JPS624269A - (+)-latifine and production thereof - Google Patents

Abstract

NEW MATERIAL:Optically active (+)-latifine expressed by formula I. USE:A medicine which is an optical isomer of (-)-latifine known as a rubefacient or tonic and a nonnatural alkaloid. PREPARATION:(R)-Dibenzyllatifine, expressed by formula III and synthesized from (R)-(E)-benzyloxy-4-(4-benzyloxyphenyl)-3-buten-2-ol, expressed by formula III and obtained from D-mannitol as a starting material is catalytically reduced with hydrogen to afford the aimed (+)-latifine.

Description

DETAILED DESCRIPTION OF THE INVENTION Part 1: The present invention relates to a novel alkaloid (+)-lateifin and a method for producing the same.

[To the East 11 (-) - Latifin has recently become a common species of Indocanus (
This is a new alkaloid discovered by extraction from the leaves of Crinum Latifolium L.).

(Kobayashi, J, Chem, Soc, Chem, Comm
un,, Hisha, 1043) The bulbs and leaves of the Indian sycamore are used as folk medicine in India and Sri Lanka, and are known for their redness and tonic effects. The (+)-latifine studied by the present inventors is an optical isomer thereof, and is a novel non-natural alkaloid.

Future developments in the pharmaceutical field are expected.

11 to 1'' The present invention provides a novel alkaloid (+)-latifine and a method for producing the same.

To 11 The present invention provides optically active (+)-latifine represented by the formula (T) and the formula (I
I) (wherein Bn represents a benzyl group) optically active (+)-latifine represented by the above formula (I), which is obtained by catalytic hydrogen reduction of optically active (R)-dibenzyl latefin represented by (Bn represents a benzyl group) This is the manufacturing method.

(+)-Latifine is a colorless crystalline solid, which has melting point, NMR, and MA compared to (-)-Latifin collected from nature.
SS gave complete agreement in each spectral data and different data only in the optical rotation measurement.

The final step of the method for producing (+)-latifine of the present invention is completed by removing the benzyl group from (R)-dibenzyllatifine by a catalytic reduction method. The catalyst used in the catalytic reduction method may be any conventional catalyst for hydrogenation reactions, but palladium on carbon catalyst is the most preferred. The solvent used is not particularly limited as long as it is inert to the reaction, but alcohol solvents are most desirable.

The reaction can be carried out in the presence of hydrogen, under normal pressure to pressurized conditions, and at a reaction temperature of room temperature to 100°C. After catalyst filtration, the reaction product is purified using conventional purification methods such as recrystallization, reprecipitation, column chromatography, etc. to obtain highly pure (+)-
You can get Latiffin.

An example of the manufacturing method of the present invention is shown in the mouthpiece, and details will be explained in Reference Examples and Examples.

Kama”” Soto-1(S)-(E)-4-benzyloxy-1
The starting compound for the synthesis of -(4-benzyloxyphenyl)-3-(2-methoxyphenyloxy)-1-butene (b) (R>-(E)-1-benzyloxy-4-
(4-Benzyloxyphenyl)-3-buten-2-ol (a) was prepared from D-mannitol as shown in the memo filed on the same day. This optically active allyl alcohol compound 1.67 g (4,64+u+ol
) and triphenylphosphine 1.83g (6,96m
Dissolve 0.77 ml (6.96 mmol) of guaiacol and 1.37 ml (6.96 mmol) of diisopropyl azodicarboxylate in THF701.
ol) was added with stirring at 0°C. After 2 hours of reaction, the solvent was removed under reduced pressure and the residue was dissolved in 20ml of 15% caustic soda aqueous solution.
1. Washed with 201 parts of water and 20 parts of saturated saline solution, and finally dried with anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography using 75 g of silica gel and a mixed solvent of n-hexane-ethyl acetate (10:1) as a developing agent.
1.04 g of the title ether compound as a colorless oil (yield: 48
%) was obtained.

