JPH06755B2 - (+)-Lattein and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel alkaloid (+)-latifine and a method for producing the same.

Conventional technology (-)-Latifin has been recently used in India Hamayu (C
rinum Latifolium L.) is a new alkaloid discovered by the extraction method. (Kobayashi, J.Chem.Soc.C
hem.Commun., 1984 , 1043) Bulbs and leaves of Indian halibut are used as folk medicines in the Sri Lanka region of India, and are known to be effective as reddening agents and tonic agents. The (+)-latifine studied by the present inventors is its optical isomer and is a novel non-natural alkaloid. Future developments in the pharmaceutical field are expected.

OBJECT OF THE INVENTION The present invention provides a novel alkaloid (+)-latifin and a method for producing the same.

Structure of the Invention The present invention provides compounds of formula (I) Optically Active (+)-Latifin and Formula (II) (In the formula, Bn represents a benzyl group) Production of an optically active (+)-latifine represented by the above formula (I), which comprises catalytically reducing an optically active (R) -dibenzyllatifine represented by hydrogen. Is the way.

(+)-Latifin is a colorless crystalline solid, and (-)-Latifin collected from nature and melting point, NMR, MA
The SS spectral data were in perfect agreement with each other and differed only in the dioptometry measurements.

The final step of the method for producing (+)-latifin of the present invention is completed by removing the benzyl group of (R) -dibenzyllatifin by a catalytic reduction method. As the catalyst used in the catalytic reduction method, any catalyst can be used as long as it is a catalyst for ordinary hydrogenation reaction, but of these, a palladium carbon catalyst is most preferable. The solvent used is not particularly limited as long as it is inert to the reaction, but an alcohol solvent is most preferable.
The reaction can be carried out in the presence of hydrogen under normal pressure to elevated pressure at a reaction temperature of room temperature to 100 ° C. The reaction product is purified by an ordinary purification method such as recrystallization, reprecipitation or column chromatography after filtering off the catalyst to obtain a highly pure (+)-
You can get a raffin fin.

An example of the production method of the present invention is shown in the following figure, and details will be described in reference examples and examples.

Reference Example 1 (S)-(E) -1-benzyloxy-4-
Synthesis of (4-benzyloxyphenyl) -3- (2-methoxyphenyloxy) -1-butene (b) The starting compound (R)-(E) -1-benzyloxy-
4- (4-benzyloxyphenyl) -3-buten-2-ol (a) was prepared as shown in the specification filed on the same day as D
-Manufactured from mannitol. 1.67 g (4.64 mmol) of this optically active allyl alcohol compound and 1.83 g (6.96 mmol) of triphenylphosphine were added to THF7.
Dissolve in 0 ml and add 0.77 ml (6.
96 mmol) and 1.37 ml (6.96 mmol) of diisopropyl azodicarboxylate were added at 0 ° C. with stirring. After reacting for 2 hours, the solvent was removed under reduced pressure, and the residue was washed successively with 20 ml of a 15% aqueous sodium hydroxide solution and 20 ml of water and 20 ml of saturated saline, and finally dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was chromatographed using 75 g of silica gel with a mixed solvent of n-hexane-ethyl acetate (10: 1) as a developing agent to obtain 1.04 g (yield 48%) of the title ether compound as a colorless oil.

[Α] _D : + 13.87 ° (C = 2.264, CHCl ₃ ) NMR δ: 3.77 (2H, d, J = 6.0Hz, -CH-CH _2- ), 3.84 (3H, s,
-OCH ₃ ), 4.64 (2H, s, -CH ₂ O-CH ₂ -Ph), 4.96 (1H, m, -CH-CH
_2- ), 5.02 (2H, s, ArOCH ₂ -Ph), 6.11 (1H, dd, J = 16.0and6.0H
z, -CH = CH-CH-), 6.58 (1H, d, 16.0Hz, -CH = CH-CH-), 6.72-7.
02 (8H, m, ArH), 7.04-7.48 (10H, m, PhH) ppm Reference Example 2 (R)-(E) -4-benzyloxy-1-
Synthesis of (4-benzyloxyphenyl) -1- (2-hydroxy-3-methoxyphenyl) -2-butene (c) 1.04 g (2.22 mm) of the ether compound obtained in Reference Example 1
ol) to N. Dissolve in 8 ml of N-dimethylaniline and reflux for 20 minutes. After the reaction was cooled, 50 ml of ether was added to dilute it, and it was diluted with 20 ml of 10% hydrochloric acid three times and saturated aqueous sodium hydrogen carbonate 20 times.
It was washed with 20 ml of saturated saline and 20 ml of saturated saline, and finally dehydrated with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography using 40 g of silica gel and a developing solvent of n-hexane-ether (5: 1) to obtain 782 mg (yield 76%) of the title phenol compound as a colorless oil.

