JPS58109470A - Preparation of 2-azetidinone derivative - Google Patents

Abstract

PURPOSE:To prepare the titled substance useful as a synthetic raw material of carbapenem compound which is an antibacterial agent, by removing the protecting group of a specific amino compound having a protecting group, and cyclizing the resultant beta-amino acid. CONSTITUTION:The chain amino acid compound of formulaIis converted to the corresponding beta-amino acid by the removal of the amino-protecting group, and then cyclized to obtain the objective compound of formula III. The removal of the amino-protecting group of the compound of formulaIis carried out by dissolving the compound in a mixture of methanol and water, adding activated zinc powder thereto, and heating in nitrogen gas stream under refluxing. The cyclization of the compound of formula II can be achieved by adding water and chloroform solution of methanesulfonyl chloride successively to a mixture of sodium bicarbonate and tetrabutyl ammonium sulfate, and stirring the mixture at room temperature in argon gas stream.

Description

[Detailed description of the invention] The present invention relates to a method for producing 2-azetidinone derivatives.

In recent years, with the discovery of chenamycin having useful biological activity, many attempts have been made to synthesize carbapenem compounds useful as antibacterial agents.

As is clear from the structural formula of carbapenems, there are various optical isomers, but it is known that optically active forms with a specific three-dimensional structure are useful as antibacterial agents.

However, since conventionally obtained carbapenems are often racemic, useful optically active forms cannot be obtained unless they are resolved through more complicated steps.

The inventor of the present invention, after completing various researches in an attempt to obtain an optically active substance having a specific steric structure without performing resolution, discovered a method of ring-closing a chain amino acid compound having a desired specific steric structure under mild conditions. They succeeded in obtaining a 2-azetidinone derivative that retained its three-dimensional structure, and completed the present invention. .

The compound represented by (hereinafter referred to as compound l) is
The corresponding β-amino acid (hereinafter referred to as compound ■) is obtained by removing the protective group of the amine group, and then the compound represented by (hereinafter referred to as compound ■) is obtained by ring-closing this. A method for producing a 2-azetidinone derivative, characterized by:

In the present invention, removal of the protecting group of the amine group of the starting material Compound I is carried out by converting Compound I into methanol-water (v/v
8: 2) Obtained by dissolving in a mixed solvent, adding active zinc powder to it, purifying it in a nitrogen stream, washing with water until the aqueous layer becomes neutral, and then washing with anhydrous methanol. I can do it.

By removing the protecting group of the amino group of compound 1, A β-amino acid (compound ■) represented by is obtained.

Ring closure of compound (1), ie, production of compound (2), can be carried out as follows. Namely, compound ■, water to a mixture of sodium bicarbonate and tetrabutylammonium sulfate.

After sequentially adding a chloroform solution of methanesulfonyl chloride, the compound
ring closure, and the resulting compound III can be isolated from the organic solvent layer by a conventional method.

The starting material compound I is J,C! , S, Chem'
, Comm.

It can be produced from the compound represented by the formula RI (hereinafter referred to as compound 2) described on page 616 of ``Compound 2'', through the steps illustrated below.

=5-6- The details of this step will be specifically explained in the reference example below.

According to the method of the present invention, a carbapenem compound having an optically active structure azabicyclo(3,2#O)-7'f ring (for example, azabicyclo(3,2
, 0) Hept-2-ene-2-carboxylic acid) To efficiently produce compound ■ useful as a raw material for synthesizing hept-2-ene-2-carboxylic acid while maintaining the three-dimensional structure of the raw material compound without going through complicated steps such as optical resolution. I can do it.

Hereinafter, the present invention will be specifically explained with reference to reference examples illustrating the production of Compound 1 from Compound 1, and examples illustrating the production of Compound 1 from Compound I.

Reference Example 1 (Production of Compound V from Compound ■) Under water cooling, lactone compound IV7.18? (20mm
Concentrated hydrochloric acid 06- was added dropwise to the methanol solution (280-) of ot), the mixture was then returned to room temperature, and after stirring for 6 hours, methanol was distilled off under reduced pressure.

The resulting residue was washed with n-hexane to remove by-produced trityl methyl ether, then dissolved in methylene chloride, washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. A brown oily crude product 240f of Compound V (lactone alcohol) was obtained.

NMR (ODOt3) δ=4.90-6.35 (5H, m), 4.05
~4. ．． 90 (IH.

m), 5.27-4.05 (3H, m), 1
．． 33~. 5.27 (5H, m) Mass (m/e
):156 (M'') This is used for the next reaction without isolation and purification.

