JPS5822480B2 - Method for producing penam derivatives - Google Patents

Description

[Detailed description of the invention] This invention relates to a method for producing penam derivatives.

More specifically, this invention provides novel intermediates for novel antibacterial penum compounds that are valuable as additives in animal feed, therapeutic agents for controlling infectious diseases caused by Durum-positive and Durum-negative bacteria, and disinfectants in hospitals. Regarding the body.

According to this invention, the formula (wherein R2 is the formula or -CH-CH2-Y; R4 is hydrogen or alkyl having 1 to 4 carbon atoms; R5 and R6 are each hydroxy, or -CH-CH2-Y); selected from the group consisting of alkoxy and benzyloxy; R7 is hydrogen or methyl; R8 has 1 to 1 carbon atoms;
4 alkyl; Y is alkoxycarbonyl having 2 to 5 carbon atoms).

A method for preparing a penam derivative of the formula %, comprising: reacting 6-1-rephenylmethylaminopenicillanic acid with an amine selected from the formula % at -30 to 30°C; React with inocyanate at 0-30°C: The resulting 6-(+-riphenylmethylamino)-3-carbamoylpenam is reacted with at least 1 mole of tertiary amine with phosphorus pentachloride, phosgene or thionyl chloride. -20~30° in the presence of
A process is provided, characterized in that the iminochloride is treated with an alkali metal or tetramethylguanidinium azide at a temperature of 0 to 30<0>C.

For convenience, the compounds of this invention are defined as ``penam'' derivatives.

Penampa is published in the Journal by S heehan et al.
of the American ChemicalS
Society, 75.3293 (1953), it is defined as having the following structure.

The term penam does not normally have any stereochemical meaning, or the stereochemistry of the penam compounds of this invention corresponds to that of natural penicillins.

Using this terminology, the well-known antibiotic penicillin G (benzylpenicillin) is called 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylic acid.

Many of the compounds of this invention are also 5-monosubstituted tetrazoles, which can exist in two isomeric forms: and.

As one skilled in the art will appreciate, the two isomeric forms represent different chemicals and are not naturally interconvertible.

The above novel penam derivative of formula ■ is a well-known intermediate,
6-1-rephenylmethylaminopenicillanic acid to C-
It can be produced through specific modification of the 3 carbonyl group.

A method for producing 6-triphenylmethylamine penicillanic acid was described by Sheehan and Henery-Logan in the Journal of the American Chemical Society.
ican Chemical 5ociety)”,
Utsubo, 5838 (1959).

In step 1, 6-(triphenylmethylamine)penicillanic acid is converted to the formula ■ 5 [where G is -C (=0) -□-R8, -CH2CH
2Y and R, R8 is as defined above, and R is of the formula: (R4, R5, R6 are as defined above) or (wherein R7 is as defined above).

). ] into an amide.

When G is -CH2CH2Y or R, the amide of formula 1 activates the 3-carboxy group of 6-()liphenylmethylamino)penicillanic acid, e.g. by mixed acid anhydride formation, and then converts the amide of formula Nf (2CH2CH2Y or It is produced by reacting R-NI2 with an amine.

For example, in the formation of a mixed anhydride, the appropriate carboxylate salt of 6-trinoenylmethylaminopenicillanic acid is suspended or dissolved in a reaction-inert organic solvent, and the resulting suspension or solution is then mixed with pivaloyl chloride, chloroformic acid lower alkyl ester, etc. Add reagents selected from

Suitable salts are, for example, alkali metal salts, such as the sodium or potassium salts; amine salts, such as the l.ethylammonium salt, pyridinium salt, N-ethylpiperidinium salt or N-N-dimethylanilinium salt.

Suitable solvents are those that serve to dissolve at least one of the reactants, mixed anhydride product, and do not react with the reactants or the product.

Examples of these solvents are chlorinated hydrocarbons such as chloroform, methylene chloride: aromatic hydrocarbons such as benzene, toluene and xylene:ethers such as diethyl ether, tetrahydrofuran, 1.2-dimethoxyethane.

The reaction is normally carried out at about -50°C to 30°C, preferably about 0°C.

At about 0°C the reaction usually takes about 1 hour. Triphenylmethylamine penicillanate and pivaloyl chloride or chloroformic acid lower alkyl ester are usually present in approximately equimolar proportions.

However, in some cases, a slight excess of the acid chloride component is used.

The product can be isolated by simply removing the insoluble material and then evaporating the solvent in vacuo to obtain the crude product.

This crude product can be used directly or further purified by methods well known in the art.

However, if desired, the mixed anhydride product need not be cultivated.

It can be used as is for reaction with amines of formula NH2CH2CH2Y or R-NI2.

Mixed anhydrides and formula R-NH2 or NI(2CH2CH2
The reaction of Y with the amine is normally carried out simply by contacting the reactants in an inert solvent for about 0.5 to 2.0 hours at about -30 to 30°C, preferably about 0°C.

