CS197218B2 - Method of producing novel silysters of azetidine-2-sulphenates - Google Patents

Description

(54) A process for the preparation of new silyl esters of azetidine-2-sulphenates

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the novel silyl esters of azetidine-2-sulfenates of formula II

where

R2 represents a hydrogen atom, an alkyl of 1 to 6 new silyl esters of azetidime-2-sulfenates, or benzyl, or a radical of formula

CH3

CH3 - Si—, /

/

CH.3

R 3 represents a hydrogen atom and

R a is hydrogen, phenylacetyl or phenoxyacetyl, or together R 3 and R a together with the nitrogen atom to which they are attached form a phthalimido group, or 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidin-1-yl, characterized in that the penicillin sulphoxide is heated

where

R 2, R 3 and R 6 are as defined above, in an inert, anhydrous solvent at 75 to 150 ° C with the exclusion of an acidic medium and in the presence of a silylating agent, namely N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide, trimethylchlorosilane, hexamethyldisilazane or mixtures thereof.

The semisynthetic production of a 7-acylamidodesacetoxycephalosporin antibiotic from penicillin starting material is of great importance since the invention of Morin and Jackson (U.S. Patent No. 3,275,626), which describes a process for converting a penicillin sulfoxide ester to a desacetoxycephalosporanic acid ester. A further improvement of this process has been suggested by Robin D. G. Cooper in British Patent No. 1,204,972. This document discloses the use of certain tertiary carboxamides or certain tertiary sulfonamides as solvents (British Patent 1 204 394). Both of these methods are associated with heating and cause the ester ester penicillin sulfoxide to be converted with much greater selectivity to the corresponding desacetoxycephalosporin esters, yet lower temperatures can still be used. U.S. Pat. No. 3,591,585 describes an improvement of the Cooper process by carrying out the conversion by heating under acidic conditions and in the presence of tertiary carboxamides. This process can be further improved by carrying out the reaction in the presence of sulfonic acid and in the presence of a means to remove the water formed in the reaction mixture and delay the reaction.

The mechanism envisaged in U.S. Patent No. 3,275,626 for converting penicillin sulfoxide in the form of an ester to an ester of desacetoxycephalosporanic acid is the formation of the sulfenic acid followed by cleavage of the S-C2 bond. The mechanism has now been identified in more detail and has been further demonstrated [R. D.G. Cooper, J.A.C. 92, (1970), pp. 5010-5011] that, under the conditions in which the reaction proceeds, a thermal equilibrium is formed between the sulfoxide starting material and the sulfenic acid intermediate. One approach to complete the conversion would be to convert the volatile sulfenic acid, which is an intermediate of the reaction, to a stable and isolatable intermediate. After isolation, this intermediate could then be converted to the corresponding desacetoxycephalosporin and, without isolation, the instantaneous conversion to the corresponding desacetoxycephalosporin can be carried out immediately.

The new silyl esters have sufficient stability to be isolated and described. In the above formula, the silicon atom is bound to three methyl groups.

The group R2 in the above formula is a carboxyl protecting group. Preferred protecting groups are, for example, alkyl of 1 to 6 carbon atoms, 2,2,2-trihalogenethyl, nitrobenzyl or a radical of formula

CH3 \

\

CH3 - Si—, /

OF

CHs

The new silyl esters are intermediates of the conversion of penicillin sulfoxide to desacetoxycephalosporin. As reported by Morin et al., Journal of the American Chemical Society 91 (1969J, pp. 1401-1407), the expansion of the penicillin ring to cephalosporin involves the oxidative cleavage of the sulfur-carbon bond to form an intermediate labile sulfenic acid having This intermediate is then converted to the resulting compound, 3-cefemcephalosporin, by ring closure Due to the equilibrium state of the reaction, it is possible for either the unstable sulfenic acid to either be converted to the resulting cephalosporin by ring closure or to Therefore, it would be highly advantageous to convert this intermediate into the form of a stable derivative which could then be reacted to give the desired cephalosporin.

The process according to the invention can be clearly distinguished from the previous processes, which also used silicon-containing compounds in connection with penicillin sulfoxide. For example, Gutowski, Tetrahedron Letters, 21 (1970), pp. 1779-1782, describes the epimerization of penicillin sulfoxide esters in reaction with a silylating agent at room temperature over several days. Belgian Patent No. 763,104 discloses a process for reacting penicillin sulfoxide by heating it to a temperature of less than 160 ° C in an anhydrous medium and in the presence of a silicon-halogen-containing compound and in the presence of at least one nitrogenous base present in an amount of at least 5 moles per mole of sulfoxide.

