(19)
(11)EP 3 266 761 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
06.05.2020 Bulletin 2020/19

(21)Application number: 16758798.9

(22)Date of filing:  23.02.2016
(51)Int. Cl.: 
C07C 231/02  (2006.01)
C07C 233/87  (2006.01)
C07C 269/06  (2006.01)
C07C 231/12  (2006.01)
C07C 269/04  (2006.01)
C07C 271/22  (2006.01)
(86)International application number:
PCT/JP2016/055223
(87)International publication number:
WO 2016/140104 (09.09.2016 Gazette  2016/36)

(54)

3-PHENYLISOSERINE DERIVATIVE PRODUCTION METHOD

VERFAHREN ZUR 3-PHENYLISOSERINDERIVATHERSTELLUNG

PROCÉDÉ DE PRODUCTION DE DÉRIVÉS DE LA 3-PHÉNYLISOSÉRINE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 03.03.2015 JP 2015041151

(43)Date of publication of application:
10.01.2018 Bulletin 2018/02

(73)Proprietor: Toray Fine Chemicals Co., Ltd.
Tokyo 101-0041 (JP)

(72)Inventors:
  • HIRAGA, Hisafumi
    Tokai-shi Aichi 476-8567 (JP)
  • NISHIKAWA, Takeshi
    Tokai-shi Aichi 476-8567 (JP)

(74)Representative: Kador & Partner PartG mbB 
Corneliusstraße 15
80469 München
80469 München (DE)


(56)References cited: : 
WO-A1-97/07110
WO-A1-03/002509
WO-A1-2012/117417
WO-A1-97/34866
WO-A1-03/002509
  
  • ZHOU Z ET AL: "A practical and efficient synthesis of taxol C-13 side chain", SYNTHETIC COMMUNICAT, TAYLOR & FRANCIS INC, PHILADELPHIA, PA; US, vol. 31, no. 23, 2001, pages 3609-3615, XP008081406, ISSN: 0039-7911, DOI: 10.1081/SCC-100107008
  • DENG, LI ET AL.: '"N-Benzoyl-(2R,3S)-3-phenylisoserine(3)"' J. ORG. CHEM. vol. 57, 1992, pages 4320 - 4323, XP009505609
  • HAYASHI, YOSHIO ET AL.: 'A NOVEL APPROACH OF WATER-SOLUBLE PACLITAXEL PRODRUG WITH NO AUXILIARY AND NO BYPRODUCT: DESIGN AND SYNTHESIS OF ISOTAXEL' J. MED. CHEM. vol. 46, no. 18, 01 January 2003, pages 3782 - 3784, XP055477630 DOI: 10.1021/JM034112N
  • SHEN, XIN ET AL.: 'AN EFFICIENT SEMI-SYNTHETIC METHOD TO CONSTRUCT DOCETAXEL VIA STERICALLY CROWDED LINEAR SIDE CHAIN ESTERIFICATION ' CHIN. J. CHEM. vol. 31, no. 1, 01 January 2013, pages 31 - 36, XP055477642 DOI: 10.1002/CJOC.201201142
  • DENIS, JEAN-NOEL: 'AN EFFICIENT, ENANTIOSELECTIVE SYNTHESIS OF THE TAXOL SIDE CHAIN' J. ORG. CHEM. vol. 51, 10 1986, pages 46 - 50, XP001146455 DOI: 10.1021/JO00351A008
  • V. KANDULA, SUBBA RAO ET AL.: 'AN ASYMMETRIC AMINOHYDROXYLATION ROUTE TO (+)-L-733,060' TETRAHEDRON ASYMMETRY vol. 16, no. 21, 31 October 2005, pages 3579 - 3583, XP027676213
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The present invention relates to a method for producing a 3-phenylisoserine derivative, which is important as, for example, an intermediate material for pharmaceuticals.

BACKGROUND ART



[0002] Compounds having a β-amino acid site such as 3-phenylisoserine derivatives are known to be compounds that are industrially useful for pharmaceuticals. Known examples of methods for producing a 3-phenylisoserine derivative include the following:
  1. (1) a method in which methyl phenylglycidate is subjected to a ring-opening reaction with hydrogen azide in the presence of boron trifluoride, and the resulting azide is subjected to benzoylation and catalytic hydrogenation to produce N-benzoyl-3-phenylisoserine methyl ester (see Patent Document 1);
  2. (2) a method in which 3-phenylisoserine is esterified in methanol, and benzoyl chloride is reacted with its concentrate in water to produce N-benzoyl-3-phenylisoserine methyl ester (see Patent Document 2); and
  3. (3) a method in which 3-phenylisoserine is reacted with benzoyl chloride in water, and the pH of the reaction liquid is changed to an acidic pH to allow precipitation of a crystalline product, followed by isolation of the product by solid-liquid separation to obtain N-benzoyl-3-phenylisoserine (see Non-patent Document 1).


[0003]  However, in the method (1), use of a highly toxic material and a highly explosive azide intermediate is required, which is industrially problematic.

