CA1152980A - PROCESS FOR PRODUCING 7-.alpha.-METHOXYCEPHALOSPORINS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
An improved process for producing a 7.alpha.-methoxy-cephalo-sporin of the formula wherein R1 and A are as defined hereinafter, or an ester, salt or amide thereof, which comprises reacting a compound of the formula

Description

~9BO
1 The present invention relates to a process for pro-ducing 7~-methoxycephalosporin derivatives. More particularly, it pertains to an improved process for producing a 7~-methoxy-cephalosporin of the formula:

~S~
R1SCH2C~H ~ 1 (I) N
OOH

wherein Rl is an organic moiety and A is a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acetoxymethyl group or a heterocyclic ring-substituted thio-methyl group, and its derivatives.
The 7-methoxycephalosporin of the formula (I) as above and its carboxyl group-substituted derivatives such as salts, esters and amides are known to be useful as an anti-microbial agent. In particular, 7-methoxy-7~-cyanomethylthio-acetamido-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-20 carboxylic acid, and 7~-methoxy-7~-(1,3,4-thiodiazol-2-thio-acetamido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are known to possess a potent antimicrobial activity against a wide variety of bacteria lJapanese Patent Publication (Kokai) No. 51-59890; J. Antibiotics, Vol. 29 (No. 9), 969 (1976)].
So far, several methods for the production of said ~: 7~-methoxycephalosporin derivatives have been known, but these methods are unsatisfactory for the commercial production-of said compounds. For example, it is reported in The Journal ` 30 of Antibiotics, Vol. 29 (No. 9), 969 (1976) that said 7~-methoxy-7~-cyanomethylacetamido-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl--- 1 -- ~

- l~S~3~

1 3-cephem-4-carboxylic acid is prepared in the following procedures:

N~

COOH _ +
COO M
(1) (2) EIO~H=~ ~ ~21~`CE2R

oo M COO M
(3) (4j OCH
> Ncc~2scH2coN~ ~

N ~ CH2R
COOH
However, the intermediate of the for~ula (4) was found ~: to be unstable and hence difficult to handle in our own experiment As the xesult of a study.on the production of 7~-methoxy-cephalosporin derivative, it has now been found that a compound of the formula:

R2so3cH2coN ~ S ~ (III) ., -OOH

- 2 -~ ~ . . . .

l~SZ980 1 which characteristically has a unique substituent, R2S03CH2CO-on the amino group at the 7-position, can advantageously be converted into the corresponding 7a-methoxycephalosporin compound and the resulting 7~-methoxycephalosporin compound can advantage-ously be employed for the production of the 7a-methoxycephalo-sporin derivatives of the formula (I) as above without removing the protective group at the 7-position.
Thus, the present invention provides a process for producing a compound of the formula:

c~
2 3C 2C ~ ~

o ~ N ~ (II) COOH

wherein R2 is a hydrocarbon moiety and A is as defined above, or its carboxyl group substituted derivative, which comprises re-acting a compound of the formula:

S
R2SO3cH2cONHT~ ~

200 ~ N ~ A (III) COOH

wherein R2 and A are defined above, or its carboxyl group-substituted derivative, with a halogenating agent in the presence of methanol and an alkali metal salt of methanol.
`~ The present invention also provides a process for producing a compound of the formula:

RlSCH2cONH~
30. ~ N ~ (I) COOH

~ ~ - -~15~0 1 wherein Rl and A are as defined above, and its carboxyl group substituted derivative, which comprises reacting a Gompound of the formula:

R2SO3CH2CONH ~ S ~ (III) O N ~ A
COOH

wherein R2 is a hydrocarbon moiety and A is as defined above, or.its carboxyl group-substituted derivative with a halogenating agent in the presence of methanol and an alkali metal salt of methanol to give a compound of the formula:

- 3 .
2 3 2 ~ S ~ (II) N

COOH

wherein R2 and A are as. defined above, or its carboxyl group-substituted derivative, and then reacting the compound of the formula (II) or its carboxyl group derivative with a thiol of the formula:

Rl-SH (IV) wherein Rl is as defined above or its salt.
As used hexein, the term "organic moiety" for Rl means any organic moiety which is inert to the reactions involved in : ~ the process of the present invention. Examples of such organic moieties are an aralkyl group (e.g. benzyl), an aryl group (e.g.
phenyl, naphthyl, etc.) ur a heterocyclic ring containing one ll:~o ~