[Α] _D : + 5.11 ° (C = 1.88, CHCl ₃ ) IR ν _max : 3350 cm ^-1 NMR δ: 3.73 (3H, s, -OCH ₃ ), 4.02 (2H, d, = CH-CH ₂ -O ),
4.44 (2H, s, -CH ₂ O-CH ₂ -Ph), 4.94 (2H, s, Ar-O-CH ₂ -Ph), 5.0
3 (1H, m, -CH-CH = CH-), 5.67 (1H, m, -CH =), 5.73 (1H, br.s, -O
H), 6.19 (1H, m, = CH-), 6.58-7.52 (17H, m, ArHandPhH) ppm MASS m / z: 466.2134 (calculated value 466.2142) Elemental analysis: measured value C 78.59, H 6.40 calculated value C 78.29 , H 6.57 Reference Example 3 (R)-(E) -4-benzyloxy-1-
Synthesis of (4-benzyloxyphenyl) -1- (2-benzyloxy-3-methoxyphenyl) -2-butene (d) Phenolic compound obtained in Reference Example 2 782 mg (1.68 mm)
ol), 0.30 ml (2.52 mmol) of benzyl bromide and 929 mg (1.68 mmol) of potassium carbonate in 15 ml of DMF.
In addition, the mixture was reacted at 80 ° C. for 15 hours. Water in the reaction solution 15
After adding ml, extraction operation was performed twice with 30 ml of ether. The extracted ether solution was treated with 20 ml of water and 20 ml of saturated saline and then dehydrated with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was mixed with 35 g of silica gel and n-hexane-ethyl acetate (15: 1) mixed solvent. Column purification was performed to obtain 829 mg (yield 89%) of the title ether compound as a colorless syrup.

[Α] _D : + 15.95 ° (C = 1.868, CHCl ₃ ) IR ν _max : 3050,1615 cm ^-1 NMR δ: 3.84 (3H, s, -OCH ₃ ), 3.99 (2H, d, J = 6.0HZ, , = C
H-CH ₂ -O), 4.55 (2H, s, -CH ₂ O-CH ₂ -Ph), 4.66 and 4.90 (each 1H,
d, J = 11.0Hz, 2′-O-CH ₂ -Ph) 4.98 (2H, s, Ar-O-CH ₂ -Ph), 5.1
4 (1H, d, J = 6.8Hz, -CH-CH =), 5.64 (1H, dt, J = 15.7and6.0Hz,
-CH = CH-CH _2- ), 6.07 (1H, dd, J = 15.7and6.8Hz, -CH-CH = CH
-), 6.64-7.14 (7H, m, ArH), 7.08-7.44 (15H, m ,, PhH) ppm MASS m / z: 566.2604 (calculated value 566.2612) Elemental analysis: measured value C 81.77, H 6.62 calculated value C 81.98, H 6.52 Reference Example 4 (R) -2- (4-benzyloxyphenyl)
Synthesis of 2- (2-benzyloxy-3-methoxyphenyl) ethyl alcohol (e) 829 mg (1.49 mmo) of the ether compound obtained in Reference Example 3
l) is dissolved in a mixed solvent of 30 ml of methanol and 10 ml of methyl chloride, and ozone gas is blown into it at -74 ° C for 35 minutes. Next, after blowing out nitrogen gas by blowing out excess ozone, 564 mg (1
4.9 mmol) in water and then gradually warm to room temperature. The solvent is removed from the reaction solution under reduced pressure, and the residue is extracted with 50 ml of ether. The extract is 20 ml of water and 2 parts of saturated saline.
After washing with 0 ml, it was dehydrated with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. 25g silica gel residue
Column purification was carried out using a mixed solvent of n-hexane and ether (1: 1) with 422 mg of the title alcohol compound.
(Yield 64%) was obtained.