[0004] The method (2) is a production method in which esterification is followed by protection of an amino group. In the method (2), 3-phenylisoserine methyl ester is obtained as an intermediate by carrying out the esterification in advance. However, since this intermediate has a free amino group and an ester moiety in the molecule, by-production of an intermolecular or intramolecular amide body may occur during the subsequent reaction for protection of the amino group. Moreover, in general, methyl ester bodies easily cause hydrolysis at the same time, resulting in a poor quality and a low yield.

[0005] In the method (3), N-benzoyl-3-phenylisoserine ester can be obtained by esterification of the crystals isolated by the solid-liquid separation. Since crystals precipitated by acid precipitation are generally very fine, the method has problems from the viewpoint of industrial production, such as requirement of a very long time for the solid-liquid separation and a high liquid-containing rate of the crystals. Patent Document 3 discloses method for processing a solution having optical isomers .to obtain a (2R,38) target isomer useful in the synthesis of taxanes. The method includes passing the solution through a chromatographic stationary phase that has a greater affinity for one of the target isomer and an optical isomer thereof. A portion of the solution with the target isomer is then collected. The solution may be a racemic mixture of (+/-)-N-CBZ-3-phenylisoserine ethyl ester.
Non-patent Document 2 discloses the conversion of a 3-phenylisoserine compound into an amino group-protected intermediate in a water solvent, wherein the obtained reaction mixture is extracted with THF in mixture with methylene chloride to isolate the intermediate.

PRIOR ART DOCUMENTS


[Patent Documents]



[0006] 

[Patent Document 1] WO 1993/010076

[Patent Document 2] WO 1997/002236

[Patent Document 3] WO 03/002509 A1


[Non-patent Document]



[0007] 

[Non-patent Document 1] The Journal of Organic Chemistry (1992), 57(15) 4320-4323

[Non-patent Document 2] Z. Zhou et al., Synthetic Communicat., Vol. 31, No. 23, 2001, 3609-3615


SUMMARY OF THE INVENTION


PROBLEMS TO BE SOLVED BY THE INVENTION



[0008] An object of the present invention is to provide an industrially suitable method for producing a 3-phenylisoserine derivative, which is important as a material for pharmaceuticals.

MEANS FOR SOLVING THE PROBLEMS



[0009] As a result of intensively study to solve the above problem, the present inventors discovered the present invention. That is, the present invention is a method for producing a 3-phenylisoserine derivative, comprising:
protecting an amino group of a compound represented by General Formula (1):

wherein R1 represents a phenyl group, or a phenyl group having a substituent; R2 represents an alkali metal, alkaline earth metal, or nitrogen base; and R3 represents a hydrogen atom,
in water or a mixed solvent containing water to obtain a compound represented by General Formula (2):

wherein R1; R2; and R3 have the meaning as defined above;
extracting with an ether solvent having four carbon atoms;
replacing at least part of the ether solvent having four carbon atoms with a C1-C4 aliphatic alcohol while removing the ether solvent having four carbon and water to perform esterification reaction; and
isolating at 0 to 30°C to obtain a 3-phenylisoserine derivative represented by General Formula (3):

wherein R1; R3; and R4 have the meaning as defined above; and R5 represents a C1-C4 alkyl group,
wherein the esterification reaction is carried out through an extraction step and a water removal step that are carried out subsequently without isolation of Compound (2) as an intermediate.

EFFECT OF THE INVENTION



[0010] In cases where a 3-phenylisoserine derivative is used as a material for a pharmaceutical, the derivative is strongly required to have a purity of not less than 99%. The present invention enables production of a 3-phenylisoserine derivative having a purity of not less than 99% by an industrially suitable method.

[0011] In the method for producing a 3-phenylisoserine derivative of the present invention, a 3-phenylisoserine derivative is precipitated as crystals. By taking advantage of low solubility of the desired product in a C1-C4 aliphatic alcohol, the product can be obtained at a purity of not less than 99% by separation from the mother liquor by a solid-liquid separation operation such as filtration or centrifugation followed by a drying step.

MODE FOR CARRYING OUT THE INVENTION



[0012] The present invention is described below in detail.

[0013] In the present invention, a compound represented by General Formula (1):

wherein R1 represents a phenyl group, or a phenyl group having a substituent; R2 represents an alkali metal, alkaline earth metal, or nitrogen base; and R3 represents a hydrogen atom,
is used as a starting material, and a reaction for protecting an amino group is carried out in advance in water or a mixed solvent containing water .

[0014] In cases where the esterification reaction described later is carried out in advance, the resulting ester body has a free amino group and an ester moiety in the molecule. Therefore, by-production of an intermolecular or intramolecular amide body occurs during the subsequent reaction for protection of the amino group, and hydrolysis reaction occurs at the same time. This leads to a low quality and a low yield.

[0015] In the present invention, water or a mixed solvent containing water is used. For the mixed solvent containing water, various solvents may be used as the component other than water. Examples of the solvents include ether solvents such as tetrahydrofuran; nitrile solvents such as acetonitrile; and ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone. The water or the mixed solvent containing water is preferably water or tetrahydrofuran containing water.

