CN112374966B - Preparation method of chloral hydrate - Google Patents

Preparation method of chloral hydrate Download PDF

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CN112374966B
CN112374966B CN202011349511.6A CN202011349511A CN112374966B CN 112374966 B CN112374966 B CN 112374966B CN 202011349511 A CN202011349511 A CN 202011349511A CN 112374966 B CN112374966 B CN 112374966B
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chloral
organic solvent
chloral hydrate
trichloroethanol
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樊启海
门阳
廖勇群
谭月
夏喜坚
张波
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Fu'an Pharmaceutical Group Chongqing Ceremony Pharmaceutical Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
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Abstract

The invention relates to the technical field of organic synthesis, and provides a preparation method of chloral hydrate. The synthesis method of chloral hydrate disclosed by the invention avoids using highly toxic chlorine gas, avoids generating monochloro-dichloro impurity in the preparation process, is environment-friendly, and is a very economic and green preparation method; the product prepared by the method has high purity, and can be used for preparing clinical medicines.

Description

Preparation method of chloral hydrate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of chloral hydrate.
Background
Chloral hydrate is a hydrate of chloral, is an aldehyde compound with long-time (6-8 h) sedation and hypnosis effect, and has the chemical name of 2, 2-trichloro-1, 1-glycol. It has quick hypnotic effect (15 min for oral administration), and can induce normal physiological sleep without drowsiness and asthenia after waking up; is hypnotic and anticonvulsant. At present, the method is mainly used for various auxiliary examinations of children clinically. Industrial use: the nickel-copper alloy is used for a semioptical nickel potential difference regulator, can remove active sulfur in plating solution, and improves potential difference. Agricultural use: it is used as intermediate for preparing trichlorfon, herbicide and other agricultural chemicals. The specific chemical structural formula is as follows:
Figure 223136DEST_PATH_IMAGE001
。
justus Liebig chlorinates anhydrous ethanol for the first time in 1832, and then the chloral (the chloral hydrate-chloral hydrate is generated by hydration with the water) is prepared by sulfuric acid treatment and distillation. Wurtz in 1857 reported the chlorination of acetaldehyde to chloral in sunlight, after which Pimer Recicher and Crae et al conducted intensive research. A large number of patents appear in countries such as the United states, germany, japan and the like in the middle of the twentieth century, and the industrial production of chloral is realized. The development and production of chloral in China are first reported in 1951, and the ethanol chlorination method is generally adopted based on the domestic actual situation. After decades of development, certain achievements are obtained, and new process patents for producing chloral by a catalytic chlorination method appear continuously. Chloral is an important chemical raw material, contains halogen and carbonyl in a molecular structure, has wide application, and is an important raw material for preparing medicines (such as chloramphenicol, chlortetracycline and thiamphenicol), pesticides (such as dichlorodiphenyl trichloroethane, trichlorfon, dichlorvos, phosphorus dibromide, calcium trichloroacetate, fenisobromolate and herbicides) and other organic chemical products (such as chloroform, trichloroacetic acid, dimethylformamide and the like).
In view of the structural particularity of the product, the synthetic routes are divided into two main categories, and chlorine gas is used and is not used in the preparation process.
Type one, chlorine gas is used in the preparation process
Route 1: preparation of ethanol by reaction with chlorine
(1) Mechanism one
Figure 377037DEST_PATH_IMAGE002
(2) Mechanism two
Figure 321859DEST_PATH_IMAGE003
In the process of preparing trichloroacetaldehyde (or chloral hydrate) by an ethanol chlorination method, mono-substituted and di-substituted intermediate states (monochloroacetal and dichloroacetaldehyde) exist, and a large amount of waste acid and byproducts (commonly called black oil) are generated: lipids, chloral acetal, ethyl monochloroacetate, ethyl dichloroacetate, ethyl trichloroacetate and hydrochloric acid.
Route 2: preparation of acetaldehyde by reaction with chlorine
Figure 267818DEST_PATH_IMAGE004
This process, like the ethanol chlorination process, has a large amount of by-products and requires the use of chlorine gas.
Type two, no chlorine gas is used in the preparation process
Route 3:
Figure 679208DEST_PATH_IMAGE005
an article published by T.A.; fomina, 1983, reports the activity of chloro-substituted epoxides and the syntheses based thereon. But the starting materials are not common and the cost is high.