The same solvents mentioned for mixed anhydride formation serve this reaction, and the reagents are usually used in approximately equimolar proportions.

As one skilled in the art will appreciate, the product should not be exposed to excess starting amine as there is a risk that the penam β-lactam will decompose.

When the reaction is carried out in an aqueous miscible solvent, the product is usually isolated by washing the reaction mixture with water and then concentrating the organic solvent to dryness in vacuo to obtain the crude product.

The crude product can be used immediately in step 2 or, if desired, can be further purified by known methods.

However, it is sometimes convenient to simply wash the reaction mixture with water and use the amide solution obtained directly in step 2.

When the reaction is carried out in a water-miscible solvent, the water-miscible solvent is first removed by vacuum evaporation and replaced with a water-immiscible solvent;
The product is then usually isolated by proceeding as described above.

The amine R-NH2 has the formula: [In the formula, either R5 or R6 is a hydroxyl group.

]., it is convenient to protect the phenolic hydroxyl group of the produced hydroxybenzylamide before proceeding to step 2.

A wide range of protecting groups known in the art for hydroxyl groups can be used for this purpose.

For example, the hydroxyl group can be protected as an alkoxymethyl group or a tetrahydropyranyl ether, or it can be silylated.

The hydroxyl group can also be converted to an alkanoyloxy group by reaction with an alkanoyllide, such as alkanoyl chloride, or to a formyloxy group by reaction with formic acetic anhydride.

A method for acylating phenolic hydroxyl groups was described by 5andler and Karo in ``Organic Functional Groove Productions''.
gani cFunctional Group Pr
eparations)” (Academic Pr.
ess, New York & London.

1968. Discussed on page 250.

If G is -C(=0)-0-R8, then 6-(
)IJ phenylmethylamino)penicillanic acid with the formula R8-
The amide of formula (1) is prepared by reaction with a suitable isocyanate where 0-C(-0) -N=C=0.

This reaction is typically carried out using virtually equimolar amounts of the reactants at temperatures between about 0°C and
The reaction is carried out by contacting in an inert organic solvent at a temperature of 30 DEG C. for about 1 to 12 hours.

The product can be isolated simply by removing the solvent in vacuo, or the product can be isolated by simply removing the solvent in vacuo, or by formula V
1 of the amide solution can be used as is in step 2.

Incyanate with the formula: R8-0-(C=0) -N=C=O has the formula: R8-0-C(=0)-NI(2
carbamate with oxalyl chloride.

Step 2 of the novel three-step reaction described above converts the product of Step 1 to the formula: R
is as defined above].

) to imidoyl chloride.

For imidoyl chloride formation, a convenient method is to dissolve the amide in a reaction-inert organic solvent and then treat the solution with phosgene and a tertiary amine.

About 1 molar equivalent of phosgene is commonly used, although up to about 2-3 molar equivalents are sometimes used.

Preferably, the tertiary amine is present in an amount equal to or greater than that of phosgene.

The reaction is carried out at a temperature of about -20°C to 30°C, preferably about 25°C, and usually takes 2 to 3 hours to complete.

From the point of view of accelerating the complete conversion to imidoyl chloride, a tertiary amine may be added as the reaction progresses.

It is sometimes advantageous to add sugen.

A large number of tertiary amines can be used in this process, such as trimethylamine, triethylamine, N-N-dimethylaniline, N-methylmorpholine, pyridine, and the like.

Typical solvents that can be used are chlorinated and carbonized. Hydrogen, such as chloroform, methylene chloride and 1,2-dichloroethane; ethers, such as tetrahydrofuran and 1,2-dichloroethane;
dimethoxyethane;

If desired, the imidoyl chloride can be isolated by evaporation of the reaction mixture, but in the case of polyimide, it is convenient to use the imidoyl chloride as is.

Several other reagents can be used in the imidoyl chloride formation reaction, such as thionyl chloride or phosphorus halides, such as phosphorus pentachloride.

Additionally, the corresponding imidoyl bromide can be used if desired.

In Step 3 of the novel three-step reaction, the imidoyl chloride is converted to a compound of the formula: (wherein G' is as described above).

) into a tetrazolylpenam compound.

In this variation, the imidoyl chloride is treated with an azide ion source; a convenient way to carry out this variation is to dissolve the imidoyl halide in a suitable solvent and then add about 1 molar equivalent (sometimes a slight excess) of the azide ion source. Add.

It is then stored at room temperature for several hours (eg, overnight) until conversion to the tetrazole is virtually complete.

The above azide ion source is tetramethylguanidiniuno.
It is azide.

A suitable solvent is one that will help dissolve both the imidoyl halide and the azide ion source, but will not react with either the reactants or the products.

As previously pointed out, this reaction takes several hours or more to complete.

