JP2002179659A - Method for producing camphorsultam - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing camphorsultam and its intermediate, relatively safely to the environment and the human body inexpensively, simply and industrially. SOLUTION: This method for producing camphorsultam comprises a first process for treating camphorsulfonic acid with a halogenating agent to obtain a camphorsulfonic acid halide, a second process for treating the camphorsulfonic acid halide with ammonium to obtain camphorsulfonamide, a third process of subjecting camphorsulfonamide to ring closure through dehydration to obtain camphorsulfonimine and a forth process for reducing camphorsulfonimine with sodium borohydride in an aqueous solution of isopropanol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing camphorsultam and intermediates thereof useful as asymmetric introduction reagents or starting materials for compounds useful as fine chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art Camphor sultam is useful as an asymmetric introduction reagent or raw material for compounds useful as fine chemicals and pharmaceuticals. Various methods for producing camphorsultam are known and are generally produced according to the following scheme. However, the following compounds 1 to 5 include cases of S-form, R-form and racemic form, respectively.

[0003]

Embedded image

In the above scheme, Towson et al. In the above scheme reacted 2.4 equivalents of thionyl chloride with 1 to give 2, and then with NH ₄ OH to give 3, which in the presence of Amberlyst. in is set to 4 (ORGANIC SYTHESIS, COLLECT
VOL. VIII, 104-105). Also, Wei
Smiller et al., in the above scheme, substituted 4 for LiAlH
Reduced by ₄ to 5 (ORGANIC SYT
HESIS, COLLECT VOL. VIII, 11
0-111). When the above-mentioned conventional production method is performed on an industrial scale, various problems occur such that chloroform is not preferable for human bodies and the environment, and LiAlH ₄ is dangerous because it is used.

In the above scheme, Capet et al. Reacted 4 equivalents of thionyl chloride with 1 in a solvent-free system to obtain 2
Then, excess thionyl chloride was removed, and in an aqueous 1,4-dioxane solution, ammonia was reacted with 2 in a molar amount 60 times the amount of 1 , to 3, and 3 was dehydrated and closed at 90 ° C. to obtain 4. In a methanol aqueous solution, 4 is reduced to 2 by using twice the molar amount of sodium borohydride to 4 to obtain 5 (SYNTHETIC COMMUNICATION).
S, 25 (21), 3323-3327 (199
5)). When the above-mentioned production method is carried out on an industrial scale, it is not preferable because the following problems occur. It is preferable that the chlorination is carried out in a solvent-free system, but since the amount of thionyl chloride used is twice as much as 1 mole, it is necessary to remove excess thionyl chloride by azeotropic distillation with toluene. . In amidation, carcinogenic 1,4-dioxane is used, which is not preferable for the human body. In the amidation, a large excess of ammonia is used to avoid hydrolysis of 2 , and a large amount of ammonia gas is generated at the time of dehydration ring closure. The amount generated is about 400 times the volume of camphorsulfonic acid, and industrial implementation is impossible. In the reduction step, an aqueous methanol solution is used, and hydrolysis of sodium borohydride occurs, so that excess sodium borohydride is required, which is not economical and generates excess hydrogen gas. Further, after extracting 5 with methylene chloride which is an environmental pollutant, the organic layer was washed,
It is isolated by concentration and recrystallization from ethanol. At this time, crystals adhere to the vessel wall (scaling occurs), which is industrially unsuitable.

As described above, various problems arise when the above-mentioned conventional manufacturing method is used industrially. Therefore, a method for producing industrially available camphor sultam and its intermediates, which has improved the above-mentioned problems (production cost, production efficiency, effects on human body and environment, simplicity, safety of reaction, etc.) The development of is desired.

