HU190534B - Improved process for preparing l-beta-phenyl-alanine and acid addition salts tereof - Google Patents

Abstract

L-beta-phenyl-alanine is prepd. by salt formation in aq. soln. from 1 mole equiv. N-acetyl-DL-beta-phenyl -alanine with 0.5-0.65 mole equivs. D-(+)-threo-2-amino -3-(4'-nitrophenyl) -propane-1,3-diol in the presence of 0.45-0.55 mole equivs. inorganic base, separating the resulting salt, liberating the N-acetyl-L-beta-phenyl -alanine by treatment with mineral acid and desacetylating it, opt. separating the resulting L-beta-phenyl-alanine in the form of its acid addition salt and opt. liberating the amino-acid from its acid addition salt. - The N-acetyl-D-beta -phenyl-alanine remaining in the mother liquor is opt. racemised, pref. without sepn., by treatment with acetic anhydride in the presence of alkali-metal-hydroxide, the resulting N-acetyl-DL-beta phenyl-alanine is returned to the process. Finally the mother liquor remaining after liberation of N-acetyl-L-beta -phenyl-alanine is opt. made alkaline to regenerate D-(+)-threo-2-amino-3-(4' nitrophenyl) propane-1,3-diol which is returned to the process.

Description

The invention relates to an improved process starting from _t lbeta-phenylalanine and acid addition salts thereof, N-acetyl-DL-feail -beta-alanine in an aqueous medium D (+) - threo-2-amino-3- (4'-nitrophenyl ) -propane-1,3-diol 'salt formation, pz N-acetyl-Lbeta-phenylalanine D - (+) - threo-2-amino-3- (4-nitrophenyl) -propane-1,3 isolating its salt with a diol by liberating and deacetylating N-acetyl L-beta-phenylalanine by mineral acid treatment, optionally converting the resulting L-beta-phenylalanine into an acid addition salt or liberating it from its acid addition salt.

The L-beta-phenylalanine intermediate is useful in the synthesis of therapeutic agents as well as in peptide chemistry.

Most of the known processes for preparing Lbeta-phenylalanine are resolved by DL-beta-phenylalanine having a protected amino group and then deprotected to give Lbeta-phenylalanine [e.g.

J. Am. Chem. Soc., 86, 2067 (1960)].

J. Pract. Chemie, 9, 104-106 (1959), Chem. Abstr., 54, 6565e (1960)], N-acetyl-DL-beta-phenylalanine, equimolar amounts of D- (♦) -threo-2-amino-3- (4-nitrophenyl) -propane-1,3- diol in aqueous medium. The aqueous solution precipitates the salt of ₍ N-acetyl-Lbeta-phenylalanine) with D - (+) - threo-2-amino-3- (4-nitrophenyl) -poran-1,3-diol, which is isolated, N-acetyl-Lbeta-phenylalanine is liberated by treatment with hydrochloric acid and then deacetylated with hydrochloric acid. The optical purity of the acetyl compound is unsatisfactory, as shown by the fact that only about 65% yield of deacetylation affords L-beta-phenylalanine which is still of acceptable quality on the basis of optical purity. the total yield of alanine is only 53-54%, and the regeneration of the resolving agent and utilization of the by-product N-acetyl-Lbeta-phenylalanine is unsolved.

It is an object of the present invention to overcome the disadvantages of the above known process and to provide an economical process for the preparation of optically pure Lbeta-phenylalanine.

It has been found that the above object is achieved by using D - (+) - threo-2-amino-3- (4-nitrophenyl) -propane-1, N-acetyl-DL-beta-phenylalanine for salt formation. 3-Diol is used in an amount of 0.5-0.65 molar equivalents and salt formation is carried out in the presence of 0.45-0.55 molar equivalent of inorganic base relative to N-acetyl-DLbeta-phenylalanine. In this way, not only is total production increased by about 30%, but it is also possible to regenerate the resolving agent used and convert the residual N-acetyl-D-beta-phenylalanine into the corresponding racemic compound, which can be traced back to the resolution.

