CN114956954A - Preparation method of 1,1-difluoro-2-iodoethane - Google Patents
Preparation method of 1,1-difluoro-2-iodoethane Download PDFInfo
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- CN114956954A CN114956954A CN202210440744.XA CN202210440744A CN114956954A CN 114956954 A CN114956954 A CN 114956954A CN 202210440744 A CN202210440744 A CN 202210440744A CN 114956954 A CN114956954 A CN 114956954A
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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Abstract
The invention provides a preparation method for preparing 1,1-difluoro-2-iodoethane in the technical field of medicine, which comprises the following steps of carrying out esterification reaction on 2, 2-difluoroethanol 2 and p-nitrobenzenesulfonyl chloride 3 to obtain a compound 2, 2-difluoroethanol sulfonate; then adding the 2, 2-difluoroethanol sulfonate into a solvent and sodium iodide to carry out exchange reaction, and distilling while carrying out the reaction to obtain the product 1, 1-difluoro-2-iodoethane. The method overcomes the defects of the prior art, has the advantages of short reaction time, high product purity and yield and the like, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to a preparation method of 1,1-difluoro-2-iodoethane, belonging to the field of medical technology (organic synthesis).
Background
The english name of 1,1-difluoro-2-iodoethane (DFIE) is: 1, 1-difluoro-2-iodoethane; CAS Registry Number(s) 598-39-0; the boiling point is 89-90 ℃; the density is 2.180.
The structural formula is as follows:
DFIE is an important intermediate for the synthesis of many new drugs, especially the hotspot for structural design of new drugs, for example:
1. the Roche Holding AG discloses the following structure:
2. the gillidd science corporation (GILEAD SCIENCES INC) discloses the following structure:
3. the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, 2021, vol. 64, # 20, p. 15503-15514), and university of Mediterran China (UNIV CENTRAL CHINA NORMAL-EP3932923, 2022, A1) disclose the following structures:
4. nowa corporation (NOVARTIS AG); disclosed in WO2008/144062, 2008, A1
Currently, the following synthesis routes of 1,1-difluoro-2-iodoethane are mainly available:
1. obtained by reacting 1, 1-difluoroethylene with hydrogen iodide gas at the temperature of 230 ℃ and 250 ℃. The 1, 1-difluoroethylene is subjected to thermal decomposition on toxic hydrogen fluoride gas, and is inflammable and explosive, and the method only has the value of theoretical research.
The reaction equation is as follows:
2. heating 1, 1-difluoroethylene gas and a large amount of hydrogen bromide gas in a closed kettle for reaction, wherein the reaction equation is as follows:
it has the disadvantage of being inconvenient to use and store.
3. 1-chloro-2, 2-difluoroethane and sodium iodide are reacted in acetone to obtain a1, 1-difluoro-2-iodoethane product; the reaction is carried out for 8 days at 160 ℃ in a closed manner, and part of the unreacted raw material 1-chloro-2, 2-difluoroethane is recovered in the post-treatment process.
The reaction equation is as follows:
the method adopts halogen exchange reaction, the reaction with sodium iodide in acetone solvent is a conventional reaction condition, and fluorine atoms have strong electron-withdrawing effect, so that the chlorine activity is too low, and the chlorine is difficult to smoothly carry out even at high sealing temperature.
4. The 2-iodine-1, 1, 1-trifluoroethane is prepared by reacting 2,2, 2-trifluoroethanol p-toluenesulfonate and sodium iodide in a diethylene glycol solvent, the reaction temperature needs to be over 120 ℃ to smoothly react, and the product is distilled while the reaction is carried out so that the balance is carried out in the positive direction. Although this is a relatively practical preparation method, no report has been found for the synthesis of 1, 1-difluoro-2-iodoethane.
The reaction equation is as follows:
in conclusion, the search for a synthetic route of 1,1-difluoro-2-iodoethane with the advantages of low raw material cost, high product purity and yield and less three wastes becomes a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to provide a novel preparation process of 1,1-difluoro-2-iodoethane, which aims to overcome the defects of the existing process and has the advantages of low raw material cost, short reaction time, high product purity and yield and the like.
