JPH026357B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides 3-cephem-4 by a novel reaction.
- It relates to a method for producing a carboxylic acid ester.

Conventionally, the method for producing 3-cephem-4-carboxylic acid ester is as follows: (1) 3-hydroxycephem-4-carboxylic acid is dehydrated, and then the obtained 3-cephem-4-carboxylic acid is treated by a conventional method. (2) 3-hydroxycepham-4-carboxylic acid is esterified by a conventional method, and then the obtained 3-
A method of dehydrating hydroxycefam-4-carboxylic acid ester is known. However, all of these methods require two steps and are not suitable for industrial use.

The inventors have discovered that 3-hydroxycepham-4
-While investigating the reactivity of carboxylic acids, when a haloformic acid ester is reacted with it in the presence of a base,
We discovered a new reaction in which dehydration unsaturation and esterification to 3-cephem occur simultaneously, and 3-cepheme-4-carboxylic acid ester is obtained in one step.
This invention has been completed.

The method of this invention is expressed by the following general formula.

(In the formula, R ¹ means an amino group or a protected amino group, and R ² means an esterified carboxy group.) Suitable examples included in each definition in the above formula are explained in detail as follows. It is.

Unless otherwise specified, the term "lower"
It has 1-6 carbon atoms, and the term "higher" refers to groups having 7 or more carbon atoms.

Protected amino groups include amino groups substituted with groups commonly used as protecting groups for their 7- or 6-position amino groups in cephalosporin and penicillin chemistry, and more specifically, acylamino groups, and groups other than acyl,
Examples include amino groups substituted with groups such as alkyl (lower) alkyl such as benzyl, phenethyl, and trityl.

Among these, the acyl moiety in the acylamino group includes aliphatic acyl, aromatic acyl and heterocyclic acyl. Here, aromatic acyl and heterocyclic acyl mean acyl containing an aromatic ring or a heterocyclic ring, respectively. Suitable examples of such acyl moieties are as follows.

Examples of aliphatic acyl include lower or higher alkanoyl groups such as formyl, acetyl, succinyl, hexanoyl, heptanoyl, and stearoyl, methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, heptyloxycarbonyl, and the like. Examples include lower or higher alkoxycarbonyl groups, and lower or higher alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, and heptanesulfonyl.

Examples of aromatic acyl include aroyl groups such as benzoyl, toluoyl, and naphthoyl; alkanoyl groups such as phenyl acetyl and phenylpropionyl; aryloxycarbonyl groups such as phenoxycarbonyl and naphthoxycarbonyl; Aryloxy (lower) alkanoyl groups such as cyacetyl and phenoxypropionyl, arylglyoxyloyl groups such as phenylglyoxyloyl and naphthylglyoxyloyl, and alkoxy (lower) alkoxy groups such as benzyloxycarbonyl and diphenylmethoxycarbonyl. Examples include carbonyl groups, arenesulfonyl groups such as benzenesulfonyl and para-toluenesulfonyl.

Examples of the heterocyclic acyl include a heterocyclic carbonyl group and a heterocyclic lower alkanoyl group. The heterocyclic moiety in the above heterocyclic carbonyl and heterocyclic lower alkanoyl group is a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom selected from nitrogen atom, sulfur atom, and oxygen atom. groups, among which preferable ones include, for example, thiazolyl group,
Isothiazolyl group, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
a 3- to 8-membered unsaturated monocyclic heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a thiadiazolyl group such as thiadiazolyl, 1,2,5-thiadiazolyl, and a dihydrothiadiazinyl group; 3-3 containing 1 to 2 sulfur atoms, such as a thienyl group, a dihydrodithinyl group, a dihydrodithiolyl group, etc.
Examples include 8-membered unsaturated monocyclic heterocyclic groups.

The above acyl moieties include, for example, lower alkyl groups such as methyl and ethyl, lower alkoxy groups such as methoxy, ethoxy, and propoxy, lower alkylthio groups such as methylthio and ethylthio, halogens such as chlorine and bromine, amino groups, and the like mentioned above. Protected amino group, cyano group, nitro group, imino group, oxo group,
Formula = N-OR ³ [In the formula, R ³ is a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, a lower alkenyl group such as vinyl, allyl, 2-butenyl, ethynyl, Protected groups such as lower alkynyl groups such as 2-propynyl, lower alkoxycarbonyl (lower) alkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, tert-butoxycarbonylmethyl, and 1-tert-butoxycarbonylethyl; It may have a suitable substituent such as a group represented by [meaning a carboxy-substituted lower alkyl group, etc.].

