JPH0465066B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The object of the present invention is to obtain a general formula that is important as an intermediate for the production of ergot alkaloids useful as pharmaceuticals. (R ¹ in the formula is an alkyl group having 1 to 3 carbon atoms substituted with a hydroxyl group or a lower alkoxy group,
^R2 is an alkyl group having 1 to 6 carbon atoms, X is a hydroxyl group or a lower alkyl group, and ^R3 is a formyl group, a nitrovinyl group, or a nitroethyl group. .

[Conventional technology]

Ergot alkaloids have α-receptor blocking effects,
It has various pharmacological actions such as antiserotonin action, smooth muscle contraction action, peripheral vasodilation action, cerebral vasodilation action, and prolactin secretion suppressing action, and is widely used clinically. Examples include a migraine treatment, a peripheral vascular disorder treatment, a senile brain dysfunction treatment, a uterine contraction agent, a uterine hemostatic agent, an antihypertensive agent, and a hyperprolactinism treatment.

The basic chemical structure of ergot alkaloids is
formula It has an ergoline structure expressed by , the effects differ significantly depending on the type, etc. For this reason, many studies have been conducted on derivatives to exert selective and specific pharmacological effects.

Most of the ergot alkaloids currently used for treatment are natural alkaloids or their semi-synthetic products.
Alternatively, it can be obtained by chemically modifying it.

Derivative research is also carried out using natural alkaloids, such as ring cleavage, hydrolysis, and substituent conversion, which requires changes in the basic structure itself, major changes in substituents, selection of substitution positions, etc. was severely limited.

Various studies have been conducted on the total synthesis of ergot alkaloids, and synthetic methods for some alkaloids have already been reported, but all of them involve a large number of steps, require a lot of effort, and have a low total yield over all steps.
It is insufficient for industrial application. [Tetrahedron Letters, 22~
Volume 23, pages 1827-1830, 1975; Chemistry Letters, 1981, 615
~Page 618] [Problems to be solved by the invention] In producing and researching ergot alkaloids, which have various pharmacological effects and are useful as pharmaceuticals, all conventional production methods require a lot of effort, The yield was low and effective research and development was not possible. Therefore, in research and development in this field, there has been a desire to develop efficient methods for producing alkaloids, synthetic intermediates, and methods for producing the same, which can be applied to various derivatives.

[Means for solving problems]

As a result of studies to find an efficient structural method for ergot alkaloids, it was discovered that various alkaloids can be easily produced in a short process by using the indole derivative of the present invention as a production intermediate.

For example, a compound represented by the general formula (1) of the present invention
General formula where R ³ is a nitroethyl group (In the formula, R ¹ , X and R ² have the same meanings as above) is ring-closed using an acid-base catalyst, and the general formula (R ¹ and R ² in the formula have the same meanings as above)
By obtaining a compound represented by and then reducing this using an appropriate reducing agent, clavine-type alkaloids such as norchanoclavine and norisochanoclavine and their derivatives can be obtained. can.

Chanoclavine, Isochanoclavine and their derivatives can be produced by introducing a methyl group into the 4-position amino group of these compounds according to a conventional method. Furthermore, from Kanoclavine, Isokanoclavine, Agroclavine, Festuclavine, Costaclavine, Setoclavine,
It can be converted into alkaloids such as Isosetoclavine, Elymoclavine, Peniclavine, and Isopeniclavine.

A compound of the present invention of general formula (), wherein R ³ is a nitrovinyl group, The compound represented by (in the formula, R ¹ , X and R ² have the same meanings as above) can be converted into the compound of general formula (c) by reduction using an appropriate reducing agent. Furthermore, by treating with sodium borohydride-hydrochloric acid, for example, reduction and ring closure can be carried out in one pot to obtain a compound of general formula (). From these compounds, various alkaloids can be easily derived as described above.

A compound of general formula () of the present invention, wherein R ³ is a formyl group, The compound represented by (in the formula, R ¹ , X and R ² have the same meanings as above) can be prepared by reacting with nitromethane in the presence of ammonium acetate.
Compounds of general formula (b) can be obtained. As mentioned above, this can be led to various alkaloids via the compound of general formula (c) or general formula (). Furthermore, by taking advantage of the properties of the formyl group and converting it into various substituents and ring-closing it, it is possible to lead to an alkaloid having a different skeleton or a different substituent.

As described above, by using the compound of general formula () of the present invention as a production intermediate, various ergot alkaloids can be produced very easily and in a short process.

The clavine-type alkaloids derived from the compound represented by the general formula () of the present invention have various pharmacological actions and are useful as pharmaceuticals. for example,
Kanoclavine is used as an antihypertensive drug because it exhibits a blood pressure lowering effect, and agroclavine is used as a labor promoting drug because it exhibits a strong uterine contraction effect.

