CN112778089B - New synthetic method of 4, 4-trifluoro-1-butanol and homologs thereof - Google Patents
New synthetic method of 4, 4-trifluoro-1-butanol and homologs thereof Download PDFInfo
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- CN112778089B CN112778089B CN202110002377.0A CN202110002377A CN112778089B CN 112778089 B CN112778089 B CN 112778089B CN 202110002377 A CN202110002377 A CN 202110002377A CN 112778089 B CN112778089 B CN 112778089B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/34—Halogenated alcohols
- C07C31/38—Halogenated alcohols containing only fluorine as halogen
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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
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- 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
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a novel synthesis method of 4, 4-trifluoro-1-butanol and homologues thereof, and relates to the technical field of organic synthesis. Mainly comprises the following steps: (1) Reacting ethyl trifluoroacetate with a Grignard reagent to obtain benzyloxy substituted alkyl-trifluoromethyl ketone; (2) Reducing benzyloxy substituted alkyl-trifluoromethyl ketone to prepare 1-benzyloxy-trifluoro substituted alkyl; (3) The 4, 4-trifluoro-1-butanol or the homolog thereof is prepared by hydrolyzing the 1-benzyloxy-trifluoro-substituted alkyl. Compared with the prior art, the invention does not use freon raw materials which pollute the air; no dangerous lithium aluminum hydride is used; high temperature reaction is not required; the raw material ethyl trifluoroacetate is cheap and easy to obtain, and the other main raw material Grignard reagent can be synthesized by using the cheap raw material.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a novel synthesis method of 4, 4-trifluoro-1-butanol and homologs thereof.
Background
4, 4-trifluoro-1-butanol, molecular formula C 4 H 7 F 3 O has a relative molecular mass of 128.09 and is colorless transparent liquid, and the structural formula is as follows:
4, 4-trifluoro-1-butanol has strong hydrogen bond forming ability due to high electronegativity of fluorine atoms, and other chemical substances react to generate more stable compounds; compared with the fluorine-containing compounds, the fluorine-containing compounds have the characteristics of small dosage, low toxicity, high drug effect, strong metabolic capability and the like in the aspects of medicinal properties such as medicines, pesticides and the like, and are widely applied as medicines with stronger biological activity and higher selectivity. 4, 4-trifluoro-1-butanol can be used for preparing lactone and lactam compounds (used as central nervous inhibitors), immunizing agents and the like in medicine; the method is also used for preparing liquid crystal materials and organic conductors, and has wide development and utilization prospects.
At present, the literature method for synthesizing 4, 4-trifluoro-1-butanol mainly comprises the following steps:
first kind: 4, 4-trifluoro butyl alcohol is generated after the reduction reaction of 4, 4-trifluoro butyl acid ethyl ester/diphenyl methyl ester or 4, 4-trifluoro butyl acid and sodium borohydride/calcium chloride and lithium aluminum hydride under the heating condition. The method has the defect that the lithium aluminum hydride has high activity, and the quenching reagent is required to be added in a strict proportion in the post-treatment, so that the method is not suitable for industrial scale-up. Meanwhile, when the post-treatment quenching is performed, a large amount of hydrogen is generated by adding water, and certain potential safety hazards exist.
Second kind: and (3) reacting trifluoromethyl ethylene with trimethyl borate at 130 ℃ in the presence of tert-butyl peroxide, and finally detecting the product in the obtained kettle residue to be no more than 5% after the reaction treatment. The method has the advantages that the yield is low, the actual synthesis value is not realized, the method uses freon raw materials which can cause air pollution, the method is not suitable for the requirements of modern environmental protection, and the reaction temperature is high, so that potential safety hazards are easy to generate.
Third kind: 4, 4-trifluoro-butylamine hydrochloride and sodium nitrite are adopted to react in perchloric acid to generate 4, 4-trifluoro-butanol, and the method not only obtains 97.5 percent of main product, but also obtains 2.5 percent of isomer product. Because of the similar chemical properties, the pure product is not easy to obtain during purification.
