JPS61204189A - Production of novel compound having penam ring - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for penicillin compounds, easily, by treating a specific thiazolidine-2-acetic acid derivative with triphenylphosphine and 2,2-dipyridyl-disulfide in acetonitrile. CONSTITUTION:The objective compound of formula II (e.g. 6-methyl-7-oxo-4- thia-1-azabicyclo[3.2.0]heptane) can be produced by treating the thiazolidine-2- acetic acid derivative of formula I [R1 and R2 are lower alkyl; A is CH2-CH2, C(CH3)2-CH(COOR), or CH2-CH(COOR) (R is H or protecting group)] with preferably equimolar amount of or slightly excess triphenylphosphine and 2,2-dipyridyl- sulfide in acetonitrile under ice-cooling-heat-refluxing.

Description

DETAILED DESCRIPTION OF THE INVENTION A method. Compounds having a penum ring, such as penicillins, are used as antibiotics.

Although many methods are known for synthesizing penam ring-containing compounds such as penicillins, there are not many methods that are satisfactory for industrial production in terms of the number of synthesis steps or treatment operations.

As a result of intensive research into a manufacturing method useful for industrial production of penum ring-containing compounds, the present inventors have discovered that the thiazolidine-2-acetic acid derivative represented by the general formula (II) obtained from readily available raw materials can be prepared using acetonitrile. They discovered that a compound having a penam ring represented by the general formula (I) can be easily obtained by treating the compound with triphenylphosphine and 2,2-dipyridyl disulfide, and after further study, they completed the present invention. did.

(I) (1? [In the formula, RCH2 is the same or different and each represents a hydrogen atom or a lower alkyl group, and A is -CH2-CH.

+, -c (CH,), -CH(COOR)+, or -
CH2-CH(COOR)- (wherein R means a hydrogen atom or a protecting group for a carboxyl group)] The method of treating with triphenylphosphine and 2,2-dipyridyl disulfide in acetonitrile of the present invention is described in Mukai5 'ama-Ohno method [J,
Am, Chem, Soc, +103+2406
(1981), but this method has never been used to synthesize a penum ring.

The present invention is a novel method that has not been described in any literature.

In practicing the invention, reactions are conducted in acetonitrile. Preferable results can be obtained when triphenylphosphine and 2,2-dipyridyl disulfide are used in equimolar amounts or slightly in excess of the starting material, compound (n).

The reaction temperature is appropriately selected between the water side and heating reflux conditions depending on the reaction scale and reaction time. Isolation of the target compound (I) from the reaction mixture is carried out by a conventional method, for example, by distilling off the solvent from the reaction mixture and subjecting the residue to a means such as column chromatography.

In the present invention, when an acid salt of thiazolidine-2-acetic acid represented by general formula (It), such as hydrochloride, is used as a starting material, an organic base such as triethylamine is added during the reaction.

In addition, thiazolidine- represented by the general formula (n) of the present invention
Although 2-acetic acids include some new compounds, they can be easily produced, for example, by methods A) and B) shown below.

and A means the same as above) In this reaction formula, specific examples of compounds represented by the general formula (IV) include cysteamine, cysteine, penicillamine, or compounds whose carboxyl groups are protected with a lower alkyl group, etc. It is a compound.

The compound of general formula (I) obtained by the method of the present invention is itself stable. In addition, the 6-position of the penum ring is active for various reactions; for example, in the compound of general formula (I), in which at least one of Ri and R2 is a hydrogen atom, various substituents can be introduced at the 6-position. It can also be used as a synthetic intermediate for other penicillins.

Reference Example 1 a) Ethyl 2-ethoxycarbonylpropionimidate hydrochloride (1000 mg, 4.8 mmol)
Cysteamine hydrochloride (542 mg, 4.8 mm
o l ) and triethylamine (482 mg,
4.8 mmol was heated under reflux in ethanol (20 ml) for 4 hours. After the solvent is distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (15 g of silica gel).

Purified with hexane-ethyl acetate (4:1) as a colorless oil.
li/-2-acetate is obtained. Yield 573mg (64
%) which is present in the IR and NMR spectra as an equilibrium mixture with ethyl gd-thiazolidine-2-acetate.

Ethyl α-mer-azo-acetate I
R(CHCI): 1730.1820cm'
.

NMR (CDCI,')δ: 1.25 (3H,t,
J=7Hz).

1, 43 (3H, d, J=7Hz), 2.97~
4.43 (7H, m).

L-Thiazo1dine--acetate-IR (CHCI
3) :3300,1640cm"'.

NMR (CDCI3) δ: 1.25 (3H,t),
1.80 (3H.

s), 2.97-4.43 (8H, m), 7.9
7-8.43 (IHL b r s).

b) Ethyl α-methyl-2- obtained in a) above
Thiazoline-2-acetate (100mg, 0.5
mmol) in methanol (3.0ml) solution, 20%
Hydrogen chloride-methanol solution (hydrogen chloride gas 2.0g,
After adjusting the pH to about 4 using methanol (10 ml), Na B H3CN (32 mg, O-5 mmol
), add hydrogen chloride-methanol solution as appropriate to keep the pH at 3 to 4, and stir for 4 hours under water cooling. After the reaction, water is added, an aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with methylene chloride. After drying the methylene chloride layer with magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (8 g of silica gel, hexane-
Purification with ethyl acetate (4:1) gives ethyl α-methylthiazolidine-2-acetate as a colorless oil. This is a mixture of diastereomers. Yield 55m
g (54%).