In the process of the present invention, a silylating agent can be used to effect the silylation of the sulfonic acid intermediate formed by heat cleavage of penicillin sulfoxide. Such an agent comprises at least one group of formula -Si (CH3) _3, and moreover should be such a group in the molecule of the agent in such a position that it can be readily removed under reaction conditions thus creating the silyl-azetidin-2-sulphenate . Mixtures of these agents may also be used. Advantageously, a mixture may be used in which each of these agents gives rise to the same protecting group. Preferred agents are N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide, trimethylchlorosilane, hexamethyldisilazane or mixtures thereof.

The conversion of penicillin sulfoxide to azetidine-2-sulfenate silyl ester is completed by heating the sulfoxide with the selected silylating agent to a temperature of 75 to 150 ^° C. The sulfoxide is heated in an inert, substantially anhydrous solvent. Any solvent that is inert to penicillin sulfoxide and the silylating agent and that has a sufficiently high boiling point to

137218 the necessary reaction temperature could be achieved. Suitable solvents are benzene, toluene, acetonitrile, dioxane, dimethylformamide, dimethylacetamide and the like. Mixtures of these solvents may also be used.

The reaction mixture containing penicillin sulfoxide is heated in the presence of the silylating agent to the temperature indicated above for the time required to effect the conversion. This time can be very short or longer depending on the reactants used. Generally, the mixture is heated for 0.5 to 24 hours. Heating is likely to aid in the cleavage of the bond between the sulfur atom and the carbon atom at the 2-position to form a sulfenic acid intermediate capable of reacting with the silylating agent. This results in the formation of a stable silyl ester of this intermediate, which is one of the novel compounds of the present invention, under the action of a silylating agent.

Since one silyl group must be used for each sulfenic acid group, at least the same molar amount of the agent as penicillin sulfoxide must be used. Some agents have such a structure that they provide 2 or more silyl groups per molecule. Accordingly, smaller molar amounts of these agents may be used. In general, an excess of 1.1 to 4 equivalents of reagent per equivalent of penicillin sulfoxide is used. As will be explained below, some starting penicillin sulfoxides may have other groups on which silylation may take place. In these cases, an additional equivalent of silyl groups must be used for each of these groups where silylation may occur.

Any of the above silylating agents can be used to make the silyl ester of the invention. However, strongly alkaline reactions should be avoided, otherwise the β-lactam ring could be split. For this reason, particular caution should be exercised when silazane is used as the silylating agent. Since the use of silazane results in the formation of ammonia during the reaction, immediate neutralization of the resulting ammonia must be ensured. This can be done by adding a small amount of acid to the reaction mixture, which reacts with ammonia at the time of its formation. The same result can be achieved by using a silazane-halogensilane mixture as the silylating agent. Halogen silane releases hydrogen halide as a byproduct of ester formation and this hydrogen halide reacts with ammonia resulting from silazane.

When halogenated silane is used as a silylating agent, caution should also be exercised with respect to the formation of hydrogen halide, since under acidic conditions immediate ring closure could occur. In order to avoid this possibility, it is preferable to use a reagent mixture containing a sufficient amount of silazane to neutralize the hydrogen halide produced by the ammonia.

The intermediate intermediate silyl ester can be isolated from the reaction mixture.

As already mentioned, the starting material for the process of the invention is 6-aminopenicillanic acid sulfoxide (APA).

If this starting material is used, three points for silylation are possible. The present process will now provide a stable silyl ester, which is an intermediate of this reaction and is formed by cleavage of the starting compound. The intermediate has the formula

The process according to the invention thus results in an intermediate from the starting material whose amino and carboxyl groups are suitably protected. It will be appreciated that the ratio of the silylating agent to the starting sulfoxide must be such that the silylating agent delivers at least 3 silyl groups per molecule of the starting material.

Penicillin sulfoxide having either a free amino group at the 6-position or a free carboxy group at the 3-position may also be used as starting materials. In such cases, the desired ratio of silylating agent to penicillin sulfoxide will be such that it delivers at least two silyl groups per molecule sulfoxide.

When R3 represents a hydrogen atom, it is highly preferred that R a has the meaning of a phenylacetyl or phenoxyacetyl group.

