WO2002004410A1

WO2002004410A1 - Process for producing sulfamate compound

Info

Publication number: WO2002004410A1
Application number: PCT/JP2001/004637
Authority: WO
Inventors: Naoyuki Koizumi; Shigeki Iwashita; Makoto Okada
Original assignee: Teikoku Hormone Mfg. Co., Ltd.
Priority date: 2000-07-11
Filing date: 2001-06-01
Publication date: 2002-01-17
Also published as: AU2001260689A1; JP2002030063A

Abstract

A process for producing a sulfamate compound which comprises reacting a hydroxylated compound with sulfamoyl chloride, characterized in that the reaction is conducted in the presence of a compound such as N,N-dimethylacetamide or 1-methyl-2-pyrrolidone and substantially in the absence of a base.

Description

Description Method for producing sulfamate compound

The present invention relates to a novel method for producing a sulfamate compound, and more particularly, to an improvement in a method for producing a sulfamate compound by reacting a sulfamoyl compound with a hydroxyl group-containing compound. Background art

Sulfamate compounds (compounds with OS ₂ NH ₂ groups) are known to exhibit various physiological activities. Synthetic research has been actively conducted, particularly in the fields of steroid chemistry, nucleic acid chemistry, and sugar chemistry. ing. As a general method for producing these sulfamate compounds, a method of reacting a hydroxyl group-containing compound with sulfamoyl chloride to form sulfamoyl is known. This sulfamoylation reaction is usually carried out in an organic solvent in the presence of an excess of a base, for example, sodium hydride or 2,6-di-t-butyl-4-methylpyridine, and in an excess of the sulfamoyl ester. This is done using C However, this sulfamoylation reaction varies widely in yield depending on the substrate, and is not a general method applicable to a wide range of compounds. Moreover, in spite of performing the reaction using an excess amount of base and an excess amount of sulfamoyl cloride, the yield is often only about tens of percent at most, which is sufficient from an industrial viewpoint. This is not a satisfactory method (for example, J. Am. Chem. Soc., Vol. 92, 3434, (1970) (Yield: 15-85%); J. Steroids, Vol. 63, 425, (1998) (Yield: 50-61%); Med. Chem., Vol. 35, 3991, (1992) (Yield: 27-66%); Tetrahedron Lett., Vol. 33, 5009, (1992) (Yield: 35-40%); Med. Chem., Vol. 41, 1315, (1998) (Yield: 41-81%) ₀

In addition, as an example where a base is not used in the sulfamoylation reaction, a method of reacting estone with sulfamoylc-lide using N, N-dimethylformamide as a solvent is known (Steroids, Vol. 61, 710, (1996)). However, the method disclosed in the literature uses 5 equivalents of sulfamoyl chloride per mol of estrone, and the reaction is performed for 12 hours, but the yield is about 80%. Not just.

An object of the present invention is to provide a sulfamate compound having generality that can be applied to various hydroxyl group-containing compounds containing various functional groups, and using a minimum amount of reagents, simple operation, and high yield. It is to provide a manufacturing method. Disclosure of the invention

The present inventors have found that in a method for producing a sulfamate compound by reacting a sulfamoyl chloride with a hydroxyl group-containing conjugate, it is possible to obtain a sulfamate compound in the presence of a certain specific compound and substantially in the absence of a base. When the reaction is carried out in a short time, the desired sulfamate compound can be obtained in a very high yield, and the sulfamoylation reaction is carried out not only with the phenolic hydroxyl group-containing compound but also with the aliphatic alcoholic hydroxyl group-containing compound. It has been found that this is a general reaction that can be widely applied to Thus, according to the present invention, in a method for producing a sulfamate compound by reacting a sulfamoyl chloride with a 7-K acid group-containing conjugate, the reaction is represented by the following formula (I)

Where:

R ¹ represents a substituted or unsubstituted lower alkyl or lower alkenyl group or a phenyl group,

R ² and R ³ each independently represent a substituted or unsubstituted lower alkyl or lower alkenyl group, or R ² and R ³ together with the nitrogen atom to which they are attached are selected from 0 and S Represents a heterocyclic group which may further contain a heteroatom represented by

R ¹ and R ² together represent a lower alkylene or lower alkenylene group which may be interrupted by a heteroatom selected from 0 and S;

A process for producing a sulfamate compound, wherein the process is carried out in the presence of the compound (b) and substantially in the absence of a base.

