FI58777C - 6BETA-ACYLAMIDOPENICILLANSYRASULFOXIDSILYLESTRAR VILKA ANVAENDES SOM MELLANPRODUKTER VID FRAMSTAELLNING AV 7BETA-ACYLAMIDO-3-METHYL-CEF-3-EMKARBOXYLSYROR - Google Patents

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. . .... ANNOUNCEMENT

VÖ9 »M <”> UTLAGONiNe * $ KmpT 58777 C / 40 Patent zyönnz-ity 10 04 1931 VSvM ”Patent sieddelat (51) Kv.ik? /Int.ci.3 C 07 D 4-99 / 32, 4-99 / 44

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(22) Hakamispilvl - Ansöknlngtdtf 29.OU.76 ^ ^ (23) Alkupiivl - GUtlfhandif 17.02.71 (41) Has become public - Bllvlt offsntllf 29 QU 76

Patent · and Register Board of Directors / 44 »Date of filing and filing. -

Patent · och reglstaretyreleen 'Amekan utltfd och utUkriften publlcarad 31.12.80 (32) (33) (31) Attempted • tuolksus - »« jlrd prlorltat 18.02.70 23.07.70 70 (71) Koninklijke Nederlandsche Gist- en Spiritusfäbriek NV , Wateringse-Weg 1, Delft, Netherlands-Nederländema (NL) (72) Jan Verveij, Leiden, Netherlands-Nederländema (NL) (7U) Berggren Oy Ab (5U) 6β-Acylamidopenicillanic acid sulfoxide silyl esters used as intermediates 7 (3-acylamido- In the preparation of 3-methyl-ceph-3-emcarboxylic acids - 60-acylamidopenicillansyrasulfoxydsilyl esters, a vigorous addition to some of the products from the preparation of 7 (3-acylamido-3-methyl-cef-3-emcarboxy) syror (62) This invention relates to novel 6e-acylamidopenicillanic acid sulfoxide silyl esters used as intermediates in the preparation of 7β-acylamidodeacetoxycephalosporanic acids.

The new penicillanic acid sulfoxide silyl esters have the general formula: 0 / CH3

R - C - NH - CH - CH

0 I I | XCH j1 I

/ -M-CH f '° - f - Y2 0 0 Y2 wherein R represents a benzyl group, an α-benzyloxycarbamoyl group, a phenoxymethyl group or a 2-ethoxynaphthyl group, and Y1, γ2 and Yj are the same or different and each represents 2,58777 1-4 an alkyl group containing a carbon atom optionally substituted by halogen atoms, or a phenyl group, and further, one of the groups Y1, Y2, Y1 may represent a chlorine atom or a ββ-acylamidopenicillanylsulfoxydicarbonyloxy group according to the group attached to the silicon atom in the above formula.

The 6α-acylamidopenicillanic acid sulfoxide silyl esters of the general formula I can be prepared by a process for the preparation of esters known per se. ββ-acylamidopenicillanic acid sulphoxide of general formula: 0 t / CH, R - C - NH - CH - CH C '

0 I H3 II

C-n-CH - C - O - R, 1 '1

CT O

wherein R 1 is as defined above and R 2 represents a hydrogen atom or a suitable cation such as sodium, potassium or calcium, e.g. by reacting with a silichloro compound of the general formula:

Y, - Si - Cl III

2 I

Y3 wherein Y1, Y2 and Y2 have the same meaning as above, but without reference to the 6β-acylamidopenicillanylsulfoxydicarbonyloxy group, under anhydrous conditions and at room temperature in the presence of at least one nitrogen-containing base, preferably in an inert organic medium.

Suitable nitrogen-containing bases are secondary or tertiary aliphatic, cycloaliphatic, aromatic or heterocyclic amines, which preferably have a pKa of 4-10 in water. Particularly preferred are hexamethylenetetramine, N-methylaniline, dimethylaniline, pyridine and pyridine substituted 3,587,77, e.g. by one or more lower alkyl or mono- or di- (lower) alkylamino groups, such as picolines, 2-ethylpyridine, 2- propylpyridine, 2,3-dimethylpyridine, 2,5 ”dimethylpyridine, 2,6-dimethylpyridine, collidines and 2-dimethylaminopyridine, or quinoline or 3-methylisoquinoline. Preferred bases are α-picoline, 2,5-dimethylpyridine, 2-dimethylaminopyridine and 3-methylisoquinoline.

Examples of suitable silicon compounds of formula III are trimethylchlorosilane, dimethyldichlorosilane, triethylchlorosilane, tri-n-propylchlorosilane, bromomethyldimethylchlorosilane, tri-n-butylchlorosilanyl, methyldiethylchloroethyl, dimethyl, silane, dimethyl -lan, (dichloromethyl) dimethylchlorosilane and methyldiphenylchlorosilane. Of the most commonly used silicone compounds in chemistry, trimethylchlorosilane and dimethyldichlorosilane are the most preferred.

