CN114195754B - R-glycerol acetonide intermediate and preparation method thereof - Google Patents

R-glycerol acetonide intermediate and preparation method thereof Download PDF

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CN114195754B
CN114195754B CN202111623532.7A CN202111623532A CN114195754B CN 114195754 B CN114195754 B CN 114195754B CN 202111623532 A CN202111623532 A CN 202111623532A CN 114195754 B CN114195754 B CN 114195754B
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dioxolane
chloromethyl
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CN114195754A (en
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李晓林
王子安
刘天柱
骆浩
刘炼
李嘉莹
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Suzhou Highfine Biotech Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/16—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers
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Abstract

The invention provides a preparation method of an R-glyceroglycol acetone intermediate, which is S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, said preparation method comprising: the S-epichlorohydrin is subjected to ring-opening condensation reaction under the action of a catalyst to obtain the S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, wherein the catalyst is selected from BF 3 ·Et 2 O、AlCl 3 、ZnCl 2 、FeCl 3 、Ti(OiPr) 4 One or more of (a) and (b). According to the preparation method provided by the embodiment of the invention, the synthetic route is short, the yield can reach more than 85%, and the e.e. value is more than 96%; in addition, the preparation method provided by the invention is simple and convenient to operate and easy to control the conditions.

Description

R-glycerol acetonide intermediate and preparation method thereof
Technical Field
The invention relates to the technical field of compound preparation, in particular to an R-glyceroglycol acetone intermediate and a preparation method thereof.
Background
Chiral glycerol formal is an important organic synthesis intermediate, is widely applied to medicines, plasticizers, solvents and the like, and can be used for synthesizing chiral molecules as cheap chiral monomers and precursors of chiral medicines and natural products with optical activity. For example, the active intermediate can be used for preparing hypoglycemic drugs, and can correct metabolic disorders such as hyperglycemia and hyperlipidemia and promote normal metabolism of sugar, protein and the like.
The R-glyceroglycol intermediate S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane is a chiral precursor of landiolol hydrochloride, which is an ultra-short-acting high-selectivity beta 1 receptor blocker, is an indispensable emergency medicine for emergency treatment of arrhythmia and the like during operation, and is favored by doctors and operation patients.
The chiral purity of the R-glyceroglycol intermediate, namely S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, is a key factor affecting the chiral purity quality in the synthesis of R-glyceroglycol. However, none of the presently disclosed synthetic methods provide high chiral purity.
Therefore, the development of a synthesis process with low cost and high chiral purity has important significance.
Disclosure of Invention
In view of the above, the invention provides a preparation method of an R-glyceroglycol acetone intermediate with low cost, simplicity and high chiral purity.
The invention also provides an R-glyceraldehyde acetonide intermediate with high chiral purity, and S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
In order to solve the technical problems, the invention adopts the following technical scheme:
according to a first aspect of the present invention, there is provided a method for preparing an R-glyceraldehyde acetonide intermediate, the R-glyceraldehyde acetonide intermediate being S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, the method comprising:
the S-epichlorohydrin is subjected to ring-opening condensation reaction under the action of a catalyst to obtain the S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, wherein the catalyst is selected from AlCl 3 、ZnCl 2 、FeCl 3 、Ti(OiPr) 4 One or more of (a) and (b).
Further, the ring-opening reaction of the S-epichlorohydrin occurs in acetone under the action of the catalyst.
Further, the molar ratio of the S-epichlorohydrin to the catalyst is 1: (0.01-0.5).
Further, the reaction temperature of the ring-opening condensation reaction is-70-40 ℃ and the reaction time is 0.5-7 hours.
Further, after the ring-opening condensation reaction is completed, a base quenching reaction is used, wherein the base comprises any one or more of sodium bicarbonate solution, sodium hydroxide solution, triethylamine and pyridine.
Further, after quenching, evaporating the solvent and purifying to obtain the refined S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane
According to a second aspect of the present invention, the R-glyceroglycol intermediate is S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, and the e.e. value of the R-glyceroglycol intermediate is 95% or more.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method provided by the embodiment of the invention, the synthetic route is short, the yield can reach more than 85%, and the e.e. value is more than 96%;
in addition, the preparation method provided by the invention is simple and convenient to operate and easy to control the conditions.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The preparation method of the R-glyceroglycol intermediate (the R-glyceroglycol intermediate is S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, hereinafter sometimes simply referred to as R-glyceroglycol intermediate) according to the embodiment of the invention comprises the following steps:
