KR100271907B1 - A production method for sulfamide - Google Patents

Abstract

The method for producing sulfamide according to the present invention comprises the step of reacting an oxycarbonylsulfamide compound and an alcohol in the presence of an azodicarboxylic acid derivative and a trivalent phosphorus compound.

In one embodiment of the present invention, the sulfamide is represented by the following general formula (I), the alcohol is represented by the following general formula (II), and the oxycarbonyl sulfamide compound is represented by the following structural formula (III) Method for producing a sulfamide, characterized in that.

R ₃ NHSO ₂ NR ¹ R ² (I)

[Wherein R ¹ and R ² are each independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic group and alkyl group substituted with these heterocyclic groups; ; R ³ is a group selected from alkyl, alkenyl, alkynyl, aralkyl, heterocyclic group, alkyl substituted with heterocyclic group and pyrrolidinyl methyl (the heterocyclic groups described above are pyranosyl, furanosyl, pipepe Lidinyl, pyrrolidinyl, azetidinone ring, cefem ring, penem ring and carbapenem ring);

R ³ OH (II)

Provided that R ³ is as defined above;

R ⁴ OOC-NHSO ₂ NR ¹ R ² (III)

Wherein R ¹ and R ² are as defined above and R ⁴ is a carboxy protecting group.

Description

[Name of invention]

Method for producing sulfamide

Detailed description of the invention

The present invention relates to a method for producing sulfamides useful for producing drugs, animal and plant medicines, polymers and stereoisomeric alcohol compounds.

In general, the preparation of sulfamides from alcohols involves four to five steps: converting the alcohol to a halogen compound or sulfonyl ester and substituting a halogen or sulfonyl ester group with an azido group to convert the azide compound. After obtaining, the azido group is reduced to an amino group. On the other hand, the alcohol is converted into a halogen compound or sulfonyl ester, the halogen or sulfonyl ester group is replaced with a phthalimido group, and then the phthaloyl group in the phthalimido group is removed using hydrazine to obtain an amino group. Sulfamid can be obtained by reacting an amine prepared by any of the above methods with a sulfamoylating agent. The resulting sulfamide is deprotected if necessary.

However, these methods have the following problems, that is, the process steps described above are complicated; When the compound to be reacted has a functional group capable of causing a side reaction in the molecule, it is necessary to introduce or remove a protecting group appropriate to the reaction conditions in each reaction step; There is a problem of requiring azide compounds and hydrazine, which are highly explosive and toxic.

The method for producing the sulfamide of the present invention comprises reacting an alcohol with an oxycarbonylsulphamide compound in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative.

In one embodiment of the invention, the sulfamide is represented by the following general formula (I), the alcohol is represented by the following general formula (II), and the oxycarbonylsulfamide compound is represented by the following general formula (III) :

R ³ NHSO ₂ NR ¹ R ² (I)

[Wherein R ¹ and R ² are independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic groups and alkyl groups substituted with these heterocyclic groups ( The heterocyclic group is selected from pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone ring, cefem ring, penem ring and carbapenem ring; R ³ is a group selected from alkyl, alkenyl, alkynyl, aralkyl, heterocyclic groups, alkyl substituted with these heterocyclic groups, and pyrrolidinylmethyl groups (the heterocyclic groups being pyranosyl, furanosyl , Piperidinyl, pyrrolidinyl, azetidinone ring, cefem ring, penem ring and carbapenem ring);

R ³ OH (II)

Wherein R ³ is as defined above;

R ⁴ OOC-NHSO ₂ NR ¹ R ² (III)

^Wherein R ¹ and R ² are as defined above and R ⁴ is a carboxy protecting group.

In another embodiment of the present invention, the method further comprises removing -COOR ⁴ .

Thus, the present invention described herein

(1) The conventional method provides a production method comprising two steps of condensation and deprotection reactions, in which a method for preparing sulfamide, which requires 4 to 5 steps, can be carried out under mild and neutral conditions;

(2) provides a convenient way to synthesize physiologically active substances such as antibacterial agents, antipyretics, analgesics, sweeteners, sleeping pills and anticonvulsants,

(3) The advantage which provides the method of manufacturing said sulfamide in high yield can be provided.

