JPS59152389A - Preparation of sulfenimine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a synthetic intermediate of antibiotic substance, in high yield, by the electrolytic reaction of beta-lactam compound with a disulfide in a water-containing organic solvent in the presence of a halide salt. CONSTITUTION:The objective compound of formula IV is prepared by the electrolytic reaction of the beta-lactam compound of formula I [>Y is group of formula IIor III (R<1> is H or carboxyl-protecting group)] with the disulfide of formula R<2>-S-S-R<2> [R<2> is (substituted) heterocyclic aromatic group] in a water-containing organic solvent in the presence of a halide salt (preferably a bromide salt), preferably with electrical quantity of 2-3F per 1mol of beta-lactam compound.

Description

[Detailed Description of the Invention] The present invention is useful! :, 7 derivative production method, more specifically the general formula [wherein R2 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaromatic ring group]. YR1 represents a hydrogen atom or a carposi acid protecting group. This invention relates to a novel method for producing a sulfenimine derivative represented by

The sulfenimine derivatives represented by the above general formula (1) include new compounds that have not been published in the literature, and these derivatives are used for the production of antibiotics such as C-6-substituted penicillis or C-7-substituted cepha-O sporisci. It is useful as an important synthetic intermediate. For example, according to the method shown in the reaction formula below, the sulfenimine derivative represented by the general formula (1) can be prepared by a simple procedure of treatment with methanol under a base or acid catalyst. O Suborishi or C-
It can be converted to benicilisi substituted with meth+cy at the 6th position.

(1) (2) (3) [In the formula, R2 and Y are the same as above. RC- represents an acyl group 1. ] In the present invention, the carboxylic acid protecting group represented by R1 includes, for example, a benzyl group, a p-nido phenylmethyl group, a diphenylmethyl group in p-meth, a diphenylmethyl group, an allyl group, a methyl group, 2,2゜2 Examples include -trichlorethyl group, 2-dichloroethyl group, and the like. Examples of the substituted or unsubstituted aryl group represented by R2 include a phenyl group, a P-nitrophenyl group, a P-methylphenyl group, a P-methylphenyl group, and a pentafluorophenyl group. Also included are substituted or unsubstituted heteroaromatic silyl groups.

According to the method of the present invention, the sulfenimine derivative represented by the above general formula (1) has the general formula [wherein] Y is the same as above. ] and a β-lactam compound represented by the general formula % formula % (5) [wherein R2 is the same as above. ] in the presence of a halide salt in a water-containing organic solvent. According to the method of the present invention, the desired sulfenimine derivative (1) can be produced in good yield directly from disulfide, which is stable and easy to handle.

General formula (4) used as a raw material in the method of the present invention
) The ratio of the β-lactam compound represented by the formula (5) to the disulfide represented by the general formula (5) is not particularly limited and can be appropriately selected from a wide range, but the ratio of the latter to the former is usually 0.5 to 0.5. , 4, preferably from equimolar to 1.5 times the molar amount. The water-containing organic solvent used in the method of the present invention does not necessarily have to be a homogeneous solvent, and preferably a heterogeneous solvent consisting of two layers of water and an organic solvent is used. Specific examples of organic solvents used as the water-containing organic solvent include, for example, methylene chloride, chloroform, carbon tetrachloride, dichloromethane paraffins such as dichloromethane, aromatic hydrocarbons such as toluene, toluene, etc. Nitriles such as 'jO dionitrile and at+-nitrile, lower carbodiic acid esters such as ethyl acetate, methyl acetate, and ethyl f-acid, alcohols such as methanol, ethanol, and tertiary ditanol, diethyl ether Examples include ethers such as , tetrahydroflag, and diochusashi, and one solvent selected from these solvent groups or a mixture of two or more solvents may be used. Preferably, a halogenated salt is used, and as the halide salt to be added, for example, a chlorine salt, a bromine salt, or an iodine salt is used, and a bromine salt is preferably used. Specific examples of bromine salts used include LiBr%NaBr, K
Examples include metal salts such as J3r, MgBr2.1)aBr2. The amount of halide salt to be added is not particularly limited and can be appropriately selected within a wide range, but is usually 0.1 to 5 times the amount of β-lactam derivative (1), preferably 0.5 to 2 times. It is better to use double.

