JPH0672986A - Production of sulfamides - Google Patents

Abstract

PURPOSE:To obtain the subject compounds useful as an intermediate for producing a medicine, a medicine for animals or plants, a stereoisomeric alcohol, etc., under mild neutral conditions in a shortened process according to a new method using an alcohol as a raw material. CONSTITUTION:An alcohol (preferably a primary alcohol) and an oxycarbonylsulfamide compound are subjected to the dehydrating condensation in the presence of a trivalent phosphorus compound (e.g. triethylphosphine) and an azodicarboxylic acid derivative (e.g. methyl azodicarboxylate) preferably at -70 to +50 deg.C for 0.5-20hr to afford the objective compounds. The reaction is preferably carried out by using the oxycarbonylsulfamide compound, trivalent phosphorus compound and azodicarboxylic acid derivative in respective amounts of 1-5 equiv. based on 1 equiv. alcohol. Furthermore, the oxycarbonylsulfamide compound is obtained by reacting, e.g. an alcohol with chlorosulfonyl isocyanate and then reacting the resultant N-chlorosulfonylcarbamic acid ester with an amine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing sulfamides which are useful in medicine, animal and plant medicines, polymer chemistry and stereochemical production of alcohol compounds.

[0002]

2. Description of the Related Art 4 to 5 steps are required to produce a sulfamide compound using alcohol as a raw material. That is, after the alcohol is changed to a halide or sulfonyl ester, the azide group is substituted to form an azide, and the azide group is reduced to an amino group, or the alcohol halide or sulfonyl ester is changed to a phthalimide group. A sulfamide compound can be obtained by substituting the phthaloyl group with hydrazine to form an amino group, condensing an amine produced by any method with a sulfamoylating agent, and deprotecting as necessary.

The operation of these steps is complicated, and when a side-reactive functional group is present in the molecule, it is essential to introduce or remove a protecting group adaptable to the reaction conditions of each step.
There is a problem that an azide compound, hydrazine and the like, which are highly explosive or highly toxic, are required.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above-mentioned drawbacks, and its purpose is useful in the production of pharmaceuticals, animal and plant drugs or their raw materials, or polymer compounds and stereoisomeric alcohol compounds. Another object of the present invention is to provide a method for producing a sulfamide.

[0005]

Meanings of abbreviations in this specification are 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 the sulfamides (I) of the present invention, the alcohol (II) and the oxycarbonylsulfamide compound (III) are added in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative. Dehydrate and condense.

The method of the present invention is illustrated in the scheme below.

[0008]

[Chemical 1]

Here, R ¹ and R ² are, for example, each independently, hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic group (eg, pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone). Ring, cephem ring, penem ring and carbapenem ring) and an alkyl having the above heterocyclic group (eg, pyrrolidinylmethyl); R ³ is, for example, alkyl, alkenyl, alkynyl, An aralkyl, a heterocyclic group (for example, pyranosyl, furanosyl, azetidinone ring, cephem ring, penem ring and carbapenem ring), an alkyl having the above heterocyclic group (for example, pyrrolidinylmethyl) R ⁴ is a protecting group for a carboxy group.

Specifically, the oxycarbonylsulfamide compound (III), the trivalent phosphorus compound and the azodicarboxylic acid derivative are added to the alcohol (II). Particularly preferably, the reaction is carried out in an aprotic inert solvent at -70 ° C to + 50 ° C for 0.5 to 20 hours to obtain the R ³ -substituted oxycarbonylsulfamide compound (IV). The desired sulfamide compound (I) can be easily produced by removing R ⁴ OOC from this product by a conventional method, if necessary.

First, each component used in the present invention will be described.

The oxycarbonylsulfamide compound (R ⁴ OOCNHSO ₂ NR ¹ R ² ) (I) used in the present invention
As the amino substituents R ¹ and R ² of, for example, hydrogen,
Alkyl, cycloalkyl, alkenyl, alkynyl,
Aralkyl, aryl, a heterocyclic group (for example, pyranosyl, furanosyl, piperidinyl, pyrrolidinyl, azetidinone ring, cephem ring, penem ring and carbapenem ring), alkyl having the above heterocyclic group (for example, pyrrolidinylmethyl) and the like can be mentioned. . Where R ¹ and R ²
And may be the same substituent or different. The carboxy protecting group R ⁴ includes, for example, alkyl, alkenyl, alkynyl, aralkyl, aryl and the like, and is preferably a group capable of easily removing the carbonic acid ester forming group. The alcohol (R ³ O used in the present invention
H) The group R ^{3 in} (II) is a carbon-containing group which includes, for example, alkyl, alkenyl, alkynyl, aralkyl, heterocyclic groups (eg pyranosyl, furanosyl, azetidinone ring, cephem ring, penem ring and Carbapenem ring), and alkyl having the above heterocyclic group (for example, pyrrolidinylmethyl). Any of these may have a substituent. Here, the substituent is a substituent that does not interfere with this reaction, such as alkyl, acyloxy, alkoxy, esterified phosphoric acid group and halogen. As the alcohol used in the present invention, the above-mentioned primary alcohols are preferable because of their high reactivity, but secondary alcohols or tertiary alcohols can also be used.

Examples of the trivalent phosphorus compound used in the present invention include trialkylphosphines such as triethylphosphine and tributylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine, methyl phosphite, ethyl phosphite, and Examples thereof include phosphite esters such as phenyl phosphate.

Examples of the azodicarboxylic acid derivative used in the present invention include azodicarboxylic acid alkyl esters such as methyl azodicarboxylate, ethyl azodicarboxylate and isopropyl azodicarboxylate; azodinitrile; azodicarboxamide; azodicarboxylic bis. Azodicarboxylic acid bisdialkylamides such as dimethylamide and azodicarboxylic acid bisdiethylamide; 1,1 ′
Examples include 1,1 ′-(azodicarbonyl) dialkyleneamine such as — (azodicarbonyl) dipyrrolidine and 1,1 ′-(azodicarbonyl) dipiperidine.

The alkyl moiety in each of the above compounds is a linear, branched or cyclic alkyl having 1 to 12 carbon atoms.
The alkyl group of is typical. For cyclic alkyl, it may have one or more heteroatoms (eg, oxygen, nitrogen and sulfur) in the ring. Examples of the alkyl moiety include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethyl, pyrrolidinyl, pentyl, isopentyl, neopentyl, cyclopentyl, cyclopropylethyl, piperidyl, hexyl. , Cyclohexyl, cyclopentylmethyl, heptyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl, dodecyl and the like. Each of these may have a substituent as described below.

The alkenyl moiety and alkynyl moiety in each of the above compounds are those in which the alkyl moiety has one or more unsaturated bonds and may have a substituent as described later.

The aralkyl moiety in each of the above compounds is
It is a combination of an alkyl moiety and an aryl moiety, and is typically an aralkyl group having 7 to 14 carbon atoms. For example,
Benzyl, phenethyl, phenylpropyl, phenylisopropyl, diphenylmethyl, methoxydiphenylmethyl, naphthylmethyl, furylmethyl, thienylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, pyridylmethyl, indolylmethyl, benzimidazolylethyl , Benzothiazolylmethyl, quinolylmethyl and the like. Each of these may have a substituent as described below.

