JPH0940620A - Optically active amino-4,4,4-trifluorocrotonate and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound containing a trifluoromethyl group at the 2-position, showing highly pharmacological action, in a high optical purity and in high yield, by reacting a specific acetate with a prescribed amino acid ester. SOLUTION: This compound of formula I [R1 is ethyl or methyl; R2 is a 1-4C alkyl ; R3 is a (substituted) lower alkali; * is an optically active center] (preferably an optically active amino-4,4-trifluorocrotonate, etc.) is obtained by reacting a trifluoroacetoacetate of formula II with an amino acid ester of formula III (preferably D-valine ester or L-valine ester) in the presence of a lower fatty acid (preferably formic acid, acetic acid, propionic acid or their mixture) substantially in the absence of a solvent, for example, at 60-80 deg.C. The amount of the fatty acid used is preferably 0.01-0.1 equivalent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active amino-4,4,4, which is an intermediate useful in the production of optically active 2-trifluoromethyl-1,4-dihydropyridines.
-Trifluorocrotonate and a process for producing the same, and a process for producing optically active 2-trifluoromethyl-1,4-dihydropyridines.

[0002]

2. Description of the Related Art Dihydropyridines are generally known as calcium channel blockers, and many of them show antihypertensive effects in mammalian cardiovascular system. Nilpadipine described in JP-B-59-48827, JP-B-61-25711 and the like is this typical compound, and its structural characteristic is that it has a cyano group at the 2-position of the 1,4-dihydropyridine skeleton. Furthermore, this nilpadipine is a mixture of a pair of optical isomers, which does not have a substituent on the 1,4-dihydropyridine skeleton and has an optically active site at the 4-position. It is also known that these optical isomer separation methods and their pharmacological actions are different. The present inventors have previously conducted structure-activity relationship studies on substituents on the dihydropyridine skeleton, and have found that those having a trifluoromethyl group at the 2-position show high pharmacological action.

[0003]

However, no useful asymmetric synthesis method or optical resolution method has been known for dihydropyridine derivatives having a trifluoromethyl group at the 2-position. Although there is a slight description in the text of Japanese Patent Laid-Open No. 5-78139, no specific description that can be implemented is made. In Japanese Patent Publication No. 6-43397, there is a description on a useful asymmetric synthesis method of dihydropyridine having an alkyl group at the 2,6 position, but there is no description about a 2-trifluoromethyldihydropyridine derivative. On the other hand, JP-A-5-140060 and JP-A-6-321877.
Is ethyl (1-ethoxycarbonylmethyl) amino-
Although there is a description about the production of 4,4,4-trifluorocrotonate, the yield is about 3%, and it is difficult to apply it to the industrial production of dihydropyridines.

[0004]

Means for Solving the Problems The inventors of the present invention firstly conducted diligent studies on the production of optically active amino-4,4,4-trifluorocrotonate, and as a result, a method for obtaining a target product with high optical purity and high yield. Found. That is, in the present invention, the scheme (1 ′)

[Chemical 7] (Wherein R1, R2 and R3 have the same meanings as described above), trifluoroacetoacetate is reacted with an optically active amino acid ester to obtain optically active amino-4,4,4-trifluorocrotonate. is there.

[0005]

The amino acid of the optically active amino acid ester appearing in the scheme (1 ') specifically means glycine, alanine, valine, leucine, isoleucine, phenylalanine, and the lower alkyl group is ,
Refers to a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl group. The reaction is carried out by dehydration condensation under heating in the presence of a catalytic amount of a lower fatty acid substantially without solvent. As the lower fatty acid, formic acid, acetic acid, propionic acid and the like are 0.0001 to 0.5 equivalent, preferably 0.001 to 0.5 equivalent, more preferably 0.01 to 0.5 equivalent.
0.1 equivalent is used. The heating is 40 ° C to 120 ° C, preferably 50 ° C to 100 ° C, more preferably 60 ° C to 8 ° C.
Performed at 0 ° C. As described above, according to the present invention, the optically active amino-4,
4,4-trifluorocrotonate can be produced. Furthermore, the optically active amino-4,4,4-trifluorocrotonate was added to the scheme (2 ′)

Embedded image (In the scheme, R1, R2, R3, R4, *, X and Y
Represents the same meaning as described above), and after the diastereoselective conjugate addition of the substituted-2-benzylideneacetoacetic acid esters in a solvent in the presence of a base at a relatively low temperature, an asymmetric auxiliary group is added. After removal by hydrolysis and subsequent reaction with ammonia or an acid addition salt thereof, dehydration in the presence of a dehydrating agent such as p-toluenesulfonic acid monohydrate gives optically active 2-trifluoromethyl-1. The 4,4-dihydropyridine derivative can be produced with high optical purity. An ether solvent such as diethyl ether or tetrahydrofuran or an aromatic solvent such as benzene or toluene is used as a reaction solvent, and n-butyl lithium or a base is used as a base.
Lithium diisopropylamide, phenyl magnesium halide and the like are used. The reaction temperature is -78 ° C to room temperature,
Preferably -78 ° C to 0 ° C, more preferably -78 ° C to
It is carried out at -20 ° C. Further, the obtained 2-trifluoromethyl-1,4-dihydropyridine derivative is hydrolyzed, or a substituent containing a functional group having high reactivity such as a haloalkyl group is previously used as X and Y in the scheme (2 ′). 2 was obtained by introducing it and subjecting it to the reaction.
It is also possible to further derivatize the trifluoromethyl-1,4-dihydropyridine compound.

As described above, the present invention provides an optically active amino-4,4,4-trifluorocrotonate, an efficient method for producing the same, and a dihydropyridine having an optically active 2-trifluoromethyl group. According to the present invention, a 2-trifluoromethyl-1,4-dihydropyridine compound useful as a therapeutic agent for hypertension and a therapeutic agent for angina can be efficiently produced according to the method for converting into a compound.

[0007]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

(Example 1) To a suspension of 200.0 g (1.10 mol) of L-valine ethyl ester hydrochloride in 1 liter of water was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize it, followed by extraction with chloroform (0.4 liter x 5 times) and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain L-valine ethyl ester (159.71 g, 1.10 mol). 198.8 g (1.17 mol) of methyl 4,4,4-trifluoroacetoacetate and acetic acid (1.5 ml) were added thereto, and the temperature was 75 ° C
The mixture was stirred for 3.5 hours. The reaction was monitored by gas chromatography (OV-17, 1.6 m, 80 ° C to 200 ° C, temperature increase at 10 ° C / min). After the completion of the reaction, the mixture was allowed to cool, the suspended matter was removed by suction filtration, and washed with toluene. The filtrate was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation (97-99 ° C / 1.2 mmHg) to give methyl (S)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotate as a colorless oil. 141.4 g (0.476 mol, yield 43%, optical purity 99.8% ee) of nate was obtained.

