JPS6226222A - Bacterial infection remedy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed description of the invention: NH-R (where R represents a hydrogen atom, R1 represents a saturated alkyl group having 1 to 4 carbon atoms, and A represents 1 hydrogen atom)
The parent represents an equivalent amount of alkali metal, alkaline earth metal, magnesium or organic amino base, and the wavy line is,! ? IIO
is a novel oxime derivative of 7-amituthiazolyl acetamidoce7allosboranic acid (indicating that R' can be in the syn position).

Examples of R' include methyl, ethyl, propyl, isopropyl, butyl, 5ee-butyl, and t-butyl groups.

Among the human bases, we can mention especially sodium, potassium, lithium, calcium or magnesium. Among the organic bases that can be represented by A,
Mention may in particular be made of trimethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, arginine or lysine.

Compounds of the present invention represented by Nh as having the 5ynld form can be represented by the following general formula.

More particularly, the subject of the invention provides that R represents a hydrogen atom, R1 represents a saturated alkyl group having 1 to 4 carbon atoms, A is a hydrogen atom, n) IJium atom or 5
It is a compound of the general formula (2) representing animal diethylamine.

Among the compounds of general formula I, mention may be made, in particular, of the compounds described in the Examples and, more specifically, the following compounds.

3-acetoxymethyl-7-(2-(2-amino-4-
thiazolyl)-2-methoxyiminoacetamide] syn isomer of Sepha-5-em-4-carboxylic acid, 5-acetoxymethyl-7-(2-(2-amino-4-
Syn isomer 1 of thiazolyl)-2-methoxyiminoacetamide]Sepha-5-em-4-carboxylic acid sodium salt 5-acetoxymethyl-7-(2-(2-aminoacetamide) obtained by the method of 7-4-thiazolyl)-2
-Methoxyimino-heptamide]Sepha-3-M-4
-carboxylic acid, 3-acetoxymethyl-7-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide)cepha-3-em-4-carboxylic acid obtained by the method described in Example 7. Sodium salt, 5-acetoxymethyl-7-
Syn isomer of the crystalline sodium salt of (2-(2-amino-4-thiazolyl)-2-methoxyiminoheptadoamide)cepha-3-em-4-carboxylic acid, 5 in hydrated or solvated form -acetoxymethyl-7-(
Syn isomer of the crystalline sodium salt of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide] heptafur 3-emu°4-carboxylic acid, 5-acetoxymethyl-7-(2-(2 -amino-4-
thiazolyl)-2-ethoxyiminoacetamide] Sepha-5-em-4-carbonyl, syn isomer and its salts with alkali metals, alkaline earth metals, magnesium or organic amino bases, 3-acetoxymethyl-7-[2 −
(2-Amino-4-4-azolyl)-2-((1-methylethoxy)imino)acetamido]Sefer 3-M-4-carboxylic acid, tyn isomer and its alkali gold 8
, salts with alkaline earth metals, magnesium or organic amino bases.

It is to be understood that the compound of the formula (1) described above can exist in the form represented by the formula (2) or (ii) in the form of a compound of the following formula (1z).

In addition, the subject matter of the invention is the following formula (7) 7-amino/cephalosporanic acid ti: the following formula n) ort' (where 1(, m, ay'', where l?' represents a saturated alkyl group having 1 to 4 carbon atoms)
The next device Σ is reacted with the IA substance or the functional derivative of this city! (where 1 (1 and t<' have the meanings given above)
The syu isomer of the compound of formula I is obtained by hydrolysis or hydrogenolysis of the member compounds in an acid medium.

(wherein R1 represents a saturated alkyl group having 1 to 4 carbon atoms), IIyn variant (formula II in which A represents a hydrogen atom)
corresponds to a compound of formula ), and in some cases the formula ■
A process for producing a compound of the general formula (2), which is characterized by forming a salt of the compound (2) by a conventional method.

In a preferred method of carrying out the above process, the 7-amine cephalosporanic acid is a functional derivative of the acid of formula H,
For example, treated with anhydrides or acid chlorides. Acid anhydrides can be formed in situ by reacting an acid with an alkyl chloroformate or dicyclohexylcarbodiimide.

other halides or other alkyl chloroformates,
Other anhydrides formed in situ by the action of dialkylcarbodiimides or other dicycloalkylcarbodiimides can also be used. Acid azides, activated acid amides or activated acid esters, such as human 1
1-xysuccinimide, p-nitrophenol <
Other acid derivatives such as the ester formed by 2,4-dinitrophenol can also be used.

When the reaction of the 7-amine cephalosporanic acid is carried out with a halide of the acid of general formula (1) or with an anhydride formed by isobutyl chloroformate, the reaction is preferably carried out in the presence of a basic agent. .

As the basic agent, for example, alkali metal carbonate N-
Trialkylamines such as methylmorpholine, pyridine or triethylamine can be chosen.

Examples of the acid hydrolyzing agent that acts on the compound (2) include formic acid, trifluoroacetic acid fermentation, and acetic acid. These acids can be used at 3% M anhydrous or as aqueous solutions. As a hydrogenolyzing agent, a zinc-acetic acid system, in particular, can be used.

To remove the t-butoxycarbonyl or trityl group, preferably anhydrous trifluoroacetic acid r19 or aqueous formic acid or l! k) Acid hydrolyzing agents such as im are used.

To de+1 the trichloroethyl group, preferably I
I! A lead-acetic acid system is used, and catalytic hydrogenation is used to prepare benzyl, dibenzyl and carbobenzyl compounds.

Compounds of formula V can be salt-formed by conventional methods. Salt formation can be carried out, for example, by combining these acids with inorganic bases such as sodium or potassium hydroxide or sodium bicarbonate or with salts of saturated or unsaturated aliphatic carboxylic acids such as diethyl acetate, ethylhexanoate or especially acetic acid. It can be produced by acting on

A preferred salt of the aforementioned acid is the lithium salt.

Salt formation can be produced by treating Ny with organic salts such as triethylamine.

For the preparation of salts, solvates of the free acid can also be used as starting materials in place of the free acid.

For example, solvates formed with water, phosphoric acid or alcohol can be used.

Dissolution with alcohol, especially ethanol/1”&lit
Qk &-,t, e.g., t, can be prepared by treating the solvate formed by phosphoric acid with a mixture of alcohol and water and then concentrating the solution.

This salt formation is preferably carried out in a solvent or solution mixture such as water, ethyl ether, methanol, ethanol or acetone.

Salts can be obtained in amorphous or crystalline form depending on the reaction conditions used.

The crystalline salts are preferably prepared by reacting the free acid or its solvate, such as the solvate formed with formic acid or ethanol, with one of the salts of the aforementioned aliphatic carboxylic acids, preferably sodium sulfate. It is created by @.

n) In the production of IJium salts, the reaction is carried out in a suitable organic solvent such as methanol. Such solvents may contain small amounts of water.

Furthermore, it is possible to convert amorphous salts into crystalline salts. For that purpose, an amorphous sodium salt (which may be in the form of a solvate with e.g. 0.5, 1.0 or 1.5 mol of water) is added with a suitable solvent (raft solvent, preferably medicinal). The Fk molecules such as /- are dissolved in fluorocarbons, then rectally or in other solvents such as ethanol, impropatol, 11-butanol,
Molten soluble It1. miscible with acetone, ether, and generally methanol. Crystallization can be caused by adding j.

If the starting material, solvent or two components contain water on opposite sides, crystals can be obtained in the form of hydrates. For example, S y of 3-acetoxymethyl-7-C2-(2-amino-4-thiazolyl)-2-methoxyimi/acetamide]cepha-5-M-4-calfone f14
The crystal tj:sodium salt of the n% compound is, for example, o5.
It can be isolated containing 1 or 15 moles of water.

The aforementioned r! of misfire IJIJ! In the A construction method, r of the formula [1
7 compounds (wherein R1 represents a saturated alkyl group having 1 to 4 carbon atoms, and alk represents an alkyl group having 1 to 4 carbon atoms) and treated with a base. After that, a compound of the following formula (wherein R' and alk have the meanings indicated above) is obtained, and a compound of formula 1. Upon treatment, a compound of the following formula V (where 12. represents a group that can be easily removed by acid hydrolysis or hydrogenolysis, and R1 represents a saturated alkyl group having 1 to 4 carbon atoms) is prepared by treating a compound of formula V with a base and then an acid.

In a preferred method of carrying out this process, the compound used to obtain the compound of formula 1v is potassium acetate. However, alkali gold 13 carbonates and acidic carbonates or dilute soda or potash can be used.