However, the conversion to the tetrazole can often be accelerated by adding an azide ion in the middle of the reaction process.

Product separation is accomplished using standard methods.

When a low-boiling chlorinated hydrocarbon is the solvent, the reaction solution is washed with dilute alkali and the organic solvent is then removed by evaporation.

When a dipolar neutral solvent is the solvent, the reaction mixture is usually first diluted with a large excess of dilute alkali, the pH is appropriately adjusted, and the product is isolated by solvent extraction.

The following examples are given solely for the purpose of further illustrating the invention.

Infrared (IR) spectra are based on potassium bromide discs (KB
The characteristic absorption band is reported in wavenumbers (cm-').

Nuclear magnetic resonance (NMR) spectra were obtained using deuterochloroform (CDC13), perdeuterodimethyl sulfoxide (DMSC)-d6) or deuterium oxide (D2).
0) Measured as a solution at 60 MHz, the peak position is tetramethyldyrane or 2,2-dimethyl-2-
It is expressed in parts per million (ppm) based on sodium silapentane-5-sulfonate.

Use the following abbreviations for peak shapes:

s- singlet; d- doublet; a- triplet; q- doublet; m
-Multiplet Example 1 6-(+-liphenylmethylamine)-2,2-dimethyl-3-[1-(4-methoxybenzyl)-tetrazol-5-yl]penam (A) 6-(triphenyl methylamine)-2,2-dimethyl-3-[N-(4-methoxybenzyl]carbamoyl]penam 86.4 P (0.8 mol) of 6-aminopenicillanic acid was added to 600 ml of anhydrous chloroform and stirred. to make a slurry, add 11.2 ml (0.4 mol) of triethylamine to this until it becomes a clear solution (about 5 minutes)
Stir at ambient temperature.

134.9P (0.44 mol) of 90% pure triphenylmethyl chloride was then added in portions at ambient temperature over a period of about 25 minutes.

Stirring was continued for a further 64 hours, then 5.6 ml of triethylamine was added.

Cool to 0-5°C and then add ethyl chloroformate (3
A cooled solution of 8 ml (0.4 mol)] in chloroform (80 ml) was added dropwise over 30 minutes while maintaining the reaction temperature at 4-9°C.

After stirring for another 15 minutes, 52.4 ml (0.4 d) (7)
4-Methoxybenzylamine was injected into the reaction medium under the surface of the solvent over a period of 30 minutes at 4-9°C.

Stirring was continued for a further 30 minutes at 3°C and 20 minutes at 6°C, during which time the reaction medium warmed to 20°C.

Then I washed it with water and then salt water.

Finally, it was dried with magnesium sulfate and 6-(triphenylmethylamine)-2,2-dimethyl-3-(N-(4-
A solution of methoxybenzyl)carbamoyl]penamnochloroform was obtained.

(B) 6-(1-liphenylmethylamine)-2.
2-dimethyl-3-(1-(4-methoxybenzyl)tetrazol-5-yl)penam 69.4? (0,120 mol) of 6-(triphenylmethylamine)-2,2-dimethyl-3- 133. containing (N-(4-methoxybenzyl)carbamoyl)penam.
To 3 ml of chloroform solution [produced by the method described above], add 132.7 ml of glue oophor A, then add 29.1 ml of glue.
d (0,360 mol) of pyridine was added.

Cool to 10°C, then stir for 15 minutes to 26°C.
．． 222 (0,126 moles) of phosphorus pentachloride were added.

Stirring was continued for 10 minutes at about 10°C and an additional 1.5 hours at ambient temperature to obtain a solution of iminochloride.

% of this iminochloride solution is 4.85 ml (0.06
0 mol) of pyridine and 2.42 ml (0.60 mol) of methanol were added at about 25° C. with stirring.

2.03 after stirring for another 15 minutes. (0,038 mol)
of ammonium chloride, then 2.59P (0,039
mol) of 95% pure sodium azide was added.

It was then stirred for a further 4 hours at ambient temperature.

At the end of stirring, 400 ml of water and 2 Q Q m,l of chloroform were added and the layers were then separated.

The organic phase was washed with water, dried over magnesium sulfate, and then concentrated in vacuo to a small volume.

This final chloroform solution was added dropwise to a large amount of diisopropyl ether with stirring, and after 30 minutes, the precipitate formed was analyzed.

This gave 6.12 6-(+-liphenylmethylamine)-2,2-dimethyl-3-1:1-(4-methoxybenzyl)tetrazol-5-yl]penam.

The IR spectrum (KBr, Tisf) of this product is 1
It shows an absorption band at 790C1rL'(β-lactam); the NMR spectrum (CDC13) shows an absorption band of 7.25 ppm (
m, aromatic ring hydrogen), 5.40 ppm (broad S,
benzyl hydrogen), 5.05 ppm (s, C-3 hydrogen),
4.50-4.30 ppm (m, C-5 and C-6 hydrogen), 3.70 ppm (s, methoxy hydrogen), 3.50
~3.10 ppm, (broad peak, NH),
It showed absorption at 1.50 ppm (s, C-2 methyl hydrogen).

