HU199388B - Improved process for producing tert-butyl ester and ether of alpha-amino acids - Google Patents

Abstract

The present invention relates to an improved process for the preparation of tert-butyl esters and / or tert-butyl ether of α-amino acids in the presence of an organic acid in a solvent medium by cooling with isobutylene. According to the present invention, the carboxyl and / or hydroxyl or sulfhydryl groups which are desired to be esterified and / or etherified are protected, and the protected amino and optionally alkyl or aralkyl protected esterification or ethers of the desired carboxylic acid. or the hydroxyl-α-amino acid derivative dissolved in dichloromethane, in the presence of 10 to 20 mole% of trifluoromethanesulfonic acid catalyst at -5 to -35 DEG C. for 1 to 4 hours at atmospheric pressure, and then reacted with isobutene. After completion of the reaction, the reaction mixture is neutralized with a tertiary amine or pyridine at the same temperature and, if desired, the protecting group is cleaved by hydrolysis or hydrolysis in acid or alkaline medium, in a manner known per se, in a tert-butylated α-amino acid derivative, and tert-butylated α obtained. an amino acid derivative, if desired, with an acid or a base It is isolated after conversion to a treatment treatment. H U 199388 A Scope of description: 5 pages -1-

Description

The present invention relates to an improved process for the preparation of t-butyl ester and / or tert-butyl ether of α-amino acids.

It is known that tert-butyl groups are widely used in peptide chemistry to protect the carboxyl and hydroxyl groups. Several reaction types are suitable for the introduction of the tert-butyl group (Synthesis, 1983, 135 and other literature). The most common of these is acid catalyzed esterification and / or etherification with isobutylene. Dioxane or dichloromethane is usually used as the solvent for the reaction. The catalyst used is p-toluenesulfonic acid, perchloric acid or, most commonly, sulfuric acid.

Isobutenization is an equilibrium reaction. Acid catalysis and high isobutene at room temperature under normal conditions [Just. Liebig’s Ann. Chem., 670, 127 (1964)] - only very slowly becomes complete within 3-4 days. The starting amino acids to be protected and their selectively protected derivatives are often only dissolved in the reaction mixture during the reaction, under vigorous stirring. Because isobutene is a gaseous mixture at room temperature (Fp: -6.6 ° C) and forms an explosive mixture with air, isobutene reactions are carried out in a closed vessel under pressure. The reactor material must also withstand corrosive conditions.

These reaction conditions, including the low temperatures required at the start and end of the reaction, require special equipment and safety measures, and the slow utilization of the target equipment also makes the utilization of capacity rather uneconomical.

Long reaction times are associated with several unwanted side effects. For example, in the presence of traces of water, hydrolysis of the ester bond already formed may occur, and metal traces may catalyze the alkylation of the aromatic amino acid ring. It is probably due to these factors that the size of the isobutenation reactions is greatly reduced by increasing the size of the reactions and the final products also require more thorough purification.

There are several methods known in the literature for catalyzing etherification reactions. For example, the etherification of phenols and alcohols with olefins is catalyzed by boron trifluoride etherate, pyridinium p-toluenesulfonate [J.

C.S., 70, 3608. (1948), J. Org. Chem., 42, 3772 (1977)]. Trifluoromethanesulfonic acid was used to isobutenate the substituted phenols at extremely low temperatures (-78 ° C) [J. Org. Chem., 51, 111 (1986)].

However, it is also known [J. Soc., Chem. Comm., 407 (1974)], used in the peptide chemistry to remove trifluoromethanesulfonic acid. At this time, various mercaptans and phenols are added to the reaction mixture to suppress secondary unwanted side reactions to bind the cleavage tert-butyl cations.

Since tert-butylated amino acid derivatives are widely used in peptide synthesis, there is a need for an isobutenization process that is safe and economically feasible under industrial conditions.

