KR840001213B1 - Improved process for the trimethyl silylation of organic compounds - Google Patents

Abstract

Trimethyl silylation of an organic compd., having at least one active H atom with hexamethyldisilazane, is carried out in the presence of 0.001-10 mol.% of a catalyst of formula X-NH-Y. X and Y are electron-withdrawing gps. or X is an electron-withdrawing gp. and Y is H or trialkylsilyl, or X and Y together form an electron-withdrawing gp. that forms a cyclic system with the N atom. Trimethyl silylthiols of formula R-S SiMe3 are new, where R is 5-or 6-membered hete-rocyclic gp. having at least one N or S as heteroatom(s), which are opt. substd. by alkyl, Ph, Me3Si, alkylamino, or Me3SiO-CO-CH2.

Description

Silylation of Organic Compounds Using Special Catalysts

The present invention relates to an advanced method for trimethylsilylation of organic compounds.

In the field of organic manufacturing chemistry, there are advances in the art of using trimethylsilyl groups to control physical properties such as evaporation and solubility of compounds and to protect the active groups of compounds (eg BE Cooper. Chem. And Ind. 1978, 794).

As the silylating agent used in large-scale industry, for example, trimethylchlorosilane, dimethyldichlorosilane and the like are used. Since the silylation reaction is an equilibrium reaction, it is essential to remove the hydrogen chloride generated in the reaction zone from the reactor as quickly as possible in order to move the equilibrium state toward the desired product generation. This method is carried out by adding a reasonable amount of tertiary amine to the reaction zone. The amine then reacts with hydrogen chloride to produce the corresponding ammonium salt, which is generally less soluble in the mixture of the reaction zone. The ammonium salt thus produced must be separated and removed before the desired product can be purified, and in order to remove and remove the desired product, a reasonable amount of dissolution must be used. In spite of this, the purified product does not exclude the remaining residues of traces of ammonium.

Examples of frequently used silylating agents include N, O (bis-trimethylsilyl) acetamide, N, N'-bis (trimethylsilyl) urea, N-trimethylsilyl-N, N'-dimethylurea, N -Trimethylsilylamidazole, trimethylsilyldiethylamine, and the like, and these compounds are frequently prepared using trimethylchlorosilane as a starting material, and thus the silylated product has to be separated from the residue of the silylating agent obtained. There is hassle and discomfort at the point. Other silylating agents used on a large scale as silylating agents include 1,1,1-trimethyl-N- (trimethylsilyl) silanamine (this is hexamethyldisilazane, well known by its short name HMDS). This is advantageous in that the byproducts of the reaction are in the gaseous state, and are easily removed from the reactor in the form of ammonia. In addition, HMDS is inexpensive, making it an interesting silylating agent in industrial processes.

However, the important closure of HMDS is that in most cases, the reactivity is very mild, and in some cases, there is no reaction at all [S. H. Langer C. S., J. Org. Chem. 23, 50 (1958). Therefore, in order to complete the reaction, use of a high temperature and / or lengthening of the reaction time is required, and such a closed end is not particularly desirable in the treatment of a compound sensitive to heat. In addition, in some cases, lung cancer requires a very large excess of HMDS.

Therefore, in carrying out the silylation process using HMDS, the catalytic treatment for reducing the reaction temperature and / or shortening the reaction time has attracted attention. Examples of catalysts include amine salts (see eg DOS 2507882), trimethylchlorosilane (see eg SHLanger CS, J. Org. Chem. 23, 50 (1958)) and sulfuric acid as an inorganic acid, for example. (See, eg, CAArmitage CS, Inorg. Synth. 15, 207 (1974)), hydrogen chloride, phosphoric acid and their ammonium salts (see for example NL 7613342), for example boron trifluoride and aluminide trichloride, etc. Lewis acids NL 7613342), bis (trialkylsilyl) sulfates (see GE 2649536), (fluoroalkyl) sulfonic acids (see GE 2557936) and imidazoles (eg DNHarpp CS, J .Amer. Chem. Soc. 100, 1222 (1978)]. However, even with the catalysts described above, in order to sufficiently change to the desired silyl derivative, a high reaction temperature and an excess of HMDS are required, and for example, a long reaction time of 48 hours or more is required. There are many cases.

It has now been surprisingly found that the silylation of various types of organic compounds with HMDS significantly accelerates the reaction by the use of certain special nitrogen compounds as catalysts.

The inventive process provides for the trimethylsilylation of organic compounds containing one or more active hydrogen atoms to hexamethyldisilaganane, in which 0.001 to 10 mole% of the catalyst represented by the following general formula is used in the reaction mixture. It is characterized by the existence of a range.

X-NH-Y

In the above general formula, X and Y are the same or different groups, each represents one electron withdrawing group, or X represents one electron withdrawing group and Y represents one hydrogen atom or one trialkylsilyl group Or one electron-withdrawing group, each of X and Y, together with a nitrogen atom to form a ring cleavage.

Suitable groups as electron withdrawing groups in the general formula of the catalyst of the present invention described above are groups such as acyl groups, sulfonyl groups and phosphoryl groups. Further details about electron aspirators are described, for example, in L.P Hammet, physical organic chemistry, McGraw Hill Book Company, New York, 1970, P.347FF, and J.D. Roberts and M. C. Caserio, Modern Organic Chemistry, W. A. Benjamin Inc., Inc., New York, 1967, P. 553FF. See, for example.

Reasonable examples of electron aspirators are due to the following general formula:

등의 기이며, 이 일반식에서 R₁과 R₂는 동일 또는 상이하는 기이고, 또 R₁과 R₂의 각기는 하나 또는 그 이상의 할로겐원자에 의하여 치환될 수도 있는 하나의 알킬기, 하나 또는 그 이상의 할로겐원자, 알킬기, 알코옥시기 또는 니트로기에 의하여 치환될 수도 있는 하나의 알릴기, 하나의 알코옥시기이거나, 하나의 할로겐원자 또는 하나의 알킬기 또는 하나의 니트로기에 의하여 치환할수도 있는 하나의 아릴옥시기, 또는 하나의 R₃R₄N기인 바, 여기에서 R₃및 R₄는 동일 내지 상이하며 또 이들의 각기가 하나의 수소원자, 하나의 트리알킬실릴기 또는 하나의 알킬기로 표시되는 기이다.

And R ₁ and R ₂ in this general formula are the same or different groups, and each of R ₁ and R ₂ is one alkyl group, one or more groups which may be substituted by one or more halogen atoms. One aryl jade, which may be substituted with one halogen group, one alkyl group, one alkyl group, or one alkyl group, which may be substituted by a halogen atom, an alkyl group, an alcohol group, or a nitro group. Is a group or one R ₃ R ₄ N group, wherein R ₃ and R ₄ are the same or different and each group thereof is represented by one hydrogen atom, one trialkylsilyl group or one alkyl group .

를 표시하며, B는

또는

기를 표시하고, 또 Z는 하나의 알킬렌기, 알케닐렌기 또는 아릴렌기이며, 이들의 기는 하나 또는 그 이상의 할로겐 원자 또는 알킬기가 치환될 수도 있는 것이다.A reasonable example of an electron withdrawing group which forms a ring series with a nitrogen atom is due to the general formula represented by -AZB-, where A is

Where B is

or

Group is represented, and Z is one alkylene group, alkenylene group or arylene group, and those groups may be substituted with one or more halogen atoms or alkyl groups.

To illustrate an electron aspirator with more reasonable action, some of the general formulas shown below:

로 표시되는 기인바, 여기에서 R₅는 하나 또는 그 이상의 할로겐원자가 치환될 수도 있는 하나의 알킬기이거나, 또는 하나 또는 그 이상의 알코옥시기 또는 니트로기에 의하여 치환될 수도 있는 하나의 아릴기이며,/ I /.

R ₅ is one alkyl group in which one or more halogen atoms may be substituted, or one aryl group which may be substituted by one or more alcoholic groups or nitro groups,

로 표시되는 기인 바, 여기에서 R₆는 하나 또는 그 이상의 할로겐원자 또는 메틸기에 의하여 치환될 수도 있는 하나의 메틸기 또는 하나의 아릴기를 표시하며, 또는 R₆는 R₇R₈N-기를 표시하되, 여기에서 R₇및 R₈은 동일 내지 상이하며 또 이들의 각기는 하나의 수소원자, 하나의 트리알킬실릴기 또는 하나의 알킬기를 표시하는 것이고,/ II /.

Where R ₆ represents one methyl group or one aryl group which may be substituted by one or more halogen atoms or methyl groups, or R ₆ represents R ₇ R ₈ N-group, Wherein R ₇ and R ₈ are the same or different and each of them represents one hydrogen atom, one trialkylsilyl group or one alkyl group,

로 표시되는 기인바, 여기에서 R₉과 R₁₀은 동일 내지 상이하며, 이들의 각기는 하나의 수소원자 또는 하나의 니트로기에 의하여 치환될 수도 있는 하나의 알코옥시기 또는 하나의 아릴옥시기를 표시하는 것이다./ III /.

R ₉ and R ₁₀ are the same as or different from each other, and each group thereof represents one alcohol atom or one aryloxy group which may be substituted by one hydrogen atom or one nitro group. will be.

A group forming a ring series together with a nitrogen atom, in particular, a proper electron withdrawing group is a group represented by the following general formula.

기이며, 여기에서 Z는 하나의 알케닐렌기이고, 이는 하나 또는 그 이상의 할로겐원자 또는 알킬기에 위하여 치환될 수도 있으며, 또는 하나 내지 그 이상의 할로겐원자에 의하여 치환될 수도 있는 하나의 아릴렌기이고,/ I /.

Wherein Z is one alkenylene group, which is one arylene group which may be substituted for one or more halogen atoms or an alkyl group, or may be substituted by one to more halogen atoms,

기인바, 여기에서 X는 O 또는 2이고, 또 Z는 하나의 알킬렌기 또는 아릴렌기를 표시하는 것이다./ II /.

This is where X is O or 2, and Z represents one alkylene group or arylene group.

Particularly preferred catalysts are the catalysts of the above-described general formulas, which are composed of an electron withdrawing group represented by the following general formula.

기이며, 여기에서 R₅는 디할로메틸기 또는 트리할로메틸기를 표시하거나 또는 하나의 메톡시기에 의하여 치환될 수도 있는 하나의 폐닐기 또는 나프틸기이며,/ I /.

Wherein R ₅ is one of the wasteyl or naphthyl groups which may represent a dihalomethyl group or a trihalomethyl group or may be substituted by one methoxy group,

기이며, 여기에서 R₆는 하나의 메틸기이거나, 또는 하나의 메틸기, 하나의 염소원자, 하나의 아미노기, 하나의 디알킬아미노기, 하나의 트리알킬실릴아미노기에 의하여 치환될 수도 있는 하나의 페닐기이고,/ II /.

Wherein R ₆ is one methyl group or one phenyl group which may be substituted by one methyl group, one chlorine atom, one amino group, one dialkylamino group, one trialkylsilylamino group,

기이며, 여기에서 R₉및 R₁₀은 하나의 메톡시기, 에톡시기, 또는 프로폭시기, 하나의 니트로기, 하나의 염소원자로 치환될 수도 있는 하나의 페닐기를 표시한다. 같은 의미에서, 질소원자와 더불어 고리계열을 형성하는 특히 바람직한 전자흡인기로는 다음에 표시하는 몇가지의 기인 바, 이는 :/ III /.

Wherein R ₉ and R ₁₀ represent one methoxy group, ethoxy group, or one phenyl group which may be substituted with a propoxy group, one nitro group, and one chlorine atom. In the same sense, a particularly preferred electron withdrawing group which forms a ring series with nitrogen atoms is due to several of the following:

기이며, 여기에서 Z는 에틸렌기, 페닐렐기, 또는 나프틸렌기이며, 이들의 각기는 임의로히 과할로겐치환할 수 있는 것이고,/ I /.

Wherein Z is an ethylene group, a phenylrel group, or a naphthylene group, and each of these groups can be optionally substituted with halogen;

기인바, 여기에서 X는 O 또는 2이고 Z는 페닐렌기를 표시한다./ II /.

Where G is O or 2 and Z represents a phenylene group.

The alkyl group, alkylene group, alkenylene group and alkoxy group described above are those having 1 to 6 carbon atoms.

Examples of the compounds having preferred catalytic properties by the above description include amides, sulfonamides, cyclic or cycloimide, cyclic or cyclosulfonimide, sulfamide, and disulfonami Drew, acylphosphoramidarts, sulfonylphosphoramidarts and imidodiphosphates.

Examples of preferred catalyst names include trichloroacetamide, trifluoroacetamide, phthalimide, 3,4,5,6-tetrachlorophthalimide, 3,4,5,6-tetrabromophthal Mead, 1,8-naphthalimide, maleimide, barbituric acid, saccharin, N-benzoyl-4-toluenesulfonamide, N- (2-methoxybenzoyl) -4-toluenesulfonamide, N- ( 1-naphthoyl) -4-toluenesulfonamide, N-benzoylbenzenesulfonamide, N- (2-methoxy-1-naphthoyl) -4-toluenesulfonamide, N- (2-methoxy-1-naph Satyl) methanesulfonamide, di (4-toluenesulfonyl) amine, dimethyl N (trichloroacetyl) phosphoramidart, di-4-nitrophenyl N (trichloroacetyl) phosphoramidart, di-4-nitro Phenyl N (p-toluenesulfonyl) phosphoramidart, diisopropyl N- (dichloroacetyl) phosphoramidart, di-0-chlorophenyl N- (4-chlorophenylsulfonyl) phosphoramidart, tetra Phenylimidodi Spart, sulfamide, N, N-dimethylsulfamide, N, N-bis (trimethylsilyl) sulfamide, 1,2-menzoisothiazol-3- (2H) one and 4-benzoyloxy-1,2- Dihydro-1-oxo-phthalazine and the like.