The acyl moiety in each of the above compounds is a carboxylic acyl group having up to 14 carbon atoms (linear, branched or cyclic alkanoyl, monocyclic or bicyclic aroyl which may have a hetero atom, aralkanoyl, arylalkenoyl). Etc.), sulfonate acyl groups having up to 14 carbon atoms (alkylsulfonyl, arylsulfonyl, etc.), C14
Up to acyl carbonate groups (alkoxycarbonyl, aralkoxycarbonyl, carbamoyl, etc.), acyl phosphate groups having up to 14 carbon atoms (phenylphosphoryl, etc.), and acyl sulfate groups (ie, sulfo). Any of the above acyl moieties may have a substituent as described below.

Typical examples of the substituents that can be bonded to the above groups include carbon functional groups having up to 10 carbon atoms (straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aralkyl, aryl, carboxylic acid). Acyl, carbamoyl, protected carboxy, cyano, etc.); nitrogen functional groups (amino, acylamino, guanidyl, ureido, alkylamino, dialkylamino, isothiocyano, isocyano, nitro, nitroso, etc.); oxygen functional groups (alkoxy, aryloxy, cyanato, etc.) Oxo, carboxylic acid acyloxy, sulfonic acid acyloxy, phosphoric acid acyloxy, etc.); sulfur functional group (alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, acylthio, thioxo, sulfo, sulfamoyl, etc.); halogen (fluorine, chlorine, bromine, Chromatography, etc. De); silyl groups (trialkylsilyl, dialkyl alkoxysilyl); and stannyl groups (trialkylstannyl) and the like.

When the group has a substituent, the carbon number of each of the above groups is the number of carbon atoms excluded from the substituent. When a sulfamide group is produced by the method of the present invention, if there is a functional group capable of causing a side reaction in the molecule of the raw material compound, a dehydration condensation reaction is carried out after protection by a conventional method, and the reaction is usually performed after the reaction is completed. May be deprotected by law.

Next, preferable reaction conditions of the present invention will be described.

The above condensation reaction and deprotection reaction are usually
It is carried out at a temperature in the range of 80 to + 100 ° C, especially -70
It is preferably carried out at a temperature in the range of + 50 ° C., and the reaction time is usually 10 minutes to 25 hours, particularly 0.5 to
20 hours is preferred. When the product is stable in the reaction solution, it may be left for a longer time. In the condensation reaction, 1 to 5 equivalents of the oxycarbonylsulfamide compound (I), 1 to 5 equivalents of the trivalent phosphorus compound and 1 to 5 equivalents of the azodicarboxylic acid derivative may be reacted with 1 equivalent of the alcohol (II). preferable. Reaction solvents used in each reaction include hydrocarbons (pentane, hexane, octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.),
Ether (diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran, etc.), ketone (acetone, methyl ethyl ketone, cyclohexanone, etc.), ester (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitro hydrocarbon (nitromethane, nitrobenzene, etc.), nitrile (Acetonitrile, benzonitrile, etc.), amide (formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), sulfoxide (dimethyl sulfoxide, etc.), organic base (diethylamine, triethylamine, cyclohexylamine, benzylamine, pyridine, (Picoline, collidine, quinoline, etc.), inert industrial solvents belonging to other series, or a mixture thereof can be exemplified. In particular, the reaction solvent used in the condensation reaction is preferably at least one selected from the group consisting of inert solvents such as tetrahydrofuran, dioxane, dichloromethane, ethyl acetate and the like. Each of the above reactions may optionally be carried out under anhydrous conditions using an inert gas and / or stirring.

The desired product is obtained by removing impurities (unreacted raw materials, by-products, solvents, etc.) from the reaction solution by a conventional method (extraction, evaporation, washing, concentration, precipitation, filtration, drying, etc.). , Usual post-treatment (adsorption, elution, distillation, precipitation, precipitation,
It can be isolated by a combination of treatments such as chromatography.

The yield of sulfamide according to the present invention is usually 50 to 90 when a primary alcohol is used as a raw material.
%.

The manufacturing method of the present invention has the following characteristics.

It is excellent in that a sulfamide compound can be derived from alcohol in two steps.

The dehydration condensation reaction proceeds under mild neutral conditions.

The reactivity of alcohols in the dehydration condensation reaction decreases in the order of primary, secondary and tertiary.

[0029] When the alcohol is an optically active center, the dehydration condensation reaction is stereospecific, S _N 2 which configuration is reversed
It is a substitution reaction. Since it is a stereospecific reaction, it is suitable as a chemical reaction for obtaining a desired stereoisomer.

Sulfamides are physiologically active substances [various substances having physiological action (CH Lee; H. Kohn J. Org. Che.
m. 1990, 55, 6098), beta-lactam antibacterial agent (Japanese Patent Application No. 3-207972), antipyretic agent, analgesic agent (A. Giraldes;
R. Nieves, C. Ochoa, C. Vera de Rey; E. Cenarruzab
eitia; B. Lasheras Eur. J. Med. Chem. 1989, 24, 49
7), Sweetener (GW Muller; GE DuBois J. Org. Ch
em. 1989, 54, 4471), sleeping pills (B. Unterhalt; GA
Hanewacker Arch. Pharm. (Weinheim) 1988, 321, 37
5), anticonvulsants (CH Lee; H. Kohn, J. Pharm. Sci.
1990, 79, 716), etc.] and is useful for preparing these. For example, (1R, 5S, 6S) -6-[(1R) -1-
Hydroxyethyl] -2 [(3S, 5S) -5-sulfamidomethylpyrrolidin-3-yl] thio-1-methylcarba-2-penem-3-carboxylic acid has a strong antibacterial activity against Gram-positive and negative bacteria. Is a new antibacterial agent. Furthermore, the production method of the present invention in which an alcohol is converted to sulfamide can also be used for chemical modification of high molecular weight polyhydric alcohol, chemical modification of natural product alcohol stereoisomer, and the like.

[0031]

EXAMPLES The present invention will be described below with reference to examples.

(Production Example) Synthesis of oxycarbonylsulfamide compound

[0033]

[Chemical 2]

Step A: Under the reaction conditions shown in Table 1 below, alcohol (R ⁴ OH) was dissolved in a solvent, chlorosulfonyl isocyanate was added dropwise, and the mixture was stirred to obtain a solution of N-chlorosulfonylcarbamic acid ester. To be This solution can be directly transferred to the treatment of the next step.

[0035]

[Table 1]

Note) The "volume" of the solvent indicates the ratio of the solvent (ml) to the alcohol (g). The same applies to each table below Table 2.

Note: "Continued" in the yield column indicates that the reaction solution was transferred to step B without post-treatment.

Step B: N under the reaction conditions shown in Table 2 below.
Add amine (R ¹ R ² NH) to the solution of chlorosulfonylcarbamic acid ester and stir. The reaction solution is neutralized and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to give an oxycarbonylsulfamide compound.

[0039]

[Table 2]

Note) "Continued" in the solvent column indicates that the reaction solution of step A was transferred to step B without purification.

The physical constants of the oxycarbonylsulfamide compound synthesized above are shown below.

1) R ¹ = R ² = H, R ⁴ = t-butyl mp. 130-131 ° C IR ν (Nujol) cm ^-1 : 3360, 3270, 1718, 1548 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 1.43 (s, 9H), 7.27
(s, 2H) Elemental analysis (C ₅ H ₁₂ N ₂ O ₄ S) Calculated: C, 30.60; H, 6.17; N,
14.28; S, 16.34 Experimental value: C, 30.39; H, 6.11; N, 14.30; S, 16.30.