As the electrolytic cell, a single cell without a diaphragm used in a normal electrolytic reaction is used, but a separate cell may also be used. Commercially available electrodes can be used as the electrodes, but platinum electrodes, carbon electrodes, platinum-surface-treated titanium electrodes, lead oxide electrodes, and the like are preferably used. The amount of current applied is not necessarily constant depending on the shape of the reaction tank and the type of solvent, but
Usually 2.5 to β-lactam compound (1)
-15F/°C, preferably 3-6F/E. Further, the current density is usually kept constant in the range of 1 rnA to 500 mA, but there is no particular limitation. Further, in the present invention, electrolysis can be performed at a terminal voltage in the range of 2 to 50V. The temperature during the electrolytic reaction of the present invention varies depending on the reaction substrate, solvent, etc. used, but it is carried out at 0 to 50°C, preferably 5 to 30°C.

The obtained product can be purified by a method such as column chromatography or recrystallization after performing a conventional extraction operation.

The sulfene derivative represented by the above general formula (1) of the present invention can also be produced by the following method. That is, Y in the general formula is the same as above. ] and a β-lactam compound represented by the general formula % formula % (5) [wherein R2 is the same as above. ] in the presence of a halide salt in a water-containing organic solvent to form a disulfide represented by the general formula [where R and >y are the same as above. ] is obtained, and then the obtained general formula (6) is obtained.
The compound of the present invention represented by the general formula (1) is produced by electrolytically reacting the sulfenamide derivative represented by the formula (1).

The electrolytic reaction between the β-lactam compound of the general formula (4) and the disulfide of the general formula (5) can be carried out under the above-mentioned electrolytic reaction conditions except that the amount of current applied is reduced. The amount of current to be applied varies depending on the shape of the reaction tank and the type of solvent, but it is usually 2 to 10 F/7, preferably 2 to 3 F/7 per mole of β-lactam compound (4). It is preferable to set it as F/'fnil.

As the amount of current applied increases, the amount of the sulfene derivative represented by the general formula (1) increases.

The electrolytic reaction of the sulfunidiamide derivative represented by the general formula (6) to be produced next can be carried out under the same electrolytic conditions as the above-mentioned sulfuric acid derivatives (1), (7) & formation, except that disulfide is not added.

Examples are given below.

Example l (4σ) (lα) 6(β)-aminopenicillacic acid benzyl ester (44
) 23"i' (0,076 mmol), phenyl disulfide 22mt (0-lenm, ol) and magnesium bromide 23W (0,13 mmol) were weighed, and 23"i" (0,076 mmol), phenyl disulfide 22mt (0-lenm, ol) and magnesium bromide 23W (0,13 mmol) were weighed, and 23"i" (0,076 mmol) and methanol ( 0
, 51R7 and water (2-) are added. Two platinum electrodes (l x I-5 gJ) were inserted into this, and electrolysis was carried out by applying a current of l Q mA for 50 minutes at room temperature while stirring vigorously. The amount of electricity to be applied is 4 p for 6(β)-amino disilicic acid base-J diester (4α).
/ mol. After the reaction mixture was allowed to stand for several minutes, the organic layer was removed, washed twice with saturated brine, and dried over Nα2SO4. After distilling off the solvent under reduced pressure, the residue was chromatographed on silica gel (developing solvent: H + Sacy ethyl acetate 50/
1), 25.6η (yield 82%) of 6-phenylsulfene trinobenicilisic acid benzyl ester (lα) was obtained.

JR spectrum (CHCl3) 3500.3059
．． 1779.1745.1649, +582+1771
11-NMR spectrum (CDC1 Eagle) δ1.44 (,
r, 3ff), 1.55 (ε, 3H), 5.21 (J.

2H), 5.75(j, IH), ? -36 (8, 5
H), 7, 18-7.69 (m, 5H) Elemental analysis Calculated value as C15H□803N2s = (
'61.13; H4,89 analysis value:, C
61,09; H4,96 Examples 2 to 6 The same method as in Example 1 was carried out except for the conditions shown in Table 1.

Example 7 (4α) (lh) 6(β)-aminobenicillacic acid besidyl ester (4(
E) 21.5”? (0.07mmol), (2
-besidithiazylyl),; sulfide 24.5■ (0,
073 mmol) and magnesium bromide hexahydrate 26■
(0.09 mmol) and add dichlormeth, y (2 m/), methanol (0.5 m/) and water (2 m/).
d) Add. Next, platinum electrode (I x 1.5i)
Insert 2 sheets and stir vigorously for 10 minutes at room temperature.
Electrolysis is carried out by applying a current of m, 4 for 90 minutes. The reaction mixture was treated in the same manner as in Example 1 to obtain 6-(2-besidithiazolyl)sulfenysinopenicilisic acid besidyl ester (i) (28 ml) (yield: 84%).