Particularly preferred catalysts are saccharin, di-4-nitrophenyl N (trichloroacetyl) phosphoramidart, di-4-nitrophenyl N (4-toluenesulfonyl) phosphoramidart and tetraphenylimidodiphosphate And so on.

The reaction is carried out at 0 ° C. to 150 ° C. with or without organic solvent. The organic solvent, regardless of its kind, should be a solvent which is inert to the reaction raw materials and reaction products and is free of or does not dissolve ammonia generated at the reaction temperature, because the concentration of ammonia is high. This is because the equilibrium reaction slows down the arrival time of equilibrium. Preferred solvents are straight chain, branched or cyclic hydrocarbons, which may be substituted with one or more halogen atoms, for example hexane, cyclohexane, dichloromethane and chloroform, for example aromatic hydrocarbons. For example, examples of alkyl esters of benzene, toluene, xylene, and carboxylic acid are, for example, ethyl acetate and butyl acetate, and examples of nitriles include acetonitrile and benzonitrile, and dimethylformamide and dimethyl sulfoxide. Seeds or mixed solvents thereof are exemplified.

Organic compounds in which one or more -OH, NH, -NH ₂ or -SH groups are bonded can be silylated by the method of the present invention. Examples of these compounds include alcohols, amines, phenols, thiophenols, acids, amides, sulfonamides, thioamides, phosphoramides, amino acids, heterocyclic compounds, penicsilanes and cephalosporanes. Derivatives, hydrazines, N-hydroxysuccinamides, hydroxylamines, thiols, and enolable ketones. Since there are a great many kinds of organic compounds which combine one or more -OH, NH, -NH ₂ or -SH, it is thought that the scope of the present invention should not be limited only to those listed above. In the case of using HMIS as the silylating agent, the effects resulting from using the catalyst of the present invention are excluded, for example, by eliminating conventional closures such as long reaction times and / or high reaction temperatures and / or the use of excessive excess silylating agents. Is the point. Therefore, according to the present invention, the silylation reaction is surely performed at any time by using a short time and / or low temperature and a slight excess of silylating agent. In addition, under these reaction conditions, a complete mixture of reactions is formed more neatly, so a purer product from this mixture is usually obtained in more yields. Another progressive effect of the present invention is that a compound which has not been silylated with HMDS in the past can be rapidly reacted by using the catalyst of the present invention. Illustrative of such compounds, S secondary alcohols [SHLanger CS, J. Org, Chem. 23 50 (1958)], phthalimide [DN Harpp CS, J. Amer. Chem. Soc. 100. 122 (1978)] and thiols and the like.

In addition, by using the production method of the present invention in the production of N, C-bis (trimethylsilyl) derivatives of peniclanic acid and cephalosporanic acid derivatives, the method is prepared in a simple and computational yield . The preparation of these derivatives was only difficult in the conventional method. [See, eg, F. Boortesi C.S., J. Pharm. Sci 66, 1767 (1977).

Another effect obtained by the present invention in the production of silyl compounds is described. For example, when N-trimethylsilylimidazole, N, N'-bis (trimethylsilyl) urea and the like are silylated with a silylating agent This does not cause contamination of the ammonium salts in these compounds, because if the contamination of ammonium salts, it will cause unnecessary side reactions.

Illustrating the present invention by way of example, it relates to the silylation of urea. Silylation of urea without catalyst requires a reaction time of 36 hours at approximately 125 ° C. as described in NL7613342. If ammonium chloride is used as a catalyst, it will require 6 hours at 118 ° C. (See Example III of the aforementioned patent). However, when saccharin is used as a catalyst according to the present invention, it is confirmed that 20 minutes is sufficient to complete the reaction.

Another reaction relates to the reaction of phenylhydrazine with HMDS. When this reaction is carried out without a catalyst, 12% is obtained at a reaction time of 12 hours at 130 ° C. [R. Fessenden C.S.J.Org. Chem. 26, 4638 (1961). When ammonium chloride is used as a catalyst, 89% of the desired product is obtained at the same reaction time. When using saccharin as a catalyst, the time required to obtain the same yield under the same reaction conditions as that of 89% using ammonium chloride as a catalyst is only 2.5 hours.

The reaction of HMDS with tertiary alcohols is known to be unreacted even with trimethylchlorosilane as a catalyst [S.H. Langer C.S.J.Org. Chem. 23, 50 (1958)], and the reaction proceeds very rapidly under the influence of the catalyst of the present invention described above. Examples of this include the use of saccharin as a catalyst, tertiary amyl alcohol reacts with HMDS to form trimethylsilyl ether in 3 hours, and 3L-4-nitrophenyl N (4-toluenesulfonyl) phosphoramidart. It can be exemplified that 2-methyl-2-hexanol reacts in only 15 minutes using a catalyst to form trimethylsilyl derivative in a yield of 92%. In the reaction of phthalimide with HMDS, it was confirmed that the use of the catalyst of the present invention had the same effect as described above. If the phthalimide is silylated with hexamethyldisilazane with imidazole as a catalyst, two days of reflux and reaction time are required [D.N. Harpp. C.S., J. Amer. Chem. Soc, 100, 1222 (1978). However, in the reaction between phthalimide and HMDS, saccharin became the catalyst to obtain this reaction in more yield within 1.5 hours.

In addition, the advanced method of the present invention also makes it possible to produce trimethylsilyl derivatives of organic compounds, which are known to be impossible to be silylated by HMDS by the methods disclosed in the literature. This is especially used for special organic thiols.

Therefore, another aspect of the present invention resides in the preparation of trimethylsilyl substituted compounds as shown in the following general formula.

RS-SiMe ₃

In the above general formula, R represents a 5- or 6-membered ring heterocyclic group having one or more nitrogen atoms or sulfur atoms as hetero atoms, which represents one or more alkyl groups, one phenyl group, one trimethylsilyl group It may be substituted by one alkylamino group or one trimethylsilyloxycarbonylmethyl group. When the above R group is exemplified, one 1,3,4-thiadiazolyl group, one 1,2,3,4-tetrazolyl group, one 1,2,3-triazolyl group, one 1, A 2,4-triazolyl group, one imidazolyl group or one pyrimidyl group can be exemplified, which is one methyl group, one phenyl group, one methylamino group, one trimethylsilyl group or one trimethylsilyl It may be substituted by an oxycarbonylmethyl group. And when the compound of the general formula mentioned above is illustrated, (5-methyl-1,3,4-thiadiazol-2-thio) trimethylsilane, 1-methyl-5-trimethylsilylthiotetrazole, 1-trimethylsilyl -5-trimethylsilylthio-1,2,3-triazole, 1-methyl-2- (trimethylsilylthio) imidazole, 1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-tria Sol, 1-phenyl-5-trimethylsilylthio-1H-tetrazole, 4,6-dimethyl-2- (trimethylsilylthio) pyrimidine, 2-methylamino-5-trimethylsilylthio-1,3,4- Thiazoleazole, trimethylsilyl 5-trimethylsilylthio-1H-tetrazolyl-1-acet, trimethylylsil 5-trimethylsilylthio-1,3,4-thiadiazolyl-2-acetar, and the like. These trimethyl silylated thiols are useful intermediates in preparing valuable compounds by novel methods. Exemplary of the above-mentioned valuable compounds are 3'-thio-substituted cephalosporins or intermediates thereof having good therapeutic activity. These substances are prepared by reacting trimethylsilylated thiols with the corresponding 3'-halo-substituted cephalosporanes. A novel method for producing these cephalosporins has been described in the patent application 80-05041. Other patent applications for trimethylsilylthio compounds include Mukaiyama CS (see Chem. Lett., 187, 1976 and Chem. Lett., 1013, 1974) and Evans CS (J. Amer, Chem. Soc. 99, 5009, 1977, see reference). Therefore, one of the characteristics of the present invention also exists in the novel compound represented by the following general formula.

RS-SiMe ₃

In the above general formula, R is a heterocyclic ring having a 5-membered ring or a 6-membered ring having a nitrogen atom or a sulfur atom as a hetero atom, and the heterocyclic group has one or more alkyl groups, one phenyl group, one trimethylsilyl group, and one It may be substituted by an alkylamino group of or one trimethyl silyloxycarbonylmethyl group. Regarding the group represented by R described above, for example, one 1,3,4-thiadiazolyl group, one 1,2,3,4-tetrazolyl group, one 1,2,3-triazolyl group, One 1,2,4-triazolyl group, one imidazolyl group or pyrimidyl group, which are one methyl group, one phenyl group, one methylamino group, one trimethylsilyl group or one trimethylsilyl oxycarb It may be substituted by a carbonylmethyl group. Illustrating the compound of the general formula described above, (5-methyl-1,3,4-thiadiazole-2-thio) trimethylsilane, 1-methyl-5-trimethylsilylthiotetrazole, 1-trimethylsilyl-5 -Trimethylsilylthio-1,2,3-triazole, 1-methyl-2- (trimethylsilylthio) imidazole, 1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole, 1-phenyl-5-trimethylsilylthio-1H-tetrazole, 4,6-dimethyl-2- (trimethylsilylthio) pyrimidine, 2-methylamino-5-trimethylsilylthio-1,3,4-thiazole Sol, trimethylsilyl 5-trimethylsilylthio-1H-tetrazolyl-1-acetar, trimethylylsil 5-trimethylsilylthio-1,3,4-thiadiazolyl-2-acetar, and the like.

In addition, another feature of the present invention is trimethylsilyl 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-1-thio) methyl-3-cepem-4-carboxylate 1- Oxide, N, C-bis (trimethylsilyl) -7-phenylacetamido-3- (1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-carboxylic acid 1-jade Seed, trimethylsilyl 7-trimethylsilylamino-3- (5-methyl-1,3,4-thiadiazolyl-2) -thiomethyl-3-cepem-4-carboxoxylat, trimethylsilyl 7-trimethylsilylamino -3- (1-trimethylsilyl-1H-1,2,3-triazolyl-5) thiomethyl-3-cepem-4-carboxylate, trimethylsil 7-trimethylsilylamino-3- (1-methyl- 1H-Tetrazolyl-5) -thiomethyl-3-cepem-4-carboxylate, trimethylsilyl 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-3- Cefem-4-carboxylat, trimethylsilyl 7-phenylacetamido-3- (1-trimethylsilyl-1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-car Eilat acid may like. These compounds are useful compounds for preparing cephalosporins having good therapeutic activity.

Persons skilled in the art may add the catalyst of the present invention to the reaction mixture in the form of gastrointestinal to the most imperative, for example, the silylated derivatives thereof and the sodium salts or other derivatives thereof are reacted. This is because it is formed into the catalyst of the present invention described above by decomposition in a mixture.

The following examples further illustrate the method of the present invention, but do not limit the present invention only with respect to the use of the compounds used in these examples.

Example 1

[Production of 1-trimethylsilyloxydodecane]

1.428)로 되는 1-트리메틸실릴옥시도데칸25.42g (98.5%)을 얻는다.A. Add 18.6 g (0.1 mol) of 1-dodecane to saccharin (90 mg; 0.5 mmol) and heat the mixture to 130 ° C. Hexamethyldisilazane (15.6 mg; 0.075 mol) is added over 8 minutes. The ammonia generated by the reaction is introduced into the water by a dried nitrogen stream and titrated with 1N hydrochloric acid. This confirms that a calculated amount of ammonia was generated 15 minutes after the start of adding hexamethyldisilazane. The reflux was continued for 10 more minutes, and excess hexamethylene disilazane was distilled off under reduced pressure and the boiling point was 120 DEG C (10.5 mmHg;

1.428) of 25.42 g (98.5%) of 1-trimethylsilyloxydodecane.

B. To 50 ml of dichloromethane, add 51 mg (0.27 mmol) of saccharin and add hexamethyldisilazane (7.8 ml; 38 mmol) to the solution while heating under reflux with 9.3 g (50 mmol) of 1-dodecane added. do. After refluxing for 1 hour by the method described in Example 1A, it was confirmed that a calculated amount of ammonia was generated.

C. To 50 ml of dichloromethane, add 9.30 g (50 mmol) of 1-dodecane and 70 mg (0.25 mmol) of dimethyl N-trichloroacetylphosphoramidart. Methyldisilazane (7.8 ml; 37.5 mmol) is added dropwise quickly. This confirms that a calculated amount of ammonia was generated by reflux for 75 minutes.

D. This preparation method was the same as described in Example 1C, but 121 mg (0.25 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidart was used as a catalyst. This reaction is completed in 40 minutes.

E. The method of D described above was carried out using 121 mg (0.25 mmol) of di-4-nitrophenyl N-toluenesulfonylphosphoramidart as a catalyst and the reaction time was completed in 60 minutes.

Example 2

[Production of trimethylsiloxycyclohexane]

Cyclohexanol (15.0 g; 0.15 mol) was silylated by adding 23.4 ml (0.112 mol) of hexamethyldisilazane in 5 minutes by the method described in Example 1A. In this silylation, 137 mg (0.75 mmol) of saccharin is used as a catalyst. An 18 minute reaction generates a calculated amount of ammonia. Next, the mixture was further refluxed for 10 minutes, followed by distillation of excess hexamethyldisilazane under reduced pressure to give 22.01 g of trimethylsiloxy cyclohexane having a boiling point of 53-55 ° C / 12 mmHg and n _D 25 of 1.4281. 85.3%).

