KR20010053805A - A process for producing amino acid or aminoalcohol with t-Butoxycarbonyl group - Google Patents

Abstract

PURPOSE: Provided is a process for producing t-butoxy carbonylated amino acid or amino alcohol by reacting an amino acid or an amino alcohol compound thereof with t-butyl chloroformate in an aqueous organic solvent. CONSTITUTION: The process comprises the steps of: reacting a phosgene with an alkali metal t-butoxide at a temperature of -10 to -25deg.C; removing the excess phosgene by a reduced pressure distillation to obtain the t-butyl chloroformate solution: reacting the t-butyl chloroformate solution with the amino acid or the amino alcohol compound thereof at a temperature of -30 to 10deg.C in an organic solvent or the aqueous organic solvent, wherein the aqueous organic solvent comprises water and the organic solvent in the ratio of 1:9 to 9:1.

Description

Process for producing amino acid or aminoalcohol with t-Butoxycarbonyl group

The present invention relates to a method for protecting an amino acid or aminoalcohol compound thereof with t-butoxycarbonyl (BOC). More specifically, the present invention relates to a method for producing a compound having an amine group protected with BOC in high yield by reacting an amino acid or an aminoalcohol compound thereof with t-butyl chloroformate.

In 1957, several teams developed a BOC protector that could be used instead of the Carbovenian period. For example, Capino introduced the BOC group as a general amino protecting group (Carpino, L.A. J. Am. Chem. Soc. 1957, 79, 98). McKay et al. Suggested the use of BOCs to protect amino acids in peptide synthesis (MacKay, et al., J. Am. Chem. Soc. 1957, 79, 4686 and J. Am. Chem. Soc. 1957, 79, 6180). The BOC group is more easily removed than the carbobenzone group under weakly acidic conditions, and the carbobenzone group is removed by catalytic hydrogenation, whereas the BOC group is not removed but is very stable. Many BOC agents have been developed so far and include, for example, t-butyl chloroformate, di-t-butyl dicarbonate, t-butyloxycarbonyl imidazole, t-butyloxy carbonyloxysuccinimide and the like.

Among these BOC agents, t-butyl chloroformate has been known to decompose at a temperature of 10 ° C. and hydrolyze so easily that it is very unstable in moisture, temperature and the like, and thus it has been considered impossible to use industrially.

Choppin and the like reacted with sodium butoxide and phosgene at -60 ° C to produce t-butyl chloroformate, which was then separated in a yield of about 20%, and the separated t-butyl chloroformate was separated from an amine compound and an organic solvent. A method for preparing a BOCylated amine compound by reacting in water has been proposed (AR Choppin and JW Rogers, J. Am. Chem. Soc. 1948, 70, 2967). Therefore, the method of choppin has the disadvantage that the yield is extremely low in obtaining the BOCylated amine and is very difficult to control the reaction conditions.

Since t-butyl chloroformate is inexpensive compared to other conventional BOC agents, it may be used commercially very advantageously if the above disadvantages are solved. The inventors of the present invention using React IR Spectroscopy unexpectedly found that t-butyl chloroformate remained relatively stable at low temperatures and reacted in aqueous conditions.

Meanwhile, t-butyl chloroformate is generally diluted with phosgene in a solvent, cooled to low temperature, and reacted by slowly adding alkali metal t-butoxide, followed by filtration to remove inorganic substances and distillation under reduced pressure. The solvent is removed and then purified to prepare. However, in the process of purely separating and purifying t-butyl chloroformate, a lot of losses occur, which causes a problem that overall yield decreases in preparing the BOCylated amine compound. The inventors of the present invention have been remarkably increased by directly reacting with an amino acid or an aminoalcohol compound thereof after removing the excess phosgene by distillation under reduced pressure after terminating the reaction without purely separating t-butyl chloroformate. A high yield of BOCylated amino acids or aminoalcohol compounds could be prepared.

The present invention provides a method for preparing t-butoxycarbonylated amino acids, characterized in that an amino acid or aminoalcohol thereof and t-butyl chloroformate are reacted in an aqueous organic solvent. This reaction can be carried out at a temperature of -30 ° C to 10 ° C.

Examples of amino acids used in the present invention include glycine, phenylglycine, alanine, phenylalanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, arginine, aspartic acid, glutamic acid, hydroxyglutamic acid, proline , Hydroxyproline, tyrosine, tryptophan and histidine. Amino acids according to the present invention include both L and D forms.