1 or more nitrogen, sulfur or oxygen atoms (e.g. pyridyl, thia-diazolyl, tetrahydrofuryl, etc.), each of which may be substituted with a lower alkyl group such as methyl, ethyl or propyl, a halogen atom such as chlorine, a cyano group, a nitro group, a hydroxy group or a lower alkoxy group such as methoxy or ethoxy. The organic moiety can also be a lower alkyl group (e.g. methyl, ethyl,propyl, etc.) which may further be substituted with a halogen atom (e.g. chlorine, fluorine), a cyano group or a nitro group. The symbol A of the formulae (I), ! 10 (II) and (III) represents a hydrogen atom, a halogen atom (e.g. chlorine), a lower alkyl group (e.g. methyl, ethyl or propyl), a hydroxy group, a lower alkoxy group (e.g. methoxy, ethoxy or propoxy~, an acetoxymethyl group or a heterocyclic ring substituted thiomethyl group such as tetrazolthiomethyl, thiadiazolylthiomethyl, thiazoylthiomethyl, isothiazoylthiomethyl, oxadiazolylthiomethyl, triazolylthiomethyl, oxazolylthiomethyl or imidazolylthlomethyl. These heterocyclic rings can be substituted with a lower alkyl group (e.g. methyl, ethyl, etc.) which can also be substituted with a carboxyl, a sulfonyl or ~20 an amino. The term "hydrocarbon moiety" for R2 means any hydrocarbon moiety which is inert to the reaction involved in the process of the present invention. Examples of such hydro-carbon moiety are an aralkyl group (e.g. benzyl) or an aryl group (e.g. phenyl, naphthyl, etc.), each of which may be substituted with a lower alkyl (e.g. methyl, ethyl or propyl), a halogen atom (e.g. chlorine), a cyano group, a nitro group, a hydroxy group or an alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.). Another example of the hydrocarbon moiety for R2 are lawer alkyl groups (methyl, ethyl, propyl) which may 30 be substituted with a halogen atom, a cyano or a nitro. T~e hydrocarbon moiety for R2 may also comprise a vinyl group or an allyl group. The '' , --- llS;~8~3 1 term "carboxyl group-substituted derivative" means salts, esters and amides of the compounds concerned. Examples of such salts are an alkali metal salt such as lithium salt, sodium salt, potassium salt, etc., an amine salt such as triethylamine salt, N,N-dimethylbenzylamine salt, N,N-diethylbenzylamine, N,~-dimethylcyclohexylamine salt, N,N-diethylcyclohexylamine salt, cyclohexylamine salt or quinoline salt. Examples of said esters are lower alkyl esters (methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl esters), trimethylsilyl ester, 2-methyl ester, trichloromethyl trichloroethyl ester,

4-methoxybenzyl ester, benzyl ester, 4-nitrobenzyl ester, phenacyl ester, diphenylmethyl ester, bis-(methoxyphenyl)methyl ester or 3,4-dimethoxybenzyl ester.
In the present invention, the compound of the formula (II) and its carboxyl group-substituted derivative can be prepared by reacting the compound of the formula (III) or its carboxyl group-substituted derivative with an alkali metal salt of methanol in the presence of methanol at a temperature of -95 to -10C in an inert solvent, and then adding a halogenating agent at the same temperature as above. The reaction usually finishes in such a short period of time as 5 minutes to 2 hours.
Thereafter, a carboxylic acid such as formic acid or acetic acid is added to the reaction mixture to decompose excess of the alkali metal salt of methanol. When the reaction mixture contains unreacted halogenating agent, a reducing agent such as trimethyl phosphite, triphenyl phosphine or sodium thiosulfate is added to the reaction mixture after or before the addition of the carboxylic acid, thereby decomposing the unreacted halogenating agent. When either the starting material or the product is unstable and likely to decompose with an alkali metal salt of ~15~98D
1 methanol or a halogenating agent, the addition of the alkali metal salt of methanol and the halogenating agent is preferably carried out in two or more times so that the decomposition may be avoided.
As an alkali metal salt of methanol, lithium methoxide, potassium methoxide or sodium methoxide, etc. is used in this process, and, among them, lithium methoxide is preferable~
These alkali metal salts are prepared in a conventional manner, for example, by adding an alkali metal into methanol or an inert solvent containing an excess amount of methanol, ana the reaction mixture may be used without isolating the alkali metal salt of methanol in the process of the present invention.
In the process of the present invention, approximately 2 to 10 equimolar amounts of the alkali metal salt of methanol is reacted with one equimolar amount of the compound of the formula (III) or its derivatives in the presence of at least one equimolar amount, preferably a large excess of methanol.
As the solvent to be used in this process, there may be exemplified dimethylformamide, dimethylacetamide, hexamethyl-phosphortriamide, ethyl acetate, toluene, tetrahydrofuran,dichloroethylene, acetonitrile, acetone, chloroform or a mixture thereof.
As the halogena*ing agent, there may be exemplified chlorine, bromine, N-haloamides such as N-chloroacetamide or N-bromoacetamide, N-haloimide such as N-chlorosuccinimide or ~; N-bromosuccinimidè; N-halosulfonamide such as N-chlorobenzene-sulfonamide and an alkyl hypohalite such as t-butyl hypochlorite_ ; Among them, t-butyl hypochlorite is particularly preferred.
The 7~-methoxycephalosporin of the formula tI) and its carboxyl group-substituted derivative can be prepared by reacting '`"'` l~S29~
1 the compound of the formula (II) or its carboxyl group-substituted derivative with the thiol of the formula (IV) or its salt Generally, the process is conducted in the presence of a base in an inert solvent, but when the starting compound of the formula (II) or the thiol is used in the form of salt, the reaction can be carried out without adding any base. The reaction temperature is not particularly limited, but it is preferable to conduct the xeaction at a room temperature or below.
As the solvent used in this process, there may be exemplified usual solvents such as dimethylformamide, dimethyl-acetamide, water, acetone, dioxane, methanol, ethanol aceto-nitrile, methylene chloride, chloroform, tetrahydrofuran, dichloroethane, benzene, toluene, pyridine, ethyl acetate or a mixture thereof.
For the production of the compound (I) or its carboxyl group-substituted derivative, the reaction mixture of the aforesaid process may be used without isolating the product.
In this case, the thiol or its salt is directly added to the reaction mixture when the reaction of the compound of the formula (II) with a halogenating agent in the presence of methanol and an alkali metal salt of methanol has finished, and for the commercial production of the compound of the formula (I), this way is quite advantageous.