2) R ¹ = R ² = H, R ⁴ = p-nitrobenzyl mp. 176 to 177 ° C. IR ν (Nujol) cm ⁻¹ : 3345, 3215, 1718, 1346, 1153 NMR δ (CD ₃ SOCD ₃ ) 200 MHz ppm: 5.30 (s, 2H), 7.54 (s,
2H), 7.65 (d, J = 8.6Hz, 2H), 8.27 (d, J = 8.6Hz, 2H),
11.33 (s, 1H) Elemental analysis (C ₈ H ₉ O ₆ N ₃ S) Calculated value: C, 34.91; H, 3.29; N,
15.27; S, 11.65 Experimental value: C, 35.00; H, 3.45; N, 15.33; S, 11.53.

3) R ¹ = R ² = H, R ⁴ = allyl mp. 119 to 121 ° C IR ν (THF) cm ^-1 : 1745, 1377, 1160 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 4.59 (dd, J ₁ = 1.2Hz, J
₂ = 4.0Hz, 2H), 5.20 ~ 5.39 (m, 2H), 5.83 ~ 6.02 (m, 1
H), 7.45 (s, 2H), 11.20 (s, 1H) Elemental analysis (C ₄ H ₈ O ₄ N ₂ S) Calculated value: C, 26.66; H, 4.47; N,
15.55; S, 17.79 Experimental value: C, 26.79; H, 4.53; N, 15.51; S, 17.71.

4) R ¹ = phenyl, R ² = H, R ⁴ = t-
Butyl mp. 147 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3246, 3190, 1699, 1356, 1141 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 1.33 (s, 9H), 7.05〜
7.36 (m, 4H), 10.25 (s, 1H), 11.23 (s, 1H) Elemental analysis (C ₁₁ H ₁₆ O ₄ N ₂ S) Calculated: C, 48.51; H, 5.92;
N, 10.29; S, 11.77 Found: C, 48.36; H, 5.91; N, 10.38; S, 11.72.

5) R ¹ = (4-diphenylmethoxycarbonyl-3-cephem) -7-yl, R ² = H, R ⁴ = t-butyl mp. 165 to 166 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3390, 3300, 1795, 1735, 1371,
1145 NMR δ (CDCl ₃ ) 200MHz ppm: 1.52 (s, 9H), 3.41, 3.52
(d, ABq, J _AB = 20Hz, J ₁ = 3.2Hz, J ₂ = 5.8Hz), 4.93 (d, J =
5.4Hz, 1H), 5.51 (dd, J ₁ = 5.4Hz, J ₂ = 10.6Hz, 1H), 6.24
(d, J = 10.6Hz, 1H), 6.63 (dd, J ₁ = 3.2Hz, J ₂ = 5.8Hz, 1
H), 6.92 (s, 1H), 7.20 ~ 7.50 (m, 10H), 7.73 (s, 1H) Elemental analysis (C ₂₅ H ₂₇ O ₇ N ₃ S ₂ ) Calculated value: C, 54.67; H, 5.03;
N, 7.65; S, 11.67 Found: C, 54.68; H, 5.03; N, 7.80; S, 11.55.

[Dehydration Condensation Using Primary Alcohol] Example 1 (benzyl alcohol or thienylmethyl alcohol is used as alcohol)

[0048]

[Chemical 3]

Under the reaction conditions shown in Tables 3 and 4 below,
Alcohol (R ³ OH) as solvent (tetrahydrofuran (TH
F) or ethyl acetate (EtOAc)), triphenylphosphine (however, tributylphosphine in 5), oxycarbonylsulfamide compound (OCSD =
R ⁴ OCONHSO ₂ NH ₂ ) and dimethyl azodicarboxylate (DMAD) or diethyl azodicarboxylate (DEAD) are added and stirred. Water is added to the reaction solution and the solution is extracted with a solvent. The extract is dried and then concentrated under reduced pressure to obtain sulfamide (sulfamide substituted with R ³ ; hereinafter referred to as condensed sulfamide) condensed with alcohol.

The operation of the condensation reaction for producing the compound 5) will be specifically described below.

Benzyl alcohol 103 μl (1 mM) was added to THF.
Dissolved in 4 ml, OCSD (R ⁴ = t-butyl) 294 mg (1.5 m
M) is added and cooled to -60 ° C. Tributylphosphine ((n-Bu) ₃ P) 294 μl (1.18 mM) and DEAD 1
After adding 89 μl (1.2 mM), the mixture is stirred for 2 hours while gradually raising the temperature to room temperature, and further stirred at room temperature for 40 minutes. Water is added to this reaction solution, diluted with ethyl acetate, the organic layer is washed with water and dried, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography to give 210 mg (73%) of condensed sulfamide as colorless crystals.

[0052]

[Table 3]

[0053]

[Table 4]

The physical constants of the product obtained above are shown below.

1) R ³ = benzyl, R ⁴ = t-butyl mp. 130 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3410, 3325, 1711, 1372, 1147 NMR δ (CDCl ₃ ) 200mHz ppm: 1.48 (s, 9H), 4.88 (s, 2
H), 5.24 (s, 2H), 7.21 ~ 7.40 (m, 5H) Elemental analysis (C ₁₂ H ₁₈ O ₄ N ₂ S) Calculated value: C, 50.33; H, 6.33;
N, 9.78; S, 11.20 Found: C, 50.27; H, 6.36; N, 9.75; S, 11.03.

2) R ³ = benzyl, R ⁴ = p-nitrobenzyl mp. 128-129 ° C IR ν (Nujol) cm ^-1 : 3374, 3280, 1711, 1351, 1161 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 4.86 (s, 2H), 5.37 (s,
2H), 7.20 ~ 7.40 (m, 5H), 7.53 (d, J = 8.6Hz, 2H), 7.96
(s, 2H), 8.19 (d, J = 8.6Hz, 2H) Elemental analysis (C ₁₅ H ₁₅ O ₆ N ₃ S) Calculated: C, 49.31; H, 4.14;
N, 11.50; S, 8.77 Found: C, 49.34; H, 4.23; N, 11.59; S, 8.59.

3) R ³ = benzyl, R ⁴ = allyl mp. 51-52 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3420, 3320, 1716, 1392, 1182 NMR δ (CDCl ₃ ) 200MHz ppm: 4.73 (d, J = 7.4Hz, 2H),
4.94 (s, 2H), 5.26 ~ 5.37 (m, 4H), 5.81 ~ 6.01 (m, 1H),
7.26 to 7.40 (m, 5H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 271.

4) R ³ = 2-thienylmethyl, R ⁴ = t-
Butyl mp. 111-112 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3412, 3315, 1713, 1392, 1148 NMR δ (CDCl ₃ ) 200MHz ppm: 1.57 (s, 9H), 5.03 (s, 2
H), 5.14 (brs, 2H), 6.97 (dd, J ₁ = 3.6Hz, J ₂ = 5.0Hz, 1
H), 7.11 (dd, J ₁ = 1.2Hz, J ₂ = 3.6Hz, 1H), 7.26 (dd, J ₁ =
1.2Hz, J ₂ = 4.8Hz, 1H) Elemental analysis (C ₁₀ H ₁₆ N ₄ O ₂ S ₂ ) Calculated: C, 41.08; H, 5.52;
N, 9.58; S, 21.93 experimental value: C, 40.90; H, 5.59; N, 9.62; S, 21.74.

5) R ³ = benzyl, R ⁴ = t-butyl The physical constants of the product obtained are the same as in Example 1) above.

Example 2 (using pyrrolidinemethanol as alcohol)

[0061]

[Chemical 4]

Under the reaction conditions shown in Table 5 below, pyrrolidinemethanol (R ³ OH) was used as a solvent (tetrahydrofuran (TH
F), benzene (Bz), ethyl acetate (EtOAc), or toluene (To)), and triphenylphosphine (PP
h ₃ ), diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIPAD), and oxycarbonylsulfamide compounds (OCSD = R ⁴ OCONHSO ₂ NH ₂ ).
And stir. The reaction solution is concentrated under reduced pressure to give condensed sulfamide.