Thousands of penicillin compounds have been described in previously known publications. In principle, any sulfoxide of these penicillin compounds can be used as a starting material in the process of the invention and can be readily obtained by known methods. For example, penicillin G (benzylpenicillin) or penicillin V (phenoxymethylpenicillin) can be converted to the corresponding sulfoxides as starting materials in the process of the invention. Both penicillin G and penicillin V can be obtained biosynthetically or by isolation from natural strains, and both of these derivatives can be cleaved to 6-APA, which can be immediately oxidized and used as starting material in the process according to the invention. This compound can itself be oxidized or acylated at the 6-position and / or esterified at the 3-position in a known manner to form the basic penicillin structures, and their sulfoxides can also be used as starting materials.

The invention will be illustrated by the following examples.

Example 1

A 50 ml three-necked flask was charged with 752 mg (2 mmol) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate. 10 ml of benzene, 0.26 ml (2 mmol) of trimethylchlorosilane and 0.21 ml (Immol) of hexamethyldisilazane are then added to the flask. The resulting mixture was stirred and refluxed at 78-80 ° C for 16 hours. The reaction mixture is then evaporated in vacuo to a residue which contains approximately quantitative yield of trimethylsilyl-3-phthalimido-4-oxo-1- (1'-methoxycarbonyl-2'-methyl-2'-propenyl jazetidine-2-sulfenate).

Analysis for C 20 H 24 N 2 O 6 Si:

calculated:

H, 5.39; N, 6.25. Found:

H, 5.55%, N 6.42%.

[.alpha.] D @ ²⁷ = -164.4 DEG (benzene).

UV _max :

220 nm (λ = 47,200),

291 nm (λ = 10,500).

IR: 2990, 2930, 1770, 1760, 1735, 1715, 1390,

1245, 874, 845 and 705 cm ^-1 .

NMR (s):

0.05 (s, 9H);

2.04 (s, 3H);

3.84 (fs, 3H),

5.07 (two overlapping s),

5.20 (6s, 1 H),

5.84 (s, AB, 2H).

7.86 (m, 4 H).

MS m / e: 448, 433, 359, 327, 299, 293,262,

239, 204, 187, 172, 160, 113, 104, 89, 73.

Example 2

To a suspension of 376 mg of methyl 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate in 10 ml of benzene was added 0.25 ml of N, O-bis- (trimethylsilyl) acetamide and the resulting reaction mixture was heated to reflux. condenser to a temperature of approximately 78 ^C C for about 22 hours. the reaction mixture was cooled to room temperature and evaporated in vacuo to give a brown gum, which has the expected NMR spectrum data confirming the formation of the trimethylsilyl ester intermediate.

Example 3

In a 50 ml three-necked flask was charged 752 mg (2 mmol) of methyl 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate in 10 ml of benzene. To the resulting mixture was added 0.26 mL (2 mmol) of trimethylchlorosilane and 0.21 mL (1 mmol) of hexamethyldisilazane, and the resulting mixture was heated at reflux overnight, then cooled to room temperature and evaporated in vacuo to give a clear mixture. This viscous liquid was examined in IR light for the presence of the .beta.-lactam ring and the mass spectrum showed the following m / e values:

448, 433, 389, 327, 359, 299, 293, 262, 239,

204, 187, 172, 160, 152, 130, 120, 113, 104, and 73.

The NMR spectrum also confirmed the expected structure of the trimethylsilyl ester intermediate.

Example 4

A mixture of 752 mg (2 mmol) of methyl 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylate, 393 mg (3 mmol) of N-trimethylsilylacetamide and 10 ml of benzene was heated to 78 ° C. about 16 hours. The reaction mixture was then cooled to room temperature and evaporated in vacuo to a glassy solid. NMR of this residue was trimethylsilyl ester.

Example 5

A three-necked 50 ml flask was charged with 994 mg (2 mmol) of p-nitrobenzyl-6-phthalmido-2,2-dimethylpenam-1-oxide-3-carboxylate, 10 ml of benzene, 0.26 (2 mmol) of trimethylchlorosilane, and 0.21 ml (1 mmol) of hexamethyldisilazane. The reaction mixture is heated to 78-80 ^° C for about 16 hours with stirring. A small amount of the solid formed is then removed by filtration. The filtrate was evaporated in vacuo to give a yellow gum which was identical to trimethylsilyl-3-phthalimido-4-oxo-1- (1'-p-nitrobenzyloxycarbonyl-2'-methyl-2 'in IR and NMR analysis). -propenyl] azetidine-2-sulfate.

NMR (CDCl3) (s):

0.05 (s, 9H);

2.09 (s, 3H);

5.14 (s, 1 H),

5.33 (two overlapping s, 2H),

5.37 (s, 2H).

5.97 (s, 2H).

7.86 (s, 4H);

7.91 (q, 4H, J = 90 and 40).

IR (CHCl3): 3050, 2960, 1840, 1785, 1725,

1640, 1500, 1100 and 846 cm ^-1 .

Example 6

Κ 50 ml of benzene are added 1.75 g (5 mmol) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylic acid, 1.3 ml (10 mmol) of trimethylchlorosilane and 1.05 ml (5 mmol) of ) hexamethyldisilazane. The reaction mixture was heated under reflux at 78-80 C ^and 4.5 h. The reaction mixture is cooled to room temperature and evaporated in vacuo to give a residue consisting essentially of trimethylsilyl-3-phthalimido-4-oxo-1- (1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl-azetidine- Of 2-sulfenate in approximately quantitative yield.

Analysis for C22H30N2O6Si2:

calculated:

52.15% C 5.97 _0/0 H, 5.53% N, 6.32%; found:

51.98% C, 5.85% H, 5.58 a / _o N, 6.18% P. [] _D ²⁷ = -45.5 ° (benzene).

IR (CHCl 3): 3010, 2960, 1795, 1775, 1740,

1725, 1382, 1250, 1063, 844 and 707 cm ^-1 .

NMR (CDCl3) ([delta]:

0.05 (s, 9H);

0.37 (s, 9H);

2.05 (s, 3H);

5.01 (s, 1 H),

5.12 (s, 1 H),

5.20 (s, 1 H),

5.84 (s, AB, 2H).

7.84 (m, 4 H).

MS m / e: 506, 491, 416, 401, 388, 300, 299,232,

230, 204, 187, 160, 147, 132, 114, 104, 73. Example 7

A 250 ml three-necked flask was charged with 50 ml of benzene, 2.6 g (approximately 20 mmol) of N-trimethylsilylacetamide and 1.75 g (5 mmol) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3- carboxylic acids. The mixture was stirred for 5 minutes, after which time all substances went into solution. The mixture was then slowly heated to reflux at 80 ° C for 5 minutes. The mixture was cooled to room temperature, at which time a small amount of solid crystallized which was collected by filtration and the filtrate was evaporated to dryness in vacuo to give a residue which was subjected to NMR analysis to confirm trimethylisilyl-3-phthalimido-4-oxo-1- (1'-trimethylsilyloxycarbonyl-2'-methyl-2'-propenyl jazetidine-2-sulfenate).

Example 8

To a solution of 380 mg (1 mmol) of methyl 6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 15 mL of anhydrous toluene maintained at 40 ° C was added 330 mg (approximately 2 mmol) of N- trimethylsilylacetamide and 0.023 ml (about 0.2 mmol) trimethylchlorosilane. The resulting mixture was heated to reflux at about 111 ^° C for about 5 hours. The reaction mixture was then cooled to room temperature and evaporated in vacuo to give a gummy brown solid. NMR analysis confirmed the presence of trimethylsilyl-3-phenoxyacetamido-4-oxo-1- (1'-methoxycarbonyl-2'-methyl-2'-propenyl) azetidine-2-sulfenate.

NMR (CDCl3):

0.05 (s, 9H2,

2.04 (β, 3H)

3.75 (s, 3H);

4.54 (s, 2H).

5.07 (s, 2H);

5.47 (s, 1H).

5.67 (q, J = 4.5 and 8.0, 1H),

6.17 (d, J = 4.5, 1H).

7.85 (d, J = 8.0, 1H).

Example 9

To 25 ml of a mixture of 60% toluene and 40% acetonitrile was added 1.25 g (2.5 mmol) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate, 1.0 g ( 7.5 mmol of N-trimethylsilylacetamide and 0.19 ml (1.5 mmol of trimethylchlorosilane) were heated at 87 ° C and held at this temperature for 20 hours to give the methylsilyl ester as the desired intermediate.

Example 10

To a mixture of 25 mL of benzene and 18 mL of dimethylacetamide was added 2.5 g (5 mmol) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate, 2 g (approximately 15 mmol) of N- trimethylsilylacetamide and 0.19 ml (1.5 mmol of trimethylchlorosilane. The reaction mixture is heated to reflux at 91 ° C for about 20 hours. After this time, the mixture is cooled to room temperature to give the desired product. trimethylsilylester.

Example 1 a d 11

To a mixture of 25 ml of dimethylacetamide and 62 ml of anhydrous toluene was added 1.31 g (10 mmol) of N-trimethylsilylacetamide and 5.0 g (10 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-1-oxide. -3-carboxylate. The mixture was stirred and refluxed at 118 ° C for 0.5 hours, then the resulting light brown solution was cooled to 80 ^° C to give the desired trimethylsilyl ester.