Example 3

[Production of 2-trimethylsilyloxy-2-methylbutane]

Hexamethyldisilazane (21.9 ml; 0.105 mole) is added while refluxing a mixture of 17.6 g (0.20 mole) of 2-methyl-2-butanol (tert-amyl alcohol) and 0.18 g (1 mmol) of saccharin. The method of silylation uses the method described in Example 1A. After 18 minutes of reaction, 50% of the calculated amount of ammonia is produced. The reaction was continued for 3.25 hours while refluxing to generate 98% of ammonia. Distillation at atmospheric pressure to boiling point 129-30 ° C .; nD22 yields 22.75 g (71%) of pure 2-trimethylsalyloxy-2-methylbutane which is 1.3980. It was confirmed by NMR analysis that the preparation of the above-mentioned direct distillation product having a boiling point of 125-129 ° C. (3.69 g) and nD22 of 1.3974 contained 88% of the desired product.

Example 4

[Preparation of 17-beta-trimethylsilyloxy-4-androsten-3-one]

Hexamethyldisilazane (246 mg; 1.5 mmol) was refluxed with a suspension of 577 mg (2.0 mmol) of 17-beta-hydroxy-4-androsten-3-one, 1.8 mg (0.01 mmol) of saccharin and 10 ml of dichloromethane. Add.

Toluene and acetone proceed with the reaction by examining thin film chromatography by Keithel Gel 60F 254 (Merek) using a mixed solvent of 9 + 1 as eluent. As a result, when refluxing for 2 hours, the starting material disappeared and a new kind of material was found. After distillation under reduced pressure by NMR spectroscopy, the product was obtained in a calculated amount, which was found to be pure 17-beta-trimethylsilyloxy-4-androsten-3-one. Its melting point is 126-128 ° C. (decomposition).

Example 5

[Preparation of 1-trimethylsilyloxy-2-propene]

To 50 ml of pentane, allyl alcohol (24.28 g; 0.418 mol) and saccharin (0.36 g; 2 mmol) are added and the mixture is heated to reflux. To this mixture is added hexamethyldisilazane (51 ml; 0.25 mol) in 7 minutes. By titrating the ammonia generated during the reaction, it is found that a calculated amount of ammonia was generated in 1.5 hours. Distillation at atmospheric pressure afforded 46.1 g (85%) of 1-trimethylsilyloxy-2-propene having a boiling point of 97-100 ° C., n _D 25 1.3943.

Example 6

[Production of penta (trimethylsilyl) fructose]

Hexamethyldisilazane (42 ml; 0.20 mol) was added in 8 minutes while refluxing a mixed solution of 7.20 g (40 mmol) of fructose, 0.07 g (0.4 mmol) of saccharin, 24 ml of chloroform and 8 ml of pyridine. The ammonia generated is absorbed in water and titrated with 1N sulfuric acid.

It was found that 0.10 moles of ammonia were generated at reflux for 1 hour. Continue reflux for half an hour, and distill off the solvent under reduced pressure at atmospheric pressure to obtain 19.63 g (90.9%) of penta (trimethylsilyl) fructose having a boiling point of 138-142 ° C./0.5 mm Hgn _D 25 = 1.4306.

Example 7

[Production of 1-trimethylsilyloxyhexane]

A. Add 5.10 g (50 mmol) of 1-hexane to 0.37 g (2.5 mmol) of phthalimide and heat to 130 ° C. using an oil bath. Hexamethyl disilazane (7.8 ml; 37.5 mmol) is added and the resulting ammonia is absorbed into water and titrated with 1 N H ₂ SO ₄ . It is found that a calculated amount of 25 mmol of ammonia occurred in 130 minutes.

B. Repeat the above experiment with 2.5 mmol of 3,4,5,6-tetrachlorophthalamide as catalyst. A calculated amount of ammonia is generated in 70 minutes.

C. Repeat the above experiment with 2.5 mmol of 3,4,5,6-tetrabromophthalimide as a catalyst. A calculated amount of ammonia is generated in 20 minutes.

D. The above experiment was repeated without adding the catalysts integrally, and a calculated amount of ammonia was generated by reflux for 205 minutes.

E. Add 10 ml (37.5 mmol) of hexamethyldisilazane to 5.10 g (50 mmol) of 1-hexane, separately adding the various catalysts listed in the following table and heating to 130 ° C in an oil bath. It was. The time (t) at which ammonia corresponding to half of the theoretical amount is generated is measured. More detailed results are described in the following table.

Example 8

[Production of (2-methyl-2-hexoxy) trimethylsilane]

A mixture of 5.80 g (50 mmol) of 2-methyl-2-hexanol and 25 mg (0.05 mmol) of di-4-nitrophenyl N-4-toluenesulfonylphosphoramidart was heated in an oil weight of 140 ° C. 7.8 ml (37.5 mmol) of hexamethyldisilazane are added. It is found that after 15 minutes of reflux, a calculated amount of ammonia is generated.

Distillation under reduced pressure yields 8.66 g (92%) of (2-methyl-2hexoxy) trimethylsilane having a boiling point of 54-60 ° C./18 mmHg and n _D 25 = 1.4074.

Example 9

[Reaction of Water with Hexamethyldisilazane]

To a mixture of 740 mg (41 mmol) of boiling reflux water and 15 ml of dried acetonitrile, 21.4 mg (0.12 mmol) of saccharin are added dropwise in 1 minute 5 ml (60 mmol) of hexamethyldisilazane.

The resulting ammonia is absorbed into water and titrated with 1 N sulfuric acid. Only four minutes after the start of the drop, half of the ammonia has already been collected. After 35 minutes, no ammonia is generated and all calculations are collected.

Example 10

[Preparation of N-trimethylsilyl-p-toluidine]

To a mixture of 17.25 g (0.16 mmol) of p-toluidine and 0.15 g (0.8 mmol) of saccharin, hexamethyldisilazane (25 ml; 0 l.12 mol) is added for 5 minutes and heated to 130 ° C. in an oil bath. . Ammonia generated during the reaction was titrated to confirm that the calculated amount of ammonia was generated by reflux for 2 hours. The reflux mixture was continued for half an hour, and the reaction mixture was distilled under reduced pressure to obtain 24.0 g (83%) of N-trimethylsilyl-p-toluidine having a boiling point of 98-102 ° C / 12-13 mmHg.

Example 11

[Production of Phenoxy (trimethyl) silane]

Hexamethyldisilazane (31 ml; 0.15 mmol) is added dropwise to a reflux solution in which 80 mg (0.4 mmol) of saccharin and 19 g (0.2 mmol) of Lenol are dissolved in 15 ml of dichloromethane. It is revealed by the neutralization titration method described above that after 25 minutes, a calculated amount of ammonia is generated.

By fractional distillation, 31.6 g (95%) of phenoxytrimethylsilane having a boiling point of 62-63 ° C./12 mmHg n _D 25 = 1.4731 is obtained.

Example 12

[Production of C-trimethylsilyloxytoluene]

10.80 g (0.1 mol) of C-cresol was dissolved in 30 ml of dichloromethane. Saccharin (90 mg; 0.5 mmol) is added and the mixture is heated to reflux and hexamethyldisilazane (15.6 ml; 0.075 mol) is added. After 30 minutes it was found that the theoretical amount of ammonia was generated. After distilling off the solvent and excess of hexamerenedisilazane, the residue was distilled under reduced pressure to give a boiling point of 46-53 ° C / 10.5-0.7mmHg; 16.91 g (93.9%) of 0-trimethylsilyloxytoluene with n _D 25 = 1.4756.

Example 13

[Preparation of (2,6-di-tert-butylphenoxy) trimethylsilane]

시간후에 정지되었다. 클로로포름을 감압증류에 의하여 제거하고 잔류물을 감압하에서 분별증류하여 비등점 : 86-90℃/0.4mmHg; n_D25=1.4812로 되는 분별증류물을 12.64g(90%)을 얻는다.Hexamethyldi was refluxed while refluxing a mixture of 20 ml of chloroform and 23 mg (0.05 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidart and 10.4 g (50 mmol) of 2,6-di-tert-butylphenol. Silazane (7,8 ml; 37.5 mmol) is added. The occurrence of ammonia

After time it stopped. Chloroform was removed by distillation under reduced pressure, and the residue was fractionated by distillation under reduced pressure, boiling point: 86-90 ° C./0.4 mmHg; Obtain 12.64 g (90%) of fractional distillate with n _D 25 = 1.4812.

Example 14

[Production of Trimethylphenylthiosilane]

A. To 25 ml of chloroform, add 135 mg (0.75 mmol) of saccharin and 16 g (0.145 mol) of thiophenol, and add hexamethyldisilazane (23.4 ml; 0.11 mol) for 10 minutes while refluxing. Titration of ammonia generated during the reaction reveals completion of the reaction at 2.66 hours reflux.

The solvent and excess hexamethylsilazane were fractionated by distillation under reduced pressure, and the residue was fractionated by distillation under reduced pressure. Boiling point: 92-95 ° C./12-13 mmHg, 24.4 g (92.1%) of trimethylphenylthiosilane having n _D 25 = 1.5270 Get

B. A mixture of 17.4 g (0.158) of thiophenol, 135 mg (0.75 mmol) of saccharin and 24.7 ml (0.12 mol) of hexamethyldisilazane was refluxed for 2 hours. By distillation, 23.9 g (83%) of trimethylphenylthiosilane having a boiling point of 88-90 ° C / 12 mmHg and n _D 25 = 1.5308 was obtained.

Example 15

[Preparation of (5-methyl-1,3,4-thiadiazolyl-2-thio) -trimethylsilane]

Hexamethyldisilazane (15.6 ml; refluxing a solution of 25 ml of toluene, 92 mg (0.5 mmol) of saccharin, and 13.2 g (0.1 mol) of 2-percapto-5-methyl-1,3,4-thiadiazole; 0.075 mole) is added.

The generated ammonia is titrated and the reaction is completed by reflux for 30 minutes. Toluene is distilled off under normal pressure, and the residue is distilled off under reduced pressure. This gives 18.63 g (91.3%) of (5-methyl-1,3,4-thiadiazolyl-2-thio) trimethylsilane having a boiling point of 150-152 ° C./15 mmHg. This distillate is a solid with a melting point of 67-69 占 폚. NMR 60 MHZ; In-house standard in CCl ₄ and tetramethylsilane (delta = 0): the single values of 0.56 and 2.42; The integration ratio is 3: 1.

Example 16

[Preparation of 1-methyl-5-trimethylsilylthiotetrazole]

To a mixture of 12 ml of ethyl acetate and 25 ml of dichloromethane, 0.582 g (5.0 mmol) of 5-methyl-1-methyltetrazole and 5.0 g (0.03 mmol) of saccharin are added and mixed. Hexamethyldisilazane (1.26 ml; 5.5 mmol) is added while refluxing the mixture. The generation of ammonia was stopped after 1 hour. The evaporative material was distilled off under reduced pressure to obtain 0.94 g of 1-methyl-trimethylsilylthiotetrazole. NMR spectrum (CC1 ₄ ): two single values 0.61 and 3.79 with integration ratio 3: 1.

Example 17

[Preparation of 1-trimethylsilyl-5-trimethylsilylthio-1,2,3-triazole]

Hexamethyldisilazane (1.52 ml; 7.3) while refluxing a mixture of 0.49 g (4.86 mmol) of 5-mercapto-1,2,3- (1H) triazole, 5 mg (0.027 mmol) of saccharin and 10 ml of ethyl acetate Mmol) is added. The generated ammonia was titrated with 1N H ₂ SO ₄ as described in Example 1A, and it was found that 2 equivalents of ammonia were generated at reflux for 30 minutes. The evaporative material was removed by distillation under reduced pressure to obtain a residue (1.19 g: 96%). The carbon tetrachloride solution thereof had NMR spectrum: Delta 0.31 (9H); 0.48 (9 Hz); 7.46 (1 H).

Example 18

[Preparation of 1-methyl-2- (trimethylsilylthio) imidazole]

Hexamethyldisilazane (1.51 ml; 7.2 mmol) with a reflux of a mixture of 1.14 g (10 mmol) of 1-methyl-2-metcaptoimidazole, 18 mg (0.1 mmol) of saccharin and 20 ml of toluene under boiling through nitrogen. Add. The generated ammonia is introduced into the water and absorbed with nitrogen. This was titrated with 1 N sulfuric acid, and it was found that a calculated amount of ammonia was generated within 40 minutes.

The reaction mixture was solid under reduced pressure, and the residue was dried again at room temperature under high pressure to obtain 1.78 g (95%) of 1-methyl-2- (trimethylsilylthio) imidazole at a melting point of 49-52 ° C. .

1 H NMR (CC1 ₄ ): 0.55 (S, 9H); 3.49 (S, 3 H); 6.48 (d, 1 H, J 2 Hz); 6.69 (d, 1H, J 2 Hz).

Example 19

[Preparation of 1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole]

9.70 g (96 mmol) of 3-mercapto-1H-1,2,4-triazole and 100 mg (0.25 mmol) of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidart and 200 ml of dichloromethane 29.2 ml (0.14 mmol) of hexamethyldisilazane is rapidly added dropwise while passing through a nitrogen stream and boiling under reflux. The generated ammonia is absorbed into water by nitrogen stream. The ammonia was titrated with 1 N sulfuric acid, and it was found that a calculated amount of ammonia was generated within 1.25 hours. Continue boiling reflux for 0.5 hours and dry the clear solution with a rotary film evaporator to give 23.1 g (98%) of 1-trimethyl-3-trimethylsilylthio-1H-1,2,4-triazole having a melting point of 90-94 ° C. Get)

1 H NMR (CC1 ₄ ): 0.52 (S, 9H); 0.55 (S, 9 H); 7.52 (S, 1 H).

Example 20

[Preparation of 1-phenyl-5-trimethylsilylthio-1H-tetrazole]

In the same manner as described in Example 19, a mixture of 1.78 g (10 mmol) of 1-phenyl-5-mercapto-1H-tetrazole and 50 ml of 1,2-dichloroethane was mixed with 2.60 ml (12.4 mmol) of hexamethyldisilazane. As a catalyst, 5 mg (0.03 mmol) of saccharin is added and reacted to silylate. Calculated amounts of ammonia are collected within 20 minutes. Continue boiling for 10 more minutes to evaporate to dryness and dry the residue to give 2.58 g (103%) of 1-phenyl-5-trimethylsilylthio-1H-tetrazole having a boiling point of 67-68 ° C.

