JPS61143379A - Production of thiazolacetic acid derivative - Google Patents

Abstract

PURPOSE:To obtain easily the titled compound useful as an intermediate for synthesizing a cephalosporin compound having antibacterial action, by reacting specific two compounds, and treating the reaction product with a hologenating agent. CONSTITUTION:A compound shown by the formula I (-COOR<2>' is carboxy or protected carboxy) is reacted with a compound shown by the formula II [R<3> is (substituted) phenyl, or lower alkyl] to give a compound shown by the formu la III, which is treated with a halogenating agent (e.g., sulfuryl chloride, Cl, Br, etc.) to give a compound shown by the formula IV (X<1> is halogen). Then, this compound shown by the formula IV is reacted with a compound shown by the formula V (R<1>' NH- is amino or protected amino) to give a compound shown by the formula VI, which is optionally deprotected to give a thiazolacetic acid derivative shown by the formula VII (-COOR<2> is as shown for -COOR<2>').

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing a thiazole acetic acid derivative represented by the following general formula, which is useful as an intermediate for the synthesis of cephalosporin compounds.

(However, R1'NH- represents an amine 7 group or a protected amino M, and -GOOR'' represents a hydroxy group or a protected hydroxy group.) (Prior art) In JP-A No. 59-51292 describes a method for producing thiazole acetic acid derivatives shown by the following reaction formula.

(However, Tr represents a trityl group.) (Object of the Invention) The present invention is directed to a thiazo-μ acetic acid derivative (
This is an attempt to provide a new method for producing I).

(Structure and Effects of the Invention) According to the present invention, the target compound (I) has the general formula (: However,
-COOR" represents a carboxy group or a protected poxy group) and a compound represented by the general formula (wherein R3 represents a substituted or unsubstituted phenylene group or lower alkyl group). is reacted to form a compound represented by the general formula % (wherein -GOOR" has the same meaning as above), and the compound (ff) is treated with a halogenating agent to form a compound represented by the general formula (where zl is halogen). represents an atom, -GOOR
” has the same meaning as above), and the compound (V) and the general formula %
() (However, R''&represents an amino group or a protected amino group) is reacted with a compound represented by the general formula (However, R''N
and -COOR'' have the same meanings as described above, and if necessary, the compound (I') can be produced by removing a protecting group from the compound (I').

In the above reaction, the group represented by the symbol 1/ is 1, for example, a hydrogen atom; or a lower alkanoyl group such as a formyl group, an acetyl group, or a piparoyl group; Alkanoyl group: lower alkoxycarbonyl V group such as methoxycarbonyl group, ethoxycarbonyl M 6 tart, -ptoxycarbonyl μ group; mono-, di- or trihalogeno-lower alkoxycarbonyl group such as trichloroethoxycarbonyl group ; Benji〃
Substituted or unsubstituted benzyloxycarbonyl group such as oxycarbonyl group, P-methoxybenziVoxycarbonyl group; benzyl group, P-methoxybenzi group, 3,
Substituted or unsubstituted phenyl lower alkyl groups such as 4-dimethoxybenzyl group are included. Groups represented by the symbol R' include 0, for example, a hydrogen atom; or a lower ay group such as a methyl group, an ethyl group, a tart group, and an -ethyl group;
Examples include a benzyl group, a P-methoxybenzyl group, a substituted or unsubstituted phenyl lower V-kyl group such as P-nitrobenzyl A/g (2); and a protecting group such as a benzhydryl group.

Furthermore, as a group represented by the symbol BS, 1, for example, phenyl 11s, substituted 4L< such as p-methylphenyl group, is an unsubstituted phenyl group, or lower a/L/kiM group such as methyl group, ethyl group, propyl group. Can be mentioned.

The reaction between compound (II) and compound ([[) can be carried out in an appropriate solvent in the presence of a deoxidizing agent. Examples of deoxidizers include alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), water-accumulating alkali metals (e.g., sodium hydride), alkali gold hydroxides, e.g., sodium hydroxide, water. Potassium oxide), etc. Examples of the solvent include evacetone, tetrahydrofuran, vinegar Methtv, dimethyst Voxite, dimethyVformamide, and the like. This reaction is carried out at -10°C to 80°C.

