KR20040050060A - An intermediate of an optically active diarylalanine, its derivatives and process for prepararing the same - Google Patents

Abstract

PURPOSE: An intermediate of an optically active diarylalanine and derivatives thereof and a process for preparing the same are provided, thereby requiring no protection of serine by using aziridine-2-carboxylic acid ester and (L)-diphenylalanine as well as (D)-diphenylalanine by stereo-specifically selecting aziridine-2-carboxylic acid ester. CONSTITUTION: The intermediate of an optically active diarylalanine and derivatives thereof represented by formula (2) are provided, wherein Ar is phenyl, phenyl substituted with 1 to 3 substituents selected from C1-C8 alkyl, halogen such as F, Cl and I, C1-C8 alkoxy, C1-C8 thioalkoxy, NO2, OH and CF3, naphthalene, N, O or S containing C1-C14 hetero aromatic ring compounds; R1 is hydrogen, C1-C8 alkyl, C1-C8 cycloalkyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, s-triazinyl or pyridinyl acyl, benzyl, C1-C8 carbohydrate residue substituted with hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl or 4-methoxyphenyl, 2,4-methoxyphenyl, or (R)-phenylethyl, or (S)-phenylethyl. The method for preparing the intermediate of an optically active diarylalanine and derivatives thereof of formula (2) comprises reacting aziridine-2-carboxylic acid ester of formula (1) with arylmagnesium halide, wherein the halide X of arylmagnesium halide is Cl or Br; the arylmagnesium halide is phenylmagnesium chloride or phenylmagnesium bromide; and R2 is C1-C10 alkyl.

Description

Optically active intermediates of diarylanine and its derivatives and preparation methods thereof {AN INTERMEDIATE OF AN OPTICALLY ACTIVE DIARYLALANINE, ITS DERIVATIVES AND PROCESS FOR PREPARARING THE SAME}

Diphenylalanine, which has one more phenyl group than phenylalanine, is an unnatural amino acid and occupies an important part of various active substances which may be candidates for pharmaceutical applications. (International patent application WO 9825965 and international patent application WO 2000039124 number).

There have been many efforts to stereoselectively make diphenylalanine, which is a kind of such unnatural amino acid. Like other amino acids, a method of optically separating racemates is also known (US Pat. No. 5,198,548). Another method is to make several chemical reactions using the stereosymmetrical arrangement of the asymmetric carbon already present in the optically active material, and they all use serine as its starting material. Even with serine, 4-oxazoline carboxylates can be prepared from serine (AMP Koskinen, et. Al. Tetrahedron Lett. 1995, 31, 5619) or oxazolidin-2-one-4-carboxyesters. And how to use it (US Pat. No. 5,623,087). All of these cases may be suitable for making (D) -diphenylalanine by having a three-dimensional arrangement of natural serine as it is by using natural serine. However, these methods are limited to the production of (D) -diphenylalanine due to the use of the three-dimensional arrangement of natural serine and are inadequate for the production of (L) -diphenylalanine, and they also remove the ring of oxazoline or oxazolidinone from serine. There is a hassle to create.

The present invention adds two moles of arylmagnesium halide to the optically active aziridine-2-carboxylic acid ester (Korean Patent Application No. 10-2000-0046387), and opens the aziridine ring with an oxygen nucleophile to hydrolyze the tertiary The present invention relates to a method for preparing optically active diarylalanine by reducing alcohol to make diarylalanineol and then oxidizing it. In particular, in the present invention, by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid ester, not only (D) -diarylalanine but also (L) -diarylalanine can be made by the same method. Namely, if the 2-position stereochemistry of the aziridine-2-carboxylic acid ester starts from (S), (D) -diphenylalanine is obtained, and from (R), (L) -diphenylalanine is obtained.

DETAILED DESCRIPTION OF THE INVENTION The present invention is to stereoselectively make diarylalanine, a type of non-natural amino acid, more particularly diphenylalanine and its derivatives, from optically active aziridine-2-carboxylic acid esters, which form an important backbone of bioactive substances. The conventional method was to use isoserine, but the present invention uses aziridine-2-carboxylic acid ester, not the conventional method using isoserine. Thus, there is no problem of protecting isocerine with a protecting group, and by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid ester, (D) -diarylalanine, more specifically (D) -diphenylalanine In addition, (L)-diarylalanine, more specifically (L)-diphenylalanine can be made in the same way.