[Α] _D : + 34.48 ° (C = 1.978, CHCl ₃ ) IR ν _max : 3450 cm ^-1 NMR δ: 1.53 (1H, s, -OH), 3.86 (3H, s, -OCH ₃ ), 4.01 (2
H, d, J = 7.0Hz, -CH ₂ -OH), 4.56 (1H, t, J = 7.0Hz, -CH-CH _2- ),
4.71 and 4.99 (1H, d, J = 11.0Hz, -CH ₂ -Ph), 6.70-7.50 (7H,
m, ArH), 7.33 (10H, s, PhH) ppm MASS m / z: 440.1998 (calculated value 440.1988) Reference Example 5 (R) -1-phthalimido-2- (4-benzyloxyphenyl) -2- (2 -Benzyloxy-3-
Synthesis of methoxyphenyl) ethane (f) 422 mg (0.959 mmol) of the product of Reference Example 212 212 mg (1.446 mmol) of phthalimide and 326 mg (1.247 mmol) of triphenylphosphine were dissolved in 12 ml of tetrahydrofuran, and cooled with diethyl azo. 0.26 ml (1.632 mmol) of dicarboxylate was added dropwise. Subsequent operations were carried out in substantially the same manner as in Reference Example 4 to obtain 519 mg (yield 95%) of the title compound as a colorless semisolid.

[Α] _D : + 14.35 ° (C = 1.714, CHCl ₃ ) NMR δ: 3.66 (3H, s), 4.18 (2H, d, J = 8Hz), 4.65 and 4.93
(1H, d, J = 11Hz), 5.17 (1H, t, J = 8Hz), 6.53-7.86 (11H, m), 7.
24 (10H, s) ppm Reference Example 6 (R) -2- (4-benzyloxyphenyl)
-2- (2-benzyloxy-3-methoxyphenyl)-
Synthesis of 1-ethylamine (g) 519 mg (0.192 mmol) of the product of Reference Example 5 was dissolved in 10 ml of ethanol to give 90% hydrazine monohydrate 159.
mg (2.743 mmol) was added and the mixture was heated under reflux for 2 hours. After cooling, the solvent was distilled off, chloroform was added to the residue, and the insoluble material was filtered. Removal of the solvent gave a colorless oil which was purified by silica gel column chromatography,
374 mg (yield 93%) of the title compound was obtained.

[Α] _D : + 29.76 ° (C = 1.942, CHCl ₃ ) NMR δ: 1.54 (2H, s), 3.12 (2H, d, J = 8Hz), 3.82 (3H,
s), 4.33 (1H, t, J = 8Hz), 4.68 and 4.99 (1H, d, J = 11Hz), 6.65-
7.45 (7H, m), 7.30 (10H, s) ppm Reference Example 7 (R) -N-formyl-2- (4-benzyloxyphenyl) -2- (2-benzyloxy-3-methoxyphenyl) -1 -Synthesis of ethylamine (h) 312 mg (0.711 mmol) of the product of Reference Example 6 was dissolved in 5 ml of pyridine, and 0.13 ml of acetic formic acid mixed anhydride under ice cooling.
(2.83 mmol) was added dropwise. After stirring at the same temperature for 45 minutes, pyridine was distilled off under reduced pressure and the residue was dissolved in ether. Subsequent operations are purified according to Reference Example 4,
297 mg (89% yield) of the title compound was obtained as a colorless glass.

[Α] _D : + 25.31 ° (C = 2.284, CHCl ₃ ) NMR δ: 3.36 (2H, m), 3.81 (3H, s), 4.47 (1H, d, J = 9H
z), 4.71 and 4.99 (1H, d, J = 11Hz), 4.95 (2H, s), 5.53 (1H, s),
6.53-7.50 (7H, m), 7.29 (10H, s), 7.96 (1H, d) ppm Reference Example 8 (R) -Methyl-2- (4-benzyloxyphenyl) -2- (2-benzyloxy-) Synthesis of 3-methoxyphenyl) -1-ethylamine (i) 297 mg (0.636 mmol) of the product of Reference Example 7 was dissolved in 7 ml of tetrahydrofuran, and 131 mg (3.18 mmol) of lithium aluminum hydride was added under ice cooling for 3 hours. Heated to reflux. 2 ml of ammonia water was carefully added dropwise under ice cooling, diluted with 30 ml of ether, and 0.7 g of celite was added. Suction filtration is performed while passing through the anhydrous magnesium sulfate layer, and the solvent is distilled off to give the title compound 217 as a colorless oil.
mg (yield 75%) was obtained.

