JP3017338B2 - New intermediate compounds for the production of indole alkaloid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to tricyclo [5.2.
1.0 ^2,6 ] dec-8-en-3-one compound and a method for producing the same. More specifically, for example,
(-)-4-exo- is a very important intermediate for producing pyrrolo- and furano [2,3-b] indoles, which are expected as therapeutic agents for senile dementia.
[2- (N-acyl-N-alkylamino) -4-alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-
The present invention relates to an on-compound and a method for producing the same.

[0002]

2. Description of the Related Art Physostigmine, a major alkaloid in carabar beans, has an anticholinesterase inhibitory action and has already been used clinically. In addition, it has been suggested that the present alkaloid may be used as a therapeutic drug for senile dementia, particularly Alzheimer's disease. However, since this alkaloid has a drawback of being extremely toxic, synthesis of many structural analogs has been attempted. However,
A general synthesis method in which substituents of pyrrolo- and furyl [2,3-b] indoles, which are basic skeletons of the present alkaloids, can be arbitrarily converted and one or both of the optical antipodes are optionally synthesized is known. Not. The present invention has been made under such circumstances.

[0003]

That is, the present invention provides a novel intermediate required for the synthesis of pyrrolo- and furyl [2,3-b] indoles represented by physostigmine and its analogs, and a process for producing the same. Is to do.

[0004]

Means for Solving the Problems The present inventors have intensively studied a route which can introduce an arbitrary substituent and can synthesize an physostigmine skeleton in an enantioselective manner. It has been found that the above problem can be solved by using a suitable compound, and the present invention has been completed.

That is, the present invention provides the following general formula (I):

Embedded image (Wherein, R, R ¹ and R ² represent an alkyl group having 1 to 3 carbon atoms or a benzyl group, and R ³ represents an alkyl group having 1 to ³ carbon atoms or a phenyl group). ) -4-ex
o- [2- (N-acyl-N-alkylamino) -4-
Alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one compound, tricyclo [5.2.1.0
^2,6 ] α- of the carbonyl group of deca-8-en-3-one
(-)-4-exo- [2- (), wherein the carbinolamine obtained by reacting with p-alkoxyphenylhydrazine is acylated, and then N-alkylated. Method for producing N-acyl-N-alkylamino) -4-alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one compound It is.

The (-)-4-exo- [2-
The (N-acyl-N-alkylamino) -4-alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one compound is as follows: As shown in the reaction formula, tricyclo [5.2.
1.0 ^2,6 ] dec-8-en-3-one as a starting material can be synthesized as follows.

Embedded image

That is, tricyclo [5.2.1.0
^2,6 ] Deca-8-en-3-one (3) is alkylated at the α-position of the carbonyl group with an alkyl halide in the presence of a base to give a monoalkyl ketone (4). This (4)
A strong acid salt such as p-alkoxyphenylhydrazine hydrochloride or sulfate is heated to reflux in hydrous pyridine to form carbinolamine (7), and then acid anhydride or acid halide in the presence of a base. Acylation and N-alkylation with an alkyl halide give (-)-4-ex
o- [2- (N-acyl-N-alkylamino) -4-
Alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one compound (I) can be synthesized.

In the synthesis method of the present invention, the Fischer indole reaction between the tricyclic monoalkyl ketone (4) and p-alkoxyphenylhydrazine proceeds stereospecifically, and only one of the stereoisomers forms a single product. Obtained as a product. The raw material (3) is prepared by a known method (ST).
akano, K .; Inomata, K .; Ogasawa
ra, J. et al. Chem. Soc. Chem. Commu
n. 1989, 271), the compound represented by the general formula (I) can be easily synthesized as one or both of the optically active compounds. In the synthesis of pyrrolo- and furyl [2,3-b] indoles as intermediates, the asymmetric center is maintained, and it is possible to synthesize a compound having the same configuration as that of nature. Examples of such compounds are (-)-phyzobenin (1) and (-)-
Physostigmine (2) can be mentioned.