The purpose of the invention is realized as follows: a preparation method of 1,1-difluoro-2-iodoethane comprises the following steps:
s1, preparation of compound 2, 2-difluoroethanol sulfonate 4: carrying out esterification reaction on 2, 2-difluoroethanol 2 and sulfonyl chloride 3 in a solvent, washing after the reaction is finished, recovering the solvent from an organic layer, and removing low-boiling-point substances under reduced pressure to obtain 2, 2-difluoroethanol sulfonate 4;
s2, preparation of compound 1,1-difluoro-2-iodoethane 1: adding a solvent and sodium iodide into a compound 2, 2-difluoroethanol sulfonate 4 to perform an exchange reaction, and performing reactive distillation to obtain a product 1;
the reaction formula is as follows:
wherein: r1 is methyl, phenyl, p-tolyl, p-nitrophenyl or m-nitrophenyl;
the metal M is lithium, sodium or potassium.
Further, in step S1: preparation of 2, 2-difluoroethanolsulfonate 4
The reaction formula is as follows:
carrying out esterification reaction on 2, 2-difluoroethanol 2 and sulfonyl chloride 3, finishing feeding, keeping the reaction for 1 hour, and reacting until the molar content is less than 1.0 percent (2/(2 + 4)); and after the reaction is finished, adding water for washing, recovering the solvent from the organic layer, and removing low-boiling-point substances under reduced pressure to obtain the 2, 2-difluoroethanol sulfonate 4.
The sulfonyl chloride 3 is methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, m-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride; p-nitrobenzenesulfonyl chloride is preferred.
The solvent used in step S1 is toluene, ethyl acetate or dichloromethane, preferably dichloromethane. The base used is triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, preferably triethylamine.
Further, in step S2: preparation of compound 1,1-difluoro-2-iodoethane 1, having the reaction formula:
adding a compound 2, 2-difluoroethanol sulfonate 4 into a solvent and iodide salt, putting into a reaction bottle, carrying out exchange reaction, gradually heating to 100-150 ℃, and collecting to obtain a crude product by a method of reaction and distillation; then rectifying the crude product to obtain a product 1,1-difluoro-2-iodoethane 1.
The solvent used in step S2 is N, N-dimethylformamide, diethylene glycol or triethylene glycol; diethylene glycol is preferred. The iodide salt is sodium iodide, potassium iodide or lithium iodide; sodium iodide is preferred.
In the present invention, the substitution of sulfonate by halogen is a Finkelstein reaction, which is a bimolecular nucleophilic substitution reaction (SN 2 reaction). The reaction is a reversible reaction, and the factors influencing the moving direction of the equilibrium of the reaction are as follows: (1) nucleophilicity of the halide ion of the metal halide, (2) size of leaving group leaving ability of the leaving group and (3) stability of one of the ions in the reaction solvent. Especially, the p-nitrobenzenesulfonate is used as a leaving group, so that the activity of a reaction substrate is greatly improved, and the harsh reaction conditions are reduced. The relative rates of leaving ability of the leaving group are roughly as follows:
compared with the prior art, the invention has the beneficial effects that:
the invention provides a new process route for preparing 1,1-difluoro-2-iodoethane (DFIE), which comprises the steps of carrying out esterification reaction on 2, 2-difluoroethanol 2 and sulfonyl chloride 3 to obtain a compound 4; then adding the compound 4 into a solvent and iodide salt for exchange reaction, and carrying out reactive distillation to obtain a product 1. Because the inventor selects and adopts a stronger p-nitrobenzenesulfonic acid leaving group, the condition that the sulfonate is replaced by iodine is mild; meanwhile, a polar solvent with high boiling point is used, and a method of collecting products by reactive distillation is adopted, so that the reaction balance is rapidly carried out in the positive direction, and the yield and the quality of the products are greatly improved.
The new preparation method provided by the invention overcomes the defects of the prior art, has the advantages of short reaction time, high product purity and yield and the like, and is suitable for industrial amplification.
Drawings
FIG. 1 is a GC spectrum of purity detection of 1,1-difluoro-2-iodoethane (DFIE) of example 1.