Example 2 6-(J liphenylmethylamine)-2,2-dimethyl-3-(1-(4-benzyloxybencyl) -r
) Shisol-5-yl]penam6-()riphenylmethylamine)-2,2-dimethyl-3-(N-(4-benzyloxybenzyl)carbamoyl]penam6-)'J phenylmethylaminepenicillane Acid (2
0,0? : 5heehan, Henery -
Logan co-authored ``1 Journal of the American Chemical Society (Journal o
f the American Chemical 5
81.5836 (1959):
N7) 7-t:)n (140ml) Stirred solution (0-5℃
) to 6.08 ml of triethylamine, then 578 m
1 of isobutyl chloroformate was added.

After 10 minutes of extraction, water (1000 ml)/acetone (3
00 ml) mixture was stirred and dissolved with 9.28 P of 4-benzyloxybenzylamine (at ambient temperature).

The resulting mixture was stirred for 4 minutes, and an additional 500 ml of water was added.

Stirring was continued for an additional 7 minutes and then extracted with ether.

The ether layer was dried over magnesium sulfate and then evaporated to dryness in vacuo.

The crude product obtained above was redissolved in 200 TLl of ether and added dropwise to 2500 ml of hexane over 10 minutes.

The precipitated solid was collected and 21.5P of 6-(+-liphenylmethylamine)=2,2-dimethyl-3-[N-(4-
Benzyloxybenzyl)carbamoyl] penum was obtained.

6-()liphenylmethylamine)-2,2-dimethyl-3-(chloro-(N-(4-benzyloxybenzyl)iminocomethyl)penam 2.01 of the above amide was dissolved in 10 ml of dry chloroform with stirring. To the resulting solution (0-5°C) was added 0.99 ml of pyridine and then 5.42 ml of a 2.26M chloroform solution of phosgene.

It was then stirred overnight at ambient temperature.

At the end of stirring, vacuum evaporate to dryness to obtain a viscous gum-like substance,
This was extracted with 100ml of ether.

The ether extract was filtered and the juice was evaporated to give the iminochloride as a yellow foam.

6-()riphenylmethylamino)-2,2-dimethyl-3-4:1-(4-benzyloxybenzyl)tetrazol-5-yl]penam The above iminochloride was dissolved in 8 ml of dry N-N-dimethylformamide. Re-dissolved.

249rI19 of potassium azide was added and the resulting cloudy solution was stirred at ambient temperature for 2.25 hours.

The solvent was evaporated under high vacuum at ambient temperature to give a brown gum.

This residue was partitioned between 60 ml of water and 150 ml of ether.

The ether phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate and finally evaporated to dryness in vacuo.

The residue is 980 m9 of 6-(triphenylmethylamine)
-2,2-dimethyl-3-(1-(4-benzyloxybenzyl)tetrazol-5-yl)henum.

Its NMR spectrum (CDC13) is 7.30 p.
pm (m, aromatic ring hydrogen), 5.45 ppm (q.

benzyl hydrogen), 5.05 ppm, (s, C-3 hydrogen), 5.00 ppm (s, benzyl hydrogen), 4.4
0ppm (m, C-5 and C-6 hydrogen), 1.40p
pm (S, C-2 hydrogen) and 0.70 ppm (s,
C-2 hydrogen) showed an absorption band.

Example 3 6-(+・Riphenylmethylamine)-2・2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam (A) 6-(1-Riphenylmethylamine)-2° 2-
A stirred slurry of dimethyl-3-(N-furfurylcarbamoyl)penam 6-aminopenicillanic acid (211' (1 mono) in chloroform (150 ml) at 25-30°C
Then 278 ml (2 mol) of triethylamine was added.

Then, 306P (1.1 mol) of triphenylmethyl chloride was added dropwise at 25-30°C over 25 minutes.

Stirring was then removed for 44 hours at ambient temperature.

522 ml (0.25 mol) of the above 6-()liphenylmethylamine)penicillanic acid solution were cooled to 4 DEG C. and then 3.5 ml of triethylamine were added.

23.75 ml of ethyl chloroformate was added at 5-10° C. with vigorous stirring.

After the addition is complete, continue stirring at about 6℃ for 30 minutes, and then
．． 431 nl of furfurylamine was injected into the reaction medium below the surface of the solvent.

Furufuri/L/7min 3 times at 10 minute intervals (5,90m
g14.22m113.54m1) were injected into the reaction medium in a similar manner.

The total amount of furfurylamine added was 22.09ml (0
, 25 mol) and the humidity was maintained at approximately 6° C. during the amine addition.

Upon completion of the amine addition, remove the cooling bath and bring the reaction medium to approximately 25°C.
The mixture was stirred for 45 minutes.

