JPS6163A - 2-alkoxyiminobutyric acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is phenyl or lower alkyl which may have a substituent group; R2 is lower alkyl). EXAMPLE:4-p-Toluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid. USE:An intermediate for preparing cephalosporin derivatives useful as an oral agent having a powerful antimicrobial activity. PREPARATION:For example, tert-butyl 4-bromo-3-oxo-butyrate expressed by formula II is reacted with a silver p-toluenesulfonate expressed by the formula TsOAg (Ts is expressed by formula III) to give a compound expressed by formula IV, which is then reacted with sodium nitrite and dimethyl sulfate one after another to afford tert-butyl 4-p-toluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrate. The resultant compound is then hydrolyzed with an acid to afford the exemplified compound expressed by formula I a.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula (syn type) [wherein B1. represents an optionally substituted phenyl group or lower alkyl group, and TL2 represents a lower alkyl group. The present invention provides a 2-alkoxyiminobutyric acid derivative represented by the following formula, which is useful as an intermediate for the synthesis of antibacterial agents σ).

That is, the compound (I) of the present invention or its reactive derivative at the carboxyl group has the formula [wherein R3 represents the formula -〇H2R5 (in the formula, R5& represents a lower alkoxy group], and 0OOJ is esterified. Indicates an optional carboxyl group. ]
- reacted with an aminocephalosporin visiting conductor [wherein al, R2, R5 and 000B4 &↓represents the same meaning as above. ] and reacted the compound with thiourea.4! - [wherein R2, IIL3 and 0OOR4 have the same meanings as described above. A cephalosporin derivative represented by the following formula can be produced.

0OO1'L4 of the compound (y) obtained in this way
The present inventors have discovered that compounds representing esters that are eliminated under physiological conditions are useful as oral agents with strong antibacterial activity (Japanese Patent Application No. 1364/1989).
No. 49).

Conventionally, y-C2-(2-aminothiazol-4-yl)
Several methods are already known for producing -2-(syn)-alkoxyiminoacetamide] cephalosporin V and conductors. For example, tetrahedron, -
Lee volume, pp. 2233-2243 (117a)
, The Journal of Ampbiotics 34
Vol., pp. 171-192 (1981), Japanese Patent Application Publication No. 1983
-10229 March, No. 53-34795, No. 54-9
Broadly speaking, these methods, which are described in No. 8795, etc., can be broadly classified as follows: is synthesized separately to form the 7-amitusephathiazole moiety. In this case, what is important is that it can be produced industrially and that the by-product of an anti-type compound, which is an unnecessary isomer, is suppressed in terms of the antibacterial activity of the alkoxyimino moiety in the 7-position side chain.

According to the research conducted by the present inventors, the former method has a high production rate of anti-isomer, and the latter method has a high production rate in the literature (
According to The Journal of Antibiotics, Vol. 34, pp. 1asa to 190), the yield is extremely poor.

Under these circumstances, the present inventors conducted research on an industrial method for producing the compound having the formula (N), and completed the present invention which allows the target compound to be obtained with a high sieving rate.

In the above formula, R4 is methyl, ethyl, propyl.

-1 sopropyl, n-butythyl, isobutyl, n
- It represents a lower alkyl group having 1 to 6 carbon atoms such as pentyl or n-hexyl group, or a phenyl group, and the phenyl group may have a substituent. Lower alkyl groups such as methyl and ethyl groups.

It may be substituted with a lower alkoxy group such as methoxy or ethoxy group, or a nitrogen atom such as chlorine or bromine. Good too. Usually, preferred R1 is phenyl or paramethylphenyl.

These include methyl and ethyl groups. R2 is methyl, ethyl, propyl, isopropyl, n-dutyl, isobutyl, n-
It refers to lower alkyl groups having 1 to 6 carbon atoms such as pentyl and n-hexyl groups, with methyl or ethyl groups being particularly preferred. R3 represents the formula -0H2R5, and the substituent R5 is methoxy.

An optionally esterified carboxyl group represented by 000R4, in which a lower alkoxy group such as an ethoxy, n-propoxy, or isopropoxy group is opened, is a carboxyl group or an alkali or alkali group such as its sodium, potassium, or dicyclohexylamine salt. Inorganic salts or organic salts such as earth metals, and K contain esterified carboxyl groups. Such esters include, for example, methyl, ethyl, tertiary butyl, benzyl,
Esters forming protective groups in the process such as phenacyl, trimethylsilyl, benzhydryl, phenyl or methoxymethyl esters or phthalidyl, alkanoyloxymethyl (e.g. acetoxymethyl,
Propionyloxymethyl, pivaloyloxymethyl,
benzoyloxymethyl group, etc.) or lower alkoxycarbonyloxymethyl or ethyl (e.g., 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxyethyl, tertiary-butyloxycarbonyloxymethyl group, etc.) under physiological conditions. Esters that are eliminated by are used.