~ ~ As the salt of the thiol, alkali metal salts (e.g.
,.~
~1 lithium, sodium or potassium salt), amine salts (e.g. triethyl-- amine salt, N,N-dimethylbenzylamine, N,N-dimethylcyclohexylamine salt, N,N-dimethylcyclohexylamine salt or dicyclohexylamine salt) and quinoline salt are preferably used in the present invention.

1152~
1 Generally, the compounds of the formulae (II) and (III) and their derivatives are very soluble in said solvents and hence very conveniently used in the process of the present invention, but some salts thereof such as dicyclohexylamine salt are relatively low in solubility. In such a case, the salt is subjected to a further reaction after dissolving in a solvent by adding an equimolar amount of an acid such as p-toluene-sulfonic acid.

The compound of the formula (III) and its carboxyl group-substituted derivative can be prepared by reacting a compound of the formula:

H2N ~ S~ (V) o N~A
COOH

wherein A is as defined above, or its derivative with a compound of the formula:

RlSO3CH2COOH (VI) wherein R is as defined above, or its reactive derivative.

The derivative of the compound of the formula (V) includes the derivatives of the compound (V) of which amino or carboxyl group is substituted. Examples of such amino-substituted derivative are salts such as hydrochloride, acetate or toluene-sulfonate or the raction product of the compound (V) with a silyl compound such as bistrimethylacetamide. Exam~les of said carboxyl group substituted derivative of the compound (VI) are an acid anhydride, an acid halide, an acid azide or an active ester. Among them, a halide thereof ~e.g. chloride) is preferred.

1~ 80 1 The reaction is usually carried out in an inert solvent such as water,acetone, dioxane, dimethylformamide, aeetonitrile, methylene chloride, tetrahydrofuran, chloroform, diehloroethane, pyridine and the like at a room temperature or below (e.g. iee-cooling), but it is not particularly limited thereto. In this process, when the compound of the formula (VI) is used in the form of a free aeid or salt, it is preferable to earry out the reaetion in the presence of a condensing agent sueh as phosphorus triehloride, or eyclohexylearbodiimide.
Moreover, the reaction may preferably be carried out in the presence of a base such as alkali metal hydrogen earbonate, trialkylamine, dialkylaniline, pyridine, or dieyelohexylamine~
An alternative method for the production of the compound ~II) as above is as follows:

2 ~ S ~ + RlSO3CH2COOH >

~J~ ~,~
O ' ~ A or its reaetive derivative COOH

RlS03CH2CONH~S~ .

N ~ A

COOH
~ .

This-proeess ean be earried out in substantially the same manner as that of the produetion of the eompound of the formula (III) - from the eompound of the formula ~V) as explained above.
The eompound of the formula ~II) can advantageously be used for the produetion of the compound of the formula (I), and they are also useful as an antimierobial agent with a good antimierobial speetrum.

.

~`` llSZ9~0 ( 1 The following examples are given to illustrate the present invention more precisely, but the present invention is not limited thereto.
Example 1 Production of tosyl~lycolic acid Glycolic acid (38 g, 0.5 mole) was dissolved in water (150 g), and sodium hydroxide (20 g, 0.5 mole) was then gradually added and dissolved. This solution was cooled to 0 to 10C with ice, and to the solution were added a solution of p-toluenesulfonyl chloride (143 g, 0.75 mole) in e~her (500 ml) and a 20 wt% aqueous sodiumhydroxide solution (100 g~
at the same time over 30 minutes with vigorous stirring. After stirring for further 3 hours at 0 to 10C, the solution wàs separated into aqueous and organic layers. The aqueous layer was acidified to a pH of 1 with conc. hydrochloric acid to precipitate a white needle-like crystal.
The crystal was filtered with Nutsche filter, washed with water (500 ml) and dried under reduced pressure at 60C

to 80C to obtain 92 g of tosylgl~colic acid.
Melting point : 135 to 137C (known value 137C) Infrared spectrum ~nujol~ : 1710 cm Synthesis of 7~-[2-(p-toluenesulfonyloxy)acetamido]cephalo-sporanic acid and its salt p-Toluenesulfonyloxyacetic acid (2.3 g, 0.01 mole) was suspended in a mixture of methylene chloride (4.6 g) and dimethyl-formamide (0.02 g~, and after adding thionyl chloride (1.19 g, 0.01 mole), the suspension was heated under reflux for 3 to 5 hours with stirring.