Embedded image As an example of a method for synthesizing these compounds, one of the compounds represented by the general formula (I), (−)-4-exo-
[2- (N-acetyl-N-methylamino) -4-methoxyphenyl] -4-endo-methyltricyclo [5.
An example using 2.1.0 ^2,6 ] dec-8-en-3-one (9) as a starting material is shown in the following figure. After cyclopentadiene is eliminated from (9) to give a cyclopentenone compound (10), the methoxy group of lactol (14) obtained by ozone oxidation treatment is demethylated to carbamoyl to give (-)-phyzobenin (1). Similarly, lactone (18) obtained by oxidation with silver carbonate using lactol (14) and reaction with N-methylamine is deacetylated, and then carbonyl of amide group is reduced to obtain (-)-. (-)-Physostigmine (2) having the same configuration as that of nature is synthesized by demethylation and carbamoylation of eszerolin (22).

Embedded image

[0009]

The present invention will be described in more detail with reference to the following examples. In the examples, the optically active (−)-4-exo-
[2- (N-acetyl-N-methylamino) -4-methoxyphenyl] -4-endo-methyltricyclo [5.
2.1.0 ^2,6 ] dec-8-en-3-one will be specifically described, but the present invention is not limited to this range.

Example 1 4-endo / exo-methyltricyclo [5.2.1.0 ^2,6 ]
Synthesis of Dec-8-en-3-one A solution of lithium diisopropylamide (formed from 5 ml of diisopropylamine, 35.6 mmol of hexane solution of 35.6 mmol of n-butyllithium in hexane) in THF was added thereto, and (-)- Tricyclo- [5.2.1.0 ^2,6 ] deca-8-
Enon (> 97% ee by HPLC, 4.38
g, 29.6 mmol of a THF solution (11 ml) were added dropwise. The temperature rise at this time was from -78 ° C to -30 ° C. After stirring for 1 hour, methyl iodide (21 ml, 33.7) was added at -30 ° C.
mmol) was added dropwise and stirring was continued at −30 ° C. for 13 hours. After the reaction was stopped by adding an aqueous solution of ammonium chloride, the reaction mixture was extracted with ether. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified on a silica gel column (130 g) using a mixed solvent of diethyl ether: hexane (1:30, volume ratio) as an eluent to obtain 4.12 g of the desired ketone as an oily mixture of epimer As obtained. IR (film) ν 1731 cm ^-1 proton NMR (CDCl ₃ ) δ 0.85 and 0.9
0 (each doublet, 3Hx1 / 2, J = 6.4H
z), 1.25-2.40 (m, 5H), 2.71-
3.26 (m, 4H), 5.94-6.20 (m, 2
H) Mass spectrum m / z 162 (M +), 65 (100
%) When the molecular formula is C ₁₁ H ₁₄ O, the calculated value is 162.104.
5, found 162.1054.

Example 2 Synthesis of carbinolamine from tricyclic ketone The mixture obtained in Example 1 (694 mg, 4.28 mmol)
And 4-methoxyphenylhydrazine hydrochloride (748 mg,
4.28 mmol) in aqueous pyridine (pyridine: water = 10:
(1 volume ratio; 5.5 ml) for 35 minutes.
After evaporating the solvent under reduced pressure, the mixture was extracted with ether, and the organic layer was washed with water, an aqueous solution of copper sulfate, an aqueous solution of sodium hydrogen carbonate and brine in that order, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column (60 g) to give diethyl ether: hexane (1: 3,
Purification was performed using the mixed solvent as an eluent to obtain 1.02 g of the target carbinolamine as colorless crystals (recrystallized from benzene). Melting point 109-111 ° C; [α] _D28 -144 ° (c
1.95, CHCl3). IR (Nujol) ν 3316, 3246, 1495 cm _-1 ;
Proton NMR (CDCl ₃ ) δ 1.04 (s, 3
H), 0.97-1.70 (m, 4H), 6.01-
6.18 (m, 1H), 6.18-6.39 (m, 1
H), 6.39-7.00 (m, 3H) Mass spectrum m / z 283 (M +), 199 (100%).
Assuming that the molecular formula is C ₁₈ H ₂₁ NO ₂ , the calculated value of the molecular weight is 2
83.1572, measured value was 283,1553. Elemental analysis calculated C, 76.30; H 7.47; N, 4.
94 found C, 76.27; H, 7.39; N, 4.8.
7