As used herein, the term "lower" means that the group or compound to which this term is attached has at most 6, preferably at most 4, carbon atoms.

Thus, "lower alkyl groups" include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Examples of the “lower alkenyl group” include vinyl, aryl, 1-propenyl, isopropyl, 2-butenyl, and 1,2-pentyl and n-hexyl. Examples include 3-butenylenyl, 2-pentenyl, and 1,4-hexenyl groups. Examples of the “lower alkylene group” include ethylene, trimethylene, tetramethylene, and pentamethylene groups, and examples of the “lower alkylene group” include propenylene, 1-butenylene, —Butenylene, 1,3-butenenylene, 1-pentenylene, 2-pentenylene, and the like.

Examples of the substituent in the “substituted or unsubstituted lower alkyl or lower alkenyl group” used in the definition of R \ R ² and R ³ include, for example, a halogen atom, a lower alkoxy group, a lower alkanoyloxy group, a lower alkylthio group. A lower alkyl or alkenyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl group, a lower alkyl carbonyl group, a lower alkyl carbonyl group, a cyano group or a cycloalkyl group. It can be substituted with one to three selected substituents. Preferred examples of the substituted or unsubstituted lower alkyl or lower alkenyl group include those substituted with one or two substituents selected from a halogen atom, a lower alkoxy group, a cyano group and a lower cycloalkyl group. Lower alkyl or lower alkenyl groups which may be mentioned.

A heterocyclic group wherein R ² and R ³ represent `` a heterocyclic group which may further contain one hetero atom selected from 0 and S together with the nitrogen atom to which they are bonded ''; Examples of the cyclic group include azetidinyl, pyrrolidinyl, piberidinyl, Examples include perhydroazepinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, thiomorpholinyl, dihydropyridyl, and tetrahydropyridyl groups.

Further, when R ¹ and R ² together represent a “lower alkylene or lower alkenylene group optionally interrupted by one heteroatom selected from 0 and S”, FT- in the formula (I) The CO—N (R ² ) — moiety forms a heterocyclic group, which includes, for example, 2-oxo-1-pyrrolidinyl, 2-oxo-11-pyridinyl, 2-oxo 1 1-Perhydroazepinyl, 4-oxo-3-oxazolidinyl, 3-oxo1-2-isoxazolidinyl, 3-oxo-14-morpholinyl, 4-oxo-3-thiazolidinyl, 3-oxo And a 1-4-thiomorpholinyl group.

Specific examples of the compound of the formula (I) that can be used in the present invention include, for example, N, N-dimethylacetamide, N, N-dimethylpropionamide, N, N-getylacetamide, N, N— Dimethylbenzamide, 1-methyl-2-pyrrolidone, 1-ethyl-12-pyrrolidone, 1-vinyl-12-pyrrolidone, 1-methyl-12-piperidone, 1-methyl-12-pyridone , N-Methylcaprolactam, N-Acetylmorpholine, 1-Acetylbiperidine, 1-Acetylpyrrolidine, 3_ (2-oxopyrrolidine_1-yl) propionitrile, 4-Acryloylmorpholine, N-Methyl I-N-vinylacetamide and the like.

The compound of the above formula (I) is preferably a liquid at ordinary temperature. In particular, in the above formula (I), RR ² and R ³ each represent a lower alkyl group, or R ³ represents a lower alkyl group; R ¹ and R ² together form a lower alkylene group Compounds where indicated, especially N, N-dimethylacetamide or 1-methyl-2-pyrrolidone, are preferred.