More preferred examples of protected amino groups as defined above include al(lower)alkanamide groups such as phenyl(lower)alkanamides such as phenyl acetamide, phenylpropionamide; Lower alkoxycarbonyl (lower) such as butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide
5 or 6 membered containing 1 sulfur atom and 1 to 2 nitrogen atoms substituted with an esterified carboxy(lower)alkoxyimino such as an alkoxyimino-substituted thiazole(lower)alkanamide Unsaturated monocyclic heterocyclic (lower) alkanamide group; 2-methoxyimino-2
- one sulfur atom substituted with lower alkoxyimino and acylamino such as thiazole (lower) alkanamide and one sulfur atom substituted with lower alkoxyimino such as (2-formamidothiazol-4-yl)acetamide;
Mention may be made of 5- or 6-membered unsaturated monocyclic heterocyclic (lower) alkanamide groups containing ~2 nitrogen atoms.

Examples of esters in esterified carboxy groups and haloformates include methyl ester, ethyl ester, propyl ester,
Lower alkyl esters such as isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, lower alkenyl esters such as vinyl ester, allyl ester, Lower alkynyl esters such as ethynyl ester and propynyl ester, acetoxymethyl ester, 1-acetoxyethyl ester, propionyloxymethyl ester, 1-propionyloxyethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, lower alkanoyloxy (lower) alkyl ester such as hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, methoxycarbonyloxymethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-( Lower alkoxycarbonyloxy (lower) alkyl esters such as isopropoxycarbonyloxy)ethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyf) Substituted or unsubstituted phenyl (lower) alkyl esters such as phenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Examples include aryl esters such as (lower) alkyl esters, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, and cumenyl esters.

More preferred examples of such esterified carboxy groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyl. oxycarbonyl, hexyloxycarbonyl,
Lower alkoxycarbonyl groups such as 1-cyclopropoxycarbonyl, benzyloxycarbonyl,
Al(lower) alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl such as phenethyloxycarbonyl, trityloxycarbonyl, diphenylmethoxycarbonyl and the like can be mentioned.

Salts include commonly used non-toxic salts;
Salts with inorganic or organic bases, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, Ethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salts, etc., and inorganic or organic acid addition salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, formates, acetates,
trifluoroacetate, maleate, tartrate,
Included are methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc., as well as salts with basic or acidic amino acids, such as salts with arginine, aspartic acid, glutamic acid, etc.

The reaction of this invention is carried out by reacting the compound () or a salt thereof with a haloformic acid ester in the presence of a base.

As the haloformic acid ester, chloroformic acid ester or bromoformic acid ester is frequently used.

As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, tertiary amines such as triethylamine and trimethylaniline, pyridine compounds such as pyridine, picoline, and lutidine, 1,5-diazabicyclo[4 , 3,0]-5-nonene, diazabicyclo compounds such as 1,5-diazabicyclo[5,4,0]-5-undecene, quaternary ammonium compounds such as Triton B, anion exchange resins, and the like.

Haloformates and bases are compounds ()
It is appropriate to use 2 times the mole or more for 3
It is preferable to use twice to four times the mole. Note that the molar numbers of the haloformic acid ester and the base may be the same or different. For example, the base may be used in excess relative to the haloformate.

This reaction usually involves acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran,
It is carried out in a solvent which does not adversely affect the reaction, such as conventional solvents such as ethyl acetate, N,N-dimethylformamide, or mixtures thereof. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or with heating.

In this reaction, R ¹ in compound ()
is an amino group or the protected amino group of R ¹ further contains an amino group or a protected amino group, a compound in which these groups are substituted with a substituted oxycarbonyl group derived from a haloformic acid ester () may be obtained, and the protecting group may be removed at that time, but these cases are also included in the present invention.

The compound () obtained by this invention has antibacterial activity and is useful as an antibiotic, especially an oral antibiotic.

Next, the present invention will be explained in more detail using examples.