Example 3 N-acylation of carbinolamine A mixture of the carbinolamine obtained in Example 2 and acetic anhydride (0.07 ml, 7.43 mmol) were stirred in pyridine at room temperature for 10 hours. After the volatile substances are distilled off under reduced pressure,
The residue was dissolved in dichloromethane, washed with 5% hydrochloric acid, sodium hydrogen carbonate, and brine in that order, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column (60 g) using ethyl acetate hexane (1: 3, volume ratio) as an eluent, and 1.73 g of amide was recrystallized from colorless crystals (diethyl ether). ). Melting point 163-164 ° C; [α] _D 28 _{-100 °} (c
1.19, CHCl ₃ ). IR (Nujol) ν 3332, 1618 cm ^-1 proton NMR (CDCl ₃ ) δ 1.08 (s, 3H
x 6/7), 1.24 (s, 3Hx 1/7) 1.24
1.68 (m, 3H), 1.96-2.18 (m, 1
H), 2.19 (s, 3H x 6/7), 2.42
(S, 3H x 1/7), 2.43-3.18 (m, 5
H), 3.80 (s, 3H x 6/7), 3.82
(S, x 1/7), 5.96-6.44 (m, 2
H), 6.60-7.04 (m, 3H ) Mass spectrum m / z 325 (M +, when 100%) Molecular formula and C ₂₀ H ₂₃ NO _3, calculated molecular weight 325.
1678, measured value was 325.1667. Elemental analysis calculated C, 73.82; H, 7.12; N,
4.30. Found C, 73.91; H, 7.25; N, 4.23.

Example 4 (-)-4-exo- [2- (N-acetyl-N-methylamino) -4-methoxyphenyl] -4-endo-methyltricyclo [5.2.1.
Synthesis of 0 ^2,6 ] dec-8-en-3-one The amide obtained in Example 3 (1.73 g, 5.32 mmol)
l) is a mixed solvent of DMF and THF (1: 1, volume ratio) 2
Stir in 0 ml, add sodium hydride (50% oil suspension, 280 mg, 5.83 mmol) at 0 ° C. and continue stirring at room temperature for 30 minutes. After addition of methyl iodide (0.66 ml, 10.6 mmol) at 0 ° C., the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 5% hydrochloric acid and extracted with ether. The extract was washed with an aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, ethyl acetate-hexane (1: 2, volume ratio) was eluted with a silica gel column (80 g) to obtain 1.70 g of a colorless foam. [Α] _D ²⁹ -147 ° (c 1.21, CHCl ₃ ) IR (film) v 1728, 1664 cm ^-1 Proton NMR (CDCl ₃ ) δ 1.06-1.91
(M, 9H), 2.35-3.25 (m, 8H), 3.
78 (s, 3H), 5.92-6.32 (m, 2H),
6.68-7.02 (m, 3H) Mass spectrum m / z 339 (M ⁺ ), 178 (100
%); The molecular formula was C ₂₁ H ₂₅ NO ₃ , the calculated molecular weight was 339.1834, and the measured value was 339.1815.

[0014]

INDUSTRIAL APPLICABILITY According to the present invention, pyrrolo- and furyl [2,3-b], which exhibit anticholinesterase inhibitory activity and are the basic skeletons of physostigmine itself and related analogs, which are attracting attention as therapeutic agents for senile dementia, Tricyclo [5,2,1,0 ^2,6 ] which is a useful intermediate for efficiently synthesizing indole compounds, and which can synthesize one enantiomer or both enantiomers if desired. A deca-8-en-3-one compound and a production method by which this compound can be efficiently synthesized can be provided.

Claims (2)

(57) [Claims] (1) The following general formula (I): (Wherein, R, R ¹ and R ² represent an alkyl group having 1 to 3 carbon atoms or a benzyl group, and R ³ represents an alkyl group having 1 to ³ carbon atoms or a phenyl group). ) -4-ex
o- [2- (N-acyl-N-alkylamino) -4-
Alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one compound. 2. Tricyclo [5.2.1.0 ^2,6 ] deca
After alkylating the α-position of the carbonyl group of 8-en-3-one, the carbinolamine obtained by reacting with p-alkoxyphenylhydrazine is acylated,
(-)-4-exo- characterized by alkylation
[2- (N-acyl-N-alkylamino) -4-alkoxyphenyl] -4-endo-alkyl (benzyl) tricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-
ON manufacturing method.