Functional readers of groups that can be easily removed by acid hydrolysis or hydrogenolysis are preferably used in the presence of triethylamine or other tertiary amino bases such as other trialgylamines, methylmorpholine or pyridine. It is a bordered trityl.

Other functional forms of groups that can be easily removed by acid hydrolysis or hydrogenolysis can also be used. Among these conductors, there is one on the spot (Krolli Mt
- butyl, tert-butyl azidoformate, trichloroethyl or benzyl chloroformate, mixed formyl acetic acid anhydride prepared in situ, benzyl or dibenzyl chloride or other halides, carbon hydrophthalic acid or N-carboxylate. It is possible to assign 1 degree of toxic phthalate.

The base used to saponify the compound of formula V is preferably soda, but other bases such as potash or parita can also be used.

The acid used to isolate the acid of formula (1) is preferably dilute hydrochloric acid, but 61. Acid or formic acid can also be used.

K, the subject of the present invention is the treatment with acids of the salts of the compounds of the formula I, in which R8 represents a group which can be easily eliminated by acid hydrolysis and R1 represents a saturated alkyl group having 1 to 4 carbon atoms. to obtain a compound of formula 1', or R5 represents a group that can be easily eliminated by hydrogenolysis and R' is 1 to 1.
Characterized by treating the salt of the compound of formula I' with 4 carbon atoms by hydrogenation and decomposition to obtain the salt of the compound of formula I'. can be attached.

1<1 represents a group that can be easily eliminated by acid hydrolysis, and R' represents a saturated argyl group having 1 to 4 carbon atoms. Acid used to hydrolyze the salt of the compound of 2) is preferably formic acid.

However, trifluoroacetic acid or ^1 acid can also be used. These levels can be used in 111 (water form), insects or as an aqueous solution.

Mountain represents a group that can be easily removed by hydrogenolysis,
Catalytic hydrogenation can be used as the hydrogenolyzing agent to act on the salt of the compound (2) in which R' represents a saturated alkyl group of 1 to 4 carbon atoms.

In addition, a compound (1 (where 1 is 1. to 4 carbons) ≦ (corresponds to the compound of the above formula 1v representing a saturated alkyl group having a child) 6;j:, the following formula ■1 (where alk4'i has the above meaning (having) with an alkylating agent to obtain a compound of the following formula (1), treating this compound with a brominating agent to obtain a compound of the following formula (2), and reacting this compound with thiourea and then with a base. Manufactured by.

The alkylating agent used to convert the compound of formula v1 to the compound of formula
9 alkyl (alkyl has 1 to 4 carbon atoms)
It is.

The brominating agent used to convert the compound of formula (1) to compound 14 (tH) of formula (1) is preferably a brominating agent.

The base used in No. i, in which thiourea is reacted with the compound of formula (2), is preferably an alkali metal b'l (acid acid salt or acidic carbonate).However, dilute soda or potassium or B[potassium may also be used. The subject of the present invention is also an alternative process for preparing compounds of formula I', which process comprises converting 7-amytuse7allosboranic acid of formula A saturated alkyl group having carbon atoms of J-) is reacted with an acid, 3'/11 isomer or a functional derivative of this acid to form the following formula (where 1 has the meaning given above) compound,
The syn isomer is obtained and the q'7 character is obtained by reacting this compound with thiourea to obtain the compound of formula B.

The reaction of 7-amitusephalosboranic acid with the acid of formula [a is carried out under the same conditions as the reaction of 7-amitusephalosboranic acid with the acid of formula (2).

The reaction between thiourea and the compound of formula (1) is preferably carried out in a neutral or acidic medium. This type of reaction is performed by Masak
It has been reported by Mr. i (JAC8, 90, 4508 (1968)).

Compounds of formula IIa used for the above-mentioned alternative methods of the invention may be prepared by combining functional derivatives of the chloracedel group with the following formula IV:
b (wherein R' represents a saturated argyl group having 1 to 4 carbon atoms, and alk represents an alkyl group having 1 to 4 carbon atoms) to form a compound of the following formula Va A compound of formula Va (1, where n I represents a saturated alkyl group having 1 to 4 carbon atoms) is prepared by treating a compound of formula Va with a base and then with an acid.

Functionality of chloroacetyl group 3j1! The conductor is preferably chloroacetic anhydride or monochloroacetyl chloride.
c is a halide.

If the reaction is carried out with a chloroacetyl halide, it is preferably carried out in the presence of the same basic reagents as mentioned above.

The base used to saponify the compound of formula VH is preferably soda, but other 1μ groups such as potash or baryta can also be used.

The acid used to isolate the acid of formula +18 is preferably a dilute salt, but acetic acid or formic acid can also be used.

The following formula vb (where R8 represents a group that can be easily eliminated by acid hydrolysis or water firs decomposition, R'b represents a saturated alkyl group having 1 to 4 carbon atoms, and aIk is 1 (representing an alkyl group having ~4 carbon atoms) (corresponding to a compound of formula V) can be easily eliminated from a compound of the following formula 1νH by metabolic water decomposition or decomposition of water b≦ Treatment with a functional derivative of the group gives a compound of the formula X T-1 which is converted by treatment with an alkylating agent.

The functional derivative of the group which can be easily eliminated by hydrolysis or hydrolysis by hydrogenolysis is preferably trityl chloride. The reaction is carried out in the presence of a base, preferably triethylamine. Other ring groups can also be used, such as trialkylamines, methylmorpholine or pyridine.

Other functionalities of groups that can be easily removed by acid hydrolysis or hydrogenolysis (? derivatives such as chloroformic acid or azide, fp t-butyl, trichloroethyl chloroformate or dibenzyl chloroformate, prepared in situ) Hybrid formyl-acetic anhydride, chlorinated or other halogenated benzyl or dibenzyl, phthalic anhydride or N-carbethoxyphthalimide may also be used. The alkylating agent used to prepare the compound of formula yb is Preferred are alkyl halide such as alkyl iodide or alkyl sulfate.

Here, since the configuration of the compound obtained from the compound of formula ■ can be maintained during synthesis, the configuration of the compound of formula ■ is the same as that of formula ■
It has been demonstrated that this is related to the configuration of the compound.

Also, the same thing or of course formula IV 8% IX' L
This also applies to compounds obtained from compounds of I and IV', since formulas tva, tvb and IV' are referred to in formula Iv.

The configuration of compounds of formula 1v depends on several parameters during the preparation of these compounds.

Therefore, the reaction of thiourea with the molding compound in an aqueous solvent, such as aqueous acetone or aqueous ethanol, or at ambient temperature, can be carried out in a substantially chemical manner using 1 to 3
It has been demonstrated that if the reaction is carried out over a very short period of time, on the order of hours, or if all of the above conditions are combined, 5ynli isomers can be obtained.

Therefore, for example, thiourea and the following formula 11 [where X represents a chlorine or bromine atom, and R'b is a hydrogen atom, a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, or 1 to
When X represents a chlorine atom (represents a saturated alkyl group having 4 carbon atoms), the curse is n I b represents a hydrogen atom or a saturated alkyl group having 1 to 4 carbon atoms (when X represents a bromine atom) thiourea, and by carrying out the reaction for a limited period of several hours. Compounds of formula IV can be prepared in the syn form by carrying out the work in an aqueous solvent or at ambient temperature or by carrying out the operation in combination with all of the above conditions.

Thus, the compounds of formula (1) obtained in Examples 1.6.8 and 11 have a syn configuration.

Compounds of general formula I are suitable for use on the one hand in Staphylococcus and Streptococcus Nt.
On the other hand, it is highly effective against Durham-positive bacteria, especially against penicillin-resistant Staphylococcus FS bacteria, and on the other hand against Durham-negative bacteria, especially Coliform, Klebsiella, Salmonella, and Proteus bacteria. It has good anti-inflammatory activity.

These properties make the pharmaceutically acceptable Cedar compounds useful in the treatment of infections caused by susceptible organisms, in particular for example staphylococcal sepsis, malignant facial or cutaneous staphylococcal infections, encephalitis, putrid or inflamed ulcers,
This makes it suitable for use as a drug in the treatment of staphylococcal infections such as anthrax, erysipelas, acute early influenza or post-influenza staphylococcal NLA infection, bronchopneumonia and pneumonia+ICa.

These ]Ji-acceptable compounds are useful in the treatment of coliosis and related infections, infections caused by Proteus, Klebsiella and Salmonella F4 bacteria, and other diseases caused by Durham-negative bacteria. It can be used as a voting agent.

The subject of the invention therefore provides the above-mentioned pyrotechnic pharmaceutical m°
It extends to pharmaceutical compositions containing as an active ingredient at least one of the compounds described in Example W, in particular the syn-linked compounds described in Example W.