Compound (I) of the present invention is a new substance, for example R1
Compound (Ia) in which R is a 4-methylphenyl group and R2 is a methyl group was synthesized by the following route.

Br0H2000H2000-1-Bu + TSOA
g J\OH 0H3 Cephalosporin derivative (P/) using the 2-alkoxyiminobutyric acid derivative (I) thus obtained as a raw material
The production will be explained below.

In the reaction of reacting compound (I) with (1) to obtain (I), (I) is used as a free form or as a reactive derivative thereof, but when used as a free form, an appropriate condensation reaction is performed. Condensing agents include di-substituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, azolide compounds such as N,N'-carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline, phosphorus oxychloride.

Examples include dehydrating agents such as alkoxyacetylene, and Vilsmeier's reagent prepared from dimethylformamide and phosphorus oxychloride. Reactive derivatives of the compound having formula (1) include acid norides, acid anhydrides, mixed acid anhydrides, and active esters.

Activated amides, acid azides, etc. are used. Mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid. Examples of active esters include p-nitrophenyl ester, pentachlorophenyl ester-N-hydroxyphthalimide ester, and N-hydroxybentriazole ester. The reaction is generally carried out in a suitable solvent, and the solvent is not limited as long as it does not affect the reaction, such as acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, dichloromethane, dimethylformamide, acetonitrile, water, etc. Mixtures of these are used.

Depending on the type of reactive derivative used in this reaction, a base may be present as necessary. Examples of bases include alkali metal compounds such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, aliphatic, aromatic, or nitrogen-containing multicyclic bases such as triethylamine, dimethylaniline, N-methylpiperidine, N- Methylpyrrolidine, pyridine.

Examples include collidine and lutidine. There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature or under cooling.

The time required for the reaction varies mainly depending on the type of acylation method, degree of reaction source, etc., but is usually from ten hours to several tens of hours. After completion of the reaction, the compound having formula (III) is collected from the reaction mixture by a conventional method (recrystallization, if necessary).
Although it can be purified by chromatography or the like, it can also be used as a raw material for the next step without being separated.

The reaction of producing compound ff) by reacting compound (1) with thiourea is usually carried out by bringing the two into contact in a suitable solvent. The solvent used is not limited as long as it does not adversely affect this reaction, but examples include water and methanol.

Solvents such as ethanol, dimethylformamide, dimethylacetamide, acetone, acetonitrile, tetrahydrofuran or mixtures thereof are used. In some cases, sodium acetate may be added to accelerate and complete the reaction.
Sometimes it is better to add a base such as bicarbonate of soda.

Although there is no particular limitation on the reaction temperature, it can usually be carried out at room temperature. The reaction time is usually several tens of minutes to several hours, although it depends on the reaction conditions. After the reaction is completed, the produced (■) is separated from the reaction mixture by a conventional method. For example, vacuum concentration, extraction, reprecipitation.

It can be isolated by chromatography or the like.

Examples of the cephalosporin compound (V) that can be produced from the compound (I) of the present invention include (111-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid (217-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (3+ r -C2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester +41 7- [2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]- 3-methoxymethyl-3-cephem-4-carboxylic acid isobutyryloxymethyl ester (517-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-meth)oxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester +61 7- [2-(2-aminothiazol-4-yl)-2-ethoxyimino Acetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester +71 7-C2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-ethoxymethyl- 3-cephem-4-carboxylic acid pivaloyloxymethyl ester (817-[2-(2-aminothiazol-4-yl)
-2-Methoxyiminoase-amide]-3-methoxymethyl-3-cephem-4-carvone rP/1-isopropyloxycarbonyloxyethyl ester (all are syn-type).