1 H NMR (CC1 ₄ ): 0.68 (S, 9H); 7.38-7. 64 (m, 3 H); 7.91-8.17 (m, 2 H).

Example 21

[Preparation of trimethylsilyl (4-chlorophenylthio) silane]

A mixture of 14.50 g (0.10 mol) of 4-chlorothiophenol and 45 mg (0.25 mmol) of saccharin is placed in a klysene vessel and heated to 120 ° C. by heating by oil weight. During this process, nitrogen is dried in the mixture. Pass the airflow Hexamethyldisilazane (20.8 ml, 0.10 mol) is added dropwise to this mixture quickly. In this way, further heating for 10 minutes causes the resulting precipitate to disappear. The generated ammonia is dissolved in water through a nitrogen stream and titrated with 1 N sulfuric acid to measure the progress of the reaction. It was found that a calculated amount of ammonia was generated within 40 minutes. The resulting product was fractionally distilled under reduced pressure to yield 19.81 g (91.5) of trimethylsilyl (4-chlorophenylthio) silane having a boiling point of 82-84 ° C / 2.0 mmHg.

Example 22

[Production of Trimethyl (4-methylphenylthio) silane]

A. By using the same method as described in Example 21, tetramethylimidodiphosphate 40mg (0.08mmol) as a catalyst, 14.70g (118mmol) of 4-methylthiophenol and 25ml (120mmol) of hexamethyldisilazane React to silylate. This silylation was found to be complete within 1 hour. The product was distilled off in vacuo to yield 22.16 g (95.4%) of trimethyl (4-methylphenylthio) silane having a boiling point of 80.5-82.0 ° C./2.5 mmHg.

B. As another method, 200 mg (0.42 mmol) of tetraphenylimidodiphosphate is added to a mixture of 11.35 g (91.5 mmol) of 4-methylthiophenol and 20.8 ml (100 mmol) of hexamethyldisilazane. . It is found that the reaction is completed within 30 minutes when using the above-described amount of catalyst. By distillation, trimethyl (4-methylphenylthio) silane having a boiling point of 79-31 ° C./2.5 mmHg is obtained in a yield of 84%.

Example 23

[Production of 4, C-dimethyl-2- (trimethylsilylthio) pyrimidine]

1.0 ml (4.8 mmol) of hexamethyldisilazane while boiling under reflux with a mixture of 0.70 g (5.0 mmol) of 4, C-dimethyl-2-mercaptopyrimidine, 10 mg (0.02 mmol) of tetraphenylimidodiphosphate and 25 ml of toluene. ) To react.

By boiling for 1.5 hours by the method described in Example 19, the calculated amount of ammonia is collected. The mixture is then evaporated and then dried to dry the residue to yield 1.08 g (102%) of 4,6-dimethyl-2- (trimethylsilylthio) pyrimidine.

1 H NMR (CC1 ₄ ): 0.43 (s, 9H); 2.32 (s, 6 H); 6.63 (s, 1 H).

Example 24

[Preparation of 2-methylamino-5-trimethylsilylthio-1,3,4-thiadiazole]

Hexamethyl while boiling under reflux with a solution of 298 mg (2.03 mmol) of 2-methylamino-5-mercapto-1,3,4-thiadiazole and 2 mg (0.004 mmol) of tetraphenylimidodiphosphate in 10 ml of ethyl acetate 0.42 ml (2.0 mmol) of disilaic acid is added to react. The generation of ammonia was completed 0.5 hours after the start of boiling by the method described in Example 19. The reaction collects 1 mmol of ammonia. The reaction was continued for 0.5 hours at boiling, and the solvent and other volatiles were removed using a rotary film prime mover. Thus, 2-methylamino-5-trimethylsilylthio-1, having a melting point of 80-82 ° C, 434 mg (97%) of 3,4-thiadiazole are obtained.

1 H NMR (CC1 ₄ ): 0.60 (s, 9H); 2.90 (d, 3H, J 5.5 Hz); 5.85 (q, 1H, J 5.5 Hz).

Example 25

[Production of trimethyl (4-bromophenylthio) silane]

10.82 g (57.2 mmol) of 4-bromothiaphenol and 25 mg (0.05 mmol) of di-4-nitrophenol-N- (4-toluenesulfonyl) phosphoramidart were catalyzed by the method described in Example 21. It is used as a solution and reacted with 8.9 ml (42.6 mmol) of hexamethyldisilazane to be silylated. Boiling for 15 minutes at reflux indicates that a calculated amount of ammonia has been generated. Sorting under reduced pressure yields 13.16 g (88.4%) of trimethyl (4-bromophenylthio) silane having a boiling point of 87-88 ° C./0.8 mmHg and an n _D 25 of 1.5652.

Example 26

[Production of trimethyl (3,4-dichlorophenylthio) silane]

Following the method described in Example 21, 8.45 mg (47.2 mmol) of 3,4-dichlorothiophenol and 7.40 ml (35.4 mmol) of hexamethyldisilazane were mixed, followed by 22 mg (0.045 mmol) of tetraphenylimidodiphosphate as a catalyst. It is reacted by using and silylated. The reaction was carried out for 35 minutes to generate a calculated amount of ammonia.

The mixture was fractionated under reduced pressure to give 11.28 g (95.3%) of trimethyl (3,4-dichlorophenylthio) silane having a boiling point of 96-97 ° C./0.8 mmHg and n _D 25 = 1.5600.

Example 27

[Preparation of trimethylsilyl-5-trimethylsilylthio-1N-tetrazolyl-1-acetate]

Hexamethyldisilazane (0.6 ml; 2.9 mmol) was boiled while refluxing a mixture of 318 mg (2.0 mmol) of 5-mercapto-1N-tetrazolyl-1-acetic acid, 5.5 mg (0.03 mmol) of saccharin and 25 ml of toluene under reflux. It is added and reacted. After 2 hours of reacting under reflux and boiling, the ammonia is completed. This reaction collects 2 mmol of ammonia. The mixture was evaporated to dryness under reduced pressure and the residue dried to give viscous oily trimethylsilyl. 5-trimethylsilylthio-1H-tetrazol-1-acetate 0.60 (100%) is obtained.

1 H NMR (CC1 ₄ ): 0.29 (s, 9H); 0.65 (s, 9 H); 4.87 (s, 2 H).

Example 28

[Preparation of trimethylsilyl 5-trimethylsilylthio-1,3,4-thiadiazolyl-2-acetate]

A mixture of 0.44 g (2.5 mmol) of 5-mercapto-1,3,4-thiadiazolyl-2-acetic acid, 5.0 mg (0.025 mmol) of saccharin and 30 ml of diclamethane was boiled under reflux with hexamethyldisilazane A calculated amount of ammonia (2.5 mmol) is collected 1.5 hours after the reaction with the addition of 0.9 ml (4.3 mmol). The mixture was evaporated to dryness and dried under reduced pressure to afford 0,80 g (100%) of trimethylsilyl 5-trimethylsilylthio-1,3,4-thiadiazolyl-2-acetat having a melting point of 45-49 ° C. Get

1 H NMR (CC1 ₄ ): 0.33 (s, 9H); 0.60 (s, 9 H); 3.37 (s, 2 H).

Example 29

[Production of trimethylsilylbenzoart]

A. Hexamethyldisilazane (15.6 ml; 0.075 mol) is added in 5 minutes while refluxing a mixed solution of 12.2 g (0.1 mol) of benzoic acid, 90 mg (0.5 mmol) of saccharin and 30 ml of dichloromethane. By titrating the collected ammonia, it is found that a calculated amount of ammonia was collected 40 minutes after the addition of hexamethylsilazane. The solvent was distilled off at atmospheric pressure and the residue was distilled under vacuum to boil point: 102-104 ° C./13 mmHg; 17.80 g (91.7%) of trimethylsilyl benzoart with n _D 25: 1.4837 is obtained.

In the absence of a catalyst, the reaction must be continued at reflux for 2.25 hours until a calculated amount of ammonia is obtained. In the two reactions described above, hexamethyldisilazane is added to produce a viscous precipitate in the reaction, but it disappears as the silylation proceeds.

B. In the above experiments, repeat using 117 mg (0.15 mmol) of sodium saccharin dihydrate instead of saccharin. Computation of ammonia generation is complete after 40 minutes of reflux. Fractional distillation yields 18.85 g (97.2%) of trimethylsilylbenzoart with boiling point: 56-57 ° C./0.5 mmHg n _D 25: 1.4843.

Example 30

[Production of trimethylsilyl trichloroacetate]

To a mixture of 31.3 ml (150 mmol) of hexamethyldisilazane and 34 mg (0.18 mmol) of saccharin, a solution of 30 ml of 1,2-dichloroethane and 12.3 mg (75 mmol) of trichloroacetic acid within 10 minutes at room temperature Drop by drop, but at this time, the dried nitrogen stream is passed through the mixture. This produces a precipitate. Next, the mixture is refluxed while boiling, whereby the first two layers are formed into a homogeneous solution, and a calculated amount of ammonia is collected. The dichloroethane is then distilled off under atmospheric pressure, whereby a small amount of small matter is separated off in the cooler. The residue was distilled under reduced pressure to obtain 14.94 g (84.9%) of trimethylsilyltrichloroacetate having a boiling point: 63-64 ° C./11 mmHg: n _D 25: 1.4360.

Example 31

[Production of trimethylsilyl 2-trimethylsilyloxybenzoart]

41.7 g (0.20 mol) of hexamethyldisilazane was added dropwise over 5 minutes while heating a mixture of 13.80 g (0.10 mol) of salicylic acid and 50 mg (0.10 mmol) of di (4-toluenesulfonyl) phosphoramidart to 130 ° C. . The generated ammonia is transferred to nitrogen stream and absorbed into water. Titration with 1 N sulfuric acid revealed that a calculated amount of ammonia occurred within 45 minutes. Fractional distillation under reduced pressure boiling point: 104-105 ° C./1.5 mmHg; n _D 25: 1.4746 obtain a trimethylsilyl 2-trimethylsilyloxy-benzo art 27.86g (98.8%).

Example 32

[Production of ethyltrimethylsilyl malonat]

A solution of 22.9 g (0.173 mol) of ethyl hydrogen valeronat, 30 mg (0.17 mmol) of saccharin, and 25 ml of dichloromethane was boiled and refluxed, and 20.8 ml (0.10 mmol) of hexamethyldisilazane was rapidly added while feeding a dried nitrogen stream. do. This results in a homogeneous solution that has been separated into two layers as the reaction proceeds. By titrating the ammonia generated, it is found that the generation of ammonia is connected after 1.5 hours. Prolonged boiling for 0.5 hours followed by fractional distillation under reduced pressure to give 34.1 g (96.6%) of trimethylsilylmalonate having a boiling point of 49.0-50.5 ° C./0.4 mmHg n _D 26: 1.4135.

Example 33

[Preparation of trimethylsilyl 5-mercapto-1H-tetrazolyl-1-acetate]

To 25 ml of 1,2-dichloroethane was added 0.30 g (1.86 mmol) of 5-mercapto-1H-tetrazolyl-1-acetic acid, 6.0 mg (0.012 mmol) of tetraphenylamidodiphosphate was added and boiled under reflux. 0.5 ml (2.4 mmol) of hexamethyldisilazane is added. One hour of boiling reflux produces one equivalent of ammonia. The mixture is dried under reduced pressure and the residue is dried to give 5-mercapto-1H-tetrazolyl-1-acetate (0.45 g (105%) with a melting point of 130-133 ° C.

1 H NMR (CDC1 ₃ ): 0.30 (s, 9H); 4.99 (s, 2 H); 14.28 (s, 1 H).

Example 34

[Production of N, N'-bis (trimethylsilyl) urea]

Hexamethyldisilazane (10 ml; 48 mmol) is added to 15 ml of ethyl acetate refluxed, followed by 73 mg (0.4 mmol) of saccharin and 2.4 g (40 mmol) of urea. Immediate generation of ammonia is completed by reflux for 20 minutes, which is confirmed by titration with 1NHCl. The evaporatives are removed under reduced pressure and the residue is dried in vacuo. This gave 8.06 g of N, N'-bis (trimethylsilyl) urea having a melting point of 219-222 占 폚 (99%).

If no saccharin is added as a catalyst, the ammonia generation is slow and it takes at least 24 hours to complete the reaction.