[0007]

Accordingly, it is an object of the present invention to produce camphor sultam and its intermediates which are relatively safe for the environment and the human body, inexpensive, convenient and industrially available. Is to provide a way.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object. As a result, in the reduction step, sodium borohydride is hardly hydrolyzed by using an aqueous solution of isopropanol. It has been found that it is not necessary to use sodium borohydride in excess, and that the amount of generated hydrogen gas can be further suppressed. Further, if ammonia water is allowed to act on camphorsulfonic acid halide in a solvent immiscible with water during amidation, hydrolysis of camphorsulfonic acid halide can be suppressed, and the amount of ammonia used can be significantly reduced, which is further preferable. I found that. Furthermore, they found that camphorsultam can be taken out as crystals by using an acid after reduction without extracting it with environmental pollutants such as methylene chloride.

That is, the present invention comprises the following steps (1):
Camphorsultam (10,10-dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane
Method for producing 3,3-dioxide): Step 1 A halogenating agent is added to camphorsulfonic acid ((7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid). To give camphorsulfonic acid halide ((7,7-dimethyl-2
-Oxobicyclo [2.2.1] hept-1-yl) methanesulfonyl halide), 2nd step: Ammonia is allowed to act on camphorsulfonic acid halide to form camphorsulfonamide ((7,7-dimethyl-2-). Oxobicyclo [2.2.1] hepta-1
-Yl) methanesulfonamide), 3rd step Campphorsulfonamide is dehydrated and ring-closed to give camphorsulfonimine (10,10-dimethyl-3).
- thia-azatricyclo [5.2.1.0 ^{1, 5]} in dec-4-ene 3,3-dioxide) obtaining a, and a fourth step an aqueous isopropanol solution, with sodium borohydride camphorsulphonic imine The step of reducing, (2) the method of (1), wherein the second step is a step of reacting camphorsulfonic acid halide with ammonia water in a water-immiscible solvent to obtain camphorsulfonamide, (3) The above-described ammonia water, comprising 4 to 10 times the molar amount of ammonia relative to camphorsulfonic acid halide.
(2) In the production method, (4) In the fourth step, sodium borohydride is added to camphorsulfonimine in an amount of 0.3
(5) after the fourth step, a step of adding an acid to the reaction solution to precipitate camphorsultam; ), (6) the acid is hydrochloric acid, the method of the above (5), (7) in an aqueous isopropanol solution, reducing camphorsulfonimine with sodium borohydride,
The present invention relates to a method for producing camphorsultam, and (8) the method for producing (7) above, wherein sodium borohydride is used in an amount of 0.3 to 0.7 times by mol based on camphorsulfonimine.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
Camphor sultam can be obtained by sequentially performing halogenation, amidation, ring closure and reduction using camphor sulfonic acid as a starting material. In the present invention, camphor sultam includes racemates and optically active forms (1S and 1R).

First Step (Halogenation) A camphorsulfonic acid halide can be obtained by reacting a camphorsulfonic acid with a halogenating agent. Specifically, camphorsulfonic acid is added to a solvent, and a halogenating agent is added thereto (preferably dropwise) to cause a reaction, whereby a camphorsulfonic acid halide can be obtained.

As the solvent in the first step, toluene, xylene, cyclohexane, chlorobenzene, nitrobenzene and the like are preferred, and toluene is particularly preferred.

The amount of the solvent to be used is generally 70 to 300 parts by weight, preferably 80 to 150 parts by weight, per 100 parts by weight of camphorsulfonic acid. If the amount is less than 70 parts by weight with respect to 100 parts by weight of camphorsulfonic acid, stirring becomes difficult, and if it exceeds 300 parts by weight, the reaction time becomes longer. Even if methylene chloride, which is an environmental pollutant, is not used as a reaction solvent, the use of the above-mentioned suitable solvent can reduce the amount of the halogenating agent used compared to the case where halogenation is performed in a solventless system. The operation for removing the excess halogenating agent can be omitted.

The halogenating agent is not particularly limited as long as it is generally used for halogenation. Examples thereof include thionyl chloride, thionyl bromide, oxalyl chloride, and phosphorus oxychloride. Is preferred.

The amount of the halogenating agent varies depending on the type of the halogenating agent used, but may be any amount as long as the halogenation can be sufficiently performed. For example, when thionyl chloride is used as the halogenating agent, the amount used is usually 1.0 to 1.5 mol per mol of camphorsulfonic acid,
Preferably it is 1.0 to 1.2 mol. If the amount is less than 1.0 mol per mol of camphorsulfonic acid, halogenation becomes insufficient, and if it exceeds 1.5 mol, the cost is increased.