[0016] In the compound represented by Formula (1) as a starting material (which may be hereinafter referred to as Compound (1)),



[0017]  R1 represents a phenyl group, or a phenyl group having a substituent. Examples of the substituent in the phenyl group having a substituent include C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogen atoms. R1 is preferably a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, or 4-chlorophenyl group, more preferably a phenyl group.

[0018] In Compound (1), R2 represents an alkali metal, alkaline earth metal, or nitrogen base. Examples of the alkali metal include lithium, sodium, and potassium. Examples of the alkaline earth metal include magnesium, calcium, and barium. Examples of the nitrogen base include primary amines such as ammonia, methylamine, benzylamine, and cyclohexylamine; secondary amines such as dimethylamine, dibenzylamine, and dicyclohexylamine; and tertiary amines such as triethylamine and tributylamine. R2 is preferably an alkali metal, more preferably lithium, sodium, or potassium, still more preferably sodium or potassium.

[0019] In Compound (1), R3 represents a hydrogen atom.

[0020] Since Compound (1) has two asymmetric carbons, there are four kinds of optical isomers. In the present invention, Compound (1) may be any single optical isomer, or any mixture of those optical isomers.

[0021] Besides Compound (1), Compound (4):

wherein R1; and R3 have the meaning as defined above,or an inorganic acid salt of Compound (4) may be used as a starting material. In cases where an inorganic acid salt of Compound (4) is used, examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and hydrofluoric acid. The inorganic acid is preferably hydrochloric acid.

[0022] Preferably, in the present invention, Compound (1), Compound (4), or an inorganic acid salt of Compound (4) is added after feeding of the water or the mixed solvent containing water.

[0023] In cases where Compound (4) or an inorganic acid salt of Compound (4) is used, it is preferred to add a base depending on the valency of the acid in order to allow the reaction for protection of the amino group to proceed advantageously. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, trimethylamine, and pyridine. The base is preferably sodium hydroxide.

[0024] Preferably, in the present invention, Compound (1), Compound (4), or an inorganic acid salt of Compound (4) is added after feeding of the water or the mixed solvent containing water, and then an amino-group protecting agent is further added.

[0025] The amount of the amino-group protecting agent to be used is preferably 0.8 to 1.2 moles, more preferably 1.0 to 1.1 moles with respect to 1 mole of the Compound (1), Compound (4), or inorganic acid salt of Compound (4).

[0026] Examples of the amino-group protecting agent used in the present invention include formic acid, acetyl chloride, benzoyl chloride, di-tert-butyl dicarbonate, and benzyl chloroformate. The amino-group protecting agent is preferably benzoyl chloride, or di-tert-butyl dicarbonate.

[0027] In cases where acetyl chloride, benzoyl chloride, or benzyl chloroformate is used as the amino-group protecting agent, generation of an equimolar of hydrogen chloride occurs as the reaction proceeds. Therefore, the hydrogen chloride is preferably removed by addition of a base. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, trimethylamine, and pyridine. The base is preferably sodium hydroxide. The amount of the base to be used is preferably 0.8 to 1.2 moles, more preferably 1.0 to 1.1 moles with respect to 1 mole of the amino-group protecting agent. Preferably, the base is added at the same time as the amino-group protecting agent, or the base and the amino-group protecting agent are alternately added. The pH of the reaction liquid in this process is preferably 7 to 14, more preferably 8 to 13, most preferably 9 to 12.

[0028] The temperature during the reaction for protection of the amino group is preferably 0 to 40°C, more preferably 10 to 30°C. The aging time after the addition of the amino-group protecting agent is preferably 30 minutes to 24 hours, more preferably 1 to 12 hours.

[0029] In the present invention, a reaction liquid containing a compound represented by General Formula (2):

wherein R1; R2; and R3 have the meaning as defined above (which may be hereinafter referred to as Compound (2)) is obtained in the manner described above.

[0030] In Compound (2), R1 represents a phenyl group, or a phenyl group having a substituent. Examples of the substituent in the phenyl group having a substituent include C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogen atoms. R1 is preferably a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, or 4-chlorophenyl group, more preferably a phenyl group.

[0031] In Compound (2), R2 represents an alkali metal, alkaline earth metal, or nitrogen base. Examples of the alkali metal include lithium, sodium, and potassium. Examples of the alkaline earth metal include magnesium, calcium, and barium. Examples of the nitrogen base include primary amines such as ammonia, methylamine, benzylamine, and cyclohexylamine; secondary amines such as dimethylamine, dibenzylamine, and dicyclohexylamine; and tertiary amines such as triethylamine and tributylamine. R2 is preferably an alkali metal, more preferably lithium, sodium, or potassium, still more preferably sodium or potassium.

[0032] In Compound (2), R3 represents a hydrogen atom.

[0033] In Compound (2), R4 represents a formyl group, acetyl group, benzoyl group, tert-butoxycarbonyl group, or benzyloxycarbonyl group. R4 is preferably a benzoyl group or a tert-butoxycarbonyl group.