JR spectrum (cllct3) l 781.17
41.1465 CrCrn-11HN? Spectrum (cnct3) 1.44 (S
, 377'), 1.54 (,9, 3#), 4.6
7 (#.

177), 5.19 (5,2H), 5.82 (1,
l, Z7'), 7.34 (-?, 5H), 7.
18-7.98 (m, 41 elemental analysis C2211□9N
Total q-value as 303S3: C56,25; H4
,08% Analysis value: C56,09; H4,38 Example 8 (4h) (IC)7(β)-
Atrinocephalosporosporic acid salt, 7-dyl ester (4b)
35-535-5WCO-12), phenyl disulfide 28w1 (0.13mm01) and sodium bromide I3f (0.125mm0L),
To this, dichloromethane (2d), methanol (0.5m
1) and water (2 mA'). Next, platinum electrode (1
, 5xlCJ) and stir vigorously.
Electrolysis is performed by applying a current of OmA for 110 minutes. The amount of electricity applied was equivalent to 6 p/mol for 7(β)-aminocephalosporic acid besidyl ester (4 h). The reaction mixture was treated as in Example 1 to obtain 7-phenylsulfeniminocephalosporic acid benzyl ester (le).
33cm (yield: 71cm) was obtained.

IR spectrum (CHCl3) 2920.1779
．． 1725.1585crn 1ENMR spectrum (CDCl2) δ2. II (S, 311>, 3.15(d,
1j7. J=18. MZ), 3.35 (d, lH, J
=1811χ), 5.19(-r, Iff), 5.
27 (&, 2H), 7.33 (!, 5
H), 7, 12-7.63 (m, 5H) Elemental analysis Calculated value as C□2H□8N203S2: C61,
43; H4, 42% Analysis value: C61,52; H4, 52% Example 9
~12 The same procedure as in Example 8 was carried out except for the conditions shown in Table 2.

Example 13 (4b) (6α) CO2CH2Ple(ld) 7(β)-aminocephaosporic acid besidyl ester (412) 33W (0,2I mm6L) and (
2-hezothiazolyl) disulfide 11k(0,I
1 mmol) and sodium bromide l 1.5 W (
0,1171LmOt), and add ;
Lumeta, 7 (2 go), methanol (0.5 ml) and water (
Add 2M). Next, insert a platinum electrode (IXl, 5 cJ) and, while stirring vigorously, apply a current of 1QmA to 105
Electrolyze by applying electricity. The amount of electricity applied corresponds to 6F/mol for 7(β)-aminocephalosporinic acid'J diester (4b). The reaction mixture was treated in the same manner as in Example 1 to give 7(β)-(2-pendithiacyl)
Sulfenaminocepha O sporic acid besidyl ester (6α) 34.51 ng (yield 67 ng) and 7-(2-pendithiacilyl)sulfunidiiminocepha O sporic acid besidyl ester (Id) 14 ng (yield 28 %)was gotten.

7(β)-(2-pendithiacilyl)sulfenaminocephalosporic acid besidyl ester (6α): IR spectrum (ClIC13) 3342.298+, 1
781,1722.1639crr! -1'HNMR spectrum (CDC13) δ2. +1 (7,3H), 3.22 (d,, Iff,
J=18ffz), 3.40C(L, IH, J=18H
1), 4.29Cc1.2E'.