Example 1 1.0 g (2.97 mmol) of 7-(2-phenylacetamido)-3-hydroxycephame-4-carboxylic acid was suspended in 10 ml of dry tetrahydrofuran and 10 ml of dry acetone, and 1.20 g (11.88 mmol, 4 times equivalent) of dry triethylamine was dissolved. ) to 20−25
Add at °C. Followed by 0.97g of ethyl chloroformate
(8.91 mmol, 3 times equivalent) at an internal temperature of 20-30℃ for 10
-Drop in 15 minutes. After continuing stirring at the same temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. Dissolve the residue in 30 ml of methylene chloride and wash sequentially with 10 ml each of saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid, and saturated aqueous sodium chloride solution. The methylene chloride layer is dried over anhydrous magnesium sulfate and concentrated to obtain 1.2 g of yellowish white crystals. This was suspended in 50 ml of isopropyl ether, washed, collected, and dried. The result was mp193-203℃ (decomposition), pale yellowish white crystals.
(2-phenylacetamide)-3-cephem-4
-Carboxylic acid ethyl ester 0.92g (yield 89.3
%).

IR spectrum (nujiol) 1770, 1720, 1660, 1630 cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.25 (3H, t, J = 8Hz), 3.55 (2H, s),
3.65 (2H, m), 4.25 (2H, q, J=Hz), 5.07
(1H, d, J=5Hz), 5.77 (1H, dd, J=5
Hz, 9Hz), 6.55 (1H, t, J=, 4Hz), 7.32
(5H, s), 9.09 (1H, d, J = 9Hz) ppm Elemental analysis (C ₁₇ H ₁₈ O ₄ N ₂ S) Calculated value C58.9, H5.2, N8.1 Experimental value C58.67, H5 .22, N8.02 Example 2 7-phenylacetamido-3-hydroxycepham-4-carboxylic acid 1.0 g (2.97 mmol)
in 10 ml of dry tetrahydrofuran and 10 ml of dry acetone and 1.20 ml of dry triethylamine.
g (11.88 mmol, 4 equivalents) at 20-25°C. Next, benzyl chloroformate 2.03g (11.88
(mmol, 4 times equivalent) was added dropwise over 10-15 minutes at an internal temperature of 20-30°C. After continuing stirring at the same temperature for 30 minutes,
Concentrate the reaction solution under reduced pressure. Dissolve the residue in 30 ml of methylene chloride, add 10 each of saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and saturated aqueous sodium chloride solution.
Wash sequentially with ml. The methylene chloride layer is dried over anhydrous magnesium sulfate and concentrated to obtain 1.2 g of brown crystals. Add this to isopropyl ether 50
ml, wash, remove, and dry.
mp157-161℃ (decomposition), pale brown crystal 7-(2-
(phenylacetamide)-3-cephem-4-carboxylic acid benzyl ester 0.87g (yield 68.5%)
get.

IR spectrum (nujiol) 1770, 1720, 1655, 1630 cm ^-1 NMR spectrum (DMSO-d ₆ ) 3.60 (2H, s), 3.65 (2H, m), 5.08 (1H, d,
J = 5Hz), 5.28 (2H, s), 5.79 (1H, dd, J
=5Hz, 8.8Hz), 6.61 (1H, t, J = 4Hz),
7.30 (5H, s), 7.41 (5H, s), 9.10 (1H, d,
J=8.5Hz) ppm Elemental analysis (C ₂₂ H ₂₀ O ₄ N ₂ S) Calculated values C64.7, H4.9, N6.9 Experimental values C63.98, H5.02, N6.79 Example 3 Using 1 g of 7-(thiophenamide)-3-hydroxycepham-4-carboxylic acid, the same procedure as in Example 1 was carried out to obtain 7-(thiophenamide)-3-cephaem-4- at mp73-92°C (decomposition). 0.88 g (yield 85.4%) of crystals of carboxylic acid ethyl ester is obtained.

IR spectrum (nujiol) 1765, 1725, 1655 cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.23 (3H, t, J = 7Hz), 3.62 (2H, m),
4.27 (2H, q, J = 7Hz), 5.15 (1H, d, J =
4.5Hz), 5.90 (1H, dd, J=4.5Hz), 8.5Hz),
6.52 (1H, t, J = 5Hz)), 7.17 (1H, dd, J
=3.5Hz, 5Hz), 7.81 (1H, d, J = 5Hz),
8.00 (1H, d, J = 3.5Hz), 9.40 (1H, d, J
=8.5Hz)ppm Example 4 The same procedure as in Example 1 was carried out using 1 g of 7-[2-tert-butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-hydroxycepham-4-carboxylic acid (syn isomer). 7-[2-3] of mp75-90℃ (decomposition)
0.65 g (63.7%) of butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid ethyl ester (syn isomer) is obtained.