[0034] In the present invention, the esterification reaction is carried out through an extraction step and a water removal step that are carried out subsequently without isolation of Compound (2) as an intermediate.

[0035] First, the extraction step is described below. In the extraction step, Compound (2) is extracted into an ether solvent having four carbon atoms. Examples of the ether solvent having four carbon atoms include tetrahydrofuran, 1,2-dimethoxyethane, diethylether, and 1,4-dioxane. The ether solvent having four carbon atoms is preferably tetrahydrofuran or 1,2-dimethoxyethane.

[0036] The amount of the ether solvent having four carbon atoms to be used is preferably 3 to 10 parts by weight, more preferably 3 to 5 parts by weight with respect to 1 part by weight of the Compound (1), Compound (4), or inorganic acid salt of Compound (4). In cases where an ether solvent having four carbon atoms is used as the mixed solvent containing water in the reaction for protection of the amino group of Compound (1), the amount of the solvent used may be taken into account.

[0037] When the ether solvent having four carbon atoms is added, a hydrophobic solvent may be added in order to increase the liquid separation performance for the water or the mixed solvent containing water. Examples of the hydrophobic solvent include toluene, xylene, chloroform, and dichloromethane. The hydrophobic solvent is preferably toluene.

[0038] The amount of the hydrophobic solvent to be used is preferably 0.5 to 3 parts by weight, more preferably 1 to 2 parts by weight with respect to 1 part by weight of the Compound (1), Compound (4), or inorganic acid salt of Compound (4).

[0039] After the addition of the extraction solvent, an inorganic acid is preferably added. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and hydrofluoric acid. The inorganic acid is preferably hydrochloric acid. The amount of the inorganic acid to be added is an amount at which the pH of the reaction liquid becomes preferably 1 to 6, more preferably 2 to 5. In cases where the inorganic acid is added after the addition of the ether solvent having four carbon, precipitation of Compound (2) does not occur, so that production of a highly concentrated slurry can be avoided, and an increase in the stirring load can therefore be avoided.

[0040] For removal of an inorganic salt derived from the water contained in the thus extracted organic layer, extraction washing may be carried out by addition of water. In this process, an ether solvent having four carbon atoms and/or a hydrophobic solvent may be added for increasing the liquid separation performance. The ether solvent having four carbon atoms and the hydrophobic solvent are preferably the same as the solvents used in the extraction step.

[0041] The water removal step is described below. In this step, water is removed in order to allow the esterification reaction, which is carried out subsequently, to proceed advantageously. The water is preferably the contained water that is contained in the extracted organic layer. In cases where a hydrophobic solvent is added, the water layer alone can be selectively removed, for example, using a concentration can equipped with a Dean-Stark apparatus by utilization of the fact that the distillate is separated into two layers, that is, an organic layer and an aqueous layer. The residual water ratio is preferably not more than 2%, more preferably not more than 1% with respect to the entire liquid.

[0042] In order to increase the crystallization yield of the product after the esterification reaction, the ether solvent having four carbon atoms is removed. Since production of a highly concentrated slurry in the can, which causes an increase in the stirring load, cannot be avoided by distillation of the ether solvent having four carbon atoms alone, the C1-C4 aliphatic alcohol used in the esterification reaction is added. In the present invention, the esterification reaction is carried out while replacing at least part of the ether solvent having four carbon atoms with a C1-C4 aliphatic alcohol.

[0043] By removing the ether solvent having four carbon atoms by distillation while adding the C1-C4 aliphatic alcohol, concentration can be achieved without causing the production of a highly concentrated slurry in the can, which causes an increase in the stirring load.

[0044] The C1-C4 aliphatic alcohol is preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, more preferably methanol or ethanol.

[0045] In the present invention, at least part of the ether solvent having four carbon atoms is replaced with a C1-C4 aliphatic alcohol. The residual ratio of the ether solvent having four carbon atoms after the concentration is preferably not more than 20%, more preferably not more than 10% with respect to the entire concentrate.

[0046] By using the thus obtained concentrate in the esterification reaction that is subsequently carried out, the esterification reaction can be carried out directly without isolation of an intermediate as crystals.

[0047] The ratio of the C1-C4 aliphatic alcohol in the solvent for performing the esterification reaction is preferably not less than 60%, more preferably not less than 70%.

[0048] The esterification reaction is preferably carried out by adding an acid chloride to the concentrate.

[0049] In the present invention, a 3-phenylisoserine derivative represented by General Formula (3):

wherein R1; R3; and R4 have the meaning as defined above; and R5 represents a C1-C4 alkyl group
is obtained by the esterification reaction.

[0050] In Compound (3), R1 represents a phenyl group, or a phenyl group having a substituent. Examples of the substituent in the phenyl group having a substituent include C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogen atoms. R1 is preferably a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, or 4-chlorophenyl group, more preferably a phenyl group.

[0051] In Compound (3), R3 represents a hydrogen atom.