Surprisingly, it has been found that the t-butyl esters and / or the space of α-amino acids. its butyl ethers can be prepared safely, in good yield, economically under industrial conditions, by subjecting the free carboxylic and / or hydroxyl or sulfhydryl groups to be esterified and / or etherified, and protected amino and optionally alkyl - or an aralkyl-protected alpha-amino acid derivative containing an unwanted carboxyl or hydroxy group which is not esterified or etherified, dissolved in dichloromethane in the presence of 10 to 20 mol% of trifluoromethanesulfonic acid catalyst at -5 to - 35 ° C isobutene for 1 to 4 hours under pressure and after the reaction, the reaction mixture is neutralized at the same temperature with a tertiary amine or pyridine and optionally hydrolyzed from the isolated tert-butylated α-amino acid derivative in an acidic or basic medium. or by hydrogenolysis, the protecting group is removed and the cap whereupon the tert-butylated α-amino acid derivative is isolated, if desired, after treatment with a salt or acid base.

The present invention can be used to convert any α-amino acid into a tert-butyl ester or ether which has a free carboxyl group or a hydroxyl or sulfhydryl group in the α-amino acid. In the process, it is preferable to use benzyloxycarbonyl or 9-fluorenyloxycarbonyl to protect the amino group. If the α-amino acid to be isobutylated contains, in addition to the carboxyl and / or sulfhydryl group to be esterified and / or etherified, but also the carboxyl and / or hydroxyl group (s) not desired to be esterified and / or etherified, then the (s) must be protected in advance by an alkyl or aralkyl group, otherwise they will react.

Derivatives having a protecting group on each functional group obtained by the reaction of the invention can be removed in a manner known per se. For example, the benzyloxycarbonyl and benzyl groups on the amino group may be removed by catalytic hydrogenation, the alkyl or aralkyl ester groups may be removed by alkaline hydrolysis, and the 9-fluorenylmethyloxycarbonyl group may be removed by treatment with an organic base.

-2HU 199388 A

Non-crystalline products may be purified by conversion to their crystalline salts or characterized by physical constants.

The reaction conditions required for the reaction according to the invention can be easily achieved under industrial conditions, even on an industrial scale. There is no need for a closed, pressure-resistant device, because of the short reaction times (1-4 hours), the corrosive conditions in the reactor are only relatively short, so it can be made of less corrosion-resistant structural material. Also, due to the rapid reaction, side reactions are suppressed. Each batch has a short residence time in the reactor, which allows economical reactor utilization.

Further details of the present invention are illustrated by the following non-limiting examples. Abbreviations used are those commonly used in peptide chemistry, as described in detail in J. Bioi. Chem., 247, 977 (1972). -OMe methoxy, Bu tert -butyl, DCHA dicyclohexylamine salt, EtOH ethanol, MeOH meta, female, DMF dimethylformamide, AcOH acetic acid, Z benzyloxy. carbonyl and ox. means oxalate.

Example 1

Z-Thr / Bu / -OH diciklohexll amine salt

(a) Isobutenization

Z-Thr-OMe (5.3 g, 20 mmol) was dissolved in dichloromethane (40 mL) and cooled to -20 ° C. At this temperature, 30 mL of isobutene (about 280 mmol) was added followed by 0.2 mL (2 mmol) of trifluoromethanesulfonic acid. The reaction mixture was stirred at -20 to -25 ° C for 2 hours. During this time, the reaction is complete according to TLC. [Merck (Kieselgel 60), 49: 1 ethyl acetate / pyridine / acetic acid / water (20: 6: 11 by volume). After chlorination with o-tolidine solution in potassium iodide. Evaluation is carried out under UV light. At this time, 0.5 ml of pyridine is added to the reaction mixture at -25 ° C and the neutral mixture is warmed to room temperature. The isobutene is evaporated and the residue is washed once with 15 ml of water, twice with 10 ml of a 1M aqueous hydrochloric acid solution and twice again with 15 ml of water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The oily residue is Z-Thr / 'Bu / -OMe. R f = 0.9 [in the system given above].