These and other advantages of the present invention will be apparent to those of ordinary skill in the art upon reading and understanding the following detailed description.

The meaning of the abbreviations used here is as follows:

Ac: Acetyl

Boc: t-butoxycarbonyl

Bz: Benzene

DCM: dichloromethane

EtOAc: ethyl acetate

Et: ethyl

Me: Methyl

PMB: p-methoxybenzyl

PNB: p-nitrobenzyl

Ph: Phenyl

THF: tetrahydrofuran

To: Toluene

t-Bu: t-butyl

In the method for producing sulfamide (I) according to the present invention, alcohol (II) and oxycarbonyl sulfamide compound (III) are reacted in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative.

The method of the present invention can be represented by the following general flowchart:

Wherein R ¹ and R ² are each, for example, hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl; A group independently selected from heterocyclic groups such as pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings and alkyl groups substituted with these heterocyclic groups ; R ³ is, for example, alkyl, alkenyl, alkynyl, aralkyl; A group selected from heterocyclic groups such as pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings and alkyl groups substituted with these heterocyclic groups; R ³ is preferably pyrrolidinylmethyl; R ⁴ is a carboxy protecting group.

Hereinafter, the present invention will be described in detail.

Oxycarbonylsulfamide compound (III), trivalent phosphorus compounds and azodicarboxylic acid derivatives are added to alcohol (II) in an inert aprotic solvent. The mixture is allowed to react for 0.5 to 20 hours at a temperature of preferably -70 ° C to + 50 ° C to obtain the oxycarbonylsulfamide compound (IV). If necessary, R ⁴ OOC is removed from the obtained product by a conventional method to obtain a sulfamide compound (I).

The preferred range of each component used in the present invention is as follows:

Examples of the amino substituents R ^l and R ^{2 in} the oxycarbonylsulfamide compound (R ⁴ OOCNHSO ₂ NR ¹ R ² ) (I) include hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl; Heterocyclic groups such as pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings and alkyl substituted with these heterocyclic groups (e.g. pyrrolidinylmethyl ) Is included. R ¹ and R ² may be the same or different substituents. Preferably, for example, the carboxy protecting group R ⁴ contains an alkyl, alkenyl, alkynyl, aralkyl and aryl, is a carbonate ester forming groups that can be readily removed.

The R ³ group in the alcohol (R ³ OH) (II) used herein is a carbon containing group, for example alkyl, alkenyl, alkynyl, aralkyl; Heterocyclic groups such as pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings and alkyl substituted with these heterocyclic groups, in particular pyrrolidinyl methyl All these groups may contain substituents. Such substituents are groups that do not inhibit the reaction, such as alkyl, acyl, acyloxy, alkoxy, sulfonyl, sulfonyloxy, esterified phosphoric acid groups and halogens.

Examples of alcohols used herein include primary, secondary and tertiary alcohols, but the above-described primary alcohols are preferred because of their high reactivity.

Examples of the trivalent phosphorus compound used herein include trialkylphosphines such as triethylphosphine and tributylphosphine; Triarylphosphines such as triphenylphosphine and tritolylphosphine; And phosphites such as methyl phosphite, ethyl phosphite and phenyl phosphite.

Examples of azodicarboxylic acid derivatives used herein include alkyl azodicarboxylates such as methyl azodicarboxylate, ethyl azodicarboxylate and isopropyl azodicarboxylate; Azodinitrile; Azodicarboxamides; Bisdialkylamides of azodicarboxylic acids such as bisdimethylamide of azodicarboxylic acid and bisdiethylamide of azodicarboxylic acid; 1,1 ′-(azodicarbonyl) dialkyleneamines such as 1,1 ′-(azodicarbonyl) dipyridine and 1,1 ′-(azodicarbonyl) diperridine.

The alkyl moiety in each of the above compounds is straight chain, branched or cyclicalkyl and is typically an alkyl group having 1 to 12 carbon atoms. Said cyclic alkyl may contain one or more hetero atoms such as oxygen, nitrogen and sulfur in its ring structure. Examples of the above alkyl moieties include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethyl, pyrrolidinyl, pentyl, isopentyl, neopentyl , Cyclopentyl, cyclopropylethyl, piperididyl, hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl and dodecyl, All these groups may contain a substituent described later.