Specific rotation: [α] D25 + 146.2 ° (c1.05,
Methanol); Elemental analysis value Calculated as C12H18F3NO4: C, 48.48; H, 6.10; N, 4.71%. Measurements: C, 48.26; H, 5.99; N, 4.78%. Mass spectrum (FD) m / e 298 (M ++ 1); 1H-NMR (CDCl3-TMS): δ8.54 (broad d, J = 10.6Hz, 1
H), 5.20 (s, 1H), 4.20 (q, J = 7.1Hz, 2H), 3.995 (dd
d, J = 11.0, 5.0, 1.1Hz, 1H), 3.73 (s, 3H), 2.23 (m,
1H), 1.27 (t, J = 7.1Hz, 3H), 1.021 and 1.018 (2d,
J = 6.9Hz and J = 6.9Hz, 6H). The optical purity of methyl (1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate is the area% under the following HPLC analysis conditions. It was calculated by

Column: CHIRALPAK AS 4.6mmφ X 250mm Mobile phase: n-hexane: 2-propanol = 50: 1 (V / V) Flow rate: 1.0 ml / min Detection: UV-254nm Temperature: 25 ° C Pressure: 15kgf / cm2 (Example 2) Methyl (R)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate (yield) was obtained from D-valine ethyl ester hydrochloride in the same manner as in Example 1. 42%, optical purity 99.4% e.
e.) got.

Specific rotation: [α] D25 -133.1 ° (c1.15,
Methanol); Elemental analysis value Calculated as C12H18F3NO4: C, 48.48; H, 6.10; N, 4.71%. Measured values: C, 47.60; H, 5.97; N, 4.83%. Mass spectrum (FD) m / e 298 (M ++ 1); 1H-NMR (CDCl3-TMS): δ8.54 (broad d, J = 10.6Hz, 1
H), 5.20 (s, 1H), 4.20 (q, J = 7.1Hz, 2H), 3.995 (dd
d, J = 11.0, 5.0, 1.1Hz, 1H), 3.73 (s, 3H), 2.23 (m,
1H), 1.27 (t, J = 7.1Hz, 3H), 1.021 and 1.018 (2d,
J = 6.9Hz and J = 6.9Hz, 6H). (Comparative Example 1) JP-A-5-110443 and JP-A-6-32
According to the method of 1877, to a suspension of 24.74 g (0.136 mol) of L-valine ethyl ester hydrochloride in 80 ml of water, 15.48 g (0.184 mol) of sodium hydrogencarbonate and 120 ml of water were added, neutralized, and extracted with chloroform ( 150 ml × 4 times) and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 19.78 g (0.136 mol) of L-valine ethyl ester. This was dissolved in 100 ml of methylene chloride and cooled to -15 ° C. A solution of 19.93 g (0.107 mol) of methyl 4,4,4-trifluoroacetoacetate in 50 ml of methylene chloride was added dropwise thereto over about 30 minutes. During this time, the liquid temperature is -15 to -10
° C. The salt formed did not solidify and precipitate from the reaction system, so methylene chloride was concentrated under reduced pressure. The obtained pale yellow colored oily substance 44.29 g was dissolved in 200 ml of ethanol, 8.17 g of acetic acid was added, and the mixture was stirred under reflux in an oil bath at 100 ° C. for 10.5 hours. During this period, the liquid temperature was 62 to 69 ° C. The reaction is gas chromatography (OV-17, 1.6m, 80 ℃ ~ 200
Temperature was raised at 10 ° C / min). After the reaction,
The mixture was allowed to cool, the suspended matter was removed by suction filtration, and washed with toluene. The filtrate was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Distill the obtained residue (99-101 ℃ / 2.0mmH
g) and methyl (S) as a colorless oil.
-(1-Ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate and ethyl (S)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-tri There were obtained 5.93 g of a 78:22 mixture of fluorocrotonates (yields 14.5% and 4.1%, optical purity 99.4% ee).

(Comparative Example 2) 28.01 g (0.201 mol) of glycine ethyl ester hydrochloride was added to 22.73 g of sodium hydrogen carbonate.
(0.271 mol) was added to 250 ml of water, neutralized, extracted with chloroform (0.15 liter × 6 times), and dried with sodium sulfate. By distilling off the solvent under reduced pressure, 16.17 g (0.157 mol) of glycine ethyl ester was obtained. Methyl 4,4,4 was added to 15.63g (0.1512mol) of this.
-Trifluoroacetoacetate 25.79g (0.140mol)
And acetic acid (0.21 ml) were added, and the mixture was stirred at 75 ° C for 3.5 hours.
Reaction is gas chromatography (OV-17, 2.1m, 80 ℃
Up to 200 ° C. and a temperature increase of 10 ° C./min). After the completion of the reaction, the mixture was allowed to cool, the suspended matter was removed by suction filtration, and washed with toluene. The filtrate was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Distill the obtained residue (85-87 ℃ / 0.1mm
Purification by Hg) gave 11.95 g (0.047 mol, 31% yield) of colorless oil ethyl (1-ethoxycarbonylmethyl) amino-4,4,4-trifluorocrotonate.