b) Deprotection by alkaline hydrolysis

The Z-THr / 'Bu / -OMet obtained in the previous step was dissolved in 25 mL of dioxane and 22 mL of a 1M aqueous sodium hydroxide solution was added. After stirring at room temperature for 1 hour, ether (25 ml) was added and the reaction mixture was acidified to pH 2 with 6M aqueous hydrochloric acid. The phases are separated. The aqueous phase was extracted with ether (2 x 25 mL). The combined organic layers were extracted three times with 35 mL of 5% aqueous sodium bicarbonate. Ethyl acetate (40 mL) was added to the combined aqueous layers and acidified with 6M aqueous hydrochloric acid. The phases were separated again and the aqueous phase was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The oily Z-Thr / 'Bu / -OH obtained as an evaporation residue was dissolved in 25 ml of ether and converted to the salt by addition of 3.8 ml of dicyclohexylamine. The salt was precipitated from the ether solution with 50 mL of n-hexane, filtered and washed with 20 mL of n-hexane. 8.3 g (82.2% of Z-Thr-OMe) are obtained in the form of the dicyclohexylamine salt of Z-Thr (Bu) -OH. Mp 125-126 ° C. [α] ²⁴ = + 9.72 ° (c = 1, in ethanol).

In the literature [Just. Liebig's. Ann. Chem., 670, 127 (1963)], isobutenation lasts for 3 days. The yield of the dicyclohexylamine salt of Z-Thr / 'Bu / -OH was 69%. Melting point: 126 to 126.6 ° C, [a] p ⁴ = + 8.2 (c = l, dimethylformamide);

[α] D = + 9.93 ° (c = 1, in ethanol).

Example 2

H-Thr / 'Bu / -O'Bu-oxalate Z-Thr-OH mole is isobutenated as described in Example 1 (a) except that 4 mmol of trifluoromethanesulfonic acid is used, and the reaction is carried out at -15 to -20 ° C for 3 hours. Workup of the reaction mixture as described gives the Z-Thr / 'Bu / -O'Bu as an oil. This was dissolved in methanol (60 mL), palladium on charcoal (0.8 g) was added and hydrogen gas was bubbled through the suspension with stirring. After 1.5 hours, the reaction was complete. At this time, the suspension was filtered and 2.52 g (20 mmol) of oxalic acid dihydrate dissolved in 10 ml of methanol were added to the filtrate. The mixture was concentrated in vacuo to a volume of 40 ml. The resulting suspension was filtered and the precipitate was washed with cold methanol (20 mL). The title crude product (5.8 g) was recrystallized from methanol (30 mL). 5.0 g (75%) of the title compound are obtained. M.p. 151-153 ° C. [a] p ⁴ = -12.4 ° (c = l, methanol).

According to the method described in the literature (J.A.C.S., 85, 201 (1963)), H-Thr / 'Bu / -O'Bu was isolated as an oil in 35% yield.

Example 3

Z-Tyr / Bu / -OH dicyclohexylamine salt

a) Isobutenation Weigh 1.8 kg (5.47 mol) of Z-Tyr-OMe per flask into a 20 L round bottom flask and dissolve with 9 L dichloromethane.

The solution was cooled to -35 ° C and 4.8 L (about 55 moles) of isobutene were added at this temperature, followed by the dropwise addition of 108 mL (1.08 moles) of trifluoromethanesulfonic acid. The reaction mixture was stirred for 1 hour at -30 ° C. The reaction was then completed by TLC (Merck Kieselgel 60, 49: 1 chloroform: methanol). Pyridine (200 mL) was added to the reaction mixture at -35 ° C, and the neutralized reaction mixture (12) was combined and warmed to room temperature. The isobutene is evaporated from the reaction mixture, and the residue is extracted once with 80 L of water, once with 60 L of hydrochloric acid, and once again with 50 L of water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Z-Tyr ('Bu) -OMe is obtained as an oily residue.

b) Alkaline hydrolysis

The Z-Tyr ('Bu) -OMet obtained above is dissolved in 45 L of dioxane, the solution is cooled to + 10 ° C and 3.15 kg (78.7 mol) of sodium hydroxide in 60 L of water are added. The reaction mixture was stirred at room temperature for 1 hour and then extracted twice with 60 L of ether. The aqueous phase was treated with 6.3 L hydrochloric acid solution 2.0 -