In order to accelerate the reaction, it is preferable to further add dimethylformamide. Dimethylformamide may be added to the solvent at the same time as camphorsulfonic acid, and the amount is preferably 0.001 to 0.5 part by weight based on 100 parts by weight of camphorsulfonic acid.

The halogenation is usually carried out in the range from room temperature to the reflux temperature of the solvent used, and is preferably carried out at 70 to 90 ° C. from the viewpoint of accelerating the reaction. The halogenation may be confirmed by gas chromatography (GC) to confirm the completion of the reaction, and is usually completed in 1 to 4 hours.
The addition (preferably, dropping) of the halogenating agent is also preferably performed within the above temperature range from the viewpoint of accelerating the reaction. A toxic gas (SO ₂ , hydrogen halide) is generated by the reaction between the halogenating agent and camphorsulfonic acid, and the generation rate of the toxic gas can be controlled by dropping the halogenating agent. Also, after adding an absorbent (for example, triethylamine, dimethylaniline, pyridine, etc.) to the system, the halogenating agent can be dropped. The dropping of the halogenating agent may be usually performed in about 30 minutes to 8 hours, depending on the amount used.

The camphorsulfonic acid halide can be isolated and purified by a conventional method, but can be subjected to the next second step (amidation) without isolation.

Second step (amidation) Camphorsulfonamide can be obtained by reacting camphorsulfonic acid halide with ammonia. Preferably, camphorsulfonamide can be obtained by allowing ammonia water to act on camphorsulfonic acid halide in a solvent immiscible with water. Specifically, by adding ammonia water to a water-immiscible solvent and adding camphorsulfonic acid halide thereto (preferably, dissolving in a water-immiscible solvent and then dropping), a camphorsulfonamide is obtained. Can be. Since the method uses a water-immiscible solvent and aqueous ammonia, the reaction system becomes a two-phase system,
Hydrolysis of camphorsulfonic acid halide can be avoided (camphorsulfonic acid halide is dissolved in a solvent that is immiscible with water), whereby the amount of ammonia used can be reduced. As a result, ammonia gas in the next step (ring closing) can be reduced. Can be reduced.

Examples of the water-immiscible solvent that can be used for the amidation include toluene, xylene, monochlorobenzene, dichlorobenzene and heptane. The solvent used in the previous step (halogenation) can be used. The reaction solution after the halogenation can be used as it is, and the operation is simplified, which is preferable.

The amount of the solvent that is immiscible with water is usually 100 to 400 parts by weight, preferably 100 to 400 parts by weight, based on 100 parts by weight of camphorsulfonic acid halide (in the case of direct amidation after halogenation, camphorsulfonic acid). Is 1
80 to 250 parts by weight.

As the ammonia, ammonia gas, aqueous ammonia and the like can be used, and aqueous ammonia is preferable from the viewpoint of ease of use and economy. The concentration of ammonia water is
Usually, it is 20 to 30% by weight, preferably 28% by weight.

The amount of ammonia to be used is not particularly limited as long as the amidation can be carried out, and is preferably based on 1 mol of camphorsulfonic acid halide (camphorsulfonic acid when direct amidation is performed after halogenation). Is 4-1
0 mol, more preferably 5 to 7 mol. When the used amount is less than 4 mol with respect to 1 mol of camphorsulfonic acid halide, the amount of camphorsulfonamide obtained decreases and exceeds 10 mol. In this case, the amount of ammonia gas generated in the next step (ring closing) increases, which makes it industrially difficult.

The amidation is preferably carried out efficiently by dropping a solution of camphorsulfonic acid halide in a water-immiscible solvent into aqueous ammonia, and the dropping depends on the amount of camphorsulfonic acid halide. Usually about 15 minutes to 8 hours, preferably 30 minutes to 5 hours, usually -1.
The heat treatment may be performed at 5 to 50C, preferably -10 to 25C.