Among these compositions, especially those in which R represents a hydrogen atom
Mention must be made of pharmaceutical compositions containing as active ff component at least one compound of the general formula (2) in which R1 represents a saturated alkyl group having 1 to 4 carbon atoms and represents a hydrogen or sodium atom.

In particular, we must mention pharmaceutical products containing the following compounds as active ingredients:

5-acetoxymethyl-7-(2-(2-amino-4-
Thiazolyl)-2-methoxyiminoacetamide]Sepha-3-em-4-carboxylic monomer, syn isomer, this compound is described in particular in Example 2.4.10 or 12.

3-acetoxymethyl-7-(2-(2-amino-4-
Sodium salt of thiazolyl)-2-methoxyiminoacetamide]cepha-3-em-4-carboxylic acid, syn
Isomers. This compound is particularly described in Example 5.

5-acetoxymethyl-7-(2-(2-amino-4-
thiazolyl)-2-methoxyimiguacetamide]Crystalline salt of Sepha-3-em-4-carboxylic acid, IJum salt, syn isomer.

At least one of the following compounds, 3-acetoxymethyl-7-(2-(2-amino-4-
3 -acetoxymethyl-7-(2-(2-amino-4-
Thiazolyl)-2-((1-methylethoxy)imino)
Acetamide] Sepha-3-M-4-carvone'f5
, s'Jn isomers and their alkali gold 5S % alkaline earth metals, magnesium or (, ■ pharmaceutically acceptable 8, C1 with organic amino bases) It can be administered intracutaneously or topically by local application to the skin and mucous membranes.

They can be solid or liquid, pharmaceutical forms commonly used in human medicine! ■For example, tablets or T1Q coated tablets, gelatin capsules,
It can come in the form of ointments, creams, and gels.

They are manufactured by conventional methods. The active ingredients can be combined with the auxiliaries commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, coco butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin. derivative,
It can be incorporated into glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

The dosage may vary depending on the condition being treated, the patient, the route of administration and the compound under consideration. This means, for example, that for the compounds described in Examples 2 or 5, between 0.250.9 and 4 I per day for oral O administration in men and 3 I per day for the intramuscular route.
0.500 times,! It can be between 7 and 1 g.

In addition to the compounds described in the Examples, the following compounds are further examples of compounds obtainable according to the present invention.

3-acetoxymethyl-7-(2-(2-ami/-4-
thiazolyl)-2-propyloxyiminoacetamide] Sepha-5-em-4-carboxylic acid, syn isomer and its salts with alkali metals, supra-alkali metals, magnesium or organic amino salts, 3-acetoxymethyl-7- (2-(2-amino-4-
deazolyl)-2-butyloxyiminoacetamide]
Sepha-3-M-4-carboxylic acid, syn isomer and its alkali gold J! S4 N Salt with alkaline earth metal, magnesium or organic amino 1-rich group, 3? Acetoxymethyl-7-(2-(2-ami7-4-thiazolyl)-2-
(2-Methylpropyloxyimino)acetamidoxafer 3-em-4-jblMnm, S)'n isomer and its salts with alkali metals, alkaline earth metals, magnesium or organic amino bases, 3-acetoxy Methyl-y-(,2-(2-amino-4
-thiazolyl) -2-(1,1-dimethylethoxyimino)acetamidoxefer 3-em-4-carboxylic acid, Syn isomer and its salts with alkali metal, alkali metal, magnesium or organic amino groups [ Mix 1 g of γ-chloro-α-methoxyimino-heptylethyl acetate, 3 CC of absolute ethanol, and α42y of ground thiourea. Stir the whole thing at ambient temperature for about 2 hours. When this is diluted with 60cc of water, the @ acid salt crystallizes out, but the whole is stirred, vacuum filtered, washed, and dried.
5■ of hydrochloride is obtained. This is dissolved in 4 CC of water at 50°C and potassium acetate is added until it becomes I) H6, and the liberated amine crystallizes out. Cool the whole, vacuum-filter,
The residue is washed with water and dried to obtain 270 W of the expected compound.

', (P = 161 °C0 The resulting compound has a syn configuration.

N', (R(CDCI, 60MH2) ppm: 4
(N-OCH3), 6.7 (thiazole ring proton)
4.6 g of the compound prepared in the above step are dissolved in methylene chloride at 92 eC at 30°C. The solution was cooled to -10°C, 19 cc of triethylamine was added, the whole was then cooled to -35°C, and 15 cc of trityl chloride from 6.1.9 was added.
Add over a period of minutes and allow the whole to return to ambient temperature. It took 1 hour and 30 minutes in total. Wash with water, then with α5N hydrochloric acid, then with acetic acid (IJum) aqueous solution. Dried, concentrated, dissolved in ether, concentrated again, then dissolved in methanol, added water and ninal, the whole crystallized, vacuum filtered, then washed with ether, and concentrated on 6.15 pm. Obtain the compound. MP-120°C. The resulting compound has a 5yrt configuration.

7.01 g of the ester obtained in B! 15cc
of dioxane. The solution was heated to 110℃ in an oil bath.
Tonashi, qcco) Add 2N soda for 5 minutes,
The whole is then left to stand for 30 minutes while stirring under reflux. Sodium salt crystallizes out. The whole was cooled, filtered in vacuo, washed with dioxane, then with erthyl, and 5.767:! of salt. Concentrate the mother liquor to obtain a secondary yield of to 179, thus a total of 6.7849 salts.

3. Add the salt of a g i to 6'5CC methylene chloride and 6
5C (: (7) The whole is washed with water, dehydrated, and concentrated to dryness to quantitatively obtain the free acid. The obtained compound has a syn configuration.

NMR (Dλ180.60MH2) pPm: 368
(N-ocHs), 6.6 (proton of thiazole ring) Step D: 6-acetoxymethyl-7-(2-(2^tritylamino-4-thiazolyl) 1 5 occ of the dried acid obtained in Step C Dissolved in dry methylene chloride of C.
L7B! Add dicyclohexylcarbodiimide from step 9,
Stir the whole thing at ambient temperature for 1 hour. The generated dicyclohexyl urea was vacuum filtered, the r liquid was cooled to -10'C, and the temperature was reduced to 1.011 7? Amino 7 Juarosboranhi 13
Add a solution of α9 CC in methylene chloride at 0C and triethylamine. Return the whole thing to ambient temperature and
cc of acetic acid was added, the whole was vacuum filtered, the residue was washed with water containing hydrochloric acid, washed with water, dehydrated, concentrated to dryness,
Wash with 0-dioxane and add 1 cc of water and 3C'C of saturated acidic sodium carbonate solution.

Mix everything, vacuum filter, wash, and concentrate to dryness.

Wash with methylene chloride, 10 CC of water and 5 CC of 1N
Washed with hydrochloric acid, decanted, washed with water, dehydrated,
Trituration in ether gives 1.747 g of crude product, which is purified by dissolving in ethyl acetate and then precipitation with ether.

A pure compound of 1255E is obtained. The resulting compound is syn
It has a steric configuration.

The gamma-chloro-alpha-methoxyiminoacetylacetate ethyl acetate used at the beginning of Example 1 was prepared as follows.

22.5. Ethyl γ-chloro-α-oximinoacetylacetate of F.I.T. is placed in 100 CC of methylene chloride.

Place the whole in a water bath and - while stirring - slowly add 27 sec of fresh diazomethane solution (containing 21.6 g/). The whole is left in contact for 5 minutes to allow excess diazomethane to decompose with a small amount of alumina. The residue is reduced to 2i% and then purified by layering on silica with methylene chloride. The expected compound of 1 j, 93 ti is obtained.

2-(2-amino-4-thiazolyl)-2 used in Example 1
-Ethyl methoxyiminoacetate was also prepared as follows.

180 g of crude ethyl tJ2-a7-ethyl-2-hydroxyiminoacetate are placed in 900 CC of pure acetone. 23
4 g of potassium carbonate was added at 10°C under nitrogen, then 1
Introduce 03CC of dimethyl sulfate.

Stir the whole thing at ambient temperature for 3 hours, add ice and stir the whole thing for 4 hours.
1 in water, extracted with methylene chloride, washed with water, dried, and the solvent was removed. 185! ! The desired compound is obtained.

The compound obtained in step a of 1971 is placed in 1j of methylene chloride and 200q of p-toluenesulfone are added. 1/1 of a solution of 1911 pure bromine dissolved in 200 CC of methylene chloride is introduced at 20'C. When the reaction starts, the remainder of the bromine solution is introduced over a period of 1 hour at about 20°C. The whole is then left at 25°C to complete the reaction. This is washed with ice water, extracted with methylene chloride, dried and the solvent is driven off. The expected compound of 268I is obtained.