After acidification to pH 2.5, the oily precipitate was extracted with 45 L of ethyl acetate. The separated aqueous layer was extracted once more with 30 L of ethyl acetate. The combined ethyl acetate layers were washed once with 60 L and once with 20 L of water and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and washed twice with 15 L of ethyl acetate. The ethyl acetate solutions were combined and 12.4 L (62 mol) of dicyclohexylamine were added to the resulting 140 L solution. The precipitated crystalline Z-Tyr ('Bu) -OH · DCHA salt was filtered off after 24 hours, washed with 10 L of ethyl acetate and dried. 29 kg (80% based on Z-Tyr-OMe) of Z-Tyr (Ou) -OH-DCHA are obtained. 156-156.5 ° C. [.alpha.] D @ ²⁰ = + 33.3 DEG (c = 1, EtOH).

In the examples above, the same result is obtained when the pyridine is replaced by triethylamine. In this case, to 1 ml of trifluoromethanesulfonic acid used as catalyst

Calculate 2.1 ml of triethylamine.

Following the previous embodiments, the following tert-butylated derivatives were prepared (mole% of the amount of trifluoromethanesulfonic acid used, the temperature and reaction time of the isobutenation reaction mixture, the yield obtained, the product). melting point and specific rotation): Z-Ser / 'Bu / -OH: 10 mol%; -20 to -25 ° C; 1h; 70%; 84-85 ° C; [α] D ²⁵ = + 21.6 ° (c = 2, EtOH);

Z-Tyr (Bu) -OH: 20%; -25 to -30 ° C; 1h; 76%; 74-75 ° C; [α] D = + 9.6 ° (c = 2, AcOH);

H-Ser / Bu / -O'Bu-HCl; 20 mol%; -15 to -20 ° C; 3h; 86%; 171-173 ° C; [Α] D = -4.9 ° (c = 2, DMF);

H-Val-O'Bu-HCl: 15 ppm; -15 to -20 ° C; 1.5 hours; 85%; 147-149 ° C; _[W = + 20.5 ° (c = 2, EtOH);

H-Asp / O'Bu / -O'Bu-ox: 20 mol%; -10 to -15 ° C; 2h; 82%; 154-157 ° C; [α] D 20 = + 7.2 ° (c = 1, EtOH);

Z-Asp / O'Bu / -OH-DCHA: 20 mol%; -5 to -8 ° C; 1h; 84%; 124-126 ° C;

[α] D ²⁵ = + 5.5 ° (c = 2.9%, AcOH)

Z-Glu / O'Bu / -OH-DCHA: 20 mol%; -5 to -8 ° C; 1h; 87%; 138-140 ° C; [α] ²⁰ D = + 7.1 ° (c = 2, MeOH).

Claims (11)