The alkenyl residue or alkynyl residue in each of the compounds described above is an alkyl residue, which has one or more unsaturated bonds in its molecule and may contain substituents described below.

The aralkyl moiety in each of the aforementioned compounds has a bonding structure of an alkyl moiety and an aryl moiety, and is typically an aralkyl group having 7 to 14 carbon atoms. Examples thereof include benzyl, phenethyl, phenylpropyl, phenylisopropyl, diphenylmethyl, methoxy diphenylmethyl, naphthylmethyl, furylmethyl, thienylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, tria Zolylmethyl, pyridylmethyl, indolylmethyl, benzoimidazolyl ethyl, benzothiazolylmethyl and quinolylmethyl, all of which may contain substituents described below.

The acyl moiety in each of the above-mentioned compounds may be a carboxylic acyl group having 14 or less carbon atoms, such as straight chain, branched chain or cyclic alkanoyl; Mono-cyclic or bicyclic aroyl, aralkanoyl and arylalkenoyl groups which may contain hetero atoms; Sulfonic acyl groups having up to 14 carbon atoms such as alkylsulfonyl and arylsulfonyl; Carbonic acyl groups having up to 14 carbon atoms such as alkoxycarbonyl, aralkoxycarbonyl and carbamoyl; Phosphoric acyl groups having up to 14 carbon atoms such as phenylphosphoryl; And sulfuric acyl groups (eg sulfo). Said acyl residue may contain the substituent mentioned later.

When each of the above groups contains a substituent, the above carbon number does not include the carbon number in the substituent.

Examples of substituents capable of bonding to each of the foregoing groups include, for example, straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aralkyl, aryl, carboxylic acyl, carbamoyl, protected carboxy and cyano Carbon functional groups having up to 10 atoms; Nitrogen functional groups such as amino, acylamino, guanidyl, ureido, alkylamino, dialkylamino, isothiocyano, isocyano, nitro and nitroso; Oxygen functional groups such as alkoxy, aryloxy, cyanato, oxo, carboxylic acyloxy, sulfonic acyloxy and phosphoric acyloxy; Sulfur functional groups such as alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, acylthio, thioxo, sulfo and sulfamoyl; Halogen such as fluorine, chlorine, bromine and iodine; Silyl groups such as trialkylsilyl and dialkylalkoxysilyl; And stanyl groups such as trialkylstanyl.

When a compound used as a starting material for preparing sulfamide by the method of the present invention has a functional group capable of causing a side reaction in the molecule, the functional group is protected by a conventional method and then subjected to condensation reaction. After carrying out, it can be deprotected by conventional methods.

Preferred reaction conditions of the present invention are as follows:

The condensation and deprotection reactions described above are generally carried out at temperatures of -80 ° C to + 100 ° C, preferably -70 ° C to + 50 ° C, for 10 minutes to 25 hours, preferably for 0.5 to 20 hours. Since the product is stable in the reaction solution, it may be left for a long time.

In the condensation reaction, reacting 1 to 5 equivalents of oxycarbonylsulfamide compound (I), 1 to 5 equivalents of trivalent phosphorus compound, and 1 to 5 equivalents of azodicarboxylic acid derivative with 1 equivalent of alcohol (H) desirable. In these reactions, any of the following solvents may be used: hydrocarbons such as pentane, hexane, octane, benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane and chlorobenzene; Ethers such as diethyl ether, methylisobutyl ether, dioxane and tetrahydrofuran; Ketones such as acetone, methyl ethyl ketone and cyclohexanone; esters such as ethyl acetate, isobutyl acetate and methyl benzoate; Nitrated hydrocarbons such as nitromethane and nitrobenzene; Nitriles such as acetonitrile and benzonitrile; Amides such as formamide, acetamide, dimethylformamide, dimethylacetamide and hexamethylphosphotriamide, and sulfoxides such as dimethyl sulfoxide; Organic bases such as diethylamine, triethylamine, cyclonuxylamine, benzylamine, pyridine, pipelin, collidine and quinoline; other types of industrial inert solvents or mixtures thereof.

