DE2531144A1 - DIALKYLAMINO ALKYLESTERS OF PENICILLIN AND THE PROCESS FOR THE PREPARATION - Google Patents

Description

Dialkylaminoalkyl esters from Penicillin and. Procedure to

their manufacture

The invention relates to dialkylaminoalkyl esters of penicillin which are useful in the treatment of mastitis. To make them becomes a penicillin alkali salt in a v / aeser-free Medium reacted with an alkyl ester of chloroformic acid and then the resulting mixed anhydride with decomposes a Ν, Ν-disubstituted amino alcohol.

The invention relates to dialkylaminoalkyl esters of penicillin of the formula

- (CH ₀ ) -C

2'n

2 -

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1A-46 7S5

in which R is a hydrogen, a lower alkyl, hydroxy or alkoxy, such as a methoxy or Ätboxygruppe, R ^{1 is} an alkyl group, n "= 0 or 1 and r is an integer from 1 to 10.

These compounds represent an interesting group of Substances used to treat mastitis (inflammation of the breasts).

The invention also relates to a process for the preparation of the compounds indicated above which is characterized thereby is that a penicillin alkali salt in an anhydrous medium with an alkyl ester of chloroformic acid converts and then cleaves the resulting mixed anhydride with a Ν, Ν-disubstituted amino alcohol. The preferred reaction medium is a ketone and the preferred alkyl ester of chloramic acid is the ethyl ester.

These compounds are made by adding a potassium salt of the corresponding penicillin with ethyl chloroformate

and an amino alcohol according to the following general equation. The reaction can be called a two-step Reaction to be viewed:

a) Implementation of a penicillin alkali salt with ethyl chloroformate forming an unstable mixed anhydride:

60988S / 1254

1A-46 7 «5

2531H4

- (CH ₂ ),

.JL

CH-CH

Il ο

(H = alkali)

b) decomposition of the mixed anhydride formed as above with an amino alcohol with the formation of unstable formic acid and the desired product:

CH-

+ HO (CH ₂ ) -N

HQ

9885/1254

.If.

1-46 7-5

Another reaction is the immediate decomposition of the hypothetical chloroformic acid due to the presence of the compound C ₉ H formed in step a)

₄ O ₂ H ₅ OM * ClMJ + O ₂ H ₅ OH + COj

The invention is explained in more detail by the following non-limiting examples:

example 1

Eenzyl-penicillin-diisopropylamino-ethyl ester (R = H; R ¹ = CH ₃ -CH-CH ₃ ; η = 1, r = 2) 37.2 g of potassium penicillin G (potassium benzyl penicillin) were taken under moderate stirring in 125 ml of anhydrous acetone in a 250 ml Erlenmeyer flask equipped with a thermometer, filler neck for liquids, a gas outlet protected from atmospheric humidity, a magnetic stirrer and external cooling,

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"* ~ ·« · 2531U4

suspended. The suspension was cooled to 0 ° C. and a precooled mixture of 13 ml of ethyl chloroformate and 25 ml of anhydrous acetone was added. A mixture of 14.5 g of diisopropylaminoethanol and 25 ml of anhydrous acetone was then added along the length of the line, the temperature being prevented from rising above 5 ° C. After adding the amino alcohol, the mixture was stirred for 20 minutes, taking care that the temperature did not rise above 5 ° C. The mixture was then removed from the cooling bath and the temperature was increased to room temperature and the alkali halide formed was filtered off and the remaining clear liquid under reduced pressure to? evaporated to a syrupy residue. This residue was redissolved in a mixture of 30 ml of cold distilled water, 60 g of crushed ice and 4 ml of 85% phosphoric acid. A precipitate was precipitated from the solution while cooling with the aid of a cold aqueous solution of potassium iodide, and the resulting slurry was washed thoroughly with very cold distilled water and redissolved in 50 ml of chloroform. The chloroform solution was washed several times with a saturated sodium chloride solution and then with a 25% aqueous solution of sodium carbonate until the petroleum fluids were alkaline, and finally washed with saturated sodium chloride solution and water. The chloroform solution was filtered through cotton in a separating funnel, the aqueous phase was separated from the organic phase and this was dried for a few minutes with anhydrous sodium sulfate, then filtered and the clear liquid was evaporated under high vacuum to a syrupy residue of completely constant weight. During the subsequent cooling, flakes were formed; Mp 55 to 60 ⁰ C, ^ i J ¹ = 1.530.

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Analyce: _{c H} MO. S.