Detailed Description
Example 1
Step 1: synthesis of Compound 4
Cooling 8.25g of 2, 2-difluoroethanol 2, 22.50g of p-nitrobenzenesulfonyl chloride 3 and 50mL of dichloromethane to 0-5 ℃ under the protection of nitrogen, starting to dropwise add 12.5g of triethylamine for esterification reaction, finishing the addition within about 2 hours, and keeping the reaction at 2-7 ℃ for 5 hours until the molar content is less than 1.0 percent (2/(2 + 4));
after the reaction is finished, adding 50mL of water, stirring for 10 minutes, washing, standing for layering, extracting the water layer with 50mL of dichloromethane, and then discarding; combining the organic layers, adjusting the pH to be 7-8 by hydrochloric acid, standing for layering, and discarding the water layer;
recovering solvent from organic layer, removing low-boiling point substance under reduced pressure, sampling, and controlling to obtain 24.95g of compound 4 with purity of 98.80% and yield of 93.5% and 2, 2-difluoroethanol content of less than 0.5%.
And 2, step: synthesis of Compound 1
In a reaction vessel equipped with a distillation apparatus, the above 24.50g of Compound 4 and 50mL of diethylene glycol were added with stirring 19.0g of sodium iodide, and the reaction mixture was slowly heated to 100 ℃ and 120 ℃ for reaction for 3 hours while distilling off the product. The obtained crude product is rectified under normal pressure, and 88-92 ℃ fractions are collected to obtain 13.2g of product 1 with the purity of 99.26 percent and the yield of 75.3 percent.
The GC spectrogram of the purity detection of the product is shown in the attached figure 1.
Example 2
Step 1: synthesis of Compound 4
Cooling 8.25g of 2, 2-difluoroethanol 2, 23.0g of p-nitrobenzenesulfonyl chloride 3 and 50mL of toluene to 0-5 ℃ under the protection of nitrogen, starting to dropwise add a 50% sodium hydroxide aqueous solution for esterification reaction, finishing the addition within about 2 hours, keeping the reaction at 2-10 ℃ for 3 hours, and reacting until the molar content is less than 1.0% in terms of 2/(2 + 4);
after the reaction is finished, adding 50mL of water, stirring for 10 minutes, washing, standing for layering, extracting the water layer with 50mL of toluene, and then discarding; combining the organic layers, adjusting the pH to be 7-8 by hydrochloric acid, standing for layering, and discarding the water layer;
the toluene solvent was recovered from the organic layer, and the end point of the desolvation was controlled by sampling, and 2, 2-difluoroethanol was less than 0.5%, whereby 25.3g of compound 4 was obtained, having a purity of 98.80% and a yield of 94.8%.
Step 2: synthesis of Compound 1
In a reaction vessel equipped with a distillation apparatus, 18.50g of potassium iodide was added to 25.0g of the above-mentioned compound 4 and 50ml of N, N-dimethylformamide under stirring, and the reaction mixture was slowly heated to 110 ℃ and 120 ℃ to react while distilling off the product until no fraction was distilled off. The obtained crude product is rectified under normal pressure, and 88-92 ℃ fractions are collected to obtain 12.35g of product 1 with the purity of 98.39% and the yield of 70.1%.
Example 3
Step 1: synthesis of Compound 4
Cooling 8.25g of 2, 2-difluoroethanol 2, 22.10g of p-nitrobenzenesulfonyl chloride 3 and 100mL of ethyl acetate under the protection of nitrogen to 0-5 ℃, dropwise adding triethylamine for esterification reaction, keeping the reaction at 2-10 ℃ for 6 hours after the addition is finished for about 2 hours, and reacting until the molar content is '2/(2 + 4) is less than 1.0%';
after the reaction is finished, adding 50mL of water, stirring for 10 minutes, washing, standing for layering, extracting a water layer with 50mL of ethyl acetate, and then discarding; combining the organic layers, adjusting the pH to be 7-8 by hydrochloric acid, standing for layering, and discarding the water layer;
and recovering the solvent from the organic layer, decompressing to remove low-boiling-point substances and water in the material, sampling and controlling, wherein the content of 2, 2-difluoroethanol is less than 0.5 percent, 23.94g of the compound 4 is obtained, the purity is 98.20 percent, and the yield is 89.60 percent.
