CH649529A5 - METHOD FOR PRODUCING N-ACYLAMIDES. - Google Patents

Description

The invention relates to a process for the preparation of N-acylamides of the general formula I.

0 0

II Ii

R / CxN ^ XX2

I.

X1

in which R represents an organic acid residue which is substituted by other functional groups; X! and X2 is in each case an alkyl radical with 1 to 6 carbon atoms, an aryl radical or an alkyl radical with 1 to 5 carbon atoms with a hetero atom from the group N, O or S or Xj and X2 together represent an alkylene group with 3 to 6 carbon atoms.

The compounds of formula (I) are known and many of them are used extensively in the pharmaceutical industry since they include, among other things, penicillin amides, which are important intermediates in the synthesis of antibiotics.

It is known that simple N-acylamides can be obtained by acylating amides by heating with an anhydride or chloride of the corresponding acid, provided that an inorganic acid is added as a catalyst, since otherwise the nitrii of the corresponding acid is predominantly obtained [D. Davidson and H. Skovronek, J. Amer. Chem. Soc. 80 (1958) 376]. In order to obtain N-acyl lactams, an analogous method was used, namely heating the corresponding lactams with anhydrides or chlorides of simple acids, such as with acetic anhydride, e.g. B. in the preparation of the N-acetyl derivatives of butyrolactam [W. Reppe et al., Ann. 596 (1955) 201], Vale-40 rolactams [C. Schotten, Ber. 21 (1888) 2242] or caprolactams [R.E. Benson and T.L. Cairns, J. Amer. Chem. Soc. 70 (1948) 2115]; as well as with benzoyl chloride, e.g. in the production of N-benzoyl derivatives of butyrolactam (W. Reppe, ibid.), valerolactams [T. B. Graves, J. Amer. Chem. Soc. 46 45 (1924) 1469] or caprolactams [L. Ruzicka, Hei. Chem. Acta 4 (1921) 478],

It has also been described that N-acetyl derivatives can be obtained by reacting the amides with isopropenyl acetate [W. Hent-schel, Ber. 23 (1890) 2395; A.W. Hoffmann, Ber. 14 (1881) so 2731; U.S. Patent 2,656,360] and with ketenes [R.E. Dunbar and W.M. Svebson, J. Org. Chem. 23 (1958) 1793].

Mumm's reaction of the iminochlorides with carboxylic acid salts is known, in which N-acylami-55 de is obtained as the end product [O. Mumm, H. Hesse and H. Volquartz, Ber. 48 (1915) 388], This reaction is used in the production of semi-synthetic penicillins as a method for the trans-acylation of benzylpenicillin with corresponding carboxylic acids [DE-PS 1 942 667; J. Cieslak et al., Rocz. 60 Chem. 45 (1971) 111]. The preparation of some N-penicillinylamides by modifying this method has also been described (A.B. A. Jansen and T. J. Russell, J. Chem. Soc. 1965,2127).

65 It is known that cephalosporins, which are important antibacterial agents, are obtained by rearranging the corresponding penicillin sulfoxide esters [R. R. Chauvette et al., J. Org. Chem. 36 (1971) 1259].

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649 529

It has recently been found that mixed anhydrides of carboxylic acids with secondary amides can be successfully obtained by the reaction of carboxylic acids with N-chlorocarbonyl secondary amides.

It has now been found that, according to the invention, N-acylamides of the formula I can be prepared by using mixed anhydrides of the formula

0 0 0

undergoes a rearrangement with COz elimination.

The mixed anhydride of formula IV is by reaction of the carboxylic acid derivative of the formula

O

II

R-C-OY II

wherein Y represents a hydrogen or an alkali metal atom, with an N-chlorocarbonyl-sec-amide or lactam of the formula

0 0 II II

Ct / 'C'VvN ^' Cv ~ "X2 ® X1

accessible. In the formulas II, III and IV, the symbols R, Xj and X2 have the meaning given above.