21 Ethyl methoxyiminoacetate 80g of thiourea was mixed with 2700C ethanol and 540C
C into water. The compound obtained in step β of 268.9 is introduced into 270 CC of ethanol under nitrogen for half an hour. Stir the whole at about 20"C for 1 hour. Cool to about 15"C and add acidic potassium carbonate in portions until pH 5. Vacuum-filter the whole, wash with water, dehydrate,
8 g of the expected compound are obtained. The compound obtained is the same as that obtained in step A.

0.9759 of the compound obtained in Example 1 with 4 Cc of 50
% aqueous formic acid for 10 minutes at 55°C.

Add 4 CC of water, vacuum filter the whole and concentrate to dryness under reduced pressure. α428
A pure compound of 9 is obtained.

Analysis: C1, H, D0. N, S2 Calculation 20% 42.19H% 3.76N% 15.37S%
14.08 actual measurement: 42.3
4.1 15.2
15.8 The resulting compound has a syn configuration.

NMR (DMSO160MHz) ppm: 2.03
(-C-CHs), doublet 9.58 J -8Hz
(CONH), 17b (proton of 4y sol ring) Min salt dishikuta hexylcarbodiimide and 7- of 40.8.9
2 in anhydrous form prepared using amitusephalosborane acid. (2-)ditylamino-4-thiazolyl)-2
- Crude 3-acetoxymethyl-7-(2-
(2-Tritylamino-4-thiazolyl)-2-(methoxyimino)acetamide]Sefer 3-em-4-carboxylic acid is dissolved in dioxane at 350 CC. While stirring, slowly add 350 CC of sulfuric ether followed by 33 CC of diethylamine. The whole is stirred for 20 minutes and the crystallized jetanolamine salt of 2-(2-)dithylamino-4-thiazolyl)-2-methoxyiminoacetic acid is removed under vacuum.

This salt is washed twice with 30 cc of the above dioxane-ether mixture to obtain a mass of 62.6:i. Concentrate Solution P to a syrupy consistency and add approximately 2.5 parts of sulfuric ether. Stir the whole thing and vacuum filter. 110.3N
The desired diethylamine salt is obtained.

The resulting compound has a syn configuration.

180 where the compound obtained in Example 5 of 56p was kept at 50°C.
Add to CC50% aqueous formic acid. The whole is stirred at 50° C. for 20 minutes and the triphenyl carbinol formed is vacuum filtered. 180cc of ethanol is added and the whole is concentrated to dryness under reduced pressure. The residue is mixed with 100 cc of water and 20 cc of water.
Dissolve it in 100 cc of water, stir for 15 minutes at 15 °C, vacuum-filter, wash with water, then with ether, and concentrate again.
5.6JF of the expected compound is obtained.

This compound is identical to that obtained in Example 2.

4 5.55 N pure 3-acetoxymethyl-7-(2-(2-amino-4
-thiazolyl)-2-(methoxyimino)acetamide]Sefer 3-M? Mix the 4-carboxylic acid with 100 CC of distilled water. Gradually add 8 g of acidic sodium carbonate while adding about 20'cc of ethanol.

Add 80cc of ethanol and 4.5g of activated carbon to this, stir the whole thing for 5 minutes, filter, wash with ethanol, and place under vacuum. a.Condense to dryness. Dissolve in 100 cc of ethanol, concentrate to dryness, and dissolve the residue in 100 cc of methanol. Two portions of acetone are added, the whole is stirred vigorously, vacuum-filtered, washed with acetone and then water. After drying under vacuum, a white product of 43.7.9 is obtained, which is rehydrated in air to a final weight of 45.2 g.

[・) 20-, +s s°±2° (08%, water)
.

Analysis: Calculation: 0%40.24H%3.313N%14.67s
%13.43 Nam4.81 actual measurement: 4α3
5,8 14,4 13.3 4.8
4 The resulting compound has a syn configuration.

NMR (/IOMHz D2 o) ppm: 2.01
(COCH3), doublet 9・ss J=8Hz (NH
CO), 6.75 (proton of thiazole) 〒3〒Emu 4-carboxylic acid Step A: 2- (2-completed minnow 4-hand Tezo 10 Ha-2
-Ethyl ethoxyiminoacetate a) 19.4.17) Ethyl γ-col-α-oximinoacetoacetate with 60 CC of acetone and 14.3 C
Place C in diethyl sulfate. The whole is cooled in a water bath for 10 minutes, 55 CC of 2N soda is added in 30 minutes, and the whole is stirred for 40 minutes.

b) Add Z6.9 thiourea to the reaction medium, heat it at 55° C. for 20 minutes, drive off the acetone, dissolve the residue in ethyl acetate, add 6.9 g of potassium carbonate and heat the whole. Stir, decant, extract with ethyl acetate, dry and concentrate to dryness. The residue of 17.4 F is separated and chromatographed on silica eluting with ether. The desired compound is recovered, dissolved in isopropyl ether, filtered in vacuo, washed and dried, 2.1
g of the desired compound @MP=129°C. The resulting compound has a syn configuration.

3, the compound obtained in step A of 161, 6 CC of dry dimethylformamide, 12 CC of cyclized methyl L/N and 1
．． 89 Cc of triethylamine is placed under inert gas. Cool the mixture to -15°C and slowly add 398I trityl chloride. The whole is left to stand for half an hour, the temperature is raised to +10°C, and the whole is then kept alive at ambient temperature for 3 hours. Add 13 CC of 1N hydrochloric acid, stir the whole, decant, wash with 1N hydrochloric acid and then with water. Extracted with methylene chloride, dried, concentrated to dryness,
．． 89 g of crude residue are obtained.

The resulting compound has a syn configuration.

7. A mixture of 89 g of the compound obtained in step B, 400 C dioxane and 19.5 CC was heated at 110 °C for 1
Heat for an hour. The mixture is filtered under vacuum, washed with an ether-dioxane mixture and then with ether alone, and dried. 625 g of the sodium salt was obtained, which was dissolved in 60 cc of methylene chloride and 20 cc of IN salt R, the two phases were stirred, 200 cc of methanol was added, the whole was decanted, washed with water and diluted with a methylene chloride-methanol mixture. Extract, dehydrate, and concentrate to give 5.85 fl of pure 2-
(2-)Ritylamino-4-thiazolyl)-2-ethoxyiminoacetic acid is isolated.

The resulting compound has a Syn configuration.

3.4 g of 2-(2-)dithylamino-4achiazolyl)-2-ethoxyiminoacetic acid obtained in Step C was heated at 34C.
Cool the suspension in methylene chloride at 970 °C.
η dicyclohexylcarbodiimide is added, the whole is washed with methylene chloride and stirred at ambient temperature for 1 hour. Dicyclohexyl urea is vacuum-filtered.

The P solution was cooled to -20°C, and to 2g of 7-amitusephalosboranic acid was mixed with 18CC of methylene chloride and tO6C.
A solution of C in triethylamine (chilled to -20°C) is added all at once.

Heat the whole thing for 1.5 hours, add 18 cc of acetic acid,
CC 1N hydrochloric acid is added, the whole is stirred, decanted, washed with water, extracted with methylene chloride, dried and concentrated to give 4.56 g of the expected compound.

The resulting compound has a syn configuration.

The compound obtained in Example 6 of 4,56 fi was added to 5 of 23CC.
Heat in 0% aqueous formic acid at 55° C. for 15 minutes, then dilute with water (50 cc) and filter the triphenyl carbinol in vacuo. The r solution is concentrated to dryness, dissolved in water, stirred, vacuum filtered, washed, and dehydrated to yield 116 ml of impure product. By concentrating the P solution, a secondary yield of 674 μm of crystalline product is obtained. 790■ in total.

Perform the following purification.

1,063 g of the crude product was made into a paste with SCC water, heated at 70 °C for 5 min, cooled, stirred for half an hour, vacuum filtered, washed, dried, and the purified product of 815315' Get the product. Dissolve this 815■ in 2 CC of water and 3 CC of acetone, vacuum filtrate the insoluble matter while heating slightly, add 3 CC of water, heat the whole to 60 °C, blow nitrogen and remove acetone. the resulting particulate matter is vacuum filtered, washed with water and then with ether;
The desired compound of 458119 is isolated.

Analysis "cty) (to o, N5 Sjl calculation:
0%43.49H%4.08N%14.92S%13.
66 actual measurement: 44.5 4.4 1-4.
8 15.3 This compound has a syn configuration.

NMR (60MHz, DMSO) ppm: 2.0
5 (OAc), &75 (proton of thiazole ring) Ethyl diiminoacetate 598 g of ethyl 2-acetyl-2-hydroxyiminoacetate are added to 200 CC of pure acetone.