~t the time when the suspension became an almost homogeneous solution, the solution was cooled to obtain a *Trade Mark - 11 -Al, ~iSZ980 1 solution of p-toluenesulfonyloxyacetic acid chloride in methylene chloride.
Using a separate reactor, 90%-purity 7-aminocephalo-sporanic acid (2.72 g) was suspended in dimethylformamide (10 g), and triethylamine (1.515 g, 0.015 mole) was dissolved therein with stirring. This solution ~las cooled to -10C to 0~C in an ice/sodium chloride bath, and to the solution was added dropwise the above methylene chloride, solution over 30 to 60 minutes with vigorous stirring. Thereafter, stirring was continued for further 60 minutes. Produced triethylamine hydrochloride was filtered and washed with dimethylformamide (2 g), and the filtrates were combined.
After adding acetone ~50 g) to the combined filtrate, dicyclohexylamine ~1.81 g, 0.01 mole) was added thereto with stirring, and thencrystals precipitated immediately. After stirring for further 1 to 2 hours, the crystals were filtered!
washed with acetone and dried under reduced pressure to obtain 4.8 g of the dicyclohexylamine salt of the objective compound ~yield : 80% based on 7-aminocephalosporanic acid).
Melting point : 173 - 175C (decomp.) NMR (CF3COOH) : ~
1 - 2.5 (20H), 2.3 (3H), 2.5 (3H), 3.4 (2H), 3.7 (2H), 4.8 (2H), 5.2 - 5.5 (3H), 5.9 (lH), 7.7 (7H), 8.2 (lH) Synthesis of 7a-methoxy---7~ [2-(p-toluenesulfonylox~)acetamido]
cephalosporanic acid and its salt The dicyclohexylamine salt of 7a-[2-(p-toluenesulfonyl-oxy)acetamido]cephalosporanic acid (10.7g) was added to a mixture of dimethylformamide (40 ml), tetrahydrofuran (16 ml) and ethyl acetate (40 ml) and p-toluenesulfonic acid (2.75 g) was 1~5~98t) 1 added thereto with stirring. This solution was cooled to -60C, and to the solution was added dropwise a lithium methoxide solution prepared from lithium (0.48 g) and methanol (26 ml) over 20 minutes.
ThereaEter, stirring was continued at -60C for further 30 minutesr and then a mixture of tert-butyl hypochlorite (3.75 g) and ethyl acetate (26 ml, diluent) was added dropwise thereto over 25 minutes. After stirring at -60C for further 10 minutes, the reaction was stopped by adding a solution of triphenyl phosphine (13 g) in ethyl acetate (60 ml) and acetic acid (2.1 ml).
The reaction solution was warmed to 5C in 40 minutes, and insolubles were filtered and washed with acetone (50 ml). The filtrates were combined, and ethyl acetate (600 ml) was added thereto. The precipitates were collected by filtration, washed with ethyl acetate and dried under reduced pressure to obtain the lithium salt of the objective compound.
IR (nujol) :~C=O 1780 cm 1 (~-lactam) NMR (CH3COOH) : ~ -2.30 (3H,s), 2.55 (3H,s), 3.60 (2H, broad s), 3.73 (3H,s), 4.86 (2H,s), 5.3 - 5.5 (3H,m), ~0 7.40 - 8.10 (4H,q), 8.50 (lH,s) mp : 179C (decomp.) Example 2 Synthesis of 7~-[2-(p-toluenesulfonyloxy)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its salt p-Toluenesulfonyloxyacetic acid (23 g) was suspended in a mixture of methylene chloride (75 g) and dimethylformamide (0.2 g), and after adding thionyl chloride (11.9 g), the suspension was heated under reflux for 3 to 5 hours with stirrin~.
3~ At the time when the suspension became an almost homo-geneous solution, the solution was cooled ta give a solution of p-toluenesulfonyloxyacetic acid chloride in methylene chloride.

115; :~8~
. . "

1 Using a separate reactor, 7-amino-3-tl-methyl-lH-tetrazole-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (32.8 g~
was suspended in dimethylformamide ~95 g), and after cooling the suspension to -10C, bistrimethylsilylacetamide (44.7 g) was gradually added dropwise thereto~ Thereafter, the suspension was warmed to room temperature and stirred until the suspended acid was completely dissolved. After cooling the solution to -30~ to -40~C, diethylaniline (14.9 g) was added, and then the above prepared methylene chloride solution was added drop-wise over 30 to 60 minutes, followed by stirring for 1 hour.
This reaction solution was poured into a mixture of ethyl acetate (200 ml) and distilled water (500 ml), and after con-fîrming that the pH of the aqueous layer was 2.0 to 2.5, the organic layer was separated. The aqueous layer was extracted with 100 ml of ethyl acetate for three times. The extracts and the above ethyl acetate layer were combined, washed with a sodium chloride-saturated water(60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure until the volume became 170 ml. Dicyclohexylamine (18.1 g) was added to the concentrated liquor, and then crystals precipitated.
After stirring for 1 hour, the crystals were collected by filtration washed with ethyl aoetate and dried under reduced pressure to give 67 g of the dicyclohexylamine salt o the objective compound.
NMR ~CF3COOHl : ~
1.0 - 1.3 (20H, m), 2.51 (3H, s), 3.1 - 3.7 ~2H, m), 3.83 ~2H, broad sl, 4.16 (3H, s), 4.3 - 4.9 (4H, m),