[0063]

[Table 5]

The physical constants of the product obtained above are shown below.

1) R ³ = (2R, 4R) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = t-butyl IR ν (CHCl ₃ ) cm ⁻¹ : 3360, 3200, 1710, 1688 NMR δ (CDCl ₃ ) 200MHz ppm: 1.43 (s, 9H), 1.53 (s, 9
H), 2.34 (s, 3H), 2.5 (m, 1H), 3.15 (dd, J = 12.2Hz, J =
6.2Hz, 1H), 3.58 (dd, J = 14.8Hz, J = 3.2Hz, 1H), 3.8 ~
4.1 (m, 2H), 4.16 (dd, J = 12.2Hz, J = 7.8Hz, 1H), 4.4 ~
4.7 (m, 1H), 6.11 (s, 2H).

2) R ³ = (2R, 4S) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = t-butyl IR ν (KBr) cm ⁻¹ : 3420, 3320, 1706 , 1686, 1666 NMR δ (CDCl ₃ ) 200MHz ppm: 1.41 (s, 9H), 1.55 (s, 9
H), 1.9 ~ 2.0 (m, 2H), 2.35 (s, 3H), 3.32 (dd, J = 11.4H
z, J = 8.2Hz, 1H), 3.6 ~ 3.9 (m, 3H), 3.9 ~ 4.1 (m, 1H),
4.5 (m, 1H), 6.15 (s, 2H).

3) R ³ = (2S, 4R) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = t-butyl IR ν (KBr) cm ⁻¹ : 3420, 3320, 1706 , 1686, 1666 NMR δ (CDCl ₃ ) 200MHz ppm: 1.41 (s, 9H), 1.55 (s, 9
H), 1.9 ~ 2.0 (m, 2H), 2.35 (s, 3H), 3.32 (dd, J = 11.4H
z, J = 8.2Hz, 1H), 3.6 ~ 3.9 (m, 3H), 3.9 ~ 4.1 (m, 1H),
4.5 (m, 1H), 6.15 (s, 2H).

4) R ³ = (2S, 4S) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = t-butyl mp. 136-140 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3380, 3220, 1707, 1696 NMR δ (CDCl ₃ ) 200MHz ppm: 1.42 (s, 9H), 1.53 (s, 9
H), 2.34 (s, 3H), 2.4 ~ 2.7 (m, 1H), 3.1 ~ 3.2 (m, 1H),
3.5〜4.22 (m, 4H), 4.5〜4.65 (m, 1H), 6.10 (s, 2H) Elemental analysis (C ₁₇ H ₃₁ N ₃ O ₇ S ₂ ) Calculated value: C, 45.01; H, 6.89;
N, 9.26; S, 14.14 Experimental value: C, 44.94; H, 6.76; N, 9.22; S, 13.88.

5) R ³ = (2S, 4S) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = p-nitrobenzyl IR ν (CHCl ₃ ) cm ⁻¹ : 3370, 3200 , 1720, 1686, 1349,
1157 NMR δ (CDCl ₃ ) 200MHz ppm: 1.41 (s, 9H), 2.31 (s, 3
H), 1.40 ~ 2.65 (m, 2H), 2.90 ~ 4.15 (m, 5H), 4.40 ~ 4.60 (m, 1H), 5.31 (dd, J
₁ = 15.2Hz, J ₂ = 13.2Hz, 2H), 6.11 (s, 2H), 7.57 (d, J =
8.6Hz, 2H), 8.26 (d, J = 8.6Hz, 2H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 533.

6) R ³ = (2S, 4S) -4-acetylthio-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = allyl IR ν (CHCl ₃ ) cm ⁻¹ : 3370, 3250, 1717, 1682, 1394,
1162 NMR δ (CDCl ₃ ) 200MHz ppm: 1.42 (s, 9H), 1.2 ~ 1.6 &
2.5 ~ 2.7 (m, 2H), 3.07 ~ 4.15 (m, 5H), 4.4 ~ 4.6 (m, 1
H), 4.62 ~ 4.71 (m, 2H), 5.28 ~ 5.44 (m, 2H), 5.81 ~ 6.0
5 (m, 1H), 6.12 (brs, 2H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 438.

7) R ³ = (2S, 4S) -4-acetylthio-1-allyloxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = allyl NMR δ (CDCl ₃ ) 2OOMHz ppm: 1.5-1.7 (m, 1H) , 2.35 (s,
3H), 2.5-2.7 (m, 1H), 3.19 (dd, J = 6.3 & 11.5Hz, 1H),
3.68 (dd, J = 3.8 & 14.5Hz, 1H), 3.9-4.3 (m, 3H), 4.3-
4.7 (m, 5H), 5.2-5.4 (m, 4H), 5.8-6.1 (m, 4H).

8) R ³ = (3S, 5S) -3-p-methoxybenzylmercapto-2-oxopyrrolidine-5-
Ylmethyl, R ⁴ = t-butyl mp. 132-134 ° C IR ν (KBr) cm ^-1 : 3370, 3345, 3245, 2900, 1695, 16
80, 1608 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 1.5 to 1.7 (m, 1H), 2.4
5 to 2.65 (m, 1H), 2.8 to 3.1 (m,
2H), 3.2 to 3.35 (m, 1H), 3.35 (s, 3H), 3.5
~ 3.7 (m, 1H), 3.81, 3.96 (ABq, J = 12.7Hz, 2H), 6.61
(s, 2H), 6.68 (t, J = 6.6Hz, 1H), 6.88, 7.25 (2d, J = 6.
6Hz, 2H × 2), 7.88 (s, 1H) Elemental analysis (C ₁₃ H ₁₉ N ₃ O ₄ S ₂ ) Calculated: C, 45.20; H, 5.54;
N, 12.16; S, 18.56 Found: C, 44.97; H, 5.52; N, 12.10; S, 18.34.

9) R ³ = (2S, 4R) -4-methanesulfonyloxy-1-t-butoxycarbonylpyrrolidin-2-ylmethyl, R ⁴ = t-butyl mp.147-1
49 ° C. IR (CHCl ₃ ) ν cm ⁻¹ : 3370, 3210, 1710, 1680 NMR δ (CDCl ₃ ) 2OOMHz ppm: 1.44 (s, 9H), 1.53 (s,
9H), 1.82 ~ 2.43 (m, 2H), 3.04 (s, 3H), 3.4 ~ 4.05 (m,
4H), 4.55 ~ 5.25 (m, 2H), 6.04 (s, 2H) Elemental analysis (C ₁₆ H ₃₁ N ₃ O ₉ S ₂ ) Calculated value: C, 40.58; H, 6.60;
N, 8.87; S, 13.54 Found: C, 40.79; H, 6.55; N, 8.68; S, 13.32.

Example 3 (using beta-lactam alcohol or thienylmethyl alcohol as alcohol)

[0075]

[Chemical 5]

Under the reaction conditions shown in Table 6 below, alcohol (R ³ OH) was dissolved in tetrahydrofuran (THF) to give triphenylphosphine (PPh ₃ ), diethyl azodicarboxylate (DEAD) and oxycarbonylsulfamide compound ( Add OCSD = t-BuOCONHSO ₂ NR ¹ R ² ) and stir. The reaction solution is concentrated under reduced pressure to give condensed sulfamide.

[0077]

[Table 6]

The physical constants of the product obtained above are shown below.