The whole is cooled in a water bath and 52 g of potassium carbonate are added followed by 25 CC of 2-iodopropane over half an hour.

Next, stir the whole thing for 2 hours, add 800cc of water and 500cc of water.
Add CC methylene chloride, vortex the whole, decant, extract with methylene chloride, dry, vacuum filter, and concentrate to isolate the desired compound of 41.5.51.

41.5 g of the compound obtained in the above step was mixed with a trace amount of p-
Place in 190cc of methylene chloride containing toluenesulfonic acid. Stir the whole thing, then add 119cc of bromine for 5
A solution of 0 cc of methylene chloride is introduced into the FNN humid temperature within 1 hour. The whole is stirred, ice-cold water is added, the whole is decanted and extracted with methylene chloride, washed with ice-cold water, concentrated and 55 g of the desired derivative are isolated.

Process C: 2? (Z-amino-4-thiazolyl)-27(
1-Methylethoxyimino)ethyl acetate 14,9.9 thiourea with 55 CC of ethanol and 10
5 cc of water and then 4 cc of a solution of 55 g of the compound prepared in step B dissolved in 5 scc of ethanol.
Add in 0 minutes. Stir the whole thing at ambient temperature for 2 1/2 hours,
Add 20cc of 10% acidic sodium carbonate aqueous solution, stir the whole, vacuum filter, wash, dry, 42.1
5 g of crude product are isolated and chromatographed on silica eluting with ether. Both fractions rich in the desired compound are collected and then concentrated, the crystals are dissolved with isopropyl ether, vacuum filtered and washed to yield the desired compound 10.7511.

The resulting compound has a syn configuration.

Step D: The compound obtained in Step C of 2-(2-)ditylamino-4-thiazono)ethyl acetate 11F was mixed with 20 CC of dry dimethylformamide 1. ; into a mixture of OCC of methylene chloride and (S, 2 CC of trimothylamine). Cool the mixture, slowly add 13.2p of trityl chloride, stir the whole for 2 1/2 hours, and heat to 43C.
Add C 1N hydrochloric acid, stir the whole, decant, wash with 40 C water, collect with methylene chloride,
Dry, vacuum-filter and concentrate to dryness to yield 27.79 of the desired compound.

The resulting compound has a syn configuration.

)) Acetic acid A mixture of the compound obtained in step 277.9, t, 5 occ of dioxane and 65 CC of 2N soda is refluxed. The sodium salt crystallizes out and the mixture is cooled, vacuum filtered, washed with a 1:1:1 dioxane mixture and dried to yield the crude sodium salt of 1.&85.9.15 15.9g of this sodium salt of .9.9
of dimethylformamide, 100 cc of water and approx.
Dissolved in a mixture of cc of water, added 30cc of 2N hydrochloric acid, expelled the methanol, diluted the residue with water, vacuum filtered, washed and dried the resulting 9,89 viscous product. Dissolve in a 50:50 methylene chloride/methanol mixture of 220 CC, concentrate to dryness, dissolve in ether, triturate, vacuum filter the crystals, wash and dry. 4.91
The desired acid is obtained. MP=-170°C.

3 aaxtg of crude product was mixed with 2 CC of methylene chloride and 1
CC of methanol, the whole was diluted with water and methylene chloride, then vortexed, the crystals were vacuum-filtered, washed with methylene chloride, then water, and dried to give a pure compound for analysis of 230 μm. Let go.

Analysis: Calculation: 0%68.77H%5.34N%&918%6.
8 fruit i: 68.6 5.5 8.8
The compound obtained has a syn configuration.

-Tritylamino? 4-Thiazolyl)-Bonic Acid 4, The acid obtained in Step E of 89.9 is added to 13.5 CC of dimethylformamide under an argon atmosphere.

After dissolution, the solution is cooled in a water bath and a solution of t62f; dicyclohexylcarbodiimide in 16 CC methylene chloride is added. Dicyclohexylurea crystallizes out. The mixture is stirred in a water bath, vacuum filtered, washed with methylene chloride, dried and the 1.424N dicyclohexyl urea is separated. The liquid is cooled in a methanol-ice bath and then a solution of 141,p 7-amino/heptaphalosboranic acid dissolved in 3° CC of methylene chloride and t45 cc of triethylamine is added. The whole was stirred at ambient temperature for 5 hours, 20cc of 1N hydrochloric acid was added, the whole was stirred, decanted, extracted with salt hymethylene, dried, vacuum filtered, and the desired compound of 905j9 was combined with the starting compound. Get a mixture.

This was dissolved in methylene chloride, stirred to initiate crystallization, and the crystals were vacuum-filtered, washed, and dried.
Obtain the first pure compound of S. Solution F is concentrated to dryness and the residue is dissolved in isopropyl ether with vigorous stirring to isolate the insoluble viscous product of the desired compound, 4,919.

The resulting compound has a syn configuration.

4, 91.9 of the crude product obtained in Example 8 was added to 30 CC of 5
Add to 0% aqueous formic acid. The whole is stirred in a water bath at 60'C, diluted with water and the resulting triphenylcarbinol is vacuum-filtered, washed with water and dried to separate the t599 triphenylcarbinol.

The r solution is concentrated to dryness, washed with water, triturated, vacuum filtered, washed with water, and dried to yield the desired compound of 8ooD9.

Dissolve 972■ of the ffl compound in 4 CC of methanol, dilute it with 20 CC of ether, vacuum filter the insoluble matter, wash, and dry to obtain the desired pure acid powder of 404Q for analysis. . MI'yo 200" (:.

Analysis: Calculation: 0%44.71H%4.38N%14.48S%
13.26 actual measurement: 445 4.5 14
．． 1 152 This compound is sy! 1 configuration.

NMR (60MHzN DMSO) ppm: 2. O,
-1(CH3Co), doublet 9.46 J-aH2(
CONH), 6.7 (proton of thianol ring) Example 1
0:3-acetoxymethyl-7ma(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide)
Sepha-3-M-4-carboxylic acid, syr + isomer 4
The syn isomer 2-(2-amino-4-thiazolyl)-2? prepared according to Step A of Example 1 of 5,8 J? Add ethyl methoxyiminoacetate to 200 CC of methylene chloride. The mixture is dried by distilling 20 cc of it, then cooled to 10° C. and 50 cc of pyridine is added. 4
11i of monochloroacetic anhydride is added and the whole is heated slightly to dissolve. Leave it in a nitrogen atmosphere at 20℃ for 6 hours, add 5CC of water, stir the whole thing, and boil it to 300CC.
of water-cooled 2N hydrochloric acid. The whole was decanted, extracted with methylene chloride, washed with water, washed with acidic sodium carbonate water, dried, passed through activated charcoal, concentrated and so
Add o cc of isopropyl ether. The compound crystallizes out. Concentrate until a thick paste is obtained, cool, vacuum filter, wash with isopropyl ether, and dry to give 45.4p of compound.

MP Mi 113℃.

A pure sample is obtained by recrystallization from a mixture of methylene chloride and isopropyl ether.

MP-118°C O NMR (CDCI, , 60MH7): (a) 1
Triple ring centered at 38 ppm, J-7Hz.

(b) a, singlet at o s ppm, (c)
Quadruplet centered at 4.44 ppm, J=7Hz.

(d) 4.351) Singlet in pfil, (e)
z271) Singlet at 9.95 pm, (f) Singlet at 9.95 pm, Add the compound obtained in step A above of 4611 to 230 cc of absolute ethanol. Then, a concentrated aqueous solution of 50 cc of pure hydroxide is added at 20° C. under a nitrogen atmosphere. The compound dissolves and the IJium salt begins to crystallize, then the medium solidifies. After 16 hours vacuum filter and wash with ethanol. The resulting salt was dissolved in water, cooled, 100 cc of 2N hydrochloric acid was added, the whole was saturated with sodium chloride, and 1
Extract with ethyl acetate containing 0% ethanol. The whole is dehydrated, passed through activated carbon, distilled under vacuum, the water is entrained in benzene, the residue is dissolved in methylene chloride and distilled to dryness.
Dissolve in methylene chloride, cool, vacuum filter, wash with methylene chloride, and dry to yield the desired compound of 54.51. MP - about 200°C. This compound is purified by recrystallization from an acetone-isopropyl ether mixture.

Analysis: C,H,0,N5CIB-'2776B Calculation:
C%34.60 H%2.9ON%15.1301%1
2.778%1t55 actual measurement: ! 14.81 2
．． 8 14.8 116 115NMR(D
MSO160MHz) (a) 3.9291) Singlet at m, (b) 4.
581) I) Singlet at m, (c,) Singlet at about 5 ppm, (d) Singlet at 7.58 ppm, (e) 12
．． Singlet at 6 ppm, Step C: 3÷Acetoxymethyl-P7-(2-(2 isomer 15, 3fi) Add the compound obtained in Step B to 80 CC of methylene chloride. Add 8 CC of triethylamine at 5 °C. 3.8 Cc of thionyl chloride and 26 cc of methylene chloride are introduced at 0° C. under nitrogen atmosphere.