the S-epichlorohydrin is subjected to ring-opening condensation reaction under the action of a catalyst to obtain the S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, wherein the catalyst is selected from BF 3 ·Et 2 O、AlCl 3 、ZnCl 2 、FeCl 3 、Ti(OiPr) 4 One or more of (a) and (b).
That is, the S-epichlorohydrin is reacted with a catalyst such as BF 3 ·Et 2 O、AlCl 3 、ZnCl 2 、FeCl 3 、Ti(OiPr) 4 And (3) carrying out ring-opening condensation reaction under the action of the catalyst to obtain the R-glyceroglycol acetone intermediate.
The reaction equation for the ring-opening condensation reaction is shown as follows:
Figure BDA0003439105800000031
preferably, the ring-opening condensation reaction of the S-epichlorohydrin occurs in acetone in the presence of a catalyst.
In the reaction, S-epichlorohydrin is ring-opened under the catalysis of the catalyst, and acetone is used as a solvent and a reaction raw material to perform condensation reaction with the solvent and the reaction raw material.
Wherein the molar ratio of the S-epichlorohydrin to the catalyst is 1: (0.01-0.5). Preferably, the molar ratio of the S-epichlorohydrin to the catalyst is 1:0.05-0.2, more preferably 1:0.1.
The reaction temperature of the ring-opening condensation reaction may be set to, for example, from-70 to 40 ℃, and more preferably from 0 ℃ to room temperature.
The reaction time may be, for example, 0.5 to 7 hours. Preferably, for example, 1 to 4 hours can be set.
In addition, after the ring-opening condensation reaction is completed, an alkali quenching reaction may be used. That is, after the reaction is performed for a predetermined time, a base, which may include, for example, any one or more of sodium bicarbonate solution, sodium hydroxide solution, triethylamine, and pyridine, is added to the reaction vessel to quench the reaction.
Further, after quenching, the solvent may be evaporated and purified to obtain the refined S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
Specifically, after quenching, evaporating the solvent or directly adding dichloromethane for extraction, washing with water, drying with anhydrous sodium sulfate, and further concentrating the solvent dichloromethane under reduced pressure to obtain the refined R-glyceroglycol acetone intermediate.
The R-glyceraldehyde acetonide intermediate of the present invention and the process for preparing the same are described in further detail below by way of specific examples.
Example 1
In a three-necked flask, 8.8g FeCl was introduced 3 Dissolving in 250mL of acetone, cooling to 0 ℃, dropwise adding 100g of S-epichlorohydrin, and keeping internal temperature for reaction for 3h.
GC detects complete reaction of the starting materials, then 50mL of aqueous sodium bicarbonate solution is added and stirred for a moment to quench the reaction, after which 250mL of methylene chloride is added and the organic phase is washed twice with 150mL of water, dried over anhydrous sodium sulfate and the solvent is concentrated under reduced pressure to give 138g of S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
The yield was 85% and the e.e. value was 97%.
Example 2
30.7g of Ti (OiPr) was placed in a three-necked flask 4 Dissolving in 250mL of acetone, cooling to 0 ℃, dropwise adding 100g S-epichlorohydrin, and keeping internal temperature for reaction for 2h.
GC detects that the raw materials are completely reacted, then 12g of triethylamine is added, after stirring for a moment, acetone is evaporated, 250mL of dichloromethane is added for extraction, 150mL of water is washed three times, anhydrous sodium sulfate is dried, and the solvent is concentrated under reduced pressure to obtain 150g of S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
The yield was 92% and the e.e. value was 99%.
In addition, in order to verify the effect of the synthesis method of the invention and the catalyst provided, the following comparative tests were also carried out:
comparative example 1
In a three-necked flask, 23g of BF was prepared 3 ·Et 2 O is dissolved in 350mL of acetone, cooled to-20 ℃, and 100g S-epichlorohydrin is added dropwise, and the internal temperature is kept for reaction for 1h.
GC detects complete reaction of the starting materials, then 18.5g of triethylamine is added and stirred for a short time to quench the reaction, after which the acetone is evaporated to dryness. And 350mL of methylene chloride was added thereto for extraction, and the organic phase was washed three times with 150mL of water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 130g of S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
Calculated, the yield was 80% and the e.e. value was 95%.
Comparative example 2
7.68g BF was charged in a three-necked flask 3 ·Et 2 O is dissolved in 250mL of acetone, cooled to 0 ℃, 100g S-epichlorohydrin is added dropwise, and internal temperature reaction is kept for 2h.
GC detects that the raw materials are completely reacted, then 6g of triethylamine is added, after stirring for a moment, acetone is evaporated, 250mL of dichloromethane is added for extraction, 150mL of water is washed three times, anhydrous sodium sulfate is dried, and the solvent is concentrated under reduced pressure to obtain 138g of S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
The yield was 83%, and the e.e. value was 95%.
As can be seen from the above examples, the method for preparing the R-glycerograde acetonide intermediate has the advantages of simple operation, low cost, high yield and high chiral purity. Wherein Ti (OiPr) is used 4 When the catalyst is used, the yield can be up to more than 92%, and the e.e. value can be more than 99%, so that the catalyst can be widely used in the biomedical industry, and is particularly preferable.
In contrast, the chiral purity of the boron trifluoride diethyl etherate serving as a catalyst can only reach 95%, and the demand of the biomedical industry is far less than that of the boron trifluoride diethyl etherate.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.

