CH649992A5 - METHOD FOR PRODUCING N-CHLOROCARBONYL LACTAMES. - Google Patents

Description

The present invention relates to a new process for the preparation of N-chlorocarbonyl lactams of the general formula I.

(D

in which X is a (CH2) m group, where m is 3, 4, 5 or 6, or one

-CH2-CH-S-C (CH) 2-CH group

1 —N — 1

-: ■ V. . |

COCH3

represents.

Some simpler N-chlorocarbonyllactams of the formula (I) are known compounds and are used in the preparation of ureidopenicillins (DE-OS 2 025 414).

It has now been found that the compounds of the formula (I) can be used generally in the preparation of mixed anhydrides, which are important intermediates for the synthesis of semisynthetic penicillins. Of particular interest is the previously unknown N3-chlorocarbonyl-Ns-acetyl-7,7-dimethyl-6-thia-3,8'-diaza-

bicyclo [3,2, l] octan-2-one, since the N8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one regenerate and convert it again into the corresponding N3 chlorocarbonyl derivative.

5 It is known that some simpler N-chlorocarbonyllactams can be obtained by hydrolysis of the l-aza-2-methoxy-cycloalk-2-en-l-carbonylchloride (DE-OS 1 939 236), which in turn is caused by the reaction of l Aza-2-methoxy-cycloalk-2-enes with carbonyl dichloride in the presence of 10 triethylamines [G. Falkenstein and H. Doer-fel, Makromol. Chem. 1969 (127) 34]. The production of N-chlorocarbonylcaprolactam by the action of CHjLi and then of carbonyl dichloride on caprolactam has also been described (DE-OS 2 025 414). 15 The preparation of simple N-chlorocarbonyl derivatives of sec-amides by the reaction of the corresponding N-trimethylsilyl derivatives of sec-amides with carbonyl dichloride has also been described; in this way N-chlorocarbonyl-N-methylacetamide and N-methylbenzamide 20 were obtained [V. F. Mironov, V. D. Seludiakov, V. P. Koziu-kov, 2ur. Obscei Him. 39 (1969) 220].

It has now been found that complex or non-complex N-chlorocarbonyllactams of the formula (I) are obtained when lactams of the general formula II

(II)

(II)

"-O W

0

in which X has the meaning given above, or their trimethylsilyl derivatives or sodium salts are reacted with carbonyldi-35 chloride.

The reaction is in a suitable inert organic solvent, preferably in methylene chloride or toluene, most advantageously at a temperature of about 0 ° C, optionally in the presence of a tert. organi-40 see base such as triethylamine as an acid binder. The reaction time can be 30 to 120 minutes with stirring.

The trimethylsilyl derivative of lactam (II) is obtained in a conventional manner by silylation using trimethylsilyl chloride 45 in an inert organic solvent, preferably in methylene chloride or toluene, at a temperature in the range from about 20 ° C. to the boiling point of the reaction mixture. The reaction is advantageously carried out in the presence of a tert. organic base such as triethylamine as 50 acid binder executed.

The conversion of the lactam (II) into its sodium salt is also carried out in a conventional manner, preferably by the action of sodium metal on the lactam.

The reagents are advantageously used in stoichiometric amounts of 55, but a small excess of the silylating agent, which is tert. Base or car bonyl dichloride, based on the lactam, use.

The product (I) obtained is isolated and purified from the reaction mixture in a conventional manner, e.g. by adding water to the reaction mixture, immediate separation of the layers, drying of the organic layer and evaporation of the solvent. Alternatively, the precipitated triethylamine hydrochloride is filtered off, the solvent is evaporated from the reaction solution and the residue is purified by distillation or - if the product is a solid product - by washing the solid residue with a suitable solvent.

The invention is illustrated by the following examples

3rd

649992

tert, but by no means restricted. (Unless otherwise noted, "%" means percent by mass.)