The `` hydroxyl-containing compound '' used as a reaction raw material in the present invention includes all organic compounds containing a hydroxyl group or a group that can be converted to a hydroxyl group that can be subjected to the sulfamoylation reaction of the present invention, for example, a phenolic hydroxyl group. Compound, a compound containing an aliphatic alcoholic hydroxyl group, a hydroxyl group-containing heterocyclic compound, and the like. Compounds containing a phenolic hydroxyl group include, in addition to ordinary phenol derivatives, derivatives of compounds having a skeleton in which one or more hydrocarbon rings / heterocycles are condensed to the benzene ring of phenol, for example, these skeletons And all compounds which may be substituted by any substituent are included. Compounds containing an aliphatic alcohol hydroxyl group include a saturated or unsaturated chain hydrocarbon having a hydroxyl group as a substituent in the hydrocarbon portion, a saturated or partially unsaturated cyclic hydrocarbon, and a bridged cyclic compound. Hydrocarbons, spiro hydrocarbons, and the like, and all derivatives in which the hydrocarbon portion of the compound thereof may be further substituted with an arbitrary substituent are included. Heterocyclic compounds having a hydroxyl group as a substituent in the heterocyclic moiety and derivatives thereof, for example, all compounds in which the heterocyclic moiety may be substituted with an arbitrary substituent are included.

Suitable hydroxyl group-containing compounds in the present invention include compounds having a physiologically active action, for example, steroids, nucleic acids, saccharides and the like having a physiologically active action.

According to the present invention, the reaction between the hydroxyl group-containing compound and the sulfamoyl chloride is carried out in the presence of the compound of the above formula (I) and substantially in the absence of a base. The ratio of sulfamoyl chloride to the hydroxyl group-containing compound is not particularly limited, but in order to achieve the intended purpose under the conditions of the present invention, usually, sulfamoyl chloride is used per mole of the hydroxyl group-containing compound. It is preferable to use at least 1 mol of chloride, especially about 1.5 to 2.5 mol.

Although the reaction time required for the sulfamoylation reaction of the present invention varies depending on the type of the hydroxyl group-containing compound used and the type of the compound of the formula (1), etc., it cannot be determined unconditionally. The reaction can be completed in about 1 Z2 to 1 Z6 as compared with the reaction time.Specifically, the reaction time is at least about 0.5 hour, preferably about 1.5 to Six hours can be mentioned.

The reaction temperature is generally from −20 ° C. to the reflux temperature of the reaction mixture, preferably from 0 ° C. to 70 ° C., and more preferably around room temperature.

In the present invention, the term "substantially in the absence of a base" refers to an amount of a base that can be combined with hydrogen chloride generated in the present sulfamoylation reaction to cause the reaction to proceed, and the reaction raw material or the compound of the above formula (I) It is used to mean that it is not added separately to the reaction system.

The term “high yield” described in the effect of the present invention is not a word indicating an absolute numerical value, but a relative expression that may vary depending on the type of the hydroxyl group-containing compound used, reaction conditions, and the like. According to the above, generally, a high yield having a sufficiently significant difference compared with the yield obtained when the reaction is carried out under the reaction conditions of the conventional method, specifically, at least 85% or more, is preferable. Can produce the desired sulfamate compound in a yield of 90% or more.

Thus, the sulfamoylation reaction of the present invention can be carried out with various hydroxyl groups containing various functional groups. It can be applied to a group-containing compound, and the desired sulfamate compound can be produced in a simple operation with a necessary minimum amount of reaction raw materials and in a high yield.o Examples

Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1

136 mg of 4-hydroxyacetophenone and 1.5 ml of N, N-dimethylacetamide were mixed, and 23 lmg of sulfamoyl chloride was added under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into saturated saline (20 ml), the product was extracted twice with ethyl acetate (20 ml), and the organic layer was washed with saturated saline (20 ml) and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent was purified by thin-layer chromatography (TLC) (developing solvent, chloroform: acetone = 9: 1), and 196 mg of 4-acetylphenyl sulfamate (yield Rate 91%).

'■ H-NMRiDMSO-dg, δ): 2.58 (3Η, s), 7.3-7.5 (2Ε, m), 8.0-8.1 (2H, m), 8.15 (2H, s).

MS (m / z): 215 (M ⁺ ), 136.