An object of the present invention is to add the aryl magnesium halide, more specifically aryl magnesium chloride or aryl magnesium bromide to the aziridine-2-carboxylic acid ester of the above formula (1) to obtain the formula (2) and then the aziridine ring Opened with an oxygen nucleophile, such as acetic acid, to obtain a compound of formula (3) and to reduce tertiary alcohol to prepare a diarylalanineol of formula (4), which does not participate in the oxidation reaction of the primary alcohol, the protecting group R which the final product will have After preparing ³ , alcohol is further oxidized to produce diarylalanine of formula (5). In addition, aziridine diarylmethanol of formula (2) and 2-amino-1,1, -diaryl-1,3-dihydroxypropane of formula (3), which are novel materials used as intermediates in the above method, It is about.

Structural Formula (1) Structural Formula (2) Structural Formula (3) Structural Formula (4) Structural Formula (5)

At this time, R ¹ is hydrogen; C ₁ -C ₈ alkyl; C ₁ -C ₈ cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; C ₁ -C ₈ hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, or 4-methoxyphenyl; 2,4-methoxyphenyl; Or (R) -phenylethyl, or (S) -phenylethyl, more preferably benzyl, (R) -phenylethyl, or (S) -phenylethyl,

R ² is hydrogen, mentholyl, or a substituted or unsubstituted C ₁ -C ₄₀ hydrocarbon radical, wherein the substituents of C ₁ -C ₄₀ hydrocarbon radical are 0-40 halogen atoms; Heteroatoms selected from the group consisting of boron, nitrogen, oxygen, sulfur, phosphorus, silicon and selenium, more preferably C ₁ to C ₁₀ or mentholyl, most preferably methyl, ethyl, propyl or mentholyl.

R ³ is hydrogen same as R ¹ ; C ₁ -C ₈ alkyl; C ₁ -C ₈ cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; C ₁ -C ₈ hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, 4-methoxyphenyl; 2,4-methoxyphenyl; Or Boc, Cbz, Fmoc, acetyl, or the like, which is (R) -phenylethyl, or (S) -phenylethyl, or replaced with a substituent acting as another nitrogen protecting group.

Ar is also phenyl; A C ₁ -C ₈ alkyl group, 1 to 3 substituents selected from the group consisting of halogen, such as F, Cl, I, C ₁ -C ₈ alkoxy, C ₁ -C ₈ thioalkoxy, NO ₂ , OH, and CF ₃ Branched phenyl; naphthalene; Or a C ₁ -C ₁₄ heteroaromatic ring compound containing an atom of N, O or S.

More specifically described as follows. First, when the alkyl ester of aziridine-2-carboxylic acid of formula (1) shown in Scheme 1 is reacted with an excess of arylmagnesium halide as a starting material, it is possible to obtain aziridine diarylmethanol of formula (2). Wherein aryl is selected from the group consisting of phenyl, C ₁ -C ₈ alkyl group, halogen such as F, Cl, I, C ₁ -C ₈ alkoxy, C ₁ -C ₈ thioalkoxy, NO ₂ , OH, and CF ₃ Compounds that can be generalized to aryl having C ₁ -C ₁₄ heterocycles containing atoms of phenyl, naphthyl and other N, O, S having from 1 to 3 different substituents can be used. Chloride or bromide is preferred.

Structural Formula (1) Structural Formula (2)

Next, as shown in Scheme 2 below, aziridine of structural formula (2) was used as a known oxygen nucleophile (see, eg, Soo-Kyung Choi, Jin-Soo Lee, Jung-Ho Kim and Won Koo Lee, J. Org.Chem. 1997, 62, 743.)) Open the ring and hydrolyze to free hydroxymethyl if necessary to obtain 2-amino-1,1, -diaryl-1,3-dihydroxypropane as shown in formula (3). Get

Structural Formulas (2) Structural Formulas (3)

Thus known hydrogenation of the hydroxyl group of the tertiary alcohol in the compounds of formula (3) in which the aziridine ring is opened (Ref. Koskinen, AMP, Hassila, H., Myllymaki, VT, Rissanen, K. Tetrahedron Lett. 1995, 36, 5619-5622, specific examples are described in Example 7) to obtain diarylalanine and, if necessary, replace the protecting group with R ³ in the functional group of nitrogen or remove the protecting group.

Structural Formulas (3) Structural Formulas (4)

Diarylaninol of Structural Formula (4) in primary alcohol state is oxidized by general oxidation reaction (see References Liu, HT, Han, IS Synth. Commun. 1985, 15, 759-764) to carboxylic acid. Diarylalanine is obtained. At this time, when the amine is properly oxidized to R ³ protected state, a protected diarylalanine having a protective group is obtained, and a free state of diphenylalanine can be obtained by removing the protecting group.

Structural Formulas (4) Structural Formulas (5)

Hereinafter, the present invention will be described in detail with reference to the following examples.