The amidation is usually carried out at -15 to 50 ° C, preferably at -10 to 25 ° C, and the completion of the reaction may be confirmed by GC. The reaction usually takes 2 to 4 hours depending on the reaction scale. finish.

The isolation and purification of camphorsulfonamide can be carried out by a conventional method, but can be directly subjected to the following third step (ring closure).

Third Step (Ring-Closed) Camphorsulfonimine can be obtained by heating camphorsulfonamide to effect dehydration and ring closure. Preferably, camphorsulfonimine can be obtained by heating the reaction solution obtained by the above preferred method as it is. It is preferable to use camphorsulfonamide obtained by the above amidation because it is simple and the amount of ammonia used for the amidation is small, so that the amount of ammonia gas generated at the time of ring closure is small.

In the ring closing step, the temperature is preferably increased stepwise because the amount of ammonia gas generated can be controlled.
After heating for 1 hour at 80 to 85 ° C and reacting at the same temperature for 1 to 3 hours, or heating to 80 to 85 ° C over 30 minutes to 6 hours and then within 1 to 4 within the same temperature range It is preferable to react for a time. The end of the ring closure may be confirmed by GC.

The isolation of camphorsulfonimine is preferably carried out by cooling the reaction solution stepwise to prevent scaling and improve crystallinity. For example, if the reaction solution is 10
Cool to about 60 ° C over a minute or more, and
Incubate (age) for ~ 30 minutes. Next, the mixture is cooled to about 20 ° C. over 30 minutes, stirred at 10 to 25 ° C. for 30 minutes to 3 hours, and then filtered and washed. It is preferable to wash in order of toluene and water. Since impurities and inorganic substances are removed by washing, high-purity wet crystals having a GC purity of 99% or more can be obtained. The obtained wet crystals can be dried under reduced pressure at a temperature of 100 ° C. or lower, but can be subjected to the next fourth step (reduction) without drying.

Fourth Step (Reduction) Camphorsultam can be obtained by reducing camphorsulfonimine with sodium borohydride in a solvent. When an aqueous solution of isopropanol is used as a solvent, sodium borohydride is hardly decomposed, so that it is not necessary to use an excessive amount of sodium borohydride, and the amount of generated hydrogen gas can be further suppressed.

The aqueous solution of isopropanol used for the reduction is represented by the following using the amounts of isopropanol and water used. The amount of isopropanol to be used is generally 200 to 400 parts by weight, preferably 250 to 350 parts by weight, per 100 parts by weight of camphorsulfonimine (dried product). The amount of water to be used is generally 50 to 200 parts by weight, preferably 80 to 150 parts by weight, per 100 parts by weight of camphorsulfonimine (dried product). When a wet crystal of camphorsulfonimine is used, the amount of water contained in the crystal should also be added to the amount of water used.

The amount of sodium borohydride to be used is preferably 0.3 to 0.7 mol, more preferably 0.4 to 0.7 mol per mol of camphorsulfonimine (dry product).
0.6 mol. If the used amount is less than 0.3 mol per 1 mol of camphorsulfonimine (dry product), the reduction becomes insufficient, and if it exceeds 0.7 mol, the cost is increased. Sodium borohydride is preferably added dropwise in the form of an aqueous solution from the viewpoint that hydrogen gas is constantly generated and the operation is industrially easy. It is carried out in the range up to the temperature, preferably at 20 to 45 ° C. The amount of water required to dissolve sodium borohydride is usually 300 parts per 100 parts by weight of sodium borohydride.
To 800 parts by weight, preferably 400 to 600 parts by weight.

When sodium borohydride is used in the form of an aqueous solution, it is preferable to further add an alkali metal hydroxide in order to enhance the stability of the aqueous sodium borohydride solution. Examples thereof include sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferred from the viewpoint of economy. The amount of the alkali metal hydroxide to be used is generally 1-4 parts by weight, preferably 2-3 parts by weight, per 100 parts by weight of sodium borohydride.

Since the reduction reaction involves generation of hydrogen gas,
It is preferable to perform the process under an inert gas (eg, nitrogen gas) stream.