It was then washed successively with 3 parts water and 1 part salt water.

Finally, it was dried with anhydrous magnesium sulfate. This gave a chloroform solution (610 ml) of 6-()liphenylmethylamine)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam.

The NMR spectrum of this solution is 7.3 ppm (17H
, m, ), 6.2ppm (tHlm), 4.35pp
m (3H1m), 4.05ppm (2H,s), 1.
6ppm (3H,s') 1.35ppm (3H,s
) showed absorption.

(B) 6-(+-rephenylmethylamine)-2・2-
Dimethyl-3-(1-furfuryltetrazol-5-yl)penam 6-(triphenylmethylamine)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam(3,0
To a stirred solution of 5P (5.7 mmol) in chloroform (8 ml) at 0° C. was added 1.35 ml (17 mmol) of pyridine, followed by 2.64 rnl of a 4.33 M solution of phosgene in chloroform.

Stirring was then continued for 1 hour at 25°C.

Chloroform, excess phosgene and pyridine were removed by vacuum evaporation and the residue was redissolved in a 5 ml chloroform layer.

The solution was cooled to 0°C and then 2.25°C. (14,
4 mmol) of tetramethylguanidinium azide was added in several portions.

Stirring was continued for 15 minutes at ambient temperature, 20 ml of chloroform and then 30 ml of water were added to adjust the pH to 6.5.

The chloroform layer was separated, washed with water, then brine, and then dried (MgSO4).

The solvent was removed by vacuum evaporation to give 3.37f of a dark red foam.

This foam was redissolved in a small amount of chloroform and adsorbed onto a chromatographic silica gel column 3.

The column was eluted with chloroform and the appropriate fractions were then evaporated in vacuo to give 6-(triphenylmethylamine).
-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam was obtained.

The NMR spectrum vector (CDC13) of this product is 7.
40 ppm (m.

16H), 6.40ppm (m, 2H), 5.50ppm
m (s, 2H), 5.20ppm (s, LH), 4.9
0 ppm (m, 2H), 1.60ppm (S, 3H
), showed absorption at 0.80 ppm (s, 3H).

Example 4 6-()liphenylmethylamino)-2,2-dimethyl-3-(1-(5-methylfurfuryl)tetrazole-
The title compound was prepared by the method of Example 3 using 5-methylfurfurylamine in place of furfurylamine.

The NMR spectrum (CDC13) of this product is 7.3
6ppm (m, 15H), 6.33ppm (m, IH
), 5.93ppm (m, IH) < 5.50ppm (s
, 2H), 5.20ppm (s, IH), 4.50p
pm (m, 2H), 3.23ppm (d, I
H), 2.26ppm (s, 3H), 1.63ppm
(s, 3H), showed absorption at 0.90 ppm (m, 3H).

Example 5 Furfurylamine in 6-(triphenylmethylamine)-2,2-dimethyl-3-(1-(2,4-dimethoxybencyl)tetrasol-5-yl)penam Example 3 -In place of dimethoxybenzylamine, the title compound was prepared from 6-(triphenylmethylamino)penicillanic acid in 146% yield.

The crude product was purified by recrystallization from a mixture of methine chloride and methanol.

The NMR spectrum (CDC13) of the product is 7.40p
pm (m, 16H), 6.45ppm (m, 2H), 5
．． 40ppm (s, 2H), 4.50ppm (m, 2H)
H), 3.75ppm (sl 3H), 3.70ppm
(s, 3H), 1.55ppm (s, 3H), 0.90
Absorption was shown in ppm (s, 3H).

Example 6 6-(triphenylmethylamine)-2,2-dimethyl-3-[1-(4-hydroxybendi)Iy) 7
Trough”-5-yl)penam(A)6-()liphenylmethylamine)-2,2-dimethyl-3-(N-(
4-Hydroxybenzyl)carbamoyl]penam 6-aminopenicillanic acid (43,2?; 0.20 mol)
To a stirred slurry in chloroform (300 ml) at ambient temperature was added 55.6 ml (0.40 mol) of triethylamine followed by 61.27 (0.22 mol) of triphenylmethyl chloride.

Stirring was continued for an additional 48 hours at ambient temperature.

Take 120 ml of this chloroform solution [containing 0,060 moles of 6-( )'
12 mol) of triethylamine were added.

It was cooled to about 4° C. in a water bath and then 6.84 mg of ethyl chloroformate was added in one portion under stirring.

Stirring was continued for 30 minutes while cooling in a water bath, then 7.57
(0,060 mol) of 4-hydroxybenzylamine was added.

Stirring was continued for 10 minutes while cooling in a water bath and then for 1 hour without cooling.

At the end of stirring, the chloroform solution was washed with water, then brine, and dried over anhydrous sodium sulfate.

The solvent was removed by vacuum evaporation to give the crude amide.