According to the present invention, L-beta-phenylalanine and its acid addition salts are prepared starting from N-acetyl-DL-beta-phenylalanine in aqueous medium with N-acetyl-L-beta-phenylalanine D - (+> threo-2-amino-3). - recovering the salt of (4-nitrophenyl) propane-1,3-diol, liberating the salt with N-acetyl-Lbeta-phenylalanine by mineral acid treatment and optionally acidifying the resulting Lbeta-phenylalanine. by converting it into a salt or liberating it from its acid addition salt, so that D - (+) - threo-2-amino-3- (4'-nitrophenyl) -propane-1,3-diol is prepared in a concentration of 0.5-0.65 molar equivalent, salt formation is carried out in the presence of 0.45-0.55 molar equivalent of inorganic base relative to N-acetyl-DLbeta-phenylalanine, optionally in the form of its acid addition salt obtained by deacetylation, and optionally remaining in the mother liquor after salt formation N-acetyl-D-beta-phenylalanine is racemized, preferably without isolation, by treatment with acetic anhydride in the presence of an alkali metal hydroxide, and the resulting N-acetyl-DL-beta-phenylalanine is recycled to the process and, optionally, N- After liberating the mother liquor after the release of acetyl L-beta-phenylalanine, D - (+) - threo-2-amino-3- (4-nitrophenyl) propane-1,3-diol is regenerated and recycled.

The inorganic base used in the process of the invention is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

It will be surprising to those skilled in the art that when a resolution of 0.5-0.65 molar equivalent is used, the total optical yield of high optical purity Lbeta-phenylalanine is about 85% based on the starting N-acetyl-DLbeta-phenylalanine, since an equimolar amount of the total yield is 53-54%, s equimoral! even with less 0.75 molar equivalents of resolving agent, the overall yield is barely 60%, as shown in Comparative Examples 1 and 2 later in the specification.

Preferably, the process of the present invention comprises heating the aqueous suspension of N-acetyl-DLbeta-phenylalanine, the resolving agent and the alkali metal hydroxide to dissolution, and then cooling. The D - (+) - threo-3- (4'-nitrophenyl) -2-aminopropane-1,3-diol salt of N-acetyl-L-beta-phenylalanine was filtered and liberated with aqueous hydrochloric acid. the salt being N-acetyl-Lbeta-phenylalanine. The latter is deacetylated by heating with hydrochloric acid and / or the Lbeta-phenylalanine hydrochloride is isolated or the L-beta-phenylalanine is precipitated by basifying the reaction mixture after deacetylation. The resolving agent is precipitated by basifying the mother liquor of N-acetyl-Lbeta-phenylalanine. The N-acetyl-D-beta-phenylalanine remaining in the filtrate after filtration of the salt of N-acetyl-L-beta-phenylalanine is usually treated with alkali metal hydroxide and acetic anhydride without isolation, usually without warming up, preferably at 80-90 ° C. . The D-enantiomer is then racemized to N-acetyl-DLbeta-phenylalanine which is precipitated by acidifying the reaction mixture. The DL compound obtained by racemization is of the same quality as the starting racemic compound and can thus be recycled to the resolving process without purification.

The process according to the invention is extremely economical in that it provides L-beta-phenylalanine with a total yield of about 85%, in addition to the conversion of N-acetyl-D-beta-phenylalanine as waste into the known process first to the racemic compound and desired product. In addition, the resolving agent used can be regenerated with minimal loss. The resulting Lbeta-phenylalanine has an optical purity greater than the optical purity of the product formed by the known process.

The invention is illustrated in detail by the following examples.

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Example 1

Sodium chloride (5 g, 125 mmol) was dissolved in 123 g of water and N-acetyl-DL-beta-phenylalanine (51.8 g, 250 mmol) was added and heated to 9 ° C. 27.6 g of D - (+) - threo-2-amino-3- (4-nitro-phenyl) -propan-1- _d- 3-ol are added and a solution is prepared at 98-100 ° C. After cooling to 20 ^° C was filtered, washed with a little water. The resulting salt was suspended in 165 g of water and acidified to pH 1 with 13 cm ^{3 of} hydrochloric acid. The precipitated N-acetyl-L-beta-phenylalanine was filtered off, washed with 0.01 N hydrochloric acid and then with water. After drying, 23.5 g (90.7%) of N-acetyl-L-beta-phenylalanine are obtained, [[α] λθ = + 46.5 ° (c = 2%, ethyl alcohol), m.p. C.

The thus obtained 23.5 g of N-acetyl-beta-L-phenylalanine was 23.5 cm ³ of water and 23.5 cm ³ of concentrated hydrochloric acid solution was added and refluxed for 1 hour under reflux. After clarification and filtration with 0.1 g of charcoal, it is filtered at + 4 ° C. After drying, 18.2 g of Lbeta-phenylalanine chlorohydrate are obtained. Workup of the mother liquor (evaporation, cooling, filtration) yielded an additional 3.3 g of product. Specific rotation for both materials [ce] pP = -16 °, (c = 2%, water). Yield 93.6%. The starting yield was 85.4% based on N-acetyl-DLbeta-phenylalanine.