Next, the method for producing the compound of the present invention will be specifically explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 7.1 g of 4-promo 3-oxobutyric acid tarjarifthyl ester! = Add 945 g of silver para-toluenesulfonate to 50 ml of dry acetonitrile and stir at room temperature for 3 days with the exclusion of light. The reaction solution is filtered and the P solution is concentrated under reduced pressure. The obtained crystals containing an oily substance are dissolved in ethyl acetate, and insoluble matter is thoroughly removed by filtration. When liquid f is concentrated under reduced pressure, a brown oil is obtained. The oily substance was separated and purified by silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, and the resulting colorless oily substance was recrystallized from ether-n-hexane to yield tert-butyl 4-paratoluenesulfonyloxy-3-oxobutyrate. Ester as colorless columnar crystals 4
．． 5F was obtained. Melting point 61-69°C NMR (0DO713) δppm: 1.43 (9H,S, tert-Tfutyl
)243 (3H+ s r 吃Iα) 3.43 (2H,S, -0H2002tBu)4.
60 (2H, S, -8o200H200-J?, 2
(1~7.90 (4H, Hey Say @) Elemental analysis value 015H20068 Calculated value: 0,5492; H, 6, 15: 8,
9°78 Actual value: 0,55.03; H,6,0
7; 8, 9.86 Example 2 Dissolve 4-paratoluenesulfonyloxy-3-oxobutyric acid tarjarifthyl ester 45f in 40ml of acetic acid and add 1°421 sodium nitrite at room temperature for 10 minutes. . After stirring for an additional 50 minutes at room temperature, 200 g of ethyl acetate was added to the reaction solution, and the ethyl acetate solution was washed with brine.

The ethyl acetate solution is dried over magnesium sulfate and concentrated to give a brown oil. When this was separated and purified by silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, 1.661 of 4-balatoluenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester was obtained as colorless crystals. Ta.

Melting point: 106-108°C (decomposition), (recrystallization solvent.

ether-petroleum ether) NMR (ono'n3) δppm: 1.52 (9H,s, tert-Butyl)
2.43 (3H, s, shi,) 5-04 (2H, s, 802 hit C0-) 7.2
0 to 7.92 (41 (, benzene ring) 10.23 (
IH,s, -Co-0-Co) Analysis value 015H19
NO7S Calculated value: 0,50.48; H,5,36; N
, 3.92; 8, 8.98 Actual value: 0, 50.
62: H, 5,08; N, 3.83: 8,8
．． 97 Example 3 4-balatoluenesulfonyloxy-3-oxo-2-
1.86 II of hydroxyiminoacetic acid tert-butyl ester is dissolved in 20 parts of dry acetone, 960 Q of anhydrous potassium carbonate and 0466- of dimethyl sulfuric acid are added under water cooling, and the mixture is stirred at room temperature for 3 hours. Reaction liquid 200
- Pour into ice water and extract with methylene chloride. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, 4-balatoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester was obtained as a pale yellow oil. 650 ■ was obtained.

NMR (oDoJ3) δppm: 1.50 (9H, s, tert-nutyl)2
．． 43 (3H,' s, 05→-)4, or (3
H,s, ft-oo5)5.05 (2H9S,
5O200H200) 7.20~7.90 (4H,
Benzene ring) Example 4 4-balatoluenesulfonyloxy-3-oxo-2-
Dissolve (syn)-methoxyiminobutyric acid targerysyl ester 471111F in 1 ml of methylene chloride, add 2 ml of trifluoroacetic acid, and stir at room temperature for 4 hours. Methylene chloride and excess trifluoroacetic acid were distilled off under reduced pressure, and the resulting brown oil was dissolved in isoprobyl ether and allowed to stand, resulting in 4-valatoluenesulfonyloxy-3-oxo-2-(syn)-methoxyimino v1 178q of acid was obtained as colorless crystals, melting point 1
31-132℃ (decomposition) Elemental analysis value 0.2H13NO7S Calculation fJL: 0.45゜72: 1(,3,84
; N, 4.45 ; Sjo, 18 Actual value: 0.4
5.50: H, 3,92; N, 4.32: 8
,9.98NMB (d-6acetone)δppm
:2.47 (3H,s, one -) 4.10 (3H,s, N-05) 5.20 C2H,S, -8020(!H2O0)1
．． 25-7.95 (4H, benzene R) 9, sc (
IH, b, s, -002H) Example 5 4-promo-3-oxobutyric acid tert-butyl ester 8.25 F,! :Silver ethanesulfonate 11.3f
50m! of dry acetonitrile and stirred and refluxed for 30 minutes. The reaction solution was thoroughly filtered and the r solution was concentrated under reduced pressure. The obtained oil is dissolved in benzene, washed twice with water and nine times with brine, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure to obtain a brown oil. When the oil was purified by silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, 4-ethanesulfonyloxy-3
-Oxobutyric acid tert-butyl ester was obtained as a yellow oil at 7.7 f 4klr.