The preparation of the intermediates according to the invention can be carried out in an inert organic solvent medium. Suitable solvents include acetonitrile, chlorobenzene, dimethylformamide, dioxane, nitrobenzene, anisole, benzene, carbon tetrachloride and especially benzyl cyanide and haloalkanes such as 1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1-chloroethane, 1,2 , 3-trichloropropane and chloroform. The process can be performed using a nitrogen-containing organic base (e.g., pyridine) itself as the reaction medium. Good combinations of organic bases and solvents are α-picoline or 2,5-dimethylpyridine with benzyl cyanide or with one of the above-mentioned haloalkanes, such as 1,2-dichloroethane, 1-bromo-1-chloroethane or chloroform.

The 66-acylamidopenicillan sulfoxide derivatives of formula II used as starting materials in the above process can be prepared by treating the corresponding 66-acylamidopenicillan derivatives with an oxidizing agent by methods known per se. To this end, the 66-acylamidopenicillan derivative is treated with an active oxygen donor such as sodium periodate, peraconate, hydrogen peroxide or iodobenzene in a ratio sufficient to oxidize the thiazolidine sulfur atom to the -SO group. The parent compound may be the free acid or a salt thereof, preferably dissolved in a solvent that is inert under the reaction conditions used. The resulting sulfoxide can be easily recovered from the reaction mixture by methods known per se.

It is preferable to start with an aminopenicillan sulfoxide derivative obtained from penicillin, which is easily prepared by fermentation, such as benzylpenicillin or phenoxymethylpenicillin.

The novel 68-acylamidopenicillanic acid sulfoxide silyl esters of the general formula I are used as intermediates in the preparation of 73-acylamidodeacetoxycephalosporanic acids according to Finnish Patent No. 55205.

In this process, the 68-acylamidopenicillanic acid sulfoxide silyl ester of formula I is heated under anhydrous conditions in the presence of at least one nitrogen-containing organic base and a silicon compound having a silicon-chloro bond, at least five moles of base in each of the penicillan sulfide . The same nitrogen-containing bases, silicon-chlorine compounds and organic media can be used in this process as described above.

Many of the 7-aminodesacetoxy-cephalosporanic acid derivatives obtained by this process have useful antibiotic activity and are therefore very important therapeutic agents.

The invention is described in more detail below by means of examples.

Example 1 Preparation of trimethylsilyl ester of 6-phenylacetamidopenicillanic acid sulfoxide.

To a suspension of 2.5 g (7.15 mmol) of benzylpenicillin sulfide in 30 mL of dry tetrachloromethane was rapidly added a solution of 1 mL (7.2 mmol) of triethylamine in 10 mL of carbon tetrachloride. After stirring for 15 minutes, a room temperature solution of 1 ml (7.9 mmol) of trimethylchlorosilane in 10 ml of tetrachloromethane was slowly added. After stirring for an additional 90 minutes at room temperature, the reaction mixture was concentrated to a volume of about 20 mL and filtered. The precipitate containing tri-ethylamine hydrochloride was washed three times with dry tetrachloromethane. The PMR spectrum was measured from the combined filtered tetrachloromethane solutions. The analysis from this book was as follows: PMR (in tetrachloromethane, values in ppm): δ: 0.32 (s, 9); 1.13 (s, 3) and 1.63 (s, 3;) 3.53 (s, 2); 4.5 ^ (s, 1); 4.95 (d, 1, J = 5 Hz); 5.90 (q, 1, J = 5 Hz and 11 Hz); 7.27 (d, 1, J = 11 Hz); 7.30 (s, 5).

Tetramethylsilane was used as an internal standard.

The new compound 6-phenyl-acetamidopenicillan sulfoxide-trimethylsilyl ester was obtained in an amorphous state by complete evaporation of the filtrate.

Example 2

Preparation of dimethylchlorosilyl ester and dimethylsilyl diester of phenoxymethylpenicillin sulfoxide.

2.6 g (0.0072 mol) of phenoxymethylpenicillin sulfoxide, 1.75 ml (0.014 mol) of dimethyldichlorosilane and 17.2 ml (0.17 mol) of α-picoline were dissolved in 35 ml of 1,2-dichloroethane and stirred for 1 hour at room temperature. temperature. The reaction formed in situ a mixture of ioxoxymethylpenicillin sulfoxide dimethyl chlorosilyl ester and di (phenoxymethyl penicillin sulfoxide) dimethylsilyl ester.