1) R ¹ = R ² = H, R ³ = ((1S, 5
R, 6S) -3-p-Methoxybenzyloxycarbonyl-1-methyl-6-[(R) -1-triethylsilyloxyethyl] -carba-2-penem) -2-ylmethyl IR ν (CHCl ₃ ) cm ^-1 : 3420, 3320, 1771, 1713, 1385,
1145 NMR δ (CDCl ₃ ) 200MHz ppm: 0.58 (q, J = 7.4Hz, 6H),
0.93 (t, J = 7.4Hz, 9H), 1.18 (d, J = 7.4Hz, 3H), 1.25 (d,
J = 6.2Hz, 3H), 1.43 (s, 9H), 3.17 (dq, J ₁ = 9.8Hz, J ₂ =
7.4Hz, 1H), 3.19 (dd, J ₁ = 6.2Hz, J ₂ = 2.8Hz, 1H), 3.80
(s, 3H), 4.14 (dd, J ₁ = 2.8Hz, J ₂ = 9.8Hz, 1H), 4.23 (d
q, J ₁ = 6.2Hz, J ₂ = 6.2Hz, 1H), 5.20 & 4.58 (ABq, J _AB = 1
3.2Hz, 2H), 5.19 (dd, J ₁ = 12.2Hz, J ₂ = 15.6Hz, 2H), 6.
88 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.6Hz, 2H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 654.

2) R ¹ = phenyl, R ² = H, R ³ =
((1S, 5R, 6S) -3-p-Methoxybenzyloxycarbonyl-1-methyl-6-[(R) -1-triethylsilyloxyethyl] -carb-2-penem)-
2-ylmethyl NMR δ (CDCl ₃ ) 200MHz ppm: 0.58 (q, J = 7.4Hz, 6H),
0.94 (t, J = 7.4Hz, 9H), 0.98 (d, J = 7.4Hz, 3H), 1.21 (d,
J = 6.2Hz, 3H), 1.43 (d, J = 8.2Hz, 9H), 2.62 (dq, J ₁ =
7.4Hz, J ₂ = 9.4Hz, 1H), 3.09 (dd, J ₁ = 5.8Hz, J ₂ = 2.8Hz,
1H), 3.80 (s, 3H), 3.86 (dd, J ₁ = 9.4Hz, J ₂ = 2.8Hz, 1
H), 4.19 (dq, J ₁ = 6.2Hz, J ₂ = 5.8Hz, 1H), 4.97 & 4.35 (A
Bq, J _AB = 17.0Hz, 2H), 5.15 (dd, J ₁ = 15.6Hz, J ₂ = 12.2H
z, 2H), 6.86 (d, J = 9.0Hz, 2H), 7.14 ~ 7.42 (m, 7H).

3) R ¹ = (4-diphenylmethoxycarbonyl-3-cephem) -7-yl, R ² = H, R ³ = 2
-Thienylmethyl IR ν (CHCl ₃ ) cm ⁻¹ : 3330, 1796, 1726, 1372, 1150 NMR δ (CDCl ₃ ) 200MHz ppm: 1.61 (s, 9H), 3.40, 3.52
(d. ABq, 2H, J _AB = 19.4Hz, J ₁ = 2.8Hz, J ₂ = 6.0Hz), 4.58
(d, J = 5.2Hz, 1H), 4.91 (dd, J ₁ = 5.2Hz, J ₂ = 9.4Hz, 1
H), 5.03 (s, 2H), 5.99 (d, J = 9.4Hz, 1H), 6.64 (dd, J ₁
= 2.8Hz, J ₂ = 6.0Hz, 1H), 6.95 (s, 1H), 6.90 ~ 7.50 (m,
13H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 642.

4) R ¹ = R ² = H, R ³ = (4-p-nitrobenzyloxycarbonyl-1-oxo-7- (2-
Thienylacetamido) -3-cephem) -3-ylmethyl (in order to transfer the double bond at the 2-position to the 3-position after the condensation reaction,
After conversion into 1-oxide by oxidation, physical constants were measured. The conditions of the oxidation reaction are shown in Reference Example 14 described later. ) Mp. 138-142 ° C IR ν (Nujol) cm ^-1 : 3360, 3270, 1786, 1725, 1350,
1152 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 1.41 (s, 9H), 3.75 &
3.83 (ABq, J _AB = 18.8Hz, 2H), 3.91 & 3.83 (ABq, J _AB = 1
5.4Hz, 2H), 4.86 & 4.52 (ABq, J _AB = 17.2Hz, 2H), 4.96
(d, J = 4.6Hz, 1H), 5.44 (dd, J ₁ = 14.4Hz, J ₂ = 16.0Hz, 2
H), 5.93 (dd, J ₁ = 4.6Hz, J ₂ = 8.2Hz, 1H), 6.94 ~ 6.99
(m, 2H), 7.38 (dd, J ₁ = 2.4Hz, J ₂ = 4.4Hz, 1H), 7.70 (s,
2H), 7.72 (d, J = 8.6Hz, 2H), 8.25 (d, J = 8.6Hz, 2H),
8.47 (d, J = 8.2Hz, 1H).

[Dehydration Condensation Using Secondary Alcohol] Example 4 (Pyrrolidinol Used as Alcohol)

[0084]

[Chemical 6]

Under the reaction conditions shown in Tables 7 and 8 below, pyrrolidinol was dissolved in a solvent (tetrahydrofuran (THF) or ethyl acetate (EtOAc)) to give triphenylphosphine (PPh ₃ ), dimethyl azodicarboxylate (DMAD) or azo. Dicarboxylate (DEAD) and oxycarbonylsulfamide compound (OCSD = R ⁴ OCONHSO ₂ NR ¹
Add R ² ) and stir. When the reaction solution is concentrated under reduced pressure, a condensed sulfamide having a structure in which the 4-position of the pyrrolidine ring is reversed from the starting material is obtained.

[0086]

[Table 7]

[0087]

[Table 8]

The physical constants of the product obtained above are shown below.

1) R ¹ = phenyl, R ² = H, R ³ = (2
S, 4S) -1- (p-Methoxybenzyloxycarbonyl) -2-methoxycarbonylpyrrolidin-4-yl, R ⁴ = t-butyl IR ν (CHCl ₃ ) cm ⁻¹ : 3340, 1745, 1702, 1361, 1144 NMR δ (CDCl ₃ ) 200MHz ppm: 1.55 (s, 9H), 1.81 to 2.39
(m, 2H), 3.00 ~ 3.40 (m, 2H), 3.48 & 3.71 (2s, 3H),
3.79 & 3.84 (2s, 3H), 4.06 ~ 4.20 (m, 1H), 4.45 ~ 4.7
0 (m, 1H), 4.85 ~ 5.14 (m, 2H), 6.80 ~ 6.95 (m, 2H), 7.
20-7.44 (m, 7H) mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 564.

2) R ¹ = R ² = H, R ³ = (2S, 4S)
-1-p-methoxybenzyloxycarbonyl-2-methoxycarbonyl pyrrolidine-4-yl, R ⁴ = t-butyl ^{_{IR ν (CHCl 3) cm -1}} : 3400, 1737, 1700, 1353, 1170 NMR δ (CDCl 3 ) 200 MHz ppm: 1.43 (s, 9H), 1.80 ~ 2.5
6 (m, 2H), 3.40 ~ 4.85 (m, 8H), 4.21 ~ 4.45 (m, 2H), 4.
92 ~ 5.20 (m, 2H), 5.20 ~ 5.50 (brs, 2H), 6.82 ~ 6.95
(m, 2H), 7.20 ~ 7.36 (m, 2H).

