JP4170990B2 - Process for producing optically active serine derivatives - Google Patents

Description

  The present invention relates to a method for producing an optically active serine derivative, and more particularly to a method for producing an optically active serine derivative known as droxidopa or a salt thereof, and a production intermediate thereof.

 Droxidopa or a salt thereof is active in the circulatory system and central nervous system, and is a useful drug as a therapeutic agent for Parkinson's disease, depression, peripheral orthostatic hypotension and the like. Droxidopa is an optically active serine derivative, whose chemical name is L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine, and has the structure of the following chemical formula 1a: Have.

 Patent Document 1 (Patent Documents 2, 3, and 4) discloses a method for separating each isomer including droxidopa from four kinds of isomers. However, there is a problem that the maximum yield cannot exceed 25% by separating from the four isomers.

 Patent Document 5 discloses a method for producing droxidopa from an N-acetyldopa derivative obtained from dopa (DOPA). However, this method has a disadvantage that high production cost is required by using dopa, which is an expensive reagent.

 Patent Document 6 discloses a method of synthesizing a chiral diol derivative and then introducing and reducing an azide group to produce droxidopa. Patent Documents 7 and 8 use a benzaldehyde derivative as a starting material. A method for producing droxidopa after producing threo-N-phthaloyl-3- (3,4-dihydroxyphenyl) serine is disclosed. However, there is a need in the art to develop new manufacturing methods in terms of commercial scale mass production and yield.

 On the other hand, Non-Patent Document 1 discloses a method for producing diastereo and enantioselective β-hydroxy-α-amino acids by condensing an aldehyde and a ketone with glycine. That is, a method of producing a D-threo- (2R, 3S) -β-phenylserine derivative by reacting a chiral complex of glycine and metal having the following structural formula with an aldehyde and a ketone is disclosed.

 Non-Patent Document 2 discloses a method for producing a β-hydroxy-α-amino acid having a fluorine atom in a side chain using the chiral complex.

 However, when an optically active serine derivative is to be produced using the prior art (that is, Non-Patent Document 1 or 2), D-threo- (2R, 3S) -3- (3,4 -Dihydroxyphenyl) serine is mainly obtained, and droxidopa L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine is very difficult to obtain purely. Further, when droxidopa is produced by the above prior art, the reaction time in a mixed solvent of triethylamine and methanol takes 3 days or more, and the threo- (2S, 3R) type and erythro- (2S, 3S) type 1: 1. A pure target compound, L-threo- (2S, 3R) -3, is produced by producing a ˜2: 1 mixture and also producing a 5-20% mixture of (2R, 3S) and (2R, 3R). The commercial application for the production of-(3,4-dihydroxyphenyl) serine, ie droxidopa, is very difficult.

Further, when droxidopa is produced by the prior art, there is a problem that the reaction (that is, the aldol condensation reaction) itself cannot proceed due to two hydroxy groups present in the phenyl ring.
U.S. Pat. No. 3,920,728 US Pat. No. 5,739,387 Japanese Patent Laid-Open No. 9-031038 Japanese Patent Laid-Open No. 9-301961 JP-A-8-231518 Japanese Patent Laid-Open No. 9-249626 JP 61-275254 A Japanese Patent Laid-Open No. 5-239025 J. Am. Chem. Soc. 107, 4252-4259, 1985 J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993

  The present invention provides a new production method capable of producing droxidopa having high optical purity in a high yield and an intermediate thereof. That is, the present invention relates to a stereoselective production method for producing droxidopa having the stereochemistry of L-threo- (2S, 3R) -β-hydroxy-α-amino acid with high purity and high yield, and an intermediate thereof. The present invention provides a chiral metal complex useful as:

 Accordingly, an object of the present invention is to provide a method for producing droxidopa.

 Moreover, the objective of this invention includes providing an intermediate useful as a manufacturing intermediate of droxidopa.

  The uniform phase of the present invention includes a step of decomposing a compound of Formula 2 with an acid in a polar organic solvent to obtain a compound of Formula 1b, and performing a hydroxylation reaction of the compound of Formula 1b. A method for producing-(2S, 3R) -3- (3,4-dihydroxyphenyl) serine or a salt thereof is provided.