The reduction is usually carried out at a temperature ranging from 0 ° C. to the reflux temperature of the solvent used, preferably at 20 to 45 ° C. The completion of the reaction may be confirmed by GC. Although depending on the amount of camphorsulfonimine, the reduction is usually completed in about 2 to 8 hours, preferably in 4 to 6 hours.

The isolation of camphorsultam is industrially preferable if no acid or water is added dropwise to the reaction solution without extraction with an organic solvent such as methylene chloride, since scaling does not occur. The acid used for the isolation preferably includes hydrochloric acid. The acid may be used in an amount that can adjust the pH of the solution to usually 3 or less, preferably 1 or less.

Specifically, after the reaction solution is cooled to 10 to 20 ° C., an acid is added (preferably, dropwise), and the pH of the solution is adjusted to 3 or less, preferably 1 or less, to precipitate crystals. Let it. The dropping of the acid is usually performed at 10 to 30 ° C. for about 5 minutes to 2 hours, depending on the amount of camphorsulfonimine.

After addition of the acid, 200 to 30 parts by weight per 100 parts by weight of camphorsulfonimine (dry product) is used.
0 parts by weight of water is added dropwise at 10 to 30 ° C. in 15 minutes to 2 hours. Next, the mixture was cooled to 0 to 10 ° C, preferably 0 to 5 ° C, and stirred at the same temperature for 30 minutes to 15 hours.
The crystals are washed and dried to remove inorganics.

For washing, a mixture of isopropanol and water cooled to about 0 to 5 ° C. may be used.
At this time, the amounts of isopropanol and water are preferably 20 to 40 parts by weight and 30 to 50 parts by weight, respectively, relative to 100 parts by weight of camphorsulfonimine (dry product).

The drying may be carried out under reduced pressure, usually at 100 ° C. or lower, preferably at 50 to 80 ° C., and is terminated as soon as the water content is confirmed to be 1% or lower by Karl Fischer method (KF method). By performing the isolation and purification of camphorsultam in these series of operations, a purity of 99% was obtained.
~ 100% camphor sultam can be obtained.

[0041]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. All units of the J value in ¹ H-NMR are Hz.

Example 1 (-)-10,10-dimethyl-3-thia-4-azato
Licyclo [5.2.1.0 ^1,5 ] dec-4-ene 3,
Preparation of 3-dioxide (camphorsulfonimine ) Dimethylformamide (23) was added to toluene (190 L).
0g) and (1S)-(+)-10-camphorsulfonic acid (190 kg, 818 mol).
Thionyl chloride (116.8 kg, 982 m
ol) was added dropwise over 2 hours and stirred at the same temperature for 2 hours. The obtained toluene solution of camphorsulfonic acid chloride was prepared separately using 28% by weight aqueous ammonia (2%).
48.7 kg, 4.1 kmol) in toluene (277
In addition to L) and cooled to -10 to -5 ° C,
The solution was added dropwise at 10 to 25 ° C over 3 hours. The acid chloride container was washed with toluene (29 L) and added to the reaction solution.
Stirred at 0-25 ° C for 2 hours. The reaction solution was cooled to 8 over 85 minutes.
After heating to 0 ° C, the mixture was stirred at 80 to 83.3 ° C for 3 hours.
The amount of generated ammonia gas was 39 m ³ . The reaction is cooled to 60 ° C. over 20 minutes and
Aged. Cool to 20 ° C over 1 hour,
Stirred at 0 ° C. for 40 minutes. The mixture was filtered at 15 ° C. and washed with toluene (57 L) and then with water (380 kg) to obtain wet crystals (177.1 kg). As a result of partial drying and analysis, it was found that the title compound contained 144.7 kg (83% yield).