[α]o: +13.87° (
C:2.264. CI(Ch)NMRδ: 3.7? (
2H, d, J=6.0Hz, -CI-CL-), 3.8
4 (3H, s, -0CH3), 4.64 (2H, s, -
CH2O-CH2-Ph), 4.96 (IH, m, -C
)1-C)1z-), 5.02(20,s, Ar0CH
2-Ph), 6.11<IH, dd, J=16.0an
d6.0Hz, -C)l=c)I-CI), 6.58(
IH, d, 16.0Hz, -CH=CH-CH-),
6.72-7.02 (8H, m, ArH), 7.04-
7.48 (IOH, m, Phil) Ppm-2(R)
Synthesis of -(E)-4-benzyloxy-1-(4-benzyloxyphenyl)-1-(2-hydroxy-3-methoxyphenyl)-2-butene (e) Ether compound 1 obtained in Reference Example 1 .04g (2,22m
mol) in 8 ml of N,N-dimethylaniline,
Reflux for 20 minutes. After cooling the reaction solution, it was diluted with 50 ml of ether, washed three times with 20 ml of 10% hydrochloric acid solution, 20 ml of saturated sodium bicarbonate solution, and 20 ml of saturated brine, and finally dehydrated with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Removed. The residue was mixed with 40 g of silica gel and n-hexane-ether (
5:1) Chromatographic purification using a developing solvent yielded 782 mg (yield 76%) of the title phenol compound as a colorless oil.
I got it.

[α] o: +5.11@(C=1.88.
CHCl5)I RvlmaX: 3350cm-
'NMRδ: 3.73 (3H, s, -0CR3),
4.02 (2H, d, =CH-CH2-0), 4.44
(2t(, s, -CH2-Q-CH2-Phn, 4.9
4(2H,5Ar-0-CH2-Ph), 5.03(I
H, m, -CH-CH=CH-), 5.67 (IH, m
, -CHz), 5.73 (IH, br, s, -0H),
6.19 (IH, m.

=CH-1,6,58-7,52(17H,m,ArH
andPbH) ppmM A S S m/z: 4
66.2134 (calculated value 466.2142) Elemental analysis: Actual value C7g, 59. )l 6.40 Calculated value C
78,29,H6,57 119-L (R)-(E)-4-benzyloxy-1-(4-benzyloxyphenyl)-1-(2-benzyloxy-3-methoxyphenyl)-2- Butene (
Synthesis of d) 782 mg (1,68 mg) of the phenol compound obtained in Reference Example 2
m+aol) and benzyl bromide 0.30i1 (2,521
1101) and potassium carbonate 929@g (1,68m
mo1) was added to 15 ml of DMF and reacted at 80°C for 15 hours. After adding 15 ml of water to the reaction solution, 3 ml of ether
Extraction operation was performed twice with 01. The extracted ether solution was mixed with water 201,
After treatment with saturated brine 201, it was dehydrated with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by a column using 35 g of silica gel and a mixed solvent of n-hexane-ethyl acetate (15:1) to obtain 829 mg (yield: 89%) of the title ether compound as a colorless syrup.

[α]o: +15.95° (C=1.868.
ClCl5)I Rv mix: 3050, 16
15cm-'NMRδ: 3.84 (3H,s, -0C
L3), 3.99 (2H, d, J"6.011z,
, =CH-CL2-0) , 4, 55(2H, s
,'-CH2-O-CHz-Ph).

4.66 and 4.90 (each IH, d, J11.OHz
, /-0-C)+2-Ph)4.98(2H,s, A
r-0-CH2-Ph), 5.14 (IH, d, J=6
．． 8Hz, -CI-CH: ), 5.64(IH, dt
, J=15.7and6.0Hz, -CH=CH-CH
2-), 6.07 (IH, dd, J=15.7and6
．． 8Hz, -CH-CI=Cfl-), 6.64-7.
14 (7H, m, input rH), 7.08-7.44 (15
n, m, phH) ppm MA S S m/z: 556.2604 (calculated value 556.2612) Elemental analysis: Actual value C81,7
7, H6,62 calculated value C81,9g, H6,52 4(R)-2-(4-benzyloxyphenyl)-2-
Synthesis of (2-benzyloxy-3-methoxyphenyl)ethyl alcohol (e) 829 mg (1°49 mmol) of the ether compound obtained in Reference Example 3 was mixed with 30 ml of methanol.
and methyl chloride 101, and -74
Bubble ozone gas for 35 minutes at ℃. Next, after blowing in nitrogen gas to drive out excess ozone, 564mg (14.9m+++ol) of sodium borohydride was added at a low temperature.
Add an aqueous solution of and then gradually warm to room temperature.