Incidentally, Japanese Unexamined Patent Publication Nos. 5-110443 and 6
In the production example of ethyl (1-ethoxycarbonylmethyl) amino-4,4,4-trifluorocrotonate by the method of -321877, the yield is described as 3%. (Example 3) 26.72 g (37.0 ml, 0.264 mmol) of diisopropylamine was placed in a 4-necked 3 liter flask which had been purged with nitrogen.
And 640 ml of tetrahydrofuran and ice-cooled, then n-butyllithium / hexane solution (about 1.6M) 167 ml (0.267mo)
l) was added dropwise over 1 hour. The mixture was stirred under ice-cooling for 30 minutes as it was, and then cooled to -78 ° C. Methyl here (S)
-(1-Ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate 65.41 g
200 ml of a tetrahydrofuran solution of (0.220 mol) was added dropwise over 2 hours, followed by stirring for 1 hour. Further, 450 ml of a tetrahydrofuran suspension solution of 88.05 g (0.220 mol) of methyl 2- {2- (4-bromobutoxy) -5-nitrobenzylidene} acetoacetate was added dropwise thereto over 2 hours. Then, after continuing stirring at around -35 ° C (-39 to -32 ° C) for 2 hours, the reaction was terminated with 620 ml of 1N-hydrochloric acid, and the mixture was stirred overnight at room temperature. When the stirring was stopped, the reaction solution separated into two layers, and the lower aqueous layer had pH = 2. The reaction mixture was separated, 6N-hydrochloric acid (500 ml) was added to the organic layer except the aqueous layer, and the mixture was stirred for 4 hours. After separating the organic layer, 300 ml of ethyl acetate was added to the aqueous layer.
3 times, and the organic layer was combined, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and dried over sodium sulfate. When the solvent was distilled off, a brown oily substance (132.5
g) was obtained, 1500 ml of ethanol was added to this oily substance, 35.64 g (0.462 mol) of ammonium acetate was added, and the mixture was stirred at room temperature for 2 hours and then at 75 ° C. for 2 hours. Ethanol was distilled off under reduced pressure, the oily residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate solution,
It was dried over magnesium sulfate. The solvent was distilled off to obtain a brown oily substance (86.4 g). To this oil, 700 m of toluene
After the addition of l, 11.53 g of p-toluenesulfonic acid monohydrate
(0.06mol) was added, and the mixture was stirred at 100 ° C for 2 hours. The reaction is TLC
(Rf 0.36 (SiO2, hexane / ethyl acetate = 2/1 v / v))
Monitored at The reaction solution was allowed to cool and the suspended matter was removed by filtration. The filtrate was washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, the aqueous layer was extracted with 200 ml of ethyl acetate, the organic layer was combined with the organic layer, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give a brown oily substance.
76.57 g (82% ee) was obtained. To 76.57 g of the obtained brown oily substance, 20 ml of ethyl acetate was added to solidify, 70 ml of diisopropyl ether was added, suction filtration was carried out, washing with diisopropyl ether and drying were carried out to obtain (+)-dimethyl.
4- {2- (4-Bromobutoxy) -5-nitrophenyl} -1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate 29.41
g (83% ee) was obtained as a yellow crude powder. The filtrate was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (hexane / ethyl acetate = 3/1 v / v) to give a yellow oil (22.20 g). 5 ml of ethyl acetate was added to the obtained yellow oil to solidify it, 50 ml of diisopropyl ether was added, suction filtration was carried out, washing with diisopropyl ether and drying gave 4.95 g of yellow crude powder (83%).
ee) was obtained. These yellow crude powders are collectively recrystallized from ethyl acetate / diisopropyl ether,
11.10 g (0.020 mol, melting point 166.6-167.5)
℃, 83.0% ee), second crystal 18.58g (0.034mol, melting point 16
6.4-167.4 ℃, 85.3% ee), third crystal 1.18g (0.00214m)
ol, melting point 165.2-166.6 ℃, 89.4% ee) and quaternary crystal 0.24g
(0.000435 mol, melting point 160.0-162.1 ° C, 89.5% ee) was obtained. These yellow powders were used together in Application Example 1.

Mass spectrometry (FD) m / e 550 (M +); 1H-NMR (CDCl3-TMS): δ 8.10 (dd, J = 9.1 and 2.8Hz,
1H), 8.06 (d, J = 2.8Hz, 1H), 6.89 (d, J = 9.1Hz, 1
H), 6.08 (s, 1H), 5.41 (s, 1H), 4.11 (d, J = 6.1Hz,
2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.53 (dt, J = 6.3 a
nd 3.0Hz, 2H), 2.43 (s, 3H), 2.16-1.97 (m, 4H). In addition, dimethyl 4- {2- (4-bromobutoxy)-
The optical purity of 5-nitrophenyl} -1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate is the area% under the following HPLC analysis conditions.
Was calculated by

Column: CHIRALCEL OD-H 4.6 mmφ X 250 mm Mobile phase: n-hexane: 2-propanol = 9: 1 (V / V) Flow rate: 1.0 ml / min Detection: UV-254nm Temperature: 25 ° C Pressure: 15 kgf / cm2 (+)-Dimethyl 4 collected by chiral HPLC
-{2- (4-Bromobutoxy) -5-nitrophenyl} -1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate Write down.

Specific rotation: [α] D25 + 179.2 ° (c0.10,
Methanol); Melting point: 167.0-169.2 ° C. (Application Example 1) (+)-dimethyl 4-obtained in Example 4
{2- (4-Bromobutoxy) -5-nitrophenyl}
-1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate 24.24 g (4
3.97 mmol) and (S) -3-amino-1- (2-methylphenoxy) -2-propanol 28.01 g (154.55 mmol, 10
Acetonitrile (240 ml) was added to 0% ee), the mixture was stirred with heating under reflux for 3 hours, allowed to cool, and the suspended matter was removed by filtration. The filtrate was evaporated under reduced pressure, the residue was dissolved in chloroform and 1N-
It was washed successively with 250 ml of hydrochloric acid, 100 ml, 100 ml, 200 ml, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a brown residue. 5.54 g of oxalic acid dihydrate was added to the obtained brown oil.
(43.94 mmol) and add ethanol to dissolve it,
The solvent was distilled off under reduced pressure, 70 ml of chloroform was added, and the precipitated solid was collected by suction filtration and washed with 80 ml of chloroform. This solid was washed with 400 ml of water and 100 ml of hexane and dried to give 16.04 g of a slightly yellow powder (chemical purity 96.8%, optical purity 98.3%).
was gotten. The residue obtained by distilling off the filtrate washed with chloroform under reduced pressure was similarly solidified from chloroform to give 1.71 g of a slightly yellow powdery second crystal (chemical purity 95.5%, optical purity 97.8%), third crystal 1.49 g. (Chemical purity 94.2%, optical purity
95.2%) and quaternary crystal 2.49g (chemical purity 97.0%, optical purity 9
4.9%) was obtained.

These light yellow powders were collectively recrystallized from 300 ml of chloroform / 8 ml of methanol (liquid temperature 60 ° C.), and 15.91 g of the first crystals of light yellow powder (chemical purity 97.6%, optical purity 98.9%), second 1.98 g of crystals (chemical purity 97.8%, optical purity 98.1%) were obtained. These slightly yellow powders were collected together and recrystallized from 350 ml of chloroform / 6 ml of methanol (liquid temperature 60 ° C) to obtain dimethyl 1,4-dihydro-4- [2- [4- {2-hydroxy-3 as light yellow crystals. -(2
-Methylphenoxy) propylamino} butoxy] -5
-Nitrophenyl] -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate oxalate 16.41 g (22.13 mmol, chemical purity 98.0%, optical purity 98.9
%)was gotten.