NMR (0DOj13) δppm: 1.32-1.
62 (9H+3H, s+t, tert-But
yl+0H30H280,-) 3.30 (2H, q, J=7.0.0H30H280
3-) 3.47 (2H,s, -0H2002-tB
u) 4.87 (2H,S, -80200H200-
) Example 6 7.7 F of 4-ethanesulfonyloxy-3-oxobutyric acid tert-butyl ester is dissolved in 50 gt of acetic acid, and 2.2 F of sodium nitrite and 0.1 gt of concentrated sulfuric acid are added under water cooling. After stirring the reaction solution at room temperature for 40 minutes, 500 g
Add ethyl acetate and wash the ethyl acetate solution with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated, yellowish brown crystals are obtained. The crystals were recrystallized from ether-petroleum ether to obtain 5.9 g of 4-ethanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester as colorless crystals. Melting point 85-87'c (decomposition) NMR (0DOJ13
) δppm: 1.47 (3H, t, J=7.Q, cl(3o1
(2so2o-)1.57 (9H,s, t-But
yl ) 3.33 (2H, q, J=r, o, O
H,0H2SO20-)5.23 (2H,s,-80
□0OH200-)10.50 (IH,s, -00
a00-) Elemental analysis value Ol. H17NO78 Calculated value: 0,40.71; H,5,81; N,
4.75; 8,10.87 Actual value: 0,40.2
9: I(,5,73; N, 4.61; s, 1
t1y Example 7 4-nitanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester 5,9
Dissolve f in 50 g/dry acetone and cool with water for 4.14 minutes.
Add anhydrous potassium carbonate (F) and dimethyl sulfate (1.81i) and stir at room temperature for 1 hour.

The reaction solution was poured into 500 gJ of ice water and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. This is benzene
When separated and purified by silica gel column chromatography using ethyl acetate as a developing solvent, 4-ethanesulfonyloxy-3-ox,so 2-(syn)-methoxyiminobutyric acid tert-butyl ester was obtained as a pale yellow oil with a yield of 3.13 y.
Obtained.

NMR (cnoJ3) δppm: 1.43 (3H, t, J=7.0.0H30H28
020-)1.50 (9H,s, t-Butyl
) 3.27 (2H, q, J=7.0. OH, (old 2SO20-) 5.18 (2H, S, -8020-0
0-) Example 8 4-promo-3-oxobutyric acid tert-butyl ester was prepared in the same manner as in Example 5. of and iron benzenesulfonate 6.5f to 4-benzenesulfonyloxy-
3.4 g of 3-oxobutyric acid tert-butyl ester was obtained as colorless needles. Elemental analysis value 014H18068 with melting point 94-96 Calculated value: 0,53.50; H, 5,78; 8,
10.20 Actual value: 0,53.49; H, 5,7
0; 8,10.16fMrL (ODOJ,)δpp
m: 1.43 (9H, s, t-Butyl)3
43 (2H+s, 000H200) 4.63 (2
H, S, -8020014200-)7.40~8.
03 (5H, m, benzene ring-H) Example 9 Example 2,! : li? [With K, 4-benzenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester is colorless from 3.4 f of 4-benzenesulfonyloxy-3-oxobutyric acid tert-isotyl ester and 900 μl of sodium nitrite. 2.91M' was obtained as needle crystals. Melting point 93-95℃ (decomposition) Elemental analysis value 014H17N07" Calculated value: 0,49.02.; H, 5,00: N,
4.08; 8,9.35 Actual value: 0.4B, 93
; H, 5,06; N, 4.01; 8,9.4
1fMR (cnc13) δppm: 1.57 (9H, s, t-Butyl) 5.07
(2H,S, 80200H200)7.40~8
．． 03 (5H, m, benzene 1-)1) 10.17
(IH, b, s, N-OH) Example 10 4-benzenesulfonyloxy-
3-oxo-2-hydroxyiminoacetic acid tert-butyl ester2. ssy and anhydrous potassium carbonate 1.8
0f and dimethyl value of 8104 ml, 4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester was immediately obtained as a one-color oil.

NMR (cDc15) δppm: 1.50 (9H,s, t-Butyl) 4.05
(3H,s, N 0OH5)5.07 (2H+
8. 80200H200) 7.30~8.00 (
5H, m, benzene fRt-H) Example 11 4-bromo-3-oxobutyric acid tert-butyl ester 6, Of,! :Methanesulfone m silver? , Tf is 40d
of dry acetonitrile and stirred and refluxed for 30 minutes. The reaction solution is thoroughly filtered, and Ffi is concentrated under reduced pressure.

The obtained oil is dissolved in benzene, washed with water, washed with Chongfu water, further washed with brine, dried over anhydrous magnesium L-acid, and the solvent is concentrated under reduced pressure to obtain a brown oil. The oil was separated and purified by silica gel column chromatography using benzene-ethyl vinegar as a developing solvent to obtain 4-methanesulfonyloxy-3-oxobutyric acid tert-butyl ester as a pale yellow oil.

