Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-09
2002-08-27
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S206000
Reexamination Certificate
active
06441187
ABSTRACT:
This application claims priority from JP 253083/2000 which is a Japanese applicable file on Jul. 9, 2001.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing camphorsultam and its intermediate, which are useful as a reagent for asymmetric induction and as a starting material for a compound useful as a fine chemical or medicament.
BACKGROUND OF THE INVENTION
Camphorsultam is useful as a reagent for asymmetric induction and as a starting material for a compound useful as a fine chemical or medicament. It can be produced by various known methods, wherein the following scheme is generally employed for the production. Note that the following compounds 1-5 includes S pounds, R compounds and racemates.
According to Towson et al., in the above-mentioned scheme,
1. 1 is reacted with 2.4 equivalents of thionyl chloride in chloroform to give 2,
2. 2 is reacted with NH
4
OH to give 3, and
3. 3 is reacted in the presence of AMBERLYST to give 4 (ORGANIC SYNTHESIS, COLLECT VOL. VIII, 104-105). According to Weismiller et al., in the above-mentioned scheme, 4 is reduced with LiAlH
4
to give 5 (ORGANIC SYNTHESIS, COLLECT VOL. VIII, 110-111).
When the above-mentioned conventional production method is practiced at an industrial level, there arise various problems that the use of chloroform is not preferable for human body and the environment, and the use of LiAlH
4
is dangerous.
According to Capet et al., in the above-mentioned scheme,
1. 1 is reacted with 4 equivalents of thionyl chloride without a solvent to give 2, and excess thionyl chloride is removed,
2. 2 is reacted with ammonia in a 60-fold molar amount relative to 1 in an aqueous 1,4-dioxane solution to give 3,
3. 3 is subjected to dehydration and ring closure at 90° C. to give 4, and
4. 4 is reduced with sodium borohydride in a 2-fold molar amount relative to 4 in an aqueous methanol solution to give 5 (SYNTHETIC COMMUNICATIONS, 25 (21), 3323-3327 (1995)).
When the above-mentioned production method is practiced at an industrial scale, the following problems unpreferably occur.
The chlorination in a non-solvent system is preferable, but the amount used of thionyl chloride is 2-fold molar amount relative to 1, which gives rise to a need to remove excess thionyl chloride by boiling with toluene.
For amidation, 1,4-dioxane (carcinogen) is used, which is not preferable for human body.
For amidation, a large excess of ammonia is used to avoid hydrolysis of 2, which causes a large amount of ammonia gas generated during dehydration and ring closure. The amount generated is about 400-fold volume relative to camphorsulfonic acid, which makes industrial production unattainable.
For the reduction step, an aqueous methanol solution is used, which causes hydrolysis of sodium borohydride, which uneconomically necessitates addition of excess sodium borohydride. What is more, an excess hydrogen gas is generated.
The obtained 5 is extracted with methylene chloride (environmental contaminant), and the resulting organic layer is washed and condensed, after which 5 is recrystallized from ethanol for isolation. During these steps, crystals adhere to the wall of the container (scaling), which is industrially undesirable.
When the above-mentioned conventional production method is industrially applied, therefore, various problems occur. Thus, the development of an industrially applicable production method of camphorsultam and an intermediate thereof is demanded, which is less associated with the above-mentioned problems (production cost, production efficiency, influence on human body and the environment, simplicity and easiness, safety of reaction etc.).
It is therefore an object of the present invention to provide an industrially applicable production method of camphorsultam and an intermediate thereof, which is comparatively safe to the environment and human body, economical, simple and easy.
SUMMARY OF THE INVENTION
According to the present invention, it has been found that the use of an aqueous isopropanol solution in the reduction step makes hydrolysis of sodium borohydride difficult, as a result of which the use of sodium borohydride in excess is obliterated and the amount of generated hydrogen gas is decreased. It has been also found that, when camphorsulfonyl halide is reacted with aqueous ammonia in a solvent immiscible with water during amidation, hydrolysis of camphorsulfonyl halide can be inhibited, which in turn more preferably reduces considerably the amount of ammonia to be used. Furthermore, by using an acid instead of extracting with an environment polluting substance, such as methylene chloride, after reduction, camphorsultam can be obtained as crystals.
Thus, the present invention relates to a production method of camphorsultam (10,10-dimethyl-3-thia-4-azatricyclo[5.2.1.0
1,5
]decane 3,3-dioxide), which includes reduction of camphorsulfonimine (10,10-dimethyl-3-thia-4-azatricyclo[5.2.1.0
1,5
]dec-4-ene 3,3-dioxide) with sodium borohydride in an aqueous isopropanol solution, wherein sodium borohydride is preferably used in a 0.3-fold to 0.7-fold molar amount relative to camphorsulfonimine.
More particularly, the present invention relates to a method for producing camphorsultam, which includes the following steps:
Step 1: reacting camphorsulfonic acid ((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid) with a halogenation agent to give camphorsulfonyl halide ((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl halide),
Step 2: reacting the camphorsulfonyl halide with ammonia to give camphorsulfonamide ((7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonamide),
Step 3: subjecting the camphorsulfonamide to dehydration and ring closure to give camphorsulfonimine, and
Step 4: reducing the camphorsulfonimine with sodium borohydride in an aqueous isopropanol solution to give camphorsultam.
In Step 2, camphorsulfonyl halide is preferably reacted with aqueous ammonia in a solvent immiscible with water, and the aqueous ammonia preferably contains ammonia in a 4-fold to 10-fold molar amount relative to camphorsulfonyl halide.
In Step 4, sodium borohydride is preferably used in a 0.3-fold to 0.7-fold molar amount relative to camphorsulfonimine.
After Step 4, an acid may be added to the reaction mixture to allow precipitation of camphorsultam. The acid used at this time is preferably hydrochloric acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following.
Camphorsultam can be obtained by successively conducting halogenation, amidation, ring closure and reduction, using camphorsulfonic acid as a starting material. In the present invention, camphorsultam encompasses a racemate and optically active compounds (1S and 1R).
Step 1 (Halogenation)
Camphorsulfonic acid is reacted with a halogenation agent to give camphorsulfonyl halide. To be specific, camphorsulfonic acid is added to a solvent, and a halogenation agent is added thereto (preferably by dropwise addition) to give camphorsulfonyl halide.
The solvent used in Step 1 is preferably toluene, xylene, cyclohexane, monochlorobenzene, nitrobenzene and the like, with particular preference given to toluene.
The solvent is generally used in an amount of 70 parts by weight—300 parts by weight, preferably 80 parts by weight—150 parts by weight, per 100 parts by weight of camphorsulfonic acid. When the amount thereof is less than 70 parts by weight per 100 parts by weight of camphorsulfonic acid, the stirring becomes difficult, and when it exceeds 300 parts by weight, the reaction time becomes longer. When the above-mentioned preferable solvents are used as reaction solvents, the amount of the halogenation agent can be reduced as compared to that in a non-solvent system, even without using methylene chloride, which has been conventionally employed for halogenation and which is an environment polluting substance. This has an effect that a step for removing an excess halogenation agent is not necessary.
The halogenation agent is not subject to any particula
Shiratani Hiroshi
Yamasaki Shigeya
Leydig , Voit & Mayer, Ltd.
Qazi Sabiha
Sumika Fine Chemicals Co., Ltd.
LandOfFree
Method for producing camphorsultam does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing camphorsultam, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing camphorsultam will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2938043