JP5205919B2 - Method for producing sulfonamide having ester group - Google Patents

Description

  The present invention relates to a method for producing a sulfonamide having an ester group.

Sulfonamides having ester groups are used as pharmaceutical building blocks. For example, Patent Document 1 discloses a method for synthesizing 3-acetoxypropanesulfonamide. Patent Documents 2, 3, and 4 disclose methods for synthesizing 3-acetoxypropanesulfonamide analogs.
JP-A-8-198878 JP-A-6-279446 International Publication No. WO2001027082 International Publication WO2006033344

  However, in the case of the conventional manufacturing method, an expensive raw material such as acetoxybromopropane is used as the raw material, which increases the manufacturing cost.

  Further, in the case of the above conventional production method, when scale up from the experimental level and industrial mass production is attempted, 3-acetoxypropanesulfonyl chloride produced in the course of production is decomposed to produce propane sultone, yield. There is concern about causing a decline.

  The present invention has been made in view of such circumstances, and provides a method for producing a sulfonamide having an ester group that can be industrially produced efficiently and inexpensively and can be purified to high purity as a crystal. It is aimed.

  The present inventor has intensively studied the above problems, adding dichloromethane as a solvent during the chlorination reaction, suppressing hydrolysis of the sulfonyl chloride, and suppressing the production of propane sultone, thereby improving the yield, The present inventors have found a method for producing a sulfonamide having an ester group that enables industrial production.

  The present invention for solving the above problems is a method for producing a sulfonamide having an ester group obtained by radical addition of a thioester to a compound having an ester group, sulfonyl chloride, and then sulfonamidation.

  As the compound having an ester group, any ester compound that is hydrolyzed by hydrochloric acid can be used. Presumably, in the case of an ester compound having a large carbon chain and a fat-solubility, there is a possibility that it will not undergo hydrolysis, so it is preferable to use an ester compound having as few carbon atoms as possible.

  As the compound having an ester group, one selected from the following is preferably used.

チオエステルとしては、チオ酢酸、チオ安息香酸を挙げることができる。このうち、チオ酢酸は、安価であるため低コスト化を図る上で好ましい。このチオエステルとしては、エステル基を有する化合物に対して等モル以上の量のチオエステルを用いることが好ましい。ラジカル付加反応を行う際の反応温度については、ラジカル付加反応が起きる範囲の出来るだけ低温から溶媒の沸点までの範囲であれば、特に限定されるものではなく、具体的には、３０℃以上から各溶媒の沸点の範囲で適宜調整することができる。反応条件については、空気存在下で反応させることが好ましい。

Examples of the thioester include thioacetic acid and thiobenzoic acid. Of these, thioacetic acid is preferable in terms of cost reduction because it is inexpensive. As this thioester, it is preferable to use an amount of thioester in an equimolar amount or more relative to the compound having an ester group. The reaction temperature for performing the radical addition reaction is not particularly limited as long as the reaction temperature is within the range from the lowest possible temperature to the boiling point of the solvent. It can adjust suitably in the range of the boiling point of each solvent. About reaction conditions, it is preferable to make it react in air presence.

  Examples of the solvent for sulfonyl chloride include organic solvents that are hardly soluble in water, such as dichloromethane, chloroform, carbon tetrachloride, heptane, hexane, and ether. Since chlorine that is flammable is blown when chlorinated sulforonitrile, it is preferable to use a halogen solvent that does not burn for safety. The amount of the solvent used is not particularly limited, but a larger amount is preferable to a smaller amount. Therefore, it is preferable to use the solvent by adjusting the amount of the solvent to a slight excess as much as possible without causing waste. As for the reaction temperature, when the temperature is high, the hydrolysis of the acetyl group is fast, and the amount of propane sultone produced increases. Therefore, it is better to keep the temperature as low as possible at 20 ° C. or lower, preferably 10 ° C. or lower in order to suppress hydrolysis. The amount of chlorine necessary for the reaction may be an amount necessary for consuming the intermediate produced from the thioester. Specifically, it is preferable that about 2.8 to 3.2 mol of chlorine is blown into 1 mol of the compound having an ester group. When the amount of chlorine is less than 2.8 mol, the yield is lowered, and when it exceeds 3.2 mol, the quality is lowered.

  In the sulfonamidation step, a general organic solvent such as ethyl acetate is used as a solvent, and ammonia gas is blown at a temperature of 30 ° C. or lower, preferably 20 ° C. or lower. At this time, as the amount of ammonia gas to be used, an amount until the intermediate sulfonyl chloride generated in the middle is eliminated by performing analysis is used. Specifically, an amount of about 2.2 mol is blown into 1 mol of the compound having an ester group.

  According to the present invention, a sulfonamide having an ester group can be mass-produced with high purity at low cost.

  Hereinafter, the effects of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1
[Production of 3-acetoxypropanesulfonamide]
24.1 kg of thioacetic acid and 138.0 kg of chloroform were charged, and 30.0 kg of allyl acetate was added dropwise over 2 hours, followed by reaction for 1 hour.

  After distilling off chloroform under reduced pressure, 341.5 kg of dichloromethane and 264.0 kg of city water were charged, and 63.6 kg of chlorine was blown in at an internal temperature of 15 ° C. or lower for 9 hours. Then, it was washed with 52.5 kg of 5% sodium sulfite water and 52.5 kg of city water, and the organic layer was dehumidified and filtered with 7.8 kg of anhydrous magnesium sulfate.

  The filtrate was concentrated and dichloromethane was distilled off, followed by charging with 251.0 kg of ethyl acetate. Thereafter, 12.0 kg of ammonia was blown in at an internal temperature of 20 ° C. or less over 6.5 hours, and filtration was performed to remove by-produced ammonium chloride. A small amount of remaining ammonium chloride was washed with 5% brine, and the organic layer was dehumidified with 11.1 kg of anhydrous magnesium sulfate and filtered.

  After concentrating the filtrate and distilling off ethyl acetate, 35.1 kg of ethyl acetate and 35.1 kg of toluene were charged. After adding the seed crystals, 66.6 kg of toluene was added dropwise, cooled and centrifuged.

得られた製品は２９．４ｋｇ、収率５４％、GC面積百分率１００．０％であった。

The obtained product was 29.4 kg, the yield was 54%, and the GC area percentage was 100.0%.

  INDUSTRIAL APPLICATION This invention can be utilized for industrial production of the sulfonamide which has an ester group which can be utilized as a building block of a pharmaceutical.

Claims (2)

A method for producing a sulfonamide having an ester group obtained by radical addition of a thioester to a compound having an ester group, sulfonyl chloride using dichloromethane as a solvent and then sulfonamidation ,
The production method wherein the compound having an ester group is allyl acetate and the sulfonamide having an ester group is 3-acetoxypropanesulfonamide . Method for producing the thioester claim 1 Symbol placement of sulfonamides is thioacetic acid.