Melting point: 80.5-82.5 ° C .; 1H-NMR (DMSO-d6, DMSO was 2.49 ppm): δ9.13 (broad s, 1H), 8.12 (dd, J = 9.0 and
2.9Hz, 1H), 7.84 (d, J = 2.9Hz, 1H), 7.19 (d, J = 9.3
Hz, 1H), 7.16-7.12 (m, 2H), 6.90 (d, J = 8.0Hz, 1H),
6.84 (t, J = 7.4Hz, 1H), 5.24 (s, 1H), 4.20-4.09 (m,
3H), 3.98 (dd, J = 10.0 and 4.9Hz, 1H), 3.92 (dd, J =
10.0 and 5.6Hz, 1H), 3.59 (s, 3H), 3.48 (s, 3H),
3.21-3.16 (m, 1H), 3.09-2.99 (m, 3H), 2.37 (s, 3
H), 2.16 (s, 3H), 1.87-1.74 (m, 4H); IR (KBr) 3348, 3115, 3013, 2950, 1722, 1718, 171
6, 1703, 1634, 1626, 1622, 1620, 1616, 1590, 1514,
1506, 1498, 1435, 1344, 1283, 1265, 1242, 1226, 1
183, 1145, 1102, 752 cm-1. (Application Example 2) Dimethyl 1,4-dihydro-4- [2- [4- {2-hydroxy-3- (2
-Methylphenoxy) propylamino} butoxy] -5
-Nitrophenyl] -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate oxalate (16.41 g) was dissolved in chloroform (1.5 liter) and washed with saturated aqueous sodium hydrogen carbonate solution (500 ml x 3). 2N-
It was washed with 100 ml of hydrochloric acid × 3 and dried over magnesium sulfate.
To the yellow oil obtained by distilling off the solvent (chemical purity 99.4%, optical purity 98.9%) was added 170 ml of isopropyl acetate under heating to solidify, suction filtration was carried out, washing with 50 ml of isopropyl acetate and drying gave Yellow crystals 14.30g (Chemical purity 99.4
%, Optical purity 99.0%) was obtained. This pale yellow crystal 13.8
Ethanol (50 ml) was added to 0 g under heating to solidify, and the mixture was collected by suction filtration, washed with 25 ml of isopropyl alcohol and dried to give dimethyl 1,4-dihydro-4 as pale yellow crystals.
-[2- [4- {2-Hydroxy-3- (2-methylphenoxy) propylamino} butoxy] -5-nitrophenyl] -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate・ Hydrochloride 8.02g (11.6
6mmol, melting point 162.0-162.5 ℃, chemical purity 99.1%, optical purity
98.4%) was obtained. The filtrate was distilled off under reduced pressure, 20 ml of ethanol was added to the residue under heating to dissolve it, and the mixture was allowed to cool, and the precipitate was collected by suction filtration, washed with 15 ml of isopropyl alcohol and dried to give a slightly yellow crystal as a second crystal. 3.65 g (5.30 mm
ol, melting point 161.4-162.8 ° C, chemical purity 99.5%, optical purity 99.
1%) was obtained. The analytical values of the combined first crystal and second crystal are shown below.

Mass spectrometry (FD) m / e 652 (M ++
1); Elemental analysis value Calculated as C31H37ClF3N3O9: Cl; 5.15%. Measured value: Cl; 5.10%. 1H-NMR (CDCl3-TMS): δ8.05 (dd, J = 10.9, 2.8Hz, 1
H), 8.02 (d, J = 2.7Hz, 1H), 7.13-7.06 (m, 2H), 6.
92 (s, 1H), 6.87 (t, J = 7.4Hz, 1H), 6.80 (d, J = 9.0H
z, 1H), 6.73 (d, J = 8.4Hz, 1H), 5.36 (s, 1H), 4.71-
4.62 (m, 1H), 4.11-3.99 (m, 3H), 3.96 (dd, J = 9.7,
6.0Hz, 1H), 3.62 (s, 3H), 3.57 (s, 3H), 3.67 (dd, J
= 12.5, 2.4Hz, 1H), 3.32-3.22 (m, 3H), 2.41 (s, 3
H), 2.18 (s, 3H), 2.23-1.92 (m, 4H); Specific rotation: [α] D25 + 147.7 ° (c1.009, methanol); IR (KBr) 3276, 2951, 1731, 1712 , 1699, 1510, 149
6, 1436, 1336, 1288, 1269, 1250, 1182, 1149, 1087,
747 cm-1. (Example 4) (R)-(1-ethoxycarbonyl-2-
(-) In the same manner as in Example 3 except that methylpropyl) amino-4,4,4-trifluorocrotonate was used.
-Dimethyl 4- {2- (4-bromobutoxy) -5-
Nitrophenyl} -1,4-dihydro-6-methyl-2
-Trifluoromethylpyridine-3,5-dicarboxylate (yield 40%, optical purity 83.0% ee) was obtained as a yellow powder.

Mass spectrometry (FD) m / e 550 (M +) 1H-NMR (CDCl3-TMS): δ 8.10 (dd, J = 9.1 and 2.8Hz,
1H), 8.06 (d, J = 2.8Hz, 1H), 6.89 (d, J = 9.1Hz, 1
H), 6.08 (s, 1H), 5.41 (s, 1H), 4.11 (d, J = 6.1Hz,
2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.53 (dt, J = 6.3 a
nd 3.0Hz, 2H), 2.43 (s, 3H), 2.16-1.97 (m, 4H). (-)-Dimethyl 4 separated by chiral HPLC.
-{2- (4-Bromobutoxy) -5-nitrophenyl} -1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate Write down.

Specific rotation: [α] D25 -188.4 ° (c0.10,
(Methanol); Melting point: 166.5-169.0 ° C. (Example 5) 1.6M n-butyllithium hexane solution (16.3 ml) was slowly added dropwise to an ice-cooled solution of diisoproamine (3.65 ml) in tetrahydrofuran (56 ml). Did (1
5 minutes). The mixture was stirred under ice cooling for 30 minutes and then cooled to -70 ° C. To this, a solution of methyl (S)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate (6.46 g, 21.7 mmol) in tetrahydrofuran (17 ml) was added dropwise over 1 hour. did. Further, after stirring for 1 hour, isopropyl 2- (3-nitrobenzylidene) acetoacetate (6.0 g, 21.7 m
A solution of (mol) in tetrahydrofuran (38 ml) was added dropwise over 1 hour. The temperature of the reaction solution was raised from -70 ° C to -30 ° C over 3.5 hours. After cooling to −50 ° C. again, 1N hydrochloric acid (35 ml) was added, and the mixture was stirred at room temperature for 24 hours. After separating the organic layer and the hydrochloric acid layer, 6N hydrochloric acid (35 ml) was added to the organic layer, and the mixture was stirred overnight. After separating the organic layer and the hydrochloric acid layer again, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the organic layer and extraction was performed 3 times. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was diluted with ethanol (70 ml) and ammonium acetate (2.51
g, 32.6 mmol), and the mixture was stirred at room temperature for 2 hours and then refluxed for 2.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added for extraction. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (SiO2, hexane / ethyl acetate = 10 /
The crude isopropyl 2-hydroxy-1,2,3,4-tetrahydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2 was obtained by purification in 1).
6.5 g of trifluoromethylpyridine-5-carboxylate were obtained as a brown oil.

Toluene (20 ml) and p-toluenesulfonic acid monohydrate (1.0 g) were added thereto, and the mixture was heated in an oil bath at 120 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture for liquid separation, and the aqueous layer was extracted twice with toluene. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (SiO2, hexane / ethyl acetate =
Purification by 10/1) yielded 4.75 g (yield 51.1%) of the desired compound as a brown oil. The obtained target product was analyzed by HPLC (DAICEL CHIRALCEL OD-H, Hexane / IPA = 50/1, 1.
The optical purity was 90 as a result of analysis by 0 ml / min, rt).
It was 6% ee.