The mixed anhydride is preferably prepared in an inert, organic, water-immiscible solvent, most advantageously in methylene chloride or toluene, and in the presence of a tert. organic base, preferably pyridine or triethylamine. The reaction preferably takes place at a temperature in the range of from -20 ° C to +10 ° C, most advantageously at about 0 ° C. The carboxylic acid can also be used in the form of an alkali metal salt, most advantageously as a sodium or potassium salt. The reaction time in the preparation of the mixed anhydride IV can usually be 5 to 30 minutes with stirring.

The rearrangement of the mixed anhydride IV is by the. Stir the mixture which is obtained in the reaction of the carboxylic acid with the N-chlorocarbonylamide or lactam, reached for 10 to 120 minutes at a temperature in the range from 0 ° C. to 40 ° C.

In both reaction stages, the reagents are usually used in equimolar ratios, although it is also possible to use an excess of up to 10 mol% of the organic base or of the N-chlorocarbonyl-sec-amide or lactam with respect to the carboxylic acid.

The advantage of the present invention in comparison with the prior art is significant, since it provides a generally applicable method for the acylation of N-amides, while the known processes are based on the preparation of simple N-acyl derivatives, such as. B. acetyl or benzoyl derivatives are limited. The inventive method is particularly suitable for acylation using sensitive carboxylic acids, eg. B. amino acids and penicillanic acid and cephalosporin acid rederivaten.

The resulting product of formula I is isolated and purified from the reaction mixture in a conventional manner, e.g. by adding cold water, stirring, separating the organic layer, washing with water, drying (e.g. Na2S04, MgS04) and evaporation of the solvent. If desired, the residue can be digested with a suitable solvent, such as n-hexane, or recrystallized from toluene-petroleum ether. Alternatively, the reaction mixture can be weak, e.g. are acidified with 0.1 N HCl, after which the organic layer is separated, washed with water and with a NaHC03 solution. The further cleaning steps are carried out in the manner explained above.

The following examples are intended to illustrate the invention, but in no way limit it.

example 1

N-6-Phenylacetamidopenicillinyl-enantholactam a) A suspension of benzylpenicillin potassium (7.4 g; 20 mmol) and pyridine (1.6 g; 20.2 mmol) in methylene chloride (100 ml) was stirred with a temperature of 0 ° C. of a solution of N-chlorocarbonyl-oenantholactam (3.8 g; 20 mmol) in methylene chloride (50 ml) was added and the reaction mixture was stirred for 40 minutes. Water was added with stirring for 5 minutes, the organic layer was then separated off, washed with water and dried (Na2SO4). After evaporation of the solvent, a foam-like product remained, Rf 0.5 (methylene chloride: ether = 4: 1).

Yield: 6.75 g (76%)

For the analysis, the product was recrystallized from the ethyl acetate: ether mixture; a crystalline product, mp. 158-161 ° C, Rf 0.5 (methylene chloride: ether = 4: 1), [a] D23 = + 185.3 ° (0.5; CH2C12) was obtained.

Analysis: C23H29N304S (443.5)

Calculated: C 62.27; H 6.59; N 9.47; S 7.22%

Found: C 62.07; H 6.62; N 9.76; S 6.04%

IR (KBr): 3390 (s), 1777 (s), 1678 (s), 1510 (m), 1375 (s),

1295 (m), 1250 (m), 1205 (s), 1130 (m) and 700 (m) cm "1. 'H NMR (CDClj) 8: 1.43 [s, C (CH3) 2]; 1 , 0-2.2 [m, ~ (CH2) 4-]; 2.35-2.85 [m, CO-CH2]; 3.60 [s, Ph-CH2]; 3.60-4.30 [m, -N-CH2-]; 5.30-5.70 [m, C3-H, C5-H, C6-H]; 6.23 [d, J = 9 Hz, NH] and 7.34 [s, CeHs] ppm.