IR (CHCI3): 3300.1720cm'
.

NMR (CDCI 3) δ: 1.30 (3H,t,
J=7Hz).

1, 31.1.34 (3H, d, J=7Hz),
2.13 (IH, brs), 2. '40~3.80
(5H, m).

4, 17 (2H, Q, J=7Hz), 4.62.
4.85 (IH, d, J==7Hz) C) Ethyl α-methylthiazolidine-2 obtained in b) above
-acetate (800 mg, 3.2 mmof)
The mixture was stirred in concentrated hydrochloric acid (7.0 ml) under water for 2 hours. Add water (2.0 ml) and stir for a further 13 hours at room temperature. The solvent is distilled off under reduced pressure, and the resulting candy-like residue is crystallized by adding an ether-acetone mixed solvent, and then filtered to obtain α-methylthianlysine-2-acetic acid hydrochloride. Yield 281 mg (45%).

IR (Nujol): 3800-2200.
1710 cm-1° NMR (DMSO-d l ) δ:
1.25 (3/2. H, d.

J=8Hz), 1.35 (3/2H, d, J=8
Hz).

2, 90-3.83 (5H, m), 4.68 (
1/2H, d.

J=9Hz), 4.90 (1/2H, d, J=8
Hz).

8, 70-11.70 (2H, br).

Reference Example 2 a) Ethyl 2-ethoxycarbonyl-2-methylpropionimidate hydrochloride (1.73 g, 7.7 mmol
), Nsteamine hydrochloride (0,88 g.

7.7 mmol) and triethylamine (0.78 g
, 7.7 mmol) in ethanol (30 ml) for 7 hours under reflux. The following treatment is carried out in the same manner as described in Reference Example 1a) to obtain ethyl α,α-dimethyl-2-thiazoline-2-acetate as a colorless oil. Yield 0.9
2g (68%).

IR (CHCI): 1725cm-'.

NMR (CDCI,) δ: 1.27 (3H,t,J
=7Hz).

1,50 (6H,s), 3.28 (2H,t,
J=8Hz).

4, 20 (2H, q, J=7Hz), 4.25
(2H, t.

J=8Hz).

b) Ethyl α,α-dimethyl-2-thiazoline-2-acetate obtained in a) above (loooomg.

5 mmol) in methanol (30 ml), a hydrogen chloride-methanol solution was added to adjust the pH to approximately 4, and then N
aB H3CN (313 mg, 5 mmol) is added, hydrogen chloride-metamer solution is added appropriately to keep the pH at 3 to 4, and the mixture is stirred for 1.5 hours under water cooling. The following treatment was carried out in the same manner as described in Reference Example 1b), and ethyl α,
α-Dimethylthiazolidine-2-acetate is obtained as a colorless oil.

Yield: 1 ton 468 mg (46%).

IR (CHCIJ): 3300, 1715cm
.

NMR (CDCI3) δ: 1.27 (3H,t,
J=7Hz).

1,28 (3H,s), 1.33 (3H,,s)
, 2.43 (LH, brs), 2.53-3.12
(3H, m)s 3.32~3.70 (IH, m)
, 4.15 (2H,q, J=7Hz).

4.60 (IH, s).

C) Ethyl α, α-dimethyl obtained in b) above
Thiazolidine-2-acetate (200mg,
0.99 mmol) in concentrated hydrochloric acid (3.5 ml)
Heat at 0°C for 5 hours. Hereinafter, α,α-dimethylthiazolidine-2-
Acetic acid hydrochloride is obtained. Yield 198 mg (95%).

1'R (Nujol): 3800-2000.1
705cm-'.

NMR (CD300) δ: 1.35 (3H, s),
1.40 (3H, s), 3.05~3.92 (4
H, m), 4.97 (IH, s).

Reference Example 3 a) Ethyl ethoxyethoxyluponylacetimidate hydrochloride (3,91 g, 0.02 mol) Cysteamine hydrochloride (2,27 g, 0.02 mo 1
) and triethylamine (2.02g, 0.02m
ol) in ethanol-71/40 mI for 2 hours in so'c. After the solvent is distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate, and then methylene chloride is distilled off under reduced pressure. The residue was recrystallized from hexane to give ethyl 2-thiazoline-2 as colorless prism crystals.
- Obtain acetate.