This crude amide was redissolved in 50 ml of chloroform and adsorbed onto a silica gel column for chromatography.

The column was eluted with chloroform and 400ml fractions were taken.

Fractions 9-15 were combined and concentrated to an oil that was triturated with methylene chloride.

After further trituration with ether 12.6: IM
'6=(triphenylmethylamine)-2,2-dimethyl-3-CN-C4-hydroxybenzyl)carbamoyl]penam, mp 166-168°C (decomposition) was obtained.

The IR spectrum of the product is 1785CrIl 1 (
β-lactam), 1675 cm' (amide I)
showed absorption.

Its NMR spectrum (CDC13) is 7.60-6.
40 ppm (m, H of 20H1 aromatic ring H1 amide), 4
．． 70-4.10 ppm (m, 5H, C-5 and C
-6 H1 benzylmethylene H, C-3 H), 2.
98 ppm (d, L H, H of amine), ■.

64ppm (s, 3H, C-2 methyl H), 1.31
Absorption was shown in ppm (s, 3H, H of C-2 methyl).

(B) 6-(triphenylmethylamine)-2,2-dimethyl-3-[1-(4-hydroxybenzyl)tetrazol-5-yl]penam6-(Jliphenylmethylamino)-2,2- Add 1 ml (1 ml) of dimethyl-3-(N-(4-hydroxybenzyl)carbamoyl) penum (prepared in Upper Cocoon; 1.69'i? (3 mmol)) to a stirred solution of chloroform (9 ml) in chloroform (9 ml).
2 mmol) of pyridine was added.

It was cooled to about 4° C. in a water bath and 0.80 ml of chlorotrimethylsilane was added.

Stirred at ambient temperature for 40 minutes and recooled to approximately 4°C.

4.3 of phosgene in chloroform (6.45 mmol)
A molar solution (1.5 ml) was added and the cooling bath was removed.

Stirring was continued for a further 15 hours and then evaporated in vacuo to remove all volatile components.

The oily residue was redissolved in 6 ml of chloroform and then cooled to approximately 4°C in a water bath.

While stirring, 0.95 f (6 mmol) of tetramethylguanidinium azide was added and stirring continued for an additional hour at ambient temperature.

At the end of stirring, add 25ml of water and then add enough lN.
The pH of the aqueous phase was brought to 10 by adding NaOH.

The chloroform layer was separated, washed with water, dried over sodium sulfate, and then evaporated to dryness in vacuo.

Dissolve the oily residue (2,3?) in a small amount of chloroform,
It was adsorbed onto a chromatography silica gel (3C1) column.

The column was eluted with chloroform and 50ml fractions were collected.

Fractions 13-19 were combined and concentrated in vacuo to 0.71
2 of 6-(triphenylmethylamino)-2.2-dimethyl-3-(1-(4-hydroxybenzyl)tetrazol-5-yl)penam was obtained.

Its IR spectrum (CDC13) is 1780 crIL
'(β; -lactam) showed absorption.

NMR spectrum (CDC13) is 7.00-6.67
ppm (m.

20H1 aromatic ring H1 phenolic H), 5.66-5.
10ppm (q, 2H, H of benzylmethylene), 5゜02ppm (sl 1H, H of C-3),' 4.6
0-4.20ppm (m, 2H, C-5 and C-6
H), 3.10 ppm (d, IH, H of amine), 1
．． 44ppm (s, 3H, C-2 methyl H), 0.7
It showed absorption at 1 ppm (sl 3H, H of C-2 methyl).

; Example 7 6-(triphenylmethylamine)-2,2-dimethyl-3-(1-(4-acetoxybenzyl)tetrazol-5-yl]penam6-()liphenylmethylamine)-2,2 -dimethyl-3-(N-(4-hydroxybenzyl)carbamoyl]penam (1,69P; 3 mmol) in a stirred solution of 1 ml (12 mmol) in chloroform (9 m, l)
of pyridine was added.

It was cooled to about 4° C. in a water bath and then 235° C. of acetyl chloride was added slowly.

Stirred at ambient temperature for 2 hours, then recooled to about 4°C.

Phosgene [4.3 in chloroform (6.45 mmol)
1.5 ml as a molar solution) was added and then the cooling bath was removed.

Stirring was continued for an additional 1.5 hours and all volatile components were removed by vacuum evaporation.

The residue was redissolved in 6 liters of chloroform and then cooled to about 4°C in a water bath.

0.95 P (6 mmol) of tetramethylguanidinium azide was added and stirring continued for an additional hour at ambient temperature.

At the end of stirring, add 25ml of water, then add enough lNN.
The pH of the aqueous phase was brought to 10 by adding aOH.

The chloroform layer was separated, washed with water, dried over sodium sulfate, and then evaporated to dryness in vacuo.