In particular, the reaction solvent used in the condensation reaction is preferably at least one selected from inert solvents such as tetrahydrofuran, dioxane, dichloromethane and ethyl acetate. All of the above reactions can be carried out, if necessary, under anhydrous conditions, using an inert gas, and / or with stirring.

The product of interest is to remove impurities such as unreacted substances, side reaction products and solvents by conventional methods such as extraction, evaporation, washing, concentration, precipitation, filtration, drying, etc., followed by adsorption, elution, distillation, precipitation, deposition and chromatography. It can be separated by conventional post-treatment such as photography.

The yield of sulfamide according to the invention is generally from 50 to 90% when primary alcohol is used as starting material. The reactivity of alcohol in the condensation reaction is reduced according to the type of alcohol in the order of primary, secondary and tertiary alcohols.

As described above, according to the present invention, in order to proceed the condensation reaction under mild and neutral conditions, an alcohol and an oxycarbonyl sulfamide compound are reacted in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative. The sulfamides can be produced by a novel method. Furthermore, in the present invention, the synthesis of sulfamide, which requires 4 to 5 steps in the conventional method, can be carried out in only two steps, namely, condensation and deprotection reaction steps, which can be carried out under mild and neutral conditions. Simplified to help. In particular, when primary alcohol is used as a starting material, the desired sulfamides can be synthesized easily and efficiently in high yield.

The features of the method according to the invention are as follows:

(1) Since sulfamides can be derived from alcohol in only two steps, the method is excellent.

(2) The condensation reaction is carried out under mild and neutral conditions.

(3) When the alcohol has an optically active center, condensation reactions are performed stereospecifically, with SN 2 substitution reactions in which the arrangement of the product is reversed with respect to the starting material (eg alcohol). Therefore, this reaction is suitable for obtaining specific forms of stereoisomers.

The method of the present invention is characterized by directly inducing sulfamides from alcohols, in particular from primary alcohols. Sulphamids are various physiologically active substances (CH Lee and H. Kohn, J. Org. Chem. 1990, 55 6098), β-lactam antibacterial agents (Japanese Patent Application No. Hei 3-207972), antipyretics, analgesics (A. Giraldes, R. Nieves, C. Ochoa, C. Vera de Rey, E. Cenarruzabeitia and B. Lasheras, Eur. J. Med. Chem. 1989, 24, 497), sweeteners (GW Muller and GE DuBois, J. Org. Chem. 1980, 54, 4471), sleeping pills (B. Unterhalt and GA Hanewacker, Arch. Pharm. (Weinheim) 1988, 321, 375) anticonvulsants (CH Lee and H. Kohn, J. Pharm. Sci 1990, 79 716), since these materials and medicaments often have sulfamides in their chemical structure. For example, (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -2 [(3S, 5S) -5-sulfamidomethylpyrrolidine- obtained in Reference Example 10 below 3-yl] thio-1-methylcarba-2-phenem-3-carboxylic acid is a novel antimicrobial agent that exhibits strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria. Furthermore, the method for producing sulfamides from alcohols according to the present invention can also be used for chemical modification of polymer polyhydric alcohols and natural alcohol stereoisomers.

EXAMPLE

Next, examples of the present invention will be described.

Production Example

[Synthesis of oxycarbonyl sulfamide compound]

Step A: To a solution of alcohol (R ⁴ OH) in a solvent, chlorosulfonyl isocyanate (CISO ₂ NCO) was added dropwise under the reaction conditions as shown in Table 1. The mixture was stirred to give an N-chlorosulfonylcarbamate solution. This solution can be used directly for the next step of reaction.

TABLE 1

Step B: After adding amine (R ¹ R ² NH) to the N-chlorosulfonylcarbamate solution under the reaction conditions as shown in Table 2, the mixture was stirred. The reaction mixture was neutralized and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to afford the oxycarbonylsulphamide compound.

TABLE 2

The physical constant of the obtained product is as follows.