Reference Example 2 (Production of Compound ■ from Compound ■) 1.4 F (2,09 m mot) of potassium hydroxide and 10 methanol were added to 2.40 t of Compound 'J obtained in Reference Example 1.
0 ml was added, and the mixture was stirred for 60 minutes at room temperature in an argon stream. Next, carbon dioxide gas was passed through this reaction solution to pH 8-9.
After that, sodium periodate 5.13F (22,
0m root) and water 100%, add 1, and at room temperature 2
Stir for hours. Add concentrated hydrochloric acid to this reaction solution to pH 5~
6, methanol was distilled off under reduced pressure, water and methylene chloride were added to the resulting residue, and the organic layer was separated.
The aqueous layer was extracted again with methylene chloride, combined with the organic layer, washed sequentially with water and saturated brine, dried over Glauber's salt, and then the solvent was distilled off under reduced pressure. ) 2.249 was obtained.

Yield: 78.9% (total from compound ■) NMR (c
rX3t3) δ=4', 87-6.70 (3H, m), 4.57 (I
H, br, s).

1.73-3.27 (5H, m) ax Mass (m/e): 142 (M+)9- Reference Example 3 (Production of Compound ■ from Compound ■) Compound ■1.42F obtained in Reference Example 2 (10 mmol) was dissolved in anhydrous methylene chloride 10-, and 1.1 mg (11
mmot), then boron trifluoride 1,48WI
After adding t (12 mmol) and stirring for 30 minutes at the same temperature,
After returning to room temperature and stirring for an additional 30 minutes, the reaction solution was extracted with a 1N aqueous sodium hydroxide solution, and the aqueous layer was washed with diethyl ether, adjusted to pH 4-5 with concentrated hydrochloric acid, and extracted with diethyl ether.

This organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound 1 (dithioacetal carboxylic acid) 1,9 Of as a pale yellow oil.

Yield 85.6% 10-NMR (CDC13) δ=10.8. ! 5 (jH, br, s,, disappeared in DIO), 4.88-6.13 (3H, m,), 4.0
0 to 4.22 (IH, dd, J=7.2, 3.2Hz)
.

2.6B to 3.10 (4H, m), 1,6 (1 to 2.
63 (7H, m) Engineering RIjam-': 2280-365
0 (br, ), 1710ax [α] name = -5,50° (c = 6.o o, O
H (:4.) Mass (mle): 232 (M") Reference Example 4 (Production of compound ■ from compound ■) Compound ■ 1.52 J (6.85 m, mol) and triethylamine 0.8'2? ( 8,22m mol
) was dissolved in 50 ml of anhydrous benzene, and 2.269 g of diphenylphosphorylacetate (
8.22 mmot) was added dropwise. After heating under reflux for 1 hour, the temperature was returned to room temperature, the solvent was distilled off under reduced pressure, and 35 me of ethylene glycol and 2.39 g of potassium hydroxide were added to the resulting residue.
(34,25m mot) and heated at 180 m under nitrogen stream.
The reaction solution was stirred for 1.5 hours at a temperature of 1.5 hours, and then the reaction solution was steam distilled to obtain an aqueous mixture of compound (1), a crude product, as parts b, p, and 120 to 160°C. Methylene chloride was added to this, and after separating the organic layer, the aqueous layer was further extracted with methylene chloride, combined with the organic layer, dried over potassium carbonate, and filtered to obtain a methylene chloride solution of compound (2). Ta.

Reference Example 5 (Production of Compound ■ from Compound ■) To a methylene chloride solution of Compound ■ obtained in Reference Example 4 was added 1 ml of pyridine in an argon stream under water cooling.

Next, trichloroethyl chloroformate 0.987!
(6.85 m mat) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, and then the mixture was returned to room temperature and stirred for 30 minutes.

Δ This reaction solution was washed successively with a 5% aqueous hydrochloric acid solution, water, and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain yellowish brown oil 1672.

This was recrystallized and crystallized from diisopropyl ether to give colorless prism crystal compound d (dithioacetal) 1.27f
I got it.