5.32 (lH, d), 5.92 (lH, q), 7.4 - 8.0 (4H, q), 8.12 ~lH, d) _ 14 -llS~g8~

1 Synthesis of 7~-methoxy-7~-[2-(p-toluenesulfonyloxy)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its salt The dicyclohexylamine salt of 7~-~2-(p-toluenesul~onyl-oxy)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid (23.1 g) and p-toluenesulfonic acid (5.5 g) were dissolved in a mixture of dimethylformamide (96 ml) and ethyl acetate (96 ml). After cooling this solution to -60C, a lithium methoxide solution prepared from lithium 10 (0.672 g) and methanol (49 ml) was added dropwise thereto over 35 minutes. Thereafter, the solution was stirred at -60C for minutes, and a mixture of tert-butyl hypochlorite (6.95 g) and ethyl acetate (48 ml, diluent) was added dropwise thereto over 45 minutes. After stirring at -60C for further 20 minutes, a lithium methoxide solution prepared from metallic lithium (0.224 g) and methanol (16.5 ml) was added dropwise over 20 minutes. After stirring at the same temperature for further 20 minutes, a mixture of tert-butyl hypochlorite ~1.74 g) and ~ ethyl acetate (12 ml, diluent) was added dropwise over 15 minutes. Thereafter, the reaction solution was stirred for further 15 minutes, and a solution of triphenyl phosphine (13 g) in ethyl acetate (60 ml) and acetic acid (4.5 ml) were added dropwise thereto. The reaction solution was then poured into a mixture of distilled water (800 ml~ and ethyl acetate (600 ml), and after adjusting the pH of the aqueous layer to 2.5 with lN hydrochloric acid, the ethyl acetate layer was separated from the aqueous layer. The aqueous layer was extracted twice w~th 200 ml of ethyl acetate. All the ethyl acetate layers were com~ined, washed with a sodium chloride-saturated water, dried over anhydrous magnesium sulfate and concentrated - 15 ~

~15Z980 1 under reduced pressure until the liquor volume became 260 ml.
After adcling dicyclohexylamine (5.9 g) to the concentrated liquor, c:arbon tetrachloride ~630 ml) was added thereto. The precipitates were collected by filtration, washed with carbon tetrachloride and dried under reduced pressure to obtain 19.2 g of the dicyclohexylamine salt of the objective compound.
IR (nujol) : 1778 cm 1 NMR (CF3COOH) : ~
1.0 - 2.3 (2nH, m), 2.49 (3H, s), 3.1 - 3.6 (2H, m), 3.60 (2H, broad s), 3.67 (3H, s), 4.10 (3H, s), 4.58 (2H, broad s), 4.76 (2H, broad s), 5.23 (lH, s), 7.35 - 7.93 (4H, q), 8.23 (lH, s) m.p. : 150C (decomp.
Example 3 Synthesis of 7a-methoxy-7~-[2-(4-pyridylthio)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid The dicyclohexylamine salt (1.81 g) obtained in Example 2 and 4-mercaptopyridine (0.233 g) were dissolved in a mixture of methylene chloride (30 ml) and dimethyl sulfoxide (0~2 ml), followed by stirring for 24 hours. The precipitates were collected by filtration, washed with methylene chloride and dried under reduced pressure to obtain the objective compound of high purity.
NMR (CF3COOH~ : ~
3.69 (5H, s), 4.15 (3H, s), 4.30 t2H, broad s), 4.3 - 4.9 (2H, q), 5.30 (lH, s), 7.8 - 8.7 (4H, q), 8.5 (lH, broad s) m.p. : 135C (decomp.) Example 4 Synthesis of 7~-methoxy-7~-cyanometh~lthioacetamido-3-1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its sodium salt ~ 1529~3 1 A mixture of cyanomethylisothiourea hydrochloride (3.03 g) and dimethylformamide (15 ml) was cooled to -50C with stirring, and a lithium methoxide solution prepared from metallic lithium (0.280 g) and methanol (21 ml) was added dropwise thereto over 10 minutes. Thereafter, the solution was stirred at -30C for further 10 minutes and poured, at -30C with stirring, into dimethylformamide (20 ml) containing the dicyclohexylamine salt (7.51 g) obtained in Example 2.
Thereafter, reaction was carried out at -20C for 1 hour, and acetic acid (2.4 ml) was added thereto. This reaction solution was then poured into a mixture of distilled water (100 ml) and ethyl acetate (100 ml), and the pH of the aqueous layer was adjusted to 2 with 2N hydrochloric acid. The ethyl acetate layer was separated from the aqueous layer, and the aqueous layer was extracted twice with 40 ml of ethyl acetate. All the ethyl acetate layers were combined, washed twice with 40 ml of a sodium chloride-saturated water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure until the liquor volume became 80 ml. A solution of sodium 20 2-ethyl-hexanoate (2.01 g) in ethyl acetate (20 ml) was then gradually added dropwise thereto. The precipitates were collected by filtration and dried under reduced pressure to obtain the sodium salt of the objective compound of high purity.
IR (nujol) : 1775 cm 1 NMR (CF3CO2H) : ~
-2.27 (3H, s), 3.55 - 3.85 (6H, not clear because of the overlapping of the peaks~, 3.72 (3H, s), 5.12 - 5.56 (2H, q), 5.31 (lH, s), 8.45 (lH, s) liS;~9E~
1 Example 5 Synthesis of 7~-methoxy-7~-[(4-carboxy-3-hydroxyisothiazole-5-yl)-thioacetamido]cephalosporanic acid 7-~ethoxy-7~-[2-(p-toluenesulfonyloxy)acetamido]cephalo-sporanic acid (9.7 g) was dissolved in methanol (90 ml), and the solution was cooled to 5C. To the solution was gradually added dropwise a solution of sodium salt trihydrate of 4-carboxy-3-hydroxy-5-mercaptoisothiazole (5.94 g) in distilled water (20 ml) with ice-cooling. Thereafter, the solution was stirred at 0C to 5C for 2 hours. Methanol was then re~moved under reduced pressurer and the solution was acidified to a pH of 1.5 with 2N hydro-chloric acid, and extracted three times with ethyi acetate.
All the ethyl acetate layers were combined, washed twice with a sodium chloride-saturated water and dried over anhydrous magnesium sulfate. Ethyl acetate was then removed under reduced pressure to obtain the objective compound of powdery form.
Example 6 Synthesis of 7~-methoxy-7~-2-(1,3,4-thiadiazolyl)thioacetamido-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its sodium salt A mixture of 2-mercapto-1,3,4-thiadiazole (0.36 g~ and dimethylformamide (2.5 ml) was cooled to -30C with stirring, and a lithium methoxide solution prepared from lithium (0.021 g) and methanol (1.5 ml) was added dropwise thereto. This solution was added at -3QC to a solution of sodium 7-methoxy-7~-~2-(p-tolucnesulfonyloxy)acetamido]-3-(1-methy~-lH-tetrazole-5-yl-thio-methylj-3-cephem-4-carboxylate (1.78 g) in dimethylformamide (12 ml). Reaction was carried out at -30C for 1 hour and then at -10C for further 3.5 hours. After adding acetic acid (0.2 ml), the reaction solution was poured into a mixture of distilled water (150 ml) and ethyl acetate (100 ml), and the pH of the 115Z~