Preferably, it is appropriate to carry out the reaction at a temperature of 10°C to 50°C.

The reaction of compound QV) with a halogenating agent can be carried out in a suitable solvent. Preferred examples of the halogenating agent include sulfuric chloride, chlorine, bromine, N-promosacrine imide, and pyridinium hydroglomide verbromide. Examples of solvents include chloroform,
Methylene chloride.

Preferred examples include carbon tetrachloride and 1,2-dichloroethane. This reaction is carried out from 0°C to 100°C, preferably from 10°C to
It is suitable to carry out at 50°C.

The reaction between compound (V) and compound (VI) can be carried out in a suitable solvent in the presence of an acid deoxidizing agent. As a deoxidizing agent, 0, for example, 11. Preferred examples include organic tertiary amines such as N-dimethylaniline, triethylamine, and pyridine. As the solvent, for example, lower vulcanol (for example, methanol/I/, ethanol, ingropanol) or a mixed solvent of these solvents and water can be suitably used. Water reaction Viio℃~80℃, preferably 70℃
It is suitable to carry out at ~qo°C.

The protective group can be easily removed from the thus obtained compound by conventional methods such as hydrolysis, solvolysis, #treatment, and reduction.

For example, the protecting group R1' of amine 7 group is formyl group, acetyl group tert, -butoxycarbonyl group, trityl group,
When the protecting group ♂' for the cyclo group or the benzhydryl group and/or the carboxy group is a tert, -butyl group or a benzhydryl group, these protecting groups can be removed by treating compound (1') with an acid. Examples of the acid include acid, trifluoroacetic acid, benzenesulfone WIN, p-)luenesulfonic acid, hydrochloric acid, and water bromide. This reaction can be carried out in a suitable solvent or in the absence of a solvent.

As the solvent, for example, water, methanol, ethanol, acetic acid, dioxane, etc. can be used. This reaction is suitably carried out at -30°C to 70°C, preferably at 10°C to 50°C. In this reaction, when trifluorocarbon is used as ':a, it is preferably carried out in the presence of anisole.

Moreover, when the protecting group R1 of the amino group is a trityl group,
Removal of the protecting group can also be carried out by heating the compound in a suitable solvent.
For example, lower carbon dioxide (for example, methanol, ethanol), water, or a mixed solvent thereof can be suitably used. This reaction is suitably carried out at a temperature of 40°C to 100°C, preferably 50'e to 80°C.

The protecting group for the amino group is benzyloxycarbonyV group, P-
Methoxybenzyloxycarponyl group, benzy/L group.

When l[iR'' of P-methoxybenzyl group or 3,4-dimethoxyhensyl group and/or carboxy group is benzyl group, P-methoxybenzyl group or P-nitrobenzyl group, removal of these protecting groups This process can be carried out by catalytic reduction of the compound in the presence of a catalyst in a hydrogen gas stream. Preferred examples of the catalyst include Padillam-barium carbonate, Badgelum-Barium carbonate, and the like. The catalytic reaction is carried out in an appropriate solvent at normal pressure to 0°C to 100°C, especially 10°C to 40°C.
It is preferable to carry out. As the solvent, for example, methanol, ethanol, tetrahydrofuran, water, etc. can be suitably used. The protecting group R'' of the amino group is a trifluoroacetyv group, pivaloyl group, methoxycarbonyl group or ethoxycarbonyl group and/or the protecting group R'' of the carboxyl group is a lower atom group such as a methoxyM group or an ethyl group.77*A / group, these protecting groups can be removed by hydrolyzing compound (I'). Hydrolysis of compound (I') can be carried out by a conventional method. This can be carried out by treatment with a reagent or an acid. Examples of γρ force reagents include hydrated alkali gold W4 (e.g., sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxide (e.g., water Examples of acids include hydrochloric acid and hydrobromic acid. Examples of solvents include lower alkanols (methanol, ethanol), dimethylformamide, and the like. A mixed solvent of a solvent and water can be suitably used. This reaction is suitably carried out at a temperature of 0 to 80°C, preferably 20 to 60°C. Furthermore, a protecting group for an amino group can be used. When W' is a chloroacetyl group, the protecting group can be removed by treating the compound (I5) with thiourea in a suitable solvent. As a solvent, for example, methanol, ethanol, water, etc. are preferably used. can do.

