JPS5962589A - Preparation of protoberberine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an antibacterial agent and antitumor agent, easily in high yield, under mild condition, by converting a specific formamide compound to an iminium salt by Bischler-Napieralski method, and heating the salt together with an alkali metal fluoride in an organic solvent. CONSTITUTION:The formaldehyde compound of formula I (R<1> and R<2> are methoxy and R<3> is H, or R<1> is H and R<2> and R<3> together form methylenedioxy) is heated together with a Lewis acid catalyst such as phosphorous oxychloride to obtain the iminium salt of formula II. The objective compound of formula IIIcan be prepared by heating the salt together with an alkali metal fluoride (prefferably cesium fluoride) in an organic solvent such as ethanol. The starting compound of formula I can be obtained by condensing the O-trimethylsilylmethylbenzaldehyde derivative of formula IV with 3,4-dimethoxyphenetylamine under heating, reducing the resultant Schiff's base of formula V, and formylating the obtained secondary amine of formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a Furo I Helbelin conductor.
, Pro) Berberine alkaloids have been found to exhibit interesting physiological activities such as antibacterial properties and iHi J arch properties.
Although various methods for producing jA conductors have been developed, none of the conventional methods has been able to add Wta because the reaction is difficult to occur under mild reaction conditions.

After reducing the condensate of rudehyde and phenethylamine, it is converted into an iminium salt by the portamidoeralsugi method, and when heated, the trimethyl 7-lyl group is nucleophilically eliminated using fluorine ions, and a berberine ring is formed. The present invention was completed by successfully obtaining protoberberine derivatives easily and in high yield under mild reaction conditions.

The method of the present invention comprises 1 (wherein R1 and R2 both represent a 7-toxy group, R3 represents a hydrogen atom, or R1 represents a hydrogen atom, and R2 and R3 together represent a methylenoxy group). show,,
) (hereinafter referred to as compound I) is heated with a Lewis acid catalyst to form an iminium salt (hereinafter referred to as compound I) represented by the general formula (wherein R1, R2 and R3 have the same meanings as above). 7. Combine with compound ■.
), and heating this in an organic solvent with an alkali metal 1.
A protoberberine derivative represented by (hereinafter referred to as compound I)
This is a method for producing I+.

In the present invention, the Lewis acid catalyst includes, for example, phosphorus chloride, phosphorus pentachloride, zinc chloride, alkali chloride, and preferably phosphorus chloride.

The organic solvent used during the formation of the bell horn ring is, for example, N,N-dimethylformamide, ethanol, etc., and 90% ethanol is particularly desirable. Formation of a berberine ring does not take place in abrotic solvents such as tetrahydrofuran, acetonate, and alkali metal salts.

Examples of such compounds include triurium difluoride, potassium fluoride, and cesium fluoride, among which cesium fluoride is the most preferable in terms of the reaction time of 9A and good yield. It's small. Even with fluorides, berberine ring formation does not occur with quaternary ammonium salts other than metal fluorides (e.g., tetrabutylammonium fluoride)1. 1!1 can be done 3. In other words, under a stream of inert gas such as argon, formamide compound 1 is heated under reflux with Ruth's acid catalyst for about 1 hour in benzene and other adsorption media. Dehydrated to form isoginoline term, iminiuno 18□1 compound 11
I4I.

Under a stream of inert gas such as argon, in an organic solvent such as 90% ethanol, compound ① is fluorinated with an arunonori metal: The proboscis is heated to reflux overnight, and the trimethyl 7-lyl group is nucleophilically denucleated by the generated fluorine ions. %f to form a -.rubelin ring, and the resulting Jl Da 41 product was purified by a conventional method to obtain Compound 1. 1. Compound 1, which is a starting raw stone, can be synthesized by the following method:
ol-limethyl7lylmethylbenzaltehyde derivative represented by (hereinafter referred to as compound ■) and 6,4-
The N'nofu' base (hereinafter referred to as compound V) represented by the general formula (in the formula, R1, R2 and R3 have the same meanings as above) was obtained by heat condensation with zometogyphenethylamine, and this was dissolved in water-containing methanol. /1 (boron reducing agent (
For example, a secondary amine (hereinafter referred to as compound 3) represented by the general formula (wherein R1, R2 and R3 have the same meanings as above)
get.

Compound (1) is formylated with formic acid and acetic anhydride in the presence of a base (eg, pyridine, nonolium carbonate, triethylamine, etc.) to obtain formamide compound (1).

The method of the present invention is a standard method that allows easy formation of a berberine ring by utilizing elimination of the trimethyllinyl group under mild reaction conditions. 11 in 1
The reaction of the present invention is useful for producing zolotoberberine derivatives in high yields.
It can also be applied to compounds having '1:X ability]1 (which is easily susceptible to change).

The protoberberin 1j conductor produced by the inventive method can be easily converted into protoberberine derivatives having antibacterial and antitumor properties.

The present invention will be explained in detail with reference to the present invention, reference examples, and examples.

See Example 1 (1) Compound ■−+ (In formula ■, R' = R2=
QC horse.

Immediately dissolve 1 (' = R2 = OC1 (3, R3 = 'H compound ■) in aqueous methanol (90%) and add VC borohydride under stirring at room temperature) IJium 012i/
After reduction for 1 hour by adding (3.2 ml) mol), most of the methanol was distilled off, and the resulting residue was extracted with methylene chloride. ' = R2; OCJ University,
, R3-H compound Vl) 1.217 (yield 91%
).

■R, neat (Q#I'): 3300a
X NMR (CDCl2) δ; 1 5 (s, IH), 2.
05 (s, 2H).