PATENT CLAIMS 1) Improved process for the preparation of α-amino acids tert-butyl ester and / or tert-butyl ether in the presence of an organic acid in a solvent medium by reaction with isobutene under cooling, characterized in that the desired carboxylic acid is esterified and / or - and / or an a-amino acid derivative containing a hydroxyl or sulfhydryl group and a protected amino or optionally alkyl or aralkyl protected or unsaturated carboxyl or hydroxyl group in dichloromethane, 10-20 mol% of trifluoromethane sulfuric acid in the presence of a catalyst at -5 to -35 ° C for 1 to 4 hours at atmospheric pressure, after which the reaction mixture is neutralized at the same temperature with a tertiary amine or pyridine and optionally isolated with tert-butylated α-amino acid derivative in a manner known per se by hydrolysis or hydrogenolysis in iron or alkaline medium, and isolation of the resulting tert-butylated α-amino acid derivative, if desired, after treatment with an acid or base. 2) The process for the preparation of the Z-Thr / 'Bu / -OH-dicyclohexylamine salt of claim 1, wherein the Z-Thr-OMe is 10 mole% trifluoromethane at -20 to -25 ° C. is reacted with isobutene for 2 hours in the presence of sulfonic acid, the resulting Z-Thr / 'Bu / -OMe is isolated by hydrolysis in basic medium to Z-Thr /' Bu / -OH, and then converted to the salt by reaction with dicyclohexylamine. 3) A process for the preparation of H-Thr / 'Bu / -O-'Bu oxalate according to claim 1, characterized in that Z-Thr-OH at -15 to -20 ° C is 20 mol% of trifluoromethane. reaction with isobutene in the presence of sulfonic acid for 3 hours, after isolation from the resulting Z-Thr / 'Bu / -O'Bu, the Z protecting group is removed by catalytic hydrogenation, 1993H The resulting H-Thr / 'BuZ-O'Bu was converted to a salt by reaction with oxalic acid. 4) A process for the preparation of Z-Ser / 'Bu / -OH according to claim 1, wherein the Z-Ser-OMe is at -20 to -25 ° C in the presence of 10 mole% trifluoromethanesulfonic acid for 1 hour. is reacted with isobutene and the resulting Z-Ser ('Bu / -OMe) is isolated after hydrolysis in basic medium. 5) A process for the preparation of Z-Tyr / 'Bu / -OH according to claim 1, characterized in that Z-Tyr-OMe is present at -25 to -30 ° C in the presence of 20 mol% trifluoromethanesulfonic acid for 1 hour. is reacted with isobutene, and the resulting Z-Tyr ('Bu) -OMe is isolated after hydrolysis in basic medium. 6) The process for the preparation of H-Ser / 'Bu / -O-'Bu hydrochloride according to claim 1, characterized in that Z-Ser-OH at -15 to -20 ° C is 20 mol% of trifluoromethane. in the presence of sulfonic acid with isobutene for 3 hours, after isolation from the resulting Z-Ser / 'Bu / -O'Bu, the Z protecting group is removed by catalytic hydrogenation and finally the resulting H-Ser /' Bu / -O'Bu is reacted with hydrochloric acid to a salt. 7) A process for the preparation of H-Val-O'Bu hydrochloride according to claim 1, wherein Z-Val-OH is present at -15 to -25 ° C in the presence of 15 mole% trifluoromethanesulfonic acid for one and a half hours. reaction with isobutene, separating the resulting Z-Val-O'Bu from the resulting Z-protecting group by catalytic hydrogenation, and finally converting the resulting H-Val-O'Bu to a salt by reaction with hydrochloric acid. 8. A process for the preparation of H-Asp / O'Bu / -O'Bu oxalate according to claim 1, wherein the Z-Asp-OH is at -10 to -15 ° C in 20 mol% of trifluoromethane. Is reacted with isobutene for 2 hours in the presence of 5-sulfonic acid, after isolation from the resulting Z-Asp / O'Bu / -O'Bu, the Z protecting group is removed by catalytic hydrogenation, Finally, the resulting H-Asp / O'Bu / -O'Bu is reacted with oxalic acid to form a salt. 9) The process for the preparation of the Z-Asp / O'Bu / -OH-dicyclohexylamine salt of claim 1, wherein the Z-Asp-OMe is at a temperature of -5 to -8 ° C with 20 mol% of trifluoro reaction with isobutene in the presence of -methanesulfonic acid for 1 hour, the resulting Z-Asp / O * Bu / -OMe is isolated after hydrolysis in basic medium and It is reacted with 20 dicyclohexylamine to form the salt. 10) A process according to claim 1 for the preparation of Z-Glu / O ^< Bu / -OH-dicyclohexylamine salt, characterized in that Z-Glu-OMe At -5 to -8 ° C, isobutene is reacted with isobutene for 1 hour in the presence of 20 mole% trifluoromethanesulfonic acid, and the resulting Z-Glu / O'Bu / -OMe is isolated after hydrolysis in basic medium and treated with di30 cyclohexylamine to form a salt. converted. 11) The process for the preparation of the Z-Tyr / Bu / -OH-dicyclohexylamine salt of claim 1, wherein the Z-Tyr-OMe is at 20 to 35 ° C in 20 mol% of tri35 fluorine. is reacted with isobutene for 1 hour in the presence of methanesulfonic acid, and the resulting Z-Tyr (Bu) -OMe is isolated after hydrolysis in basic medium and converted to the salt by reaction with dicyclohexylamine.