Examples of the organic solvent mixed with water in the aqueous organic solvent used for the reaction of the amino acid or amino alcohol compound according to the present invention with t-butyl chloroformate include aliphatic hydrocarbons such as normal hexane, pentane, butane, heptane, tetrahydrofuran And aliphatic ethers such as diethyl ether, dibutyl ether and dimethoxy ethane, aromatic hydrocarbons such as benzene and toluene. In general, the mixing ratio of these organic solvents with water is higher in yield as the ratio of organic solvent to water increases, but it is preferable to use the ratio of 1: 9 to 9: 1 in consideration of the cost of the organic solvent.

The present invention also reacts phosgene with alkali metal t-butoxide, and removes excess phosgene under reduced pressure from the reaction solution to obtain a t-butyl chloroformate solution. The t-butyl chloroformate solution is used as an amino acid. Or it provides a method for producing t-butoxycarbonylated amino acid or aminoalcohol characterized in that the reaction of the aminoalcohol with a temperature of -30 ℃ to 10 ℃.

Phosgene is dissolved in the cooled organic solvent before reacting with the alkali metal t-butoxide. The organic solvent used at this time is, for example, aliphatic hydrocarbons such as normal hexane, pentane, butane, heptane, aliphatic ethers such as tetrahydrofuran, diethyl ether, dibutyl ether, dimethoxy ethane, aromatic hydrocarbons such as benzene, toluene, etc. This includes. Alkali metal t-butoxide used in the reaction with phosgene includes sodium t-butoxide, potassium t-butoxide, lithium t-butoxide and the like. The reaction of the phosgene with the alkali metal t-butoxide may generally proceed at −10 ° C. or lower, preferably at −20 ° C. to −25 ° C. The phosgene is generally used in the amount of 1 to 10 equivalents, preferably 1.5 to 2.5 equivalents.

In a reactor different from the one in which the t-butyl chloroformate solution was prepared, the amino acid or its aminoalcohol was dissolved in the same or different solvent as the solvent used to prepare the t-butyl chloroformate solution, and the reaction mixture was kept at 0 ° C or lower. Cool. 1 to 3 equivalents of base is added and stirred. To this reaction mixture is slowly added the t-butyl chloroformate prepared earlier. After stirring for 3 hours at a reaction temperature of 0 to 10 ℃, water is added to dissolve all the inorganic material and separated from the organic layer. The separated organic layer may be distilled under reduced pressure to remove the organic solvent to obtain t-butylcarbonylated amino acid or aminoalcohol.

Bases that can be used when reacting the t-butyl chloroformate solution with amino acids or aminoalcohols thereof are any of inorganic bases (eg, NaOH, KOH, Na ₂ CO ₃ ) or organic bases (eg, TEA). However, the reaction of t-butyl chloroformate solution with amino acids or aminoalcohols can be achieved without base.

The invention will be specifically illustrated by the following examples. However, these embodiments are intended to be described in more detail to enable those skilled in the art to easily practice the present invention, and should not be understood as limiting the scope of the present invention.

Example 1

Preparation of t-butyl chloroformate

After putting 200 ml of normal hexane into a 500 ml four-necked reaction vessel, the reactor internal temperature was cooled to -20 ° C. 30 g (1.5 equiv) of phosgene was added quickly and 20 g of sodium t-butoxide was added slowly over 1 hour. Then the reaction was stirred at -25 ° C to -20 ° C for about 1 hour. Excess phosgene was removed by distillation under reduced pressure to give a t-butyl chloroformate solution as a white slurry. This solution was used as it is for reaction with amine which is the next reaction.

Example 2

Preparation of t-butyl chloroformate

Tetrabutylfuran was used as the organic solvent and the same process as in Example 1 was carried out to obtain t-butyl chloroformate.

Example 3

Preparation of t-butyl chloroformate

Toluene was used as the organic solvent and the same process as in Example 1 was carried out to obtain t-butyl chloroformate.

Example 4

Preparation of t-butyl chloroformate

Dimethoxyethane was used as an organic solvent and the same process as in Example 1 was carried out to obtain t-butyl chloroformate.