This reaction is suitably carried out at a temperature of 20°C to 80°C, preferably 20°C to 50°C.

In the above reaction, the starting compound (1[) has ninety two optical isomers having one asymmetric carbon atom in the molecule, but all the reactions of the present invention proceed without racemization. If an optically active form of compound (1[) is used as a raw material compound, the target compound (I) can be easily obtained as an optically active form. Also, the target compound (I)
is a compound in which the oximino group is in the 2 (i.e. syn) configuration and F! Although there are compounds with (that is, anti) configuration, the reaction of the present invention produces compound (I) in which the oximino group is mainly in the 2-configuration.

The object compound (I) of the present invention obtained as described above is useful as an intermediate for the synthesis of cephalosporin compounds. It is useful as a synthetic intermediate for phosphorus compounds.

In addition, the raw material compound (supplied optically active substance is 1, for example, optically active 3
-Hydroxy-2-pyrrolidone (AataChamia
a 5 oandinavioa, , B 34, 7
3 ]--733rd edition (1980)) and a compound represented by the general formula % (where 1g represents a halogen atom and R1 has the same meaning as above). can.

Example 1 (1) 2-Hydroxyimino-3-oxobutyric acid Kojusen M Esthe/l/3.21 was added to acetone 2F+ff+/
I understand it.

4.21 potassium carbonate and (R1-3-(p-
Add 7.6y- of tosyloxy)-2-pyrrolidone and stir at room temperature for 15 hours. The mixture @ is concentrated to dryness under reduced pressure. Cold water for the residue 50-? Beforehand, the mixture is extracted with ethyl acetate. After drying the extract, the extract was concentrated to dryness under reduced pressure to obtain 1Zl-2-(((3S)-2-pyrrolidone-3-
I/L/)oximino]-3-oxobutyric acid ethyl ester 3.3F? obtain.

NMR(00013)δ: 1.32 (3H, t, J=7Hz), 2.00 (3
1.

auto), 2.04-2.86 (2TI, ff1),
3.3-3.7 (28.

111), 4-36 (2H, q, J=7E[z)
, 4.96 (1!1.

6, Jgs7Hz) +7.5(II, broad s
)+21 (Kl-2-[((3El)-2-pyrrolidone-3-i/I/)oximino-3-oxobutyric acid ethyl ester A/2.4F in methylene chloride 15rn
Dissolve in l.

Add 1.61 sulfuryl chloride to the solution and stir at 15-25°C for 20 hours. The mixture is concentrated under reduced pressure to remove the solvent. The entire residue is dissolved in chloroform and the solution is washed with water. After drying the chloroform solution, the chloroform solution was concentrated to dryness under reduced pressure to obtain crude (Z)-2-(((3S)-2-pyrrolidon-3-yl)oximino]-3-oxo-4-chlorobutyric acid ethyl V ester. This crude product was dissolved in 20% of ethanol, and 1.0% of thiourea was added to the solution.
01 and N,N-dimethyM aniline 1.2 F? Add and stir at 20-25°C for 2 hours. The mixture is concentrated under reduced pressure to remove all the solvent. Dissolve the residue in chloroform,
The solution is washed with water and aqueous sodium bicarbonate solution.

After drying the chloroform solution, it is concentrated under reduced pressure to remove the solvent. The residue was crystallized with isopropanol and collected by filtration to give ml-2-(2-amino/thiazo-A/-4-iA/)-2-(((3S)-2-pyrrolidone-3 −i/
I/) Oximino]ethyl acetate ester, 2p was obtained.