Route 4:
Figure 680924DEST_PATH_IMAGE006
an article published by Zakharkin, l.i. 1988 reports the order of addition of lithium and aluminum hydrides to butadiene and isoprene in THF solution. The method has difficulty in obtaining materials.
Route 5:
Figure 19983DEST_PATH_IMAGE007
this route is reported in US 4754088, which uses ethylene as starting material and requires higher reaction conditions, such as temperatures up to 150 ℃ or pressures, and severe reaction conditions than the ethanol chlorination process and the acetaldehyde chlorination process.
The industrial production of chloral in China mainly adopts an ethanol chlorination method production process. Chlorine and ethanol react at room temperature to generate monochloroacetaldehyde, dichloroacetaldehyde is generated when the reaction temperature reaches 70 to 80 ℃, and trichloroacetaldehyde is generated when the reaction temperature reaches 80 to 90 ℃. The specific process is to slowly introduce chlorine into the absolute ethyl alcohol, control the temperature to about 60 ℃, and finally, raise the temperature to about 100 ℃. Absorbing hydrogen chloride gas with water to generate 30-36% hydrochloric acid water solution, wherein the reaction is basically finished when the hydrogen chloride stops releasing. The reaction is usually catalyzed by ferric chloride, ethyl halide, etc. After the reaction was completed, distillation was carried out, and the distillation was stopped when the overhead temperature was raised to 100 ℃. Then rectifying to obtain distillate with the temperature of over 94 ℃ which is pure chloral. Adding a small amount of limestone or sodium bicarbonate for processing to obtain refined product. The chloride byproducts such as dichloroethane, chloroethane and the like are washed with water, washed with alkali, dried, condensed, distilled and packaged for producing pesticides.
The chlorination of ethanol to produce chloral is a chemical reaction controlled by dynamics, has slow speed, complex process and various intermediate products, and produces a large amount of waste and waste tail gas. According to the calculation of a reaction theory: the hydrogen chloride gas is 1.24 tons when 1 ton of chloral is produced annually according to the calculation that 5mol of hydrogen chloride gas is required to be produced for each 1mol of chloral. The chlorination tail gas of the ethanol chlorination method contains about 92 percent of hydrogen chloride, and the balance of chloroethane, chlorine, ethanol, chloromethane, carbon tetrachloride, phosgene, aldehydes and the like. Cooling, falling film absorption to obtain hydrochloric acid as byproduct, adiabatic absorption to remove residual hydrogen chloride, and dechlorination in dechlorinating tower. The dechlorinated gas is cooled, compressed and condensed into crude chloroethane, and the noncondensable gas is evacuated. The chlorinated tail gas has the risk of combustion explosion, and the chloroethane tail gas frequently explodes in the water washing tower, so that not only is great economic loss caused, but also the production safety is seriously threatened. The reason for the explosion of combustion may be that a mixed gas of ethyl chloride and chlorine forms a combustible mixed gas when the chlorine concentration is high.
Disclosure of Invention
Against the background, the invention aims to provide a preparation method of chloral hydrate, which solves the defects that toxic gas chlorine is needed to be used, product impurities are more, and a large amount of toxic waste gas is discharged in the prior art, and avoids safety risks in the production process.
The invention adopts the following technical scheme:
the designed synthetic route is as follows:
Figure 554870DEST_PATH_IMAGE008
a process for the preparation of chloral hydrate, said process comprising the steps of:
a. after trichloroacetyl chloride is dissolved in an organic solvent, trichloroethanol is prepared by reduction reaction under the action of a reducing agent.
b. The trichloroethanol is subjected to oxidation reaction under the action of an oxidant and a catalyst to prepare the chloral.
c. Reacting chloral with water, and recrystallizing by using benign organic solvent and bad organic solvent to obtain chloral hydrate.
Further, in the preparation method of the chloral hydrate, the reaction temperature in the step a is-10 to 10 ℃;
the reaction temperature in the step b is-10 to 0 ℃, and the reaction temperature in the step c is-10 to 10 ℃.
Further, in the above method for preparing chloral hydrate, the reducing agent used in step a is one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride, and potassium aluminum hydride.
Further, in the above preparation method of chloral hydrate, the molar ratio of the reducing agent to the trichloroethanol in the step a is (1.5 to 2.5): 1.
further, in the preparation method of the chloral hydrate, the reaction time in the step a is 1 to 4 hours.