Mass spectrometry (FD) m / e 428 (M
+); Specific rotation: [α] D25 + 117.9 ° (c0.630, methanol) IR (KBr) 3384, 2978, 1708, 1704, 1698, 1534, 150
3, 1352, 1321, 1283, 1221, 1074, 788 cm-1; 1H-NMR (CDCl3-TMS) δ8.125 (t, J = 1.98Hz, 1H), 8.0
74 (ddd, J = 0.85, 2.30, 8.30Hz, 1H), 7.621 (d, J = 7.7
0Hz, 1H), 7.443 (t, J = 7.93Hz, 1H), 6.182 (s, 1H),
5.147 (s, 1H), 4.979 (quint., J = 6.26Hz, 1H), 3.711
(s, 3H), 2.427 (s, 3H), 1.265 (d, J = 6.20Hz, 3H),
1.113 (d, J = 6.25Hz, 3H). (Application 3) (+)-isopropyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoro Methylpyridine-5
-Carboxylate (4.30 g, 10.0 mmol, optical purity 9
A 0.6% ee) methylene chloride (10.0 ml) solution was slowly added dropwise to ice-cooled concentrated sulfuric acid (8.0 ml). The reaction mixture was stirred under ice cooling for 1 hour and then slowly poured into ice water. Chloroform was added to this, and it extracted 3 times. The obtained organic layer is
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated powder solid was washed with isopropyl ether to give (+)-1,4-dihydro-3-methoxycarbonyl-6-methyl-4-.
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylic acid as a pale yellow powder 2.86 g
(Yield 73.8%) was obtained.

The resulting carboxylic acid was subjected to HPLC (CHIRAL AGP,
1.01M phosphate buffer pH 7.0, 0.2 ml / min, r.
t.), the optical purity was 93.6% ee.

Mass spectrometry (FD) m / e 386 (M +); Melting point: 180.0-181.0 ° C. (decomposition) Specific rotation: [α] D25 + 139.0 ° (c0.502, methanol). 1H NMR (CDCl3-TMS) δ8.103 (t, J = 1.95Hz, 1H), 8.0
8-8.06 (m, 1H), 7.634 (d, J = 7.70Hz, 1H), 7.445 (t, J =
7.93Hz, 1H), 6.349 (s, 1H), 5.166 (s, 1H), 3.720 (s,
3H), 2.454 (s, 3H). (Application 4) (+)-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
Triethylamine (0.72 ml) was added to a mixture of 2-trifluoromethylpyridine-5-carboxylic acid (1.0 g, 2.59 mmol) and dibromohexane (4.0 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into saturated aqueous sodium hydrogen carbonate, chloroform was added, and the mixture was extracted 3 times. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and hexane (100 ml) was added to the obtained residue. The supernatant was removed and the resulting oily substance was purified by column chromatography (SiO2, chloroform) to give (+)-6-bromohexyl 1,4.
-Dihydro-3-methoxycarbonyl-6-methyl-4
-(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate as a brown oil 1.
1 g was obtained. Isopropyl ether (9.0 ml)
When recrystallized by adding, 0.85
g (yield 60.0%) was obtained. The resulting bromohexyl compound was analyzed by HPLC (DAICEL CHIRALCEL OD-H, Hexane / IPA = 15/1,
When the analysis was performed using 1.0 ml / min, rt), the optical purity was 100% ee.

Melting point: 93.5-94.5 ° C. Specific rotation: [α] D25 + 141.0 ° (c0.525, methanol); 1H-NMR (CDCl3-TMS) δ8.11-8.10 (m, 2H), 8.09-8.0
6 (m, 1H), 7.63−7.61 (m, 1H), 7.453 (t, J = 7.90Hz,
1H), 6.229 (s, 1H), 5.165 (s, 1H), 4.099 (dt, J = 6.
65, 1095Hz, 1H), 4.031 (dt, J = 6.60, 10.90Hz, 1H),
3.723 (s, 3H), 3.383 (t, J = 6.70Hz, 2H), 2.448 (s, 3
H), 1.84-1.78 (m, 2H), 1.62-1.59 (m, 2H), 1.417 (qu
int., J = 7.65Hz, 2H), 1.29-1.24 (m, 2H). (Application example 5) (+)-6-bromohexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (670 mg, 1.22 mmol) and (S) -2-hydroxy-3-phenoxypropylamine (610 mg, 3.66 mmol) in acetonitrile (8 ml) The mixture was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, chloroform was added, and the mixture was extracted 3 times. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (SiO2, chloroform / methanol =
When purified by 10/1), 6-{(S) -2-hydroxy-
3-phenoxypropylamino} hexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4-
630 m of (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate as a yellow oil.
g (yield 81.3%) was obtained.

1H-NMR (CDCl3-TMS) δ8.108 (t, J = 1.93
Hz, 1H), 8.073 (dd, J = 2.35, 8.30Hz, 1H), 7.619 (d,
J = 7.70Hz, 1H), 7.446 (t, J = 7.95Hz, 1H), 7.279 (d
t, J = 1.05, 7.98Hz, 2H), 6.956 (t, J = 7.30Hz, 1H),
6.917 (d, J = 7.95Hz, 2H), 6.256 (s, 1H), 5.163 (s, 1
H), 4.13-3.98 (m, 5H), 3.716 (s, 3H), 2.906 (dd,
J = 3.80, 12.20Hz, 1H), 2.805 (dd, J = 8.20, 12.25Hz,
1H), 2.439 (s, 3H), 1.62-1.55 (m, 2H), 1.52-1.46
(m, 2H), 1.35-1.26 (m, 2H), 1.26-1.20 (m, 2H). 6-{(S) -2-hydroxy-3-phenoxypropylamino} hexyl 1,4-dihydro-3- Methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
To a mixture of 2-trifluoromethylpyridine-5-carboxylate and methanol (4.0 ml) was added 1N hydrogen chloride in methanol (2.0 ml). After stirring for 30 minutes, methanol was distilled off under reduced pressure. Chloroform was added to the obtained residue and dried over anhydrous sodium sulfate. When the solvent was again distilled off under reduced pressure, (+)-6-{(S) -2-hydroxy-3-phenoxypropylamino} hexyl 1,
4-dihydro-3-methoxycarbonyl-6-methyl-
4- (3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate hydrochloride was obtained as a pale yellow foam.