Therefore, a process route of 4, 4-trifluoro-1-butanol which is suitable for industrial production and has economic benefit is found, and homologs with the same or similar functions can be synthesized through the process route, so that the method has great social and market benefits.
Disclosure of Invention
The invention provides a novel synthesis method of 4, 4-trifluoro-1-butanol and homologues thereof, which aims to solve the problems in the prior art.
In order to achieve the technical purpose, the invention adopts the following technical scheme: the ethyl trifluoroacetate is used as a starting material, and the synthetic route is as follows:
the method specifically comprises the following steps:
s1, reacting ethyl trifluoroacetate with a Grignard reagent to prepare a compound shown in a formula (I);
s2: the compound of the formula (I) is subjected to reduction reaction to prepare a compound of the formula (II);
s3: the compound of formula (II) is subjected to hydrolysis reaction to obtain 4, 4-trifluoro-1-butanol and homologs thereof;
wherein n is a natural number from 1 to 5.
In the invention, in the step S1, a format reagent is dripped into ethyl trifluoroacetate at the temperature of minus 20 ℃, then the reaction is carried out by slowly recovering to room temperature, and after the reaction is completed, the compound of the formula (I) is obtained through post-treatment.
Further, the post-treatment step in the step S1 is to add the reaction solution prepared in the step S1 into water, adjust the pH to 5.0-6.8 by dilute hydrochloric acid, collect the organic phase and concentrate to obtain the compound of formula (I).
In the invention, in the step S2, after the compound of the formula (I) and hydrazine hydrate react in an organic solvent for 2 hours at room temperature, potassium tert-butoxide is slowly added in batches, the reaction is continued at room temperature, and after the reaction is completed, the compound of the formula (II) is obtained through post treatment.
Preferably, in the step S2, the organic solvent is dimethyl sulfoxide.
Further, the post-treatment step in the step S2 is that the reaction liquid prepared in the step S2 is added into ice water, the reaction liquid is regulated to be neutral by dilute hydrochloric acid, then extraction is carried out by ethyl acetate, and organic phases are combined and concentrated to obtain the compound shown in the formula (II).
In the invention, in the step S3, after the compound of the formula (II) is dissolved in an organic solvent, lewis acid is added under the condition of ice water bath, then the reaction is continued at room temperature, and after the reaction is completed, 4-trifluoro-1-butanol and homologues thereof are obtained through post-treatment.
Further, the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform and toluene; the Lewis acid is one or more selected from ferric trichloride, aluminum trichloride, hydrobromic acid and trifluoroacetic acid.
Preferably, the organic solvent is selected from dichloromethane; the lewis acid is selected from ferric trichloride.
Preferably, the post-treatment step in the step S3 is to pour the reaction solution prepared in the step S3 into water, suction-filter the organic phase, concentrate and rectify to prepare the 4, 4-trifluoro-1-butanol and the homolog pure product thereof.
Compared with the prior art, the invention has the advantages that: the freon raw material which can pollute the air is not used; no dangerous lithium aluminum hydride is used; high temperature reaction is not required; the raw material ethyl trifluoroacetate is cheap and easy to obtain, and the other main raw material Grignard reagent can be synthesized by using the cheap raw material.
Detailed Description
The invention is further illustrated by the following examples which are intended to be illustrative of the methods of the invention, including but not limited to the examples.
Example 1
(1) Preparation of the Compound (2-Benzyloxyethyl) -trifluoromethyl ketone of formula (I)
700mL of 2-benzyloxy-ethyl magnesium chloride (1M) is added dropwise into 1000mL of ethyl trifluoroacetate at the temperature of minus 20 ℃, the reaction is slowly restored to the room temperature, the reaction is carried out for 6 hours, the mixture is poured into 1000mL of water, the pH is regulated to 5.0-6.8 by hydrochloric acid, an organic phase is collected, the solvent is dried by spinning to obtain (2-benzyloxy-ethyl) -trifluoromethyl ketone, and the crude product is temporarily overweight and directly used for the next reaction.