NMR (ono13) δppm: 1.47 (9H,s) 3.14 (3H,s) 3.47 (2H,s) 4.89 (2H,s) Example 12 4-methanesulfonyloxy-3-oxo Butyric acid tert-butyl ester 1. Dissolve Of in 10 g+/ml of glacial acetic acid and add 386 wg of sodium nitrite and 1 drop of concentrated sulfuric acid under water cooling. After stirring the reaction solution at 10℃ for 20 minutes,
Add ethyl acetate and wash with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and then condensed, yellowish crystals are obtained.

When the crystals are recrystallized from ether-petroleum ether, 4-methanesulfonyloxy-3-oxo-
730 ml of 2-hydroxyiminoacetic acid tert-butyl ester was obtained. Melting point 103-104℃ (decomposition) NMR (ODOJ13 + on3cocn,) δpp
m1.56 (9H,s) 3.20 (3)1. s) 5.23 (2H, s) 11.93 (1H, s) Elemental analysis value 09H15NO7S Calculated value: 0,38.47; H, 5,38; N,
4.99; 8,11.41 Actual value: 0,38.4
1; H, 5, 37: N, 4.87: S, 11
．． ．． 32 Example 13 4-methanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester 2.8
Dissolve F in 3◎d dry cicada acetone and cool on ice for 2. ．． 0
7. Add I anhydrous potassium carbonate and 1.6m diethyl sulfate! Stir at warm temperature for 1 hour.

The reaction solution was poured into 300ml of ice water and extracted with ethyl acetate. The extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified by silica gel column chromatography using benzene-Sumori 100% as a developing solvent, 4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyric acid tert-glutyl ester was obtained as a colorless oil. 31 f
Obtained.

NMR (0DOj3) δppm: 1.27 (3H, t, J==7.Q') 1.54
(9H, 8) ・ 3.19 (3H, 8) 4.20 (2H, q, J=7.0) 54B (2
H,s) Example 14 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester 1
．． Dissolve 56F in 5wl of trifluoroacetic acid and hold at room temperature for 1
Stir for an hour. Concentrating the reaction solution yields a dark-colored oil. If the oil is left overnight, it will crystallize. Acetone <, @.

When the crystals obtained by concentration after treatment with decolorizing charcoal are recrystallized from methylene chloride-petroleum ether, 4-ethanesulfonyloxy-3-oxo-2-
995 ml of (syn)-methoxyiminobutyric acid was obtained. Melting point 85.5-89℃ NMR (heavy acetone) δppm: 1.40 (3H, t, J=7.Q, cH, aH2
so2o-)3.34 (2H,q, J=7.0.
cH3an2so2o-)4.13 (3H,s,
-aop-oo-)0H3 5,33 (2H,S, -80200H200-)11
．． 10 (IH, b, s, 0022) Elemental analysis value
CTHuOqNS Calculated value: 0,33.23; H, 4,38; N,
5.54: S, 12.67 Actual value: c, 33.1
6; H, 4,29; N, 5.49; 8,12
．． 67 Example 15 In the same manner as in Example 14, 4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester 80011& and trifluoroacetic acid 5 vtl were used to prepare 4-benzenesulfonyloxy-3
-Oxo-2-(syn)-methoxyiminobutyric acid was obtained as crystals.

NMR (heavy acetone) δppm: 4.06 (3H,s, Q-00H5) 5.17 (
2H,S, -802-0-an2oo-)7.37~
8.03 (5H, m, benzene: /1-4) 10.33
(IH,S, -00!) Example 16 4-methanesulfonyloxy-
From 3-oxo-2-(syn)-ethoxyiminobutyric acid tert-butyl ester 1.31 F and trifluoroacetic acid 10s+t, 4-methane, sulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyric acid is light brown. 980 grams of oil were obtained.