Claims (3)

1. A preparation method of an R-glyceroglycol intermediate, wherein the R-glyceroglycol intermediate is S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, and the preparation method is characterized by comprising the following steps:
the S-epichlorohydrin is subjected to ring-opening condensation reaction in acetone under the action of a catalyst to obtain the S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane, wherein the catalyst is Ti (OiPr) 4 The molar ratio of the S-epichlorohydrin to the catalyst is 1: (0.01-0.5), wherein the reaction temperature of the ring-opening condensation reaction is-70-40 ℃ and the reaction time is 0.5-7 hours.
2. The method according to claim 1, wherein after the ring-opening condensation reaction is completed, a base quenching reaction is used, and the base includes any one or more of sodium bicarbonate solution, sodium hydroxide solution, triethylamine, and pyridine.
3. The preparation method according to claim 2, wherein after quenching, the solvent is evaporated and purified to obtain the refined S- (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane.
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CN100506814C (en) * 2007-02-08 2009-07-01 北京化工大学 Method of synthesizing landiolol hydrochloride
CN102532089B (en) * 2011-12-22 2014-05-14 凯莱英医药集团（天津）股份有限公司 Method for preparing chirality glycerol acetonide
CN106608863A (en) * 2015-10-23 2017-05-03 北京创立科创医药技术开发有限公司 Preparation method of landiolol hydrochloride
CN111909127A (en) * 2019-05-07 2020-11-10 浙江省化工研究院有限公司 Synthesis method of 8-tert-butyl-2-chloromethyl-1, 4-dioxaspiro [4,5] decane
CN111138421A (en) * 2019-12-26 2020-05-12 上海英诺富成生物科技有限公司 Antifungal water-soluble compound and preparation method and application thereof

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