(2) Preparation of the Compound 1-benzyloxy-4, 4-trifluorobutane of formula (II)
Dissolving the (2-benzyloxy ethyl) -trifluoromethyl ketone obtained in the previous step in 900mL of DMSO, adding 50g of hydrazine hydrate, reacting for 2 hours at room temperature, slowly adding 200g of potassium tert-butoxide in batches, continuing to react for 12 hours at room temperature after the addition is finished, pouring into ice water, adjusting hydrochloric acid to be neutral, extracting with 300mL of ethyl acetate for three times, merging organic phases, and spin-drying to obtain 1-benzyloxy-4, 4-trifluoro butane, wherein the crude product is temporarily overweight and directly used for the next reaction.
(3) Preparation of 4, 4-trifluoro-1-butanol
Dissolving 1-benzyloxy-4, 4-trifluoro butane obtained in the previous step in 500mL of dichloromethane, adding 150g of anhydrous ferric trichloride under ice water bath, reacting for 12 hours after the temperature is restored to room temperature, pouring into water, suction-filtering to collect an organic phase, spin-drying dichloromethane, rectifying to obtain 70g of pure product, and obtaining the total yield of three steps of 78%.
Example 2
The preparation process was essentially the same as in example one, except that:
in the step (3), the organic solvent is 1, 2-dichloroethane, the Lewis acid is aluminum trichloride, and the total reaction yield of the three steps is 75%.
Example 3
The preparation process was essentially the same as in example one, except that:
in the step (3), the organic solvent is chloroform, the Lewis acid is hydrobromic acid, and the total reaction yield of the three steps is 69%.
Example 4
The preparation process was essentially the same as in example one, except that:
in the step (3), the organic solvent is toluene, the Lewis acid is trifluoroacetic acid, and the total reaction yield of the three steps is 57%.
Example 5
(1) Preparation of the Compound (6-benzyloxyhexyl) -trifluoromethyl ketone of formula (I)
700mL of 6-benzyloxy-hexyl magnesium chloride (1M) is added dropwise into 1000mL of ethyl trifluoroacetate at the temperature of minus 20 ℃, the reaction is slowly restored to the room temperature, the reaction is carried out for 6 hours, the mixture is poured into 1000mL of water, the pH is regulated to 5.0-6.8 by hydrochloric acid, an organic phase is collected, the solvent is dried by spinning, thus obtaining (6-benzyloxy hexyl) -trifluoromethyl ketone, and the crude product is temporarily overweight and directly used for the next reaction.
(2) Preparation of the Compound 1-benzyloxy-8, 8-trifluoro-octane of formula (II)
Dissolving the (6-benzyloxyhexyl) -trifluoromethyl ketone obtained in the previous step in 900mL of DMSO, adding 50g of hydrazine hydrate, reacting for 2 hours at room temperature, slowly adding 200g of potassium tert-butoxide in batches, continuing to react for 12 hours at room temperature after the addition is finished, pouring into ice water, adjusting hydrochloric acid to be neutral, extracting with 300mL of ethyl acetate for three times, merging organic phases, and spin-drying to obtain 1-benzyloxy-8, 8-trifluoro octane, wherein the crude product is temporarily overweight and directly used for the next reaction.
(3) Preparation of 4, 4-trifluoro-1-butanol homologs
Dissolving 1-benzyloxy-8, 8-trifluoro octane obtained in the previous step in 500mL of dichloromethane, adding 150g of anhydrous ferric trichloride under ice water bath, reacting for 12 hours after the temperature is restored to room temperature, pouring into water, filtering to collect an organic phase, spinning to dry dichloromethane, rectifying to obtain 71g of pure product, and the total yield of three steps is 55%.
Example 6
The preparation process is basically the same as in example five, except that:
in the step (3), the organic solvent is 1, 2-dichloroethane, the Lewis acid is aluminum trichloride, and the total reaction yield of the three steps is 48%.
Example 7
The preparation process is basically the same as in example five, except that:
in the step (3), the organic solvent is chloroform, the Lewis acid is hydrobromic acid, and the total reaction yield of the three steps is 44%.