Calculated for C ₂ ^ II ₇₁₅ N ₃ O ₄ S: 62.45 7.64 9.10 13, f6 6.95

Found: 62.50 7, i'1 9.35 13.58 6.76

(Difference)

IR spectrum in KBr tablets: 3265, 3065,? 9ü5, 1797, 1729,

1663, 1550 cm " ¹ (main bands)

MMR spectrum in CC1 _Z , (at 60 MHz): i £ / doublet, integral of 12 (AIkVl-CTi ₃ ) J, 1.49 // binglet, integral of 6 (geminal CH ₃ on the thiazolidine ring) J, 2.55-3.1 ξ / multiplet, integral of 4 (CII and CH _? N) _7, 3.52 ^ / singlet, integral of 2 (CHp, aromatic) J, 4.04 if / triplet, integral of 2 (CH ₂ bound to. Carboxyl) J, 4.34 ^ "/ pinglet, integral of 1 (proton at C ⁵ in the thiazolidine ring)" /, 5.43 S / singlet, integral of 2 (protons at C and C 'in the lactam ring) ~ / un | 7.25 ^ / ^ ingu3.ett, integral of 5 (aromatic) J ~ /. ^

The product is soluble in common organic solvents, insoluble in water and ligroin.

Example 2

Methicillin diethylamino ethyl ester

(R = -OCH ₃ , in 2- and 6-position; R ¹ = -CH ₉ -CH ₃ , η = 0; r = 2)

12.6 g methicillin natriura monohydrate (2,6-dimethoxyphenylpenicillin) were added to 45 ml anhydrous in a 100 ml Erlenmeyer flask equipped as above with moderate stirring Acetone suspended. The suspension was cooled to 0 C and a pre-cooled mixture of 2.85 ml of ethyl chloroformate and 8 ml of anhydrous acetone were added. Subsequently was

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_ · 1Λ-46 7H-5

* * 2531H4

a mixture of 4.1 ml of diethylaminoethanol and 8 ml of anhydrous acetone was slowly added so that the temperature did not rise above 5 ° C. After addition of the amino alcohols, the mixture was stirred for 20 minutes, again taking care that the temperature did not rise above 5 ° C. The Genisch was then removed from the cooling bath and the temperature increased to room temperature and. the resulting alkali halide is filtered off and the remaining clear liquid is evaporated under reduced pressure to a syrupy residue. This residue was redissolved in chloroform, the solution was washed a few times with saturated aqueous sodium chloride solution and then with a 2% aqueous solution of sodium carbonate until the ash liquid was alkaline and finally washed again with a saturated sodium chloride solution and water. The chloroform solution is filtered through our wool into a separating funnel and the aqueous phase is separated from the organic phase and this is dried for a few minutes with anhydrous sodium sulfate, filtered off and the clear liquid is evaporated under high vacuum until a semi-solid redispersible This back ^c and was treated with excess anhydrous zither, leaving some insoluble impurities which were filtered off. The transparent solution was then concentrated in vacuo and cooled. A solid crystallized out; mp = 96 to ^v 3 ? ° C.

Analysis:

CHN ο S Calculated for C ₂₃ H ₃₃ N ₃ O ₆ S: 57.60 6.94 8.76 20.01 6.69?!

Found: 58.13 6.97 0.94 19.40 6.56 *

(Difference)

IR spectrum (in CCl ₄ ): 3450, 2935, 2833, 1003, 1760, 1695,

1603, 1500 cm " ¹ (main bands).

5/1254

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- * · 2531H4

NMR spectrum with CCl ₄ (at 60 MIJz): 0.9Ö 6 '/ triplet, integral of 6 (alkyl CH ₃ ) J ₁ 1.540 / doublet, integral of 6 (geminal CH ₃ on the thiazolidine ring) J, 2.38 - P., 77 <f / flultiplet, integral of 6 (CH ₂ -N) J ₁ 3.76 ^ / singlet, integral of 6 (CH ₅ -O) J, 4.14 <J * / triplet , Integral of 2 (CII ₂ bound to carboxyl) _ /, 4.25J ¹ / J singlet, integral of 1 (proton on C in the thiazolidine ring) ~ /, 5.5-5, - 5 "f / multiplet , Integral of 2 (protons at C and C 'in the lactam ring) J ₁ 6.25 (ί / ["triplet, integral of 3 (aromatic) _7 and 7.2 ^ /" integral of 1 (amide proton) _7 .

The product was soluble in alcohol, acetone and chloroform, slightly soluble in ether and insoluble in water and ligroin.

Patent claims :

509885/1254

Claims (4)

P a t e η t a η s ρ r ü c h e ι
jy. Dialkyl arainoalkyl esters of penicillin of the general formula :-( CH ₂ ) _n -C .0- (CH ₂ ) _r -N in which R is a hydrogen atom, a lower alkyl, Ilydroxy or alkoxy, preferably I-ethoxy or ethoxy group, R ^! is an alkyl group, η = O or 1 and r is an integer from 1 to 10. 2. Process for the preparation of the compounds according to claim 1, characterized in that an Al! £ ali salt of a penicillin is used in an anhydrous medium reacts with an alkyl ester of chloroformic acid and the resulting mixed anhydride with an N, N-disubstituted Amino alcohol decomposes. 3. The method according to claim 2, characterized in that g e k e η η - draws works. that one is in a ketone as the reaction medium 509885/1254 1-46 785 4. The method according to any one of claims 2 or 3, characterized It is indicated that the ethyl ester is used as the alkyl ester of chloroformic acid. SO9885 / 1254