J=9Hz), 4.72-5.07 (m, 2H)
, 5.23 (z, 2H), 7.32 (J= ,
5H), 7, 13-7.95 (711, 4H) Elemental analysis Calculated value as C22H engineering, N303S3: C5
6,25; H4,08% Analysis value: (?56-52; H4,1O thia-(
2-Pendithiacilyl) sulfethiminocephalosporic acid Beni J! ester (ld): JR (spectrum) 2920.1779.1725.1585
cm-1 1HNMR (CDC13) δ2.1+ (j, 5H), 3.15C (L, IH, x
sBz), 3-35 (d, lH, 18Hz), 5
．． 19 (j, IH), 5.27 (,?, 2H),
7.33 (5,5H), 7,12-7.63 (m
, 5H) Elemental analysis Calculated value as C2□H□8N203S2 2061. +3; H4, +2 coefficient analysis value: C61,52; H4,52% Example] 4 (4α) (6b) 6(β)-Atrinobenicilacyic acid benzyl ester (4
α) + 24 ”? (0-4 mmol) and 2-pendithiasilyl disulfide l 37v (0,4
1mm0L) and magnesium bromide 74v (0-1
Weigh out Lmol) and add dichlormethane (1(
1+/), methanol (2.5 m/), and water (10 ml) were added. Next, two platinum electrodes (2 x 1.5 i) were inserted, and a current of 30 mA was applied for 50 minutes at room temperature while stirring vigorously. Electrolysis was performed.The amount of electricity applied was 6 (
β)-Aminopenicilisic acid besidyl ester (4α) corresponds to 3 p/mol. The reaction mixture is treated in the same manner as in Example 1 to obtain 6(β)-(2-pendithiacyl)sulfethyaminobenicilasic acid besidyl ester (6b) 176Tq (yield 92%).

IR spectrum (CHCl3) 3290.3050
．． 3019.1780.1740.1495crn-1
'HNMR spectrum (cnct3) δ1.46 (j, 3j!7), 1.61 (,?
, 3H), 4.24 (d.

lH, J=10H1), 4.50 (7,1M), 4.7
6CdcL, IH, J = 10H1, 4H1), 5.16
Cs, 2M), 5.63 (', IH, J=477z)
, 7, 14-7.94 (m, 9H) elemental analysis C
Calculated value as 22H2□03N3S: C56,01
; II 4-49% Analysis value: C55,77; H'1.47% Example
15-19 The same procedure as in Example 14 was carried out except for the conditions shown in Table 3.

Example 20 (6h) (Ih) 6(β)-(2-besidithiazylyl)sulfethyaminopenicilasic acid benzyl ester (6b) 28,5''
Q (0.06 mmol) and magnesium bromide hexahydrate 26 m? (0.09 mrnol) was weighed out, dichloromethane (2 ml) and methanol (0.
5d) and water (27nl). Next, platinum electrode (1
, 5XI Cd), and electrolysis is performed by applying a current of 10 mA for 20 minutes at room temperature while stirring vigorously. The reaction mixture was treated as in Example 1 to give 6-(
23 my (yield: 881%) of besidyl 2-besisothiazyl)sulfethiminopenicillascilate (IA) was obtained.

The NMR and JR spectra of the product completely matched those of the standard sample obtained in Example 7.

Example 21 C“02CII2ph (6a) Co2CH2Ph (Id) 7(β)-(2-Besidithiazolyl)sulfunidiaminosepha O sporic acid besidyl ester (6cL) 25
-5 W (0.06 mmol) and 8# sodium bromide (0.08 mm01) were weighed, and to this were added diluted salt (2 units), methanol (0.5 ml), and water (2 units). . Next, platinum electrode (IXl, 5C
J) Insert two sheets and stir vigorously.lQm,,'
Electrolysis is performed by applying a current of ( ) for 54 minutes.The amount of electricity applied is 7
Corresponds to (5 p/mol) for (β)-(2-besidithiazylyl)sulfenaaminocephalosporic acid besidyl ester (4d,). The reaction mixture was prepared in Example 1.
When treated in the same manner as 7-(2-be,'/sothiazolyl)
15 μm (yield: 62 μm) of sulfeniminocephalosporosporic acid benzyl ester (1d) is obtained.

The JR,'H NMR spectrum of product (1d) completely matched the spectrum of the standard product obtained in the example.

(that's all)

Claims (1)

[Claims] ■ A general formula is shown. Here, R1 represents a hydrogen atom or a carposi acid protecting group. ] A β-lactam compound represented by the general formula % Formula % [In the formula, R2 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaromatic ring group. ] in the presence of a halide salt in a water-containing organic solvent to form a disulfide represented by the general formula [where R2 and >y are the same as above]. ] Sulfure υi! is characterized by obtaining the sulfure derivative represented by ! Method for producing rainbow derivatives. (2) The method according to claim 1, wherein R2 is a substituted or unsubstituted 2-besizothiazylyl group or a substituted or unsubstituted phenyl group. (2) The method according to Claim 1J% or Claim 2, wherein the halide salt is a bromine salt. (2) The method according to any one of claims 1 to 3, wherein the water-containing organic solvent is a heterogeneous solvent consisting of two layers: an aqueous layer and an organic layer.