Yield 72.3% 12-m, p, 62.5-64.0°C NMR (CDC1B) δ = 4.93-6.16 (3H,,i), 4.73 (2
H, 8), 4.07 (IH, t, J=7.OH2)
, 3.86-4.26 (disappeared with IH, m, DlO)
, 2.83 (4H, t, J = 51 (z), 235 (2H
.

t, J = 6.5Hz), 1.66-2.20
(5H, m) M'ass (mle): 3
82 (M) [α) = -6,200 (cm2.o
[+, cncz3) Reference Example 6 (Production of Compound X from Compound ■) Compound f) obtained in Reference Example 5 (1,6511, (4,40
m mol) in 11 ml of Maisui acetonitrile,
2.86 m of methyl iodide was added to this in an argon stream at room temperature.
1 (45,9m mot), anhydrous sodium carbonate 570
mf (7,10 mmot) and 5.7 ml of water were added in sequence, methylene chloride was added to the residue, washed successively with water and saturated brine, dried over Glauber's salt, and the solvent was distilled off under reduced pressure.
A brown oily Compound X (aldehyde) 1.37 f was obtained.

13- NMR (・0DOt3) δ=9.73 (IH, d, J=1.6Hz), 4.90
~6.10 (5H, m).

4. 70 (2H, s), 3.73 (2H, m,
1H disappears with DIO).

2.79 (2H, da, J=6.1.6 Hz), 2.
40 (2H, t, J=6H2) IRν cm: 3410,1720.
17 [10ax Mass (mle): 292 (M″) [α].

= +1.66° (0 = 44.86, CjHO4) Reference Example 7 (Production of Compound 1 from Compound X) Compound X obtained in Reference Example 6 1.37 r and pyridinium dichromate 2.48 mot) was dissolved in anhydrous dimethylformamide, and stirred at room temperature in an argon stream for 24 hours.

This reaction solution was added to water 507, extracted with diethyl ether, the organic layer was washed with water, and then extracted with a 1N aqueous sodium hydroxide solution. The aqueous layer was washed with diethyl ether, adjusted to pH 4-5 with concentrated hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with water and saturated brine in that order, dried over sodium sulfate, and dissolved under reduced pressure. Distill the cicada to obtain yellow oily compound 1 (carboxylic acid)
1.221 was obtained.

Yield 9t, Q6' (total from compound ■) N MR
(CD0R3) δ=8J3~8.87 (3H, m, 2H disappears at D20)
, 4.87-6.23 (3H, m), 4.77 (IH
,s), 3.77-4.33(IH,m)neat
' -+ Engineering Rν cm: 3420.3680~2250 (
br,).

aX 720 Mass (mle): 266 (M”-42) [α]
ゎ=+0.64° (C226.40, 0HC13)
Example (Production of Compound ■ from Compound I) (1) Compound 1304++y obtained in Reference Example 7 (1 m
Mat) was dissolved in 6 mJ of methanol-water (v/v; 8:2) mixed solvent, and activated zinc powder (commercially available zinc powder was washed with a 5% aqueous hydrochloric acid solution, and then washed with water until the aqueous layer became neutral. 690 (10.6 m mot) was added and heated under reflux in a nitrogen stream for 45 hours. This reaction solution is
It was filtered, and the P solution was concentrated under reduced pressure. The resulting residue was dissolved in water, washed with diethyl ether, and then the solvent was distilled off under reduced pressure to obtain 119 mp of compound (1) (β-amino acid) as a water-containing substance.

(2) Compound ■119■ (922m
mat).

Sodium bicarbonate 368mg (3,69m mot)
, tetraphthylammonium sulfate) 54.6
(138 mmot) to a mixture of 1.4 tons of water and 1. ．． Then 0.14 ml of methanesulfonyl chloride (1,
81 mmol) in chloroform was added thereto, and the mixture was stirred at room temperature in an argon stream for 24 hours.

An organic layer was separated from the reaction solution, washed successively with saturated sodium chloride water and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained residue was subjected to silica gel column chromatography, and diethyl ether-hexane (v/v;
3:1) Colorless, oily compound ■795■ was obtained from the stream.

Yield 776% N MR (CDCl3') δ=6.90 (IH, br, ', s, disappeared at D20)
, 4.83-6.16 (3H, m), 3.67 (I
H, m), 3.03 (IH, ddd.

J=44,5,2Hz), 2.66(iH,
ddd, J=14°3, IHz), 2.33(2H,t
, J=6Hz)OHC43-+.

Ding Rν cm, 3250.17
55ax Mass (mle): 84 (M”-27) Patent applicant Taisho Pharmaceutical Co., Ltd. Agent Patent attorney Tomizo Kitagawa 17-

Claims (1)

[Scope of Claims] 1) The compound represented by: is converted into the corresponding β-amino acid by removing the protective group of its amine group, and then this is ring-closed to obtain the compound represented by: A method for producing a 2-azetidinone derivative.