Comparative Example I (Use of Equimolar Amount of Resolution Agent)

26.25 g (0.122 mol) of D - (+ - 1 Hreo-2-amino-3- (4-nitrophenyl) -propane-1,3-diol and 25.9 (0.125 mol) of N-acetyl- DL-beta-phenylalanine was suspended in water (125.2 cm ³ ) and dissolved at 90 DEG C. After standing at room temperature for two days, the salt of N-acetyl-L-beta-phenylalanine was filtered off and dried (24 g). salt was obtained which was suspended in 63 cm @ ^{3 of} hydrochloric acid with stirring. The resulting N-aceul-Lbeta-phenylalanine was filtered off and dried to give 10.6 g (yield 81.5) of a specific rotation of + 40.1 ° C. c = 2%, ethyl alcohol).

10.6 N-acetyl-L-beta-phenylalanine was deacetylated in 18 cm ^{3 of} 21% hydrochloric acid solution for 1 hour, then cooled to 4 ° C, the hydrochloride salt filtered and dried. The resultant 7.9 g of Lbeta-phenylalanine hydrochloride salt is dissolved in 79 cm ^{3 of} methanol and adjusted to pH 7 with pyridine. The precipitated Lbeta-phenylalanine is filtered off, washed with water and dried. The resulting 5.5 g (65%) of L-beta-phenylalanine had a specific rotation at -23 ° C (c = 2%, water). total yield: 53.5%, based on N-acetyl-DL-phenylalanine.

II. Comparative Example (Use of 0.75 molar equivalent of resolving agent)

Sodium hydroxide (2.5 g, 62.5 mmol) was dissolved in 132 g of water and N-acetyl-DL-beta-phenylalanine (51.8 g, 250 mmol) was added and heated to 90 ° C. 40.1 g (187.5 mmol) of D - (+) - threo-2-amino-3- (4-nitrophenyl) -propane-1,3-diol are added and heated to 98-100 ° C. prepare a solution. After cooling to 20 ° C, it is filtered, washed with a little water. The salt of N-acetyl-Lbeta-phenylalanine was suspended in 165 g of water and acidified to pH &gt; 1 with 12 cm ^{3 of} concentrated hydrochloric acid. The N-acetyl-Lbeta-phenylalanine was filtered at 20 ° C, washed with 0.01 N hydrochloric acid and then with water. After drying (85%) of N-acetyl-beta-L-phenylalanine 22 "g, [<x} rf ¹ ♦ 46.5 °, (c = 2%, ethanol). ^υ

22 g of N-acetyl-lbeta-phenylalanine 22 cm ³ of water and 22 cm ³ of concentrated hydrochloric acid solution was added and refluxed for 1 hour under reflux. After clarification and filtration with 0.1 g of activated carbon, adjust the pH to 6.5-7 with 50-70 ° C ammonium hydroxide solution and, after cooling to 25 ° C, filter the L-beta-phenylalanine, water and then with anhydrous ethyl alcohol. The wet material was slurried in 25 cm ^{3 of} anhydrous ethyl alcohol, refluxed, filtered at 30 ° C, washed with a small amount of ethyl alcohol and dried. 12.9 g (87%) lbeta-phenylalanine obtained fajp = + 34 ° (c ^s 2%, water), a total yield of 62.5%. ¹

Example 2

5 g (125 mmol) of sodium hydroxide are added in 132 ml of water, 51.8 g (250 mmol) of N-acetyl-DL-beta-phenylalanine are added and the mixture is heated to 90 ° C. 27.6 g of D - (+) - threo-2-amino-3- (4-nitrophenyl) propane-1,3-diol are added and the solution is stirred at 98-100 ° C. The solution is cooled to 20 ° C, the precipitated salt is filtered off and washed with a little water.

The resulting wet salt is suspended in 165 ml of water and acidified to pH 1 with 12 ml of concentrated hydrochloric acid. The precipitated N-acetyl-L-beta-phenylalanine was filtered at 20 ° C, washed first with 0.01 N hydrochloric acid, then with water, and dried.

23.57 g (91%) of N-acetyl-Lbeta-phenylalanine are obtained, Μθ = * 46.5 ° C (c = 2%, eranol).