1 aqueous layer was adjusted to 2.5 with 2N hydrochloric acid.
The organic layer was separated from the aqueous layer, and the aqueous layer was extracted twice with 100 ml of ethyl acetate.
All the organic layers were combined, washed twice with a sodlum chloride-saturated water and dried over anhydrous magnesium sulfate. After concentration, the residue was crystallized from isopropyl alcohol using sodium 2~ethyl-hexanoate. The crystal was collected by filtration and dried under reduced pressure to obtain the sodium salt of the objective compound.
IR (nujol) : 1775 cm 1 NMR (d6-DMSO) : ~
3.1 - 3.8 (2H, q), 3.41 (3H, s), 3.93 (3H, s), 4.15 -4.40 (4H, m), 4.93 (lH, s), 9.48 (lH, s), 9.57 (lH,s) Example 7 Synthesis of 7~-methoxy-7~-cyanomethylthioacetamido-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its sodium salt 7~-[2-(p-Toluenesulfonyloxy)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g) was dissolved in dimethylformamide (24 ml) with stirring. This solution was~cooled to -50C, and to the solution was gradually added dropwise a lithium methoxide solution prepared from metallic lithium (0.056 g) and methanol (4 ml). After stirring for 30 minutes, tert-butyl hypochlorite (0.434 g) was added dropwise.
After stirring for 20 minutes, a lithium methoxide solution prepared from metallic lithium (0.028 g) and methanol (2 ml) was gradually added dropwise. After stirring for 30 minutes, tert-butyl hypoclllorite (0.434 g) was added dropwise. After 20 minutes, an ~lCCH2SLi solution, which was obtained by adding li5;~

1 lithium methoxide [prepared from metallic lithium tO.17 g) and methanol (12 ml), at -30C with stirring, to a mixture of cyanomethylisothiourea hydrochloride (1.82 g) and dimethyl-formamide (9 ml)],was added to the rea~tion solution. The reaction solution was stirred at -30~C for 1.5 hours and then at -10C for further 20 minutes. After adding acetic acid (2 ml), the reaction solution was poured into a mixture of distilled water (200 ml) and ethyl acetate (100 ml), and the pH of the aqueous layer was adjusted to 2.5 with 2N hydrochloric acid. After separating the organic layer, the aqueous layer was extracted twice with 50 ml of ethyl acetate. All the organic layers were combined, washed twice with sodium chloride-saturated water, dried over anhydrous magnesium sulfate and treated with activated carbon. After concentration under reduced pressure, the residue was crystallized as sodium salt from isopropyl alcohol using sodium 2-ethylhexanoate. The crystal was collected by filtration and dried under reduced pressure to obtain sodium 7~-methoxy-7~-cyanomethylthioacetamido-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate.
The IR spectrum and NMR spectrum of this compound agreed completely with those of the compound obtained in Example 4.
Compounds represented by the formula, RSO3CH2COOH, could be synthesized in the same manner as in Example 1 or Acta. Chem. Scand. 22, 2043 (1968). The starting compounds shown below were obtained in the same manner as in Examples 1 and 2, and the objective compounds shown below were prepared from the starting compounds in the same manner as in Example 1 or 2.

RS03CH2cONH T l ~ ~ > RS03CH2CNH ~ S ~
Starting Objective ¦ l l compound O ~ N ~ A compound ~ N ~ A
COOW COOW' R A Starting compound Objective compound _ _ (W= ~ N ~ ) (~ a) NMR(CF3COOH):~ IR(nujol): ~C=O
C 3 ~ CH3- 1.0-2.4(20H,m), 1768 cm 1 2.37(3H,s), 2.52 NMR(CF3COOH):
(3H,s), 3.2-3.7 2.41(3H,s), 2.50 (2H,m), 3.53(2H, (3H,s), 3.2-3.5 broad s), 4.70 (2H,m), 3.63(3H,s), (2~,s), 5.23(1H,d), 4.78(2H, broad s), 5.71(1H,q), 7.4- 5.23(1H,s), 7.4-7.9 8.0(4H,q), 8.10 (4H,q), 8.35(1H,s) (lH,d) m.p.: 175-180C(decomp~