¹ H-NMR (CDCl ₃ ) δ: 0.87
(S, 3H), 1.09 (s, 3H), 1.48 (m,
1H), 1.78 (m, 1H), 2.07 (m, 2
H), 2.26 (m, 1H), 2.39 (d, 1H, J
= 20), 2.80 (dm, 1H, J = 19), 2.9.
8 (d, 1H, J = 13), 3.18 (d, 1H, J =
14)

Example 2 (-)-10,10-Dimethyl-3-thia-4-azato
Licyclo [5.2.1.0 ^1,5 ] decane 3,3-dio
Production of oxide (Camphor sultam) Isopropanol (457.4 kg) under nitrogen gas stream
The wet crystal (177 kg) of Example 1 was added to a mixture of water and water (112 kg), and sodium hydroxide (280 g) and sodium borohydride (12.9 kg) were dissolved in water (72.3 kg). 30 to 40 ° C
For 2 hours. After stirring at the same temperature for 2 hours under a nitrogen gas stream, completion of the reaction was confirmed by gas chromatography (GC). After cooling the reaction solution to 10-20 ° C, 10-30
35% hydrochloric acid was added at 1 ° C. for 1 hour to adjust the pH of the reaction solution to 1
And the crystals were precipitated. At this time, the used amount of 35% hydrochloric acid was 42.4 kg. 14 water (326 kg)
After dropping at １９19 ° C. for 1 hour, stirring at 0 to 5 ° C. for 1 hour, filtration and crystallization of isopropanol (45.7 kg)
And a mixture of water (58 kg). 55-80
The title compound (114.1 was dried under reduced pressure at
kg) (yield 78%, purity 99.99%).

¹ H-NMR (CDCl ₃ ) δ: 0.94
(S, 3H), 1.13 (s, 3H), 1.31 (m,
1H), 1.46 (m, 1H), 1.84-2.00
(M, 5H), 3.08 (d, 1H, J = 14), 3.
16 (d, 1H, J = 14), 3.42 (m, 1H),
4.13 (brs, 1H)

Example 3 (+)-10,10-Dimethyl-3-thia-4-azato
Licyclo [5.2.1.0 ^1,5 ] dec-4-ene 3,
Preparation of 3-dioxide (camphorsulfonimine) Toluene (400 ml) was added with dimethylformamide (0.5 ml) and (1R)-(-)-10-camphorsulfonic acid (400 g, 1.722 mol), and 74 was added thereto. Thionyl chloride (245.83) at ~ 77 ° C.
g, 2.066 mol) over 2 hours and 10 minutes.
Stir at 77-78 ° C for 2 hours. The toluene solution of the obtained camphorsulfonic acid chloride was separately prepared,
28% by weight aqueous ammonia (523.6 g, 8.61 mo)
l) was added to toluene (540 ml), and the solution was cooled to -5 to 0 ° C and added dropwise at 2 to 16 ° C over 90 minutes. The acid chloride container was washed with toluene (60 ml), added to the reaction solution, and stirred at 16 to 22 ° C for 2 hours. The reaction solution was heated to 80 ° C over 55 minutes, and then stirred at 80 to 85 ° C for 2 hours. The reaction solution was cooled to 60 ° C over 25 minutes and aged at 51 to 60 ° C for 15 minutes. It cooled to 20 degreeC over 40 minutes, and stirred at 17-20 degreeC for 2 hours.
Filtration, toluene (120 ml) and then water (800 m
1) to obtain wet crystals (329.71 g). Dry at 50-60 ° C under reduced pressure to give the title compound (283.96
g, yield 77.3%, purity 99.9% (GC)).

¹ H-NMR (CDCl ₃ ) δ: 0.87
(S, 3H), 1.09 (s, 3H), 1.47 (m,
1H), 1.79 (m, 1H), 2.06 (m, 2
H), 2.26 (m, 1H), 2.39 (d, 1H, J
= 19), 2.77 (dm, 1H, J = 19), 2.9.
7 (d, 1H, J = 13), 3.18 (d, 1H, J =
13)