The resultant N-acetyl-Lbeta-phenylalanine (22 g) was added to a mixture of water (22 ml) and concentrated hydrochloric acid (22 ml) and refluxed for 1 hour. After clarification with 0.1 g of activated carbon, filter, adjust the pH to 6.5-7 with aqueous ammonium hydroxide at 50-70 ° C, cool the suspension to 25 ° C, filter the wash with ethanol. The still wet product is suspended in 25 ml of anhydrous ethanol at reflux, cooled to 30 ° C, filtered, washed with a small amount of ethanol and squeezed. 16.83 g (96%) of L-beta-phenylalanine are obtained, [α] ^{25 D} = ⁺ 34 ° C, (c = 2% water). overall yield: 87.3%. In the mother liquor after recovery of the salt of N-acetyl-Lbeta-phenylalanine with D- ( ⁺ ) - threo-2-amino-3- (4'-nitrophenyl) -propane-1,3-diol - Contains N-acetyl-D-beta-phenylalanine - Dissolve 0.8 g of solid sodium hydroxide and add 31.5 g of acetic anhydride. The temperature of the mixture spontaneously rises to about 90 ° C. The mixture was cooled to 20 °, acidified to pH 1 with concentrated hydrochloric acid, filtered, washed with 0.01 N aqueous hydrochloric acid, then water, and dried. 25 g of N-acetyl-DLbeta-phenylalanine. yielding the same quality as the starting racemic compound.

The mother liquor after recovery of N-acetyl-Lbeta-phenylalanine contains the resolving agent. The mother liquor was basified to pH 9 with concentrated aqueous ammonium hydroxide, filtered, washed with a little water and dried. 23.5 g of D - (*) - threo-2-amino-3- (4'-nitrophenyl) propane-1,3-diol are obtained, which can be re-used without further purification.

Example 3

The procedure described in Example 2 was followed except that 12 ml of concentrated hydrochloric acid was added to the mother liquor containing N-acetyl-D-beta-phenylalanine to adjust the pH to 11. The precipitated N-acetyl-D-beta-fenfl-32

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-alanine was filtered off, washed first with 10 ml of 0.01 N hydrochloric acid and then with a little water. 25.4 g of N-acetyl-D-beta-phenylalanine are isolated, which is added to a solution of 5.1 g of solid sodium hydroxide in 51 ml of water, 32 g of acetic anhydride is added, and the warmed solution is cooled to 20 ° C. acidified to pH * 1 with concentrated hydrochloric acid, the precipitate was filtered off, washed with 0.01 N hydrochloric acid and water and finally dried to give 23. g of N-acetyl-β-beta-phenylalanine, m.p. 169-171 ° C. [o] y {= 0. (c = 2, 'C ethanol).

Claims (3)

PATENT CLAIMS An improved process for the preparation of L-beta-phenylalanine and its acid addition salts starting from N-acetyl-DL-beta-phenylalanine) in D - (*) - threo-2-amino-3- (4-nitrophenyl) in an aqueous medium ) -propane-1,3-diol, salt formation of N-acetyl-L-beta-phenylalanine D - (*) - threo-2-amino-3- (4-nitrophenyl) -propane-1,3 isolating its salt with a diol, liberating and deacetylating N-acetyl-Lbeta-phenylalanine from the salt by treatment with a mineral acid, optionally converting the resulting L-beta-phenylalanine into an acid addition salt or liberating it from its acid addition salt, by using D - (+) - threo-2-amino-3,4-nitrophenyl) -propane-1,3-diol in an amount of 0.5-0.65 molar equivalents for salt formation and salt formation with N-acetyl-DLbeta in the presence of 0.45-0.55 molar equivalents of inorganic base relative to phenylalanine, optionally with the acid addition salt of Lbeta-phenylalanine obtained by deacetylation. and, if desired, racemizing the N-acetyl-D-beta-phenyl-ylanine remaining in the mother liquor after salt formation, preferably without isolation, by treatment with ethyl acetate and the resulting N-acetyl-DLbeta. -ferylalanine is recycled to the process, and finally, by deactivating the D-(*) - threo-2-8mino-3- (4-nitrophenyl) alkaline base after liberating the N-acetyl-Lbeta-phenylalanine. -propane-1,3-diol is regenerated and recycled to the process. 2. The l. The process of claim 1, wherein the inorganic base is an alkali metal hydroxide. 3. The process according to claim 2, wherein the alkali metal hydroxide is sodium hydroxide.