Process for preparing esters of N-acylated amino acids with acid-labile keto protective group functions

Abstract

The present invention relates to a novel process for the esterification of N-acylated amino acids which contain an acid-labile keto protective group under alkaline conditions without using a polar aprotic solvent, in which the N-acylated amino acid with acid-labile keto protective group prepared in situ is esterified using an alkyl halide or a mono- or dialkyl ester of sulfuric acid.

Claims

1. A process for preparing a compound of formula (I) ##STR00019## wherein R.sup.1 is straight-chain or branched C.sub.1-C.sub.6 alkyl or benzyl, R.sup.2 is straight-chain or branched C.sub.1-C.sub.6 alkyl or phenyl optionally substituted by methyl, ethyl, fluorine, chlorine, methoxy or ethoxy, R.sup.3 and R.sup.4 independently of one another are an OR.sup.5 or SR.sup.5 radical or together are an —O(CHR.sup.6).sub.nO— radical or together are an ═NR.sup.7 radical, wherein R.sup.5 is straight-chain or branched C.sub.1-C.sub.6 alkyl, R.sup.6 is hydrogen, methyl, ethyl or phenyl, n is 2 or 3, R.sup.7 is straight-chain or branched C.sub.1-C.sub.6 alkyl, phenyl, benzyl or 4-methoxybenzyl, comprising reacting a compound of formula (II) ##STR00020## wherein M is sodium, potassium or an NR.sup.8.sub.4 group, wherein R.sup.8 is hydrogen or straight-chain or branched C.sub.1-C.sub.6 alkyl with a compound of formula (III) ##STR00021## wherein Y is fluorine, chlorine or bromine, to give a compound of formula (IV) ##STR00022## in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, and subsequent thereto the compound of formula (IV) is reacted with an alkylating reagent of formula (V) or (VI) ##STR00023## wherein Z is chlorine, bromine or iodine and R.sup.9 is hydrogen, sodium, potassium or the radical R.sup.1, in the presence of a base and a solvent or solvent mixture, which is not polar aprotic.

2. The process according to claim 1, wherein R.sup.1 is methyl, ethyl, n-propyl, n-butyl or benzyl, R.sup.2 is phenyl, optionally substituted by methyl, ethyl, chlorine, methoxy or ethoxy, R.sup.3 and R.sup.4 independently of one another are an OR.sup.5 radical or together are an —O(CHR.sup.6).sub.no— radical or together are an ═NR.sup.7 radical, R.sup.5 is straight-chain C.sub.1-C.sub.6-alkyl, R.sup.6 is hydrogen, methyl, ethyl or phenyl, n is 2 or 3, R.sup.7 is straight-chain or branched C.sub.1-C.sub.6 alkyl, phenyl, benzyl or 4-methoxybenzyl, M is sodium or potassium, Y is fluorine or chlorine, Z is chlorine, bromine or iodine, R.sup.9 is hydrogen, sodium, potassium or the radical R.sup.1.

3. The process according to claim 1, wherein R.sup.1 is methyl, ethyl, n-propyl or n-butyl, R.sup.2 is phenyl, optionally substituted by methyl, ethyl or chlorine, R.sup.3 and R.sup.4 are an OR.sup.5 radical or together are an —O(CH.sub.2).sub.2O— radical, R.sup.5 is methyl, ethyl, n-propyl or n-butyl, M is sodium or potassium, Y is chlorine, Z is bromine or iodine, R.sup.9 is hydrogen, sodium, potassium or the radical R.sup.1.

4. A process for preparing a compound of formula (I-1) ##STR00024## comprising reacting a compound of formula (II-1) ##STR00025## wherein M is sodium or potassium, with a compound of formula (III-1) ##STR00026## to give a compound of formula (IV-1) ##STR00027## wherein M is sodium or potassium, in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, and subsequent thereto the compound of formula (IV-1) is reacted with dimethyl sulfate in the presence of a base and a solvent or solvent mixture, which is not polar aprotic.