[0052] In Compound (3), R4 represents a formyl group, acetyl group, benzoyl group, tert-butoxycarbonyl group, or benzyloxycarbonyl group. R4 is preferably a benzoyl group or a tert-butoxycarbonyl group.

[0053] In Compound (3), R5 represents a C1-C4 alkyl group. R5 is preferably a methyl group, ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, isobutyl group, or tert-butyl group, preferably a methyl group or ethyl group.

[0054] Examples of the acid chloride to be used in the esterification reaction include thionyl chloride, oxalyl chloride, and acetyl chloride. The acid chloride is preferably thionyl chloride.

[0055] The temperature during the esterification reaction is preferably 0 to 30°C, more preferably 0 to 20°C. The aging time after the addition of the acid chloride is preferably 30 minutes to 6 hours, more preferably 1 to 3 hours.

[0056] After the aging, the 3-phenylisoserine derivative is isolated at 0 to 30°C. The 3-phenylisoserine derivative is preferably precipitated as crystals by crystallization. By taking advantage of low solubility of the desired product in the C1-C4 aliphatic alcohol, the desired product can be obtained at high purity by separation from the mother liquor by a solid-liquid separation operation such as filtration or centrifugation followed by a drying step. In this process, in cases where a concentration isolation operation is carried out at a temperature of about 50°C for the purpose of increasing the crystallization yield of the desired product, the desired product cannot be obtained at high purity because of a decrease in the purity.

EXAMPLES



[0057] The present invention is described below by way of Examples.

[0058]  In the Examples, the chemical purity was measured by the following method.

<Chemical Purity Analysis Method>


Sample Preparation



[0059] About 20 mg of each sample was accurately weighed, and placed in a 25-mL measuring flask. The sample was then diluted by adding 50% aqueous acetonitrile solution to the marked line.

[0060] Analysis conditions for high-performance liquid chromatography (HPLC)

Column: Mightsil RP-18 GP 4.6-mm diameter × 250 mm, 5 µm (Kanto Chemical Co., Inc.)

Mobile phase: A: 20 mM aqueous sodium dihydrogen phosphate solution (whose pH was adjusted to 2.1 with phosphoric acid)
B: acetonitrile

Program composition: A/B = 90/10 (Minute 0 to 10) → A/B = 30/70 (Minute 25) → A/B = 30/70 (Minute 25 to 35) → A/B = 90/10 (Minute 40) → A/B = 90/10 (Minute 40 to 45)

Flow rate: 1.0 mL/minute

Column temperature: 40°C

Measurement wavelength: 254 nm

Sample volume: 10 µL

Retention time:

20.2 minutes (N-benzoyl-3-phenylisoserine)

22.2 minutes (N-benzoyl-3-phenylisoserine methyl ester)

22.1 minutes (N-tert-butoxycarbonyl-3-phenylisoserine)

24.6 minutes (N-tert-butoxycarbonyl-3-phenylisoserine methyl ester)


Example 1



[0061] In a 2-L four-necked flask equipped with a thermometer, condenser, and stirrer, 120 g (0.551 mol) of (2R,3S)-3-phenylisoserine hydrochloride was placed, and 720 g of water and 91.9 g (1.103 mol) of 48% aqueous sodium hydroxide solution were further added thereto. At about 20°C, 79.1 g (0.562 mol) of benzoyl chloride was added dropwise to the resulting mixture while the pH in the system was kept at 9 to 12 by addition of 46.9 g (0.562 mol) of 48% aqueous sodium hydroxide solution. The resulting mixture was subjected to aging at almost the same temperature for 1 hour. Subsequently, 360 g of tetrahydrofuran and 120 g of toluene were added to the mixture, and then 58.6 g (0.562 mol) of 35% aqueous hydrochloric acid solution was added dropwise thereto at about 20°C. The pH of the reaction liquid after the dropwise addition was 2.2. To the organic layer separated after leaving the reaction liquid to stand, 120 g of water, 120 g of tetrahydrofuran, and 120 g of toluene were added, and then extraction washing was carried out. After leaving the resulting liquid to stand, the separated organic layer was placed in a 2-L four-necked flask equipped with a thermometer, condenser, stirrer, and Dean-Stark apparatus, and then concentrated under reduced pressure while removing the contained water. To the resulting concentrate, 840 g of methanol was added, and concentration under reduced pressure was continued until the liquid in the can reduced to 650 g. The internal liquid after the concentration contained 1.1% water and 9.7% tetrahydrofuran. Subsequently, 68.9 g (0.579 mol) of thionyl chloride was added dropwise thereto at about 20°C, and the resulting mixture was cooled to about 5°C, followed by filtering of the precipitated crystals, washing of the crystals with 80 g of methanol, and then drying of the crystals under vacuum to obtain 141.3 g of (2R,3S)-N-benzoyl-3-phenylisoserine methyl ester as white crystals (chemical purity: 99.3%, yield: 85.6%).
1H-NMR (CDCl3, 400 MHz) δppm: 7.78-7.76 (m, 2H), 7.53-7.29 (m, 8H), 6.98 (d, 1H), 5.75 (d, 1H), 4.64 (d, 1H), 3.84 (s, 3H), 3.29 (d, 1H)
m.p.: 183-185°C