(W= ~ N ~ ) ~ H

~ NMR(CF3COOH):~ IR(nujol): ~C=O
-CH2- 1.0-2.3(20H,m), 1780 cm OCOCH 2.30(3H,s), 3.0-3.6 NMR(CF3COOH):
(2H,m),3.4-3.8 1.0-2.4(20H,m), (2H,q), 4.74 2.30(3H,s), 3.1-3.6 (2H,s), 5.07-5.47 (2H,m), 3.3-3.8 (3H,m), 5.85(lH,q), (2H,not clear because 7.5-8.7(8H,m) of overlapping) 3.60(3H,s), 4.82(2H, broad s), 5.19(lH,s), 5.12-5.55(2H,q), 7.5-8.7(8H,m) m.p.: 170-180C(decomp.) _ , 11 ~298~

R A Startlng compound Objectiv~ compound ~ H ~ (W' = Na) N - N NMR(CF3COOH): ~ IR(nujol): ~C=0 1772 cm 1.0-2.3(20H,m), NMR(CF3COOH): 3.52 -CH2S ~ N 3.1-3.6(2H,m), 3.78 (3H,s), 3.5-3.6(2H, CH3 (2H,broad s) 4.13 not clear because of (3H,s), 4.2-4.8(4H, overlapping), 4.08(3H,s) r m), 5.19(lH,d), 5.82 4.52~2H, broad s), 4.70 (lH,q),7.5~8.7(8H,m) (2H, broad s), 5.13 (lH,s), 7.5-8.7(8H,m) m.p.: 185C (decomp.
(W= -C(CH3)3) (W= -C(CH3)3) NMR(CDC13):~ IR(nujol): UC=0 1785 cm 1.55(9H,s), 2.07 NMR(CDC13): 1.55(9H,s), CH3- (3H,s), 2.45(3H,s), 2.06(3H,s), 2.44(3H,s), -CH2OCOCH3 3.2-3.7(2H,q), 4.52 3.1-3.7(2H, not clear (2H, broad s), 4.7- because of overlapping), 5.2(3H,m), 5.77(1H,q) 3.50(3H,s), 4.53(2H, 7.28-7.85[5H:(4H,q) broad s), 4.7-5.1(2H,q), +lH] 5.00(lH,s), 7.29-7.86[5H:
(4H,q)+lH]
m.p.: 150C (decomp.) (W= ~ N ~ ) (W'= ~ N ~ ) NMR(CF3COOH):~ IR(nujol): VC=0 1780 cm 1 N- N 1.0-2.3(20H,m), ¦NMR(CF3COOH):
CH3- CH2S ~ / 3.1-3.6(2H,m), 1.0-2.3(20H,m), CH3 3.27(3H,s), 3.1-3.5(2H,m), 3.70(2H,broad s) 3.28(3H, s),3.63(2H, .

llSZ980 .. .. . .
R A Starting compound Objective compound .__ 4.12(3H,s), 4.2-4.8 broad s), 3.69t3H,s), (2H,q), 5.00(2H,s), 4.10(3H,s), 4.57 5.26(1H,d), 5.89 (2H, broad s), 5.00 (lH, q), 8.03(1H,d) (2H, s), 5~25(1H,s), 8.24(lH, s) m.p.: 170C (decomp.) __ ......... . .
(W= ~ N ~ ) (W'=(CH3)2~H CH
IR(nujol):vC=0 1780cm NMR(CF3COOH): ~ NMR(CF3COOH): ~
1.0-2.3(20H,m), 2.24(3H,s), 2.93 2.25(3H,s),3.0-3.6 ~6H,d), 3.29(3H,s), CH3- -CH2OCOCH3 (2H,m), 3.28(3H, s), 3.3-3.7(2H, not clear 3.44-3.89(2H,q), because of overlapping~, 4.8-5.5(5H,m),5.93 3.68(3H,s), 4.32(2H, (lH,q), 8.03(1H,d) d), 5.01(2H, broad s), 5.26(lH, s), 5.0-5.5 (2H,not clear because of overlapping 7~3-7.6 (5H,m),8.29(1H, broad s) m.p.: 165C (decomp.) . _ _ . . ............ . .