Example 5

Preparation of t-butyl carbamate

50 ml of a 25% aqueous ammonia solution was added to a 500 ml four-neck reaction vessel, and the temperature inside the reactor was cooled to 0 ° C. T-butyl chloroformate obtained in Example 1 was slowly added. After completion of the addition, the mixture was stirred for about 1 hour, and the organic solution layer and the aqueous solution layer were separated. The separated organic solution layer was distilled under reduced pressure to remove the organic solvent, thereby obtaining t-butyl carbamate as a white solid in a yield of 50%. Melting point: 106 ° C to 108 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45 (9H, s, t-butyl) 4.70 (2H, s, -NH ₂ ), IR (nujol) 3445, 3330, 3259, 3202, 3012, 2954, 1681, 1607, 1461, 1448 1392, 1379 cm ^-1

Example 6

Preparation of t-butyl N-phenyl carbamate

100 ml of tetrahydrofuran and 2 equivalents (38.7 g) were added to a 500 ml four-neck reaction vessel, and the reactor internal temperature was cooled to 0 ° C. The t-butyl chloroformate obtained in Example 2 was slowly charged into the reaction mixture. After the addition was completed, the mixture was stirred for about 1 hour, and 100 ml of water was added thereto, followed by stirring. The reaction solution was separated and the organic solution layer was distilled under reduced pressure to remove the organic solvent to give a pale yellow solid. This solid was recrystallized to obtain pure t-butyl N-phenyl carbamate in 80% yield. Melting point: 136 ℃

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45 (9H, s, t-butyl), 6.946 (1H, t, aromatic), 7.267 (2H, q, aromatic), 7.46 (m, 2H, aromatic ), IR (nujol) 3313, 2929, 2858, 2596, 2013, 1690, 1649, 1460 cm ^-1

Example 7

Preparation of 2-cyano-1- (N-t-butoxycarbonyl) ethylaminoacetic acid ethyl ester

100 ml of toluene and 0.5 equivalent (16.5 g) of (2-cyanoethylamino) acetic acid were added to a 500 ml four-neck reaction vessel, and the temperature inside the reactor was cooled to 0 ° C. The t-butyl chloroformate obtained in Example 3 was slowly added to the reaction mixture. After the addition was completed, the mixture was stirred for about 4 hours. It was confirmed that the reaction was completed by thin layer chromatography, and 100 ml of water was added to the reaction solution, followed by layer separation. The separated organic solvent layer was distilled under reduced pressure to remove toluene to give the title compound as a yellow oil in 80% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.5 (9H, s, t-butyl), 4.2 (2H, q), 3.48 (2H, s), 2.96 (2H, t), 2.54 (2H, t), 1.3 (3H, t) IR (neat) 2975, 2939, 2248, 1741, 1695, 1497, 1395, 1370 cm ^-1

Example 8

Preparation of 4- (N-t-butoxycarbonyl) aminomethylene-1- (N-t-butoxycarbonyl) pyrrolidin-3-one

0.7 equivalent (25 g) of 4-aminomethylene-1- (N-t-butoxycarbonyl) pyrrolidin-3-one was added to a 500 ml four-necked reaction vessel, which was dissolved in 100 ml of dimethoxyethane and 35 ml of water. The reactor internal temperature was cooled to 0 ° C. and 1 equivalent of potassium hydroxide (13.7 g) was added. The t-butyl chloroformate obtained in Example 4 was slowly added to the reaction mixture. After the addition was completed, the mixture was stirred for about 30 minutes, and the reaction was confirmed by using HPLC, and 130 ml of 10% hydrochloric acid was added. The layers were separated and the organic solution layer was put back into the reaction vessel and crystallized with IPA and water to obtain the pure title compound in a yield of 60%. Melting Point: 158 ° C to 162 ° C

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.5 (18H, s, t-butyl), 4.24 (1H, s, = CH-N), 4.30 (2H, s, -CH _2- ), 4.32 (2H, s, -CH _2- ), IR (nujol) 3252, 3175, 2914, 1731, 1720, 1697,1608 cm ^-1

Example 9

Preparation of t-butyl carbazate

11.3 ml (1 equivalent) of 80% hydrazine was added to a four-neck 500 ml reactor, and 100 ml of THF was added thereto. The reactor internal temperature was cooled to 0 ° C., and t-butyl chloroformate synthesized in Example 2 was slowly added thereto. After the addition was completed, the mixture was stirred for about 3 hours. After the reaction was completed, 100 ml of water was added and the layers were separated to obtain an organic solvent layer. The organic solution layer was distilled under reduced pressure to remove the organic solvent to give a yellow oil. This oil was crystallized from normal hexane to give the pure title compound in 70% yield. Melting Point: 38 ℃ to 40 ℃

¹ H NMR (300MHz, CDCl ₃ ) 1.5 (9H, s, t-butyl) δ IR (nujol) 3371, 3327, 3217, 3014, 2934, 1692, 1617, 1608 cm ^-1