2.90 (t, 4H,), 3.66 (s, 2H).

3.85 (s, 6H,), 3.75 (s, roH).

6.50-6.80 (m, 5H) Mass (
m/s: 417 (M”) (2) Compound Vl-,t 19 (
2.6 mmol) and 1.32 f of formic acid acetic anhydride (
15 mmol) were mixed and heated at 80°C for 1 hour, the pyridine was distilled off under reduced pressure, and the residue was dissolved in methylene chloride. This solution was mixed with 1% hydrochloric acid, water, saturated bicarbonate, and 1% sodium bicarbonate. After washing in this order, dry with sodium sulfate, rub, θ,
The solvent was distilled off under υ1 pressure, and a pale brown oily compound I-
1 (JX,, in I R' = R'' = OCH3,
Compound 1) t 1a y (yield 100
% Tsui mouth (!f /'X n, [<νneat (Cnl-1): 1660 strokes la
x NMR (CDC/,, )δMo2.00 (d,,2H)
, 2.80 (m, 2H,).

3.40 (m, 2H), 85 (s, 12H).

4.15, 445 (sX2 total - Tal 2H).

6.50-6.75 (m, 5H)'.

8.0'0, 8.23 (SX2. Total 1H) Mas
s (m/e): 445 (M) Reference Example 2 (1) Compound IV 2 (Formula ■ has O-c R1=H
, R2-R3= -〇-CH2-OJ compound ■) 1
．． 2 ft' (5,08 mmol) and 0.92 i? of 6,4-dimethoquinophenethylamine? (5.08 mmol) and operated according to Reference Example 1 (1) to obtain pale yellow oily compound ■-2 (in formula ■, R'=H, R2-
19 g (yield 96%) of R'--0-C1-12-0- compound ■) was obtained 3, IRνgZ x (c”r')' 330
ONMR (CDC1l) δ = 1.25 (S, IH)
, 2.12(s, 2B).

2.90 (m, 4H), 3.70 (r+, 2H).

3.90 (s, 6H), 5.90 (s, 2H).

65-70 (■ ding +, 5H) Mass (m/e): 401 (M) (2)
Compound Vl-21.9 g (4.7 mmol) and formic acid acetic anhydride2. Using Of (23.5 mmol), the procedure was carried out according to Reference Example 1 (2) to obtain pale yellow oily compound 1-2.
(Compound 1 of formula I, R'=H, R2-c-〇-CH2-) 1.84 f (yield 91%) was obtained.

■R, maX (cl, I), 165°N M R
(CDOt3) δ:=+2.05(m, 2H),
2.75 (m, 2H).

3.40 (m, 2H), 3.85 (s, 6H).

4.30 (m, 2H), 5.90 (s, 2H).

6.5-7.0 (m, 5H).

7.95,8.20(r;X2.)-ClIH)Mas
S (m/e): 429 (M)'ノ 〃111
Example 1 1-nor: J No. 1-, compound 1-, 0.2 f (0
, 45 millimeters) -\Nseno 15m/! It can be used in
To this, xychloride 1), / 0.3 1 q (2
After adding 1 mmol of benzene to the mixture, the mixture was heated under reflux for 111 minutes, and then the benzene was removed under reduced pressure to obtain 0.25 g of Compound 1). .

This was heated at 90°C under an argon atmosphere without any preparation.
Cesium fluoride 410 mg in % ethanol 20me
(Heat under reflux overnight with 2.7 mmol, 71., 1.
Most of the ethanol was distilled off to 11-"l, and the residue was
)'/Monia After making it alkaline, extract it with benzene.
This Bearsen extract was washed with water, dried over potassium carbonate, and then the solvent was distilled off, resulting in a residue: I-('':
OCH3,R″: Compound of H) 0.11
! F (yield 70%) was obtained.

m, p, 158-159°C NMR (CDCl3) δ = 2.20-3.
80 (m, 9H), Ro82 (S.

12H), 6.50-6.80 (m, 4H); Mass
(m/e): 355 (M) Example 2 Compound +-,, o, asy (t9a mmol) was dissolved in 40 m12 of benzene, and 078/(4
6 mmol) in Example 1,
Pale yellow foamy compound 112 (R1=H in formula 11,
R'! -R3nee〇-0H2-0- compound 11)
1.1 f was obtained.3, 0.1 g (0.23 mmol) of this was mixed with 0.1 g (0.23 mmol) of cesium fluoride in 5 me of 90% ethanol under a stream of argon.
15 i? (1 ml mol) and heated under reflux for 2 hours, and treated according to Example 1 to obtain compound III 2 as a pale yellow oil.
(In formula I11, R'=H, 1-R'' =-0-
Compound III of aH2-〇-) o, 06 q (
A yield of 77% was obtained. .

Engineering Rν (cm), 2750.1610aX NMR (cDc4.) δ'-'2.20~3.80 (
m, 9H), 3.80 (s, 6H).

5.85 (s, 2H), 6.50-6.70 (m, 5H
) ; MasS (m/e) Roro 9 (M) Special π Applicant: Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1) - General formula (wherein R' and R2 both represent a methoxy group, R3 represents 1 and a hydrogen atom, or R1 represents a hydrogen atom,
1 (2 and W together form a dithylenedioxy group]J scraps.) By heating a formamide compound represented by the formula (2 and W together form a dithylenedioxy group) with a Lewis acid catalyst, The iminium salt represented by the general formula (wherein R1, R2 and W have the same meanings as above) is obtained by heating it together with an alkali metal compound in an organic solvent. A method for producing a glotoberberine derivative.