3) R ¹ = R ² = H, R ³ = (2S, 4S)
-1-p-methoxybenzyloxycarbonyl-2-methoxycarbonyl pyrrolidine-4-yl, R ⁴ = p-nitrobenzyl ^{_{IR ν (CHCl 3) cm -1}} : 3420, 1727, 1348, 1221 NMR δ (CDCl 3) 200 MHz ppm: 1.94 to 2.60 (m, 2H), 3.5
0 ~ 3.85 (m, 8H), 4.30 ~ 4.50 (m, 2H), 4.92 ~ 5.21 (m, 4H), 6.80 ~ 6.92 (m, 2
H), 7.20 ~ 7.34 (m, 2H), 7.49 (d, J = 8.6Hz, 2H), 8.21
(d, J = 8.6Hz, 2H).

4) R ¹ = R ² = H, R ³ = (2R, 4S)
-1-p-methoxybenzyloxycarbonyl-2-methoxycarbonyl pyrrolidine-4-yl, R ⁴ = p-nitrobenzyl ^{_{IR ν (CHCl 3) cm -1}} : 3424, 1701, 1610, 1347, 1122 NMR δ (CDCl ₃ ) 200 MHz ppm: 2.15 ~ 2.4 (m, 2H), 3.3
~ 3.6 (m, 1H), 3.57, 3.76 (2 × s, 3H), 3.80 (s, 3H),
3.7 ~ 3.95 (m, 1H), 4.25 ~ 4.5 (m, 2H), 4.9 ~ 5.3 (m, 5
H), 6.8-8.25 (m, 8H).

Example 5 (using cyclohexanol as alcohol)

[0094]

[Chemical 7]

Under the reaction conditions shown in Table 9 below, cyclohexanol was dissolved in tetrahydrofuran (THF) to give triphenylphosphine (PPh ₃ ), diethyl azodicarboxylate (DEAD) and oxycarbonylsulfamide compound (OCSD = t- Add BuOCONHSO ₂ NR ¹ R ² ) and stir. The reaction solution is concentrated under reduced pressure to give condensed sulfamide.

[0096]

[Table 9]

The physical constants of the product obtained above are shown below.

1) R ¹ = R ² = H mp. 79-80 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3410, 3310, 1701, 1372, 1148 NMR δ (CDCl ₃ ) 200MHz ppm: 0.99-2.16 (m, 10H), 1.5
6 (s, 9H), 4.15 (tt, J ₁ = 12Hz, J ₂ = 3.6Hz, 1H), 5.33 (s,
2H).

2) R ¹ = phenyl, R ² = H mp. 137 to 139 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3320, 1702, 1369, 1147 NMR δ (CDCl ₃ ) 200MHz ppm: 0.8 to 1.87 (m, 10H), 1.55
(s, 9H), 3.84 (tt, J ₁ = 12.0Hz, J ₂ = 3.6Hz, 1H), 7.18 ~
7.40 (m, 5H) Elemental analysis (C ₁₇ H ₂₆ N ₄ O ₄ S ₂ ) Calculated: C, 57.60; H, 7.39;
N, 7.90; S, 9.04 Experimental value: C, 57.78; H, 7.42; N, 7.94; S, 8.95.

[Reference Example] Reference Example 1 [Deprotection with CF ₃ COOH] The condensed sulfamide having a t-butoxycarbonyl protecting group obtained in 1) of Example 1 was mixed with 15 volumes of dichloromethane and 15 volumes of anisole. Dissolve, add 15 volumes of trifluoroacetic acid under ice cooling, stir for 50 minutes, remove cooling bath and stir for 1 hour. The reaction mixture was concentrated and the residue was crystallized from a mixture of ether-petroleum ether (1: 6),
Colorless crystals of benzylsulfamide are obtained. Yield: 9
0%.

Mp. 107-108 ° C IR ν (Nujol) cm ^-1 : 3330, 3260, 1336, 1151 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 4.07 (d, J = 6.4Hz, 2
H), 6.64 (s, 2H), 7.09 (t, J = 6.4Hz, 1H), 7.20 ~ 7.40
(m, 5H) Elemental analysis (C ₇ H ₁₀ O ₂ N ₂ S) Calculated: C, 45.14; H, 5.41;
N, 15.04; S, 17.22 Experimental value: C, 45.04; H, 5.42; N, 15.12; S, 17.10.

Reference Example 2 [Deprotection with CF ₃ COOH] 3 volumes of anisole and 5 volumes of trifluoroacetic acid were added to the condensed sulfamide having a t-butoxycarbonyl protecting group obtained in 8) of Example 2 at room temperature. After stirring for 30 minutes,
Concentrate under reduced pressure. When the residue was crystallized with dichloromethane,
(3S, 5S) -3-p-Methoxybenzylmercapto-5-sulfamidomethyl-2-pyrrolidone is obtained. Colorless crystals. Yield: 68%.

Mp. 132-134 ° C IR ν (KBr) cm ^-1 : 3370, 3345, 3245, 2900, 1695, 16
80, 1608 NMR δ (CD ₃ SOCD ₃ ) 200MHz ppm: 1.5 to 1.7 (m, 1H), 2.4
5 to 2.65 (m, 1H), 2.8 to 3.1 (m, 2H), 3.2 to 3.35 (m, 1H),
3.35 (s, 3H), 3.5 ~ 3.7 (m, 1H), 3.81, 3.96 (ABq, J = 1
2.7Hz, 2H), 6.61 (s, 2H), 6.68 (t, J = 6.6Hz, 1H), 6.8
8, 7.25 (2d, J = 6.6Hz, 2H × 2), 7.88 (s, 1H) Elemental analysis (C ₁₃ H ₁₉ N ₃ O ₄ S ₂ ) Calculated value: C, 45.20; H, 5.54;
N, 12.16; S, 18.56 Found: C, 44.97; H, 5.52; N, 12.10; S, 18.34.

Reference Example 3 [Deprotection with CF ₃ COOH] The fused sulfamide having t-butoxycarbonyl and a diphenylmethyl protecting group obtained in 3) of Example 3 was dissolved in a mixed solution of 6 volumes of dichloromethane and 6 volumes of anisole. While cooling with ice, 6 volumes of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 90 minutes. Ether and petroleum ether were added to the reaction solution, and the precipitated crystals were collected by filtration to give 7- [N- (2-
A pale yellow powder of thienylmethyl) sulfamoylamino] -3-cephem-4-carboxylic acid is obtained. Yield: 5
6%.

Mp. 62-63 ° C IR ν (KBr) cm ^-1 : 3250, 1770, 1715, 1337, 1145 NMR δ (CD ₃ OD) 200MHz ppm: 3.68 & 3.52 (ABX of AB
q), (2H, J _AB = 19.2Hz, J _AX = 2.8Hz, J _BX = 5.8Hz), 4.41 (d
d, J ₁ = 15.2Hz, J ₂ = 17.4Hz, 2H), 5.04 (d, J = 4.8Hz, 1
H), 5.31 (d, J = 4.8Hz, 1H), 6.62 (dd, J ₁ = 2.8Hz, J ₂ = 5.
8Hz, 1H), 6.95 (dd, J ₁ = 5.0Hz, J ₂ = 3.4Hz, 1H), 7.07 (d
d, J ₁ = 3.4Hz, J ₂ = 1.0Hz, 1H), 7.32 (dd, J ₁ = 1.2Hz, J ₂ =
5.0Hz, 1H) UV λ (MeOH) nm: 235.6 (ε11000) MIC μg / ml: Staphylococcus aureus JC-1 strain 6.3; S. epidermid
is 3.1.