b) A suspension of benzylpenicillin potassium (7.4 g; 20 mmol) in methylene chloride (100 ml) was mixed with 10 drops of triethylamine with stirring at a temperature of 0 ° C. and then with a solution of N-chlorocarbonyl- oenantholactam (3.8 g; 20 mmol) in methylene chloride (50 ml) was added over the course of 20 minutes. The reaction mixture was at a temperature of 90 minutes

0 C stirred and finally worked up in the manner described under a).

Yield: 5.17 g (58.3%)

Example 2

N-6-Phenylacetamidopenicillinyl-butyrolactam A suspension of benzylpenicillin potassium (7.4 g; 20 mmol) and pyridine (1.6 g; 20 mmol) in methylene chloride (100 ml) was mixed with stirring at a temperature of 0 ° C a solution of N-chlorocarbonyl-pyrrolidin-2-one (2.95 g; 20 mmol) in methylene chloride (50 ml) was added dropwise over the course of 10 minutes. The reaction mixture was then heated to 40 ° C. and stirred for 30 minutes, after which it was continued for 30 minutes without heating

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was stirred. The contents were cooled to + 5 ° C, cold water (+ 5 ° C, 50 ml) was added with stirring for 5 minutes, the organic layer was separated, washed again with water, dried (MgS04), filtered and the solvent became removed by evaporation. A foam-like product remained; Rf 0.35 (methylene chloride: ether = 4: 1).

Yield: 5.36 g (66.8%)

For the analysis, the product was crystallized from the ethyl acetate: ether: n-hexane mixture. The crystalline product had an mp of 152-156 ° C, an Rr of 0.35 (methylene chloride: ether = 4: 1) and an [a] D23 = + 90.9 ° (0.5; CH2C12).

Analysis: C20H23N3O4S (401.4)

Calculated: C 59.83; H 5.77; N 10.47%

Found: C 59.58; H 6.27; N 10.21%

IR (KBr): 3340 (m), 1775 (ns), 1737 (s), 1680 (vs), 1515 (s), 1365 (s), 1310 (s), 1255 (s), 720 (m) and 705 (m) cm-K'H NMR (CDC13) §: 1.37 and 1.40 [2s, C (CH3) 2]; 1.75-2.32 [m, -CH2-]; 2.35-2.85 [m, -CO-CH2-]; 3.63 [s,

Ph-CH2];

3.50-4.00 [m, N-CH2]; 5.35-5.75 [m, C5-H and C6-H]; 5.87 [s, C3-H]; 6.34 [d, J = 9 Hz, NH] and 7.34 [s, C6H5] ppm.

Example 3

N-6-phenylacetamidopenicillinyl-caprolactam A suspension of benzylpenicillin potassium (7.4 g; 20 mmol) and pyridine (1.6 g; 20.2 mmol) in methylene chloride (100 ml) was stirred with a Chlorocarbonyl caprolactam solution (3.7 g; 21 mmol) in methylene chloride (20 ml) was added over the course of 10 minutes. The reaction mixture was stirred for 90 minutes at a temperature of 0 ° C., and cold water (+5 ° C., 50 ml) was then added. It was worked up as in Example la) to isolate the product. A foam-like mass was obtained which was crystallized from an ethyl acetate: ether mixture (1: 1). Mp 157-163 ° C; Rf 0.60 (CH2C12: ether = 4: 1); [a] D23 = + 180.6 ° (0.5; CH2C12) Yield: 6.6 g (77.2%)

IR (KBr): 3345 (m), 1775 (vs), 1678 (vs) cm-1 »H NMR (CDC13) 8: 1.41 and 1.42 [2s, C (CH3) 2]; 1.40-2.0 [m, - (CH2) 3]; 2.5-2.8 [m, -COCH2-]; 3.67 [s, Ph-CH2]; 3.70-4.0 [m, N-CH2]; 5.35-5.67 [m, Cs-H and C6-H]; 5.7 [s, C3-H]; 6.23 [d, J = 8 Hz, NH]; 7.38 [s, C6H5] ppm.