Analysis of the PMR books of both components of this mixture was as follows: Phenoxymethylpenicillin sulfoxide-dimethylchlorosilyl ester: 6: 0.59 (s, 6); 1.30 (s, 3); 1.73 (s, 3); 4.55 (s, 2); 4.76 (s, 1); 5.28 (d, 1, J = 4.5 Hz); 6.15 (q, 1, J = 11 and 4.5 Hz); 6.80-7.90 (m, 5); 8.30 (d, 1, J = 11 Hz).

Di (phenoxymethylpenicillin sulfoxide) dimethylsilyl ester: <5: 0.39 (s, 6); 1.30 (s, 3); 1.73 (s, 3); 4.55 (s, 2); 4.76 (s, 1); 5.28 (d, 1, J = 4.5 Hz); 6.15 (q, 1, J = 11 and 4.5 Hz); 6.80-7.90 (m, 5); 8.30 (d, 1, J = 11 Hz).

Tetramethylsilane was used as an internal reference.

58777 6

Example 3 Preparation of dimethyl chlorosilyl ester and dimethylsilyl diester of 6- (α-benzyloxycarbamoylphenylacetamido) penicillanic acid sulfoxide.

2.6 g (0.0072 moles) of 6- (α-benzyloxycarbamoylphenylacetamido) -penicillanic acid sulfoxide, 1.75 ml (0.014 moles) of dimethyldichlorosilane and 17.2 ml (0.17 moles) of α-picoline were dissolved. To 35 ml of 1,2-dichloroethane and the mixture was stirred for 2 hours at room temperature. The resulting ester of 6- (α-benzyloxycarbamoylphenylacetamido) -penicillin sulfoxide dimethylchlorosilyl ester (monoester) and di- [N- (α-benzyloxycarbamoylphenylacetamido) -penicillin sulfoxide N-dimethylsilyl ester (di-methyl) ester next: Monoester: 6: 0.56 (s, 6); 1.23 (s, 3); 1.68 (s, 3); A, 52 (s, 1); 5.07 (d, 1, J = 4.5 Hz); 5.11 (s, 2); 5.46 (d, 1, J = 6 Hz); 6.00 (q, 1, J = 10 and 4.5 Hz); about 7.50 (m, 5); 8.15 (d, 1, J = 10 Hz).

Diesters: 6; 0.35 (s, 6); 1.23 (s, 3); 1.68 (s, 3) and 4.52 (s, 1); 5.07 (d, 1, J = 4.5 Hz); 5.11 (s, 2); 5.46 (d, 1, J = 6 Hz); 6.00 (q, 1, J = 10 and 4.5 Hz); about 7.50 (m, 5); 8.15 (d, 1, J = 10 Hz).

Tetramethylslanan was used as an internal reference.

Example 4 Preparation of 2-ethoxy-naphthylpenicillin sulfoxide trimethylsilyl ester.

A mixture of 2.6 g (6 mmol) of 2-ethoxynaphthylpenicillin sulfoxide, 20 ml of chloroform, 20 ml (200 mmol) of α-picoline and 4.8 ml (36 mmol) of trimethylchlorosilane was stirred for 2 hours at room temperature. The PMR spectrum analysis of the obtained compound, 2-ethoxynaphthylpenicillin sulfoxide trimethylsilyl ester, was as follows (mixture of CDCl 3 and DMSO): δ: 0.32 (s, 9); 1.27 (s, 3); 1.44 (t, 3, j = 7Hz); 1.66 (s, 3); 4.19 (q, 2, J = 7Hz); 4.54 (s, 1); 5.24 (d, 1, J = 4.5 Hz); 6.28 (dd, 1, J = 11 Hz and 4.5 Hz); about 7.50 (m. 7) ·

Tetramethylsilane was used as an internal reference.

Example 5

Preparation of phenoxymethylpenicillin sulfoxide trimethylsilyl ester.

7 58777

A mixture of 36.6 g (0.1 mol) of phenoxymethylpenicillin sulfoxide, 360 ml (3.6 mol) of α-picoline and 8 ml (0.6 * 1 mol) of trimethylchlorosilane in 360 ml of chloroform was stirred at room temperature for one hour. I drive. The trimethylsilyl ester of phenoxymethylpenicillin sulfoxide was formed in situ in the reaction.

The PMR spectrum analysis of the obtained compound (in a mixture of CDCl 3 and d 2 -pyridine) was as follows: 6: 0.3 * 4 (s, 9); 1.23 (s, 3); 1.70 (s, 3); 44,449 (s, 2); 4.61 (s, 1); 4.96 (d, 1, J = 4.5 Hz); 6.04 (q, 1, J = 11 and 4.5 Hz); 6.72-7.42 (m, 5); 8.15 (d, 1, J = 11 Hz).

Tetramethylsilane was used as an internal reference.

Example 6

Preparation of dimethyl (t-butyl) silyl ester of benzylpenicillin sulfoxide.