Therefore, the compound of the general formula () of the present invention is extremely important as an intermediate for the production of ergot alkaloids useful as pharmaceuticals.

The compound of general formula () of the present invention can be produced as follows.

That is, the expression 4-iodo-3-indolecarbaldehyde represented by and the general formula (In the formula, ^{R 1 ,} ) can be prepared, and this compound of general formula (a) can be prepared by
A compound of general formula (b) can be produced by reacting with nitromethane in the presence of ammonium acetate. Furthermore, by reducing the compound of general formula (b) with a suitable reducing agent, such as sodium borohydride, the compound of general formula (
The compound c) can be produced.

A compound of the present invention represented by the general formula () in which R ¹ is a hydroxymethyl group and X is a methoxy group is a compound represented by the general formula (R ² and R ³ in the formula have the same meanings as above)
It can also be produced by reacting the compound represented by with 70% m-chloroperbenzoic acid in a suitable solvent.

The compounds of formula (), general formula (d) and general formula () used as starting materials in these production methods can be produced by methods described in literature or similar methods. [Chem.Pharm.Bull., Volume 32, Pages 5064-5065,
1984, Journal of Organic Chemistry (J.Org.Chem.), Volume 25, Pages 1673-1674, 1960] In order to suitably carry out the method for producing the compound of the general formula () of the present invention, 4-Iodo-3-indole carbaldehyde represented by is dissolved in an inert solvent such as N,N-dimethylformamide, and an excess amount of triethylamine and 5 to 6 times equivalent amount of general The olefin derivative represented by the formula (), a small amount of palladium acetate, and tetra-n-butylammonium bromide are added, and the mixture is heated and stirred at about 100° C. for 2 to 5 hours in a sealed tube. After the reaction, the desired compound of general formula (a) is obtained by treatment and purification according to conventional methods. The obtained compound of general formula (a) is dissolved in an appropriate amount of nitromethane,
The compound of general formula (a) and equimolar amounts of ammonium acetate are added to this, and the mixture is heated and stirred at 80 to 120°C for 1 to 20 hours. After cooling, the mixture is treated and purified according to conventional methods to obtain the target compound of general formula (b). The compound of general formula (b) is dissolved in an inert solvent such as methanol, 3 to 4 equivalents of sodium borohydride are added, and the mixture is stirred at room temperature for about 30 minutes. After adding an appropriate amount of water, the mixture is carefully neutralized with 2N hydrochloric acid, the solvent is distilled off, and the residue is extracted with an inert organic solvent such as methylene chloride. The extract is treated and purified according to conventional methods to obtain the target compound of general formula (c).

In addition, in the reaction using the compound of general formula (d) as a starting material, the compound of general formula (d) is dissolved in an inert organic solvent, for example, a mixed solvent of methylene chloride and methanol, and 2 to 5 times equivalent m - Add chlorperbenzoic acid and stir at room temperature for 3-5 hours. After the reaction is completed, the desired product is obtained by treatment and purification according to conventional methods.

The compounds of the general formula () of the present invention, particularly the compounds of the general formulas (b) and (c), can be ring-closed,
By reduction, it can be led to the clavin type alkaloid of the seed tube.

For example, in a compound of general formula (c), R ¹ , R ²
Norcanoclavine and norisokanoclavine can be produced in 2 steps from a compound in which one of the hydroxymethyl groups is a methyl group and the other is a methyl group, kanoclavine and isokanoclavine can be produced in 4 steps, and 5 steps. can produce agroclavine. In addition, it can lead to alkaloids such as festuclavine, costaclavine, setoclavine, isocetoclavine, erimoclavine, peniclavine, and isopeniclavine.

All of these alkaloids exhibit useful pharmacological effects and are useful as pharmaceuticals. For example, canoclavine is used as an antihypertensive drug because it exhibits a blood pressure lowering effect, and agroclavine is used as a labor stimulant because it exhibits a strong uterine contraction effect.

〔Example〕

The content of the present invention will be explained in more detail with reference to the following examples. Note that all melting points of compounds in each example are uncorrected.

Example 1 4-(3-hydroxymethyl-3-methoxy-
1-Buten-1-yl)-3-indolecarbaldehyde 4-iodo-3-indolecarbaldehyde
Dissolve 100.9 mg in 1 ml of N,N-dimethylformamide, and add 0.3 ml of triethylamine and 2-methoxy-2-methyl-3-buten-1-ol.
254 mg, palladium acetate 7.1 mg and tetra-n-
14.2 mg of butylammonium bromide was added, and the mixture was heated and stirred in a sealed tube at 98 to 100°C for 3 hours. After cooling, the reaction mixture was added with a methylene chloride-methanol mixed solvent (95:
5) was added, insoluble matter was filtered off through a silica membrane, and the solvent was distilled off under reduced pressure. An appropriate amount of water was added to the residue, extracted with a mixed solvent of methylene chloride and methanol (95:5), washed with saturated brine and water, and dried over anhydrous sodium sulfate. The residual oil was purified by silie gel column chromatography (elution solvent: methylene chloride:methanol = 95:5) to obtain colorless prismatic crystals of 4-(3-hydroxymethyl-3-methoxy-1).
88.4 mg (91.7%) of -buten-1-yl)-3-indolecarbaldehyde was obtained.