The whole is left at 0° C. for 15 minutes and then 7 CC of triethylamine are added. A solution of 13.69 7-amitusephalosboranic acid in 100 cc of methylene chloride and 14 cc of triethylamine is introduced at 0° C. under a nitrogen atmosphere. The whole is brought back to 20°C and then stirred for 1 hour.The solution is distilled to dryness under vacuum at about 30-35°C.

The residue was dissolved in 250 cc of water and passed through activated carbon.
Add 50 cc of 2N hydrochloric acid. The precipitate is vacuum-filtered and washed with water. The crude product obtained is suspended in 80 CC of ethanol. Add 7 CC of triethylamine at +5°C.

Then 15 CC of 4N sulfuric acid is added at once with stirring at +5°C and the compound crystallizes out after 15 minutes. vacuum filter,
After making a paste and washing with ethanol and then with ether and drying under vacuum, 18.6 g of the expected compound are obtained.

[α)”−+26°±1 (1% dimethylformamide).

N8(R(DMSo, 60MHz) (a) Singlet at 2.03 ppm, (b) 3.
901) I) Singlet in m, (c) 4.38 ppm
Singlet at (d) 7451) Singlet at pm.

Step D = 3-acetoxymethyl-7-(2-(2-amino-4-thiazolyl)-2-mer) 5, 32 g of θ obtained in Step C was dissolved in 106 CC of water and 912 CC of thiourea. Suspend 1g at 20°C.
of acidic potassium carbonate. After dissolution, the whole is stirred at about 20° C. for 6 hours under a nitrogen atmosphere. A gummy precipitate begins to form after about an hour and a half.

Then add 30 CC of water and 3 CC of formic acid. The whole is cooled to 5°C, vacuum filtered and washed with water containing 10% formic acid. The residue is dissolved in 30 cc of water containing triethylamine at about 5°C. At 5 DEG C., 3 CC of formic acid are added and the precipitate is vacuum-filtered and then made into a paste and washed with aqueous water. Removes dark brown gum and is for water-based use? Collect and treat with activated charcoal to obtain a 6° clear yellow solution, which is saturated with ammonium sulphate.

Vacuum filter the precipitate, make a paste with water, vacuum filter,
Wash with water to obtain precipitate A.

Saturating the mother liquor with ammonium sulfate produces a precipitate, which is vacuum filtered and washed three times with the minimum amount of water to form precipitate B.
get. Combine precipitates A and B and dissolve with ethanol,
Stir at 20°C for 1 hour and at 0°C for 16 hours. Vacuum filtration, washing with ethanol then ether and vacuum drying yields &47 g of the desired compound, the syn isomer.

NMR (DMSO160MHz) (a) 2. Singlet at O3ppm, (b) Singlet at 3.55 pI)m, (C) 5
．． Doublet at 19 ppm, J=sHz.

(d) Singlet at 6.8 ppm.

This compound is the same as that obtained in Examples 2 and 4.

Ethyl 4,69 K9 ethyl 2-acetyl-2-hydroxyiminoacetylacetate (corresponding to 4,21 Kg of pure compound) is introduced into 211 pure anhydrous acetone.

Add 6.1 K9 charcoal-fermented potassium at 20-25°C.

Stir this suspension for 10 minutes and then at 20-25°C for 3 hours.
．． 72 Add K9 dimethyl sulfate. 20-2 total
Stir at 5°C for 3 hours. It is then poured into 1261 demineralized water and extracted four times with 51 and then with 2A' methylene chloride. Overall 10! ! Wash with demineralized water. Dehydrated, vacuum 2 filtered, 2I! of methylene chloride.

Then, vacuum distillation is performed to obtain the desired compound of 4.88 Ky.

Rf = 0.7 (layer chromatography on silica gel, eluent 9:1 methylene chloride/ethyl acetate).

This compound is the same as that obtained in step α of Example 1.

3,53 The compound obtained in step A of KF was 18.61
of methylene chloride and 3.51 parts of p-)luenesulfonic acid. A solution of 2.96 bromine dissolved in 3.51 methylene chloride was added to the above solution at a temperature of 22℃±1.
Add over 30 minutes while keeping at ℃. Evolution of hydrogen bromide gas is observed 15 minutes after this introduction. The whole is stirred at 22° C. for 45 minutes, then placed in a separate flask and washed twice with 14 g of cold demineralized water. The wash water is extracted twice with 151 methylene chloride. It is then dried, filtered, washed with methylene chloride and distilled in vacuo to give the desired compound 4.731.

This compound is the same as that obtained in step β of Example 1.

2-methoxyiminoethyl acetate, 5ynJ compound 143 KP of thiourea with 35 of ethanol and ZIA
Add to t of demineralized water. The whole is stirred for 10 minutes at 20°C, then at 20-25°C, a solution of the compound prepared in Step 8B of 4.730111 in 3.557 ethanol is added. The whole was stirred at 20-25°C for 3 hours, then cooled to 15-20°C, and the 22-B
e Neutralize to pH 7 with ammonia.

The whole is stirred for a further 15 minutes at 20-25°C.

Vacuum-filtered and washed 5 times with t81 demineralized water, 2.947
The desired compound 9 is obtained. MP=162℃.

This compound is identical to that obtained in Example 1, Step A and γ-.

The compound obtained in step C of syn isomer 3,41 Ky is mixed with 17 J of methylene chloride and 2.27 J of triethylamine. Stir the whole thing for 15 minutes, then stir at 20-25°C under nitrogen. 4. Add s s Kq of trityl chloride in 1 hour. The whole is stirred under nitrogen at 20-25° C. for 20 hours, causing crystallization of the triethylamine salt or salt.

The liquid is poured into a separate flask and washed with 10 g of 0.5N cold saline and then twice with 1α21 of water-cold demineralized water. Extract the wash water with 1.71 methylene chloride. Drain, filter and wash with 171 methylene chloride. A crude product of 0 8,425 Kp is obtained which is distilled to dryness under vacuum at a temperature below 50°C.

This product is redissolved in 8.41 methanol at 20-2.5°C and 2.8 m of demineralized water is added over 1 hour at 20-25°C with stirring to initiate crystallization. Stir the whole thing for another hour, vacuum filter, and t7 with 25% water.
Paste it three times with 1 methanol and dry at 40° C. to obtain the desired compound of 7.165 KP.

This compound is the same as that obtained in Example 1, Step B″″c.

The compound obtained in the 4.175KF process was 20.91
of ethanol. The whole is refluxed under nitrogen with stirring. Complete dissolution is from 55°C.

5.235 J of 2N soda are introduced under reflux under nitrogen. Early crystallization occurs. The whole is stirred at reflux under nitrogen for 1 hour. Bring to 20-25°C and keep at this temperature for 2 hours. Vacuum filter, wash with 2.11 ethanol/ethanol and dry to give 4.02 KP of the expected compound.

The compound obtained in step C of isomer 500I (corresponding to the dry compound of 440.9) is placed in 2.51 methylene chloride. 2 for 2 minutes at 20-25℃ while stirring under nitrogen!
Add approximately 1N hydrochloric acid. The whole thing is under nitrogen at 20-25℃.
Stir for 2 hours. Decant the methylene chloride phase and wash three times with 2/2 portions of demineralized water. 1 wash water! Extract with methylene chloride. Dehydrated, added 25I charcoal, filtered under vacuum, washed with methylene chloride, distilled to dryness, 481
A crude product of J is obtained. This is dissolved with 2.1 Jl of isopropyl ether. Vacuum-filter and wash twice with 420 CC of isopropyl ether. Vacuum drying to constant weight yields the desired compound 424.6.9.

This compound is the same as that obtained in step C of example 1.

200y of the 2-(2-)dithylamino-4-thiazolyl)-2-methoxyimino i1e obtained in step F, followed by 1200cc of methylene chloride are placed in the flask. The suspension is heated to reflux while stirring under an argon atmosphere, and then 6]OCC of methylene chloride is distilled off at normal pressure. The residue is brought to 18 DEG -20 DEG C. and then 5.4 g of dicyclohexylcarbodiimide dissolved in 54 cc of methylene chloride are introduced while maintaining the above temperature. The whole was stirred under argon at 18-20°C for 1 hour, and then at this temperature a solution immediately made by dissolving 614I of 7-amitusephalosboranic acid in 900 CC of methylene chloride and 65 CC of triethylamine was stirred for 15 minutes. Add with .