Further, in the preparation method of the chloral hydrate, the distillation temperature in the step a is 45-85 ℃.
Further, in the preparation method of chloral hydrate, the molar ratio of the oxidant to the trichloroethanol in the step b is (1.2 to 2.5): 1.
further, in the above preparation method of chloral hydrate, the reaction time in the step b is 0.5-2 hours.
Further, in the preparation method of the chloral hydrate, the dosage of the catalyst in the step b is 1-5%.
Furthermore, in the preparation method of chloral hydrate, the molar ratio of water to chloral in the step c is (1.0 to 2.0): 1.
Further, in the above method for preparing chloral hydrate, the reaction solvent in step c is one or more of dichloromethane and ethyl acetate.
Further, in the above method for preparing chloral hydrate, the poor solvent in step c is one or more of n-hexane and n-heptane.
Further, in the preparation method of the chloral hydrate, the crystallization temperature in the step c is-10 to 10 ℃.29
Further, in the preparation method of chloral hydrate, the crystallization time in the step c is 1 to 2 hours.
Further, the preparation method of the chloral hydrate comprises the following specific steps:
a. dissolving trichloroacetyl chloride serving as a raw material in an organic solvent, cooling to-10 to 10 ℃, adding an oxidant with a molar ratio of (1.5 to 2.5), reacting for 1 to 4 hours under heat preservation, then performing extraction and extinguishment, extracting and layering by using the organic solvent to obtain a solvent of the trichloroethanol, and distilling and separating at 45 to 85 ℃ to obtain a pure product of the trichloroethanol.
b. Dissolving trichloroethanol in an organic solvent, adding 1-5% of a main catalyst and 10-20% of an equivalent weight cocatalyst, cooling to-10 ℃, and adding the materials according to the molar ratio of (1.2-2.5): 1, reacting for 0.5 to 2 hours under the condition of heat preservation, then extracting and separating, and concentrating an organic layer to obtain the chloral.
c. Dissolving chloral in a benign solvent, cooling to-10 to 10 ℃, adding water with a molar ratio of (1.0 to 2.0): 1 to react for 0.5 to 1.0 hour, then adding a poor solvent, crystallizing at-10 to 10 ℃ for 1 to 2 hours, filtering, and drying to obtain a chloral hydrate dried product.
The invention has the following beneficial effects:
compared with the prior art for preparing chloral hydrate by using ethanol or acetaldehyde to react with chlorine at home:
1. the chloral hydrate obtained by the process has no complex intermediate product, high product purity and less impurities.
2. The process of the invention takes trichloroacetyl chloride as a starting material, and the trichloroacetyl chloride is a cheap product which is very easily obtained by the market. The process of the invention avoids using chlorine and is friendly to environment. The problems of tail gas poison and the risk of explosion and combustion caused by the chlorine process are also avoided.
3. The total yield of the process reaches more than 60 percent.
Therefore, the process is a green and environment-friendly preparation process with strong operability and high economic benefit.
Description of the drawings:
FIG. 1: liquid phase diagram of chloral hydrate synthesized by the embodiment of the invention.
The specific implementation mode is as follows:
the invention is further described in connection with the following specific examples, which are intended to be illustrative of the invention and are not to be construed as limiting the invention.
Preparation of trichloroethanol:
Figure 137161DEST_PATH_IMAGE009
example 1
Adding 50g of trichloroacetyl chloride, 200g of ethanol and 300g of dichloromethane into a 2L three-necked bottle, cooling to-10 to 10 ℃, adding 20.80g of sodium borohydride, and keeping the temperature for reaction for 2 hours after the addition is finished. Then 900g of dilute acid is added, standing and layering are carried out, the water layer is extracted by 300g of dichloromethane again, a dichloromethane layer is synthesized, reduced pressure distillation is carried out at the temperature of 45-60 ℃, and trichloroethanol fractions are collected to obtain 34g of pure trichloroethanol with the purity of 99 percent and the yield of 83 percent.
Example 2
Adding 50g of trichloroacetyl chloride, 220g of ethanol and 320g of dichloromethane into a 2L three-necked bottle, cooling to minus 10 to 10 ℃, adding 25.00g of potassium borohydride, and keeping the temperature for reaction for 1 hour after the addition is finished. Then adding 900g of dilute hydrochloric acid, standing for layering, extracting a water layer with 300g of dichloromethane, synthesizing a dichloromethane layer, distilling at 45-60 ℃ under reduced pressure, and collecting a trichloroethanol fraction to obtain 35g of a pure product of trichloroethanol with the purity of 99% and the yield of 85%.
Example 3