[Α] _D : + 28.76 ° (C = 1.794, CHCl ₃ ) NMR δ: 1.93 (1H, s), 2.35 (3H, s), 3.08 (2H, d, J = 8H
z), 3.81 (3H, s), 4.60 (1H, t, J = 8Hz), 4.69 and 4.98 (1H, d, J = 1
1Hz), 6.63-7.56 (7H, m), 7.32 (10H, s) ppm Reference Example 9 (R) -N-methyl-N-formyl-2- (4
Synthesis of -benzyloxyphenyl) -2- (2-benzyloxy-3-methoxyphenyl) -1-ethylamine (j) 217 mg (0.479 mmol) of the product of Reference Example 8 was dissolved in 1.5 ml of pyridine and iced. Cold acetic formic acid mixed anhydride 0.1
0 ml (1.92 mmol) was added dropwise. Pyridine was distilled off under a reaction reduced pressure for 40 minutes, and the residue was dissolved in ether. Subsequent operations were carried out according to Reference Example 4 to obtain 179 mg (yield 80%) of the title compound as a colorless glass.

[Α] _D : + 32.64 ° (C = 0.774, CHCl ₃ ) NMR δ: 2.60 and 2.66 (3H, s), 3.64 (2H, d, J = 8Hz), 3.82
(3H, s), 4.53 (1H, t, J = 8Hz), 4.70 and 4.96 (1H, d, J = 11Hz), 4.
96 (2H, s), 6.63-7.50 (7H, m), 7.31 (10H, s), 7.67 and 7.82 (1
H, bs) ppm Reference Example 10 Synthesis of (R) -dibenzyllatifin (II) 170 mg (0.383 mmol) of the purified product obtained in Reference Example 9 was dissolved in 8.6 ml of benzene, and 0.23 ml of phosphorus oxychloride was added.
(1.94 mmol) was added and the mixture was heated under reflux for 45 minutes. Benzene was distilled off under reduced pressure, and the residue was washed 3 times with 10 ml of n-hexene. Dissolve it in 10 ml of 10% hydrous methanol,
Sodium borohydride 143mg (3.83mm under ice cooling)
ol) was added and the mixture was stirred at the same temperature for 1 hour. When the foaming was stopped by heating at 50 ° C, the solvent was distilled off under reduced pressure, the residue was dissolved in 60 ml of ether, and washed with 30 ml of water and 30 ml of saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and this was purified by preparative thin layer chromatography,
132 mg (76% yield) of the title compound was obtained as a colorless oil.

[Α] _D : + 4.31 ° (C = 0.882, CHCl ₃ ) NMR δ: 2.26 (3H, s), 2.68 (2H, d, J = 4Hz), 3.30 and 3.85
(1H, d, J = 14Hz), 3.80 (3H, s), 3.91 and 4.80 (1H, d, J = 10Hz),
4.23 (1H, t, J = 4Hz), 4.92 (2H, s), 6.60-7.45 (7H, m), 7.21 (1
0H, s) ppm Example 1 Synthesis of (+)-latifin (R) -Dibenzyllatifin 13 obtained in Reference Example 10
2 mg (0.291 mmol) was dissolved in 7 ml of ethanol to obtain 10
% Paradium carbon catalyst 36mg was added, and it was 55 in a hydrogen stream.
The mixture was warmed to ℃ and stirred for 24 hours. The catalyst was suction filtered while passing through the theolite layer, and the solvent was removed under reduced pressure to obtain a yellowish brown crystal. This was recrystallized from 4 ml of ethanol to obtain 75 mg of yellow prism-shaped (+)-latifin (yield 10
0%).

Melting point: 213-217 ° C (decomposition) [α] _D : + 9.39 ° (C = 0.362, CH ₃ OH) NMR δ: 2.31 (3H, s), 2.63 and 2.89 (1H, d, J = 10Hz), 3.4
3 and 3.63 (1H, d, J = 14Hz), 3.80 (3H, s), 4.24 (1H, t, J = 5Hz),
6.61 and 6.82 (1H, d, J = 9Hz), 6.62 and 6.88 (2H, d, J = 8Hz) ppm Effect of the Invention The present invention enables the production of new pharmaceutical ingredient (+)-latifin by an organic synthetic means. It was It is also possible to apply the method of the present invention to supply (-)-latifin.

Claims (2)

[Claims] 1. A formula (I) Optically active (+)-latifin represented by. 2. Formula (II) The method for producing (+)-latifine obtained by catalytically reducing (R) -dibenzyllatifine represented by