Colorless prism crystal Melting point: 78-80℃ (ethyl acetate-n-hexane) R (film): ν max 3460, 1648, 1084 cm ^-1 NMR (CD ₃ OD) δ: 1.50 (3H, s), 3.23 (3H, S), 3.56
(2H, s), 6.03 (1H, d, J=16.0Hz),
6.93-7.50 (3H, m), 7.96 (1H, s), 8.03
(1H, d, J = 16.0Hz), 9.60 (1H, s) MS: m/e 228 [M ⁺ -31 (OMe)] Example 2 4-(3-hydroxymethyl-3-methoxy-
1-Buten-1-yl)-3-(2-nitrovinyl)indole 4-(3-hydroxymethyl-3-methoxy-
70.4 mg of 1-buten-1-yl)-3-indolecarbaldehyde was dissolved in 5 ml of nitromethane, 20.8 mg of ammonium acetate was added thereto, and the mixture was heated on an oil bath at 88°C.
The mixture was heated and stirred for 9 hours. After cooling, add an appropriate amount of saturated saline and methylene chloride-methanol mixed solvent (95:
After adding 5) and shaking well, the organic layer was separated. The aqueous layer was further extracted with a methylene chloride-methanol mixed solvent, and both solutions were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from methanol to give orange-red prismatic crystals of 4-(3-hydroxymethyl-3-methoxy-1-buten-1-yl)-3.
-(2-nitrovinyl)indole 48.0 mg was obtained.
The recrystallized mother liquor was subjected to silica gel preparative thin layer chromatography (developing solvent: methylene chloride: methanol =
95:5) to obtain an additional 27.8 mg of the desired product. Total yield 75.8 mg (92.3%).

Orange-red prismatic crystal Melting point: 164-165℃ (methanol) IR (KBr): ν max 3380, 3150, 1605, 1295, 1244cm
^-1 NMR (pyridine-d ₅ ) δ: 1.67 (3H, s), 3.41 (3H, s), 3.93
(2H, s), 6.31 (1H, d, J=15.6Hz),
6.92-7.50 (3H, m), 7.38 (1H, d, J=
15.6Hz), 7.77 (1H, d, J = 12.8Hz), 7.99
(1H, s), 8.76 (1H, d, J = 12.8Hz) MS: m/e 302 (M ⁺ ) Elemental analysis value (as C ₁₆ H ₁₈ N ₂ O ₄ ) C% H% N% Calculated value 63.56 6.00 9.27 Actual value 63.54 6.01 9.08 Example 3 4-(3-hydroxymethyl-3-methoxy-
1-Buten-1-yl)-3-(2-nitroethyl)indole 4-(3-hydroxymethyl-3-methoxy-
503.9 mg of 1-buten-1-yl)-3-(2-nitrovinyl)indole was dissolved in 25 ml of methanol, 209.8 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for about 30 minutes. After the reaction was completed, an appropriate amount of water was added and the mixture was carefully neutralized using 2N hydrochloric acid, methanol was distilled off, and the remaining solution was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give pale yellow prismatic crystals of 4-(3-
Hydroxymethyl-3-methoxy-1-butene-
1-yl)-3-(2-nitroethyl)indole
415.5mg was obtained. The recrystallized mother liquor was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride: methanol = 95:5) and further purified to 61.2
mg of target product was obtained. Total yield 476.7 mg (94.0%).

Colorless prism crystal Melting point: 125.5-126.5℃ (Ethyl acetate-n-hexane) IR (KBr): ν max 3350, 3250, 1545, 1336, 1049cm
⁻¹ NMR (10% CD ₃ OD in CDCl ₃ ) δ: 1.40 (3H, s), 3.24 (3H, s), 3.49
(2H, t, J=7.6Hz), 3.52 (2H, s), 4.53
(2H, t, J = 7.6Hz), 5.99 (1H, d, J =
16.0Hz), 6.87 (1H, brs), 6.95~7.20 (3H,
m), 7.10 (1H, d, J = 16.0Hz), 9.10 (1H,
br) MS: m/e 304 (M ⁺ ) Elemental analysis value (as C ₁₆ H ₂₀ N ₂ O ₄ ) C% H% N% Calculated value 63.14 6.62 9.20 Actual value 62.97 6.69 9.20 Example 4 4-(3- Hydroxymethyl-3-methoxy-
1-Buten-1-yl)-3-indolecarbaldehyde 4-(3-methyl-1,3-butadiene-1-
35.0 mg of yl)-3-indolecarbaldehyde,
Dissolve in a mixed solvent of 5 ml of methylene chloride and 1 ml of methanol, add 49 mg of sodium hydrogen carbonate,
Next, a solution of 37.5 mg of 70% m-chloroperbenzoic acid dissolved in 1 ml of methylene chloride was added, and the solution was dissolved at room temperature for about 1 hour.
Stir for hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethylene chloride:
Purify with methanol = 99:5) to give pale yellow crystals.
17.8 mg (41.4%) was obtained. The physical constants of this substance all matched those of the compound obtained in Example 1.