In the formula, R ¹ and R ² are each independently benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, or C _1. a -C ₄ alkyl, M is Cu ^2+, a Ni ^2+, or Zn ^2+.

 Another aspect of the present invention provides a compound of formula 2 below.

In the formula, R ¹ , R ² , and M are as described above.

 According to another aspect of the present invention, there is provided a compound represented by Formula 3 below.

  In the formula, M is as described above.

 The production method of the present invention can produce L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine or a salt thereof with high purity and high yield using a low-valent reaction reagent. The compound of Chemical Formula 2 and / or Chemical Formula 3 can be usefully used as an intermediate for producing droxidopa.

 According to one embodiment of the present invention, a step of decomposing a compound of Formula 2 with an acid in a polar organic solvent to obtain a compound of Formula 1b and performing a hydroxylation reaction of the compound of Formula 1b include droxidopa ( That is, a process for producing L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine) or a salt thereof is provided.

In the formula, R ¹ and R ² are each independently benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, or C _1- C ₄ alkyl and M is Cu ²⁺ , Ni ²⁺ , or Zn ²⁺ .

In the production method of the present invention, when both R ¹ and R ² are benzyl, it is desirable because the hydroxylation reaction can be easily advanced.

In the production method of the present invention, the polar organic solvent is selected from the group consisting of C _{1 to} C ₇ alcohols, tetrahydrofuran, acetonitrile, dimethylformamide, and mixed solvents thereof, and preferably methanol can be used. In addition, as the acid used to produce the compound of Formula 1b, any of inorganic acid and organic acid can be used, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoroacetic acid can be used, Desirably, hydrochloric acid can be used.

 The amount of the acid used varies depending on the type of acid used, but about 20 equivalents or more, desirably about 30 equivalents, can be used with respect to 1 equivalent of the compound of Chemical Formula 2. The decomposition reaction of the compound of Formula 2 can be performed at -10 to 100 ° C, preferably about 50 ° C, for about 10 minutes to 5 hours, preferably about 1 hour.

Intermediate remaining after the decomposition reaction, ie D-2- [N- (N′-benzylprolyl)
Amino] benzophenone can be recovered more than 90%, does not cause racemization, and can be used continuously in the next reaction, which is very advantageous economically.

 The hydroxylation reaction may be performed by adding hydrogen in the presence of a metal such as Pd / C, Pt and an acid (eg, HCl, HBr, etc.). The solvent can be reacted at −10 to 100 ° C., preferably about 20 ° C., using a polar organic solvent (for example, ethanol) as described above.

 In the production method of the present invention, the compound of the chemical formula 2 can be produced by reacting the compound of the chemical formula 3 and the compound of the chemical formula 4 in the presence of a base.

In the formula, R ¹ , R ² , and M are as described above.

Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide, potassium hydroxide and barium hydroxide; sodium methoxide, Alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide; NHR ³ R ⁴ (R ³ and R ⁴ are the same or different and each is C ₁ -C ₇ alkyl); NH ₂ R ⁵ (R ⁵ is an alkyl of C ₁ ~C _9); may be selected from the group consisting of NaNH _2; NaH; 4 amine hydroxides such as tetrabutylammonium hydroxide and benzyltrimethylammonium hydroxide. Of these, alkali metal alkoxide (for example, sodium methoxide), NaH, or NaNH ₂ can be desirably used in order to maximize the stereoselectivity. The amount of the base used varies depending on the type of base used, but about 3 equivalents or more, desirably about 7 equivalents, can be used with respect to 1 equivalent of the compound of Chemical Formula 3.

 The reaction between the compound of Formula 3 and the compound of Formula 4 is an asymmetric aldol condensation reaction and can be performed by reacting in a polar organic solvent (for example, the polar organic solvent, preferably methanol) for about 1 hour. The amount of the compound of formula 4 used is preferably about 1 equivalent per 1 equivalent of the compound of formula 3. However, since the compound of Chemical Formula 4 is relatively inexpensive, it is desirable to use it in an excess amount with respect to the compound of Chemical Formula 3.