Stir the whole thing at 20°C for 1 hour and 30 minutes (pH=6.
5-7). Then 5 occ of acetic acid was added and the whole was heated to 20
C. for 15 minutes with stirring and then vacuum-filtered to remove unreacted 7-amitusephalosboranic acid.

The whole is washed 4 times with 200 CC of methylene chloride. The organic solution is washed three times with 400 CC of demineralized water and then dried over magnesium sulfate. Filter in vacuo, wash twice with 200 cc of methylene chloride, and evaporate to dryness under reduced pressure and an argon atmosphere. The dry oily residue is dissolved in 700 CC of dioxane at 20-25°C with stirring under an argon atmosphere. At a temperature below 30 DEG C., 300 cc of a dioxane-methylene chloride mixture is distilled off under reduced pressure and an argon atmosphere. The residue was brought to 20°C ± 2°C, then 500°C
Add cc of sulfuric ether. Then add 52 CC of diethylamine.

After about 10 minutes, 2↓(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid crystallizes.

Leave for 1 hour at 20°C under argon. Pass vacuum r, 1
Wash three times with 0 occ dioxane-ether sulfate solution. The recovered diethylamine salt was dried and weighed 113.6g.
obtain. The organic solution is precipitated in 3251 isopropyl ether for 30 minutes with stirring. While stirring15
Let stand for a minute and then pass through vacuum. Washing twice with 400 cc of isopropyl ether and drying under vacuum gives 182 g of the same compound as obtained in Example 3.

Example 1 of 182 g of diiminoacetamide] Sepha-3-2
The compound obtained in step 1 was added to 347 CC of formic acid and 87 CC of demineralized water at 28-30°C while stirring under an argon atmosphere.
will be introduced. Crystallization of completely dissolved triphenylcarbinol occurs.

The whole is kept stirring under argon for 2 hours and 30 minutes at 28-30 DEG C. and then precipitated in a mixture of 1740 cc of demineralized water and 8471 ammonium sulfate for 15 minutes without stirring. Stir everything and leave for 30 minutes. Vacuum filter, wash twice with 174 cc of demineralized water,
Vacuum drying at 0° C. yields 147 g of a mixture of the expected compound and triphenylcarbinol. Crude product at 735C
Make a paste in CRI & acid ether at 18-20°C for 1 hour.

Vacuum filtered and washed twice with 147cc of sulfuric ether;
Drying at 25-30°C gives 89 g of the expected compound.

The compound is made into a paste in 44.5 CC of ethanol with stirring under nitrogen. The suspension is brought to 45-50°C with stirring and kept under these conditions for 1 hour. Then stir at 18-20°C for 1 hour. Vacuum filtered, washed twice with A5CC ethanol, vacuum dried at 20°C, 76.85. The desired compound of F is obtained.

This compound is introduced into 230 CC of acetic acid. The whole is stirred under nitrogen for 15 minutes and then 77cc of demineralized water is added. Then add 700 CC of water to this solution. The whole is left stirring for 1 hour at 18-20°C, then 269 g of ammonium sulfate is added over about 10 minutes, the whole is left to stand for 15 minutes, then 185 fl of charcoal is added. The whole is left stirring for 15 minutes, vacuum filtered and washed with 77CC demineralized water containing 25% acetic acid.

154 CC's t! Crystallization is aided by adding the p-acid at 18-20° C. with stirring, adding a starting amount of the final compound, and then scraping. The whole thing was heated to 18-20℃ for 2 hours.
Stirring is then continued for 2 hours at 0-+5°C. Vacuum filter and wash four times with 770C demineralized water containing 5% formic acid.

Vacuum dry at 20-25°C. The product 49.4511 is obtained in the form of the formate salt.

The resulting formate salt was dissolved in 250 cc of ethanol for 45'
Stir at ~50°C for 1 hour to form a paste, then leave at 18-20°C for 1 hour. Vacuum filtered, 50C
Wash twice with ethanol (C).

After drying at 20°C and then at 35-40°C for 10-15 hours, the desired compound 45.4511 is obtained.

[α), = +64.5 (concentration of α5% in dead water containing 0.5% NaHCO).

This compound is identical to that obtained in Examples 2.4 and 10.

S obtained according to example 2.4.10 or 12 of 198J
3-acetoxymethyl-7-(2-(
65 2-amino-4-thiazolyl)-2-methoxyiminoacetamide
Dissolve CC in a 1 molar methanol solution of sodium acetate. The whole was allowed to crystallize for 35 minutes at ambient temperature, 40 cc of ethanol was added in 1 hour, stirring was continued for 2 hours and 30 minutes in an ice water bath, the whole was vacuum-filtered and 10 cc of a 1=1 methanol-#-1 tanhol mixture was added. twice using IQcc+7
) Wash twice with ethanol and then twice with 20 cc of ethanol, vacuum dry at 45 °C for 2 h,
After vacuum drying in a fermentation desiccator for 48 hours, 16.1
91, a congealing compound of F is obtained.

The reaction is carried out avoiding contact with atmospheric temperature to obtain a compound having the following physical properties.

H2O (Karl-Fischer method) = 0.2% Analysis: C,,H! ,0. N5S2N2ri47Z5 calculation: 0
%40.24H%&38N%14.678%15.45
Na%4.81 actual measurement: 39.9 3.5 1
4.5 1 & 1 4.8 This compound rehydrates when discharged into air.

The Xg spectrum (Debbie-Scherrer method) confirms the crystallinity of the obtained compound.

It is also possible to use isopropanol instead of ethanol to crystallize the desired compound.

Example 14: Crystalline sodium salt of 3-acetoxymethyl-7-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide)cepha-3-m-4-carboxylic acid % Sulfm isomer monoamino 4-thiazolyl)-2-methoxyiminoacetamide]Sepha-3-nimu-4-carboxylic acid, 3yn
Solvates with isomers and formic acids 87, 3-acetoxymethyl-7-["2-(2-)ditylami/-4-thiazolyl)-2-methoxyiminoacetamide] Sepha- prepared according to Example 3 of J. 3
The diethylamine salt of -Em-4-carboxylic acid is added in small portions to a mixture of 220 cc of pure alcohol and 220 cc of water with stirring. The whole is stirred at 50°C for 30 minutes, cooled, and 30.1J (7) IJ phenylcarbinol is separated. Pour 450 cc of water into the P solution, remove the slight precipitate with carbon, and concentrate the whole under vacuum at 40° C. until a precipitate forms. 200 cc of absolute ethanol is added and the whole is cooled on ice, filtered, washed with ethanol and then ether, and dried in vacuo.

31.1 J of the desired compound is obtained.

Analysis: C1, H,, N50. S, 'HCO□H-
H, 0 = 541.5 calculation 20% 393H% 4.08 N
%13.48S%12.34H, 0%346 actual measurement:
59.2 4,1 13.2 12.8
4.1515! The freshly made solvate obtained from step i is dissolved in 7 sec of methanol and the solution is treated with 4.5 I potassium acetate and 31 I activated carbon.

After filtration, add 5 CC of Improper Tool under stirring. After 16 hours at 0.degree. C., the crystals are separated, washed with ethanol and then with ether and dried under vacuum at 50.degree. C. for 2 hours.

7.95 g of the expected compound are obtained.

The compound is then left briefly in the atmosphere.

The following analysis results are obtained.

Analysis: C,,H,,N,NaO? S2・IH20=4
95.5 calculation 20% 38.78 H% 3.66 N% 14
．． 14 N2%4.648%1294 actual measurement: 38
．． 52 g of the 6 3.7 1;8 4.6 13.2 hydrate solvate with formic acid obtained in step A of Example 14 are dissolved in a mixture of 51 96% ethanol and 550 CC water. Concentrate the whole to a volume of approximately 300 CC. During this concentration process the solvate begins to crystallize. The whole is cooled in a water bath for 1 hour, filtered, washed with a little ethanol and dried under vacuum at ambient temperature in the presence of concentrated sulfuric acid.

44, lit of the desired compound is obtained.

Analysis: C,, Hl, N, O, S, 60.8 mole Ct
Hs 0H=492.3 Calculation 20% 42.94H%4.
46 N% 14.238% 1302 Actual measurement: 43.
The solvate with ethanol obtained in the process of 0 4.4 14,1 12.93 Il was added to 60 CC of water at 0°C, then 0, dissolved in 6 CC of water.
Add 504 g of acidic carbonate while stirring. Filter the neutral solution and immediately lyophilize. The product is then exposed to the atmosphere for a period of time.

The following analytical crystals are obtained.