Example 8
The preparation process is basically the same as in example five, except that:
in the step (3), the organic solvent is toluene, the Lewis acid is trifluoroacetic acid, and the total reaction yield of the three steps is 38%.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A novel synthesis method of 4, 4-trifluoro-1-butanol and homologs thereof is characterized in that ethyl trifluoroacetate is used as a starting material, and the synthesis route is as follows:
the method comprises the following steps:
s1, reacting ethyl trifluoroacetate with a Grignard reagent to prepare a compound shown in a formula (I);
s2: the compound of the formula (I) is subjected to reduction reaction to prepare a compound of the formula (II);
s3: the compound of formula (II) is subjected to hydrolysis reaction to obtain 4, 4-trifluoro-1-butanol and homologs thereof;
wherein n is a natural number from 1 to 5;
the process of step S2 is as follows: and (3) after reacting the compound shown in the formula (I) with hydrazine hydrate in dimethyl sulfoxide for 2 hours at room temperature, slowly adding potassium tert-butoxide in batches, continuously reacting at room temperature, adding the prepared reaction liquid into ice water after the reaction is completed, adjusting the reaction liquid to be neutral by dilute hydrochloric acid, extracting by ethyl acetate, merging organic phases, and concentrating to obtain the compound shown in the formula (II).
2. A novel synthesis of 4, 4-trifluoro-1-butanol and its homologs according to claim 1, characterized in that: in the step S1, a format reagent is dripped into ethyl trifluoroacetate at the temperature of minus 20 ℃, then the reaction is carried out after the reaction is carried out slowly and the room temperature is restored, and the compound of the formula (I) is obtained after the post-treatment after the reaction is completed.
3. A novel synthesis of 4, 4-trifluoro-1-butanol and its homologs according to claim 2, characterized in that: the post-treatment step in the step S1 is that the reaction liquid prepared in the step S1 is added into water, the pH is regulated to 5.0-6.8 by dilute hydrochloric acid, then an organic phase is collected and concentrated to obtain the compound shown in the formula (I).
4. A novel synthesis of 4, 4-trifluoro-1-butanol and its homologs according to claim 1, characterized in that: in the step S3, after the compound of the formula (II) is dissolved in an organic solvent, lewis acid is added under the condition of ice water bath, then the reaction is continued at room temperature, and after the reaction is completed, 4-trifluoro-1-butanol and homologues thereof are obtained through post-treatment.
5. The novel synthesis method of 4, 4-trifluoro-1-butanol and its homologs according to claim 4, wherein: the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform and toluene; the Lewis acid is one or more selected from ferric trichloride, aluminum trichloride, hydrobromic acid and trifluoroacetic acid.
6. The novel synthesis method of 4, 4-trifluoro-1-butanol and its homologs according to claim 5, wherein: the organic solvent is selected from dichloromethane; the lewis acid is selected from ferric trichloride.
7. The novel synthesis method of 4, 4-trifluoro-1-butanol and its homologs according to claim 6, wherein: the post-treatment step in the step S3 is to pour the reaction liquid prepared in the step S3 into water, suction-filter the organic phase, concentrate and rectify to prepare the 4, 4-trifluoro-1-butanol and the homolog pure product thereof.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1286693A (en) * | 1997-12-23 | 2001-03-07 | 舍林公开股份有限公司 | 11 'beta'-halogen-7 'alpha'-substd estratrienes, method for producing pharmaceutical preparations contg. said 11 'beta'-halogen-7 'alpha'-substd estratrienes and use of same for producing medicaments |
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| AU2016360886B2 (en) * | 2015-11-24 | 2021-04-15 | Centre National De La Recherche Scientifique | Method for synthesizing iodo- or astatoarenes using diaryliodonium salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1286693A (en) * | 1997-12-23 | 2001-03-07 | 舍林公开股份有限公司 | 11 'beta'-halogen-7 'alpha'-substd estratrienes, method for producing pharmaceutical preparations contg. said 11 'beta'-halogen-7 'alpha'-substd estratrienes and use of same for producing medicaments |
Non-Patent Citations (1)
| Title |
|---|
| Assessing the bioisosterism of the trifluoromethyl group with a protease probe;Jagodzinska, Monika等;《ChemMedChem》;第4卷(第1期);第49-51页 * |
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