Step 2: synthesis of Compound 1
In a reaction vessel equipped with a distillation apparatus, 23.20g of the above compound 4 and 50ml of triethylene glycol were added with stirring 15.0g of lithium iodide, and the reaction mixture was slowly heated to 120 ℃ and 130 ℃ to react while distilling off the product until no fraction was distilled off. The crude product is rectified under normal pressure, and fractions at 88-92 ℃ are collected to obtain 12.80g of product 1 with the purity of 98.59% and the yield of 75.6%.
Example 4
Step 1: synthesis of difluoroethanol p-toluenesulfonate
Cooling 8.25g of 2, 2-difluoroethanol 2, 19.5g of p-toluenesulfonyl chloride and 100mL of ethyl acetate to 0-5 ℃ under the protection of nitrogen, dropwise adding triethylamine to perform esterification reaction, keeping the reaction at 2-10 ℃ for 6 hours after the feeding is finished for about 2 hours until the molar content of the 2, 2-difluoroethanol 2 is less than 1.0% ";
after the reaction is finished, adding 50mL of water, stirring for 10 minutes, washing, standing for layering, extracting a water layer with 50mL of ethyl acetate, and then discarding; combining the organic layers, adjusting the pH to be 7-8 by hydrochloric acid, standing for layering, and discarding the water layer;
recovering solvent from the organic layer, decompressing to remove low boiling point substance, sampling and controlling, wherein the content of 2, 2-difluoroethanol is less than 0.5 percent, 21.73g of crude 2, 2-difluoroethanol p-toluenesulfonate is obtained, the purity is 99.26 percent, and the yield is 92.1 percent.
Step 2: synthesis of Compound 1
In a reaction vessel equipped with a distillation apparatus, 22.5g of potassium iodide was added to 20.00g of the crude difluoroethanol p-toluenesulfonate and 50ml of triethylene glycol under stirring, and the reaction mixture was slowly heated to 160 ℃ to start the reaction and to continue the distillation until no fraction was distilled off. The obtained crude product is rectified under normal pressure, and 88-92 ℃ fractions are collected to obtain 9.56g of product 1 with the GC purity of 97.52% and the yield of 59.1%.
Example 5
Step 1: synthesis of difluoroethanol mesylate
Cooling 8.25g of 2, 2-difluoroethanol 2, 11.5g of methanesulfonyl chloride and 100mL of dichloromethane to 0-5 ℃ under the protection of nitrogen, starting to dropwise add 10% sodium carbonate aqueous solution for esterification reaction, finishing the addition within about 2 hours, keeping the reaction at 2-10 ℃ for 6 hours, and reacting until the molar content is '2, 2-difluoroethanol 2 is less than 1.0%';
after the reaction is finished, adding 50mL of water, stirring for 10 minutes, washing, standing for layering, extracting the water layer with 50mL of dichloromethane, and then discarding; combining the organic layers, adjusting the pH to be 7-8 by hydrochloric acid, standing for layering, and discarding the water layer;
the organic layer was recovered with the solvent dichloromethane and the low boiling point material was removed under reduced pressure to give 14.26g of crude 2, 2-difluoroethanol mesylate in 89.1% yield.
Step 2: synthesis of Compound 1
In a reaction flask equipped with a distillation apparatus, 14.0g of the above crude difluoroethanol methanesulfonate and 50ml of diethylene glycol were added with stirring 15.0g of potassium iodide, and the reaction mixture was slowly heated to 160 ℃ to start the reaction with distillate generation, and the distillation of the product was continued until no distillate was distilled off. The obtained crude product is rectified under normal pressure, and 88-92 ℃ fractions are collected to obtain 8.80g of product 1, wherein the GC purity is 98.12%, and the yield is 52.6%.
In step 1 of examples 1-5, the sulfonyl chloride can be methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, m-nitrobenzenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride; the final yields of examples 1-3 above are significantly greater than those of examples 4-5, mainly due to the use of p-nitrobenzenesulfonyl chloride. The solvent used may be toluene, ethyl acetate or dichloromethane, preferably dichloromethane. The base used may be triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, preferably triethylamine.
The solvent used in step 2 of examples 1-5 was N, N-dimethylformamide, diethylene glycol or triethylene glycol; diethylene glycol is preferred. The iodide salt is sodium iodide, potassium iodide or lithium iodide; sodium iodide is preferred.