Example 2



[0062] In a 300-mL four-necked flask equipped with a thermometer, condenser, and stirrer, 10 g (0.046 mol) of (2R,3S)-3-phenylisoserine hydrochloride was placed, and 50 g of water, 40 g of tetrahydrofuran, and 7.7 g (0.092 mol) of 48% aqueous sodium hydroxide solution were further added thereto. At about 20°C, 11.0 g (0.051 mol) of di-tert-butyl dicarbonate was added dropwise to the mixture, and the mixture was then subjected to aging at about 40°C for 4 hours. Subsequently, 10 g of toluene was added to the mixture, and then 7.2 g (0.069 mol) of 35% aqueous hydrochloric acid solution was added dropwise thereto at about 20°C. The pH of the reaction liquid after the dropwise addition was 5.0. After leaving the resulting liquid to stand, the separated organic layer was placed in a 200-mL four-necked flask equipped with a thermometer, condenser, stirrer, and Dean-Stark apparatus, and then concentrated under reduced pressure while removing the contained water. To the resulting concentrate, 50 g of methanol was added, and concentration under reduced pressure was continued until the liquid in the can reduced to 35 g. The internal liquid after the concentration contained 1.0% water and 8.6% tetrahydrofuran. Subsequently, 5.7 g (0.048 mol) of thionyl chloride was added dropwise thereto at about 10°C, and the resulting mixture was cooled to about 5°C, followed by filtering of the precipitated crystals, washing of the crystals with 10 g of methanol, and then drying of the crystals under vacuum to obtain 8.1g of (2R,3S)-N-tert-butoxycarbonyl-3-phenylisoserine methyl ester as white crystals (chemical purity: 99.0%, yield: 60.0%).
1H-NMR (CDCl3, 400 MHz) δppm: 7.37-7.29 (m, 5H), 5.40 (d, 1H), 5.22 (d, 1H), 4.49-4.48 (m, 1H), 3.84 (s, 3H), 1.62 (s, 1H), 1.43 (s, 1H)
m.p.: 131-133°C

Example 3



[0063] The same operation as in Example 1 was carried out except that 1,2-dimethoxyethane was used instead of tetrahydrofuran as the extraction solvent in the extraction step of Example 1. As a result, 137.5 g of (2R,3S)-N-benzoyl-3-phenylisoserine methyl ester was obtained as white crystals (chemical purity: 99.5%, yield: 83.3%).

Comparative Example 1



[0064] The same operation as in Example 1 was carried out except that toluene was used instead of tetrahydrofuran as the extraction solvent in the extraction step of Example 1. As a result, (2R,3S)-N-benzoyl-3-phenylisoserine as an intermediate could be hardly extracted into the organic layer. In order to evaluate the performance of the extraction solvent, solubility of (2R,3S)-N-benzoyl-3-phenylisoserine was investigated for comparison. The results are shown in Table 1.

Comparative Example 2



[0065] The same operation as in Example 1 was carried out except that cyclopentyl methyl ether was used instead of tetrahydrofuran as the extraction solvent in the extraction step of Example 1. As a result, (2R,3S)-N-benzoyl-3-phenylisoserine as an intermediate could be hardly extracted into the organic layer. In order to evaluate the performance of the extraction solvent, solubility of (2R,3S)-N-benzoyl-3-phenylisoserine was investigated for comparison. The results are shown in Table 1.

Comparative Example 3



[0066] The same operation as in Example 1 was carried out except that methyl-tert-butyl ether was used instead of tetrahydrofuran as the extraction solvent in the extraction step of Example 1. As a result, (2R,3S)-N-benzoyl-3-phenylisoserine as an intermediate could be hardly extracted into the organic layer. In order to evaluate the performance of the extraction solvent, solubility of (2R,3S)-N-benzoyl-3-phenylisoserine was investigated for comparison. The results are shown in Table 1.

Comparative Example 4



[0067] The same operation as in Example 1 was carried out except that acetonitrile was used instead of tetrahydrofuran as the extraction solvent in the extraction step of Example 1. As a result, (2R,3S)-N-benzoyl-3-phenylisoserine as an intermediate could be hardly extracted into the organic layer. In order to evaluate the performance of the extraction solvent, solubility of (2R,3S)-N-benzoyl-3-phenylisoserine was investigated for comparison. The results are shown in Table 1.
[Table 1]
 Protecting groupSolvent speciesSolubility (20°C)Solubility (40°C)
Example 1 Benzoyl group Tetrahydrofuran 9.2 wt% 11.6 wt%
Example 2 tert-Butoxycarbonyl group Tetrahydrofuran 10.1 wt% 12.2 wt%
Example 3 Benzoyl group 1,2-Dimethoxyethane 12.7 wt% 13.6 wt%
Comparative Example 1 Benzoyl group Toluene <0.1 wt% <0.1 wt%
Comparative Example 2 Benzoyl group Cyclopentyl methyl ether 0.4 wt% 0.4 wt%
Comparative Example 3 Benzoyl group Methyl-tert-butyl ether 0.2 wt% 0.4 wt%
Comparative Example 4 Benzoyl group Acetonitrile 2.2 wt% 2.9 wt%


[0068] Table 1 shows comparison of the solubilities of N-protected-3-phenylisoserine in the extraction solvents. It can be seen that N-protected-3-phenylisoserine shows high solubilities in the solvents used in the Examples.