[Condensation Reaction Using Primary Alcohol]

Example 1

[Use benzyl alcohol or thienylmethyl alcohol]

Triphenylphosphine (or sample No. 5) under the reaction conditions shown in Tables 3 and 4 while stirring the mixture in a solution of alcohol (R ³ OH) in a solvent [tetrahydrofuran (THF) or ethyl acetate (EtOAc)]. Tributylphosphine), oxycarbonylsulfamide (OCSD = R ⁴ OCONHSO ₂ NH ₂ ) and dimethyl azodicarboxylate (DMAD) or diethyl azodicarboxylate (DEAD) were added.

The reaction mixture was diluted with water and extracted with solvent.

The extract was dried and concentrated in vacuo to give sulfamide, a condensation product of OSCD and alcohol. This form of sulfamide is hereinafter referred to as "condensed sulfamide".

The condensation reaction for preparing Sample No. 5 is described in detail below.

To a solution of 103 μl (1 mmol) of benzyl alcohol in 4 mL of tetrahydrofuran (THF) was added 294 mg (1.5 mmol) of oxycarbonylsulfamide (OCSD: R ⁴ = t-butyl). The mixture was cooled to -60 ° C. To this mixture was added 294 μl (1.18 mmol) tributylphosphine ((n-Bu) ₃ P) and 189 μl (1.2 mmol) diethyl azodicarboxylate (DEAD). The mixture was stirred for 2 hours while gradually raising to room temperature and for 40 minutes at room temperature. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with water, dried and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give 210 mg of condensed sulfamide (yield: 73%) as colorless crystals.

TABLE 3

TABLE 4

The physical constants of the obtained product are as follows:

The obtained physical constants are the same as those obtained in Sample No. 1.

Example 2

[Use of pyrrolidinemethanol derivative]

Pyrrolidinemethanol derivative (R ³ OH) was dissolved in a solvent [tetrahydrofuran (THF), benzene (BZ), ethyl acetate (EtOAc) or toluene (To)] while stirring the mixture as shown in Table 5 Triphenylphosphine (PPh ₃ ), diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIPAD), and oxycarbonyl sulfamide (OCSD-R ⁴ OCONHSO ₂ NH ₂ ) under reaction conditions ) Was added. The reaction mixture was concentrated in vacuo to give condensed sulfamide.

TABLE 5

The physical constants of the obtained product are as follows:

Example 3

[using β-lactam alcohol or diethylmethyl alcohol]

Triphenylphosphine (PPh ₃ ), diethyl azodicarboxylate (DEAD) and under the reaction conditions as shown in Table 6 while stirring the mixture in a solution of alcohol (R ³ OH) in tetrahydrofuran (THF) and Oxycarbonylsulfamide (OCSD = t-BuOCONHSO ₂ NR ¹ R ² ) was added. The reaction mixture was concentrated under vacuum to give condensed sulfamide.

TABLE 6

The physical constants of the obtained product are as follows:

1) R ¹ = R ² = H, R ³ = ((1S, 5R, 6S) -3-p-methoxybenzyloxycarbonyl-1-methyl-6-[(R) -1-triethylsilyloxy Ethyl] -carba-2-phenem) -2-ylmethyl

2) R ¹ = phenyl, R ² = H, R ³ = ((1S, 5R, 6S) -3-p-mesoxybenzyloxycarbonyl-1-methyl-6-[(R) -1-triethyl Silyloxyethyl] -carba-2-phenem) -2-ylmethyl

3) R ¹ = (4-diphenylmethoxycarbonyl-3-cepem) -7-yl, R ² = H, R ³ = 2-thienylmethyl

4) R ¹ = R ² = H, R ³ = (4-p-nitrobenzyloxycarbonyl-1-oxo-7- (2-thienylacetamido) -3-cepem) -3-ylmethyl

Physical constants were measured after conversion to 1-oxide by oxidation to move the 2-position double bond to the 3-position. Oxidation reaction conditions are described in Reference Example 14 below.

Melting point 138-l42 ℃

[Condensation Reaction Using Secondary Alcohol]

Example 4

[Using pyrrolidine]

Triphenylphosphine (PPh ₃ ), dimethyl azodicarboxyl under the reaction conditions shown in Tables 7 and 8 with stirring the mixture in a solution of pyrrolidinol dissolved in a solvent [tetrahydrofuran (THF) or ethyl acetate (EtOAc)] Rate (DMAD) or diethyl azodicarboxylate (DEAD), and oxycarbonylsulfamide (OCSD = R ⁴ OCONHSO ₂ NR ¹ R ² ) were added.