Example 4

N- (N-oxide-6-phenoxyacetamidopenicillinyl) -onantholactam A solution of phenoxymethylpenicillin-N-oxide (6.6 g; 18 mmol) and pyridine (1.6 g; 20.2 mmol) in methylene chloride (100 ml) was added a solution of N-chlorocarbonyl-onantholactam (3.8 g; 20 mmol) in methylene chloride (50 ml) was added with stirring at −20 ° C. The reaction solution was stirred at 0 ° C. for 120 minutes, then cold water (+2 ° C., 50 ml) was added, and the reaction solution was finally worked up in the manner described in Example 1a). There remained a foam-like product with an Rf value of 0.45 (CH2C12: ether = 4: 1); [a] D23 = + 75.3 ° (0.5; CH2C12).

Yield: 6.94 g (81%).

IR (CH2C12): 3370 (s), 1795 (vs), 1685 (vs) cm "1.

'H NMR (CDC13) 8: 1.34 and 1.80 [2s, -C (CH3) 2]; 0.9-2.15 [m, - (CHJ; 2.20-2.60 [m, -CO-CH2-]; 3.0-3.5 [m, -N-CH2-];

4.5 [s, PhCH2]; 4.9 [s, C3H]; 5.07 [d, J = 4 Hz, C5-H]; 6.03 [2d, J = 4.10 Hz, C6-H]; 6.4-7.5 [m, C6H5]; 8.34 [d, J = 10 Hz, NH] ppm.

Example 5

N-6-phenoxyacetamidopenicillinyl-N-phenyl-acetamide

A solution of N-chlorocarbonyl-s acetanilide (9.85 g; 50 mmol) in toluene (100 ml), cooled to 0 ° C., was washed with pyridine (4.0 g; 50 mmol) and then with phenoxymethylpenicillin (17.5 g ; 50 mmol) added. The mixture was stirred for 30 minutes at a temperature of 0 ° C, then 0.1 N hydrochloric acid (50 ml) was added, the organic layer was separated, washed with water and a saturated NaHCO 3 solution and again with water . After drying, the solvent was removed by distillation, after which a foam-like mass remained, which was then digested with n-hexane. A crystalline mass with an mp of 65 to 67 ° C. was obtained.

Yield: 17.45 g (74%).

For analysis, a sample was chromatographed on a silica gel acid and eluted with a methylene chloride: ether-20 mixture (10: 1), after which a product with an mp of 78-80 ° C was obtained; Rf 0.58 (CH2C12: ether = 4: 1); [a] D23 = + 154.3 ° (0.5; CH2C12).

Analysis: C24H25N3OsS (467.5)

Calculated: C 61.66; H 5.40; N 8.99%

25 Found: C 61.42; H 5.13; N 9.17%

IR (CH2C12): 1780 (s), 1700 (vs), 1600 (m), 1510 (s), 1490 (s),

1560 (m), and 1230 (vs) cm-1.

! H NMR (CDC13) 8: 1.66 [s, -C (CH3) 2]; 2.00 [s, CH3CO]; 4.50 [s, -OCH2J; 5.4-5.65 [m, C5-H and C6-H]; 30 5.75 [s, C3-H]; 6.7-7.6 [m, C6H5 and CONH] ppm.

Example 6

6-Phenylacetamidopenicillinyl-N-phenyl-acetamide A suspension of benzylpenicil-35 lin potassium (18.62 g; 50 mmol) and pyridine (4.0 g; 50 mmol) in methylene chloride (100 ml) cooled to 0 ° C was added a solution of N-chlorocarbonyl acetanilide (9.85 g; 50 mmol) in methylene chloride (50 ml) was added and the mixture was stirred at this temperature for 2 hours. The reaction mixture was worked up in the manner described in Example 5 and the product was isolated in the form of a foam-like mass.