Example 1

Acquisition of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol

Dissolve ethyl- (2S)-[N- (R) -phenylethyl] aziridine-2-carboxylate (413 mg, 1.89 mmol) in 10 mL of THF solution, lower the temperature to -78 ^o C, and then THF solution. Phenyl bromide (.2.98M 1.91 mL, 5,67 mmol) in the middle is added. The solution is then stirred at -78 ^o C for 2 hours and 5 mL of water is added to terminate the reaction. The reaction mixture is heated to room temperature and the organic layer is separated. The water layer is extracted five times with 10 mL of ethyl acetate solvent and all organic layers are collected. The combined organic layers are washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 590 mg of the product as a white solid. [a] _D ²⁴ = +34.0 (c = 0.53, in CHCl ₃ ), 1 H NMR (200 MHz, CDCl 3) δ 7.37-6.86 (m, 15H), 3.81 (br, 1H), 2.76 (q, J = 6.6 Hz, 1H), 2.49 (dd, J = 6.5 Hz, 1H), 2.02 (d, J = 3.6 Hz, 1H), 1.53 (d, J = 6.5 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H).

Example 2

Acquisition of (2R)-[N- (S) -phenylethyl] aziridine-2-diphenylmethanol

Ethyl- (2R)-[N- (S) -phenylethyl] aziridine-2-carboxylate instead of ethyl- (2S)-[N- (R) -phenylethyl] aziridine-2-carboxylate The reaction is carried out as in Example 1 to obtain the target compound. [α] _D ²⁴ = -33.5 (c = 0.44, in CHCl ₃ )

Example 3

Acquisition of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane

To a solution of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol (590 mg, 1.79 mmol) in 9 mL of methylene chloride is added 0.31 mL of acetic acid (5.37 mmol). . The mixture is stirred for 4 hours at room temperature and 2 mL of saturated sodium bicarbonate solution is added to terminate the reaction. The organic layer is separated and the water layer is extracted five times with 4 mL of methylene chloride solution. The combined organic layers are washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and dissolved in 8 mL of ethanol. KOH (105 mg, 1.98 mmol) was added to the solution, stirred at room temperature, and the solution was concentrated under reduced pressure. The concentrated solution is dissolved in 3 mL of water and extracted 5 times with 4 mL of methylene chloride each time. The extracted organic layer is washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 520 mg of the product as a white solid. [a] _D ²⁴ = +13.1 (c = 1.0, in CHCl ₃ ), 1 H NMR (300 MHz, CDCl 3) δ 7.42-6.95 (m, 15H), 4.11 (br, 1H), 3.77 (m, 2H), 3.58 (dd, J = 11.81 Hz, 1H), 3.38 (m, 1H), 1.29 (d, J = 6.87 Hz, 3H). mp: 78-80 ^o C

Example 4

Acquisition of (2R)-[N- (S) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane

Example using (2R)-[N- (S) -phenylethyl] aziridine-2-diphenylmethanol instead of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol Get the product as in 3. [α] _D ²⁴ = -13.6 (c = 1.0, in CHCl ₃ )

Example 5

Acquisition of (D) -diphenylalanineol

(2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane (150 mg, 0.432 mmol) was dissolved in 3 mL of formic acid and dilute in this solution. 30 mg of hydroxypalladium is added. The solution is then hydrogenated in a closed vessel at a pressure of 100 psi and the solution is stirred at room temperature for 6 hours. The reaction is then concentrated by distillation under reduced pressure and 5 mL of concentrated hydrochloric acid is added. Then, the solution was concentrated under reduced pressure again, and the obtained solid was recrystallized from ethyl acetate to obtain 85 mg of the title compound as a white solid. [α] _D ²⁴ = -41.5 (c = 0.25, in CHCl ₃ ) mp: 109-112 ^o C

Example 6

Acquisition of (L) -diphenylalaninol

(2R)-[N- (S) -phenylethyl] amino- instead of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane The reaction was carried out as in Example 5 using 1,1, -diphenyl-1,3-dihydroxypropane to obtain (L) -diphenylalaninol. [α] _D ²⁴ = +40.1 (c = 0.33, in CHCl ₃ )

Example 7

Acquisition of N-Boc- (D) -diphenylalaninol

Dissolve (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane (329 mg, 0.947 mmol) in 5 mL of formic acid and add to this solution. Add 60 mg of hydroxypalladium. The solution is then hydrogenated at 100 psi in a closed container and the solution is stirred for 6 hours at room temperature. The reaction was then concentrated by distillation under reduced pressure and 2.5 mL of NaOH solution was added thereto. To this solution is added (Boc) ₂ O (248 mg, 1,14 mmol) and 2.00 mL of EtOAc. The solution is then stirred at room temperature for 4 hours and then separated by an organic layer. The water layer is extracted four times with 3 mL of EtOAc each time. The extracted organic layer is washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 250 mg of the product as a white solid. [a] _D ²⁴ = -22.2 (c = 1.0, in CHCl ₃ ), 1 H NMR (500 MHz, CDCl 3) δ 7.33-7.16 (m, 10H), 4.63 (m, 1H), 4.47 (br, 1H), 4.15 (d, J = 10.74, 1H), 3.67 (dd, J = 9.16 Hz, 1H), 3.47 (dd, J = 10.93, 1H), 1.34 (s, 9H)

