operate, high in product chemical and optical purity, suitable for industrial production and the like.
Detailed Description
The invention will be better understood by the following examples which are set forth in detail but are not to be construed as limiting the invention.
Example 1
Preparation of intermediates of formula 1
Acetonitrile (155 kg), NBS (99 kg), o-chloroacetophenone (66 kg), p-toluenesulfonic acid monohydrate (8 kg) were added to the reaction vessel. And heating to 60-70 ℃, stirring for 3-4 hours, sampling and detecting by HPLC (high performance liquid chromatography) until the reaction is qualified, adding sodium bicarbonate aqueous solution (180 kg), sodium sulfite aqueous solution (148 kg), isopropyl acetate (175 kg) into a reaction kettle, concentrating an organic phase until no liquid flows out, stopping concentrating, and discharging to obtain the intermediate (204.5 kg) in the formula 1, wherein the oil mass yield is 154.9%.
Example 2
Preparation of intermediates of formula 1
Isopropyl acetate (150 kg), NBS (99 kg), o-chloroacetophenone (66 kg) and p-toluenesulfonic acid (7.8 kg) were charged into the reaction vessel. Heating to 60-70 ℃, stirring for 3-4 hours, sampling and detecting by HPLC until the reaction is qualified, adding sodium bicarbonate aqueous solution (180 kg), sodium sulfite aqueous solution (148 kg), isopropyl acetate (175 kg) into a reaction kettle after the reaction is qualified, extracting, separating a water layer, concentrating an organic layer until no liquid flows out, stopping concentrating, and discharging to obtain the intermediate (195.0 kg) in the formula 1, wherein the mass yield of oily matter is 147.7%.
Example 3
Preparation of sodium tetrazole
Methanol (86 kg) was added to the reaction vessel. Sodium hydroxide solid (20 kg in total) is added in portions, the temperature is controlled at 40-50 ℃, tetrazole (35 kg) is added, and stirring is carried out for 1 hour after the addition. Concentrating under reduced pressure to dry, adding methyl tert-butyl ether (150 kg), stirring for crystallization for 1 hr, and pressure filtering to obtain wet tetrazole sodium product.
Example 4
Preparation of tetrazolium potassium
Methanol (86 kg) is added into the reaction kettle, then potassium hydroxide solid (29.0 kg in total) is added in portions, the temperature is controlled to be 40-50 ℃, tetrazole (35 kg) is added, and stirring is carried out for 1 hour after the addition. Concentrating under reduced pressure to dry, adding methyl tert-butyl ether (150 kg), stirring for crystallization for 1 hr, and pressure filtering to obtain wet tetrazole potassium product.
Example 5
Preparation of intermediates of formula 2
Adding isopropyl acetate (960 kg) and an intermediate (960 kg) in a reaction kettle, stirring, adding the whole batch of tetrazole sodium wet product prepared in the embodiment 3, heating to 70-80 ℃, stirring for 15-20 hours, taking a reaction liquid for detection until the reaction liquid is qualified, adding drinking water (200 kg), layering, concentrating an organic phase, adding methyl tertiary butyl ether (600 kg) for crystallization, filtering, collecting filtrate, adding isopropanol (340 kg) for crystallization, and obtaining the intermediate (75.6 kg) in the formula 2, wherein the molar yield is 39.78% (calculated by o-chloroacetophenone), and the HPLC purity is 99.2%.
Example 6
Preparation of intermediates of formula 3
Toluene (300 kg) and triethylamine (170 kg) were added to a reaction vessel under nitrogen protection, the temperature was controlled at 0-20℃and formic acid (77 kg) was added dropwise. At the end of the addition, the intermediate of formula 2 (75 kg) and the catalyst (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (0.23 kg) were added and stirred. And (3) taking the reaction liquid, detecting until the reaction liquid is qualified, adding water for quenching after the reaction liquid is qualified, and directly concentrating an organic layer until the organic layer is dried to obtain an intermediate (71.3 kg) of the formula 3, wherein the yield is 93.60%, the HPLC purity is 99.05%, and no isomer is detected.
Example 7
Preparation of intermediates of formula 3
Dichloromethane (350 kg) and triethylamine (170 kg) are added into a reaction kettle under the protection of nitrogen, the temperature is controlled to be 0-20 ℃, and formic acid (77 kg) is added dropwise. At the end of the addition, the intermediate of formula 2 (75 kg) and the catalyst (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (0.23 kg) were added and stirred. And (3) taking the reaction liquid, detecting until the reaction liquid is qualified, adding water for quenching after the reaction liquid is qualified, concentrating the organic layer until the organic layer is dried, and crystallizing by using toluene and n-heptane (toluene: n-heptane=1:5) to obtain an intermediate (68.5 kg) in the formula 3, wherein the yield is 89.92%, the HPLC purity is 99.32%, and no isomer is detected.