Yield 2.25g (85%) Melting point 57-59°C.

b) 3 ml of methanol of ethyl 2-thiazoline-2-acetate (173 mg, 1 mmol I) obtained in a) above
Add a 20% hydrogen chloride-methanol solution (2.0 g of hydrogen chloride gas, 10 ml of methanol) to the solution and adjust the pH to approximately
Adjust to 4. While stirring under water cooling, Na BH3CN (
63 mg, 1 mmol), and add hydrogen chloride-methanol solution as appropriate to keep the pH at 3 to 4 for about 0.3 m
1) Stir for 30 minutes under water cooling. Reference example 1 below. Treated in the same manner as described in b), ethylthiazolidine-2-
Acetate is obtained as a colorless oil.

Yield: 114 mg (85%).

IR (CHCI): 3300.1720cm'.

NMR (CDCI,) δ: 1.27 (3H,t,
J=7Hz).

2, 15 (IH, brs), 2.80 (2H, d
, J=8Hz).

2,88~3.82 (4H,m), 4.17 (2
H,q.

J=7Hz), 4.83 (IH,tt J=6Hz
).

C) Using equimolar amounts of ethyl propiolate, cysteamine hydrochloride and triethylamine, each is reacted in ethanol at room temperature for 10 hours. This reaction mixture will be described as Reference Example 1 below. Purification is carried out in the same manner as described in a) to obtain ethylthiazolidine-2-acetate. Yield 65%. The physical properties of this product were consistent with those obtained in b) above.

d) Ethylthia/lysine-2-acetate obtained in b) or C) above is stirred in concentrated hydrochloric acid for 1 hour under water cooling. Next, half the amount of water to the reaction solution was added, and the mixture was further stirred overnight. The solvent is removed under reduced pressure.

Thiazolidine-2-acetic acid hydrochloride is obtained by treating in the same manner as described in Reference Example 1.0). Melting point 103-105℃
.

IR (KBr): 2770-2260.1
715cm'NMR (DMSO-d,) δ: 2.95
~3.78 (6H, m).

4,93 (IH, dd, J=6.0 and 8.0
Hz), 9.0-11.0 (2H, b r).

Example 1 α-Methylthiazolidine-2-acetic acid hydrochloride (150 mg, o, 78 mmol) obtained in Reference Example 1.0)
, triphenylphosphine 7 (240mg, 0.9
2 mmol) and 2,2-dipyridyl disulfide (202 mg, 0.92 mmol) in acetonitrile (75 ml) was added triethylamide 7 (77 mg w 0.76 mmol) with stirring under the water side.
) and stirred for an additional 4 hours under water cooling. After distilling off the solvent at room temperature under reduced pressure, silica gel column chromatography (18 g of silica gel, hexane-ethyl acetate, 5:1
) to give 6-methyl-7-oxo-4 as a colorless oil.
-Thia-1-azabicyclo[3,2,O-cohebutane is obtained. Yield 76 mg (70%), MSm/z: 1
43 (M)t 11588, 87.56°IR (CHCI): 1760 cm-'.

NMR (CDC13) δ: 1.42 (3H, d, J
=7.5Hz).

2, 65-3.30 (4H, m), 4.15 (I
H,ddd.

J = 10.5, 5.5 and 3.5Hz), 4.62
(IH.

J=1.4Hz).

Example 2 α,α-dimethylthiazolindine-2-acetic acid hydrochloride (100 mg, 0.47 mmol) obtained in Reference Example 2.0)
), triphenylphosphine o, 511Jmmo 1), 2,2-dipidyldisphide (130mg, 0.59 mmol) and triethylamide 7 (48mg, 0.47 mm
ol) was treated with acetonitrile (50 ml) in the same manner as in Example 1 to obtain 6,6-dimethyl-7-oxo 4
-thia-1-azabicyclo[3,2,0 cohebutane is obtained as colorless crystals.

Yield 52 mg (71%). Melting point: 34°C.

MSm/z: 157 (M”), 129.88.
87.70°IR (CHCl3): 1755 cm'.

NMR (CC1,) δ: 1.15 (3H, s),
1.45 (3H.

s), 2.45-3.15 (3H, m), 3.9
0 to 4.30 (IH, m), 4.70 (IH, s)
.

Example 3 Reference example 3. d) Thiazolidine-2-acetic acid hydrochloride (
0, OIM, acetonitrile solution), triphenylphosphine (1,2 mo 1 etc. ff1), 2゜2-dipyridyl disulfide (1,2 mo 1 equiv.), and triethylamine (1,1 mo 1 equiv.) were stirred for 3 hours under water cooling. . Thereafter, the same procedure as in Example 1 was carried out to obtain 7-oxo-4-thia-1-azabicyclo[3,2,O-cohebutane as a colorless oil.

IR (CHCl, ): 1775 cm-'.

High resolution MSm/z calculation value (as C, H7NO8): 129.0248 (M
), actual value: 129.0272 (M ).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 are the same or different and each represents a hydrogen atom or a lower alkyl group, and A is
H_2-, -C(CH_3)_2-CH(COOR)-
or -CH_2-CH(COOR)- (where R means a hydrogen atom or a protecting group for a carboxyl group)] with triphenylphosphine and 2,2-dipyridyl disulfide in acetonitrile. A method for producing a compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R_1, R_2 and A mean the same as above).