mp: 109-111 ^o C

Example 8

Acquisition of N-Boc- (L) -diphenylalaninol

(2R)-[N- (S) -phenylethyl] amino-1 instead of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane The reaction was carried out as in Example 7 using 1,3-diphenyl-1,3-dihydroxypropane to obtain the desired compound. [α] _D ²⁴ = +21.4 (c = 1.0, in CHCl ₃ )

Example 9

Acquisition of N-Boc- (D) -diphenylalanine

Dissolve N-Boc- (D) -diphenylalaninol (180 mg, 0.80 mmol) in 7 mL of acetone and add Jones reagent until the solution turns red. The reaction mixture is then stirred and when the starting material is gone the reaction is terminated by addition of isopropyl alcohol. After passing the reaction through a celite filter, the passed solution was distilled under reduced pressure and 10 mL of EtOAc was added thereto. The water layer was once again obtained with an organic layer three times using 5 mL of EtOAc each of which was collected, washed with 20 mL of saturated sodium chloride solution, removed with anhydrous sodium sulfate, and the desired compound. [a] _D ²⁴ = -35.8 (c = 0.71, in MeOH), mp. 148-150 ^o C.

Example 10

Acquisition of N-Boc- (L) -diphenylalanine

The reaction was carried out as in Example 9 using N-Boc- (L) -diphenylalaninol instead of N-Boc- (D) -diphenylalaninol to obtain the desired compound. [α] _D ²⁴ = +36.4 (c = 0.46, in MeOH)

The present invention is to stereoselectively make diphenylalanine and its derivatives from optically active aziridine-2-carboxylic acid esters, which are a type of non-natural amino acids that form an important skeleton of physiologically active substances. The use of aziridine-2-carboxylic acid esters eliminates the problem of protecting serine with protecting groups, and by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid esters, it is possible to select not only (D) -diphenylalanine (L) Diphenylalanine can be made in the same way.

Claims (6)

Compound of formula (2): Structural Formula (2) Ar is phenyl; A C ₁ -C ₈ alkyl group, 1 to 3 substituents selected from the group consisting of halogen, such as F, Cl, I, C ₁ -C ₈ alkoxy, C ₁ -C ₈ thioalkoxy, NO ₂ , OH, and CF ₃ Branched phenyl; naphthalene; Or a C ₁ -C ₁₄ heteroaromatic cyclic compound comprising an atom of N, O or S, R ¹ is hydrogen; C ₁ -C ₈ alkyl; C ₁ -C ₈ cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; C ₁ -C ₈ hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, or 4-methoxyphenyl; 2,4-methoxyphenyl; Or (R) -phenylethyl or (S) -phenylethyl. The compound of formula (2) according to claim 1, wherein R ¹ is benzyl or (R) -phenylethyl or (S) -phenylethyl. A process for preparing the compound of formula (2) according to claim 1 by reacting the aziridine-2-carboxylic acid ester of formula (1) with an arylmagnesium halide: Structural Formula (1) Structural Formula (2) Ar is phenyl; A C ₁ -C ₈ alkyl group, 1 to 3 substituents selected from the group consisting of halogen, such as F, Cl, I, C ₁ -C ₈ alkoxy, C ₁ -C ₈ thioalkoxy, NO ₂ , OH, and CF ₃ Branched phenyl; naphthalene; Or a C ₁ -C ₁₄ heteroaromatic cyclic compound containing an atom of N, O or S, and R ¹ is hydrogen; C ₁ -C ₈ alkyl; C ₁ -C ₈ cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; C ₁ -C ₈ hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, or 4-methoxyphenyl; 2,4-methoxyphenyl; Or (R) -phenylethyl, or (S) -phenylethyl, R ² is hydrogen, mentholyl, substituted or unsubstituted C ₁ -C ₄₀ hydrocarbon radicals, wherein a substituent of C ₁ -C ₄₀ hydrocarbon radicals is 0-40 halogen atoms; And a heteroatom selected from the group consisting of boron, nitrogen oxygen, sulfur, phosphorus, silicon and selenium, halide X represents F, Cl, Br, I. 4. The method of claim 3 wherein the halide X of the arylmagnesium halide is Cl or Br. The method of claim 4, wherein the arylmagnesium halide is phenylmagnesium chloride or phenylmagnesium bromide. The compound of formula (2) according to claim 3, wherein R ² is C ₁ -C ₁₀ alkyl.