To a solution of 10.5 g (30 mmol) of benzylpenicillin sulfoxide and 4.2 ml (30 mmol) of triethylamine in 50 ml of benzene was added a solution of 4.8 (32 mmol) of dimethyl (t-butyl) chlorosilane. In 25 ml of benzene. After 1 hour, the precipitate was removed by filtration and concentrated to dryness. 14.1 g of benzylpenicillin sulfoxide dimethyl (t-butyl) silyl ester were obtained.

PMR (benzene-d6; 60 Mc; δ values in ppm; tetramethylsilane as internal reference): 6: 0.18 (s, 6); 0.79 (s, 3); 0.84 (s, 9); 1.43 (s, 3); 3.31 (s, 2); 4.11 (d, 1; J = 4.5 Hz); 4.75 (s, 1); 5.92 (dd, 1; J = 4.5 Hz and J = 10 Hz); 7.15 (s, 5); 7.38 (d, 1; J = 10 Hz).

Example 7

Preparation of phenoxymethylpenicillin sulfoxide (dichloromethyl) dimethylsilyl ester.

To a stirred mixture of 3.7 g (10 mmol) of phenoxymethylpenicillin sulfoxide, 1.4 ml (10 mmol) of triethylamine and 15 ml of benzene were added a solution of 1.5 ml (10 mmol) of (dichloromethyl) dimethylchlorosilane. In 5 ml of benzene. After half an hour stirring the mixture was concentrated to dryness. The residue consisted of phenoxymethylpenicillin sulfoxide (dichloromethyl) dimethylsilyl ester with the impurity triethylammonium chloride.

Δ 58777 PMR (CDCl 3; 60 Mo; δ values in ppm; tetramethylHsilane as internal reference): δ: 0.58 (s, 6); 1.31 (s, 3); 1.75 (s, 3); 4.52 (s, 2); 4.64 (s, 1).

5.08 (d, 1 J - 4.5 Hz); 5.54 (s, 1); 6.05 (dd, lj j = ^, 5 Hz and J = 10.5 Hz); 6.85-7.25 (m, 5); 8.27 (d, 1; J = 10 and 5 Hz)!

Example 8

Preparation of phenoxymethylpenicillin sulfoxide methyldiphenylsilyl ester.

To a mixture of 3 * 7 ε (10 mmol) of phonoxymethylponicillin · * sulfoxide, 1.4 ml (10 mmol) of triethylamine and 15 ml of benzene were added with stirring a solution of 2.7 ml (10 mmol) of methyl diphenylchlorosilane in 7 ml: in benzene. After half an hour stirring the solvent was evaporated in vacuo and carbon tetrachloride was added to the residue. After filtration, the filtrate was concentrated in vacuo. The residue consisted of phenoxymethylpenicillin sulfoxydimethyldiphenylsilyl ester.

PMR (CDCl 3; 60 Mc; δ values in ppm; tetramethylsilane as internal reference): 6: 0.92 (s, 3); 1.02 (s, 3); 1.69 (s, 3); 4.52 (s, 2); 4.75 (s, 1); 4.95 (d, 1; J = 4.5 Hz); 6.05 (dd, 1; J = 4.5 Hz and J = 10.5 Hz); 6.82-7.75 (m, 15); 8.30 (d, 1; J = 10.5 Hz).

Claims (1)

9 58777 Claim 6g-Acylamido-penicillanic acid sulfoxide silyl esters used as intermediates in the preparation of 7β-acylamido-3-methyl-ceph-3-emcarboxylic acids, characterized in that they have the general formula 0 / K XCH 3 R - C - NH - CH - CH C i! wherein CH represents a benzyl group, an α-benzyloxycarbamoyl-benzyl group, a phenoxymethyl group or a 2-ethoxynaphthyl group, and Y 1, Y 2 and Y 1 are the same or different and each represents an alkyl group having 1 to 4 carbon atoms optionally substituted by halogen atoms, or a phenyl group, and in addition, one of Y 1, Y 2, Y 2 may represent a chlorine atom or a 6g-acylamidopenicillanyl sulfoxidecarbonyloxy group according to the group is attached to a silicon atom in the above formula and wherein R is as defined above. 6S-Acylamido-penicillansyrasulfoxydsilyl ester, which is a solid product with the presence of 7B-acylamido-3-methyl-cef-3-emcarboxylic acid, is converted to the corresponding form of 0 X ch3 R - C - NH - CH oii Tch3 γ C -N-CH - C - 0 - Si - Y „a I 2 color R betecknar en benzylgrupp, α-benzyloxycarbamoylbenzylgroup, phenoxymethylgroup or 2-ethoxynaphthylgroup, och Y-,, Y„ och Y-. business id 3