Description

EXAMPLES

Example 1

sodium 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate

(1) ##STR00013##

(2) A solution of 47.3 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 150 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 108 ml of water is initially charged in a 600 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The pH of the slightly cloudy solution is 12.9. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 36.5 g [168 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 23 ml of toluene is subsequently metered in within one hour. At the same time, 25.1 g of 32% sodium hydroxide solution [201 mmol NaOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. This gives 220 g of a cloudy yellow solution, which can be used in the next step without further work-up. HPLC analysis (acid) shows a proportion of 75.4% of 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (alongside 24.0% 4-chloro-2,6-dimethylphenylacetic acid and 0.1% toluene).

Example 2

sodium 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate

(3) ##STR00014##

(4) A solution of 18.92 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 60 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 7.5 ml of toluene is subsequently metered in within one hour. At the same time, 23.6 g of 32% sodium hydroxide solution [188 mmol NaOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. A third of the aqueous phase has 9.1 g of 32% sodium hydroxide solution added to it at room temperature, as a result of which a solid precipitates out. This solid is filtered off and dried. This gives 1.8 g of yellowish solid, which, according to .sup.1H NMR analysis, consists of 69.2% of the title compound.

(5) HPLC analysis (acid): 82.6% 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (alongside 14.1% 4-chloro-2,6-dimethylphenylacetic acid).

(6) Ion chromatography: 7.26% sodium (theoretical value: 5.7%)

(7) .sup.1H NMR (600 MHz, D.sub.2O): δ=1.6-1.7 (m; 2H). 1.73-1.8 (m; 2H), 1.9-2 (m; 2H), 2.05-2.13 (m; 2H), 2.3 (s; 6H), 3.7 (s; 2H), 4.03 (s; 4H), 7.12 (s; 2H) ppm.

(8) More solid precipitates from the filtrate. After drying, this gives 3.4 g of solid, which, according to .sup.1H NMR analysis, consists of 67.3% of the title compound.

(9) Both solid fractions add up to a yield of 44% of theory (scaled up to the whole batch).

(10) A second third of the aqueous phase has 9.1 g of 32% sodium hydroxide solution added to it at 50° C., as a result of which a solid precipitates out. Stirring is carried out at 50° C. for 15 minutes, the mixture is allowed to cool to room temperature, and stirring is carried out for a further 30 minutes. The solid is filtered off and dried. This gives 9.1 g of yellowish solid, which, according to quantitative .sup.1H NMR analysis, consists of 67.8% of the title compound, corresponding to a yield of 76.5% of theory (scaled up to the whole batch).

Example 3

Potassium 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate

(11) ##STR00015##

(12) A solution of 18.84 g of potassium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 76.2% (corresponding to 60 mmol; the remainder is essentially potassium carbonate and potassium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 6.5 ml of toluene is subsequently metered in within one hour. At the same time, 22.9 g of 45% potassium hydroxide solution [184 mmol KOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. Half of the aqueous phase has 13.7 g of 45% potassium hydroxide solution added thereto, as a result of which two phases form. The phases are separated and the lower phase (24.7 g) is concentrated under reduced pressure. This gives 15.7 g of yellowish solid, which, according to quantitative NMR analysis, consists of 67.7% of the title compound, corresponding to a yield of 84.4% of theory (scaled up to the whole batch). HPLC analysis (acid): 77.9% 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro [4.5]decane-8-carboxylic acid (alongside 12.4% 4-chloro-2,6-dimethylphenylacetic acid and 9.3% toluene). Ion chromatography: 11.6% potassium (theoretical value: 9.3%).

(13) .sup.1H NMR (600 MHz, D.sub.2O): δ=1.5-1.6 (m; 2H). 1.65-1.7 (m; 2H), 1.8-1.9 (m; 2H), 1.95-2 (m; 2H), 2.22 (s; 6H), 3.67 (s; 2H), 4 (s; 4H), 7.09 (s; 2H) ppm.