The reaction mixture was condensed under vacuum to give condensed sulfamide with 4-array inverted to the starting material.

TABLE 7

TABLE 8

The physical constants of the obtained product are as follows.

1) R ^l = phenyl, R ² = H, R ³ = (2S, 4S) -1- (p-methoxybenzyloxycarbonyl) -2methoxycarbonyrrolidin-4-yl, R ⁴ = t -Butyl

2) R ¹ = R ² = H, R ³ = (2S, 4S) -1-p-methoxybenzyloxycarbonyl-2-methoxy carbonylpyrrolidin-4-yl, R ⁴ = t-butyl

3) R ¹ = R ² = H, R ³ = (2S, 4S) -1-p-methoxybenzyloxycarbonyl-2-methoxy carbonylpyrrolidin-4-yl, R ⁴ = p-nitro benzyl

4) R ¹ = R ² = H, R ³ = (2S, 4S) -1-p-methoxybenzyloxycarbonyl-2-methoxy carbonylpyrrolidin-4-yl, R ⁴ = p-nitro benzyl

Example 5

[Using cyclohexane]

Triphenylphosphine (PPh ₃ ), diethyl azodicarboxylate (DEAD) and oxycarbonylsulfa under the conditions as shown in Table 9 while stirring the mixture in a solution of cyclohexanol in tetrahydrofuran (THF) Mid (OCSD = t-BuOCONHSO ₂ NR ¹ R ² ) was added. The reaction mixture was concentrated in vacuo to give condensed sulfamide.

TABLE 9

The physical constants of the obtained product are as follows.

[Reference Example]

Reference Example 1

[Deprotection by CF ₃ COOH]

The condensed sulfamide having t-butoxycarbonyl protecting group obtained as Sample No. 1 of Example 1 was dissolved in a mixed solution of dichloromethane (15 volumes) and anisole (15 volumes) under ice cooling, and then trifluoro Acetic acid (15 volumes) was added. The mixture was stirred for 50 minutes, then the ice bath was removed and stirred for 1 hour. The reaction mixture was concentrated, and the residue was recrystallized from a mixed solution of ether and petroleum ether (1: 6) to obtain benzyl sulfamide.

Colorless crystal yield: 90%

Reference Example 2

[Deprotection by CF ₃ COOH]

Anisole (3 volumes) and trifluoro acetic acid (5 volumes) were added to the condensed sulfamide having the t-butoxycarbonyl protecting group obtained as sample number 8 of Example 2. The mixture was stirred at rt for 30 min and concentrated in vacuo. The residue was recrystallized from dichloromethane to give (3S, 5S) -3-p-methoxybenzylmercapto-5-sulfamidomethyl-2-pyrrolidone.

Colorless crystals. Yield: 68%

Reference Example 3

[Deprotection by CF ₃ COOH]

The condensed sulfamide having t-butoxycarbonyl and diphenylmethyl protecting group obtained as sample No. 3 of Example 3 was added to a mixed solution other than dichloromethane (6 vol.) Anisole (6 vol.) Under ice cooling. After dissolving, trifluoro acetic acid (6 volumes) was added. The mixture was stirred at room temperature for 90 minutes, and then the reaction mixture was diluted with ether and petroleum ether to give 7- [N- (2-thienylmethyl) sulfamoylamino] -3-cef-4-carboxylic acid as a pale yellow powder. It was obtained by separating. Yield 56%.

Reference Example 4

[Deprotection by H ₂ ]

Condensed sulfamide with p-nitrobenzyloxycarbonyl protecting group obtained as sample number 2 of Example 1 was dissolved in tetrahydrofuran (10 volumes), and 10% palladium-carbon (0.2 wt%) was added as a catalyst. . The mixture was stirred in hydrogen for 1 hour. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from a mixture of ether and petroleum ether to obtain benzylsulfamide having the same physical constants as those obtained in Reference Example 1.