Example 35

[Preparation of N-trimethylsilyl-trichloroacetamide]

A mixture of 16.24 g (0.10 mol) of trichloroacetamide, 15 mg (0.08 mmol) of saccharin, 25 ml of toluene and 15 ml (0.07 mmol) of hexamethyldisilizane was refluxed in a preheated oil bath (120 ° C.) for 30 minutes. 22.58 g (96.3%) of N-trimethylsilyl-trichloroacetamide (prepared product) having evaporative material evaporated under reduced pressure and dried under reduced pressure at 50 ° C. in a step where no generation of ammonia was confirmed. Get

Example 36

[Production of N-trimethylsilylbenzoamide]

To 15 ml of toluene is added a mixture of saccharin (40 mg; 0.22 mmol) and benzoamide (5.0 g; 41.3 mmol) heated to reflux. Hexamethyldisilazane (6.4 ml; 31 mmol) is added and transferred to the water by nitrogen stream passing ammonia through the reactor. Titration with 1N H ₂ SO ₄ reveals that all calculated ammonia was generated in 15 minutes. The solvent and the light fraction of hexamethyldisilazane are removed by distillation under reduced pressure to obtain 8.04 g (101%) of N-trimethylsilylbenzoamide having a melting point of 111-114.5 占 폚 as a residue.

The above experiment was repeated without adding saccharin. As a result, ammonia corresponding to 82% of the theoretical amount was generated in 15 minutes, and ammonia corresponding to 88% of the 82% occurred in 50 minutes.

Example 37

[Production of N-trimethylsilyl-4-nitrobenzamide]

A. 4-Nitrobenzamide (5.0 g: 30.1 mmol) in hexamethyl disilazane (purity 93%) in 20 ml of butyl acetate refluxed in the presence of saccharin (50 mg; 0.27 mmol) in accordance with the method described in Example 18. 4.7 ml: 21 mmol) of the solution. The theoretical amount of ammonia is generated in 15 minutes.

The evaporative was evaporated under reduced pressure to give N-trimethylsilyl-4-nitrobenzamide (7.2 g; 100%) with pale brown (dark blue) and melting point: 130.5-134.5 ° C.

B. Hexamethyldisilazane (4.5 ml 22 mmol) was refluxed while refluxing a mixture of 5.0 g (30.1 mmol) of 4-nitrobenzamide, 100 mg (0.5 mmol) of 1,8-naphthalimide and 20 ml of butyl acetate. Add. After 35 minutes of reflux, a calculated amount of ammonia is generated.

Without the addition of the catalyst, the same experiment was repeated, whereby 16% of the calculated ammonia was generated at reflux for 15 minutes; Ammonia, equivalent to 83% of the calculation, is generated by reflux for one hour.

Example 38

[Production of N-trimethylsilyl-alpha, alpha-dimethylpropionamide]

To 15 ml of refluxed toluene, 5.0 g (49.5 mmol) of alpha and alpha-dimethylpropionamide and 10 mg (0.05 mmol) of saccharin are added, and 7.7 ml (37 mmol) of hexamethyldisilazane is added in 15 minutes. After 45 reflux, the ammonia is completely stopped. Distillation under vacuum and drying yielded 8.04 g (98%) of N-trimethylsilyl-alpha, alpha-dimethylpropionamide having a melting point of 101-105.5 ° C. According to NMR analysis, the purity of the product is 92%.

Example 39

[Production of N-trimethylsilylacetamide]

A mixture of 5.90 g (0.1 mol) of acetamide and 55 mg (0.3 mmol) of saccharin is heated to 130 ° C. and 15.6 ml (0.075 mol) of hexamethylsilazane is added in 3 minutes.

It was found that a calculated amount of ammonia was generated 35 minutes after starting the addition of hexamethyldisilazane according to the method described in Example 1A. The reflux is continued for another 10 minutes while evaporating the excess hexamethyldisilazane under reduced pressure and vacuum drying. This gives 12.80 g (97.7%) of N-trimethylsilylacetamide having a purity of 95% by NMR analysis.

Example 40

[Production of N-trimethylsilylurethane]

Hexamethyldisilazane (15.6 ml; 0.075 mol) was added in 2 minutes while refluxing a mixture of 8.9 g (0.1 mol) of urethane, 183 mg (1 mmol) of saccharin and 10 ml of toluene. The theoretical amount of ammonia is generated in 30 minutes. The reflux is continued for 15 minutes while the solvent and excess of hexamethyldisilazane are removed under reduced pressure and the residue is vacuum distilled. By this means the boiling point: 73 ° C./12 mm Hg; 15.6 g (96.9%) of N-trimethylsilylurethane having n _{D 25} : 1.4268 is obtained.

Example 41

Preparation of N, N'-bis (trimethylsilyl) malonamide

7.5 ml (36 mmol) of hexamethyldisilazane is added while refluxing a mixture of 3.06 g (0.03 mol) of malonamide, 18.3 mg (0.1 mmol) of saccharin, 50 ml of ethyl acetate and 5 ml of pyridine. It was found that 30 mmol of ammonia was generated at reflux for 1 hour by titrating the generated ammonia with 1 N sulfuric acid. The evaporative material is evaporated in vacuo and the residue crystallizing upon standing is vacuum dried to yield 7.32 g (99%) of N, N1-mis (trimethylsil) malonamide having a melting point of 72-76 ° C.

NMR spectrum (CDC1 ₃ ): delta 0.24 (s, 18H); 3.20 (s, 2 H); 6.5 (broad, 2H).

B. The same experiment as in A was carried out except that 30 ml of butyl acetate was used as the solvent. A calculated amount of ammonia was generated in 15 minutes. Melting point of the residue: 71-80 ° C. The yield for such purposes of A is 6.72 g (91%).

Example 42

[Production of N-trimethylsilylcaprolactam]

A mixture of 22.6 g (0.2 mol) of caprolactam, 0.73 g (3 mmol) of saccharin and 40 ml (0.19 mol) of hexamethyldisilazane was refluxed for 3.5 hours, and no ammonia was observed. The dark brown (brown) reaction complete mixture was distilled under vacuum to obtain 21.64 g (58.5%) of N-trimethylsilylcaprolactam having a boiling point of 103-106 ° C / 12mmHg.

Example 43

[Production of trimethylsilyl saccharin]

Boil-off reflux with nitrogen flow into a mixture of 1.83 g (10 mmol) of saccharin, 10 mg (0.02 mmol) of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidart and 20 ml of acetonitrile 2 ml (9.6 mmol) of hexamethyldisilazane is added to react. The generated ammonia is transferred to a nitrogen stream, dissolved in water, and titrated with 1 N sulfuric acid. A calculated amount of ammonia is generated in 0.5 hours. The solvent and other evaporables are evaporated off by rotary evaporation and then the residue is dried under vacuum to give 2.50 g (98%) of trimethylsilyl saccharin with a melting point of 90-92 ° C.

1 H NMR (CC1 ₄ ): 0.53 and 0.57 (both numbers are 9H); 7.66-8.13 (m, 4 H).

13C NMR (CDC1 ₃ , 20MHZ, internal standard interval TMS): -1.2; -0.4; 1.8; 120.5; 121.4; 123.6; 124.8; 133.3; 133.8; 134.8.

Example 44

[Production of N-trimethylsilylbenzenesulfonamide]

Hexamethyldisilazane (15.6 ml; 75 mmol) was added while refluxing a liquid in which 15.72 g (0.1 mol) of benzenesulfonamide and 18 mg (0.1 mmol) of saccharin were suspended in 45 ml of ethyl acetate. Nitrogen air is passed through the mixture during the reaction and absorbed in water so that the ammonia generated can be identified. By titrating with 1N H ₂ SO ₄ , it was found that a calculated amount of ammonia was generated by the reaction for 25 minutes. The residue from which the evaporative substance was evaporated in vacuo was N-trimethylsilylbenzenesulfonamide which had a melting point of 62-63 占 폚.

Example 45

[Production of N-trimethylsilylmethanesulfonamide]

Hesamethyldisilazane (5.1 ml; 24.5 mmol) is added while refluxing a mixture of 3.0 g (31.6 mmol) of methanesulfonamide, 20 mg (0.11 mmol) of saccharin and 15 ml of toluene. In order to build ammonia generated in the reaction mixture, a nitrogen stream is passed through the reaction mixture, and the ammonia accompanying the nitrogen stream is absorbed into water and titrated with 1N H ₂ SO ₄ . This resulted in a calculated amount of ammonia 20 minutes after reflux. The solvent and excess hexamethyldisilazane are evaporated in vacuo. The solid residue is then vacuum dried. Melting point: The yield of N-trimethylsilylmethanesulfonamide at 69-74.5 ° C. was 5.22 g (99.5%).

The above experiment was repeated without adding saccharin. This generates a calculated amount of ammonia in 35 minutes. By this production method, 5.25 g (100%) of N-trimethylsilylsulfamide having a melting point of 68-72.5 占 폚 is obtained.

Example 46

[Production of N-trimethylsilylthioacetamide]

Hexamethyldisilazane (17.2 ml; 82 mmol) was added in 10 minutes while refluxing a mixture of 11.3 g (0.15 mol) of thioacetamide, 0.14 g (0.75 mmol) of saccharin, and 50 ml of toluene. The ammonia generated by the reaction is transferred to a dried nitrogen stream and absorbed in water, and titrated with 1 N HCl. This resulted in a calculated amount of ammonia generated 1.5 hours after the addition of hexamethyldisilazane. Toluene and excess hexamethyldisilazane are distilled off at atmospheric pressure and the residue is distilled under vacuum to afford 13.12 g (59.2%) of N-trimethylsilylthioacetamide with a bead point of 97-99 ° C./0.7 mmHg.

Example 47

[Production of N-trimethylsilyl diphenylphosphamidart]

Hexamethyldisilazane (3.2 ml; 15.4 mmol) is added to a liquid in which 5.0 g (20.1 mmol) of diphenylphosphoramidart and 36 mg (0.20 mmol) of saccharin are added to 35 ml of refluxed toluene. Nitrogen gas is introduced into the mixture during the reaction, and the ammonia generated is absorbed into water and titrated with 1N of H ₂ SO ₄ . A calculated amount of ammonia is generated in 15 minutes. Continue reflux for 10 more minutes and evaporate the solvent. Melting point: 83-86.5H ₂ SO ₄ N-trimethylsilylphosphoramidart (6.69 g) is obtained.

This experiment is repeated without the addition of saccharin. 15 minutes reflux produces 26% of the calculated ammonia, and 1 hour reflux produces 69% of the calculated ammonia.

Example 48

[Production of N, O, O-tris (trimethylsil) -DL-serine]

91 mg (0.5 mmol) of saccharin is added to a suspension of 10.50 g (0.1 mol) of DL-serine and 30 ml of toluene. 52.2 ml (0.25 mol) of hexamethyldisilazane is added while heating the mixture to reflux. The dried nitrogen stream is passed through the mixture in the reaction and induced absorption into water to confirm the amount of ammonia generated. Titration with 1 N of H ₂ S0 ₄ revealed that 3 equivalents of ammonia were generated in 3 hours (2 equivalents of ammonia was generated in 1 hour). Toluene and excess hexamethyldisilazane were evaporated in vacuo and the residue was distilled in vacuo to boil point: 87-89 ° C./0.5-0.6 mmHg; N, O, O-tris (trimethylsilyl) -DL-serine-22.92 g (76.2%) is n _D 25: 1.4213.

Example 49

[Preparation of trimethylsilin-d, 1-alpha-trimethylsilylaminopropionat]

A mixture of 8.90 g (0.1 mol) of d, 1-alanine and 50 mg (0.1 mmol) of di-4-nitrophenyl N-4-toluenesulfonylphosphoramidart was placed in a preheated (140 ° C.) oil bath. 41.6 ml (0.2 mol) of hexamethyldisilazane is added. The calculated amount of ammonia is generated by reflux for 2 hours, which is confirmed by the absorption by water and titration with 1N H ₂ SO ₄ . The colorless solution was distilled under vacuum to boil point: 78-81 ° C./18 mm Hg; 20.72 g (88.9%) of trimethylsilyl d1-alpha-trimethylsilylaminopropionat with n _D 25: 1.415 is obtained.

Example 50

[Production of N-trimethylsilylsuccinamide]

A. To a suspension of 50 ml of toluene and 19.80 g (0.2 mol) of succinimide, saccharin (458 mg; 2.5 mmol) and hexamethyldisilazane (31.5 ml; 0.15 mol) were added and refluxed for 2 hours. 15 minutes after the addition of the silylating agent, the solution becomes a clear pale yellow solution. If reflux is continued, the color becomes brown. The reaction mixture is cooled, filtered and the solvent is evaporated off and the vacuum distilled. Thus boiling point; 31.04 g (90.8%) of N-trimethylsiline succinimide at 86-88 ° C./1.3 mmHg are obtained.

B. 9.90 g (0.1 mol) of succinimide and 0.24 g (0.5 mmol) of di-4-nitrophenyl N-4-toluenesulfonylphosphoramidart are suspended in 50 ml of dichloromethane and hexamethyldisila in a refluxing liquid. 15.6 ml (0.075 mol) of the glass is added in a few minutes. The nitrogen stream is passed through the mixture during the reaction to transfer the ammonia to be absorbed in water. The progress of the reaction is confirmed by titration of the generated ammonia. Thus, ammonia is generated when boiling under reflux for 1.5 hours. When ammonia corresponding to 90% of the theoretical amount is generated, boiling and refluxing are continued for 2 hours, and then the solvent is distilled off at atmospheric pressure and the residue is distilled under reduced pressure, boiling point: 118-119 ° C / 15.36 g (89.8%) of N-tromethylsilylsuccinimide having 18 mmHg and n _D 25: 1.4745 is obtained.

Example 51

[Production of N-trimethylsilylphthalimide]

A mixture of 36.8 g (0.25 mol) of phthalimide, 0.92 g (5 mmol) of saccharin and 75 ml (0.36 mol) of hexamethyldisilazane was placed in an oil bath heated to 120 ° C. The generation of ammonia begins immediately and after 30 minutes it becomes a clear solution. Continue reflux for 60 minutes from this time. The evaporative material is evaporated under vacuum and 50 ml of petroleum ether (boiling point: 80-110 ° C) is added and evaporated to dryness. A residue is obtained that is almost colorless and has a melting point of 66-68 ° C., which is in agreement with literature data on N-trimethylsilylphthalimide. Known structures for this compound were confirmed by NMR spectrum. Yield 54.89 g (100%).