Adding 50g of trichloroacetyl chloride, 200g of methanol and 360g of trichloromethane into a 2L three-necked bottle, cooling to-10 to 10 ℃, adding 20.80g of potassium borohydride, and reacting for 1 hour under the condition of heat preservation after the addition. Then 900g of dilute hydrochloric acid is added, standing and layering are carried out, the water layer is extracted by 360g of trichloromethane, a dichloromethane layer is synthesized, reduced pressure distillation is carried out at the temperature of 45-60 ℃, and a trichloroethanol fraction is collected, so that 34g of a pure product of trichloroethanol with the purity of 99% and the yield of 83% is obtained.
Preparation of trichloroacetaldehyde:
Figure 655867DEST_PATH_IMAGE010
example 4
20.00g of trichloroethanol and 130.00g of dichloromethane are sequentially added into a 1L three-necked bottle, the temperature is reduced to-5 ℃ under mechanical stirring, and then 0.20g of TEMPO and 2.00g of sodium bromide are added. When the internal temperature is-5 ℃, beginning to drop 128.40g of sodium hypochlorite solution, and controlling the internal temperature not to exceed-3 ℃. After about 1h, TLC detection showed complete reaction, and 10g sodium thiosulfate was added for quenching and stirring for 15min. The layers were then separated, the aqueous layer was extracted once more with 50ml dichloromethane, and the organic layers were combined. The organic layer was distilled at 40-50 ℃ under atmospheric pressure to remove DCM to give a pale yellow residue. Then, reduced pressure distillation is carried out again, and fractions with gas phase temperature of more than 55 ℃ are collected. About 14.69g of colorless liquid was obtained with a yield of about 74.5% and a purity of 98%.
Example 5
20.00g of trichloroethanol and 150g of chloroform are sequentially added into a 1L three-necked bottle, the temperature is reduced to-5 ℃ under mechanical stirring, and then 1.00g of TEMPO and 4g of potassium bromide are added. When the internal temperature is-5 ℃, 150.0g of potassium hypochlorite solution is dripped, and the internal temperature is controlled not to exceed-3 ℃. After about 1h, TLC detection showed complete reaction, and 12g sodium thiosulfate was added for quenching and stirring for 15min. The layers were separated, the aqueous layer was extracted once more with 50ml of chloroform, and the organic layers were combined. The organic layer was distilled at 40-50 ℃ under atmospheric pressure to remove DCM to give a pale yellow residue. Then, reduced pressure distillation is carried out again, and fractions with gas phase temperature of more than 55 ℃ are collected. About 15g of colorless liquid was obtained in about 75% yield with a purity of 98%.
Preparation of chloral hydrate
Figure 349016DEST_PATH_IMAGE011
Example 6
10.00g of chloral and 26g of dichloromethane are added in turn into a 100ml three-necked flask, and the temperature is reduced to 0-10 ℃ under magnetic stirring. Slowly dripping 1.00g of purified water when the internal temperature is 5 ℃, stirring for 30min after dripping, dripping 19.80g of n-hexane when the internal temperature is reduced to below 5 ℃, keeping the temperature and crystallizing for 2h after 15min, filtering, washing a filter cake by 6.6g of n-hexane, and drying a wet product under reduced pressure for 12h to obtain 8.0g of white solid with the yield of about 97 percent and the purity of 99.9 percent
Example 7
10.00g of chloral and 30g of chloroform are sequentially added into a 100ml three-neck flask, and the temperature is reduced to 0-10 ℃ under magnetic stirring. Slowly dripping 1.00g of purified water when the internal temperature is 5 ℃, stirring for 30min after dripping, dripping 30g of n-hexane when the internal temperature is reduced to below 5 ℃, carrying out heat preservation and crystallization for 2h, filtering, washing a filter cake with n-hexane, and drying a wet product under reduced pressure for 12h to obtain 7.8g of a white solid, wherein the yield is 95 percent, and the purity is 99.8 percent
Example 8
10.00g of chloral and 26g of dichloromethane are added in turn into a 100ml three-necked flask, and the temperature is reduced to 0-10 ℃ under magnetic stirring. Slowly dripping 1.00g of purified water when the internal temperature is 5 ℃, stirring for 30min after dripping, dripping 20.00g of n-heptane when the internal temperature is reduced to be below 5 ℃, keeping the temperature and crystallizing for 2h, filtering, washing a filter cake with 10g of n-heptane, and drying a wet product under reduced pressure for 12h to obtain 7.9g of white solid, wherein the yield is 96% and the purity is 99.9%.
The invention successfully prepares high-purity chloral hydrate, provides a green, economic, environment-friendly and high-benefit synthetic route and method for preparing chloral hydrate, and has great promotion effect on further research on the quality of chloral hydrate and quality control and safety risk control in the production process.