Comparative Example 5



[0069] The same operation as in Example 1 was carried out except that a concentration isolation operation was carried out after performing dropwise addition of thionyl chloride and increasing the temperature to about 50°C. As a result, 117.4 g of (2R,3S)-N-benzoyl-3-phenylisoserine methyl ester was obtained as white crystals (chemical purity: 77.7%, yield: 55.3%). However, impurities remained in an amount of as much as about 20%, and the yield largely decreased.

Comparative Example 6



[0070] As a comparative example, a method for obtaining N-benzoyl-3-phenylisoserine ester by esterification of crystals isolated by solid-liquid separation is described.

[0071] In a 300-L four-necked flask equipped with a thermometer, condenser, and stirrer, 10 g (0.046 mol) of (2R,3S)-3-phenylisoserine hydrochloride was placed, and 100 g of water and 7.7 g (0.092 mol) of 48% aqueous sodium hydroxide solution were further added thereto. At about 20°C, 6.6 g (0.047 mol) of benzoyl chloride was added dropwise to the resulting mixture while the pH in the system was kept at 9 to 12 by addition of 3.8 g (0.046 mol) of 48% aqueous sodium hydroxide solution. The resulting mixture was subjected to aging at almost the same temperature for 1 hour. Subsequently, 4.8 g (0.046 mol) of 35% aqueous hydrochloric acid solution was added dropwise thereto at about 20°C. The pH of the reaction liquid after the dropwise addition was 2.7. The content of the can after the dropwise addition was in a state of a whipped slurry of fine crystals. The slurry was transferred to a Kiriyama funnel, and suction filtration was carried out by reducing the pressure to perform solid-liquid separation. As a result, not less than two hours were required to obtain (2R,3S)-N-benzoyl-3-phenylisoserine as wet crystals. The wet crystals were dried under reduced pressure, and then quantified. As a result, 11.0 g of dry crystals were obtained (chemical purity: 94.2%, yield: 84.2%, loss on drying: 66.1%). Subsequently, 100 g of methanol was added to the crystals, and 4.6 g (0.039 mol) of thionyl chloride was added dropwise thereto at about 20°C. The resulting mixture was cooled to about 5°C, and the precipitated crystals were collected by filtration, followed by washing with 10 g of methanol and drying under vacuum to obtain 6.8 g of (2R,3S)-N-benzoyl-3-phenylisoserine methyl ester as white crystals (chemical purity: 98.2%, process yield: 58.7%, total yield: 49.4%).

INDUSTRIAL APPLICABILITY



[0072] By the method for producing a 3-phenylisoserine derivative of the present invention, a 3-phenylisoserine derivative having a purity of not less than 99% can be obtained. A 3-phenylisoserine derivative having a purity of not less than 99% is useful as a material for pharmaceuticals.


Claims

1. A method for producing a 3-phenylisoserine derivative, comprising:
protecting an amino group of a compound represented by General Formula (1):

wherein R1 represents a phenyl group, or a phenyl group having a substituent; R2 represents an alkali metal, alkaline earth metal, or nitrogen base; and R3 represents a hydrogen atom,
in water or a mixed solvent containing water to obtain a compound represented by General Formula (2):

wherein R1, R2 and R3 have the meaning as defined above and R4 represents a formyl group, acetyl group, benzoyl group, tert-butoxycarbonyl group, or benzyloxycarbonyl group; extracting with an ether solvent having four carbon atoms;
replacing at least part of the ether solvent having four carbon atoms with a C1-C4 aliphatic alcohol while removing the ether solvent having four carbon atoms and water to perform esterification reaction; and
isolating at 0 to 30°C to obtain a 3-phenylisoserine derivative represented by General Formula (3):

wherein R1, R3 and R4 have the meaning as defined above; and R5 represents a C1-C4 alkyl group,
wherein the esterification reaction is carried out through an extraction step and a water removal step that are carried out subsequently without isolation of Compound (2) as an intermediate.
 
2. The method for producing a 3-phenylisoserine derivative according to claim 1, wherein the ether solvent having four carbon atoms is tetrahydrofuran or 1,2-dimethoxyethane.
 
3. The method for producing a 3-phenylisoserine derivative according to claim 1 or 2, wherein the C1-C4 aliphatic alcohol is methanol or ethanol.
 
4. The method for producing a 3-phenylisoserine derivative according to claim 1 or 2, wherein R4 is a benzoyl group or tert-butoxycarbonyl group.
 