M, p, 160-163℃ [α] Tetsu -15,90 (C-1, methanol-/L/)N
MR(DMlIO-d@)a: .

1-27 (3H, t, J = 7 Hz) * 1
．． 93-2.60 (2”-'I)-3,1-3,5
(2H,ai)-4-32(2''*q-'-7Hg),
4.74 (IF5t, J-7Hg), 8.93 (I
II.

s), 7.30 (211, s), 7.96 (III, 5
) fi / 4-1 sea IW-4-4v) -2-C (<
3s>-2-pyrrolidon-3-i/I/)oximino]acetic acid ethyl ester 1. Add OF and stir at 20°C for 1 hour. The mixture was brought to pH 5 with 1O sonoric acid, and the 811 compound was concentrated under reduced pressure to remove methanol.

The residue was adjusted to PI (3) with 10 liters of hydrochloric acid, and the mixture was cooled with water. )-2-(((3g)-2-pyrrolidone-3-i A/)
730IIP is obtained.

M, p, 199-200℃ C decomposition) [α] Amase 5
0.8° (Cco1. Water) N M R (D O+
NaHCOi) δ:2.0-2.7(21
1, m), 3.3-3.6 (2R, m).

4.95 (IFI, t, J-8k), 6.90
(Ill +!) Compounds listed in the table below were prepared based on Example 1 above. All compounds in the table above are in the 1!+ configuration.

(Note 1): Solvent of l'1MH: CDCIg (Note 2):
(a) %' -: 1g, 8° (C-1, diminutive + p
v*Vmuamide) (Note s>: ca) v-21,5° (C steal 1. methanol) (Note 4): [α) DI'-342° (C-1
, dimethypho-V-mamide) (Group): Cbg: BendiV-oxycarbonyl [Preparation of raw material compound] (R1-3-hydroxyF-2-pyrrolidone (Aata
2N sodium hydroxide 15- is added to the solution at room temperature to dissolve the suspension. This solution was cooled to -3 to 5°C, and 5.7y of p-)sil chloride was added to the solution and stirred at the same temperature for 1 hour. blend? After stirring overnight at 10-15°C, the mixture is brought to pH 2 with 2N salt #10&. The mixture is concentrated under reduced pressure to remove the acetone. The residue is extracted with chloroform, and the extract is washed with saturated saline and dried. The chloroform solution is concentrated under reduced pressure to remove the solvent. By crystallizing the residue with ether and recrystallizing it from ethyl acetate,
1R)-3-(p-)yloxy)-2-pyrrolidone 3
．． Get 5 no.

p, 148-149℃ [α]π +17.7° (C,=1, methanol-/L
/) NMR (CDCIg) δ: 2.0-2.7 (211, +11), 2.43 (3FI
,! l) 3.1-3.5 (21!, +m), 4.91
(IH, t, J-711g) 7.2 (lEi, broa
d), 7.32 (2F1.d, 2m9Hz 7.84
(2H, d, J-9tlz)・---1

Claims (1)

[Claims] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (However, -COOR^2 represents a carboxy group or a protected carboxy group) and the general formula ▲ Numerical formula , chemical formulas, tables, etc. ▼ (III) (However, R^3 represents a substituted or unsubstituted phenyl group or lower alkyl group.) By reacting with a compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. There is a compound represented by ▼(IV) (However, -COOR^2' has the same meaning as above.), and the compound (IV) is treated with a halogenating agent to form the general formula ▲mathematical formula, chemical formula, table etc.▼(V) (However, X^1 represents a halogen atom, -COOR^
2' has the same meaning as above. ), and the compound (V) and the general formula R^1
'NH-CS-NH_2 (VI) (However, R^1'NH- represents an amino group or a protected amino group.) By reacting with a compound represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼(I') (However, R^1'NH- and -COOR^2' have the same meanings as above.) If necessary, the protecting group is removed from the compound (I'). There are general formulas that are characterized by A method for producing a thiazole acetic acid derivative represented by: