NL8003891A - IMPROVED METHOD FOR THE SILYLATION OF ORGANIC COMPOUNDS WITH 1,1,1-TRIMETHYL-N- (TRIMETHYLSILYL) SILANAMINE BY CATALYSIS WITH CERTAIN NITROGEN CONTAINING COMPOUNDS. - Google Patents

Description

ar 2 - 1 -

Improved process for the silylation of organic compounds with 1,1,1-trimethyl-N- (trimethylsilyl) -silanamine by catalysis with certain nitrogen-containing compounds.

The invention relates to an improved method for the trimethylsilylation of organic compounds.

In preparative organic chemistry there is a growing interest in the use of the trimethylsilyl group, both for protecting reactive groups and for influencing physical properties such as, for example, volatility and solubility (see, for example, BE Cooper, Chem. And Ind 1978, 794)

Widely used silylating agents are trimethylchlorosilane and dimethyl dichlorosilane. Since silylation reactions are equilibrium reactions, it is necessary to withdraw the hydrogen chloride formed from the reaction in order to shift the equilibrium to the desired product side. This can be done by adding, for example, a suitable tertiary amine, for example triethylamine, pyridine or ΙΓ, ΙΓ-dimethylaniline, to the reaction mixture. The amine reacts with the hydrogen chloride to form the corresponding ammonium salt, which is often sparingly soluble in the reaction medium. The removal of this ammonium salt is usually necessary before the product can be further purified, necessitating the use of fairly significant amounts of a suitable solvent. However, it is often unavoidable that traces of ammonium salt are still present in the product.

Other commonly used silylating agents, e.g.

Ν, Ο-bis-trimethylsilylacetamide, K, N, -bis-trimethylsilyl-urea, \ N-trimethylsilyl-N, N *-diphenylurea, trimethylsilylimidazole and trimethylsilyldiethylamine, have the drawback that the product of k \ 8 0 0 3 8 9 1 - 2 - «> the remainder» left by the silylating agent must be separated.

Another widely used silylating agent is 1,1,1-trimethyl-N- (trimethylsilyl) silanamine (better known by its trivial name hexamethyldisilazane, HMDS), which has the advantage that the only by-product is the gaseous, and thus easy to remove ammonia. In addition, HMDS is a relatively inexpensive reagent, which makes it attractive for industrial scale applications.

However, a major drawback of HMDS is that in many cases it reacts slowly or even not at all with certain substances (see, for example, SH Langer et al., J. Org. Chem. 23, 50 (1958)) · As a result high reaction temperatures and / or long reaction times are necessary to complete the silylation, which makes the method less attractive, and even makes it unsuitable for heat-sensitive compounds. Therefore, much attention has been paid to the catalysis of silylation reactions with HMDS, in order to be able to lower the reaction temperature and / or shorten the reaction time. Examples of such catalysts are salts of amines (see, for example, DOS 2507882), trimethyl-20 chlorosilane (see, for example, SH Langer et al., J. Org. Chem. £ 3, 50 (1958)), inorganic acids such as sulfuric acid (see, for example, DA Armitage et al., Inorg Synth V5 207 (1974)) hydrochloride, phosphoric acid, and their ammonium salts (see for example NL 7613342),

Lewis acids such as boron trifluoride and aluminum trichloride (see also NL 7613342), bis-trialkylsilyl sulfates (see for example DOS 2649536), (fluoro) alkyl sulfonic acid (see for example DOS 2557936) and imidazole (see for example DN Harpp et al., J. Amer. Chem. Soc .

100, 1222 (1978)). However, even with these known catalysts, an excess of HMDS and sometimes very long reaction times, up to 48 hours, are still required to effect sufficient conversion to the desired silyl derivative.

Surprisingly, it has now been found that the silylation of many classes of organic compounds with HMDS can be greatly accelerated by using certain nitrogen-containing compounds as the catalyst.

The improved process of the invention relates to the trimethylsilylation of organic compounds, carrying one or more active hydrogen atoms, with hexamethyldisilazane, characterized in that 0.001 to 10 mol% of one or 8003891 * * - - 3 - more catalysts are added with the general formula

X - NH - Y

wherein X and Y are the same or different and each represents an electron withdrawing group, or X represents an electron withdrawing group and Y represents a hydrogen atom or a trialkylsilyl group »or X and Y together represent an electron withdrawing group» which, together with the nitrogen atom, forms a cyclic system *

Examples of suitable electron-withdrawing groups 10 can be represented by the formulas: 0 0 0

l | II II

R - CR - S - and R "R0F -" where R and R0 are the same or different Ί I | jiai ά 0, each representing an alkyl group optionally substituted by one or more halogen atoms, or optionally substituted by one or more halogen atoms , alkyl * -, alkoxy or nitre groups substituted aryl group, or an alkoxy group, or an aryloxy group optionally substituted by a halogen atom, an alkyl group or a nitro group, or a group R ^ R ^ N- where R ^ and R 1 are the same or different and each represents a hydrogen atom, a trialkylsilyl group or an alkyl group.

Examples of suitable electron withdrawing groups which form a cyclic system with the nitrogen atom can be represented by the formula: - A - Z - B -, where A is a group 0 0 0 0

il tl II II

- C -, B represents a group - C - S02 - S »C - NH - C - 0

II

or a group - c (OCCgH2) = N -, and Z represents an alkylene, alkenylene or arylene group optionally substituted by one or more halogen or alkyl groups.

Particularly suitable electron withdrawing groups are represented by the formulas: 0

R 1 - C -, wherein R 1 represents an alkyl group optionally substituted by one or more halogen atoms, or an aryl group optionally substituted by one or more alkoxy or nitro groups, 8003891 j ΐ O - 4 -

_ "I

Rg - S -, wherein Rg represents a methyl group, or an aryl group optionally substituted by one or more halogen or methyl groups, or Rg represents a group R ^ RgN- in which Rg and Rg are the same or different and each represents a hydrogen atom, a represents trialkylsilyl group or an alkyl group, 0

II

C111J R9R10P wherein Rg and R10 are the same or different and each represents an alkoxy group or an aryloxy group optionally substituted by a halogen atom or a nitro group.

Examples of particularly suitable electron-withdrawing groups which form a cyclic system with the nitrogen atom are represented by the formulas: 0 0

I! II

^ I 7. c - z - c wherein Z represents an alkenylene group optionally substituted by one or more halogen atoms or alkyl groups or an arylene group optionally substituted by one or more halogen atoms, 0

II

^ "II_7 - C - 2_ S0x wherein x is 0 or 2, and 2. represents an alkylene or arylene group. Typically, particularly preferred are catalysts of the above general formula wherein the electron withdrawing groups are represented by the formulas: 0 £ IJ Rj. - I where R *. a trihalomethyl, or an phenoxy or naphthyl group optionally substituted by a methoxy group, 0 '- TL J Rg - J -, wherein Rg represents a methyl group or an optionally substituted phenyl group, an amino group or a tri-methylsilylamino group, 0 III JR ^ R ^ wherein R ^ and R1Q represent a methoxy group or a phenyl group optionally substituted by a nitro group

Likewise, are preferred catalysts in which the electron-generating groups which form a cyclic system with the nitrogen atom are represented by the formulas: 8003891% -5-

A "V

I 'ƒ - Ü - Z _ E - »in which Z represents an ethylenylene group or an optionally perhalo-substituted phenylene or naphthylene group, 0 f IIJ -Ö - Z - SO ^, where x is 0 or 2, and Z is a phenylene group proposes.

In this specification, alkyl, alkylene, alkenylene and alkoxy groups are meant to include both straight and branched groups having up to six carbon atoms.

Examples of classes of compounds according to the above definitions which have the desired catalytic properties are amides, sulfonamides, cyclic and open imides, cyclic and open sulfonimides, sulfamides, disulfonamides, acyl phosphoramidates, sulfonylphosphoramidates and imidodiphosphates.

Suitable catalysts are, for example, tricnboracetamide, trifluoroacetamide, phthalimide, 3,4,5'-tetrachlorophthalimide, 3,4,5,6-tetrabromophthalimide, 1,8-naphthalimide, maleimide, barbituric acid, saccharin, N-benzoyl-4-toluenesulfonamide , N-benzoylbenzenesulfonamide, N- (2-methoxy-1-naphthoyl) -4-toluenesulfonamide, N- (2-methoxy-t-naphthoyl) methanesulfonamide, di (4-toluenesulfonyl) amine, dimethyl-1-tries / 20 chloracetylphosphoramidate di-4-nitrophenyl-N-trichloroacetylphosphoramidate, di-4-nitrophenyl-N-4-toluene sulfonylphosphoramidate,

X

y

X

κ 8003891 - 6 - tetraphenylimidodiphosphate, sulfamide, N, Nf-bis (trimethylsilyl) sulfamide, 1,2-benzisothiazol-3 (2H) -one and 4-benzoyloxy-1,2-dihydro-1-oxo-1 taalazine

Particularly suitable catalysts are saccharin, di-4-5 nitrophenyl-N-trichloroacetylphosphoramidate, di-4-nitrophenyl-N-4-toluenesulfonylphosphoramidate and tetraphenylimidodiphosphate.

The reaction can be carried out with or without organic solvent at temperatures ranging from 0 to 150 ° C. Any solvent to be used should be a solvent which is inert to both the starting materials and the products, and preferably should be a solvent in which little or none of the ammonia formed during the reaction dissolves at the temperature at which the reaction is carried out because, due to equilibrium settings, the reaction rate will slow down at a high ammonia concentration. Suitable solvents are straight, branched and cyclic hydrocarbons, which may be substituted with one or more halogen atoms, for example hexane, cyclohexane, methylene chloride and chloroform, aromatic hydrocarbons, for example benzene, toluene and xylene, alkyl esters of carboxylic acids, for example ethyl acetate and butyl acetate, nitriles, for example, acetonitrile and benzonitrile, dimethylformamide, dimethyl sulfoxide, or mixtures thereof.

Organic compounds bearing one or more -ΟΗ, ΝΗΝΗ or -NH2 groups can be silylated by the method of the invention. Examples are alcohols, phenols, thiophenols, acids, sulfonamides, phosphoramides, amino acids, heterocycles, penicillin and cephalosporin derivatives, hydrazines, N-hydroxy succinimides and enolisable keto compounds. Due to the large number of classes of organic compounds bearing one or more -ΟΗ, ΝΗΝΗ or NH, groups, the above list is not intended to limit the general scope of this invention.

The use of the catalysts described in the invention has eliminated the original drawbacks of using HMDS as a silylating agent, namely long reaction times and high reaction temperatures. The silylation reactions can now be carried out in a short time and / or at a low reaction temperature, usually a small excess of silylating agent being sufficient. In addition, a cleaner reaction mixture results in these reaction conditions, yielding a purer product 8003891 i% - 7 - and in many cases a higher yield. Another advantage of the improved process is that compounds which are known not to contain HMDS reacting without the presence of a catalyst, can now be silylated in a short time using the catalysts of the invention. Examples of such compounds are tertiary alcohols (see SH Langer et al., J. Org. Chem. 23., 50 (1958)) and phthalimide (see DN Harp et al., J. Amer. Chem. Soc. 100, 1222 (1978)).

Furthermore, application of the method according to the invention makes it possible to make N, 0-bis (trimethylsilyl) compounds from penicillin and cephalosporin derivatives, compounds which are otherwise difficult to prepare with HMDS (see for example F * Bortesi c * s ·, J · Pharm · Sci · 66, 1767 (1977)) ·

A further advantage of the present process for the preparation of silylated compounds consists in that, insofar as these compounds in turn can find use as a silylating agent, such as, for example, N-trimethylsilylimidazole, N, N * bis-trimethylsilylurea, etc., these are not contaminated with ammonium salts, which may give rise to undesired side reactions when these silylating agents are used.

An example which clearly illustrates the present invention is the silylation of urea. Silylation of urea without a catalyst took 36 hours at about 125 ° C, as described in NL 7613342. Using ammonium chloride as a catalyst, it took another 6 hours at 118 ° C . (example III of ifeafcst. said patent) ·

However, if one uses saccharin, one of the catalysts of the invention, then a reaction time of only 20 minutes is sufficient for the completion of the reaction. Another example is the reaction of phenylhydrazine with HMDS. Without catalyst, a yield of 12% was obtained after 12 hours at 130 ° C (S · Fessenden et al., J. Org. Chem. 26, 4638 (196L)). Using ammonium chloride as a catalyst, a yield of 89% was obtained. obtained under the same conditions. However, if one uses saccharin, one of the catalysts of the invention, then only 2.5 hours are required to obtain the same yield of silylated product. Also, reactions with tertiary alcohols with HMDS, which were known not to react with HMDS, also in the presence of trimethylchlorosilane as a catalyst (see SH Langer et al., J. Org. Chem. 23, 50 (1958)), now proceed rapidly to very rapidly under the influence of the above-described catalysts. For example, t-amyl alcohol reacts with 8003891-8 saccharin as a catalyst over a period of three hours to the trimethylsilyl ether, and 2-methyl-2-hexanol reacts with di-4-nitro-enyl-N-4-toluenesulfonyl-£ os oramidate as a catalyst in only 15 minutes in 32% yield to the trimethylsilyl derivative. The reaction of phthalimide with HMDS also shows the advantages of using the catalysts of the invention. The silylation of phthalimide with hexamethyldisilazane as a silylating agent and imidazole as a catalyst requires two days of reflux. (D.N. Harpp et al., J. Amer. Chem. Soc. 100, 1222 (1978)). It has now been found that the reaction proceeds completely within 1.5 hours with saccharin as a catalyst, even if a smaller amount of hexamethyldisilazane is used.

The following examples are intended to further illustrate the method of the invention, but without limiting the invention to the use of these compounds.

t 8003891 ï * - 9 -

Example 1. Preparation 1-trimethylsilyloxydodecane (a) Saccharin (90 mg, 0.5 mmol) was added to 18.6 g (0.1 mol) 1-dodecanol, and the mixture was heated to 130 ° C. Hexamethyldisilazane (15.6 ml; 0.075 mol) was added over 8 minutes. The ammonia released during the reaction was passed through water in a dry nitrogen stream and titrated with 1 N HCl. It was found that the calculated amount of ammonia was generated in 15 minutes after the start of the addition of the hexamethyldisilazane. Reflux was continued for an additional 10 minutes, the excess hexamethyldisilazane was distilled off under reduced pressure and the residue was vacuum distilled. Yield 25.42 g (98.5%) of 1-trimethylsilyloxydodecane, b.p. 120 ° c / o, 5 mm Hg; n ^ 1.4268.

(b) Hexamethyldisilazane (7.8ml; 38mmol) was added to a refluxing solution of 9.3g (50mmol) 1-dodecanol and 51mg (0.27mmol) saccharin in 50ml dichloromethane. In the manner described in Example 1a, it was found that the calculated amount of ammonia had developed after 1 hour of reflux.

(c) A solution of 9.30 g (50 mmol) of 1-dodecanol and 70 mg of 20 (0.25 mmol) of dimethyl-IT-trichloroacetylphosphoranzdate in 50 ml of dichloromethane was heated to reflux and hexamethyldisilazane (7.8 ml 37.5 mmole) was added dropwise quickly by means of a pressure Galvanized dropping funnel. The calculated amount of ammonia was found to have developed after 75 minutes of reflux.

(D) This preparation was performed as described in Example 1c, however 121 mg (0.25 mmol) of di-4-nitrophenyl-N-trichloroacetylphosphoramidate was used as the catalyst. The reaction ended after 40 minutes.

(e) Under the conditions as described in Example 1c, using a reaction time of 60 minutes using 121mg (0.25mmol) di-4-nitrophenyl-1T-p-toluene-sulfonylphosphoramidate as catalyst.

Example 2. Preparation of trimethylsilyloxycyclohexane.

In the manner described in Example 1a, cyclohexanol (15.0 g; 0.15 mol) was silylated with 23.4 ml (0.112 mol) of hexamethyldisilazane, which was added over 5 minutes. The silylation was catalyzed with 137 mg (θ, 75 mmol) of saccharin. The calculated amount of ammonia was developed in 18 minutes. Reflux was continued for an additional 10 minutes, excess hexamethyldisilazane 8003891-10 * 4.

was distilled off under reduced pressure and the residue was. vacuum distilled yielding 22.01 g (85.3%)

O

trimethylsilyloxycyclohexane was obtained, bp 53-55 C / l 2 nun Hg, n ^ 1.4281.

5

Example 3. Preparation 2-methyl-2-trimethylsilyloxybutane. Hexamethyldisilazane (21.9 ml; 0.105 mol) was added to a refluxing mixture of 17.6 g (0.20 mol) 2-methyl-2-butanol and 0.18 g (1 mmol) saccharin. The course of the silylerihg was followed as described in example 1a. It was found that 50% of the calculated amount of ammonia was generated in 18 minutes. Reflux was continued for 3.25 hours after which 98% of the calculated amount of ammonia had evolved. By distillation at normal pressure, a yield of 22.75 g (71%) of pure 2-methyl-2 -22 -15-trimethylsilyloxybutane was obtained, b.p. 129-130 C; tb 1.3980.

o. 22 υ

A pre-fraction with kpt. 125-129 C (3.69 g) with n ^ 1.3974, according to 1 H NMR analysis, contained 88% of the title compound.

Example 4 »Preparation 178-trimethylsilyloxy-androst-4-en-3-one 20 Hexamethyldisilazane (246 mg; 1.5 mmol) was added to a refluxing solution of 577 mg (2.0 mmol) 17β-hydroxy-androst-4 and 3-one and 1.8 mg (0.01 mmol) of saccharin in 10 ml of dichloromethane. The course of the reaction was followed by thin layer chromatography on diesel gel 60 ^ 54 (Merclc) with a 9 to 1 mixture of toluene and acetone as eluent. It was found that after 2 hours of refluxing the starting material was no longer present and a new product had been formed. It was determined by 1 H NMR spectroscopy that the product, obtained in quantitative yield after evaporation of the solvent in vacuo, was 17P-trimethylsilyloxy-

O

30 androst-4-en-3-on. The melting point of the product was 126-128 C (dec.).

Example 5. Preparation 1-trimethylsilyloxy-2-propene.

Allyl alcohol (24.28 g; 0.418 mol) and saccharin (θ, 36 g; 2 mmol) were added to 50 ml pentane and the mixture was heated to the reflux temperature. Hexamethyldisilazane (51 ml; 0.25 mol) was added to the mixture over 7 minutes. Titration of the ammonia formed during the reaction found the calculated amount to develop in 1.5 hours. Distillation at 8003891 4 * - 1 L - normal pressure gave a yield of 46.1 g (8 5) of O 1-trimethylsilyloxy-2-propene, bp * 97-100 C, n ^ 1.3943 *

Example 6 * Preparation of penta (trimethyisilyl) fructose 5 Hexamethyldisilazane (42 ml; 0.20 mol) was added dropwise over 8 minutes to a refluxing mixture of 7.20 g (40 mmol) fructose, 0.07 g (0.4 mmol) ) saccharin, 24 ml of chloroform and 8 ml of pyridine * The developed ammonia was absorbed in water and titrated with 1 NH2 SO2. It was found that after an hour of reflux, 0.20 mol of ammonia had been developed. * The reflux was continued for half an hour. the solvents were distilled off at normal pressure * The residue was vacuum distilled to yield 19.63 g (90.9%) penta (trimethylsilyl) fructose, bp * 138-142 c / 0 * 5 mm Hg ; n ^ 2 * 5 1.4306 * 15

Example 7 * Preparation 1-trimethylsilyloxyhexane (a) 5.10 g (50 mmol) 1-hexanol was mixed with 0.37 g (2.5 mmol)

"O

phthalimide and heated in an oil bath to 130 C * Hexamethyldisilazane (7.8 ml; 37.5 mmol) was added and the evolution of ammonia was followed by taking it up in water and titrating with 1 N HgSO 2. that the calculated amount of 25 mmol of ammonia was developed in 130 minutes * (b) The experiment was repeated with 2.5 mmol. 3,4,5,6-tetrachlorophthalimide as catalyst * The calculated amount of ammonia was developed in 70 minutes * (c) The experiment was also repeated with 2.5 mmol 3,4,5,6-tetrabromophthalimide as catalyst * It was found that the calculated amount of ammonia was developed in 20 minutes * ~ (d) A reaction without the addition of catalyst was also carried out and in this case it was found that the calculated amount of ammonia had developed after 205 minutes * (e) 5 10 g (50 mmol) of 1-hexanol were mixed with the catalysts listed in the table below, the mixture was heated to 130 ° C in an oil bath, and 7.8 ml (37.5 mmol) of hexamethyl-disilazane was added * The time (t) in which half of the theoretical amount of the ammonia was developed was measured * Further details can be found in the table * 8003891 - 1 2 - catalyst mol% t (miauten) catalyst none - 22 maleimide 5.0 9 1.8-naphthalimide 5 0 8 1,2-benzisothi azole-3 (2H) -one 5 »0 9 4-benzoyloxy-1,2-dihydro-1-oxo-phthalazine 5» 0 7 3 »4» 5 »δ-tetrabromophthalimide 2.0 4 3» 4 »5» δ-tetrachlorophthalic acid 2.0 4 barbituric acid 2.0 12 dimethyl-N-trichloroacetylphosphoramidate 0.1 7 saccharin 0.5 4 di-4-nitrophenyl-N-trichloroacetylphosphoramidate 0.1 1.5 di-4-nitrophenyl -N-4-toluenesulfonylsoramidate 0.1 1.5 di-4-nitrophenyl-N-trichloroacetylphosphoramidate 0.01 3 di-4-nitrophenyl-N-4-toluenesulfonylphos £ oramidate 0.001 6 tetraphenyl imidodiphosphate 0.1 1 tetraphenyl imidodiphosphate 0.001 13 8003891 "13"

Example 8. Preparation 2-methyl-2-trimethylsilyloxyhexane

A mixture of 5.80g (50mmol) 2-methyl-2-hexanol and 25mg (0.05mmol) di-4-nitrophenyl-N-4-toluenesulfonylsoramidate was added

O

placed in a 140 ° C oil bath, then 7 8 ml (37 5 mmol) of 5 hexamethyldisilazane was added. It was found that the calculated amount of ammonia had evolved after refluxing for 15 minutes. After vacuum distillation, a yield of 8.66 g (92%) of 2-methyl-o.

2-trimethylsilyloxyhexane obtained; bpt 54-60 C / 18 mm Hg; 24

Up 1.4074.

10

Example 9 «Preparation N-trimethylsilyl-p-toluidine Hexamethyldisilazane (25 ml; 0.12 mol) was added over 5 minutes to a mixture of 17.25 g (0.16 mol) p-toluldine and 0.15 g (0 , 8

O

mmol) saccharin, which was heated to 130 ° C in an oil bath. Titration of the ammonia generated during the reaction found that the calculated amount had evolved after 2 hours of reflux. Reflux was continued for an additional half hour and the reaction mixture was vacuum distilled to give a yield of 24.0 g (83%) of N-trimethylsilyl-p-toluidine, b.p.

98-102 ° c / l 2-13 mm Hg.

Example 10. Preparation 2-trimethylsilyloxytoluene · 10.80 g (θ, 1 mol) of O-cresol was dissolved in 30 ml of dichloromethane. Saccharin (90mg; 0.5mmol) was added, the mixture heated to reflux 25 and hexamethyldisilazane (15.6ml; 0.075 mol) was added. The calculated amount of ammonia was found to develop in 30 minutes. After evaporation of the solvent and excess hexamethyldisilazane, the residue was vacuum distilled, yielding 16.91 g (93.9> O 2-trimethylsilyloxytolum), bp 46-53 ° C, 5-0.7 mm Hg; n ^ 1.4756 *

In a comparative reaction without the addition of saccharin, reflux was required for 3.75 hours to develop the calculated amount of ammonia.

Example 11. Preparation 2,6-di-sec-butyl-1-trimethylsilyloxy-benzene Hexamethyldisilazane (7.8 ml; 37.5 mmol) was added to a reflux mixture of 10.4 g (50 mmol) 2 »6 -di-sec-butyl-enol, 23 mg (0.05 mmol) di-4-nitro-enyl-N-trichloroacetyl-osforamidate and 20 ml of chloroform. The development of ammonia ceased after 3.5 hours 8003891-14 ” refluxes. The chloroform was distilled off under reduced pressure and the residue was fractionated to give a yield of

O

12.64 g (90¾) of the title compound were obtained, b.p. 86-90 C / O, 4 mm Hg; η ^ 1.4312.

5

1 P

Example &. Preparation of trimethylsilyl benzoate

Hexamethyldisilazane (15.6 ml; 0.075 mol) was added over 5 minutes to a refluxing solution of 12.2 g (0.1 mol) benzoic acid 10 and 90 mg (0.5 mmol) saccharin in 30 ml dichloromethane. the ammonia that was generated was found to form the calculated amount in 40 minutes after the start of the addition of the hexamethylsisilazane. The solvent was distilled off at normal pressure and the residue was vacuum distilled to give a yield of 17.80 g (91.7%) of trimethyl% silyl benzoate, bp 102-104 C / 13 mm Hg; n ^ 1.4837.

In a reaction without a catalyst, it was necessary to reflux for 2.25 hours to develop the calculated amount of ammonia.

In both cases, after the addition of the hexamethyldisilazane, a thick precipitate formed which disappeared during the silylation.

Example 13 »Preparation N, K * -bis (trimethylsilyl) urea Hexamethyldisilazane (10ml; 48mmol) was added to 2.4g 25 (40mmol) urea and 73mg (0.4mmol) saccharin in 15ml refluxing ethyl acetate . The development of the ammonia started immediately and was refluxed after 20 minutes, which was demonstrated by titration with 1 N HCl. The volatile material was evaporated under vacuum and the residue dried in vacuum. 8.06 g of 30N, -bis (trimethylsilyl) urea, mp * 219-222 ° C (99%) was obtained. Without the addition of saccharin as catalyst, the development of ammonia is slow and the reaction had to continue for at least 24 hours. to expire completely.

Example 14. Preparation N-trimethylsilyl-trichloroacetamide A mixture of 16.24 g (0.10 mol) trichloroacetamide, 15 mg (0.08 mmol) saccharin, 25 ml toluene and 15 ml (0.07 mol) hexamethyldisilazane was added placed a preheated oil bath

O

(120 c) and refluxed for 30 minutes, after which 8003891 “15 ** of ammonia was no longer detectable · The volatile compounds were

O

evaporated under vacuum and the residue dried under vacuum at 50 ° C. The crude N-trimethylsilyl-trichloroacetamide had a

O

mp 75-85 C and dissolved clearly in petroleum ether # 5. Yield: 22.58 g (96.3%).

Example 15 «Preparation N-trimethylsilylbenzamide To 15 ml of toluene, saccharin (40 mg; 0.22 mmol) and benzamide (5.0 g; 41.3 mmol) were added, and the resulting mixture was heated to reflux # Hexamethyldisilazane (6.4 ml; 31 mmol) was added and the ammonia released was passed into water by means of a nitrogen stream which was passed over the reaction mixture # Titration with 1 N HgSO4 led to the conclusion that the calculated amount of ammonia developed in 15 minutes used to be. Solvent and excess hexamethyldisilazane were evaporated in vacuo to leave a residue of 8.04 g (101%) of N-trimethylsilylbenzamide, m.p. 111-114.5 ° C #

The experiment was repeated without the addition of saccharin, in which case 82% of the theoretical amount of ammonia was found to be generated in 15 minutes and 88% in 50 minutes.

Example 16. Preparation N-trimethylsilyl-4-nitrobenzamide (a) 4-Nitrobenzamide (5.0g; 30.1mmol) was treated with hexamethyldisilazane (4.7ml, 93% pure; 21mmol) in 20ml reflux. The butyl acetate in the presence of saccharin (50 mg; 0.27 mmol) in the manner described in Example 18. The calculated amount of ammonia was developed in 15 minutes. Evaporation of the volatile compounds in vacuo gave a light brown residue

O

N-trimethylsilyl-4-nitrobenzamide (7.2 g; 100%), mp. 130.5-134.5 C. 30 (b) Hexamethyldisilazane (4.5ml; 22mmol) was added to a refluxing mixture of 5.0g (30.1mmol) 4-nitrobenzamide, 100mg (0.5 mmol) 1,8-naphthalimide and 20 ml butyl acetate. The calculated amount of ammonia had developed after 35 minutes.

The same experiment was performed without a catalyst, in which case only 16% of the calculated amount of ammonia was generated after 15 minutes of refluxing; after an hour of reflux, 83% of the calculated amount had developed # 8003891 «-“ 16 ”

Example 17 »Preparation N-trimethylsilyl-α, α-dimethylpropionamide To 5.0 g (49.5 ramol) α, α-dimethylpropionamide and 10 mg (0.05 ramol) saccharin in 1 ml of refluxing toluene was added in 15 minutes 7 .7 ml (37 mmol) of hexamethyldisilazane added · After 45 minutes of refluxing, the development of ammonia was completely finished · Evaporation and drying in vacuo gave 8.04 g (98%) of N-trimethylsilyl-

O

a, a-dimethylpropionamide, m.p. 101-105.50

Example 18, Preparation N-trimethylsilylacetamide 10 A mixture of 5.90 g (0.1 mol) acetamide and 55 mg (0.3 mmol)

O

saccharin was heated to 130 ° C and 15 * 6 ml (θ> 075 mol) of hexamethyl-disilazane was added over 3 minutes · In the manner described in Example 1a, it was found that the calculated amount of ammonia was generated in 35 minutes after starting the addition of the hexamethyldisilazane. Reflux was continued for a further 10 minutes, the excess hexamethyldisilazane was evaporated under reduced pressure and the solid residue was dried in vacuo. 12.80 g (97.7%) of N-trimethylsilylacetamide of greater than 95% purity were obtained according to 1 H NMR analysis.

20

Example 19. Preparation N-trimethylsilyl urethane Hexamethyldisilazane (15.6 ml; 0.075 mol) was added over 2 minutes to a refluxing mixture of 8.9 g (0.1 mol) urethane, 183 mg (1 mmol) saccharin and 10 ml toluene . The calculated amount of ammonia was developed in 30 minutes. Reflux was continued for an additional 15 minutes, the solvent and excess hexamethyldisilazane were removed under reduced pressure and the residue was vacuum distilled. 15.6 g (96.9%) of N-trimethylsilylurane / 25 thane were obtained, b.p. 73 C / 12 mm Hg n ^ 1.426830

Example 20. Preparation N, N * bis (trimethylsilyl) malon diamide (a). 7.5 ml (36 mmol) hexamethyldisilazane was added to a refluxing mixture consisting of 3.06 g (0.03 mol) malonic acid diamide, 18 3 3 mg (0.1 mmol) saccharin, 50 ml ethyl acetate and 5 ml pyridine · 35 Titration of the developed ammonia with 1 N sulfuric acid found that 30 mmol had been formed after one hour of reflux. The volatile material was evaporated in vacuo, and the residue, which crystallized after some time, was dried in vacuo. 7.32 g (99%)

N, N-bis (trimethylsilyl) malon diamide, mp 72-76 C

8 0 0 3 8 9 f -17-. 1 H NKR spectrum (CDCl 3): & 0.24 (s, 18 H); 3.20 (s, 2H); 6.5 (wide, 2H).

(b) The same experiment with 30 ml of butyl acetate as a solvent required reflux for 15 minutes to obtain the calculated amount of ammonia

O

5 to develop. The melting point of the residue was 71-80 ° C.

Yield 6.72 g (91%).

Example 21. Preparation N-trimethylsilyl caprolactam

A mixture of 22.6 g (0.2 mol) caprolactam, 0.73 g (4 mmole) saccharin and 40 ml (0.19 mol) hexamethyldisilazane was refluxed for 3.5 hours, after which no ammonia evolution was observed .

The dark brown reaction mixture was vacuum distilled to yield 21.64 g (58.5%) of F-trimethylsilyl caprolactam.

received, kpt. 103-106 C / 12 mm Hg. -15

Example 22 Preparation N-trimethylsilylbenzenesulfonamide Hexamethyldisilazane (15.6 ml; 75 mmol) was added to a refluxing suspension of 15 72 g (0.1 mol) benzenesulfonamide and 18 mg (0.1 mmol) saccharin in 45 ml ethyl acetate. A nitrogen stream was passed over the reaction mixture and passed through water to determine the amount of ammonia generated. Titration with 1 N found that the calculated amount of ammonia was released in 25 minutes. The residue of N-trimethylsilyl-benzenesulfonamide, which after evaporation of the volatiles in

O

Vacuum was obtained, m.p. from 62-63 C.

Example 23 * Preparation N-trimethylsilylmethanesulfonamide Hexamethyldisilazane (5.1ml; 24.5mmol) was added to a refluxing mixture consisting of 3.0g (31.6mmol) methanesulfonamide, 20mg (0.11mmol) saccharin and 15 ml of toluene. A nitrogen stream was passed over the reaction mixture to remove the evolved ammonia, after which the ammonia absorbed in water was titrated with 1 N HgSO 2 · It was found that after 20 minutes of reflux the calculated amount of ammonia had evolved. The solvent and the excess hexamethyldisilazane were evaporated in vacuo. The solid residue was dried in vacuo. The yield of N-trimethylsilyl-

O

methanesulfonamide was 5.22 g (99.5%), mp. 69-74 C.

The experiment was repeated without the addition of saccharin. In that case, the calculated amount of ammonia was unwrapped in 35 minutes 8003891 "1 8". Refining in the manner described above gave a yield

O

of 5.25 g (100%) of N-trimethylsilylsulfonamide, m.p. 68-72.5 C.

Example 24 »Preparation N-trimethylsilylthioacetamide Hexamethyldisilazane (17.2ml; 82mmol) was added over 10 minutes to a refluxing mixture consisting of 11.3g (0.15 mol) thioacetamide, 0.14g (0.75mmol saccharin and 50 ml of toluene.

The ammonia formed in the reaction was introduced into water by dry nitrogen flow and titrated with 1N HCl.

It was found that after 1.5 hours of reflux after the addition of the hexamethyldisilazane, the calculated amount of ammonia had developed. The toluene and excess hexamethyldisilazane were distilled at normal pressure and the residue was vacuum distilled to give a yield of 13.12 g (59.2%) of N-trimethylsilylthio-5-acetamide, b.p. 97-99 C / 0.7 mm Hg.

Example 25. Preparation N-trimethylsilyldiphenylphosphoramidate Hexamethyldisilazane (3.2 ml; 1 5.4 irunol) was added to 5 * 0 g (20.1 mmol) diphenylphosphoramidate and 36 mg (0.20 mmol) ^ saccharin in 35 ml refluxing toluene . A nitrogen stream was passed over the reaction mixture and the generated ammonia was absorbed in water and titrated with 1 N HoSO · The calculated amount of ammonia was formed in 15 minutes. Reflux was continued for an additional 10 minutes and the solvent was evaporated in vacuo. The N-trimethylsilyldiphenylphosphoramidate obtained had a melting point

O

83-86.5 C. The experiment was repeated without the addition of saccharin. After refluxing for 15 minutes, 26% of the calculated amount of ammonia was formed, and after an hour 69%.

Example 26. Preparation N, 0,0-tris (trimethylsilyl) -DL-serine To a suspension of 10.50 g (0.1 mol) DL-serine in 30 ml toluene was added 91 mg (0.5 mmol) saccharine . The mixture was heated to reflux and 52.5 ml (θ25 mol) of hexamethyldisilazane was added. A stream of dry nitrogen was passed over the reaction mixture and passed into water to determine the amount of ammonia generated. Titration with 1 N H 2 SO 2 found that three equivalent ammonia were generated in three hours (two equivalents were developed after one hour). The toluene and excess hexamethyldisilazane were evaporated in vacuo and 8003891

V

19 “residue was vacuum distilled to yield 22.92 g (76.2%) Ν, Ο, Ο-tris (trimethylsilyl) -DL-serine; kpt · 87-89 * 0 / 0.5-0.6 nun Hg; 1.4213.

Example 27. Preparation trimethyl-d, 1,1-a-trimethylsilylaminopropionate A mixture of 8.90 g (0.1 mol) d, 1-alanine and 50 mg (0.1 mmol) di-4-nitrophenyl-N -4-toluene sulfonyl oxosamidate was placed in a preheated oil bath (140 ° c) and 41.6 ml (0.2 mol) hexamethyldisilazane was added. After two hours of reflux, the calculated amount of ammonia had evolved (0.1 mol), which was determined by pouring it into water and titrating with 1 N H 2 SO 2.

The colorless solution was vacuum distilled to yield 20.72 g (88.9%) of trimethylsilyl-d, 1-α-trimethylsilylaminopropio. Was obtained, b.p. 78-81 C / 18 mm Hg; n ^ 1.4145 * 15

Example 28 »Preparation N-trimethylsilylsuccinimide · (a) To a reacting suspension consisting of a mixture of 50 ml of toluene and 19.80 g (0.20 mol) of succinimide, saccharin (458 mg; 2.5 mmol) and hexamethyldisilazane (31.5 ml; 0.15 mol) was added, and the reflux was continued for 2 hours. Fifteen minutes after the addition of the silylating agent, a pale yellow solution had begun to brown as the reflux continued. The reaction mixture was cooled, filtered and the residue was vacuum distilled after evaporation of the solvent. 31.04 g of 25 (90.8%) N-trimethylsilylsuccinimide was obtained with a bpt. of O 23 86-88 C / 1.3 mm Hg; n ^ 1.4726.

(b) To a refluxing suspension of 9.90 g (0.1 mol) succinimide and 0.24 g (0.5 mmol) di-4-nitrophenyl-N-4-toluenesulfonyl phosphoramidate in 50 ml dichloromethane was added 15.6 ml (0.075 mol) of hexamethyldisilazane in a few minutes. The generated ammonia was entrained with a stream of nitrogen passed over the reaction mixture and passed into water. The course of the reaction was followed by titration of the evolved ammonia. It was found that after 1 1/2 hours of refluxing, the development of the ammonia stopped. At that time, 90% of the calculated amount of ammonia had been released. Boiling was continued for an additional 2 hours, after which time the solvent was distilled off at normal pressure. 15.26 g (89.8%) of N-trimethylsilyl succinimide were obtained by fractionation under reduced pressure; kpt. 118-119 * 0/18111111 Hg; n ^ 25 1.4745 * 8003891 - 20 -

Example 29. Preparation N-trimethylsilylphthalimide. A mixture consisting of 36.8 g (θ 25 mol) phthalimide, 0.92 g (5 mmol) saccharin and 75 nil (θ, 36 mol) hexamethyldisilazane was placed in an oil bath at 120 ° C had been preheated. The development of ammonia started immediately and after 30 minutes a clear solution was obtained. The mixture was then refluxed for 60 minutes. The volatile components were evaporated in vacuo, 50 ml of petroleum ether (bp 80-110 ° C) was added, and then evaporated to dryness again. The nearly colorless residue had a mp of 66-68 ° C.

Example 30, Preparation N-trimethylsilylimidazole

To a mixture of 13.62 g (0.2 mol) imidazole and 28 mg (0.15 mmol) saccharin heated to 100 ° C, 31.5 ml (0.15 mol) hexamethyldisilazane was added dropwise over 45 minutes . During this addition, the bath temperature was raised from 100 ° C to 140 ° C. After the addition of the hexamethyldisilazane, the mixture was stirred at a bath temperature of 140 ° C for 30 minutes. The excess hexamethyldisilazane was evaporated under reduced pressure and the residue was vacuum distilled. 22.52 g (97.5%) of N-trimethylsilylimidazole were obtained, b.p. 103-105 ° C / 22 mm Hg, n ^ 23 * 5 1.4740.

Example 31, Preparation 1,3-bis (trimethylsilyl) -5,5-dimethylhydantoin.

Hexamethyldisilazane (80 ml; 0.38 mol) was added over 30 minutes to a refluxing suspension of 40 mg (0.22 mmol) saccharin and 38.45 g (0.30 mol) 5,5-dimethylhydanthol in 50 ml of toluene.

The development of the ammonia started immediately. After half of the hexamethyldisilazane was added, all the solid had dissolved. After the addition of the hexamethyldisilazane, reflux was continued for an additional hour, the toluene was distilled off and the residue was dried in vacuo at 45 ° C. 79.0 g (97%) of 1,3-bis (trimethylsilyl) -5'-5-dimethylhydantolne were obtained, m.p. 46-49 ° C.

Example 32. Preparation N-trimethylsilyl-2-oxazolidone

Saccharin (10 mg; 0.05 mmol) and 2-oxazoli-don of 94 ml were added to 25 ml of toluene. » purity (10.0 g; 108 mmol) was added and the mixture was heated to reflux. Hexamethyldisilazane (14.3; 69 mmol) was added over 10 min, and reflux was continued for 1 h · 8003891-21 ammonia evolution was then completely complete · The solvent was evaporated in vacuo and the residue was vacuum distilled, yield 14.6 g (85%) N-trimethylsilyl-2-oxazolidone, b.p. 62 DEG C./2.2 mm @ -1. 23 1.4529.

5

Example 33, Preparation i-trimethylsilyl-1H-1,2,4-triazole To a mixture consisting of 10.35 g (0.15 mol) 1H-1,2,4-triazole and 127 mg (0.75 mmol) saccharin, which had been heated to 126 ° C, 23.4 ml (0.11 mole) of hexamethyldisilazane was added. The development of ammonia started immediately. After refluxing for 30 minutes, the calculated amount of ammonia was developed, which was demonstrated by the method described in Example 1a. After vacuum distillation, a yield of 19.37 g (91.6%) of 1-trimethyl-silyl-1H-1,2,4-triazole, b.p. 76.5-78.0 ° C / l2 mm Kgj n ^ 25 1.4592.

15

Example 34. Preparation trimethylsilyl 6-aminopenicillanate 30 (a) To a refluxing suspension containing 1.08 g (5 mmol) 6-aminopenicillanic acid and 20 mg (0.11 mmol) saccharin in 20 ml dichloromethane was added hexamethyl disilazane (1.0 ml , 4.8 mmol). After refluxing for 0.5 hours, an almost clear solution was obtained, indicating that the dichloromethane insoluble 6-amino-35 penicillanic acid had been converted to the soluble trimethylsilyl ester. Omission of the saccharin extended the reaction time to 4 hours * (b) To a suspension of 1.08 g (5 0 mmol) 6-aminopenicillanic acid and 30 mg (0.11 mmol) dimethyl N-trichloroacetylphosphoramidate in 20 ml refluxing dichloromethane, hexamethyldisilazane 8003891-22 (1.0ml; 4.8mmol) was added. After refluxing for 40 minutes, a clear solution was obtained, indicating that the 6-aminopenicillanic acid insoluble in dichloromethane had been converted to the soluble trimethylsilyl ester.

(C) A suspension of 1.08 g (5.0 mmol) 6-aminopenicillanic acid, 20 mg (0.11 mmol) saccharin and 15 ml chloroform (alcohol-free) was heated to reflux, after which hexamethyldisilazane (0.75 ml ; 3.6 mmol) was added. After 20 minutes of reflux, an almost clear solution was obtained, indicating that the chloroform-insoluble 6-aminopenicillanic acid had been converted to the soluble trimethylsilyl ester.

(d) To a suspension of 1.08 g (5.0 mmol) of 6-aminopenicillanic acid and 53 mg (0.11 mmol) of di-4-nitrophenyl-N-trichloroacetylphosphoramidate in 20 ml of refluxing dichloromethane, 1.0 ml (4, 8 mmol) hexamethyl-15 disilazane. After refluxing for 25 minutes, a clear solution was obtained, indicating that the dichloromethane-insoluble 6-aminopenicillanic acid had been converted to the soluble trimethylsilyl ester *

Example 35. Preparation Trimethyl-trimethylsilylaminopenicillanate 20 To a refluxing suspension of 0.86 g (4 mmol) of 6-aminopenicillanic acid, 12 mg (0.07 mmol) of saccharin and 25 ml of chloroform became hexamethyldisilazane (2.5 ml; 12 mmol). After refluxing for 20 minutes, a clear solution was obtained. After refluxing for 2 hours, the volatile material was evaporated in vacuo at a bath temperature of 40 ° C. The clear, colorless oil remaining was dissolved in 4 ml dry tetra. From the 1 H NMR spectrum of this solution, it was determined that 90 # of trimethylsilyl-6-trimethylsilylaminopenicillanate was present.

Example 36. Preparation trimethylsilyl-6-D (-) - α-aminophenylacetamido penicillanate.

6-D (-) - α-aminophenylacetamidopenicillanic acid (3.49 g; 10 mmol) was suspended in 35 ml of dichloromethane and saccharin (92 mg; 0.5 mmol) was added. The mixture was heated to reflux and 1. 55 ml (7.4 mmol) of hexamethyldisilazane was added · A clear, colorless solution was obtained after 25 minutes, indicating that the penicillanic acid derivative insoluble in dichloromethane had been converted to the soluble trimethylsilyl ester.

A comparative reaction in which no saccharin was added gave a clear solution after 50 minutes of reflux.

Example 37, Preparation trimethylsilyl-7-amino-3-methyl-3-cefera-4- 8003891-23 carboxylate (a) To a refluxing solution of 1.07 g (5.0 mmol) 7-amino-3-methyl- 3-ce-em-4-carboxylic acid in 20 ml of chloroform (quality stabilized with ethanol), hexamethyldisilazane (1.25 ml; 5 6 nunol) and saccharin (20 mg; 0.11 mmol) were added. nitrogen passed over the reaction mixture caused the resulting ammonia to be expelled, and the system to be kept under anhydrous conditions · After refluxing for 25 minutes, a clear, yellowish solution was obtained, indicating that it was in chloroform insoluble carboxylic acid was converted to the soluble trimethylsilyl ester. Omission of saccharin from the reaction mixture extended the reaction time to 3.5 hours.

(b) As described in Example 42a, a clear solution was obtained by a mixture consisting of 20 ml of dichloromethane (alcohol-free), 1.07 g (5.0 mmol) of 7-amino-3-methyl-3- cefem-4-carboxylic acid, 1.05 ml (5 mmol) hexamethyldisilazane and 20 mg (0.11 mmol) saccharin for 10 minutes to reflux · The same experiment with 6.1 mg (θ, 03 mmol) saccharin took 20 minutes to reflux obtain a clear solution · Without saccharin, the reaction lasted 2.5 hours · (c) To a refluxing suspension of 1.07 g (5.0 mmol) 7-amino-3-methyl-3-cephem-4 - carboxylic acid in 20 ml of dichloromethane, 20 mg (0.11 mmol) of saccharin and 0.75 ml (3.6 mmol) of hexamethyldisilazane were added · After refluxing for 30 minutes, a clear solution was obtained * A comparative reaction without saccharin lasted 3. 5 hours to obtain a clear solution · (d) Trichlorine was added to a refluxing suspension of 1.50 g (7.0 mmol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 20 ml of dichloromethane. - acetamide (82 mg; 0.5 mmol) and hexamethyldisilazane (1.05 ml; 5.0 30mmol) added · After refluxing for 50 minutes a clear solution was obtained · Without addition of trichloroacetamide, a reaction time of 210 minutes was required to obtain a clear solution * (e To a refluxing suspension of 1.07 g (5 mmol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 20 ml of dichloromethane were sulfamide 35 (10 mg; 0.1 mmol) and hexamethyldisilazane (0, 75 ml; 3.6 mmol) added · After refluxing for 2 hours, a clear solution was obtained. Omitting the sulfamide extended the reaction time to obtain a clear solution up to 210 minutes.

8003891 - 24 - * * "* (f) To a refluxing mixture consisting of 25 ml of dichloromethane, 1.07 g (5 mmol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 26 mg (o, 11 mmol) N, N, bis (trimethylsilyl) sulfamide hexamethyl-disilazane (0.75 ml; 3-6 mmol) was added · After two hours of reflux, a clear solution was obtained · The same experiment without the addition of N N * -bis (trimethylsilyl) sulfamide required reflux for 210 minutes to obtain a clear solution. (G) In the manner described in Example 42, the reaction lasted 35 minutes using N-benzoylbenzenesulfonamide 10 (41 ». 4 mg; 0.1 5 mmol) as catalyst · (h) In the manner described in Example 42, the reaction lasted 135 minutes using N- (2-methoxy-1-sodium) -4-toluenesulfonamide (51.8 mg; 0.15 mmol) as a catalyst. (I) In the manner described in Example 42f, the reaction lasted 150 minutes using N- (2-methoxy-1-sodium) methanesulfo *! - amide (42.8 mg; 0.16 mmol) as a catalyst r (j) Hexamethyldisilazane (528 mg; 3.28 mmol) was added to a refluxing suspension of 1.08 g (5.0 mmol) 7-amino-3-methyl-3-ce-em-4-carboxylic acid, 10 mg (0.05 mmol) saccharin and 20 ml of dichloromethane.

The clear solution obtained after refluxing for one hour was evaporated to dryness, and the residue was dried under vacuum at room temperature. * The residue (1.48 g) was analyzed by quantitative 1 H NMR using an internal standard.

In this way, it was found that the yield of trimethylsilyl-7-25 amino-3-methyl-3-ce-em-4-carboxylate was 93% based on the tri-methylsilyl ester peak. Only one trace of trimethylsilyl-3-methyl- 7-trimethylsilylamino-3-ce-em-4-carboxylate could be detected in the 1 H NMR spectrum · (k) Di-4-nitrophenyl-N-4-toluene sulf was added to 40 ml of chloroform (pre-analysis quality, alcoholic) Onyl isophorainidate (12mg; 0.024mmol) was added and the mixture was refluxed for half an hour to remove any impurities present containing active hydrogen atoms. The ammonia released during this period was removed by slow nitrogen flow over the reaction mixture. Then 1.07 g (5 5 0 mmol) of 7-amino-3-methyl-

3-cephem-4-carboxylic acid was added and reflux was continued under the same conditions, the nitrogen stream now being passed into water to absorb the generated ammonia. The amount of ammonia generated was determined by titration with 0.1N

8003891-Sulfuric acid · It was found that a clear solution was obtained after 10 minutes of reflux (currently 25 ml of the sulfuric acid solution had been used) and that 50 ml of sulfuric acid solution, indicating complete disilylation, had been used after 35 minutes of reflux.

5

Example 38. Preparation trimethylsilyl-7-trimethylsilylamino-3-methyl-3-cell-4-carboxylate

A mixture consisting of 0.80 g (3 »7 mmol) 7-amino-3-methyl-3-ce-fem-4-carboxylic acid, 1.87 ml (11.6 mmol) hexamethyldisilazane, 8.8 mg 10 ( 0.048 mmol) saccharin and 20 ml of chloroform were heated to reflux. After 10 minutes a clear solution was obtained. After refluxing for 2 hours, the volatile material was evaporated under vacuum (bath temperature 50 ° C). The solid residue was dissolved in 5 ml of tetra. From the 1 H NMR spectrum of this solution, it could be concluded that 80% Ο, Ο-disesylated product was present (by comparing the ratio of the N-tri- methylsilyl and 0-trimethylsilyl signals) · *

Example 39. Preparation trimethylsilyl-3-methyl-7-enylacetamido-20 3-cell-4-carboxylate 1-oxide.

(a) Hexamethyldisilazane (1 »25 ml; 6.0 mmol) was added to a refluxing suspension of 1.4 g (4 mmol) 3-methyl-7-enylacetamido-3-ce-em-4-carboxylic acid 1-oxide in 25 ml of dichloromethane. After refluxing for 30 minutes, a clear solution was obtained, indicating that the silylation was complete.

(b) The experiment was repeated using 13 mg (0.04 mmol) of di-tosylamine as a catalyst. After refluxing for 8 minutes, a clear solution was obtained.

(c) Using 74.8 mg (0.66 mmol) of 2,2,2-trifluoroacet-30 amide as a catalyst, a clear solution was obtained after refluxing for 15 minutes.

(d) A mixture consisting of 1.033 g (3.1 mmol) 3-methyl-7-phenyl-acetamido-3-cephem-4-carboxylic acid 1-oxide, 42 mg (0.15 mmol) N-benzoyl-4- toluene sulfonamide and 25 ml of dichloromethane were heated to reflux. Hexamethyldisilazane (0.57 ml; 2.73 mmol) was added, and reflux was continued for an additional 5 minutes to yield a clear, light brown solution. A comparative reaction without a catalyst gave a clear solution after 45 minutes.

8003811 ~ 26 ~ Λ '' -J '*

Example 40. Preparation trimethylsilyl-3-acetoxymethyl-7-amino-3-cephem-4-carboxylate

To a refluxing suspension of 0.82 g (3.0 inmol) 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid in 1.5 ml dichloromethane, 5 saccharin (11 mg; 0.06 mmol) and hexamethyldisilazane (θ, β3 ml; 3.0 mmol) added # After refluxing for 10 minutes, a clear solution was obtained, indicating that the chloroform-insoluble carboxylic acid had been converted to the soluble trimethylsilyl ester # The same experiment was also performed without the addition of 10 saccharin # In that case had to be refluxed for 50 minutes to obtain a clear solution #

Example 41 »Preparation trimethylsilyl-3-acetoxymethyl-7-trimethyl-silylamino-3-cephem-4-carboxylate 15 On a refluxing suspension of 1.08 g (4 mmol) 3-acetoxymethyl-7-amino-3-cephem-4 -carboxylic acid, 15 mg (θ, mmol8 mmol) saccharin and 25 ml chloroform, hexamethyldisilazane (2.5 ml; 12 mmol) was added. The mixture, which was clear after 10 minutes, was refluxed for 2 hours.

After evaporation of the solvent and the excess hexa-20-methyl disilazane under vacuum at a bath temperature of 40 ° C, a brown, oily residue was obtained. This was dissolved in 4 ml dry tetra, filtered and studied by 1 H NMR. Trimethylsilyl-3-acetoxy-methyl-7-trimethylsilylamino-3 "Cefem-4-carboxylate was found to be present for at least 80 #.

25

Example 42 # Preparation trimethylsilyl-7-trimethylsilylamino-3- (5-methyl-1,3,4-thiadiazolyl-2) -thiomethyl-3-cephem-4-carboxylate. A mixture consisting of 0.85 g (2.5 mmol) ) 7-amino-3 (5-methyl-1,3,4-thiadiazolyl-2) thiomethyl-3-cephem-4-carboxylic acid, 12 mg (0.07-30 mmol) saccharin and 25 ml chloroform was heated to reflux and hexamethyldisilazane (1.6 ml; 7.7 mmol) was added · A clear solution was immediately formed # After refluxing for two hours 8003891-27 - the volatile compounds evaporated under reduced pressure, and the clear, viscous residue was dried in 4 ml tetra dissolved. From the 1 H HMR spectrum of this solution, it was determined that at least 80% of trimethylsilyl-7-trimethylsilylamino-3- (5-methyl-5, 1,3,4-thiadiazolyl-2) -thiomethyl-3-cephem-carboxylate was formed.

Example 43 Preparation of trimethylsilyl-3-methyl-7-enylacetamido-3-cephem-4-carboxylate 1-oxide.

142 mg (0.41 mmol) 3-methyl-7-phenylacetamido-3-ce-em-4-carboxylic acid 10 1-oxide and 0.5 mg (0.003 mmol) saccharin were suspended in 3 ml deuterochloroform * 9-Methylanthracene ( 57 mg; 0.297 mmol) was added as an internal standard for quantitative 1 H NMR analysis. Hexamethyldisilazane (0.05ml; 0.24mmol) was added, and the mixture was refluxed for 10 minutes. The resulting clear, light yellow solution was cooled to room temperature. By comparing the integration ratios of the trimethylsilyler peak of the trimethylsilyl-3-methyl-7-enylacetamido-3-cephem-4-carboxylate Ί-oxide formed and the methyl peak of the added 9-methylanthracene, 1 H NMR, spectrum of this solution, the yield of trimethylsilyl-3-methyl-7-phenyl-acetamido-3-cell-4-carboxylate 1-oxide was 97%.

Example 44. Preparation 1-trimethylsilyl-2-enylhydrazine 90mg (0.5mmol) saccharin was added to 10.8g (0.1mmol) phenylhydrazine and the resulting mixture was heated to 130 ° C. Hexamethyldisilazane (15.6 ml; 0.075 mol) was added and reflux continued for 2.5 hours. In the manner as described in Example 1a, it was found that after 2 hours of refluxing the calculated amount of ammonia had developed. Vacuum distillation of the mixture gave a yield of 16.15 g (89.7%) of 1-trimethylsilyl-2-phenylhydrazine, bp. 112-116 ° C / 11 mm Hg; n ^ 2 "5 1.5241.

Example 45. Preparation N-trimethylsilyloxysuccinimede. A mixture of 5 6o g (47.2 mmol) N-hydroxysuccinimide (purity 97%) and 46 mg (0.25 mmol) saccharin was heated to 130 ° C, after which 7 , 8 ml (37.5 mmol) of hexamethyldisilazane was added. Violent ammonia development immediately occurred, which ended 15 minutes after the addition of hexamethyldisilazane was started. The mixture was cooled, the excess hexamethyldi-8003891 "23% silazane was distilled off under reduced pressure, and the residue fractionated to yield 7.70 g (87.2%) N-trimethylsilyloxysuccinimide, bp · 109- 110 ° C / 0.4 mm Hg, mp. 55-57 ° C 5

Example 46, Preparation 1-trimethylsilyloxycyclohexen-3-one 8.4 g (72 mmol) cyclohexanedione-1,3 (96% purity) and 70 mg (0.38 mmol) saccharin were mixed with 60 ml (288 mmol) hexa- methyl disilazane. The mixture was placed in a preheated oil bath and refluxed · Titration of the ammonia released during the reaction found that the calculated amount was released in 50 minutes · Reflux was continued for an additional 10 minutes, the excess hexamethyldisilazane was evaporated in vacuo and the residue was vacuum distilled · 10.67 g (80.5%) of 15 l-trimethylsilyloxycyclohexen-3-one, b.p. 119-121 ° C / 2.0 mm Hg.

Example 47 «Preparation ethyl 3-trimethylsilyloxy-2-butenoate A mixture consisting of 9.75 g (75 mmol) ethyl acetoacetate and 70 mg (0.38 mmol) saccharin was heated to 130 ° C in an oil bath, 20 hexamethyl disilazane (60 ml; 288 mmol) was added, and the mixture was refluxed for 1.5 hours · The excess hexamethyldisilazane was distilled off under reduced pressure and the residue was vacuum distilled to yield 12.71 g (84%) ethyl-3-trimethylsilyloxy -2-butenoate was obtained; bp 102-104 ° C / 25 16 mm Hg 8003891

Claims (6)

1 · Process for the trimethylsilylation of organic compounds bearing one or more active hydrogen atoms with hexamethyl-disilazane, characterized in that 0.001 to 10 mol% of one or more catalysts of the general formula X - HH - Y are added in which X and Y are the same or different and each represents an electron withdrawing group, or X represents an electron withdrawing group and Y represents a hydrogen atom or a trialkylsilyl group, or X and Y together represent an electron withdrawing group, which together with the nitrogen atom form a cyclic system poses * 152. A method according to claim 1, characterized in that the electron-withdrawing groups can be represented by the formulas: 0 0 0 II II II R - C-, R - S and RRP ~, in which R and R are equal or equal i. || 1 c. 1a 0 20 are different and each represents an alkyl group optionally substituted by one or more halogen atoms, or an aryl group optionally substituted by one or more halogen atoms, alkyl alkoxy or nitro groups, or an optionally substituted by a halogen atom, an alkyl group or a nitro group substituted aryloxy group, or a group R ^ R ^ N- in which R ^ and R ^ are the same or different and each represents a hydrogen atom, a trialkylsilyl group or an alkyl group and the electron withdrawing groups forming a cyclic system with the nitrogen atom , can be represented by the formula: - A - Z - B where A represents a group 0 0 0 0 II „il li II - C -, B represents a group - C -, - S02 -, - S -C-NH -C- O or a group - C ^ OCCgH ^) = N '-, and Z represents an optional alkylene, alkenylene or arylene group substituted by one or more halogen or alkyl groups · 8003891 - 30 ”χ \> 4tc 3. A method according to claim 2, characterized in that the electron-withdrawing groups are represented by the formulas: 0, II, - C -, in which an alkyl group optionally substituted by 5 or more halogen atoms, or an optionally by one or more alkoxy or nitro groups represents substituted aryl group, 0 fII 7 R ,. - S -, in which R ,. a methyl group, or an aryl group optionally substituted by one or more halo or methyl groups, or Rg represents a group R ^ RgN- in which R ^ and Rg are the same or different and each represents a hydrogen atom, a trialkylsilyl group or represents an alkyl group, 15. II / "III JR ^ R QP -, wherein R 1 and R 1, are the same or different and each represents an alkoxy group or an aryloxy group optionally substituted by a halogen atom or a nitro group * and the electron withdrawing groups containing the nitrogen-20 atom form a cyclic system, represented by the formulas: o 0 r 7 I '11 / Ij -CZC-, wherein Z represents an alkenyl group optionally substituted by one or more halogen or alkyl groups or an arylene group optionally substituted by one or more halogen atoms , 0 - «II / Ily-CZ - S0x-, where x is 0 or 2, and Z represents an alkylene or arylene group · 30 4 · Process according to claim 3, characterized in that the electron withdrawing groups are represented by the formulas : 0 - 7 M / IJ Re; - C -, in which R 1 represents a trihalomethyl, or an phenoxy or naphthyl group optionally substituted by a methoxy group, 0 r 7 11 / II J Rg - s in which Rg represents a methyl group or one possibly by 0 one methyl group substituted phenyl group, an amino group or 8003891 - --ff '- 31 - represents a trimethylsilylamino group, 0 _ II / III ƒ R „R ΛΡ-, where Rn and R. _ a methoxy group or an -7 9 io yi ü represent a phenyl group substituted by a nitro group, and the electron withdrawing groups which form a cyclic system with the nitrogen atom are represented by the formulas: 0 0 _ ii ii ^ Iy-CZC-, wherein Z is an ethylenylene group or an optional perhalo substituted phenylene or naphthylene group, 0 ^ - II ^ / lly-CZ-S0 where x is 0 or 2, and Z represents a phenylene group · Process according to claim 4, characterized in that the catalyst is trichloroacetamide, trifluoroacetamide, phthalimide, 3,4,5,6-te chlorophthalimide, 3,4,5,6-tetrabromophthalimide, 1,8-naphthalimide, maleimide, barbituric acid, Saccharin, N-benzoyl-4-toluenesulfonamide, T-benzoylbenzenesulfonamide, II- (2-methoxy-1-sodium toyl) -4-toluenesulfonamide, N- (2-methoxy-1-sodium) methanesulfonamide, di (4-toluenesulfonyl) amine, dimethyl-N-trichloroacetylphosphoramidate, di-4-nitrophenyl-N-trichloroacetylphosphoramidate, di-4-20 nitrophenyl-1-4-toluene-sulfonylphosphoramidate, tetraphenylimido-diphosphate-diphosphate N * -bis (trimethylsilyl) sulfamide, 1,2-benzisothiazol-3 (2H) -one or 4-benzoyloxy-1,2-dihydro-i-oxo-phthalazine is · 6. Process according to claim 4, characterized in that the catalyst is saccharin, di-4-nitro-enyl-N-trichloroacetyl-oxamidate, di-4-nitro-enyl-H-4-toluenesulfonylphosphoramidate or tetraphenylimido diphosphate. 8003891