Example 4 (+)-10,10-Dimethyl-3-thia-4-azato
Licyclo [5.2.1.0 ^1,5 ] decane 3,3-dio
Production of Oxide (Camphor Sultam) Under a nitrogen gas stream, a mixture of isopropanol (674 g) and water (214.8 g) was mixed with the crystal of Example 3 (21
4.8 g, 1.007 mol) was added thereto, and water (1
07.4 g) in which sodium hydroxide (410 mg) and sodium borohydride (19.1 g) were dissolved was added dropwise at 31 to 43 ° C. over 2 hours and 34 minutes. After stirring at 30 to 40 ° C. for 6 hours under a nitrogen gas stream, the completion of the reaction was confirmed by GC. Since 3.4% of the raw material remained, a solution in which sodium borohydride (2.86 g) and sodium hydroxide (60 mg) were dissolved in water (16.1 ml) was further cooled to 38 ° C. under a nitrogen gas stream at 2 ° C. In minutes. 7
The mixture was stirred at 8-83 ° C for 3 hours and 30 minutes. After cooling the reaction solution to 15 ° C., 35% hydrochloric acid was added thereto at the same temperature over 8 hours to adjust the pH of the reaction solution to 1, and crystals were precipitated. 3 at this time
The amount of 5% hydrochloric acid used was 72.4 g. At 15 ° C, 1
Water (537 g) was added over 9 minutes and cooled to 5 ° C.
After stirring at 0-3 ° C for 15 hours, the mixture was filtered and the crystals were washed with a cooled mixture of isopropanol (46.5 g) and water (86 g). The title compound (153.42 g) was obtained by drying under reduced pressure at 55-60 degreeC (yield 70.40g).
8%, purity 99.97%).

¹ H-NMR (CDCl ₃ ) δ: 0.94
(S, 3H), 1.13 (s, 3H), 1.31 (m,
1H), 1.46 (m, 1H), 1.86-2.01
(M, 5H), 3.09 (d, 1H, J = 14), 3.
14 (d, 1H, J = 14), 3.44 (m, 1H),
4.07 (brs, 1H)

The same amount of (1S)-(+)-10 as in Example 1
After chlorination using camphorsulfonic acid under the conditions of Capet et al., The chlorinated product was converted to amide using ammonia water containing a 60-fold molar amount of ammonia with respect to (1S)-(+)-10-camphorsulfonic acid. When the ring is heated and closed, ammonia gas is expected to be generated at 753 m ³ . On the other hand, in Example 1, only 39 m ³ was generated, and it can be said that the method of the present invention is an industrially preferable method.

[0051]

According to the present invention, fine chemicals and pharmaceuticals
Camphor sultam and its intermediates useful as asymmetric introduction reagents or raw materials can be obtained by a method which is relatively safe for the environment and the human body, inexpensive, simple, and industrially available.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Yamagata Saki Shigeya 3-1-1 Utajima, Nishiyodogawa-ku, Osaka Sumitomo Finechem Co., Ltd. F-term (reference) 4C033 AA12 AA19

Claims (8)

[Claims] 1. A method for producing camphorsultam, comprising the following steps: 1st step, a step of reacting a camphorsulfonic acid with a halogenating agent to obtain a camphorsulfonate halide, 2nd step, ammonia is added to the camphorsulfonate halide. Reacting to obtain camphorsulfonamide, third step, dehydrating and ring-closing camphorsulfonamide to obtain camphorsulfonimine, and fourth step, reducing camphorsulfonimine with sodium borohydride in an aqueous isopropanol solution. 2. The production method according to claim 1, wherein the second step is a step of obtaining camphorsulfonamide by reacting ammonia water with camphorsulfonic acid halide in a solvent immiscible with water. 3. The aqueous ammonia contains 4 to 10 moles of ammonia relative to camphorsulfonic acid halide.
The method according to claim 2. 4. In the fourth step, sodium borohydride is added to camphorsulfonimine in an amount of from 0.3 to
The production method according to claim 1, wherein 0.7 times by mole is used. 5. The method according to claim 1, wherein after the fourth step, a step of adding an acid to the reaction solution to precipitate camphorsultam is performed.
The production method according to any one of the above. 6. The method according to claim 5, wherein the acid is hydrochloric acid. 7. A method for producing camphorsultam, comprising reducing camphorsulfonimine with sodium borohydride in an aqueous isopropanol solution. 8. The production method according to claim 7, wherein the sodium borohydride is used in an amount of 0.3 to 0.7 times mol of camphorsulfonimine.