Specific rotation: [α] D25 + 88.4 ° (c0.505,
Methanol); 1H-NMR (CDCl3-TMS) δ9.605 (broad s, 1H), 8.687
(broad s, 1H), 8.091 (d, J = 0.80Hz, 1H), 8.03 (d, J
= 8.30Hz, 1H), 7.614 (d, J = 7.75Hz, 1H), 7.470 (t, J =
7.68Hz, 1H), 7.247 (t, J = 8.48Hz, 2H), 6.948 (t, J =
7.35Hz, 1H), 6.869 (d, J = 8.00Hz, 2H), 6.337 (s, 1
H), 5.139 (s, 1H), 4.654 (broad s, 1H), 4.10-3.94
(m, 4H), 3.707 (s, 3H), 3.34-3.21 (m, 2H), 3.07-2.
99 (m, 2H), 2.421 (s, 3H), 1.88-1.82 (m, 2H), 1.60-
1.54 (m, 2H), 1.36-1.29 (m, 2H), 1.28-1.17 (m, 2H). (Example 6) Methyl (R)-(1-ethoxycarbonyl-2-methylpropyl) amino-4, (-)-Isopropyl 1,4-dihydro-3- as in Example 5, except that 4,4-trifluorocrotonate was used.
Methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate was obtained with a yield of 73.3%. The obtained target compound was analyzed by HPLC (DAICEL CHIRALCEL OD-H, Hexane / IPA = 50/1, 1.0
ml / min, rt), the optical purity was 91.4%
It was ee.

Specific rotation: [α] D25 -128.1 ° (c0.65
5, methanol). (Application Example 6) (-)-isopropyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5
-Carboxylate (4.80 g, 11.2 mmol, 91.4% e.
(−) − in the same manner as in Application Example 3 except that e.) is used.
1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylic acid as a pale yellow powder 3.
44 g (yield 79.5%) was obtained.

The obtained carboxylic acid was subjected to HPLC (CHIRAL AGP,
1.01M phosphate buffer pH 7.0, 0.2 ml / min, rt)
When analyzed using, it was 92.7% ee.

Specific rotation: [α] D25 -140.0 ° (c0.51
0, methanol); 1H-NMR (CDCl3-TMS) δ8.103 (t, J = 1.95Hz, 1H), 8.0
8-8.06 (m, 1H), 7.634 (d, J = 7.70Hz, 1H), 7.445 (t,
J = 7.93Hz, 1H), 6.349 (s, 1H), 5.166 (s, 1H), 3.720
(s, 3H), 2.454 (s, 3H). (Application 7) (−)-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
-2-Trifluoromethylpyridine-5-carboxylic acid
(-)-6-Bromohexyl 1,4-dihydro-in the same manner as in Application Example 4 except that (1.0 g, 2.59 mmol) was used.
3-Methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-
0.78 g of carboxylate as pale yellow needle crystals
(Yield 54.7%) was obtained. The resulting bromohexyl compound was analyzed by HPLC (DAICEL CHIRALCEL OD-H, Hexane / IPA = 15/1, 1.
When analyzed using 0 ml / min, rt), the optical purity was 100% ee.

Melting point: 93.5-94.5 ° C. Specific rotation: [α] D25 -139.1 ° (c0.510, methanol); 1H NMR (CDCl3-TMS) δ8.11-8.10 (m, 2H), 8.09-8.
06 (m, 1H), 7.63-7.61 (m, 1H), 7.453 (t, J = 7.90H
z, 1H), 6.229 (s, 1H), 5.165 (s, 1H), 4.099 (dt, J =
6.65, 1095Hz, 1H), 4.031 (dt, J = 6.60, 10.90Hz, 1
H), 3.723 (s, 3H), 3.383 (t, J = 6.70Hz, 2H), 2.448
(s, 3H), 1.84-1.78 (m, 2H), 1.62-1.59 (m, 2H), 1.4
17 (quint., J = 7.65Hz, 2H), 1.29-1.24 (m, 2H). (Application 8) (−)-6-bromohexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl- 4-
(-)-6- in the same manner as in Application Example 5 except that (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (600 mg, 1.09 mmol) was used.
{(S) -2-Hydroxy-3-phenoxypropylamino} hexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2
-Trifluoromethylpyridine-5-carboxylate was obtained as a pale yellow foam.

Specific rotation: [α] D25 -108.5 ° (c0.50
5, methanol); 1H-NMR (CDCl3-TMS) δ9.612 (broad s, 1H), 8.694
(broad s, 1H), 8.10-8.06 (m, 2H), 7.610 (d, J = 7.75
Hz, 1H), 7.464 (t, J = 7.88Hz, 1H), 7.245 (t, J = 8.50
Hz, 2H), 6.945 (t, J = 7.38Hz, 1H), 6.870 (d, J = 7.80
Hz, 2H), 6.310 (s, 1H), 5.141 (s, 1H), 4.647 (broa
ds, 1H), 4.10-3.94 (m, 4H), 3.705 (s, 3H), 3.34-3.
27 (m, 1H), 3.27-3.17 (m, 1H), 3.07-2.99 (m, 2H),
2.419 (s, 3H), 1.88-1.82 (m, 2H), 1.60-1.54 (m, 2
H), 1.37-1.30 (m, 2H), 1.26-1.19 (m, 2H). (Example 7) A solution of diisoproamine (30.5 ml) in ice-cooled tetrahydrofuran (460 ml) was added with 1.6 M n-butyl. A lithium hexane solution (136 ml) was slowly added dropwise (20 minutes). The mixture was stirred under ice cooling for 30 minutes and then cooled to -69 ° C. To this, a solution of methyl (S)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate (53.8 g, 0.18 mol) in tetrahydrofuran (140 ml) was slowly added dropwise (1.5 time). After stirring for 1 hour, isopropyl 2- (3-nitrobenzylidene) acetoacetate (50.0 g, 0.18
A tetrahydrofuran (320 ml) solution of (mol) was slowly added dropwise (2 hours). The reaction temperature was gradually increased from -68 ° C to -30 ° C (3.5 hours). After cooling to −50 ° C. again, 1N hydrochloric acid (500 ml) was added, and the mixture was stirred at room temperature for one day. After separating the organic layer and hydrochloric acid layer, 6N hydrochloric acid (4
00 ml) was added and the mixture was stirred for 4 hours. After separating the organic layer and the hydrochloric acid layer again, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the organic layer for liquid separation, and the aqueous layer was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, isopropanol (500 ml) and ammonium acetate (30 g, 0.39 mol) were added to the obtained residue (about 90.3 g),
The mixture was stirred at room temperature for 2 hours and then refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure (about 160 g). Ethyl acetate (400 ml) and saturated aqueous sodium hydrogen carbonate (500 ml) were added to the mixture for liquid separation, and the aqueous layer was extracted twice with ethyl acetate (300
ml x 2). The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and toluene (750 ml) was added to the obtained residue (about 88.0 g).
And p-toluenesulfonic acid monohydrate (15 g) were added, and 12
Heat in an oil bath at 0 ° C. for 1 hour. At this time, the generated water (about 3 ml) was removed using Dean Stark.
Saturated aqueous sodium hydrogen carbonate (400 ml) was added to the reaction mixture for partitioning, and the aqueous layer was extracted twice with toluene. The obtained organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate.
Removal of the solvent under reduced pressure gave crude (+)-isopropyl 1,
4-dihydro-3-methoxycarbonyl-6-methyl-
4- (3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (79.7 g) was obtained as a yellow oil. The resulting crude product was analyzed by HPLC (DAI
CEL CHIRALCEL OD-H, Hexane / IPA = 50/1, 1.0 ml / min, U
When analyzed using V254nm, rt), the optical purity was about 90% ee.