Ansprüche

1. Verfahren zum Herstellen von einem 3-Phenylisoserin-Derivat, umfassend: Schützen von einer Aminogruppe einer Verbindung, die durch die allgemeine Formel (1) repräsentiert ist:

wobei R1 eine Phenylgruppe oder eine Phenylgruppe, die einen Substituenten aufweist, repräsentiert;
R2 ein Alkalimetall, Erdalkalimetall oder eine Stickstoffbase repräsentiert; und
R3 ein Wasserstoffatom repräsentiert,
in Wasser oder einem gemischten Lösungsmittel, das Wasser umfasst, um eine Verbindung zu erhalten, die durch die allgemeine Formel (2) repräsentiert ist:

wobei R1, R2 und R3 die Bedeutung haben, wie vorstehend definiert, und R4 eine Formylgruppe, eine Acetylgruppe, eine Benzoylgruppe, eine tert-Butoxycarbonylgruppe oder eine Benzyloxycarbonylgruppe repräsentiert; Extrahieren mit einem Etherlösungsmittel, das vier Kohlenstoffatome aufweist;
Ersetzen von mindestens einem Teil des Etherlösungsmittels, das vier Kohlenstoffatome aufweist, durch einen aliphatischen C1-C4 Alkohol, wobei das das Etherlösungsmittel, das vier Kohlenstoffatome aufweist, und Wasser entfernt werden, um eine Veresterungsreaktion durchzuführen; und
Isolieren bei 0 bis 30 °C, um ein 3-Phenylisoserin-Derivat zu erhalten, das durch die allgemeine Formel (3) repräsentiert ist:

wobei R1, R2 und R3 die Bedeutung haben, wie vorstehend definiert; und R5 eine C1-C4 Alkylgruppe repräsentiert,
wobei die Veresterungsreaktion durch einen Extraktionsschritt und einen Wasserentfernungsschritt durchgeführt wird, die nacheinander ohne eine Isolation der Verbindung (2) als ein Zwischenprodukt durchgeführt werden.
 
2. Verfahren zum Herstellen von einem 3-Phenylisoserin-Derivat nach Anspruch 1, wobei das Etherlösungsmittel, das vier Kohlenstoffatome aufweist, Tetrahydrofuran oder 1,2-Dimethoxyethan ist.
 
3. Verfahren zum Herstellen von einem 3-Phenylisoserin-Derivat nach Anspruch 1 oder 2, wobei der aliphatische C1-C4 Alkohol Methanol oder Ethanol ist.
 
4. Verfahren zum Herstellen von einem 3-Phenylisoserin-Derivat nach Anspruch 1 oder 2, wobei R4 eine Benzoylgruppe oder tert-Butoxycarbonylgruppe ist.
 


Revendications

1. Procédé pour produire un dérivé de 3-phénylisosérine, comprenant :
la protection d'un groupe amino d'un composé représenté par la formule générale (1) :

dans laquelle R1 représente un groupe phényle, ou un groupe phényle portant un substituant ; R2 représente un métal alcalin, un métal alcalino-terreux ou une base azotée ; et R3 représente un atome d'hydrogène,
dans de l'eau ou un mélange solvant contenant de l'eau, pour que soit obtenu un composé représenté par la formule générale (2) :

dans laquelle R1, R2 et R3 ont les significations telles que définies ci-dessus et R4 représente un groupe formyle, un groupe acétyle, un groupe benzoyle, un groupe tert-butoxycarbonyle, ou un groupe benzyloxycarbonyle ;
l'extraction avec un solvant de type éther ayant quatre atomes de carbone ;
le remplacement d'au moins une partie du solvant de type éther ayant quatre atomes de carbone par un alcool aliphatique en C1 à C4, tout en éliminant le solvant de type éther ayant quatre atomes de carbone et l'eau pour que se déroule la réaction d'estérification ; et
l'isolation à 0 à 30°C pour que soit obtenu un dérivé de 3-phénylisosérine représenté par la formule générale (3) :

dans laquelle R1, R3 et R4 ont les significations telles que définies ci-dessus ; et R5 représente un groupe alkyle en C1 à C4,
dans lequel la réaction d'estérification est mise en œuvre par l'intermédiaire d'une étape d'extraction et d'une étape d'élimination de l'eau qui sont mises en œuvre subséquemment sans isolation du composé (2) en tant qu'intermédiaire.
 
2. Procédé pour produire un dérivé de 3-phénylisosérine selon la revendication 1, dans lequel le solvant de type éther ayant quatre atomes de carbone est le tétrahydrofurane ou le 1,2-diméthoxyéthane.
 
3. Procédé pour produire un dérivé de 3-phénylisosérine selon la revendication 1 ou 2, dans lequel l'alcool aliphatique en C1 à C4 est le méthanol ou l'éthanol.
 
4. Procédé pour produire un dérivé de 3-phénylisosérine selon la revendication 1 ou 2, dans lequel R4 est un groupe benzoyle ou un groupe tert-butoxycarbonyle.
 




REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description