Reference Example 4 [Deprotection with H ₂ ] The fused sulfamide having a p-nitrobenzyloxycarbonyl protecting group obtained in 2) of Example 1 was dissolved in 10 volumes of tetrahydrofuran to give 10% palladium-carbon. 0.2% by weight and stirred in hydrogen for 1 hour. The reaction solution from which the catalyst was filtered off was concentrated under reduced pressure, and the residue was crystallized from an ether-petroleum ether mixed solution to obtain colorless crystals of benzylsulfamide having the same physical constants as in Reference Example 1.
Yield: 77%.

Reference Example 5 [Deprotection with H ₂ ] The p-nitrobenzyl ester obtained in Reference Example 9 described below was catalytically reduced in the presence of 10% palladium-carbon in the same manner as in Reference Example 4 to give 7 -(2-thienylacetamido) -3-sulfamidomethyl-3-cephem-4-
A carboxylic acid is obtained. 20% total yield from Reference Example 9.

IR ν (Nujol) cm ⁻¹ : 1755, 1660, 1340,
1150 NMR δ (D ₂ O) 200MHz ppm: 2.76 & 2.96 (ABq, J _AB = 17.6
Hz, 2H), 3.16 ~ 3.32 (m, 4H), 4.44 (d, J = 4.6Hz, 1H),
4.95 (d, J = 4.6Hz, 1H), 6.34 ~ 6.41 (m, 2H), 6.68 ~ 6.7
3 (m, 1H) UV λ (H ₂ O) nm: 236 (ε12600) MIC μg / ml: Streptococcus haemolyticus C-203 strain 0.1; Streptococcus pneumoniae type I 0.2.

Reference Example 6 [Deprotection with Palladium] The condensed sulfamide having an allyloxycarbonyl protecting group obtained in 3) of Example 1 was dissolved in 10 volumes of benzene, and 0.3 equivalent of triphenylphosphine and 2-ethyl were added. 1.5 equivalents of ethyl acetate solution of hexanoic acid sodium salt and tetrakistriphenylphosphine palladium 0.02
Equivalents are added sequentially and stirred for 30 minutes at room temperature. The reaction solution is diluted with ethyl acetate, washed with water, dried, concentrated under reduced pressure, and toluene is added to the residue for crystallization to give benzylsulfamide pale yellow crystals having the same physical constants as in Reference Example 1. Yield: 64%.

Reference Example 7 [Deprotection with AlCl ₃ ] A 7.5 volume solution of p-methoxybenzyl ester of p-methoxybenzyl ester in dichloromethane described below was mixed with 6 equivalents of aluminum chloride in a mixed solution of 15 volumes of dichloromethane and 15 volumes of anisole. The solution was added at -55 ° C and stirred for 25 minutes. The reaction solution is poured into a solution of 18 equivalents of sodium acetate in 21 volumes of water. Separate the aqueous layer, wash with dichloromethane,
After desalting and concentrating, (1S, 5R, 6S) -6-
A colorless foam of [(R) -1-hydroxyethyl] -2-sulfamidomethyl-1-methylcarba-2-penem-3-carboxylic acid is obtained. Yield: 32%.

IR ν (KBr) cm ⁻¹ : 3300, 1745, 1325, 11
50 NMR δ (D ₂ O) 200MHz ppm: 1.14 (d, J = 7.4Hz, 3H), 1.2
9 (d, J = 6.2Hz, 3H), 3.34 (dq, J ₁ = 7.4Hz, J ₂ = 9.4Hz, 1
H), 3.44 (dd, J ₁ = 2.4Hz, J ₂ = 6.2Hz, 1H), 4.19 (dd, J ₁ =
9.4Hz, J ₂ = 2.4Hz, 1H), 4.24 (dq, J ₁ = 6.2Hz, J ₂ = 6.2Hz,
1H), 4.49 & 3.78 (ABq, J _AB = 15.6Hz, 2H) UV λ (H ₂ O) nm: 267.4 (ε4500) MIC μg / ml: Streptococcus haemolyticus C-203 strain 0.1; E. coli EC-14
Share 0.2.

Reference Example 8 [Deprotection with AlCl ₃ ] When p-methoxybenzyl ester obtained in Reference Example 12 to be described later is deprotected in a mixed solution of anisole and dichloromethane with aluminum chloride in the same manner as in Reference Example 7,
(1S, 5R, 6S) -6-{(R) -1-Hydroxyethyl] -2- (phenylsulfamoylamino) methyl-1-methylcarba-2-penem-3-carboxylic acid is obtained. Yield: 22%.

IR ν (KBr) cm ⁻¹ : 1730, 1665, 1405, 11
50 UV λ (MeOH) nm: 227.1 (ε8900), 271.4 (ε4200) MIC μg / ml: Streptococcus lactis JC-1 strain 0.2; Streptococcus pneumoniae type I
0.1.

Reference Example 9 [Deprotection with CF ₃ COOH] The fused sulfamide having a t-butoxycarbonyl protecting group obtained in 4) of Example 3 was treated in the same manner as in Reference Example 1 in a mixed solution of dichloromethane and anisole, Deprotection with trifluoroacetic acid gives 7- (2-thienylacetamide)-
3-sulfamidomethyl-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained. Reduction of this product according to the formulation of Reference Example 5 gives the corresponding free acid.

Reference Example 10 [Deprotection with AlCl ₃ ] (1S, 5R, 6S) -6-[(1R) -1-Hydroxyethyl] -2 [(3S, 5S) -5- (N-sulfamoyl-t -Butoxycarbonylamino) methylpyrrolidin-3-yl] thio-1-methylcarba-2-penem-3-carboxylic acid diphenylmethyl ester was treated with aluminum chloride in a mixed solution of dichloromethane and anisole in the same manner as in Reference Examples 7 and 8. Deprotection with (1R,
5S, 6S) -6-[(1R) -1-Hydroxyethyl] -2-[(3S, 5S) -5-sulfamidomethylpyrrolidin-3-yl] thio-1-methylcarba-2-
Penem-3-carboxylic acid is obtained.

IR ν (KBr) cm ⁻¹ : 3400, 1750 MIC μg / ml: Staphylococcus aureus JC-1 strain <0.003; Streptococcus haemolyticus C-203 strain <0.003.

Reference Example 11 [Deprotection with NaOMe] The fused sulfamide having an acetyl protecting group obtained in 4) of Example 2 was dissolved in toluene and 4.9 at -35 ° C.
2M-sodium methoxide in methanol was added,
Stir for 30 minutes. The reaction mixture is diluted with water, the aqueous layer is taken, acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. If the residue was crystallized from a toluene-hexane mixture, (2
S, 4S) -1-t-Butoxycarbonyl-2- (N-
Sulfamoyl-t-butoxycarbonylamino) methyl-4-mercaptopyrrolidine is obtained. Yield: 69
%. Colorless crystals.

Mp. 92 to 93 ° C. IR ν (CHCl ₃ ) cm ⁻¹ : 3380, 3220, 1718, 1680 NMR δ (CDCl ₃ ) 2OOMHz ppm: 1.2 to 1.5 (m, 1H), 1.42
(s, 9H), 1.54 (s, 9H), 1.82 (d, J = 6.2Hz, 1H), 2.5 ~ 2.7
(m, 1H), 4.09, 3.05 (ABX, J = 12.0Hz, J = 7.4Hz, J = 8.2H
z, 2H), 4.06, 3.62 (ABX, J = 15.0Hz, J = 10.8Hz, J = 3.2H
z, 2H), 4.2 to 4.6 (m, 1H), 6.08 (s, 2H) Elemental analysis (C ₁₅ H ₂₉ N ₃ O ₆ S ₂ ) Calculated value: C, 43.78; H, 7.10;
N, 10.21; S, 15.58 Found: C, 43.64; H, 7.10; N, 10.19; S, 15.34.