This crude product (75.1 g) was dissolved in methylene chloride (120 ml) and slowly added dropwise to ice-cooled concentrated sulfuric acid (115 ml). The reaction mixture was stirred for 1 hour under ice cooling, and then slowly added dropwise to ice water (50 minutes). Chloroform was added to this, and the mixture was separated.
It was extracted twice. The obtained organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the obtained crude crystals, and suction filtration was performed. The crystals were thoroughly washed with isopropyl ether and dried under reduced pressure to obtain 28.4 g of the target compound as a pale yellow powder. The solvent in the filtrate was distilled off again under reduced pressure, and the resulting residue (70.5 g) was mixed with chloroform (1
00 ml) and hexane (116 ml) were added. The precipitated crystals are suction filtered, washed with isopropyl ether and dried under reduced pressure to give (+)-1,4-dihydro-3-.
7.1 g of methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylic acid were obtained.

The obtained carboxylic acid (35.5 g) was dissolved in chloroform (400 ml), and hexane (400 m) was added thereto.
l) was added and the mixture was recrystallized to obtain 31.1 g of the desired half ester as pale yellow crystals. HPLC
(CHIRAL AGP, 1.01M phosphate buffer pH 7.0, 0.2 ml
/ min, rt), the optical purity was 100% e.
It was e.

Melting point: 180.0-181.0 ° C. (decomposition); 1H-NMR (CDCl3-TMS) δ8.103 (t, J = 1.95Hz, 1H), 8.0
8-8.06 (m, 1H), 7.634 (d, J = 7.70Hz, 1H), 7.445 (t,
J = 7.93Hz, 1H), 6.349 (s, 1H), 5.166 (s, 1H), 3.720
(s, 3H), 2.454 (s, 3H). (Application 9) (+)-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
2-Trifluoromethylpyridine-5-carboxylic acid (1.0 g, 80.3 mmol) was added to methylene chloride (120 ml) -DMF.
It was dissolved in a mixed solvent (30 ml) and ice-cooled. Thionyl chloride (7.0 ml) was slowly added dropwise (15 minutes) under ice cooling.
Stir for 1.5 hours. Add 6-bromohexanol (17.4
g, 96.3 mmol) in methylene chloride (60 ml) was slowly added dropwise (40 minutes). After stirring for 1 hour, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate under ice cooling, ether was added, and the layers were separated. The aqueous layer was extracted twice with ether. The obtained organic layer was washed with a 3% aqueous sodium hydroxide solution and saturated saline, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, isopropyl ether was added to the obtained crude crystals and suction filtration was performed. By thoroughly washing the crystals with isopropyl ether and drying under reduced pressure,
(+)-6-Bromohexyl 1,4-dihydro-3-
22.2 g of methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate was obtained as pale yellow crystals.
The obtained bromohexyl compound was analyzed by HPLC ((DAICEL CHIRALCE
When the analysis was carried out using L OD, Hexane / IPA = 15/1, 1.0 ml / min, rt), the optical purity was 100% ee.

(Recrystallization of Bromohexyl Form) (+)-6-Bromohexyl 1,4-obtained by the above method
Dihydro-3-methoxycarbonyl-6-methyl-4-
24.0 g of (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate was dissolved in 18 ml of ethyl acetate at 50 ° C. 80 ml of hexane was slowly added to this solution, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were suction filtered and washed with isopropyl ether. The obtained crystal was dried under reduced pressure to obtain 20.4 g of the objective compound as a pale yellow needle crystal.

Melting point: 93.5-94.5 ° C 1H-NMR (CDCl3-TMS) δ8.11-8.10 (m, 2H), 8.09-8.0
6 (m, 1H), 7.63-7.61 (m, 1H), 7.453 (t, J = 7.90Hz,
1H), 6.229 (s, 1H), 5.165 (s, 1H), 4.099 (dt, J =
6.65, 1095Hz, 1H), 4.031 (dt, J = 6.60, 10.90Hz, 1
H), 3.723 (s, 3H), 3.383 (t, J = 6.70Hz, 2H), 2.448
(s, 3H), 1.84-1.78 (m, 2H), 1.62-1.59 (m, 2H), 1.4
17 (quint., J = 7.65Hz, 2H), 1.29-1.24 (m, 2H). (Application 10) (+)-6-Bromohexyl 1,4-
Dihydro-3-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (20.1 g, 36.6 mmol) and (S) -2-hydroxy-3-phenoxypropylamine (18.4 g, 109.8 mmol, 98.4% ee) Of acetonitrile (240 ml) was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, chloroform was added, and the layers were separated. The aqueous layer was extracted twice with chloroform. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (WAKOGEL C-200, 1.7 kg, CHCl3 / MeOH.
= 20/1 to 5/1) for purification. From HPLC, it was divided into five fractions according to purity. (I) 0.56g, 76.7%,
(II) 1.46g, 93.2%, (III) 4.93g, 94.2%, (IV) 11.8
7g, 95.1%, (V) 0.84g, 95.8%, (VI) 0.37g, 62.7
%. Yellow oil.

This oily substance 6-{(S) -2-hydroxy-3-phenoxypropylamino} hexyl 1,4-
Dihydro-3-methoxycarbonyl-6-methyl-4-
(3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (the above-mentioned fraction (III) +
To a mixture of (IV), 16.3 g,> 94%) and methanol (170 ml) was added 1N hydrogen chloride in methanol (80 ml). After stirring for 30 minutes, methanol was distilled off under reduced pressure. Chloroform was added to the obtained residue and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the resulting residue, and reprecipitation was carried out, resulting in (+)-
6-{(S) -2-hydroxy-3-phenoxypropylamino} hexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
12.4 g of 2-trifluoromethylpyridine-5-carboxylate hydrochloride was obtained as a pale yellow powder.
The analysis results of the obtained compound are as shown below.