Example 4

Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate

(14) ##STR00016##

(15) 310.0 g [0.486 mol] of a 16.6% solution of sodium carbonate in water, 15.4 g of water and 110.4 g [0.371 mol] of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate with a purity of 75.0% (the remainder is essentially sodium carbonate and sodium hydroxide) are initially charged at room temperature into a 1000 ml reaction vessel with overhead stirrer, pH electrode, baffle and metering unit. The pH of the suspension is 13.9. The pH is adjusted to 11.8 at 20° C. by addition of 37.8 g of an 18.8% hydrochloric acid. A solution of 88.8 g [0.409 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 67.6 g of toluene is subsequently metered in within three and a half hours. After the metering in has been completed, stirring is carried out for a further hour at 20° C., 166.1 g of toluene are added thereto, and the reaction mixture is heated to 80° C. At 80° C., 3.1 g [0.007 mol, purity 99%] of methyl tri-n-octylammonium chloride (Aliquat 336) are added thereto and 136.1 g [1.074 mol, purity 99.5%] of dimethyl sulfate are subsequently metered in in two hours. Before cooling to 20° C., the mixture is stirred for a further hour at 80° C. The product that precipitated out during the dimethyl sulfate metering is subsequently filtered off and the filter cake is washed twice with in each case 458 g of water and twice with in each case 176 g of toluene. After drying, this gives 115.6 g [0,285 mol] of methyl-8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate with a purity of 97.6% (HPLC, external standard). This corresponds to a yield of 77%.

Example 5

Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate

(16) ##STR00017##

(17) A solution of 159.5 g [0.600 mol] of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 80.4% (the remainder is essentially sodium carbonate and sodium hydroxide) in 441.8 ml of water is initially charged in a 1000 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The pH of the slightly cloudy solution is 13.3. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 8.2 g of 31% hydrochloric acid. A solution of 130.0 g [0.599 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 113.4 g of toluene is subsequently metered in within two and a half hours. At the same time, 86.9 g [0.695 mol NaOH] of 32% sodium hydroxide solution is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C. and during this the pH is kept at 11.8 by further addition of 32% sodium hydroxide solution. The reaction mixture is heated to 20° C. At 20° C., 24.6 g [0.060 mol, purity 99%] of methyl-tri-n-octylammonium chloride are added thereto, and 153.0 g of dimethyl sulfate [1.201 mol, purity 99.0%] are metered in in one and a half hours. In parallel to the dimethyl sulfate metering, 23.0 g [0.184 mol NaOH] of 32% sodium hydroxide solution is metered in such that the pH remains constant at 11.8. The reaction mixture is stirred for a further hour and a half at 20° C. and during this the pH is kept at 11.8 by further addition of 32% sodium hydroxide solution. In the phase of further stirring, the reaction mixture has 146.1 g of toluene added thereto, in order to be able to better disperse the solid forming. At the end of the further stirring period, the solid is filtered off and successively washed with 300 g of water and three times with in each case 150 g of toluene. After drying the solid, this gives 214.3 g [0.482 mol] of the desired product with a purity of 89.1% (HPLC, external standard). This corresponds to a yield of 80%.

Example 6

11-(4-Chloro-2,6-dimethylphenyl)-12-hydroxy-1,4-dioxa-9-azadispiro[4.2.48.25]tetradec-11-en-10-one

(18) ##STR00018##

(19) 4.9 g [12.37 mmol] of methyl-8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate in 20 ml of anhydrous N,N-dimethylformamide are initially charged and 5.57 g [30.9 mmol] of a 30% solution of NaOMe in methanol are then added thereto. The reaction mixture is heated for three hours at 80° C. and the methanol is distilled off. Stirring is subsequently carried out for a further 16 hours at 110° C. The reaction mixture is stirred in at room temperature to a mixture of 100 ml of water and 25 ml of glacial acetic acid. The precipitated solid is filtered off with suction, washed twice with water and dried. This gives 4.4 g of a light beige solid with a purity of 97.3% according to HPLC analysis. This corresponds to a yield of 95% of theory.