Example 52

[Production of N-trimethylsilylimidazole]

A mixture of 13.62 g (0.2 moles) of imidazole and 28 mg (0.15 mmol) of saccharin is added dropwise over 45 minutes while heating to 100 ° C. with 31.5 ml (0.15 moles) of hexamethylsilazane. In this step, the temperature of the oil bath is raised from 100 ° C to 140 ° C. After the addition of hexamethyldisilazane is complete, the mixture is further stirred at 140 ° C. for 30 minutes. Excess hexamethyldisilazane is evaporated under reduced pressure and the residue is distilled under vacuum. This gives 22.25 g (79.5%) of N-trimethylsilylimidazole having a boiling point of 103-105 ° C./22 mmHg and n _D 25: 1.4740.

Example 53

[Production of 1,3-bis (trimethylsilyl) -5,5-dimethylhydantoin]

Hexamethyldisilazane (80 ml; 0.38 mol) is added over 30 minutes while lubricating a suspension of 50 ml of toluene, 40 mg (0.22 mmol) of saccharin and 38.45 g (0.30 mol) of 5,5-dimethylhydantoin. The invention of ammonia begins soon. When hexamethyldisilazane corresponding to half of the required amount is added, all solids in the reaction mixture are liquefied. After the addition of hexamethyldisilazane is completed, refluxing is continued for another hour, toluene is distilled off and the residue is vacuum dried at 45 ° C. This gives 79 g (97%) of 1,3-bis (trimethylsilyl) -5,5-dimethylhydantoin having a melting point of 46-49 ° C. According to NMR analysis, the purity of this compound is 91%.

Example 54

[Preparation of N-trimethylsilyl-2-oxyzolidone]

To 25 ml of toluene, saccharin (10 mg: 0.05 mmol) and 2-oxazolyldon (10.0 g; 108 mmol) with a purity of 94% are added, and the mixture is heated to reflux. Hexamethyldisilazane (14.3 ml: 69 mmol) is added for 10 minutes and refluxing is continued for 1 hour. The generation of ammonia is completely determined by the above-mentioned time. The solvent was evaporated under vacuum and the residue was distilled under vacuum to boil point: 62 ° C./0.2 mmHg; n _D 23: 14.6 g (85%) of N-trimethylsilyl-2-oxazolidone is obtained.

Example 55

[Preparation of 1-trimethylsilyl-1,2,4-triazole]

A mixture of 10.35 g (0.15 mol) of 1,2,4-triazole and 127 mg (0.75 mmol) of saccharin is added while heating to 126 ° C., 23.4 ml (0.11 mol) of hexamethylmesilazane. The generation of ammonia begins soon. The calculated amount of ammonia was generated by reflux for 30 minutes in the same manner as described in Example 1A. By vacuum distillation, boiling point: 76.5-78.0 ° C./12 mmHg; 19.37 g (91.6%) of 1-trimethylsilyl-1,2,4-triazole is obtained.

Example 56

[Preparation of trimethylsilyl C-aminophenicilanat]

A. Add 1.08 g (5.0 mmol) of C-aminophenicylic acid and 20 mg (0.11 mmol) of saccharin to 20 ml of dichloromethane and add hexamethyldisilazane (1.0 ml; 4.8 mmol) to the refluxed suspension. Substantially clear solution at reflux of 0.5 hour, which means that C-aminophenicylic acid insoluble in dichloromethane was converted to soluble trimethylsilyl ester. Without the addition of saccharin, the reaction time is extended to 4 hours.

B. Hexamethyldisilazane (1.0 ml) in a suspension obtained by adding 1.08 g (5.0 mmol) of C-aminophenicylanic acid and 30 mg (0.11 mmol) of N-trichloroacetylphosphoramidart to 20 ml of refluxed dichloromethane. 4.8 mmol) is added. Clear solution at reflux for 40 minutes means that 6-aminophenicylic acid, which is insoluble in dichloromethane, has been changed to soluble trimethylsilyl ester.

C. Hexamethyldisilazane (0.75 ml; 3.6 mmol) while refluxing a suspension of 1.08 g (5.0 mmol) of C-aminophenicylic acid, 20 mg (0.11 mmol) of saccharin and 15 ml of chloroform (without alcohol). Add). After 20 minutes of reflux, the solution becomes substantially transparent, which means that 6-aminophenicylic acid, which is insoluble in chloroform, is changed to soluble trimethylsilyl ester. Excluding saccharin in this reaction, the reaction time is extended to 1.5 hours.

D. Hexamethyl disila in a suspension consisting of 1.08 g (5.0 mmol) of 6-aminophenicsilane acid, 53 mg (0.11 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidart, and 20 ml of dichloromethane being refluxed. 1.0 ml (4.8 mmol) of the glass is added. After 25 minutes of reflux, the solution becomes a clear solution, which means that 6-aminophenicylanic acid, which is insoluble in dichloromethane, is converted into a soluble trimethylsilyl ester of the target product.

Example 57

[Preparation of trimethylsilyl 6-trimethylsilylaminophenicilanat]

Hexamethyldisilazane (2.5 ml; 12 mmol) is added to a refluxed suspension of 0.86 g (4 mmol) of 6-aminophenicsilane acid, 12 mg (0.07 mmol) of saccharin and 25 ml of chloroform. After 20 minutes of reflux, the solution becomes a clear liquid. After refluxing for 2 hours, the evaporative material was evaporated in a 40 ° C. hot water bath. It is concluded that 90% of trimethylsilyl C-trimethylsilylaminophenicilanate is present in the solution from the NMR spectrum of the colorless transparent oil dissolved in 4 ml of dried carbon tetrachloride.

Example 58

[Preparation of trimethylsilyl 6-D-(-)-alpha-aminophenylacetamidophenicilanath]

6-D-(-)-alpha-aminophenylacetamidophenisilane acid (3.49 g; mmol) is suspended in 35 ml of dichloromethane and saccharin (92 mg; 0.5 mmol) is added. 1.55 ml (7.4 mmol) of hexamethyldisilazane is added while heating the mixture to reflux. 25 minutes reflux to a colorless transparent liquid, which means that the above-mentioned peniclanic acid, which is insoluble in dichloromethane, has been changed to soluble trimethylsilyl ester as a target.

The above experiment was performed without adding saccharin, and a clear liquid was formed at reflux for 50 minutes.

Example 59

[Preparation of trimethylsilyl 6- [D-(-)-alpha-aminop-trimethylsilyloxyphenylacetamido] phenicilat]

6- [D-(-)-alpha-amino-p-hydroxyphenylacetamido] Hexadecane with a reflux of 0.13 g (2 mmol) peniclanic acid, 5 mg (0.027 mmol) of saccharin and 15 ml of dichloromethane 0.7 ml (3.4 mmol) methyldisilazane is added. After 20 minutes of reflux, the solution becomes a transparent solution, which is further refluxed for 1 hour. The solvent is evaporated in vacuo and the residue is dried in vacuo. Residual solids (1.15 g) were identified as N, C-bis (trimethylsilyl) derivatives of the starting materials described above by NMR spectrum.

In the contrast experiment without the addition of saccharin, it takes half an hour to reach a clear solution.

Example 60

[Preparation of trimethylsilyl C-trimethylsilylaminophenicilanat 1-oxide]

According to the method described in Example 72, 465 mg (2.0 mmol) of 6-aminophenicylanic acid 1-oxide was converted into 1.6 ml (7.7 mmol) of hexamethylsilazane in 20 ml of chloroform in 1.0 mg (0.002 mmol) of tetraphenylimidophosphate. ) As a catalyst and silylated. After 1.5 hours, the calculation of ammonia is complete. After boiling for 1.75 hours, the reaction mixture was evaporated to dryness using a rotary membrane evaporator, and then added again with 10 ml of carbon tetrachloride. The residue is dissolved in carbon tetrachloride.

1 _H NMR: 0.11 (s, 9H); 0.33 (s, 9 H); 1.17 (s, 3 H); 1.65 (s, 3 H); 2.36 (d, 1 H, J 12.8 Hz); 4.45 (s, 1 H); 4.45, 4.76 and 4.72 (dd and s, 2H, J4.5 Hz).

Example 61

[Preparation of trimethylsilyl 6-trimethylsilylaminophenylsilanat 1,1-dioxide]

In the same manner as in Example 60, 506 mg of 6, aminophenicylanic acid 1,1-dioxide (which has a water content of 6%) was dissolved in 20 ml of chloroform in 1.9 ml (0.1 mmol) of hexamethyldisilazane. Silylation using 1.0 mg (0.002 mmol) of nitrophenyl N-trichloroacetylphosphoramidart as a catalyst. A calculated amount of ammonia was generated in 3.25 hours. The solvent is separated off under reduced pressure. The residue (0.76 g) was found to be completely dissilylated by 1 H NMR spectrum.

1 _H NMR (CC1 ₄ ): 0.14 (s, 9H); 0.34 (s, 9 H); 1.33 (s, 3 H); 1.53 (s, 3 H); 2.27 (d, 1 H, J 14 Hz); 4.28 (s, 1 H); 4.47 (d, 1 H, J4.5 Hz); 4.60 and 4.85 (dd, 1 H. J4.5 and 14 Hz).

Example 62

[Preparation of trimethylsilyl 7-amino-3-methyl-3-cepem-4-carboxylate]

A. Hexamethyldisilazane (1.25 ml; refluxing with 1.07 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid suspended in 20 ml of chloroform (which is pa quality stabilized with ethanol); 6 mmol) and saccharin (20 mg 0.11 mmol). Slowly passing the dried nitrogen stream through the mixture during the reaction to remove the ammonia from the reaction zone keeps the reaction zone dry. 25 minutes of reflux resulted in a yellow clear liquid, which means that the above-mentioned starting carboxylic acid, which was insoluble in chloroform, was changed to soluble trimethylsilyl ester.

In the absence of adding saccharin in the reaction mixture, the reaction time is lengthened to 3.5 hours.

B. 20 ml of dichloromethane (alcohol completely removed), 1.07 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid, 1.05 g (5 mmol) of hexamethyldisilazane and 20 mg of saccharin ( 0.11 mmol) and reflux for 10 minutes in accordance with the method of Example 62A to obtain a transparent solution.

If the same experiment is carried out with addition of only 6.1 mg (0.03 mmol) of saccharin, the reflux time to obtain a clear solution is 20 minutes, and when it is performed without saccharin, the reflux time is 2.5 hours.

C. 20 mg (0.11 mmol) of saccharin and 0m75 ml of hexamethyldisilazane, while refluxing a suspension in which 1.07 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid was added to 20 ml of dichloromethane. 3.6 mmol) is added. Obtain a transparent solution after reflux for 30 minutes. Comparative experiments without addition of saccharin took 3.5 hours to obtain a clear solution.

D. Trichloroacetamide (82 mg; 0.5 mmol) and hexamethyldisilazane were suspended and refluxed with 1.50 g (7.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid in 20 ml of dichloromethane. (1.05 ml; 5.0 mmol) is added. 50 minutes to obtain the reflux clear solution. When performed without addition of trichloroacetamide, it takes 210 minutes to obtain a clear solution.

E. 1.07 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid was added to 20 ml of dichloromethane and refluxed to give sulfamide (10 mg; 0.1 mmol) and hexamethylenedisilazane (0.75). ml; 3.6 mmol) is added. After 2 hours of reflux, a clear solution is obtained. If it is carried out without addition of forest pamide, it takes 210 minutes to obtain a transparent solution.

F. 25 ml of dichloromethane, 1.07 g (5 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid and 26 mg (0.11 mmol) of N, N ¹ -bis (trimethylsilyl) sulfamide were refluxed. Add. After 2 hours of reflux, a clear solution is obtained.

When the same experiment is performed without addition of N, N ¹ -bis (trimethylsilyl) sulfamide, it takes 210 minutes to obtain a transparent solution.

G. In the method described in Example 62F, when using N-benzoylbenzenesulfonamide (41.4 mg; 0.15 mmol) as the catalyst, the reaction time is 35 minutes.

H. In the process described in Example 62F, the reaction time is 135 minutes when using N- (2-methoxy-1-naphthoyl) -4-toluenesulfonamide (54.8 mg; 0.15 mmol) as a catalyst.

I. In the process described in Example 62F, the reaction time is 150 minutes when using N- (2-methoxy-1-naphthoyl) methanesulfonamide (42.8 mg; 0.16 mmol) as a catalyst.

J. Hexamethyldisilazane (528 mg; 3.28 mmol) refluxing a suspension of 1.08 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid with 10 mg (0.05 mmol) of saccharin and 20 ml of dichloromethane. Add). A clear solution is obtained at reflux for 1 hour, which is evaporated to dryness and the residue is dried at room temperature under vacuum. The residue (1.48 g) is analyzed by NMR quantitative analysis by in-house standard method. Thus, the yield of trimethylsilyl 7-amino-3-methyl-3-cepem-4-carboxylate is 93% when calculated as the highest point of the trimethylsilyl ester. By NMR spectrum, trimethylsilyl 3-methyl-7-trimethylsilylamino-3-cepem-4-carboxylate is only a trace.