Example 1 N-chlorocarbonyl-pyrrolidin-2-one a) Tolrene (100 ml) is mixed with pyrrolidin-2-one (8.5 g, 0.1 mol) and triethylamine (10.1 g, 0.1 mol) , and with stirring and constant nitrogen flow, trimethylchlorosilane (10.86 g, 0.1 mol) is introduced at 25 ° C. The reaction mixture is stirred at 40 ° C. for 30 minutes and then cooled to 0 ° C. The precipitated precipitate of the triethylamine hydrochloride is filtered off with suction and the mother liquor is mixed with a 20% solution of carbonyl dichloride in toluene (52 ml) with stirring at 0 ° C. over a period of 30 minutes. The reaction mixture is stirred for 1 hour and then the solvent is evaporated to an oily residue. The residue is distilled at a mp. Of 112-116 ° C / 0.13 Pa. Yield: 10.5 g (71.2%) of a colorless oil.

Analysis: C5H6N02C1 (147.56)

Calc .: C 40.69 H 4.10 N 9.49 Cl 24.03% Found: C 40.55 H 4.43 N 9.71 Cl 25.20% IR spectrum (film): 1810 (vs ), 1764 (m), 1720 (s), 1350 (m),

1265 (s), 1227 (m), 1170 (s), 1095 (m), 885 (w) cm1 "'H NMR (CDC13) S: 1.78-2.90 (m, CH2CH2CO), 3.65 -4.35 (m, CH2N).

b) A solution of pyrrolidin-2-one (8.5 g, 0.1 mol), triethylamine (10.1 g, 0.1 mol) and methylene chloride (100 ml) is mixed with trimethylchlorosilane (10.86 g, 0 , 1 mol) with stirring at a temperature of 25 ° C. The reaction mixture is stirred for 1 hour at a temperature of 40 ° C., then it is cooled to 0 ° C. and carbonyl dichloride (10 g, 0.11 mol) is entered in the course of 30 to 40 minutes. The reaction mixture is stirred for 1 hour and then water (60 ml) is added with stirring and maintaining the temperature at 0 ° to + 5 ° C. for 5 minutes. The organic layer is deposited, dried and processed as ad a).

Yield: 13 g (88.2%) of an oily product with the same characteristics as ad a)

c) The sodium melt (2.3 g, 0.1 mol) in toluene (120 ml), kept at 110 ° C., is mixed with a solution of pyrrolodin-2-one (8.5 g, 0.1 mol ) in toluene (20 ml) over 30 minutes. The reaction mixture is stirred for 1 hour, then cooled to 0 ° C. and added dropwise

A 20% solution of carbonyl dichloride in toluene (52 ml) was added for 30 minutes. The reaction mixture is stirred for a further hour at 0 ° C., the sodium chloride separated off is filtered off and the mother liquor is concentrated to an oily residue, which is further treated as ad a).

Yield: 9.7 g (66%) of an oily product with the same characteristics as ad a).

d) A solution of pyrrolidin-2-one (8.5 g, 0.1 mol), triethylamine (10.1 g, 0.1 mol) and toluene (80 ml) is cooled to 0CC and with stirring at a temperature from 0 ° C in the course of 30 minutes with a 20% solution of carbonyl dichloride in toluene (52 ml). The reaction mixture is stirred for 1 hour and then the excreted triethylamine hydrochloride is filtered off with suction, while the mother liquor is concentrated to an oily residue.

Yield: 11.8 g (80%) of an oily product with the same characteristics as ad a).

e) A solution of pyrrolidin-2-one (8.5 g, 0.1 mol), triethylamine (10.1 g, 0.1 mol) and methylene chloride (100 ml) is cooled to 0 ° C and for 15 to Carbonyl dichloride (10 g, 0.11 mol) is added for 20 minutes. The 5 reaction mixture is stirred at 0 ° C. for 2 hours and then water (50 ml) is added. The organic layer is separated off, dried and concentrated to an oily residue, which is purified as in a). Yield: 12.3 g (83%) of an oily product with the same characteristics as a).

Example 2 N-chlorocarbonyl-oenantholactam

15 Trimethylchlorosilane (3.2 ml, 25 mmol) is added to a solution of enantholactam (3.17 g, 25 mmol), triethylamine (2.53 g, 25 mmol) and toluene (30 ml) with stirring at 25 ° C and then the reaction mixture is stirred for a further 2 hours at a temperature of 50 ° C. After the solution has cooled to 0 ° C, a 20% solution of carbonyl dichloride in toluene (13 ml) is added over 30 minutes. The reaction mixture is stirred at 0 ° C. for 1 hour and then the triethylamine hydrochloride which has separated out is filtered off with suction. 25 The mother liquor is concentrated to an oily residue. Yield: 4.14 g (87.4%), mp 103-105 ° C / 0.13 Pa (with decomp.).