Example 1 and d 12

To a mixture of 50 ml of benzene and 37.5 ml of dimethylacetamide was added 5.0 g (10 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate. To the resulting solution was added 1.26 mL (10 mmol) of trimethylchlorosilane and 1.05 mL (5 mmol) of hexamethyldiisilazane. The mixture was heated to 95 ^° C for 14.5 hours and the resulting dark red mixture was then cooled to room temperature to give the desired trimethylsilyl ester.

Example 13

A mixture of 5.0 g (10 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 60 ml of dioxane was thoroughly mixed and heated to 40 ° C. To the warm mixture was added 1.26 mL (10 mmol) of trimethylchlorosilane and 10.05 mL (5 mmol) of hexamethyldisilazane. The resulting mixture was slowly heated to 100 ° C and held at this temperature for 5 hours, at which time the color of the solution changed from light yellow to light brown. The mixture was then cooled to 40 ^Q C to give the desired trimethylsilyl.

Example 14

A solution of 1.41 g (3 mmol) of p-nitrobenz 1-6-phenylacetamido-2,2-dimethylpenam-1-oxide-3-carboxylate in 30 ml of dioxane was stirred and 17 ml of anhydrous benzene was added to the resulting solution, followed by 730 mg. (4.5 mmol) of N-trimethylsilylacetamide and 0.06 ml of trimethylchlorosilane. The resulting mixture was heated to reflux at 84 ° C for 16 hours. The solution is then cooled to give the desired trimethylsilyl ester.

Example 15

To 20 mL of dioxane was added 700 mg (3 mmol) of 6-aminopenicillanic acid as the sulfoxide and the resulting mixture was heated to 60 ^° C. To the heated solution was added a small drop of trifluoroacetic acid followed by 1.3 g (approximately 10 mmol) of N -trimethylsilylacetamide. Trifluoroacetic acid is added to neutralize triethylamine, which may be present as an impurity in N-trimethylsilylacetamide. The mixture was heated to reflux for about 3 hours, at which time the mixture turned reddish brown, but the mixture remained clear. The mixture was then evaporated in vacuo to give a reddish-brown gum.

Example 1 a d 16

To 90 ml of anhydrous benzene was added 3.5 g (10 mmol) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylic acid and 5 g of distilled N-trimethylsilylacetamide. The mixture was stirred at room temperature for 15 minutes and then heated to reflux at 80-82 ° C and stirred for an additional 5 hours. The mixture is then cooled to give the desired trimethylsilyl ester.

Example 17

To a stirred mixture of 1.75 g (5 mmol) of 6-phthalimido-2,2-dimethylpenam-1-oxide-3-carboxylic acid in 45 mL of benzene was added

1.3 ml (10 mmol) of trimethylchlorosilane and 1.05 ml (5 mmol) of hexamethyldisilazane. The mixture was refluxed at 80 ° C for 5 hours. The resulting mixture containing the desired trimethylsilyl ester is used directly to produce cephalosporin.

Claims (3)

SUBJECT A process for the preparation of novel silyl esters of azetidine-2-sulfenates of the general formula II wherein R2 represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, 2,2,2-trihalogenethyl, nitrobenzyl or a radical of formula VYNALEZU CH3 \ \ CH3 - Si—, z of CH3 R 3 represents a hydrogen atom, and R a represents a hydrogen atom, phenylacetyl or phenoxyacetyl, or together R 3 and R a together with the nitrogen atom to which they are attached form a phthalimido group, or 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidin-1-yl, characterized by The process of claim 1 wherein the penicillin sulfoxide of Formula I is heated R 2, R 5 and R d are as defined above, in an inert, anhydrous solvent at 75 to 150 ° C with the exclusion of an acidic environment and in the presence of a silylating agent 14, namely N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide, trimethylchlorosilane , hexamethyldisilazane or mixtures thereof. 2. The process of claim 1, wherein penicillin sulfoxide is used in which R4 is hydrogen, phenylacetyl or phenoxyacetyl or forms R3 and R4 together with the nitrogen atom to which they are attached, a phthalimido group. 3. The method of claim 1, wherein penicillin sulfoxide is used in which R3 and R4 together with the nitrogen atom to which they are attached form 2,2'-dimethyl-3-nitroso-5-oxo-4- phenylimidazolidin-1-yl. Severography, n. P., Plant 7, Most