Example 8
Preparation of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate crude product
DMF (44 kg) and N, N' -carbonyldiimidazole (95 kg) were added to the reaction vessel, the temperature was controlled at 0 to 15 ℃, DMF solution (115 kg) of the intermediate of formula 3 was added dropwise to the vessel, ammonium acetate (54 kg) was added, and stirring was completed. Sampling and detecting until the product is qualified, adding water (500 kg) for crystallization, centrifuging and drying to obtain a crude product of the benananate (69.4 kg), wherein the molar yield is 81.65%, the HPLC purity is 99.56%, and no isomer is detected.
Example 9
Preparation of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate
Adding the crude product of the benananate (65 kg) and the ethyl acetate (117 kg) into a decoloring kettle, adding active carbon (3.35 kg), stirring for 1 hour, press-filtering, adding n-heptane (380 kg) into filtrate, controlling the temperature to be 20-30 ℃, stirring until solid is separated out, continuously cooling to 0-10 ℃, and stirring for 1 hour to obtain the refined product of the benananate (60.5 kg), wherein the molar yield is 87.25%, the HPLC purity is 99.98%, and no isomer is detected.
Claims (10)
1. A process for the preparation of (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate, comprising the steps of:
(a) The intermediate 2-bromo-2-chloroacetophenone of formula 1 and tetrazolium salt undergo substitution reaction to prepare the compound of formula 2 intermediate 1- (2-chlorophenyl) -2- (1, 2,3, 4-tetrazol-2-yl) ethan-1-one;
(b) The intermediate of the formula 2 is subjected to catalytic reduction to prepare an intermediate (R) -1- (2-chlorophenyl) -2- (2H-tetrazol-2-yl) ethane-1-ol of the formula 3;
2. the preparation method according to claim 1, wherein the intermediate of formula 3 is further prepared into (R) -1- (2-chlorophenyl) -2- (tetrazol-2-yl) ethyl carbamate by carbamation;
3. The preparation method of claim 1, wherein the intermediate 2-bromo-2-chloroacetophenone of formula 1 is prepared from o-chloroacetophenone through bromination;
4. the preparation method according to claim 1, wherein the tetrazolium salt in the step (a) is one or more of tetrazolium sodium salt, tetrazolium potassium salt and tetrazolium lithium salt, and preferably the tetrazolium salt is tetrazolium sodium.
5. The preparation method according to claim 1, wherein the tetrazolium salt in the step (a) is prepared by reacting tetrazolium with a base, wherein the base is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, and lithium bicarbonate, preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and more preferably sodium hydroxide.
6. The preparation method according to claim 1, wherein the reaction temperature of the tetrazolium salt in the preparation of step (a) is 20-50 ℃, preferably 40-50 ℃, and the reaction solvent of the tetrazolium salt in the preparation of step (a) is an organic solvent, wherein the organic solvent is one or more of methanol, ethanol, methyl tert-butyl ether and n-heptane.
7. The preparation method according to claim 1, wherein the substitution reaction solvent in the step (a) is one or two of an organic solvent or an inorganic solvent, the organic solvent is one or more of isopropyl acetate, ethyl acetate, methyl tert-butyl ether and isopropanol, the inorganic solvent is water, and the substitution reaction temperature in the step (a) is 50-100 ℃, preferably 70-90 ℃.
8. The preparation method according to claim 1, wherein the step (a) of purifying the substitution reaction product adopts a recrystallization operation, which comprises dissolving and filtering to remove main impurities by using a solvent with small polarity, wherein the solvent with small polarity is one or more of methyl tertiary butyl ether, n-heptane and diethyl ether, the dissolution temperature is 15-40 ℃, preferably 20-30 ℃, the recrystallization adopts a solvent with large polarity to purify the filtrate as intermediate 2, the solvent with large polarity is one or more of isopropanol, methanol, tertiary butanol and water, and the recrystallization temperature is 10-30 ℃, preferably 10-15 ℃.
9. The preparation method of the catalyst according to claim 1, wherein the catalytic reduction reaction system in the step (b) is a triethylamine and formic acid system, the catalyst is (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride, the catalytic reduction reaction temperature in the step (b) is 20-30 ℃, the catalytic reduction reaction solvent in the step (b) is an organic solvent, and the organic solvent is one or more of toluene, dichloromethane and isopropyl acetate.
10. The preparation method according to claim 3, wherein the bromination reaction is performed under the action of a catalyst, the catalyst is one or two of p-toluenesulfonic acid and p-toluenesulfonic acid monohydrate, the bromination reaction is performed under the action of an organic solvent, the organic solvent is one or more of acetonitrile, ethyl acetate, isopropyl acetate and tetrahydrofuran, and the reaction temperature of the bromination reaction is 60-80 ℃, preferably 60-70 ℃.
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| CN202311703603.3A CN120136801A (en) | 2023-12-11 | 2023-12-11 | A preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazolyl-2-yl)ethyl carbamate |
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| CN202311703603.3A CN120136801A (en) | 2023-12-11 | 2023-12-11 | A preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazolyl-2-yl)ethyl carbamate |
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