The solvent of the reaction solution was removed under reduced pressure, and the residue was dissolved in 50 ml of ether.
Extract with The extract is washed with water 201 and saturated saline 201, then dehydrated with anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The residue was purified by column using 25 g of silica gel and n-hexane-ether (1:1) mixed solvent to obtain 422 mg of the title alcohol compound (yield 64
%) was obtained.

[α]o: +34.48° (C=1.978.
CHCl3) IR ν: 3450 cm-' NMR δ: 1.53 (IH, s, -0H), 3.86
(3H, s, -0CH3) 4.01 (2H, d, J near, 0) 1z, -CH2-0H), 4.56 (Ill, t
, J=7, OH2, -CH-CH2-), 4.71 and 4
．． 99 (each IH, d, J = 11.0Hz, -CH2-P
h), 6.70-7.50 (7H, m, ArH), 7.
33 (IOH, s, PhH) ppm M A S S m/z: 440.1998 (calculated value 440.1988) pot] [down knee 5 (R)-
Synthesis of 1-phthalimido-2-(4-benzyloxyphenyl)-2-(2-benzyloxy-3-methoxyphenyl)ethane (f) Product 422+ag(
0,959 mmol) Phthalimide 212+ag (1,
446 mmol) and triphenylphosphine 326
B (1,247 mmof) in tetrahydrofuran 121
Dissolve diethyl azodicarboxylate in 0.0% and cool with water.
26 ml (1,63:12++i+ol) was added dropwise.

The 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 in the form of a colorless semi-solid.

[α Ko D: +14j5 ° (C
=1.714. CHCl, )NMRδ: 3.66 (3
1(,s>,4.18(2H,d,J=Il)lz),
4.65 and 4.93 (IH, d, J=lIHz), 5.
17 (IH, t, J=8Hz), 6.53-7.86 (
IIH, m), 7.24 (IOH, s) ppm 11 Katsu-6(R)-2-(4-benzyloxyphenyl)-2
-(2-benzyloxy-3-methoxyphenyl)-1
- Synthesis of ethylamine (g) Product 519m of Reference Example 5
g (0,912 m + ool) was dissolved in ethanol 101, and 159 mg (2,743
mmol) and heated under reflux for 2 hours. After cooling, the solvent was distilled off, chloroform was added to the residue, and insoluble matter was filtered. Removal of the solvent gave a colorless oil, which was purified by silica gel column chromatography to obtain 374 mg (yield 93%) of the title compound.

[α co: +29.76 °
(C=1.942.CHCl3) NMRδ: 1.
54 (2H, s), 3.12 (2H, d, J=8Hz)
, 3.82 (3H, s), 4j3 (IH, t, J=8H
z>, 4.68 and 4.99 (1B, d.

JllHz>, 6.65-7.45 (7H, m), 7.
30(10H,s)ppm119-7(R)-N-formyl-2-(4-benzyloxyphenyl)-2-(2
Synthesis of -benzyloxy-3-methoxyphenyl)-1-ethylamine (h) 312 mg (0,711 mmol) of the product of Reference Example 6 was dissolved in pyridine 51, and acetic acid formic acid mixed anhydride was added to the solution after cooling with water.
, 13 ml' (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. After that, purification was carried out according to Reference Example 4, and 297 +++ g of the title compound was obtained as a colorless glass.
(yield 89%).

[α] o: +25.31' (C・2.2
84. CHCl, )NMRδ: 3.36 (2H, m)
, 3.81(31,s), 4.47(It(,d.

J・9) 1z), 4.71 and 4.99 (IH, d, J=
11Hz), 4.95 (2H.

s), 5.53 (IH, s), 6.53-7.50 (7
H,a), 7.29(,10H,s), 7.96(I
H, d) ppm 8 (R)-N-methyl-2-(4-
Synthesis of benzyloxyphenyl)-2-(2-benzyloxy-3-methoxyphenyl)-1-ethylamine (+) 297 mg (0,636 mmol) of the product of Reference Example 7 was dissolved in tetrahydrofuran 71, and dissolved in aqueous ammonia under water cooling. 21 was carefully added dropwise, and after diluting with ether 301, 0.7 g of Celite was added. The mixture was filtered with suction while passing through an anhydrous magnesium sulfate layer, and the solvent was distilled off to obtain 217 mg (yield: 75%) of the title compound as a colorless oil.