Example 2

The same operation as in Example 1 was repeated except that 124 mg of 4-methoxyphenol was used instead of 4-hydroxyacetophenone, to obtain 187 mg of 4-methoxyphenylsulfamate (92% yield).

H-NMR (DMSO-d ₆ , 5): 3.76 (3H, s), 6.9-7.1 (2H, m), 7.1-7.3 (2H, m), 7.83 (2E, s).

MS (m / z): 203 (M ⁺ ), 123.

Example 3

The crude product obtained in the same manner as in Example 1 'except that 4-hydroxyacetophenone was replaced by 3-hydroxyestradi-1,3,5 (10) -trien-1-17-one 27 Omg Was purified by TLC (developing solvent, chloroform: acetone = 19: 1) to give 328 mg (94% yield) of 17-oxoestra-1,3,5 (10) -trien-3-yl sulfamate. Obtained.

-NMR (DMSO-d ₆ , 5): 0.84 (3H, s), 2.87 (2H, dd, J = 3.8, 8.6 Hz), 6.98 (1H, d, J = 2.4 Hz), 7.02 (1H, dd, J = 2, 4, 8.5 Hz), 7.35 (1H, d, J = 8.5 Hz), 7.86 (2H, s).

MS (m / z): 349 (M ⁺ ), 270.

Example 4

In Example 1, 3-hydroxyestradione 1,3,5 (10) -trien-1 17-one 27 Omg in place of 4-hydroxyacetophenone 1-methylone in place of N, N-dimethylacetoamide The same operation was performed using 2-pyrrolidone, and the resulting crude product was purified by TLC (developing solvent, chloroform: acetone = 19: 1) to give 17-oxoestra-1,3,5 (10 334 mg (96% yield) of triene-1-yl sulfamate were obtained.

Example 5

In Example 1, instead of 4-hydroxyacetophenone, 3-hydroxy-17a-homo-17a-oxaestra-1,3,5 (10) -triene-1 The same operation was performed using 286 mg of 7-one. After reacting for 6 hours, the reaction mixture was added to water, and the crude product obtained by filtration was subjected to TLC (developing solvent, chloroform: methanol = 19: 1 ) To give 326 mg (89% yield) of 17-oxo-17a-homo-17a-oxastra-1,3,5 (10) -trien-3-yl sulfamate.

-Thigh R (DMSO-d ₆ , 6): 1.28 (3Η, s), 1.4-1.7 (2H, m), 1.78 (1H, dt, J = 3.5, 13.0 Hz), 1-9-2.1 (3H, m), 2.6-2.8 (1H, m), 2.8-2.9 (2H, m), 6.98 (1H, d, J = 2.6 Hz), 7.03 (1H, dd, J = 2.6, 8.5 Hz), 7.36 (1H , d, J = 8.6 Hz), 7.88 (2H, s).

MS (m / z): 365 (M ⁺ ), 286.

Example 6

3-Hydroxy-17a-homo-17a-oxaestra-1,3,5 (10) -Trien-17-one 300 mg and 1-methyl-12-pyrrolidone 1.9 ml are mixed, and the mixture is mixed with ice under ice cooling. 0.6 ml of an acetonitrile solution of 303 mg of lid was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added to water, and the crude product obtained by filtration was recrystallized from tetrahydrofuran-ethyl acetate to give 17-oxo-17a-homo-17a-oxaestra_1,3,5 (10) -triene-3- 324 mg (yield 85%) of yl sulfamate was obtained.

Example Ί

In Example 1, the same operation was carried out using 314 mg of 17,17- (ethylenedioxy) estler 1,3,5 (10) -trien-1-ol instead of 4-hydroxyacetophenone. The crude product was purified by TLC (developing solvent, The mixture was purified with 10: 1) to obtain 17,17- (ethylenedioxy) estra-1,3,5 (10) -trien-3-yl sulfamate (336 mg, yield 86%).

^ -NMR (DMSO- _ds , <5): 0.81 (3H, S), 2.1-2.3 (1H, m), 2.3-2.4 (1H, m), 2.7-2.9 (2H, m), 3.7-3.9 (4H, m), 6.96 (1H, d, J = 2.5 Hz),

7.01 (1H, dd, J = 2.5, 8.5 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.85 (2H, s).