¦ ~ ¦ ( <~11~> ¦
IR: ~C=0 1760 cm IR: uC=0 1770 cm ~ - N MMR(CF3COOH): ~ NMR(CF3COOH): ~
2H5- -CH2S ~ / 1.43(3H,t), 1.0- 1.43(3H,t), 1.0-2.4 CH3 2.4(20H,m),3.1- (20H,m), 3.0-3.6 3.6(2H,m),3.40(2H,q), (2H,m), 3.42(2H,q), ~52980 R A Starting compound Objectlve compound ¦
_ 3.80(2H, broad s), 4.13 3.6(2H, not clear (3H, s), 4.1-4.8(4H, m), because of overlapping), 4.97(2H, broad s), 5.23 3.67(3H,s), 4.12(3H,s), (lH, d), 5.90(lH,q), 4.55(2H, broad s), 8.00(1H,d) 4.97(2H, broad s), 5.23(1H,s~,6.0-6.9 (2H, broad s), 8.23 (lH,s) (W = H) (W'= ~ N ~ ) NMR(CF3COOH): ~ NMR(CF3COOH): ~
3.80(2H,s),4.10 1.0-2.3(20H,m), 3.0-N- N
CH2- -CH2S~ N (3H,s), 4.57(2H,s), 3.6(2H,m), 3.5-3.7 N 4.65(2H,s), 4.67 (5H, not clear because CH3 (2H,s), 5.23(lH,d), of overlapping) 5.86(lH,q), 7.46 4.06(3H, s)~ 4.55 (5H,s), 7.93(lH,d) (2H,s), 4.61(2H,s), -4.67(2H,s), 5.18(1H,s~ r 7.43(5H,s~, 8.03(1H,s) (W= ~ N ~ ) (W~- ~ N ~ ) NMR(CF3COOH): ~ NMR(CF3COOH): ~
N -INl 1.0-2.3(20H,m), 1.0-2.3(20H,m), 3.1-H2=CH- CH2S ~ ~ 3.0-3.6(2H, broad s), 3.6(2H, broad s), CH3 3.70(2H,s), 4.13 3.65(2H,s), 3.72(2H,s) r (3H,s), 4.33-4.76 4.13(3H,s), 4.61(2H,s), (2H,q), 4~87(2H,s~, 4.90(2H,s), 5.27(1H,s), 5.24(1H,d), 5.90(1H, 6.31-6.94(3H,m), 8.28 q), 6.3-6.7(3H,m) (lH,s) _ 8.13(lH,d) _ liS2980 Starting compound Objection compouna (W = ~ N ~ ) (W'= ~ N ~ ) NMR(CF3COOH): ~ NMR(CF3cOOH):
-1.0-2.3(20H,m), 1.0-2.3(20H,m), 3.1-3.6(2H, broad 3.1-3.6(2H, broad s), CH2=CHCH2- -CH2S ~ ~ s), 3.77(2H,s), 3.65(2H,s), 3.72 CH 4.0-4.2(5H,m),4.3- (3H,s), 4.13(3H,s), 3 4.7(2H,q), 4.97 4.15(2H,d), 4.62(2H,s), (2H,s), 5.20(1H,d), 5.03(2H,s), 5.27(1H,s), 5.43-6.17(4H,m), 5.47-6.17(3H,m), 8~22 7.99(lH,d) (lH,s) Compounds obtained in the same manner as in Examples 1 and 2 and thiols were treated in the same manner as in Examples 3 to 6 to obtain the compounds described below.

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Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound of the formula:

wherein A is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, an acetoxymethyl group or a heterocyclic ring-substituted thiomethyl group and R2 is an aralkyl group, an unsubstituted aryl group, an aryl group substituted with a lower alkyl group, a lower alkyl group, a vinyl group or an allyl group, and its ester, salt and amide, which comprises reacting a compound of the formula III:

(III) wherein R2 and A are as defined above, or its ester, salt or amide with a halogenating agent in the presence of methanol and alkali metal salt of methanol.

2. A process as claimed in claim 1 wherein R2 is an aralkyl group, an unsubstituted aryl group, an aryl group substituted with an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms.

3. A process as claimed in claim 1 wherein R2 is a benzyl group, a phenyl group, a naphthyl group, a methyl group, an ethyl group, or a propyl group.

4. A process as claimed in claim 2, wherein said halogenating agent is t-butyl hypochlorite.

5. A process as claimed in claim 2, wherein said alkali metal salt of methanol is lithium methoxide.

6. A process as claimed in claim 2, 4 or 5, wherein the amount of said alkali metal salt of methanol is 2 to 10 equimolar amounts per one equimolar amount of the compound of the formula III.

7. A compound of the formula:

wherein R2 and A are as defined in claim 1 when produced by the process of claim 1 or an obvious chemical equivalent.

8. A compound of the formula:

.
wherein R2 and A are as defined in claim 2 when produced by the process of claim 2 or an obvious chemical equivalent.

9. A compound of the formula:

wherein R2 and A are as defined in claim 3 when produced by the process of claim 3 or an obvious chemical equivalent.
10. A process for producing a compound of the formula:

wherein R1 is a lower alkyl group which may be substituted with a halogen atom, a cyano group or a nitro group; an aralkyl group; an aryl group or a heterocyclic ring containing one or more nitrogen, sulfur or oxygen atoms, said aralkyl group, aryl group and heterocyclic ring being unsubstituted or sub-stituted with a lower alkyl group, a halogen atom, a cyano group, a nitro group, a hydroxy group or a lower alkoxy group, or its ester, salt or amide which comprises reacting a compound of the formula:

Claim 10 continued ...

wherein R2 is an aralkyl group, an unsubstituted aryl group, an aryl group substituted with a lower alkyl group, a lower alkyl group, a vinyl group or an allyl group, and A is as defined above, or its ester, salt or amide with a halogenating agent in the presence of methanol and an alkali metal salt of methanol, and then reacting the resulting compound of the formula:

wherein R2 and A are as defined above, or its ester, salt or amide with a thiol of the formula:
. R1 - SH

wherein R1 is as defined above, or its salt.

11. A process as claimed in claim 10 wherein R2 is an aralkyl group, an unsubstituted aryl group, an aryl group substituted with an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms.

12. A process as claimed in claim 10 wherein R2 is a benzyl group, a phenyl group, a naphthyl group, a methyl group, an ethyl group, or a propyl group.