Analysis: C, 6H,, N, Na0, 8. @t5I(2
0==504.47 calculation 20% 38.09H%3.8N
%13.88 actual measurement: 3a2 3,9 13.
6Emu-4-carboxylic acid crystalline sodium 4,95F
The syn isomer 3-acetoxymethyl-7-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]sepha-3-em- Add 5 CC of ethanol to the 4-carboxylic acid, then add 1 cc of ethanol while stirring in an ice water bath.
Add 0 CC of 1 molar acidic carbonic acid (IJ) aqueous solution. After dissolving, add 15cc of ethanol and heat the whole to 30℃.
Concentrate under vacuum, dissolve in ethanol and dry to constant weight. A powder is obtained which is dissolved in 15 cc of methanol. To start crystallization, leave the whole thing in the refrigerator overnight. Separate 3.407 # of crystalline product.

α5! The amorphous IJium salt obtained according to Example 15 of I was dissolved in 2 CC of methanol and 025 CC of n
- Slowly add the butanol while stirring. Chill the whole thing in the refrigerator at about 6°C for 48 hours.

The crystals are washed with a small amount of cold methanol and dried under vacuum at 40° C. for 5 hours in the presence of concentrated sulfuric acid.

0.2 g of crystalline product is obtained.

This compound is left in the atmosphere for a short time.

Analysis: C,,H,,N,NaO,S,-15H20=
504.47 calculation: 0% 38.09 H% 3.8 N%
13.880%26.96 Actual measurement: 38.4
3,8 13.8 271 carried out under similar operating conditions, very slightly different crystal bodies were obtained containing, for example, (L5 mol of water or 1 mol of water or 1 mol of methanol).

The X-ray spectra (Devier-Scherrer method) of the compounds obtained above confirm these crystalline properties.

Example 18 An injectable preparation with the following formulation was prepared.

3-acetoxymethyl-7-(2-(2-amino-4-
Thiazolyl)-2-methoxyiminoacetamide]Sepha-3-M-4-carboxylic acid -1
−−−−−−−−−−−−−1−−S OO■ Sterile aqueous adjuvant −1−−−−−−−−−−−−−Amount sufficient to make 5 CC Example 19 The following formulation made an injectable preparation.

3-acetoxymethyl-7-(2-(2-ami7-4-
Thiazolyl = 2-methoxyiminoacetamide] Sodium salt of Sepha-3-M-4-carvone
−−−−−−−−−−500 ■ Sterile aqueous auxiliary agent −＋＋＋＋
+ +++---Amount Sufficient to Make 5 CC Example 20 An injectable preparation with the following formulation was prepared.

5-acetoxymethyl-7-(2-(2-amino-4-
thiazolyl)-2-(1-methylethoxyimino)acetamidoxefer 3-em-4-carboxylic acid
-1-------= 500119 Sterile aqueous adjuvant--
-1----------Example 21 that is sufficient to provide 5 CC Gelatin capsules corresponding to the following formulation were made.

3-acetoxymethyl-7-(2-(2-amino-4-
Thiazolyl)-2-methoxyiminoacetamide]Sepha-3-M-4-carboxylic acid-11
----------1--Y1 250 ■Example 22 Gelatin capsules corresponding to the following formulation were made.

3-acetoxymethyl-7-(2-(2-amino-4-
Sodium salt of (thiazolyl)-2-methoxyiminoacetamido)cepha-3-em-4-carboxylic acid
----------1---, 250jlii1 Example 23 Gelatin capsules corresponding to the following formulation were made.

3-acetoxymethyl-7-(2-(2-amino-4-
thiazolyl)-2-(1-methylethoxyimino)aceto-xefer 3-dimu-4-carboxylic acid ---
-------------250 Dyne Vitro Activity Prepare a set of test tubes in which the same amount of sterile nutrient medium is dispensed. Dispense increasing amounts of the study compound into each tube and then inoculate each tube with the bacterial strain. Incubate in an incubator at 37°C for 24 hours (2゛4H) or 48 hours (
48H) After incubation, inhibition of proliferation is assessed by light transmission. This is the minimum inhibitory concentration M, 1.
C, (expressed as μm1/Cta") is determined.

The following results were obtained.

[The compound referred to as compound A is 3-acetoxymethyl-
A) Example 2.4
．． The activity of compounds 10 and 12 was determined by Esc in mice.
An experimental infection of H. herichia Col1 was studied. gscbCrchia Co11(T)026 B6 from Institut Pasteur diluted to 7 with distilled water
Groups of 10 mice with an average body weight of 21.5 f/s were infected by intraperitoneal injection of 0.5 CC of a 24-hour culture of the strain in nutrient broth.

/! ! One hour, five hours, and 24 hours after staining, a predetermined amount of the compound was subcutaneously injected or orally administered.

Mortality was recorded for 8 days.

The results were as follows.

B) Performed under similar conditions and diluted to 115.5] i:5 cherichia, Col i (T
) A 24-hour culture of strain 026B6 with an average body weight of 22
．． The following results were obtained for compounds of Examples 2.4.10 and 12 by intraperitoneal injection into groups of mice 5.9.

The activity of the compound of Example 5 was determined using Salmonella in mice.
Experimental infection with S. typhimurium was studied.

Groups of 10 mice with an average body weight of 20.5 g were treated with f3a1mOne I diluted to 1/75 with distilled water.
A 24-hour #j feed of oxoid broth of S. latyphimurium S 210 strain [15CCt--infected by intraperitoneal injection.

A given amount of compound was administered by subcutaneous injection 1 hour, 4 hours, 8 hours, 24 hours, and 52 hours after infection.

Experimental Infection with Proteus Mirabilis The activity of the compound of Example 7 was determined in mice by proteus Mirabilis.
experimental infection with S. labilis was studied.

Proteus Mirabilis A diluted to - was administered to groups of 10 mice with an average body weight of 221 kg.
24-hour culture of oxoid broth of 235 strains α5 CC
was infected by intraperitoneal injection.

A given compound 1 was administered by subcutaneous injection 1 hour, 4 hours, and 24 hours rgJ after infection.

The results were as follows.

Study of Acute Toxicity in Mice by Intravenous Route The acute toxicity of the compound of Example 5 was investigated in female mice weighing 19-21 J (CDI Swiss mice (pedigree CH, without specific pathogens).
(Rrver-France)) using 8-10 patches per dose.

Animals were kept in an isolated animal unit (temperature 21°C ± 1°C,
A solution of the compound of Example 5 at a concentration of 100 da/g in pyrogen-free sterile distilled water is kept under observation for 4 days with adequate feed and drinking water. shall be. Change the volume of this to the tail vein and 1
Inject at a rate of yil/min.

Therefore, the lethal dose is 2.000 m9/higher than 9.0 Symptoms: No signs of poisoning were observed during the injection or during the observation period.

A set of test tubes is prepared in which the same amount of sterile nutrient medium is dispensed. Increasing amounts of the test compound are dispensed into each tube and each tube is then inoculated with the bacterial strain. After incubation for 18 hours at 37°C in an incubator,
Inhibition of proliferation is assessed by light transmission. This is the minimum inhibitory concentration M, 1. C.

(expressed as μN/l:jK") is determined.

The compounds used for comparison are as follows.

C@fotiam: 7β-[2-(aminothiazol-4-yl)acetamide)-! 5-(((1-(2-
(6R, 7R) -5-carbamoyloxymethyl-7-(2-(2 -7 Ryl)-2-(methoxyimino)acetamide]Sefu-3-M-4-carboxylic acid The following results were obtained.

PHARMACOLOGY OF THE COMPOUNDS OF THE INVENTION AND SOME COMPOUNDS According to the dilution method in liquid media described above, the minimum inhibitory concentration M of the following compounds: 1. C, (p i /C2+1') was determined.

The compounds used are as follows.

Compound P: 3-acetoxymethyl-7-(2-
(2-Amino-4-thiazolyl)-2-methoxyiminoacetamide] Sodium cef-3-M-4-carboxylate, syn isomer.

Compound B Near β-[α-methoxyimino-α-(2-aminothiazol-4-yl)acetamide] sodium cephalosporanate (described in Example 61 of JP-A-51-149296).

Compound C nia β-(2-aminothiazol-4-ylglycylamide) sodium cephalosporanate (compound described in Example 2 of Japanese Patent No. 8, 1983-149296).

Claims (1)

[Claims] 1. The following formula I ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (Here, R^1 represents a saturated alkyl group having 1 to 4 carbon atoms, and A is hydrogen A bacterial infection characterized in that it consists of at least one compound representing an atom or equivalent of an alkali metal, an alkaline earth metal, magnesium or an organic amino base; the wavy line indicates that the group OR^1 is in the syn position. disease treatment agent.