MS (m / z): 393 (M ⁺ ), 314.

Example 8

In the same manner as in Example 1 except that 136 mg of 3-phenyl-1-propanol was used instead of 4-hydroxyacetophenone, 183 mg (yield: 85%) of 3-phenylpropylsulfamate was obtained.

-NMR (DMSO-d ₆ , δ): 1.8-2.0 (2Η, m), 2.66 (2Η, t, J = 7.7 Hz),

4.02 (2E, t, J = 6.4 Hz), 7.1-7.4 (5H, m), 7.41 (2H, s).

MS (m / z): 215 (M ⁺ ), 117.

Example 9

In the same manner as in Example 1, 136 mg of 3-phenyl-1-propanol was used instead of 4-hydroxyacetophenone, and 1-methyl-2-pyrrolidone was used instead of N, N-dimethylacetamide. Thus, 201 mg (94% yield) of 3-phenylpropyl sulfamate was obtained.

Example 10

In Example 1, instead of 4-hydroxyacetophenone, 17yS-hydro The same operation was carried out using 288 mg of xiandrosyl 4-en-3-one to obtain 335 mg (91% yield) of 3-oxoandrosta-1-en-17) 3-yl sulfamate. .

^ -NMR (DMSO-d ₆ , 5): 0.78 (3H, s), 1.16 (3H, s), 4.25 (1H, t, J = 8.4 Hz), 5.62 (1H, S), 7.32 (2H, s) ).

MS (m / z): 367 (M ⁺ ), 270.

Claims

The scope of the claims

1. In a method for producing a sulfamate compound by reacting a sulfamoyl chloride with a hydroxyl group-containing compound, the reaction is represented by the following formula:

Where:

R ¹ represents a substituted or unsubstituted lower alkyl or lower alkenyl group or a fluorine group,

R ² and R ³ each independently represent a substituted or unsubstituted lower alkynole or lower alkenyl group, or R ² and R ³ together with the nitrogen atom to which they are attached are selected from 0 and S A heterocyclic group which may further comprise one heteroatom,

R ¹ and R ² together represent a lower alkylene or lower alkenylene group which may be interrupted by one heteroatom selected from 0 and S, in the presence of a compound of and substantially in the absence of a base A method for producing a sulfamate compound.

2. The compound of formula (I) is N, N-dimethylacetamide, N, N-dimethylpropionamide, N, N-getylacetamide, N, N-dimethylbenzamide, Methyl-2-pyrrolidone, 1-ethyl-1-2-pyrrolidone, 1-vinyl-2- Pyrrolidone, 1-methyl-12-piridone, 1-methyl-2-pyridone, N-methylcaprolactam, N-acetylmorpholine, 1-acetylbiperidine, 1-acetylpyrrolidine, 3- 2. The method according to claim 1, wherein the method is selected from (2-oxopyrrolidine-1f1) propionitrile, 4-acryloylmorpholine and N-methyl-N-vinylacetamide.

3. The claim 1 wherein R \ R ² and R ³ each represent a lower alkyl group, or R ³ represents a lower alkyl group and R ¹ and R ² together represent a lower alkylene group. The method described in.

4. The method according to claim 1, wherein the compound of the formula (I) is N, N-dimethylacetamide or 1-methyl-2-pyrrolidone.

5. The method according to claim 1, wherein the reaction is carried out using 1.5 to 2.5 moles of sulfamoyl chloride per mole of the hydroxyl group-containing compound.

6. The method according to claim 1, wherein the hydroxyl group-containing compound is a compound having a fininol hydroxyl group.

7. The compound containing a phenolic hydroxyl group is 3-hydroxy-17a-homo-

7a — Oxaestradi 1, 3, 5 (10) — Trien 1 17 Lord — The scope of claim 1 that is on.

8. Use of the compound of the formula (I) according to claim 1 in a sulfamoylation reaction of a hydroxyl-containing compound.

9. A sulfamate compound produced by the method according to claim 1.