This resulted in crude 6-(triphenylmethylamine)-2.
2-dimethyl-3-[1-(4-acetoxybenzyl)
Tetrazol-5-yl:penam was obtained and purified by chromatography.

In the above method, equimolar amounts of formic acid-acetic acid mixed anhydride and chloromethyl methyl ether were used instead of acetyl chloride, and 6-(triphenylmethylamine)-2,2-dimethyl-3-[:1-( 4-formyloxybenzyl)
Tetrazol-5-yl]penam, 6-()IJl phenylmethylamino-2,2-dimethyl-3-(1-C4
-(methoxymethoxy)hensylcotetrazole-5-
Il) got a penum.

Example 8 6-(Ul,lphenylmethylamino)-2,2-dimethyl-3-[1-(ethoxycarbonyl)tetrazol-5-yl]penam(A)6-()liphenylmethylamine)-2・2-dimethyl-3-(N-ethoxycarbonylcarbamoyl)
Penam 4.582 (10 mmol) of 6-(+-riphenylmethylamine)penicillanic acid and 1.45 ml (10 mmol) of triethylamine were dissolved in 75 ml of acetonitrile and, with stirring, dissolved in 5 ml of acetonitrile] , 15P (10 mmol) of ethoxycarbonyl isocyanate was added.

Stirred at about 25° C. for 16 hours, then removed the solvent by vacuum evaporation.

The residue was redissolved in chloroform, water and bicarbonate.
It was washed successively with sodium chloride solution and sodium chloride solution.

It was then dried over anhydrous magnesium sulfate and evaporated in vacuo.

The residue was redissolved in chloroform, washed with dilute HCI,
Dry over magnesium sulfate and evaporate again in vacuo.

This gave a crude product which was then purified by chromatography using silica gel as adsorbent and column eluting with 4 v/v % ethanol in chloroform.

6-()'l phenylmethylamino)-2,2-dimethyl-3-(N-(ethoxycarbonyl)carbomoyl]
Penum's final yield is 2.54? (yield 48%).

(B) 6- () IJl phenylmethylamino-
2,2-dimef-3-(1-(ethoxycarbonyl)
529m9 (1 mmol) of 6-(triphenylmethylamine)-2,2-dimethyl-3-CN-(1-oxycarbonyl)carbamoyl]penam and 240m9 (3 mmol) of pyridine. was dissolved in 25 ml of methylene chloride, and while stirring, 208 ml (1 mmol) of phosphorus pentachloride was added at OoC.

The mixture was stirred at 0°C for 0.5 hours and at about 25°C for 2 hours.

The solvent and excess pyridine are then removed by vacuum evaporation,
The residue was redissolved in 15ml of chloroform.

The mixture was cooled to 0° C. and 0.47 P (3 mmol) of tetramethylguanidinium azide was added in portions while stirring.

Stirring was continued for 2 hours at ambient temperature and 15 ml of chloroform was added followed by 30 ml of water.

The pH was adjusted to 6.5, and the chloroform layer was separated.

The chloroform layer was washed with water, then brine, and dried over anhydrous sodium sulfate.

The solvent was removed by vacuum evaporation to yield crude 6-(+=Jphenylmethylamino)-2,2-dimethyl-3-'1il-(ethoxycarbonyl)tetrazol-5-yl]penam.

The crude product was purified by chromatography on silica gel.

Example 9 6-(Jliphenylmethylamine)-2,2-dimethyl-3-(1,-(2-me)-xycarbonylethyl)tetrazol-5-yl)penam(A)6-()IJl Phenylmethylamino-2,2-dimethyl-3-[:N-
(2-Methoxycarbonylethyl)carbomoyl]penam 35 g of 6-(t'phenylmethylamino)penicillanic acid was dissolved in 250° C. dry chloroform without ethanol and heated to 0-3° C. for 11.5 hours without stirring. 7ml of triethylamine was added.

7.3 ml of ethyl chloroformate was added dropwise to a second solution prepared in 155 ml of dry chloroform without ethanol at 0-6°C under stirring.

Stirring was continued for an additional 10 minutes. Thereby, a chloroform solution of 6-(J'J phenylmethylamino)penicillanic acid mixed anhydride was obtained.

In another flask, 10.73L? β-alanine methyl ester hydrochloride and 22 sulfuric anhydride 1-'Jium,
A β-alanine methyl ester solution was prepared by adding 11.71'/l of triethylamine to the slurry in 115 ml of dry chloroform without ethanol at about 10°C.

Stirring was continued for an additional 10 minutes.

This amino-ester solution was added dropwise to the mixed anhydride solution at 3-6° C. under stirring.

After the addition was completed, stirring was continued for an additional 2 hours.

At the end of stirring, it was washed successively with 3 parts water and 1 part brine.

It was then dried over anhydrous sodium sulfate and evaporated in vacuo.
0. IP crude 6-(toIJ phenylmethylamino)-2
・2-dimethyl-3-(N-(2-methoxycarbonylethyl)carbamoyl) penum as a convex solid (mp=6
0-70°C).