The product obtained was dissolved in methylene chloride and chromatographed on a silica gel column. Elution with a methylene chloride: ether mixture 45 (10: 1) gave a crystalline product, mp. 82-85 ° C; Rf 0.50 (CH2C12: ether = 4: 1); [a] D23 = + 185.1 ° (0.5; CH2C12). Yield: 15.8 g (70%)

Analysis: C24H2SN304S (451.5)

Calc .: C 63.38; H 5.59; N 9.30%

50 Found: C 63.52; H 5.82; N 9.57%

IR (CH2C12): 1780 (vs), 1710 (vs), 1690 (vs), 1490 (s), 1370

(m), 1230 (vs) cm-1.

'H NMR (CDCI3) 8: 1.46 and 1.55 [s, -C (CH3) 2]; 2.0 [s, COCH3]; 3.67 [s, CH2]; 5.3-5.65 [m, Cs-H and C6-H]; 55 5.75 [s, C3-H]; 6.23 [d, J = 10 Hz, CONH];

6.95-7.5 [m, C6H5]; 7.33 [s, N-C6H5] ppm.

Example 7 N-6-PhenyIacetamidopenicilIinyl-60 N-propylbenzamide

A suspension of potassium benzicpenicillin potassium (18.62 g; 50 mmol) and pyridine (10 drops) in toluene (200 ml) cooled to 0 ° C was washed with an N-chlorocarbonyl-N-propyl-benzamide solution (11.25 g; 50 mmol) in toluene (50 ml) and stirred for 1 hour at 0 ° C. The reaction mixture was then mixed with water (+5 ° C, 100 ml), the organic layer was separated, washed again with water and after drying (Na2S04) it became

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649 529

Solvent removed by evaporation. The solid residue was recrystallized from a toluene: petroleum ether mixture (1: 1). A crystalline product with an mp of 122-125 ° C. was obtained.

Yield: 16.5 g (69%)

For the analysis, a sample was crystallized from the same solvent and a product with FP. Obtained 128-129 ° C; Rf 0.61 (CH2C12: ether = 4: 1); [a] D23 = + 155.1 ° (0.2; CH2C12).

Analysis: C26H29N304S (479.5)

Calc .: C 65.12; H 6.10; N 8.76%

Found: C 64.97; H 6.35; N 8.92%

IR (KBr): 3340 (m), 2960 (m), 1770 (s), 1670 (vs), 1520 (m),

1565 (s), 1500 (vs), 1210 (vs), 1120 (s) cm "1.

! H NMR (CDC13) 8: 0.78 [t, J = 8 Hz, C-CH3]; 1.15-1.75 [m, C-CH2-C]; 1.43 and 1.60 [s, C2- (CH3) 2]; 3.20-4.20 [m, N-CHJ;

3.65 [s, CH2CO]; 5.13 [s, C3-H]; 5.40-5.70 [m, C5-H and Ce-H]; 6.13 [d, J = 9 Hz, CONH]; 7.32 and 7.58 [s, C6H5] ppm.

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Claims (3)

649 529 2. The method according to claim 1, wherein R is a heterocyclic radical, in particular a 4-thia-l-azabicyclo [3,2,0] heptane radical. 2nd PATENT CLAIMS 1. Process for the preparation of N-acylamides of the general formula 0 o II il r / c \ n / c \ x2 X1 I. O R-C-OY II in which Y is a hydrogen or an alkali metal atom and R has the meaning given above, with an N-chlorocarbonyl-sec-amide or lactam of the formula m io in which Xi and X2 have the meaning given above, and the mixed anhydride of the formula in which R denotes an organic acid residue which is substituted by other functional groups; X! and X2 is in each case an alkyl radical with 1 to 6 carbon atoms, an aryl radical or an alkyl radical with 1 to 5 carbon atoms and a hetero atom from the group N, O or S or X1 and X2 together represent an alkylene group with 3 to 6 carbon atoms, characterized in that that you have a carboxylic acid derivative of the formula 25th in which R, Xx and X2 are defined as above, undergoes rearrangement with C02 elimination. 3. The method according to any one of claims 1 and 2, wherein Y is potassium as the alkali metal atom.