Example 63

[Preparation of trimethylsilyl 7-trimethylsilylamino-3-methyl-3-cepem-4-carboxylate]

A. To 40 ml of chloroform (which contains ethanol in the preliminary test), di-4-nitrophenyl N-4-toluenefonylphosphoramidart (12 mg 0.024 mmol) is added to any kind of active hydrogen atom. Reflux during reflux so that even the substance is lost. During this time, the dried nitrogen stream over the reaction mixture is slowly passed through to remove the ammonia generated from the reaction zone. Next, reflux was continued under the same conditions by adding 1.07 g (5.0 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid, and 0.1N sulfuric acid was absorbed by absorbing ammonia transferred to the nitrogen stream into water. Titrate with. Thus, a clear solution was obtained after reflux for 10 minutes (25 ml of sulfuric acid solution was used at this time), and 50 ml of sulfuric acid solution was used after 35 minutes of reflux, indicating the completion of disilylation.

B. A mixture of 0.80 g (3.7 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid, 1.87 ml (11.6 mmol) of hexamethyldisilazane, 8.8 mg (0.048 mmol) of saccharin and 20 ml of chloroform Heated to reflux. After 10 minutes reflux, a clear solution is obtained. After refluxing for 2 hours, the evaporative material is evaporated in a vacuum (bath temperature is 50 ° C). The residual solid is dissolved in 5 ml of carbon tetrachloride. The NMR spectrum of this solution concludes that 80% of N, C-disilylated derivatives are present. (By comparing with the indicators of N-trimethylsilyl and C-trimethylsilyl)

Example 64

[Preparation of trimethylsilyl 3-methyl-7-phenylacetamido-3-cepem-4-carboxylate 1-oxide]

A. Hexamethyldisilazane (1.25 g; 6.0 mmol) was added to a mixture of 1.4 g (4 mmol) of 3-methyl-7-phenylacetamido-3-cepem-4-carboxylic acid 1-oxide and 25 ml of dichloromethane. Add.

A clear solution is obtained after completion of the silylation for 30 minutes, indicating completion of the silylation.

B. Di-tosylamine 13 mg (0.04 mmol) (tosing means “toluenesulfonyl”) as catalyst and the above experiment is repeated. After 8 minutes reflux, a clear solution is obtained.

C. In the experiment of Example 64B described above, using 74.8 mg (0.66 mmol) of 2,2,2-trifuluroacetamide as a catalyst, a clear solution was obtained after 15 minutes of reflux.

D. A mixture of 1.083 g (3.1 mmol) of 3-methyl-7-phenylacetamido-3-cepem-4-carboxylic acid 1-oxide, 42 mg (0.15 mmol) of N-benzoyltoluenesulfonamide and 25 ml of dichloromethane Heat reflux. Hexamethyldisilazane (0.57 ml; 2.73 mmol) is added and the reflux is continued for 5 minutes to give a clear pale brown solution. In a comparative experiment without the addition of a catalyst, a clear solution is obtained at reflux for 45 minutes.

E. Hexamethyl Di in a mixture of refluxed 3-methyl-7-phenylacetamido-3-cefe-4-carboxylic acid seed 1.04 mg (3.0 mmol) with 14.5 mg (0.3 mmol) formamide and 30 ml dichloromethane Silazane (0.5 ml; 2.4 mmol) is added. A clear solution is obtained after 45 minutes of reflux.

In the control room without the addition of formamide it takes 75 minutes to obtain a clear solution.

Example 65

[Preparation of trimethylsilyl 7-phenylacetamido-3-methyl-3-cepem-4-carboxylate 1-alpha-oxide]

The compound described above comprises 0.17 g (0.5 mmol) of 7-phenylacetamido-3-methyl-3-cepem-4-carboxylic acid 1-alpha-oxide, 0.88 mg (0.005 mmol) of saccharin and hexamethyldisilazane. A mixture of 0.065 ml (0.31 mmol) and 5 ml of deuterochloroform is prepared by boiling reflux for 30 minutes. This product was produced quantitatively by 1 H NMR spectrum.

1 H NMR (CDC1 ₃ ): 0.33 (s, 9H); 2.18 (s, 3 H); 3.98 (ABq, 2H, J 16.5 Hz); 3.58 (s, 2 H); 4.47 (d, 1 H, J4.5 Hz); 5.29 and 5.42 (dd, 1H, J 4.5 and 8 Hz); 7.13 (d, 1 H, J 8 Hz); 7.29 (s, 5 H).

Example 66

[Preparation of trimethylsilyl 7-formamido-3-methyl-3-cepem-4-carboxylate 1-oxide]

1.34 g (5.0 mmol) of 7-formamido-3-methyl-3-cepem-4-carboxylic acid 1-oxide (96%), 5.0 mg (0.1 mmol) of detraphenylimidodiphosphate and 50 ml of dichloromethane 0.62 m (3.0 mmol) of hexamethyldisilazane is added to the suspension in boiling reflux. A calculated amount of ammonia is generated in 80 minutes. After evaporation of the evaporative material under reduced pressure, 1.63 g (99%) of pale yellow trimethylsilyl 7-formamido-3-methyl-3-cepem-4-carboxylate 1-oxide is obtained.

The test on the properties of the obtained product is as follows: 106 mg of 7-formamido-3-methyl-3-cepem-4-carboxylate 1-oxide, 0.5 mg of saccharin, 3 ml of deuterochloroform and hexamethyl A mixture of 0.05 ml of disilazane is boiled under reflux for 1 hour. From the 1 H NMR spectrum of the solution thus prepared, it was confirmed that the silylation was performed quantitatively by the integration ratio between the trimethyl indicator and the 7-yang growth indicator.

1 H NMR (CDC1 ₃ ): 0.32 (s, 9H); 2.16 (s, 3 H); 3.23 and 3.68 (ABq, 2H, J 18 Hz); 4.53 (d, 1 H, J4.5 Hz); 5.97 and 6.11 (dd, 1H, J 4.5 and 9.8 Hz); 7.20 (d, 1 H, J 9.8 Hz); 8.31 (s, 1 H).

Example 67

[Preparation of trimethylsilyl 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-3-cepem-4-carboxylate 1-oxide]

1115 mg (0.25 mmol) of 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-3-cepem-4-carboxylic acid 1-oxide was prepared according to the method described in Example 75. Silicin in 0.12 ml of hexamethylsilazane (0.48 mmol) for 1.5 hours, using 0.048 mg (0.00026 mmol) of saccharine in 2 ml of deuterochloroform as a catalyst.

1 H NMR (CDC1 ₃ ): 0.33 (s, 9H); 3.54 (s, 2 H); 3.54 (s, 2 H); 3.25, 3.58, 3.88, 4.21 (ABq, 2H, J 19 Hz); 3.83 (s, 3 H); 4.66,4.29,4.43,4.66 (ABq, 2H, J 13 Hz); 4.44 (d, 1 H, J 4.5 Hz); 5.99 (dd, 1H, J 4.5 and 10 Hz); 6.82 (d, 1 H, J 10 Hz); 7.27 (s, 5 H).

Example 68

[Bis (trimethylsilylation) of 7-phenylacetamido-3- (1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-carboxylic acid 1-oxide]

According to the method described in Example 76, 130 mg (0.29) of 7-phenylacetamido-3- (1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-carboxylic acid 1-oxide Mmol) under reflux with 0.10 ml (0.48 mmol) of hexamethyldisilazane using 1.0 mg (0.002 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidart as a catalyst in 2 ml of deuterochloroform. Boil for 1 hour and change to its bis (trimethylsilyl) derivative. From the NMR spectrum, it can be concluded that this product consists of two isomers that differ in the position of the trimethylsilyl group in the triazole ring.

1 H NMR (CDC1 ₃ ): 0.25 and o. 28 (2s, together 9H); 0.49 and 0.53 (2s, together 9H); about 3.2-4.7 (m, 7 H); 5.95 (dd, 1H, J4.5 and 9 Hz); 6.82 and 6.98 (2d, together 1 H, in both J 9 Hz); 7.28 (s, 5 H); 7.65 and 7.85 (2s, together 1 H).

Example 69

[Preparation of trimethylsilyl 3-acetoxymethyl-7-amino-3-cefe-4-carboxylate]

Saccharin (11 mg; 0.06 mmol) and hexamethyldisilazane (0.63 ml; 3.0 with 0.82 mg (3.0 mmol) of 3-acetoxymethyl-7-amino-3-cepem-4-carboxylic acid suspended in 15 ml of dichloromethane. Mmol) is added. After 10 minutes of reflux, the solution becomes a transparent solution, which means that the carboxylic acid insoluble in chloroform has been changed to soluble trimethylsilyl ester.

The same experiment is performed without the addition of saccharin. In this case, reflux for 50 minutes should be continued until it becomes a transparent solution.

Example 70

[Preparation of trimethylsilyl 7-trimethylsilylamino-3-acetoxymethyl-3-cepem-4-carboxylate 1-oxide]

A suspension of 1.08 g (4 mmol) of 3-acetoxymethyl--7-amino-3-cepem-4-carboxylic acid 1-oxide, 1 mg (0.08 mmol) of saccharin and 25 ml of chloroform was prepared under reflux with hexamethyldisilazane ( 2.5 ml; 12 mmol) is added. The mixture becomes clear after 10 minutes and refluxed for 2 hours. The temperature of the bath is 40 ° C., the solvent is evaporated under vacuum and the excess of hexamethyldisilazane is evaporated to obtain an oily residue. This material is dissolved in 4 ml of dried carbon tetrachloride, filtered and referred to NMR analysis. It is found that at least 80% of trimethylsilyl 7-trimethylsilylamino-3-acetoxymethyl-3-cepem-4-carboxylate 1-oxide is present.

Example 71

[Preparation of trimethylsilyl 7-trimethylsilylamino-3- (5-methyl-1,3,4-thiadiazolyl-2) -thiamethyl-3-cepem-carboxylate]

0.85 g (2.5 mmol) of 7-amino-3- (5-methyl-1,3,4-thiadiazolyl-2) thiomethyl-3-cepem-4-carboxylic acid, 12 mg (0.07 mmol) of saccharin and 25 ml of chloroform The mixture was reacted with hexamethyldisilazane (1.6 ml; 7.7 mmol) under heating under reflux. This reaction immediately yields a clear solution. After continuing the reaction under reflux for 2 more hours, the volatiles were evaporated under reduced pressure and the clear viscous residue was dissolved in 4 ml of dried carbon tetrachloride. The solution was referred to NMR spectrum analysis and at least 80% of trimethylsilyl. It is found that it is obtained.

Example 72

[Preparation of trimethylsilyl 7-trimethylsilylamino-3- (1-trimethylsilyl-1H-1,2,3-triazolyl-5) thiomethyl-3-cepem-4-carboxylate]

20 ml of chloroform, 1.65 ml (80 mmol) of hexamethyldisilazane and 1.0 mg (0.002 mmol) of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidart are mixed. The mixture was refluxed by passing the dried nitrogen stream over the reacted mixture, introducing ammonia into water and titrating with 1 N sulfuric acid until no ammonia was generated. The reaction for 1.5 hours gives 2.6 mmol of ammonia. Next, 0.632 g (2 mmol) of 7-amino-3- (1H-1,2,3-triazolyl-5) thiomethyl-3-cepem-4-carboxylic acid was added to the above reaction zone and ammonia was no longer present. Continue boiling under the same conditions until it does not occur. After 1.75 hours, 3 mmol of ammonia is generated. After evaporation to dryness under reduced pressure, 5 ml of carbon tetrachloride is added and repeatedly evaporated to dryness. The residue (1.13 g) is dissolved in dried carbon tetrachloride.

1 H NMR: 0.11 (s, 9H); 0.28 (s, 9 H); 0.52 (s, 6 H); 1.41 (d, 1 H, J 12 Hz); 3.40 and 3.80 (ABq, 2H, J 18 Hz); 3.75 and 4.29 (ABq, 2H, J 13.5 Hz); 4.49 and 4.75, 4.73 (dd and s, 2H, J4.8 Hz); 7.57 (s, 1 H).

IR (CC1 ₄ ): 3400,1795,1720,1380,1270,865 cm ^-1 .

Example 73

[Preparation of trimethylsilyl 7-trimethylsilylamino3- (1-methyl-1H-tetrazolyl-5) thiomethyl-3-cepem-4-carboxylate]

1.64 g (4.6 mmol) of 7-amino-3- (1-methyl-1H-tetrazolyl-5) thiomethyl-3-cepem-4-carboxylic acid (91% content) in the same manner as described in Example 72 And 30 ml of chloroform and 3.0 ml (14.4 mmol) of hexamethyldisilazane were reacted for 2 hours, and then silylated. At this time, 5.0 mg (0.01 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidart is added to the reaction zone as a catalyst. The mixture is concentrated by evaporation using a rotary film evaporator to foam and again dried in vacuo to yield 2.21 g (103%) of the desired product as described above.

1 H NMR (CC1 ₄ ): 0.11 (s, 9H); 0.34 (s, 9 H); 1.43 (d, 1 H, J 12 Hz); 3.66 (s, 2 H); 3.90 (s, 3 H); 4.14 and 4.51 (ABq, 2H, J 13.5 Hz); 4.58, 4.83 and 4.82 (dd and S, 2H, J 4.5 Hz).

Example 74

[Preparation of trimethylsilyl 7-D- (C-trimethylsilyl) mandelamido-3- (1-methyl-1H-tetrazolyl-5) thiomethyl-3-cepem-4-carboxylate

3.23 g (6.3 mmol) of 7-D-(-) mandelamido-3- (1-methyl-1H-tetrazolyl-5) thiomethyl-3-cepem-4-carboxylic acid (90%; cephamandol), A turbid mixture of 10.0 mg (0.02 mmol) of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidar, 1.90 ml (9.1 mmol) of hexamildisilazane and 30 ml of dichloromethyl was boiled under reflux. Let's do it. The ammonia produced is introduced into the water by using a nitrogen stream passing through the reaction zone. After titration with 1 N sulfuric acid, it was found that the production of ammonia was completed within 0.5 hours of the reaction. In this case a total of 65 ml of sulfuric acid was consumed. The solid remaining after evaporation to dryness under reduced pressure was washed with a mixture of 20 ml of petroleum ether and 5 ml of ethyl acetate to obtain 3.1 g (81%) of the desired product; The results of the 1 H NMR spectrum analysis correspond to those known in the literature.