Mass spectrometry (FD) m / e 636 (M ++ 1); Specific rotation: [α] D25 + 102.8 ° (c0.530, methanol); Melting point: 114.5-116.0 ° C; IR (KBr) 3371 , 3329, 2944, 2860, 2790, 1725, 1670,
1686, 1645, 1627, 1532, 1497, 1131, 1103, 1082, 7
54, 692 cm-1; 1H-NMR (CDCl3-TMS) δ9.605 (broad s, 1H), 8.687
(broad s, 1H), 8.091 (d, J = 0.80Hz, 1H), 8.03 (d, J
= 8.30Hz, 1H), 7.614 (d, J = 7.75Hz, 1H), 7.470 (t, J =
7.68Hz, 1H), 7.247 (t, J = 8.48Hz, 2H), 6.948 (t, J =
7.35Hz, 1H), 6.869 (d, J = 8.00Hz, 2H), 6.337 (s, 1
H), 5.139 (s, 1H), 4.654 (broad s, 1H), 4.10-3.94
(m, 4H), 3.707 (s, 3H), 3.34-3.21 (m, 2H), 3.07-2.
99 (m, 2H), 2.421 (s, 3H), 1.88-1.82 (m, 2H), 1.60-
1.54 (m, 2H), 1.36-1.29 (m, 2H), 1.28-1.17 (m, 2H). (Example 8) 1.6 M in a solution of ice-cooled diisoproamine (7.8 ml) in tetrahydrofuran (115 ml). N-Butyllithium hexane solution (35 ml) was slowly added dropwise (2
0 minutes). The mixture was stirred under ice cooling for 30 minutes and then cooled to -69 ° C. Methyl (S)-(1-ethoxycarbonyl-2-methylpropyl) amino-4,4,4-trifluorocrotonate (13.5 g) in tetrahydrofuran (3
5 ml) solution was slowly added dropwise (for 50 minutes). After stirring for 1 hour, a solution of isopropyl 2- (3-nitrobenzylidene) acetoacetate (18.0 g) in tetrahydrofuran (80 ml) was slowly added dropwise (70 minutes). The reaction temperature was gradually increased from -68 ° C to -30 ° C (1.5 hours). After cooling to −50 ° C. again, 1N hydrochloric acid (125 ml) was added, and the mixture was stirred at room temperature for 24 hours. After separating the organic layer and the hydrochloric acid layer, 6N hydrochloric acid (100 ml) was added to the organic layer, and the mixture was stirred for 5 hours. After separating the organic layer and the hydrochloric acid layer again, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the organic layer for liquid separation, and the aqueous layer was extracted twice with ethyl acetate (250 ml × 2). The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue (about 29.3
Isopropanol (130 ml) and ammonium acetate (7.6 g) were added to g) and the mixture was refluxed for 3 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. Ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) were added to the mixture for liquid separation, and the aqueous layer was extracted twice with ethyl acetate (100 ml × 2). The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue (about 27.8
Toluene (190 ml) and p-toluenesulfonic acid monohydrate (3.8 g) were added to g), and the mixture was heated in an oil bath at 120 ° C. for 1 hour. At this time, the generated water was removed using Dean Stark. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to separate it,
The aqueous layer was extracted twice with toluene. The obtained organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate.

The toluene solution obtained was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane /
Purification with ethyl acetate = 2/1) yielded the desired (+)
15.23 g of -6-bromohexyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate was obtained. HPLC (DAICEL CHIRAL
CEL OD-H, Hexane / IPA = 15/1, 1.0 ml / min, UV254nm, r.
The optical purity was 88% e.
It was e. (Example 8) (+)-in the same manner as in Example 4 except that dimethoxyethane was used instead of tetrahydrofuran.
1,4-dimethyl 4- {2- (4-bromobutoxy)
-5-Nitrophenyl} -1,4-dihydro-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate (39% yield, 82.0% ee) was obtained as a yellow powder.

[0042]

INDUSTRIAL APPLICABILITY According to the present invention, the optically active 2-trifluoromethyldihydropyridine derivative and its pharmacologically acceptable salt can be produced by an industrially useful method.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Takeshi Hamaya 125-1-508 Nakagawa, Arai City, Niigata Prefecture (72) Inventor Yoichiro Ueda 2-chome 13-28-402 Kawaguchi, Tsuchiura City, Ibaraki Prefecture (72) Inventor Kiyotaka Ito 1279-207 Higashi-Futami, Futami-cho, Akashi-shi, Hyogo (72) Inventor Kimio Esumi 1-5-11-305, Sumiyoshi Yamate, Higashinada-ku, Kobe-shi, Hyogo

Claims (8)

[Claims] 1. Formula (1): (In the formula, R1 represents an ethyl or methyl group, R2 represents a lower alkyl group having 1 to 4 carbon atoms, R3 represents a lower alkyl group optionally substituted by a benzene ring, and * represents an optically active center. Means) an optically active amino-
4,4,4-Trifluorocrotonate. 2. The optically active amino-4,4,4-trifluorocrotonate according to claim 1, wherein R3 is an isopropyl group. 3. The (S) -amino-4,4,4-trifluorocrotonate according to claim 1, wherein R1 is a methyl group, R2 is an ethyl group, and R3 is an isopropyl group. 4. The (R) -amino-4,4,4-trifluorocrotonate according to claim 1, wherein R1 is a methyl group, R2 is an ethyl group, and R3 is an isopropyl group. 5. The formula (2): (In the formula, R1 has the same meaning as described above) and trifluoroacetoacetate represented by the formula (3): (In the formula, R2, R3 and * have the same meanings as described above.)
A method for producing optically active amino-4,4,4-trifluorocrotonate, which comprises reacting the amino acid ester represented by the formula (11) with a lower fatty acid in a substantially solvent-free manner. 6. The method for producing an optically active amino-4,4,4-trifluorocrotonate according to claim 5, wherein the lower fatty acid is selected from formic acid, acetic acid, propionic acid, or a mixture thereof. 7. The method for producing an optically active amino-4,4,4-trifluorocrotonate according to claim 5, wherein the amino acid ester is D-valine ester or L-valine ester. 8. The formula (4): (Wherein X and Y each independently represent a hydrogen atom, a lower alkyl group, a halo lower alkyl group, a halogen, a nitro group or a lower alkyleneoxy group, and the lower alkyleneoxy group is a phthalimido group, a methanesulfonyloxy group or a benzene group. Sulfonyloxy group, p-toluenesulfonyloxy group, m-nitrobenzenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, chlorine group,
It may be substituted with a bromine group or an iodine group. R4 represents a lower alkyl group, a halo lower alkyl group, and a lower alkyl group, and the lower alkyl group is a phthalimido group,
Methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, m-nitrobenzenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, chlorine group, bromine group or iodine group) Substituted 2-benzylidene acetoacetic acid esters and the formula (1): (Wherein R1, R2, R3 and * have the same meanings as described above), the optically active amino-4,4,4-trifluorocrotonate is reacted, and then ammonia or an acid addition salt thereof is reacted. And then dehydration is performed, which is represented by the formula (5): (Wherein R1, R4, X and Y have the same meanings as described above), and a process for producing an optically active dihydropyridine.