Reference Example 12 [Deprotection with HCl] The condensed sulfamide having a triethylsilyl protecting group obtained in 2) of Example 3 was dissolved in 14 volumes of acetonitrile, and 7.5 equivalents of acetic acid and concentrated hydrochloric acid were added at -30 ° C. Add 15 equivalents and stir for 1 hour 25 minutes. The reaction solution is poured into a mixed solution of sodium bicarbonate water and ethyl acetate, the organic layer is separated, washed with water, dried and concentrated under reduced pressure to give (1S, 5R, 6S) -2- (N-phenylsulfamoyl-Nt). -Butoxycarbonylamino) methyl-6-{(R) -1-hydroxyethyl]-
A colorless foam of 1-methylcarba-2-penem-3-carboxylic acid p-methoxybenzyl ester is obtained. Yield: 74%.

IR ν (CHCl ₃ ) cm ⁻¹ : 3340, 1770, 1715,
1369, 1147 NMR δ (CDCl ₃ ) 200MHz ppm: 1.03 (d, J = 7.2Hz, 3H),
1.29 (d, J = 6.2Hz, 3H), 1.42 (s, 9H), 2.66 (dq, J ₁ = 7.2Hz, J ₂ = 8.8Hz, 1H), 3.1
5 (dd, J ₁ = 2.6Hz, J ₂ = 6.2Hz, 1H), 3.80 (s, 3H), 3.88 (d
_{d, J 1 = 8.8Hz, J} 2 = 2.6Hz, 1H), 4.20 (dq, J 1 = 6.2Hz, J 2 =
6.2Hz, 1H), 4.98 & 4.35 (ABq, J _AB = 17.0Hz, 2H), 5.17
(dd, J ₁ = 12.2Hz, J ₂ = 23.2Hz, 2H), 6.87 (d, J = 9.0Hz, 2
H), 7.12 to 7.41 (m, 9H) mass spectrometry (SIMS) m-NBA m / z: [M +
H] ⁺ 616.

Reference Example 13 [Deprotection with HCl] The condensed sulfamide having a triethylsilyl protecting group obtained in 1) of Example 3 was desilylated with acetic acid-concentrated hydrochloric acid in acetonitrile in the same manner as in Reference Example 12. If it becomes,
(1S, 5R, 6S) -2- (N-sulfamoyl-t
-Butoxycarbonylamino) methyl-6-[(R)-
A colorless foam of 1-hydroxyethyl] -1-methylcarba-2-penem-3-carboxylic acid p-methoxybenzyl ester is obtained. Yield: 79%.

IR ν (CHCl ₃ ) cm ⁻¹ : 3420, 1770, 1713,
1369, 1147 NMR δ (CDCl ₃ ) 200MHz ppm: 1.19 (d, J = 7.4Hz, 3H),
1.32 (d, J = 6.2Hz, 3H), 1.44 (s, 9H), 3.21 (dq, J ₁ = 9.8
Hz, J ₂ = 7.4Hz, 1H), 3.24 (dd, J ₁ = 2.8Hz, J ₂ = 6.2Hz, 1
H), 3.80 (s, 3H), 4.18 (dd, J ₁ = 9.8Hz, J ₂ = 2.8Hz, 1H),
4.23 (dq, J ₁ = 6.2Hz, J ₂ = 6.2Hz, 1H), 5.19 & 4.57 (AB
q, J _AB = 17.2Hz, 2H), 5.21 (dd, J ₁ = 12.2Hz, J ₂ = 21.2Hz,
2H), 5.43 (s, 2H), 6.89 (d, J = 8.6Hz, 2H), 7.38 (d, J
= 8.6Hz, 2H) Mass spectrometry (SIMS) m-NBA m / z: [M + H] ⁺ 540.

Reference Example 14 [Oxidation with m-CPBA] The 1-position sulfide 2-position double bond isomer produced in 4) of Example 3 was dissolved in a mixed solution of 15 volumes of dichloromethane and 3 volumes of methanol, and the mixture was cooled with ice. Add 1.5 equivalents of 80% metachloroperbenzoic acid and stir for 30 minutes. Dimethyl sulfide is added to the reaction mixture, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and water, and dried. The solution was concentrated under reduced pressure to give 7- (2-thienylacetamido) -3- (N-sulfamoyl-t.
-Butoxycarbonylamino) methyl-3-cephem-
A colorless powder of 4-carboxylic acid p-nitrobenzyl ester 1-oxide is obtained. The physical constants of the product are shown in 4) of Example 3.

Reference Example 15 [Reduction with AcCl-KI] The oxide obtained in Reference Example 14 was dissolved in 12 volumes of acetone, 10 equivalents of potassium iodide and 6 equivalents of acetyl chloride were added at -35 ° C, and the mixture was stirred for 50 minutes. . The reaction mixture was washed with aqueous sodium hydrogen carbonate and water and concentrated under reduced pressure to give 7- (2-thienylacetamido) -3- (N-sulfamoyl-t-butoxycarbonylamino) methyl-3-cephem-4-carboxylic acid p-nitrobenzyl. An ester is obtained. Colorless powder. Yield: 55%.

Mp. 108-124 ° C IR ν (CHCl ₃ ) cm ⁻¹ : 3400, 1786, 1722, 1688, 1147 NMR δ (CDCl ₃ ) 200MHz ppm: 1.51 (s, 9H), 3.55, 3.40
(ABq, J = 18.2Hz, 2H), 3.86 (s, 2H), 5.03, 4.66 (ABq, J
= 16.8Hz, 2H), 4.96 (d, J = 4.8Hz, 1H), 5.32 (s, 2H),
5.39 (s, 2H), 5.88 (dd, J ₁ = 4.8Hz, J ₂ = 9.4Hz, 1H), 6.3
5 (d, J = 9.4Hz, 1H), 6.98 ~ 7.30 (m, 3H), 7.56, 8.21 (2
d, J = 9.0Hz, 2H × 2) Elemental analysis (C ₂₆ H ₂₉ O ₁₀ N ₅ S ₃ ) Calculated value: C, 46.76; H, 4.37;
N, 10.49; S, 14.40 Found: C, 46.70; H, 4.52; N, 10.67; S, 14.37.

[0126]

According to the present invention, an alcohol is reacted with an oxycarbonylsulfamide compound in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative, and dehydration condensation is carried out under mild neutral conditions. With the new reaction,
Sulfamides can be manufactured. As described above, the synthesis of the sulfamide compound, which required 4 to 5 steps in the conventional method, was shortened to two steps of dehydration condensation reaction and deprotection reaction which can be carried out under mild neutral conditions. Particularly when a primary alcohol is used as a raw material, the target sulfamide can be efficiently and easily synthesized in high yield.

The obtained sulfamides are physiologically active substances (various substances having physiological actions, beta-lactam antibacterial agents, antipyretics, analgesics, sweeteners, sleeping agents, anticonvulsants, etc.).
It is useful for preparing these because it corresponds to the partial structure of.

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Claims (1)

[Claims] 1. A method for producing sulfamides, which comprises a step of dehydration-condensing an alcohol and an oxycarbonylsulfamide compound in the presence of a trivalent phosphorus compound and an azodicarboxylic acid derivative.