NMR (heavy acetone) δppm: 1.30 (3H, t, J=7.Q, η0OH20H
3) 5.20 (2H, S, -8020CJ500-)
10.28 (IH, S, oo 2 ships) Reference example 1 4-balatoluenesulfonyloxy-3-oxo-2-
(Syn)-methoxyiminobutyric acid 464 is suspended in 20% methylene chloride, cooled to -5°C, added with 0.204 L of triethylamine, and stirred for 5 minutes to form a solution. Add N7yd oxalyl chloride and 1 drop of dimethylformamide to this solution and stir at -5°C for 20 minutes. When the solvent is distilled off, 4-valatoluenesulfonyloxy-3-
Oxo-2-(syn)-methoxyiminoacetic acid chloride is obtained. Meanwhile, 530 caps of each paratoluenesulfonate of T-amino-3-methoxymethyl-3-cephem-4-carboxylic acid hivaloyloxymethyl ester were dissolved in 20 ml of methylene chloride and 0.394 g/ml of diethylaniline was added at -5°C. Additionally, a solution prepared by dissolving the above acid chloride in 10 g/methylene chloride is added. After stirring for 5 minutes at -5'c, concentrate the solvent. The resulting residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid. Dry with magnesium sulfate and concentrate.
A brown oil is obtained. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, 7-1-balatoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminonotyrylamino)-3-methoxymethyl- 3-cephem-4-
Carboxylic acid pivaloyloxymethyl ester was obtained as a colorless foam 51111F, NMIIL (ODO
JI3) δppm: 1.22 (9H, s, ter
t-Butyl) 2.43 (3H, S, o5 difference-
) 3.30 (3H,s, 3rd place-00H3) 3.51
(2H,s, 2-oH2-)4.10 (3H,S
, d-09! ! ! , )4.27 (2H,S, 3
position -0H2-)4.97 (IH,d,'J='5.
0.6th place - and) 5.07 (2H,S, -8O200
H200-) 5.53-5.97 (3H
, m, 7-position and ester's 00H20-) 7.20-7.93 (5H, m, 7-position- and Hensen's ring) Reference example 2 7-amino-3-methoxymethyl-3-cephem- 4-
A solution prepared by dissolving 360 μl of carboxylic acid benzhydryl ester and 300 μl of diethylaniline in 5 yxl of methylene chloride was prepared by the method of Reference Example 1, and 4-paratoluenesulfonyloxy-3-oxo-2-(syn)- A 10 resistant solution of methoxyiminobutyric acid chloride in methylene chloride is added dropwise at -5°C. After stirring for 30 minutes under water cooling, the reaction solution was washed with dilute hydrochloric acid and brine, dried over sulfur and magnesium, the solvent was distilled off, and the residue was purified by silica gel column chromatography. 3-oxo-2-(syn)-methoxyiminobutyrylamino)-
3-methoxymethyl-3-cephem-4-carboxylic acid
Benzhydryl ester was obtained as a slightly yellow powder.

Yield 420■ NMR (oDoJ3) δppm: 2.43 (3H,s) 3.30 (3H,s) 3.53 (21(,s) 4.08 (3H,s) 4.29 (2H,Q) 5.00 (IH, d) 5.09 (2H, s) 5.65 (IH, d, d) 6.90 (IH, s) 7.2 to 7.8 (MH, brs) Reference example 3? -(4-halatoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3
- Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (510 μl) was added with 5 liters of ethanol K IW Kashi 76 μg of thiourea and 841 #g of sodium acetate, and then 3 μg of water was added. Add little by little,
Stir at room temperature for 3 hours and 30 minutes. Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. Dry over magnesium sulfate and concentrate to give a pale brown foam. When this was separated and purified using silica gel column chromatography, 7-[2-
(2-aminothiazo-#-4-yl)-2-(syn)-
Methoxyiminoacetamide]-3-methoxymethyl-
392 ml of 3-cephem-4-carboxylic acid pivaloyloxymethyl ester were obtained as a colorless foam.

NMR, (cDo15) δppm: 1.22
(9)(,s, tert-Butyl)3.
30 (3H,s, 3rd place-00H3) 3.53 (2
H, S, 2&-1) 4.00 (3H, s, N 0OH2) 4.30 (
2H, s, 3-G) 5.0 et al. (1) 1. d,
J = 5.0.6th place - 2) 5.70 ~ 6.315 (5H
, m, once the 7th position, the side chain -N, and the ester's 〇C〇0
-) 6.63 (IM, =, aminothiazole ring 5th position -H
) 8.27 (IH, a, J = 9.0.7 position - trace) ゛Reference Example 4 According to the method of Reference Example )-methoxyiminobutyrylamino)-3-medoxymethyl-3-
Cephem-4-carboxylic acid propionyloxymethyl ester 4'90IIy, 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3- Cephem
4-Carboxylic acid propionyloxymethyl ester 3
I got 10 hits.

NMRCoDo15) δppm: 1.17 (3H, t) 2.41 (2H, q) 3.28 (3H, s) ・ 3.51 (2H, Q) 4.02 (3H, 8) 4.27 (2H, s) 5.08 (1B, d) 5.6~6.2 (5H, m) 6.67 (IH,s) 11G (IH, d) Reference example 5 The following compound was obtained by the same reaction as in Reference Example 3.