Example 10

Preparation of N- (t-butoxycarbonyl) -L-alanine

15 g (0.168 mole) of L-alanine was added to a 500 ml four-necked reactor, and 100 ml of water and 100 ml of organic solvent were added thereto. The temperature inside the reactor was cooled to 0 ° C. and 13.5 g (2 equivalents) of caustic soda was added. T-butoxy chloroformate synthesized in Example 1 was slowly added. The reaction solution was stirred for 4 hours and the layers were separated. The aqueous layer was placed back into the reactor and the pH was adjusted to 1-2 with 35% hydrochloric acid. 200 ml of ethyl acetate was added to the reaction mixture and extracted. The reaction solution was separated and the organic solvent was dried over magnesium sulfate and distilled under reduced pressure to remove the organic solvent to obtain a yellow oil. The oil was crystallized by adding normal hexane to give the title compound in 70% yield. Melting point: 80-82 ° C

¹ H NMR (300MHz, CDCl ₃ ) δ 1.42 (3H, s, methyl), 1.5 (9H, s, t-butyl) IR (nujol) 3380, 1736.5, 1690, 1525 cm ^-1

Example 11

Preparation of N- (t-butoxycarbonyl) -L-phenylalanine

Into a 500 ml four-necked reactor, 28 g (0.168 mole) of L-phenylalanine was added, followed by 100 ml of water and 100 ml of an organic solvent. The temperature inside the reactor was cooled to 0 ° C. and 13.5 g (2 equivalents) of caustic soda was added. T-butoxy chloroformate synthesized in Example 1 was slowly added. The reaction solution was stirred for 4 hours and the layers were separated. The aqueous layer was placed back into the reactor and the pH was adjusted to 1-2 with 35% hydrochloric acid. 200 ml of ethyl acetate was added to the reaction mixture and extracted. The reaction solution was separated and the organic solvent was dried over magnesium sulfate and distilled under reduced pressure to remove the organic solvent to obtain a yellow oil. The oil was crystallized by adding normal hexane to give the pure title compound in 80% yield. Melting point: 86-88 ° C

¹ H NMR (300MHz, CDCl ₃ ) δ1.281 (s, t-butyl), 1417 (s, t-butyl), 2.908, 3.083, 3.19, 4.398, 4.622, 4.99, 6.59, 7.29 to 7.19, 11.2 IR (nujol) 3315, 3101, 3091, 1712, 1649, 1606 cm ^-1

Example 12

Preparation of N- (t-butoxycarbonyl) -imidazole

11.5 g (0.168 mole) of imidazole was added to a 500 ml reactor, and 100 ml of tetrahydrofuran was added thereto. 17 g (0.168 mole) of triethylamine were added. The reactor internal temperature was cooled to 0 ° C. and t-butyl chloroformate synthesized in Example 2 was slowly added. The reaction mixture was stirred for 4 hours and filtered after the reaction was complete. The organic solvent was removed by distillation under reduced pressure and crystallized with normal hexane to obtain the pure title compound in 80% yield. Melting point: 147-150 ° C.

The method of the present invention is commercially advantageous because it uses a low-cost t-butyl chloroformate to BOC the amino acid or aminoalcohol thereof and provides a high yield of the BOCylated amino acid or aminoalcohol while easily controlling the reaction conditions. .

Claims (9)

A method of preparing a t-butoxycarbonylated amino acid or aminoalcohol compound, characterized by reacting an amino acid or an aminoalcohol compound thereof with t-butyl chloroformate in an aqueous organic solvent. The process of claim 1 wherein the mixing ratio of water and organic solvent in an aqueous organic solvent is from 1: 9 to 9: 1. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of -30 ° C to 10 ° C. The phosgene is reacted with an alkali metal t-butoxide, and excess phosgene is removed by distillation under reduced pressure from the reaction solution to obtain a t-butyl chloroformate solution, and the t-butyl chloroformate solution is used as an amino acid or an aminoalcohol compound thereof. Reacting with to produce a t-butoxycarbonylated amino acid or aminoalcohol compound. The method of claim 4, wherein the reaction of the phosgene with the alkali metal t-butoxide is carried out at -10 ° C to -25 ° C. A process according to claim 4 or 5, characterized in that the reaction of t-butyl chloroformate with an amino acid or aminoalcohol compound is carried out in an aqueous organic solvent. 7. The process of claim 6, wherein the reaction is carried out at a temperature of -30 ° C to 10 ° C. The method of claim 6, wherein the mixing ratio of water and organic solvent in the aqueous organic solvent is 1: 9 to 9: 1. The method of claim 6, wherein the reaction is carried out in the presence of a base.