JPS61277673A - Novel thiazolidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is lower alkyl; R2 is a protecting group of COOH). EXAMPLE:A compound expressed by formula II. USE:An intermediate for compounds having penam ring, e.g. penicillins. PREPARATION:A compound expressed by formula II or III is reacted with readily available cysteamine, etc. as a starting material in an inert solvent while stirring to afford the aimed compound expressed by formula I. The above- mentioned compound is hydrolyzed with concd. hydrochloric acid to give a 5-lower alkyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane hydrochloride, which is, without isolation, treated with triphenylphosphine and 2,2-dipyridyl disulfide in acetonitrile to afford the aimed individually stable compound, having the penam ring expressed by formula IV and useful as an intermediate for pen icillins.

Description

[Detailed description of the invention] The present invention relates to novel thiazolidine derivatives.

More specifically, the present invention relates to thiazolidine derivatives represented by general formula (I).

R blind (in the formula, R means a lower alkyl group, R2 means a protecting group for a carboxyl group) The thiazolidine derivative represented by the general formula (I) of the present invention is a new compound and has various penam rings. It is used as an intermediate for the synthesis of compounds.

Although many methods are known for chemically synthesizing compounds having a penum ring such as penicillins, there are not many methods that are suitable for industrial production in terms of the number of synthesis steps or treatment operations.

As a result of intensive research into a method for synthesizing a compound having a penum ring, the present inventors have found that the thiazolidine derivative represented by the general formula (I) of the present invention can be produced in just a few steps using an easily available raw material such as cysteamine as a starting material. What we can manufacture;
They discovered a method for obtaining a penum ring-containing compound from the compound of general formula (I) by easy means, and conducted further studies to complete the present invention.

The thiazolidine derivative represented by the general formula (I) of the present invention can be synthesized, for example, according to the two methods A) and B) shown below.

(II) From compound (n) of reaction formula A) and cysteamine, compound (
Reaction for producing I) and compound (In) of reaction formula B)
The reaction for producing compound (I) from and cysteamine is similar to that described above, and is easily carried out by stirring in an inert solvent. Note that when an acid salt of cysteamine, such as hydrochloride, is used as a raw material, it is preferable to react in the presence of a base, such as an organic base such as triethylamine.

In the compound represented by the general formula (I) of the present invention, Rt
The lower alkyl group represented by is, for example, an alkyl group having 1 to 3 carbon atoms, and specifically, a methyl group, an ethyl group, a propyl group, etc.

The protecting group for the carboxyl group represented by R2 is not particularly limited as long as it is inert during the reaction A) or B), but it is usually a lower alkyl group such as a methyl group or an ethyl group.

The compound represented by the general formula (I) of the present invention is easily converted into a compound having a penum ring represented by the general formula (fV).

(In the formula, R1 means the same as above) General formula (I)
The compound represented by the general formula (■) can be produced from the compound represented by, for example, by subjecting the general formula (I) to a hydrolysis reaction using concentrated hydrochloric acid to form 5-lower alkyl-7-oxo-4-thia-
This is carried out by converting 1-azabicyclo[3,2,0)hebutane into a hydrochloride salt, and then treating this product with triphenylphosphine and 2,2-dipyridyl disulfide in acetonitrile without isolation and purification.

The compound represented by this general formula (rV) is itself stable. Furthermore, the 6-position of the penam ring is active in various reactions and various substituents can be introduced therein, and it can also be used as a synthetic intermediate for other penicillins.

EXAMPLES The present invention will be explained in more detail by giving examples below.

Compound (1) 0.981 g (0.01 mol) cysteamine 1.138 g (0.01 mol) and triethylamine 1. Olg (0.01 mol) in methanol 30m
Stir in 1 at room temperature for 20 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 5:1) to obtain 1.02 g of compound (2).
get.

Mass spectrum m/z: 175 (M), 16
0IR spectrum (CHCI): 3480,17
30cm-'NMR spectrum (CDCI) δ
: 1.85 (3H.

s), 2.49 (IH+brs)+2.
88 (2H+s).

2.93-3.57 (4H, m), 3.71 (3H
,s) Example 2゜ Compound (3) 2.32 g (0.02 mol), cysteamine hydrochloride 2.27 g (0.02 mol), triethylamine 2.02 g (0.02 mol) and methanol θOm
Compound (2) 2 was prepared in the same manner as in Example 1 using
．． Obtain 98g. The physical properties of this product were consistent with those obtained in Example (1).

The following procedure was carried out in the same manner as in Example 1 using 2.803 g (0.02 mol) of compound (4), 2.272 g (0.02 mol) of cysteamine hydrochloride, 2.02 g (0.02 mol) of triethylamine and 50 ml of methanol. Treated compounds (
5) 2. Obtain 35 g of E.

Mass spectrum m/z: 189 (M), 18
01R spectrum (CHCI3): 3340-173
0cm NMR spectrum (CDCI) δ:
0.99 (3H.

t), t, 92(2H,Q), 2.83(IH
,brs).

2,77~3.53 (4H,m), 2.83
(2H,s).

Reference Example 1 Compound (2) obtained in Example (1) 0.584 g (
3.33 mol) was added dropwise with 10 ml of 1-hydrochloric acid under water cooling, and the mixture was stirred for 30 minutes. Then, 5 ml of water is added dropwise, and the mixture is stirred at room temperature for 12 hours. The aqueous hydrochloric acid solution is distilled off under reduced pressure below 20"C, and the resulting residue is subjected to the next reaction without purification.

Triphelphosphine 1.049 g (3,99 mmol), 2,2-dipyridyl disulfide o, sstg
(3,99 mmol) and a solution of the above residue in 330 ml of acetonitrile was added 0.370 g of triethylamine.
(3.87 mmol) and stirred at room temperature for 3 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 0.144 g of compound (8).

Mass spectrum m/z: 143 (M), 115.
1011R spectrum (CHCI): 176
5cm-'NMR spectrum (CDCI) δ:
1.7g (3H.

s), 2.84-3.40 (3H, m), 3.
2E3 (2H.

s), 4.13 (IH, ddd, J = 3.8
．． 5.8゜11.4Hz) Reference Example 2゜Compound (5) obtained in Example 3 0.5g, a Hydrochloric acid 1
After hydrolyzing in the same manner as in Reference Example 1 using 0ml and 3ml of water, 0.832g of triphenylphosphine
The compound (7 ) 0.087g 78ru.

Mass spectrum m/z: 157 (M), 129.
115IR spectrum k (CHCI): 17
85cm-'NMR spectrum (CDCI) δ
: 1.05 (3H.

t) + 1.99 (2H, q), 2.80~3
．． 52 (3H.

m), 3.19 (2H, s), 4.14 (IH
,ddd.

Claims (1)

[Claims] A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 means a lower alkyl group, and R_2 means a protecting group for a carboxyl group).