A) 7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester NMR (oncJ5) δppm: 1.30 (3H,t) 1.61 (3H ,d) 3.32 (3H,s) 3.57 (2H,8) 4.03 (3H,,s) 4.30 (21,S) 4.21 (2H,q) 5.10 (IH, d) 5.6-6.2 (3H, m) fi, 70 (IH, S) 6.92 (IH, q) 8.20 (1)1. d) n) 7-(2-(2-aminothiazol-4-yl)-
・2-(syn)-methoxyiminoacetamide]-3-
Methoxymethyl-3-cephem-4-carboxylic acid isobutyryloxymethyl ester NMR (OD (+45) δppm: 1.20 (6
H,d) 2.66 (IH,5eptet) 3.21 (3H,s) 3.40 (2H,q) 4.01 (3H,,s) 4.16 (2H,s) 5.05 (IH , d ) 5.6-6.2 (5H, m ) 6.65 (IH, s ) 8.06 (IH, d ) c) y-(2-(2-aminothiazol-4-yl')
-2-(syn)-methoxyiminoace)7mi)")-3
-Ethoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester NMR (ODOJ,) δppm: 1.19 (
3H,t ) 1.24 (9H,S ) 3.49 (2H, (1) 3.58 (2H,S ) 4.06 (3H,s ) 4.37 (2H,S ) 5.07 (IH , d ) 5.57 (2H, s ) 5.88 (2H,'s ) 6.04 (IH, d, d ) 6.76 (IH, S ) 7.90 (IH, d ) D) 7- (2-(2-aminothiazol-4-yl)-
2-(syn)-ethoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester NMR (0DOJ3) δppm: 1.22 (9H, s) 1.31 (3H, t) 3.30 (3H,S) 3.53 (2H,8) 4.28 (2H,q) 4.30 (2H2s) s, of (IH,a) 5.7~6.2 (5H, m) 6.76 (IH, s) 7.70 (1)1. d) Reference Example 6 7-(4-halatoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3
-methoxymethyl-3-cephem-4-carboxylic acid 65
0η, thiourea 183■, sodium acetate 148~. A mixture of 7s/methanol was reacted at room temperature for 5 hours, and ?
-r:2-(2-aminothiazol-4-yl)-2-
Methoxyiminoacetamide]-3-methoxymethyl-
3-cephem-4-carboxylic acid 360 wII was obtained. Add Honjima to 3 ml of methanol and add 1 s/ml of a 2M solution of sodium 2-ethylhexanoate in ethyl acetate to form a solution. Part of the solvent was distilled off under reduced pressure, and the precipitated crystals were collected by adding ethyl acetate and washed with ethyl acetate to obtain the above sodium salt of the carboxylic acid. Collection 1i35
0 Cape NMRδ (DM80-n2o) ppm: 3.
18 (3H,S) &34 (2H,br) 3.87 (3H,s) 4゜25 (2H,S) 5.00 (1)i, d) 5.59 (IH,d,d) 6. 74 (IH,s) 7.26 (2H,br) 9.52 (IH,d) Reference Example 7 4-ethanesulfonyloxy-3-okino 2-(syn)-, methoxyiminobutyric acid 480119 was converted to methylene chloride 20- Dissolve and cool to -5°C Q, 26311/triethyl aquine and 0.2.2 m4 oxalyl P.

Add lido and 1 drop of dimethylformamide: 2 ts at ℃.
Stir for 0 minutes. When the solvent is distilled off, 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride is obtained.

On the other hand, T-amino-3-methoxymethyl-3-cephem-
Dissolve 690 kg of 4-carboxylic acid pivaloyloxymethyl ester paratoluenesulfone 12 salt in 20 wl of methylene chloride, add 0.51-l of diethylaniline at -5°C, and then dissolve the above acid chloride in 101 methylene chloride. Add the liquid.

After stirring for 10 minutes at −5° C., the solvent is concentrated. The resulting residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid and water. After drying with 9 um of magnesium sulfate and concentrating, a brown foam is obtained. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, a colorless foam was obtained as 7-(4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutrylamino)-
632 N of 3-methoxymethyl-3-cephem-4-carvone cape pivaloyloxymethyl ester was obtained.