The present invention is not limited to the above-mentioned embodiments, and based on the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some technical features without creative efforts according to the disclosed technical contents, and these substitutions and modifications are all within the protection scope of the present invention.
Claims (8)
1. A preparation method of 1,1-difluoro-2-iodoethane is characterized in that: comprises the following steps
S1, preparation of compound 2, 2-difluoroethanol sulfonate (4): carrying out esterification reaction on 2, 2-difluoroethanol (2) and sulfonyl chloride (3), washing after the reaction is finished, recovering the solvent from an organic layer, and removing low-boiling-point substances under reduced pressure to obtain 2, 2-difluoroethanol sulfonate (4);
s2, preparation of compound 1,1-difluoro-2-iodoethane (1): adding a solvent and sodium iodide into a compound 2, 2-difluoroethanol sulfonate (4) to carry out exchange reaction, and carrying out reactive distillation to obtain a product (1);
the reaction formula is as follows:
wherein: r1 is methyl, phenyl, p-tolyl, p-nitrophenyl or m-nitrophenyl;
the metal M is lithium, sodium or potassium.
2. The process for the preparation of 1,1-difluoro-2-iodoethane as claimed in claim 1, wherein:
in step S1: preparation of 2, 2-difluoroethanolsulfonate (4)
The reaction formula is as follows:
carrying out esterification reaction on 2, 2-difluoroethanol 2 and sulfonyl chloride (3) in a solvent, after the addition is finished, keeping the reaction for 1 hour until the molar content is less than 1.0 percent (2/(2 + 4)); after the reaction is finished, adding water for washing, recovering the solvent from the organic layer, and removing low-boiling-point substances under reduced pressure to obtain the 2, 2-difluoroethanol sulfonate (4).
3. The process for the preparation of 1,1-difluoro-2-iodoethane as claimed in claim 2, wherein: the sulfonyl chloride 3 is methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, m-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride; p-nitrobenzenesulfonyl chloride is preferred.
4. The process for the preparation of 1,1-difluoro-2-iodoethane as claimed in claim 2, wherein: the solvent used in step S1 is toluene, ethyl acetate or dichloromethane.
5. The process for the preparation of 1,1-difluoro-2-iodoethane as claimed in claim 2, wherein: in step S1, the base used is triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
6. The process for the preparation of 1,1-difluoro-2-iodoethane as claimed in claim 1, wherein:
in step S2: preparation of compound 1,1-difluoro-2-iodoethane (1) having the reaction formula:
adding a compound 2, 2-difluoroethanol sulfonate (4) into a solvent and iodide salt, putting the mixture into a reaction bottle, carrying out exchange reaction, gradually heating to 100-150 ℃, and collecting a crude product by a method of reaction and distillation; then rectifying the crude product to obtain the product 1,1-difluoro-2-iodoethane (1).
7. The process according to claim 6, wherein the reaction mixture comprises 1, 1-difluoro-2-iodoethane: the solvent used in step S2 is N, N-dimethylformamide, diethylene glycol or triethylene glycol.
8. The process according to claim 6, wherein the reaction mixture comprises 1, 1-difluoro-2-iodoethane: in step S2, the iodide salt used is sodium iodide, potassium iodide or lithium iodide.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030013756A1 (en) * | 1999-12-13 | 2003-01-16 | Jo Jaechon | 3-methyl -chromane or thiochromane derivatives |
| US20030092695A1 (en) * | 1999-12-13 | 2003-05-15 | Jo Jaechon | Metal salts of 3-methyl-chromane or thiochromane derivatives |
| CN113307720A (en) * | 2021-04-16 | 2021-08-27 | 浙江巨化技术中心有限公司 | Preparation method of 1, 1-difluoro-2-iodoethylene |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030013756A1 (en) * | 1999-12-13 | 2003-01-16 | Jo Jaechon | 3-methyl -chromane or thiochromane derivatives |
| US20030092695A1 (en) * | 1999-12-13 | 2003-05-15 | Jo Jaechon | Metal salts of 3-methyl-chromane or thiochromane derivatives |
| CN113307720A (en) * | 2021-04-16 | 2021-08-27 | 浙江巨化技术中心有限公司 | Preparation method of 1, 1-difluoro-2-iodoethylene |
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