Claims (5)

1. A preparation method of chloral hydrate comprises the following steps:
a. trichloroacetyl chloride is dissolved in an organic solvent, and a reducing agent is added for reduction reaction to prepare trichloroethanol;
b. under the action of oxidant and catalyst, the trichloroethanol is oxidized to prepare chloral;
c. reacting chloral with water to obtain chloral hydrate,
wherein, the reducing agent in the step a is sodium borohydride or potassium borohydride,
in the step b, the oxidant is selected from one or more of sodium hypochlorite, potassium hypochlorite and sodium hypobromite, the catalyst contains a main catalyst and a co-catalyst, the main catalyst is 2, 6-tetramethylpiperidine-nitrogen-oxide, and the co-catalyst is potassium bromide or sodium bromide.
2. The preparation method according to claim 1, wherein the organic solvent in step a is one or more selected from methanol, ethanol, dichloromethane and chloroform.
3. The method of claim 1, wherein the chloral hydrate obtained from step c is crystallized from a benign organic solvent and a poor organic solvent to obtain chloral hydrate.
4. The production method according to claim 3, wherein the poor organic solvent is one or two selected from n-hexane and n-heptane, and the benign organic solvent is one or two selected from ethyl acetate and dichloromethane.
5. The method according to any one of claims 1 to 4, comprising in particular the steps of:
a. dissolving trichloroacetyl chloride in an organic solvent, cooling to-10 ℃, adding 1.5-2.5 equivalent of reducing agent in batches, keeping the temperature at-10 ℃ for reaction for more than 1h, adding a reagent for quenching reaction, extracting and layering the system to obtain an organic solution of trichloroethanol, and distilling and separating to obtain a pure trichloroethanol;
b. dissolving trichloroethanol in an organic solvent, adding 1-5% of a main catalyst and 10-20% of a cocatalyst, cooling to-10-0 ℃, adding 1.5-2.5 equivalents of an oxidant for oxidation reaction, performing extraction separation after the reaction is finished to obtain an organic solution of the chloral, and performing distillation separation to obtain a pure product of the chloral;
c. dissolving trichloroacetaldehyde in benign organic solvent, adding water at-10 deg.c to react for 1-2 hr, dropping bad organic solvent for crystallization, filtering and washing to obtain high purity chloral hydrate.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB668275A (en) * 1947-05-03 1952-03-12 Fmc Corp Process for producing chloral and intermediates therefor
US5414139A (en) * 1993-04-21 1995-05-09 Kureha Chemical Industry Co., Ltd. Process for the manufacture of monochloroacetaldehyde trimer and chloral
CN101863832A (en) * 2010-06-13 2010-10-20 湖北远成药业有限公司 Method for producing miconazole nitrate on industrialized basis
CN102898346A (en) * 2012-03-28 2013-01-30 刘锋刚 Preparation method of vilazodone hydrochloride intermediate
CN109020813A (en) * 2017-06-12 2018-12-18 北京大学 A kind of new method preparing alpha-brominated -3,4- dimethoxyphenylacetic acid ethapon ester

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB668275A (en) * 1947-05-03 1952-03-12 Fmc Corp Process for producing chloral and intermediates therefor
US5414139A (en) * 1993-04-21 1995-05-09 Kureha Chemical Industry Co., Ltd. Process for the manufacture of monochloroacetaldehyde trimer and chloral
CN101863832A (en) * 2010-06-13 2010-10-20 湖北远成药业有限公司 Method for producing miconazole nitrate on industrialized basis
CN102898346A (en) * 2012-03-28 2013-01-30 刘锋刚 Preparation method of vilazodone hydrochloride intermediate
CN109020813A (en) * 2017-06-12 2018-12-18 北京大学 A kind of new method preparing alpha-brominated -3,4- dimethoxyphenylacetic acid ethapon ester

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