IR spectrum (CH2C12): 1787 (s), 1715 (vs) cm "1.

30 Example 3

3-chlorocarbonyl-8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one a) A suspension of 8-acetyl-7,7- dimethyl-6-thia-3,8-35 -diazabicyclo [3,2,1] octan-2-one (2.14 g, 10 mmol) in dry

Triethylamine (1.01 g, 10 mmol) and trimethylchlorosilane (1.086 g, 10 mmol) are added to kenem toluene (30 ml). The reaction mixture is stirred for 3 hours at 50 ° C.

then cooled to 0 ° C. and 40 drops of a 20% solution of carbonyl dichloride in toluene (5.2 ml) were added dropwise over the course of 15 minutes and stirring was continued for 3 hours. The crystals of the triethylamine hydrochloride which have separated out are filtered off with suction and the mother liquor is evaporated to a solid residue. The residue is suspended in cold 45 ether (5 ml) and filtered.

Yield: 2.35 g (85%) of the product, mp 105-107 ° C. IR spectrum (CH2C12): 1800 (s), 1730 (s), 1660 (vs), 1400

(s), 1290 (s), 1200 (vs), 1160 (s), 1110 (m) cm "1.

> H NMR (CDCI3) S: 1.46; 1.68 and 1.53; 1.68 [4 S, 2 C-50 (CH3) 2]; 2.22; 2.30 (2 S, COCHs); 3.70-4.30 (m, C4H2), 4.43; 5.08 (2S, QH), 5.70; 6.20 (2 m, CSH).

b) A suspension of 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one (2.14 g, 10 mmol) in dry

55 nem methylene chloride (20 ml) is mixed with triethylamine (1.01 g, 10 mmol) and trimethylchlorosilane (1.08 g, 10 mmol). The reaction mixture is stirred for 1 hour at the boiling point of the solution, then it is cooled to 0 ° C., and a 20% solution w of carbonyl dichloride in toluene (5.2 ml) is added dropwise over the course of 15 minutes. Cold water (20 ml) is added to the reaction mixture, the layers are separated and the organic layer is washed with water (2 × 20 ml). After drying, the solvent is evaporated to a dry residue, to which ether (5 ml) is added, and the crystalline precipitate is filtered off with suction.

Yield: 2.12 g (76.8%) of a product with the same characteristics as ad a).

649992

4th

c) A suspension of 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one (2.14 g, 10 mmol) in dry kenem Triethylamine (1.01 g, 10 mmol) is added to toluene (30 ml) and cooled to 0 ° C. The reaction mixture is mixed with a 20% solution of carbonyl dichloride in toluene (5.5 ml) and stirred for 3 hours at the same temperature. After adding cold water, the organic layer is separated off, washed with water and processed as in a).

Yield: 2.30 (83%) of a product with the same characteristics as ad a).

d) A suspension of 8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one (2.14 g, 10 mmol) in dry kenem Triethylamine (1.01 g, 10 mmol) is added to methylene chloride (20 ml) and the mixture is cooled to 0.degree. A 20% solution of carbonyl dichloride in toluene (5.5 ml) is added dropwise to the reaction mixture in 30 minutes and stirring is continued for 3 hours. After adding water and processing as ad a), a product with the same characteristics as ad a) is obtained.

Yo yield: 2.9 g (79%).

v

Claims (2)

649992 2nd PATENT CLAIMS 1. Process for the preparation of N-chlorocarbonyllactams of the general formula I (I) in which X is a - (CH2) -m group, where m is 3, 4, 5 or 6 or one -CH2-CH-S-C (CH3) 2-CH group ! n— • ^ I. COCH3 represents characterized in that lactams of the general formula (II) X, H-N II 0 in which X has the meaning given above, or their trimethylsilyl derivatives or sodium salts are reacted with carbonyldichloride at a temperature of about 0 ° C. in an inert solvent. 2. The method according to claim 1, characterized in that the reaction optionally in the presence of a tert. organic base is executed.