The compound of Formula 3 is prepared by reacting D-proline with benzyl chloride to produce DN-benzylproline, and reacting DN-benzylproline with 2-aminobenzophenone to form D-2. -[N- (N'-benzylprolyl) amino] benzophenone, and the D-2- [N- (N'-benzylprolyl) amino] benzophenone, M (ie, Cu ²⁺ , Ni ²⁺ or Zn ²⁺ ) or a hydrate thereof, and a step of reacting glycine. The production method of the compound of Chemical Formula 3 is summarized by Reaction Formula 1 as Reaction Formula 1.

  The step of reacting D-proline with benzyl chloride to produce DN-benzylproline can be performed in an alcohol such as isopropyl alcohol in the presence of a base such as potassium hydroxide. The reaction is complete in about 6 hours at about 40 ° C.

The step of reacting DN-benzylproline and 2-aminobenzophenone to produce D-2- [N- (N′-benzylprolyl) amino] benzophenone is performed in the presence of thionyl chloride (SOCl ₂ ). This can be done using a normal organic solvent such as dichloromethane. That is, the reaction can be carried out by slowly adding thionyl chloride (SOCl ₂ ) dropwise while maintaining a dichloromethane solution of DN-benzylproline at about −20 to −30 ° C. and then gradually adding 2-aminobenzophenone. .

And D-2- [N- (N′-benzylprolyl) amino] benzophenone,
The step of reacting a salt containing M (that is, Cu ²⁺ , Ni ²⁺ , or Zn ²⁺ ) or a hydrate thereof and glycine is performed using an alcohol such as methanol in the presence of a base such as potassium hydroxide as a solvent. Can be used at about 40-50 ° C. Examples of the salt containing Cu ²⁺ , Ni ²⁺ , or Zn ²⁺ include nitrate form (eg, Ni (NO ₃ ) ₂ ), halogen salt form (eg, NiCl ₂ , NiBr _2, etc.), acetate form ( For example, Ni (OAc) ₂ ), or sulfate form (eg, NiSO ₄ ). Further, as the hydrate of the salt containing Cu ²⁺ , Ni ²⁺ , or Zn ²⁺ , various forms of hydrate can be used, preferably Ni (NO ₃ ) ₂ .6H ₂ O can be used. .

 The production method of the present invention can be summarized as the following reaction formula 2 when the compound of the chemical formula 3 is represented by the overall reaction formula using the starting material as a starting material.

According to another aspect of the present invention, there is provided a compound of formula 2 and / or a compound of formula 3 useful as an intermediate for the production of droxidopa.

In the formula, R ¹ , R ² , and M are as described above.

 Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrating the present invention, and the present invention is not limited to the examples.

[Example 1. Production of DN-benzylproline]
A suspension of D-proline (115 g, 1 mol), potassium hydroxide (168.3 g, 3 mol), and isopropyl alcohol (1 L) was stirred at 40 ° C. After the suspension became transparent, benzyl chloride (137.3 g, 1.1 mol) was gradually added and stirred at 40 ° C. for 6 hours. After the reaction solution was cooled to 0 to 5 ° C., the pH was adjusted to 5 to 6 with concentrated hydrochloric acid (145 mL). The reaction solution was diluted with chloroform (3 L) and stirred for 18 hours, and the produced potassium chloride was removed by filtration. The filtrate was concentrated and recrystallized with acetone to produce 161.8 g (yield 79%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm): δ7.2~7.4 (m, 5H), 4.0~4.4 (dd, 2H), 3.8 (dd, 1H), 3.6~ 3.7 (m, 1H), 2.8 (dd, 1H), 1.8-2.4 (m, 4H)
[Α] _D ²⁵ = + 28.4 (c = 1, EtOH)
Melting point = 174-175 ° C.