NMR (oDaj3) δppm: 1.22 (9H, s, t-nutyl)1.
43 (3M, t, J=7.9.0H30B28
020-)3.27 (2H,q, J=7.Q,
0) 130! ! ! 8020-)3.30 (3H,s
, 3rd place-00HI)3-54 (2H1b-s-2
position-〇〇2-)4.13-(3H,s, crystal-oOH5)
4.21i (2H,s, 3rd-5-)5.00 (
IH, d, J = 5.0.6 position - 2) 5.27 (2H
,8,-80200H200-)54D ~5.97
(3H, m, 7th position and ester 10OH20) T, ss (IH, d, J = 9.0.7th position - peek) Reference Example 8? -(4-ethanesulfonyloxy-3-oxo-2-
(syn)-methoxyimisoptylyl amino)-3-
Dissolve 632 μm of methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester in 8 μm of ethanol, add 91 μg of thiourea and 146 μg of sodium acetate, and then add 3 μg of water little by little. 5 hours at room temperature 3
Stir for 0 minutes. Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. Dry with magnesium sulfate and concentrate. and a brown foam was obtained. When this was separated and purified using a silica gel column with 20 columns, 1-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-, which is the same as the compound obtained in Reference Example 3, was obtained.
3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester as a colorless foam 44
011F was obtained.

Reference Example 9 Purified in the same manner as Reference Example 1 to produce 4-benzenesulfonyloxy-
3-oxo-2-(syn)-methoxyiminobutyric acid 350
T
-(4-benzenesulfonyloxy-3-okino-2-
(C<)-Methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester as a pale yellow foam at 510 W
Obtained.

NMR (cDO13) δppm: 1.22 (9H,s, t-Butyl) 3.30
(3H,s, 3rd-QOHt, )3.52 (2
H, b, s, 2nd position -0H2-)4, IQ (3H,S
, N-0CH,)4.27 (2H,S, 3rd-c
vH2-)4, H(IH, d, J=5.0.6 position-H
) s, oa (2H, S, 5O200H200) = 5.80-5.90 (3H, m, once the 7th position and the ester's 0OH20-,) 7.40-8.03 (5H, m, benzene ring- H) Reference Example 10 7-(4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4 was prepared in the same manner as in Reference Example 3.
-carboxylic acid pivaloyloxymethyl ester s1om
y From 76 g of tothiourea, 7-[2=(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacedeamide]-3-methoxymethyl-3-cephem-
4 to carboxylic acid pivaloyloxymethyl ester 00
4 obtained.

Reference Example 11 In the same manner as in Reference Example 1, 4-methanesulfonyloxy-
3-oxo-2-(syn)-methoxyiminobutyric acid 440
■ and 7-amino-3-methoxymethyl-3-cephem-
From 4-carvone M1-isopropyloxycarbonyloxyethyl ester 370■, 7-(4-methanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-
Cephem-4-carboxylic acid 1-inpropyloxycarbonyloxyethyl ester as pale yellow powder 4a
OS was obtained.

NMR (ODOJ3) δppm: 1.28 (6)1. d, J=6.0. Esther's? -00-0-OH(OH,)2) 1.55 (3H, d, J=6.0. Ester 〇-Co2-OH(OH3)00-) 3.17 (3H,S, 0H38020-) 3.
30 (3H,s, 3rd place -oCHB) = 3.53 (2H,bs, 2nd place -〇H2-)Y
= 4, f3 (3H, S, N-00H5) 4.24
(2H, s, 3rd place - bite o-) 4.80-5.10
(2H, m, 6-H and ester 543 (2H
,s, 8020di0O-)5.77 (1H,d,
d, J=5.0. J=9.0.7th) 6.83
(IH, m, ester 10020H(OH3)O-)
7.58 (IH, d, J=9.0.7th place - Takuichi)
Reference Example 12 In the same manner as in Reference Example 3, 7-(4-methanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4
- From carboxylic acid 1-isopropyloxycarbonyloxyethyl ester 480 ■ and thiourea 152 cape,
T-(2-(2-aphthiazol-4-yl)-2-
390 sy of (syn)-methoxyiminoacedo]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester was obtained as a colorless powder.

NMIIL (0DO13)δppm: 1.28 (
6H, d, J=6.0. x, x, Te/L's -oco
oan(aI(3)2) = 1.55 (3H, d, J=6.0. -C of ester
o20H(OH5)0- ) = 3.27 (3H,S, 3rd place -00H3) 3.53
(2H, bs, 2nd place ~ ra) 3.97 < 3H
,S,'E-00H,' )4.30 (2H,S,
3rd place -oI+2o-)4.60~5.15 (2H,
m, 6th position -H and ester 5.70-6.40 (3
H, m, -N on the 7th position -〇 and the side chain 5-f sol ring
1-12)

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Syn type) [In the formula, R_1 represents a phenyl group or lower alkyl group that may have a substituent, and R_2 represents a lower alkyl group. shows. ] An alkoxyiminobutyric acid derivative represented by