IR spectrum (nujiol) 1785, 1725, 1685, 1635cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.27 (3H, t, J = 7Hz), 1.47 (9H, s),
3.62 (2H, m) 4.25 (2H, q, J=7Hz), 4.65
(2H, s), 5.17 (1H, d, J=5Hz), 5.91 (1H,
dd, J = 5Hz, 9Hz), 6.53 (1H, t, J = 4
Hz), 7.95 (1H, d, J = 2Hz, 9.17 (1H, d, J
= 2Hz), 9.55 (1, d, J = 9Hz) ppm Example 5 The same procedure as in Example 2 was carried out using 1 g of 7-[2-tert-butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-hydroxycepham-4-carboxylic acid (syn isomer). 7-[2-3] of mp75-88℃ (decomposition)
0.78 g (67.9%) of butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid benzyl ester (syn isomer) is obtained.

IR spectrum (nujiol) 1795, 1735, 1695, 1640 cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.45 (9H, s), 3,62 (2H, m), 4.65 (2H,
s), 5.18 (1H, d, J=5.5Hz), 5.28 (2H,
s), 5.97 (1H, dd, J=5.5Hz, 9Hz), 6.61
(1H, m), 7.43 (5H, s), 7.95 (1H, d, J
= 2Hz), 9.18 (1H, d, J = 2Hz), 9.60 (1H,
d, J=9Hz), ppm Example 6 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3
Approximately 1 g of an oil obtained by the same procedure as in Example 1 using 1 g of -hydroxycefam-4-carboxylic acid (syn isomer) was subjected to column chromatography (development) using 20 times the weight of silica gel. as the first fraction (solvent chloroform),
7-[2-methoxyimino-2-(2-ethoxycarbonylaminothiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid ethyl ester (syn isomer) at mp108-120℃ (decomposition)
0.2 g of powder (yield 16%) was obtained.

IR spectrum (nujiol) 1780, 1730, 1680, 1640 cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.26 (6H, t, J = 7Hz), 3.65 (2H, m),
3.90 (3H, s), 4.27 (4H, q, J=7Hz),
5.17 (1H, d, J = 5.5Hz), 5.90 (1H, dd, J
=5.5Hz, 9Hz), 6.55 (1H, m), 7.33 (1H,
s), 9.68 (1H, d, J=9Hz), 12.00 (1H,
br, s) ppm Elemental analysis (C ₁₈ H ₂₁ O ₇ N ₅ S ₂ ) Calculated values C44.7, H4.4, N14.5 Experimental values C43.84, H4.45, N13.73 As the following fractions, 7-[2-Methoxyimino-2-(2-formamidothiazol-4-yl)acetamide] at mp232-235℃ (decomposition)
0.33 g (yield 32.2%) of crystals of -3-cephem-4-carboxylic acid ethyl ester (syn isomer) is obtained.

IR spectrum (nujiol) 1770, 1720, 1685, 1655 cm ^-1 NMR spectrum (DMSO-d ₆ ) 1.25 (3H, t, J = 7Hz), 3.62 (2H, m),
3.93 (3H, s), 4.28 (2H, q, J=7Hz),
5.19 (1H, e, J = 5Hz), 5.93 (1H, dd, J =
5Hz, 8.5Hz), 6.57 (1H, t, J = 3Hz), 7.45
(1H, s), 8.53 (1H, s), 9.70 (1H, d, J
= 8.5Hz), 12.57 (1H, br s) ppm Elemental analysis (C ₁₆ H ₁₇ O ₆ N ₅ S ₂ ) Calculated value C43.7, H3.9, N15.9 Experimental value C43.53, H3.84, N15.89

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ means an amino group or a protected amino group) 3-Hydroxycepham-4-carboxylic acid or a salt thereof is reacted with a haloformic acid ester in the presence of a base. , general formula (In the formula, R ² means an esterified carboxy group, and R ¹ has the same meaning as above.)
Method for producing cefem-4-carboxylic acid ester.