Colorless crystals. Yield: 77%

Reference Example 5

[Deprotection by H ₂ ]

Similar to Reference Example 4, the p-nitrovanzyl ester obtained in Reference Example 9 below was hydrogenated in the presence of 10% palladium-carbon to give 7- (2-thienylacetamido) -3-sulfamidomethyl-3- Cefem-4-carboxylic acid was obtained. Yield: 20% total starting from Reference Example 9.

Reference Example 6

[Deprotection by palladium]

Condensed sulfamide having an allyloxycarbonyl protecting group obtained as Sample No. 3 of Example 1 was dissolved in benzene (10 vol), triphenylphosphine (0.3 equiv), sodium 2-ethylhexanoate in ethyl acetate (1.5 equiv) and palladium tetrakistrifenylphosphine (0.02 equiv) were added sequentially.

The mixture was stirred at rt for 30 min, then the reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated in vacuo. The residue was recrystallized with toluene to obtain benzylsulphamide having the same physical constant as that obtained in Reference Example 1. Light yellow crystals. Yield 64%.

Reference Example 7

[Deprotection by AlCl ₃ ]

P-methoxybenzyl obtained in Reference Example 13 described below in dichloromethane (7.5 volumes) in a solution of aluminum chloride (6 equivalents) dissolved in a mixed solution of dichloromethane (15 volumes) and anisole (15 volumes) at -55 ° C. A solution of the ester was added. After the mixture was stirred for 25 minutes, the reaction mixture was added to a solution of sodium acetate (18 equivalents) in water (21 volumes). The aqueous layer was taken, washed with dichloromethane, desalted and concentrated to give (1S, 5R, 6S) -6-[(R) -1-hydroxyethyl] -2-sulfamidomethyl-1-methylcarba- 2-phenem-3-carboxylic acid was obtained as a white foam. Yield 32%.

Reference Example 8

[Deprotection by AlCl ₃ ]

Similarly to Reference Example 7, the p-methoxybenzyl ester obtained in Reference Example 12 below was deprotected with aluminum chloride in a mixed solution of anisole and dichloromethane to give (1S, 5R, 6S) -6-[(R) -1-hydroxyethyl] -2- (phenylsulfamoylamino) methyl-1-methylcarba-2-pentem-3-carboxylic acid was obtained. yield. 22%.

Reference Example 9

[Deprotection by CF ₃ COOH]

Similarly to Reference Example 1, the condensed sulfamide having the t-butoxycarbonyl protecting framework obtained as Sample No. 4 of Example 3 was deprotected with sulfur trifluoroacetic acid in a mixed solution of difluoromethane and anisole. 7- (2-thienylacetamido) -3-sulfamidomethyl-3-cepem-4-carboxylic acid p-nitrobenzyl ester was obtained. The product was hydrogenated in a similar manner to Reference Example 5 to obtain the corresponding free acid.

Reference Example 10

[Deprotection by AlCl ₃ ]

Similar to Reference Examples 7 and 8, (1S, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -2 ((3S, 5S) -5- (N-sulfamoyl-t-part Deoxycarbonylamino) methylpyrrolidin-3-yl] thio-1-methylcarba-2-phenem-3-carboxylic acid diphenylmethyl ester was deprotected with aluminum chloride in a mixed solution of dichloromethane and anisole ( 1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -2-[(3S, 5S) -5-sulfamidomethylpyrrolidin-3-yl] thio-1-methylcarr Bar-2-phenem-3-carboxylic acid was obtained.

Reference Example 11

[Deprotection by NAOMe]

The condensed sulfamide with acetyl protecting framework obtained as sample number 4 of Example 2 was dissolved in toluene at −35 ° C., and then a 4.92 M sodium methoxide solution in methanol was added. The mixture was stirred for 30 minutes and then the reaction mixture was diluted with water. The aqueous layer was taken, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and water, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from a mixed solution of toluene and hexane to give (2S, 4S) -1-t-butoxycarbonyl-2- (N-sulfamoyl-t-butoxycarbonylamino) methyl-4-mercaptopyrroli Got Dean.

Yield: 69%, colorless crystals.