Example 75

[Preparation of trimethylsilyl 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-3-cepem-4-carboxylate]

A solution of 1 ml of dichloromethane and 0.048 mg (0.00026 mmol) of saccharin was charged into a 25 ml round bottom flask and the solvent was evaporated under reduced pressure. Subsequently, 113 mg (0.25 mmol) of 7-phenylacetamido-3- (1-methyl-1H-tetrazolyl-5-thio) methyl-3-cepem-4-carboxylic acid was weighed in a container and 2 ml of duterochloroform was weighed. And 0.05 ml (0.25 mmol) of hexamethyldisilazane are added to react. At this time, the mixture of the reaction zone is stirred at room temperature while slowly passing through the nitrogen stream dried on the reaction zone. After 10 minutes, you will have an almost transparent solution. After further stirring for 1 hour, the NMR spectrum yielded the following clear solution, from which it was found that the silylation proceeded quantitatively.

1 H NMR (CDC1 ₃ ): 0.31 (s, 9H); 3.58 (s, 2 H); 3.64 (s, 2 H); 3.86 (s, 3 H); 4.33 (s, 2 H); 4.88 (d, 1 H, J 4.5 Hz); 5.78 (dd, 1H, J 4.5and 9 Hz); 6.22 (d, 1 H, J9 Hz); 7.27 (s, 5 H).

Example 76

[Preparation of trimethylsilyl 7-phenylacetamido-3- (1-trimethylsilyl-1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-carboxylate]

In a 25 ml round bottom flask, 2 ml of a solution containing 0.25 mg (0.005 mmol) of di-4-nitrophenyl N-trichloroacetylphosphoramidar is added and evaporated to dryness under reduced pressure. Subsequently, 103 mg (0.25 mmol) of 7-phenylacetamido-3- (1H-1,2,3-triazolyl-5-thio) methyl-3-cepem-4-carboxylic acid was weighed out in a container and deuterochloroform Add 2 ml of the added liquid. Next, 0.10 ml (0.48 mmol) of hexamethyldisilazane is added to the reaction while boiling under reflux. Boil another 45 minutes and evaporate to dryness under reduced pressure to give 144 mg of the desired product.

1 H NMR (CDC1 ₃ ): 0.28 (s, 9H); 0.53 (s, 9 H); 3.23, 5.53, 3.64, 3.95 (ABq, 2H, J 18 hz); 3.61 (s, 2 H); 3.68, 3.90, 4.15, 4.39 (ABq, 2H, J 13 Hz); 4.88 (d, 1 H, J 4.5 Hz); 5.78 (dd, 1H, 1, J 4.5 and 9 Hz); 6.53 (d, 1 H, J 9 Hz); 7.33 (s, 5 H); 7.66 (s, 1 H).

Example 77

[Preparation of trimethylsilyl 3-methyl-7-phenylacetamido-3-cef-4-carboxylate]

A suspension is made by mixing 142 mg (0.41 mmol) of 3-methyl-7-phenylacetamido-3-cefe-4-carboxylic acid, 0.5 mg (0.003 mmol) of saccharin and 3 ml of deuterochloroform. 9-methylanthracene (57 mg; 0.297 mmol) is added as an internal reference for NMR quantitation. Hexamethyldisilazane (0.5 ml; 0.24 mmol) was added and the mixture was refluxed for 10 minutes to react. A clear, pale yellow solution is obtained, which is cooled to room temperature. Synthesis of the maximum point of the trimethylsilyl ester of trimethylsilyl 3-methyl-7-phenylacetamido-3-cef-4-carboxylate and the methyl maximum point of 9-methylanthracene added by NMR spectrum analysis of this solution. By comparing the ratios, the yield of trimethylsilyl 3-methyl-7-phenylacetamido-3-cefe-4-carboxylate is 97%.

Example 78

[Preparation of trimethylsilyl 7-trimethylsilylamino-3-methyl-3-cepem-4-carboxylate-1-beta-oxide and 1-alpha-oxyde]

A. 122 mg (0.53 mmol) of 7-amino-3-methyl-3-cepem-4-carboxylic acid 1-beta-oxide and 0.5 mg of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidart (0.001 mmol) and 0.2 ml (0.96 mmol) of hexamethyldisilazane are added to the suspension with 2 ml of dichloromethane while stirring. The reaction is boiled under reflux for 6 minutes while passing through a stream of dried nitrogen over the reactants to obtain a clear solution. Boil for an additional 40 minutes and then dry the mixture by evaporation on a rotating film evaporator. The solid residue is vacuum dried at room temperature. This gives 208 mg of trimethylsil 7-yltrimethylsilylamino-3-methyl-3-cepem-3-carboxylate 1-beta-oxide.

1 H NMR (CDC1 ₃ ): 0.14 (s, 9H); 0.36 (s, 9 H); 1.99 (d, 1 H, J 14 Hz); 2.16 (s, 3 H); 3.19, 3.60 (Aq, 2H, J 18 Hz); 4.34 (d, 1 H, J 4.5 Hz); 4.62, 4.86 (dd, 1H, J 4.5 and 14 Hz).

B. Trimethylsilyl 7-trimethylsilylamino-3-methyl-3-cepem-4-carboxylate 1-alpha-oxide is obtained in the same manner.

1 H NMR (CDC1 ₃ ): 0.17 (s, 9H); 0.34 (s, 9 H); 1.54 (d, 1 H, I 13 Hz); 2.13 (s, 3 H); 3.37 and 3.97 (ABq, 2H, J 17 Hz); 4.44 (d, 1 H, H4.5 Hz); 4.80 and 5.02 (dd, 1H, J 4.5 and 13 Hz).

Example 79

[Production of 1-trimethylsilyl-2-phenylhydrazine]

90 mg (0.05 mmol) of saccharin is added to 10.8 g (0.1 mmol) of phenylhydrazine and the mixture is heated to a temperature of 130 ° C. Reflux is continued for 2.5 hours after the addition of hexamethylsilazane (15.6 ml; 0.075 mmol). The reflux was continued for 2 hours according to the method described in Example 1A, resulting in a calculated amount of ammonia. The mixture was distilled under vacuum to have a boiling point of 112-116 ° C./11 mm Hg; 16.15 g (89.7%) of 1-trimethyl-2-phenylhydrazine having n ^D ₂₅ : 1.5241.

Example 80

[Production of N-trimethylsilyloxysuccinimide]

7.8 ml (37.5 mmol) of hexamethyldisilazane is added to a mixture of 5.60 g (47.2 mmol) of N-hydroxysuccinimide (purity 97%) and 46 mg (0.25 mmol) of saccharin while heating to 130 ° C. . As the production of ammonia begins immediately, the ammonia production ends 15 minutes after the addition of hexamethyldisilazane begins. The mixture was cooled, the laying fraction of hexamethyldisilazane was distilled off under reduced pressure, and the residue was classified to give N-trimethylsilyl oxysuccinimide (boiling point: 109-110 ° C / 0.4mmHg, melting point: 55-57 ° C). 7.70 g (87.2%) is obtained.

Example 81

[Preparation of N-benzoyl-N, O-bis (trimethylsilyl) hydroxylamine]

Hexamethyldi, while boiling a mixture of 1.21 g (8.8 mmol) of benzohydroxyminic acid and 5 mg (0.01 mmol) of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidar and 10 ml of dichloromethane under reflux 4.2 ml (20.2 mmol) of silazane is added dropwise and reacted to form a precipitate. Boiling for 15 minutes at reflux completes the generation of ammonia and gives a clear solution. 2.35 g (95%) of N-benzoyl-N, O-bis (trimethyl) silylhydroxylamine is obtained after evaporating off the volatiles under reduced pressure.

1 H NMR (CC1 ₄ ): 0.26 (s, 9H); 0.30 (s, 9 H); 7.2-7.4 (m, 3 H); 7.6-7.8 (m, 2 H).

Example 82

[Production of N-trimethylsilyloxy-4-toluenesulfonamide]

Hexamethyldisilazane (1.0 ml; 4.8 mmol) while boiling a mixture of 0.94 g (5.0 mmol) of N-hydroxy-4-toluenesulfonamide, 5 mg (0.01 mmol) of tetraphenylimidodiphosphate and 20 ml of dichloromethane under reflux. Add. The generated ammonia was titrated with 0.1 N sulfuric acid to confirm that the reaction was completed 50 minutes after the onset of ammonia. The ammonia generated in this case is 2.5 mmol. The reaction mixture was evaporated to dryness to afford 1.29 g (100%) of N-trimethylsilyloxy-4-toluenesulfonamide (melting point, 87-90 ° C.).

1 H NMR (CC1 ₄ ): 0.17 (s, 9H); 2.43 (s, 9 H); 2.43 (s, 3 H); 6.90 (s, 1 H); 7.20, 7.34, 7.69, 7.83 (q, 4H).

Example 83

[Production of 1-trimethylsilyloxycyclohexen-3-one]

8.4 g (72 mmol) of cyclohexanedione-1,3 (96% purity), 70 mg (0.38 mmol) of saccharin and 60 ml (288 mmol) of hexamethyldisilazane are mixed. The mixture is refluxed in a preheated oil bath. It is confirmed that the calculated amount of ammonia is generated in 50 minutes by titrating ammonia generated during the reaction. The reflux is then continued for another 10 minutes and the excess of hexamethyldisilazane is evaporated in vacuo and the residue is vacuum midstreamed. This gives 10.67 g (80.5%) of 1-trimethylsilyloxycyclohexen-3-one having a boiling point of 119-121 ° C./2.0 mmHg.

Example 84

[Production of ethyl 3-trimethylsilyloxy-2-butenoart]

A mixture of 9.75 g (75 mmol) of ethyl acetoacetate and 70 mg (0.38 mmol) of saccharin is heated to 130 ° C. in an oil bath. Hexamethyldisilazane (60 mg; 288 mmol) is added and refluxed for 1.5 h. The excess of hexamethyldisilazane is distilled off under reduced pressure and the residue is distilled under vacuum to give 12.71 g (84%) of ethyl-trimethylsilyloxy-2-butenoart having a boiling point of 102-104 ° C / 16 mmHg.

Example 85

[Production of 1-trimethylsilyloxybutane]

To a solution of either of the catalysts indicated on the check below in 15 ml of dichloromethane, add a solution of 1.48 g (20.0 mmol) of butanol-1 in 10 ml of dichloromethane. 2.50 ml (12.0 mmol) of hexamethyl disilazane are added while heating the mixture to reflux. Measure the time (t) at which half of the calculated ammonia is generated. More detailed results can be found on the check below.

Example 86

[Preparation of N, N-dimethyl-N'-trimethylsilylsulfamide]

Hexamethyldisilazane (3 ml; 14.4 mmol) is added while refluxing a mixture of 2.48 g (20 mmol) of N, N-dimethylsulfamide, 9 mg (0.05 mmol) of saccharin, and 30 ml of toluene.

It is confirmed by the method already described that a calculated amount of ammonia is generated by reflux for 1 hour. The evaporative material is evaporated under reduced pressure and the residue is dried at room temperature to yield 3.96 g (101%) of N, N-dimethyl-N'-trimethylsilylsulfamide having a melting point of 83-86 ° C.

Example 87

[Production of trimethylsilyltrimethylsilylthioacetate]

Hexamethyldisilazane (4.0 ml) while refluxing a solution in which 1.20 g (13.0 mmol) of mercaptoacetic acid and 18 mg of di-4-nitrophenyl N- (4-toluenesulfonyl) phosphoramidart were added to 10 ml of toluene. 19.2 mmol) is added. Based on the methods listed above, it was found that a calculated amount of ammonium (13 mmol) occurred 25 minutes after the start of reflux. Rotating film evaporator evaporates off volatiles and stores the residue in vacuum for 0.5 hours. 2.87 g (93.4%) of trimethylsilyltrimethylsilylthioacetate is obtained.

1 H NMR (CCl ₄ ): 0.28 (s, 9H); 0.32 (s, 9 H); 3.01 (s, 2 H).

Claims (1)

In trimethylsilylating an organic compound having one or more active hydrogen atoms with hexamethyldisilazane, a catalyst represented by formula (I) is present in the reaction mixture in the range of 0.001 to 10 mol%. Or a catalyst presenting a compound which can be produced in the above amounts.

In the above description, X and Y are the same or different electron withdrawing groups, and the electron withdrawing groups are groups selected from acyl groups, sulfonyl groups, phosphoryl groups and the like represented by the following general formula:

Wherein R ₁ and R ₂ are the same or different and each of them is an alkyl group of 1 to 6 carbon atoms, halogen, an alkyl group of 1 to 6 carbon atoms or alkoxy which may be substituted by one or more halogen atoms An alkoxy group or one in which an allyl group of 6 to 14 carbon atoms, one halogen atom, one alkyl group, or one nitro group may be substituted, in which one or more groups containing a group or nitro group may be substituted Or an aryloxy group or R ₃ and R ₄ are the same or different, each group being one hydrogen atom, one alkyl group containing 1 to 6 carbon atoms, or one trialkylsilyl group to which the alkyl group is bonded Select from one R ₃ R ₄ N group or the like.