[Example 2. D-2- [Production of N- (N′-benzylprolyl) amino] benzophenone]
D-N-benzyl-proline (100 g, 487 mmol) in dichloromethane (500 mL) solution of thionyl chloride while maintaining -20 to-30 ° C. The _{(SOCl 2) (35.5mL, 487mmol} ) was slowly added dropwise. The mixture was stirred while maintaining at −10 ° C. until the reaction solution became transparent, and then a solution of 2-aminobenzophenone (86.5 g, 438 mmol) in dichloromethane (250 mL) was gradually added dropwise while maintaining at −30 ° C. After confirming that the acyl chloride was consumed during the reaction, the reaction mixture was cooled to 0 ° C. and an aqueous sodium carbonate solution was added. The reaction mixture was extracted with dichloromethane, washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized and filtered with ethanol to produce 126 g (yield 74%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 7.0 to 8.62 (m, 14H), 3.6 to 4.0 (d, 2H), 3.4 (dd, 1H), 3.1 to 1.8 (m, 6H)
[Α] _D ²⁵ = + 133.1 (c = 0.5, MeOH)
Melting point = 100-100.5 ° C.

[Example 3. Glycine-Ni-D-2- [Production of N- (N′-benzylprolyl) amino] benzophenone]
D-2- [N- (N′-benzylprolyl) amino] benzophenone (60 g, 156 mmol), Ni (NO ₃ ) ₂ .6H ₂ O (91 g, 312 mmol), glycine (58.5 g, 780 mmol) in methanol (600 mL). After the temperature was raised to 40-50 ° C. and the reaction mixture turned green, a solution of potassium hydroxide (61.3 g, 1.1 mol) in methanol (250 mL) was added dropwise. After stirring for 1 hour while maintaining the temperature at 45-55 ° C, the temperature was lowered to 10 ° C and acetic acid (55 mL) was slowly added dropwise. Water was added to bring the reaction mixture to 2.5 L and stirred for 6 hours. The produced solid was filtered and washed with water to produce 58 g (yield 75%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 8.2 to 6.6 (m, 14H), 4.4 (d, 1H), 3.68 (s, 2H), 3.5 (d, 1H) 3.9 to 1.8 (m, 7H)
[Α] _D ²⁵ = −2005 (c = 0.5, MeOH)

Example 4 Production of 1-hydroxy-1- (3,4-dibenzyloxyphenyl) glycine-Ni-D-2- [N- (N′-benzylprolyl) amino] benzophenone
[Method 1] Under a nitrogen stream, 3,4-dibenzyloxybenzaldehyde (18.4 g, 58 mmol), sodium methoxide (20 mL 28% in MeOH, 90 mmol), glycine-Ni-D-2 -[N- (N'-benzylprolyl) amino] benzophenone (20 g, 40 mmol) and methanol (50 mL) were added and stirred. After stirring for 1 hour and confirming that the reaction was completed, undissolved 3,4-dibenzyloxybenzaldehyde was removed by filtration. The filtrate was slowly added dropwise to 20% acetic acid (40 mL) and then the resulting solid was filtered. The obtained solid was washed with water and dried to produce 26.8 g (yield 82%) of the red title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 8.6 to 6.0 (m, 27H), 5.2 to 3.5 (d, 8H), 4.6 to 1.4 (m, 7H)
[Α] _D ²⁵ = + 563.2 (c = 0.5, CHCl ₃ )

[Method 2] Lithium (0.18 g, 25 mmol) was dissolved in methanol (10 mL), and glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone (at room temperature under a nitrogen stream) 5 g, 10 mmole) was added. After stirring for 10 minutes, 3,4-dibenzyloxybenzaldehyde (6.4 g, 20 mmol) was added and stirred at 50 ° C. for 30 minutes. The reaction mixture was filtered to remove undissolved 3,4-dibenzyloxybenzaldehyde. The filtrate was slowly added dropwise to 20% acetic acid (10 mL) and then the resulting solid was filtered. The obtained solid was washed with water and dried to obtain 6.53 g (80%) of the red title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 8.6 to 6.0 (m, 27H), 5.2 to 3.5 (d, 8H), 4.6 to 1.4 (m, 7H)
[Α] _D ²⁵ = + 563.2 (c = 0.5, CHCl ₃ )

[Example 5. Production of L-threo- (2S, 3R) -3- (3,4-dibenzyloxyphenyl) serine]
1-hydroxy-1- (3,4-dibenzyloxyphenyl) glycine-Ni-D-2- [N- (N′-benzylprolyl) amino] benzophenone (5 g, 6 mmol) in methanol (75 mL) and 5N -Suspended in a mixed solvent of hydrochloric acid (37.5 mL) and heated to 50 ° C. After stirring for 1 hour, it was confirmed that the reaction was complete. The methanol in the reaction mixture was concentrated and the pH was adjusted to 6.6 with aqueous ammonia. The produced solid was filtered and washed with water. The solid was completely dried and then suspended in acetone and filtered. The obtained solid was dried to produce 2.2 g (93% yield) of the title compound.