Example 5 4-(3-hydroxymethyl-3-methoxy-
1-buten-1-yl)-3-(2-nitrovinyl)indole 4-(3-hydroxymethyl-3-methoxy-
51.0 mg of 1-buten-1-yl)-3-indolecarbaldehyde was dissolved in 3 ml of nitromethane, 67.0 mg of ammonium acetate was added thereto, and the mixture was heated on an oil bath for 108~
The mixture was heated and stirred at 113°C for about 1 hour. After cooling, an appropriate amount of saturated brine was added and extracted with methylene chloride. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from methanol-water to give 59.0 mg of red-orange prism crystals.
(99.2%). The physical constants of this substance are shown in Example 2.
All of the results were consistent with those of the compound obtained in .

Example 6 4-(3-hydroxymethyl-3-methoxy-
1-buten-1-yl)-3-(2-nitrovinyl)indole 1-[3-(2-nitrovinyl)indole-4
-yl]-3-methyl-1-buten-3-ol
1.015g was dissolved in 40ml of N,N-dimethylformamide, 504.9mg of ammonium chloride was added thereto, and the mixture was heated and stirred on an oil bath at 120-132°C for 2 hours. After distilling off the solvent under reduced pressure, 60 ml of a saturated aqueous sodium hydrogen carbonate solution and 20 ml of water were added, followed by extraction with a mixed solvent of methylene chloride and methanol (95:5). After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain light brown prismatic crystals of 4-(3-methyl-1,3
-butadien-1-yl)-3-(2-nitrovinyl)indole was obtained.

Light brown prismatic crystal Melting point: 154-156℃ (decomp.) (methanol) IR (KBr): ν max 3220, 1600, 1509, 1235 cm ^-1 NMR (pyridine-d ₅ ) δ: 2.12 (3H, s), 4.90 ~5.25 (2H, m),
6.79 (1H, d, J = 15.2Hz), 7.27 (1H, d,
J=15.2Hz), 6.95-7.50 (3H, m), 7.72
(1H, d, J=12.8Hz), 7.96 (1H, s),
8.70 (1H, d, J = 12.8Hz), 13.13 (1H, brs) The obtained crude crystals were dissolved in 60ml of methylene chloride-methanol mixed solvent (1:1), and 70%-m
-Add 1.676g of chlorperbenzoic acid and let it cool for about 30 minutes at room temperature.
Stir for hours. After the reaction was completed, a saturated aqueous sodium hydrogen carbonate solution was added, the mixture was thoroughly shaken, and the organic layer was separated. The aqueous layer was further extracted with methylene chloride, both solutions were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride:methanol = 99:1) to obtain 460.1 mg (total yield: 40.8%) of orange-red prism crystals. The physical constants of this substance all matched those of the compound obtained in Example 3.

〔Effect of the invention〕

The compound of the general formula () of the present invention can be converted into various ergot alkaloids very easily and in a short process. For example, in the compound of general formula (), a compound of formula (c) in which R ³ is a nitroethyl group can be ring-closed and reduced to lead to canoclavine, isokanoclavine, etc. Isokanoclavine can be converted to agroclavine by treatment with thionyl chloride. In addition, it can lead to festuclavine, setoclavine, isocetoclavine, erimoclavine, beniclavine, isopeniclavine, etc.

These alkaloids have various pharmacological effects and are useful as pharmaceuticals. For example, canoclavine is used as an antihypertensive drug because it has a blood pressure lowering effect, and agroclavine is used as a labor promoting drug because it has a strong uterine contraction effect.

By using the compound of the general formula () of the present invention as a synthetic intermediate, various pharmaceuticals having an ergot alkaloid skeleton as described above can be efficiently produced.

Claims (1)

[Claims] 1. General formula (R ¹ in the formula is an alkyl group having 1 to 3 carbon atoms substituted with a hydroxyl group or a lower alkoxy group,
^R2 is an alkyl group having 1 to 6 carbon atoms, X is a hydroxyl group or a lower alkoxy group, and ^R3 is a formyl group, a nitrovinyl group, or a nitroethyl group.