[α ko. : +28.76°
(C=1.794.ClCl,)NMRδ: 1.93
(IH, s), 2j5 (3H, s), 3.08 (2H,
d.

JJHz), 3.81 (3H, s), 4.60 (IH,
t, J=8Hz>,4.69 and 4.9g(1)[,d,
J・l1flz), 6.63-7.56 (7H,!+
), 7.32 (IOH, s) ppm 119-% (R)-N-methyl-N-formyl-2-
4-benzyloxyphenyl)-2-(2-benzyloxy-3-methoxyphenyl)-1-ethylamine (
Synthesis of 217 mg (0.479 mmol) of the product of Reference Example 8 was dissolved in 1.51 liters of pyridine, and 0.10 ml (1.92 mmol) of acetic formic acid mixed anhydride was added dropwise over water cooling.

After reacting for 40 minutes, pyridine was distilled off under reduced pressure, and the residue was dissolved in ether. Thereafter, purification was carried out in accordance with Reference Example 4 to obtain colorless glassy title compound 179a+g (yield: 80%).

[(Z]D: +32.64° (C=0.772
．． CIClCl5)N δ: 2.60 and 2.66
(3H,s), 3.64(2H,d, J=8[1z)
, 3.82(3H,s>, 4.53(IH,t, J=8
Hz), 4.70 and 4.96 (IH, d, J=IIHz
), 4.96 (2H, s), 6.63-7.50 (7H
, m) 7jl(IOH,s>, 7.67 and 7.82(I
179 mg (0,383 mm01
) in benzene 8,61, phosphorus oxychloride 0.2
3+al (1,94ma+ol) was added and heated under reflux for 45 minutes. Benzene was distilled off under reduced pressure, and the residue was washed three times with 10 ml of n-hexane. Dissolve it in 10 ml of 10% diluted methanol, and add 1 ml of sodium borohydride under water cooling.
43 mg (3.83 mmol) was added and stirred at the same temperature for 1 hour. After heating to 50"C and foaming subsided, 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 brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. This was purified by preparative thin layer chromatography to obtain 132 mg (yield 76%) of the title compound as a colorless oil.

[α]. : + 4jl' (C・0.882.
CIClCl5)N δ: 2.26 (3H, s),
2.68 (2H, d, J=4Hz)j, 30 and 3.85
<LH, d, J=14Hz), 3.80 (3H, s),
3.91 and 4°80 (IH, d, J = 10Hz), 4.
23 (IH, t, J=4Hz), 4.92 (2H, s)
, 6.60-7.45 (7H, m), 7.21 (IOH
, s) p'pm+M A S S m/z: 465.
2295 (calculated value 465.2302) real [1(+)
-(R)-Dibenzyllatifine 1 obtained in Synthesis of Latifin Reference Example 10
32 mg (0,291 mmol) was dissolved in 7 ml of ethanol, 36 mg of 10% baradium carbon catalyst was added, and the mixture was heated to 55°C in a hydrogen stream and stirred for 24 hours. Suction filter the catalyst while passing it through a Celite layer.

The solvent was removed under reduced pressure to obtain tan crystals. This was recrystallized from 4 ml of ethanol to give a yellow prism-like (+>-
75 mg (yield 100%) of Latifin was obtained.

Melting point: 213-217°C (decomposition) [α]
o: +9j9° (C=0.362.
CH30H) NMRδ: 2.31 (3Ls), 2.6
3 and 2.89 (IH, d, J = lOHz), 3.43
and 3.63 (In, d, J = 14 Hz), 3.80 (3
H, S).

4.24 (IH, t,, h5Hz>, 6°61 and 6.8
2 (IH, d, J・9Hz) 6.62 and 6.88 (2H
, d, J=81(z)ppmIQ11 The present invention has made it possible to produce a new pharmaceutical ingredient (+)-latifin by organic synthesis means.

It is also possible to supply (-)-latifine by applying the method of the present invention.

Claims (2)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) Optically active (+)-latifin represented by. (2) Formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) A method for producing (+)-latifine, which is obtained by catalytic hydrogen reduction of (R)-dibenzyllatifine.