The crude product was extracted into refluxing ether, filtered, and purified by treating the p-liquid with activated carbon, followed by reprecipitation by adding petroleum ether.

(B) 6-(+-rephenylmethylamine)-2・2-
Dimethyl-3-(1-(2-methoxycarbonylethyl)tetrazol-5-yl)penam The amide 2g described in A above was dissolved in 5 ml of dry chloroform without ethanol and heated at about 0° C. with stirring. 1.36 ml of pyridine was added followed by phosgene solution (620~ dissolved in 4 ml of dry chloroform without ethanol).

Stirred for 25 hours at ambient temperature, then the solvent was removed by evaporation in vacuo.

The residue was redissolved in 9 ml of dry chloroform without ethanol and 580 rr19 of tetramethylguanidinium azide was added.

After stirring for 45 minutes, 2001rb9 of tetramethylguanidinium azide was added to the mixture.

The mixture was then stirred for 18 hours to ensure complete conversion to tetrazole.

Sufficient saturated sodium bicarbonate solution was then added to bring the pH of the aqueous phase to 7.6.

The chloroform layer was separated, washed with pH 5 water, pH 7 water, dried over anhydrous sodium sulfate and finally evaporated in vacuo.

This gave a crude product of 2.19P which was recrystallized from methanol], 11P (48% yield) to produce a product (m
ploo~105°C) was obtained.

NMR spectrum # (CDCl s ) is 7.40 pp
m (m, 15H), 5.15ppm (s, IH), 3.
80ppm (m, 4H), 3.70ppm (s13H)
, 3.10ppm (t, 2H), 1.70ppm (s,
3H) and 1.17 ppm (s, 3H), further indicating that the product contained solvated methanol.

Reference example 1 6-amino-2,2-dimethyl-3-[1-(ethoxycarbonyl)tetrazol-5-yl]6-()'J phenylmethylamino) of penum 554η) = 2.
2-dimethyl-3-1:1-(dioxycarbonyl)
Tetrazol-5-yl]penam was dissolved in 2 ml of acetone, and a solution of p-toluenesulfonic acid/water (190 ml) in acetone (1 ml) was added while stirring.

Stirring was continued for an additional 3 hours and then evaporated in vacuo to remove the acetone.

The residue was slurried in ether, filtered and dried to give the title compound as its p-)luenesulfonate salt.

This p-4 luenesulfonate was mixed with 15 ml of water and 15 ml of water.
1 and chloroform.

The pH of the aqueous phase was adjusted to 7.0, and the chloroform layer was separated.

The chloroform layer was dried over sodium sulfate and then evaporated in vacuo to give the title compound as its free base.

Reference example 2 6-()riphenylmethylamine)-2,2-dimethyl-3-(5-tetrazolyl) penum 600 m9 of 6-
(1-Riphenylmethylamino)-2,2-dimethyl-
3-(1-(2-methoxycarbonylethyl)tetrazol-5-yl)penam (containing about 4.5% methanol) was dissolved in 1 ml of chloroform and stirred.
Diazabicyclo[4.3.0]non-5-ene (375
, 2 my) in chloroform (0.5 d) was added.

Stirring was continued for an additional 3 hours, and then an additional 2 ml of chloroform was added for dilution.

It was washed quickly with 5 ml of 2N HCl, and then an additional 5 ml of 2N HCl was added.

Cool to about 0°C and calculate the precipitated solid to 323
The title compound of rn9 (yield 71%) was obtained.

NMR spectrum (DMSO-do) is 7.40
ppm (m, 15H), 5.30ppm (s, IH)
, 4.6Qppm (m, 2H), 1.58ppm (s,
3H) and 0.78 ppm (s, 3H).

Claims (1)

[Claims] Formula 1 (wherein R2 is the formula or -CH2-CH2-Y; R4 is hydrogen or alkyl having 1 to 4 carbon atoms; R5 and R6 are each hydroxy and 1 to 4 carbon atoms; selected from the group consisting of alkoxy and benzyloxy; R7 is hydrogen or methyl; R8 has 1 to 1 carbon atoms;
Y is alkoxycarbonyl having 2 to 5 carbon atoms), wherein 6-triphenylmethylaminopenicillanic acid is prepared from the formula NH2-CH2-CH2-Y. React with the selected amine at -30-30°C or with an isocyanate of the formula % where R8 is as defined above; the resulting 6
Treatment of -(triphenylmethylamine)-3-carbamoylpenam with phosphorus pentachloride, phosgene or thionyl chloride in the presence of at least 1 mole of tertiary amine at a temperature of -20 to 30°C yields the iminochloride. a process characterized in that the iminochloride is treated with an alkali metal or tetramethylguanidinium azide at a temperature of 0 to 30°C.