JPS58185553A - Alpha-protected oxyimino-beta-keto-gamma-halogenobutyric acid - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is halogen: Y and Z incorporate to form a group, =NR<5> (R<5> is protected hydroxyl)], its salt or ester. EXAMPLE:Ethyl alpha-ethoxyimino-2-aminothiazol-4-ylacetate hydrobromide. USE:A synthetic intermediate of antibacterials. PREPARATION:The customary halogenation of a compound of formula II such as a beta-ketobutyric acid bearing a protected oxyimino group in the alpha-position gives the compound of formula I . In the compound of formula I , methyl, phenyl or acetyl is cited as a protecting group for the hydroxyl and methyl, tolyl or benzyl for the carboxyl. The protected oxyimino group has syn- and anti-forms theoretically.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound having the formula (wherein,
R5 represents a group represented by a protected hydroxyl group. ], its base or ester, and its production method.

The compound of the present invention, its right or ester, has the formula % Formula % 1 where B12 represents a lower alkoxy group or an optionally protected amino group. By reacting with a compound represented by the formula [In the formula, R13 is a hydroxyl group or an optionally protected amino group, the others are the same as above, Table f. ], the resulting compound CXIV) is a useful synthetic intermediate for the preparation of compounds of the formula Indicates the group. [Symbols in the formula have the same meanings as above. It is useful for producing compounds represented by the following.

In compound [1], X and Y together form -NR
5, and R5 represents a preserved hydroxyl J&. As a protecting group for such a hydroxyl group, the present invention 14iI
Any group may be used as long as it does not inhibit each reaction in IK, and usually lower alkyl groups such as methyμ and ethyl, aryl groups such as phenyl and thiene, and y)v groups such as acetyl and benzoyl are used. During the compound [expletive]
XFi woodcutter, bromine.

Indicates halogens such as iodine and fluoride. The ti, and the groups may be retained. Such holding groups include acidic conditions and alkaline conditions.

Any group may be used as long as it can be removed under mild conditions such as release conditions, and is selected from those generally used as carboxyl group holding groups in peptide synthesis, such as methyl, ethyl, and propyl.

Isopropyl, butyl, sec-butyl, isobutyl.

Alkyl groups such as tertiary glutyl, direct alkyl groups such as β-methyμsulfonyl ethyl, trichloroethyl, diphenylmethyl, ary/l' groups of phenyl, tolylunato,
l)-tertiary buty-phenyl, p-nitrophenyl/
Nat's Wt aryl group, benzyl.

7-fulky A' group such as phenethyl and tolbendyl.

p-methquinbenzyl, p-nitrobenzyl/L/nato substituted afkyl, etc. are used. This compound
is preserved and is strictly 5yn- with respect to the 9oximino group.
and anti-isomers exist, both of which are equally useful synthetic intermediates.

Compound [-M] can be obtained by halogenating β-ketobutyric #lIA having a corresponding oximino group protected at the α-position using a conventional method.

5fi! Example 1 α-ethquinimino-β-ketobutyric acid ethyl ester 18
．． 7f was dissolved in 100s/chloroform, and a solution of 15.9f bromine dissolved in 20s/chloroform was gradually added dropwise while cooling with water. After stirring for 30 minutes, the mixture was returned to the original temperature and stirred for an additional 1.5 hours. The reaction mixture was washed with water, precipitated in a sodium hydrogen hydroxide bath, further washed with water, and dried over magnesium sulfate. After solvent distillation, ethanol-7'
Add 250sr, add 15.2f of thiourine, and reflux for 2 hours.

After cooling, the solvent was distilled off under reduced pressure and 250 d of water was added to the residue to precipitate a solid. This was taken out, washed with water, and then dried.
7.9f is obtained. Yield: 55%.

Elemental analysis value C, Ii, 4N303SBr needle value: C
, 33, 34; H4, 35+ N 12.9&wS value: c 32.52+ II 3.98; x 12.
92 Nuclear magnetic resonance spectrum of this product (100MHz, d6
-1) in M2O) is 1.30 and 1.32 ppm K2
Bridges ethyl group methyl hydrogen triplet, 4.28 and 4
, a quadruple coat of ethyl group methylene water volume of 2 h at 37 ppm+, a single line of hydrogen at the 5-position of thiazole at 7.63 ppm, 9
, 12 pprn shows a wide single resonance line of amino group hydrogen.

East Example 2 (1) Ethyl α-methoxyimino-ρ-keto acetate 27.
31 was dissolved in 120 d of chloroform, and 25.3 f of ice to bromine was bathed in 30 mK of chloroform.
Drop in minutes. Thereafter, the mixture was allowed to react at room temperature for 1 hour. The reaction product was washed with dilute sodium chloride solution and water, and the organic layer was dried. The bath agent is distilled off to obtain crude ethyl acetate as an oil.

(2) The entire amount of ice crystals is placed in an ethanol-A/250 mK bath, thiourea 249 is added thereto, and the mixture is heated to reflux during avf.

After cooling, take one precipitate and wash with ethanol. The nine crystals obtained were ethylcotetrahydrofuran acetate (1:1)
Suspend the mixture in 300 m/ml, add 10% aqueous sodium bicarbonate solution for 200 s/ml, and separate the F#4' pigeons. After drying, the solvent was distilled off and the resulting crystals were washed with ether to obtain α-methoxyimino-α-(2-aminothiazol-4-yA/)grill ethyl. 16.86F
, melting point 112-113°C.

Elemental analysis value C8H, N303S *tJ: value: C41,91i H4,84 dormitory I8 value:
c 41,20; H4,70 nuclear magnetic resonance spectrum/
L/(60MHz, in CDCl3) is 4.04 ppm
single line of methoxy hydrogen, thiazole 1 at 7.44 ppm
A single resonance line of hydrogen at position 15 is shown.

Claims (1)

[Claims] (In formula 11C, X represents a halogen atom, and Y and 2 together represent a group represented by the formula -NJ?5 (1?5 represents a protected hydroxyl group) ] Compounds, their mounds or esthetics ~ (In the formula, Y and 2 together represent a group represented by MU = NR5 (R5 represents a layered hydroxyl group)) In the formula 1, the XFi halogen atom is replaced by Y, ZV1, the same t as above.
9 is a method for producing an ester of a compound represented by III] and its salt.