Reference Example 12

[Deprotection by HCl]

The condensed sulfamide with triethylsilyl protecting group obtained as Sample No. 2 of Example 3 was dissolved in acetonitrile (14 volumes), and then acetic acid (7.5 equivalents) and concentrated hydrochloric acid (15 equivalents) were added at -30 ° C. . The mixture was stirred for 1 hour 25 minutes and then the reaction mixture was placed in a mixture of aqueous sodium bicarbonate and ethyl acetate. The organic layer is taken, washed with water, dried and concentrated in vacuo to give (1S, 5R, 6S) -2- (N-phenylsulfamoyl-Nt-butoxycarbonylamino) methyl-6-[(R) -1- Hydroxyethyl] 1-1-methylcarba-2-phenem-3-carboxylic acid p-methoxybenzyl ester was obtained. White foam.

Yield 74%.

Reference Example 13

[Deprotection by HCl]

Similar to Reference Example 12, the condensed sulfamide having the triethylsilyl protecting group obtained as Sample No. 1 of Example 3 in acetonitrile was desilylated with acetic acid and concentrated hydrochloric acid to give (1S, 5R, 6S) -2- ( N-sulfamoyl-t-butoxycarbonylamino) methyl-6-[(R) -hydroxyethyl] -1-methylcarba-2-phenem-3-carboxylic acid p-methoxybenzylester white Obtained in foam. Yield: 79%.

Reference Example 14

[deprotection by m-CPBA]

The product obtained as Sample No. 4 of Example 3 having a double bond in 2-position was dissolved in a mixed solution of dichloromethane (15 volumes) and methanol (3 volumes) under ice cooling, and 80% m-chloro-perbenzoic acid ( 1.5 equiv) was added. The mixture was disturbed for 30 minutes, then the reaction mixture was diluted with dimethylsulfide and ethyl acetate, washed with aqueous sodium bicarbonate and water, dried and concentrated in vacuo to 7- (2-thienylacetamido) -3- (N-Sulfamoyl-t-butoxycarbonylamino) methyl-3-cepem-4-carboxylic acid p-nitrobenzyl ester-1-oxide was obtained as a white powder. Yield 23%. The physical constant of the product was the same as the physical constant of the product obtained in Sample No. 4 of Example 3.

Reference Example 15

[Reduction by AcCl-KI]

Potassium iodide (10 equivalents) and acetyl chloride (6 equivalents) were added to a solution of the oxide obtained in Reference Example 14 in acetone (12 volumes) at -35 ° C. The mixture was stirred for 50 minutes, then the reaction mixture was washed with aqueous sodium bicarbonate and water and concentrated in vacuo to give 7- (2-thienylacetamido) -3- (N-sulfamoyl-t-butoxycarbonylamino ) Methyl-3-cepem-4-carboxylic acid p-nitrobenzyl ester was obtained as a white powder. Yield 55%.

Various other modifications will be apparent to those of ordinary skill in the art and will readily be able to make these modifications without departing from the scope of the present invention. Accordingly, the claims appended hereto are not intended to be limited to the description set forth herein, so that the claims should be construed broadly.

Claims (2)

Reacting the oxycarbonylsulfamide compound represented by the following structural formula (III) with the alcohol represented by the following structural formula (II) in the presence of an azodicarboxylic acid derivative and a trivalent phosphorus compound. The manufacturing method of the sulfamide shown by following General formula (I) formed by. R ³ NHSO ₂ NR ¹ R ² (I) Provided that R ¹ and R ² are each independently selected from the group consisting of alkyl substituted with hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic group and heterocyclic group Wherein the heterocyclic group is selected from the group consisting of pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings; R ³ Is a group selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, heterocyclic group, alkyl substituted with a heterocyclic group and pyrrolidinyl-methyl, wherein the heterocyclic group is pyranosyl, fura Nosyl, piperidinyl, pyrrolidinyl, azetidinone rings, cefem rings, penem rings and carbapenem rings); R ³ OH (II) Wherein R ³ is as defined above; R ⁴ OOC-NHSO ₂ NR ¹ R ² (III) Wherein R ¹ and R ² are as defined above and R ⁴ is a carboxy protecting group. The method of claim 1, further comprising removing the -COOR ⁴ group.