Melting point = 119.5-120.4 ° C.
¹ H-NMR (DMSO-d ₆ , ppm): δ 7.25-6.8 (m, 13H), 5.1 (s, 4H), 5.0 (d, 1H), 3.25 (d, 1H)

[Example 6. Production of L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine]
L-threo-3- (3,4-dibenzyloxyphenyl) serine (7 g, 18 mmol) was suspended in ethanol (400 mL), and concentrated hydrochloric acid (100 mL) and 10% Pd / C (600 mg) were added. Thereafter, hydrogenolysis was carried out at 1-2 atm and room temperature. The reaction mixture was filtered to remove Pd / C and the filtrate was concentrated. The obtained reaction mixture was dissolved in ethanol, and the pH was adjusted to 5 with a mixed solution of diethylamine and ethanol. The reaction mixture was allowed to stand at 0 ° C. for 24 hours, and the resulting solid was filtered and washed with ethanol and ether to produce 3.16 g (yield 85%) of the title compound.

¹ H-NMR (D ₂ O / NaOH, ppm): δ 6.5 (dd, 2H), 6.4 (d, 1H), 4.7 (d, 1H)
[Α] _D ²⁵ = −39 (c = 1,1NHCl)
Melting point = 232-243 ° C.

  The production method of the present invention is used for the production of L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine or a salt thereof, and the compound of Formula 2 and / or 3 is L-threo. -(2S, 3R) -3- (3,4-dihydroxyphenyl) serine is usefully utilized as an intermediate in the production of a salt thereof.

Claims (9)

Decomposing the compound of Formula 2 with an acid in a polar organic solvent to obtain a compound of Formula 1b;
A method for producing L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine or a salt thereof comprising the step of performing a hydroxylation reaction of the compound of Formula 1b:

In the formula, R ¹ and R ² are each independently benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, or C _1- C ₄ alkyl,
M is a Ni ^2+. The method according to claim ^1, wherein R ¹ and R ² are both benzyl. The process according to claim 1, wherein the polar organic solvent and wherein the C ₁ -C ₇ alcohol, tetrahydrofuran, acetonitrile, dimethylformamide, and those selected from the group consisting of a mixed solvent.   The production method according to claim 1, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoroacetic acid.   The production method according to claim 4, wherein the hydroxylation reaction is performed by adding hydrogen in the presence of a metal and an acid. The compound of Formula 2, a compound of compound formula 4 of the formula 3 according to any one of claims 1 to 5, wherein the is obtained by reacting in the presence of a base Production method:

Wherein R ¹ , R ² and M are as defined in claim 1. The base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide, NHR ³ R ⁴ (R ³ and R ⁴ may be the same or different, C ₁ -C ₇ alkyl), NH ₂ R ⁵ (R ⁵ is alkyl of C ₁ ~C _9), the method according to claim 6, characterized in that it is selected from quaternary amine hydroxides, NaH, and the group consisting of NaNH ₂ . The compound of Formula 3 is
Reacting D-proline with benzyl chloride to produce DN-benzylproline;
Reacting the DN-benzylproline with 2-aminobenzophenone to produce D-2- [N- (N′-benzylprolyl) amino] benzophenone;
D-2- [N- (N′-benzylprolyl) amino] benzophenone, M (Ni ²⁺
) Or a hydrate thereof, and a step of reacting glycine, and the method according to claim 6. Compound of the following chemical formula 2:

In the formula, R ¹ and R ² are, each independently, benzyl, p- nitrobenzyl, p- fluorobenzyl, p- trifluoromethyl benzyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl or C ₁ ~, C ₄ alkyl,
And M is a Ni ^2+.