JPH0234344B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The object of the present invention is to provide a compound of general formula (Either one of R ¹ and R ² in the formula is substituted with a hydroxyl group or a lower alkoxy group, and has a carbon number of 1
-3 alkyl group or formyl group, the other is an alkyl group having 1 to 6 carbon atoms, and R ³
is a nitro group or a lower alkoxycarbonylamino group).

The compound of general formula () of the present invention has α-receptor blocking action, anti-serotonin action, etc., and is useful as a migraine therapeutic agent or a hypertension therapeutic agent.

In addition, the compound of the general formula () of the present invention can be easily converted into various ergot alkaloids, especially clavine-type alkaloids, in a short process, and is extremely useful as an intermediate for the production of pharmaceuticals having an ergot alkaloid skeleton. be.

[Prior art] Ergot alkaloids have α-receptor blocking action,
It has various pharmacological effects 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 in order 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, including 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 and are difficult to collect. The ratio 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 method for producing ergot alkaloids, the 1,3,4,5-
We have discovered that various alkaloids can be produced extremely easily and in a short process by using tetrahydrobenz[cd]indole derivatives as intermediates.

For example, a compound represented by the general formula () of the present invention in which either R ¹ or R ² is a hydroxymethyl group and the other is a methyl group is reduced using an appropriate reducing agent. By this, ergot alkaloids such as Norchanoclavine, Norisochanoclavine, Chanoclavine, Isochanoclavine, etc. can be easily obtained. Kanoclavine, isokanoclavine, etc. can be converted into Agroclavine, Festuclavine, etc. by ring closure using a conventional method. In addition, Costaclaine, Setoclavine,
It can also be easily converted into alkaloids such as isosetoclavine, elymoclavine, peniclavine, and isopeniclavine.

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

Further, the compound of the general formula () of the present invention is α-
It exhibits receptor blocking action, anti-serotonin action, etc., and is also useful as a migraine treatment or hypertension treatment.

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

That is, the general formula (wherein X is a hydroxyl group or a lower alkoxy group, and R ¹ and R ² have the same meanings as above) is treated with an acid-base catalyst, such as hydrochloric acid-sodium borohydride. A compound of the general formula () in which R ³ is a nitro group, the general formula (R ¹ and R ² in the formula have the same meanings as above)
A compound represented by can be produced.

Furthermore, by reducing the nitro group of the compound of general formula (Ia) using a reducing agent, such as zinc amalgam, and then reacting it with a chlorocarbonate in the presence of a base, a compound of general formula () can be obtained.
R ³ is a lower alkoxycarbonylamino group,
general formula (R ⁴ in the formula is a lower alkyl group, R ¹ and
R ² has the same meaning as above) can be produced. General formula of the present invention ()
When producing a compound in which either R ¹ or R ² is a formyl group, it is preferable to protect the formyl group with an appropriate protecting group, such as ethylene acetal, in advance during the reaction.

The compound of general formula () used as a starting material in the production method of the present invention is a new compound,
It can be manufactured as follows.

That is, the expression 4-iodo-3-indolecarbaldehyde represented by and the general formula A compound represented by the formula (R ¹ , R ² and X have the same meanings as above) is reacted with the compound represented by the formula (R 1 , R 2 and Then, the general formula A compound represented by (in the formula, R ¹ , R ² and X have the same meanings as above) is obtained. This compound was then reacted with nitromethane in the presence of ammonium acetate to form the general formula It can be produced by obtaining a compound represented by (in the formula, R ¹ , R ² and can.

In these reactions, for compounds in which either R ¹ or R ² is a formyl group, it is preferable to protect the formyl group in advance during the reaction.

The compounds of the present invention of general formula (Ia) in which R ¹ is a hydroxymethyl group or formyl group and R ² is a methyl group are those of the formula It can also be produced by oxidizing the compound represented by with gelene dioxide.

In these production methods, the compounds of formula (), general formula (), and formula () used as starting materials can be produced by methods described in literature and methods similar thereto. [Chem.Pharm.
Bull.), vol. 32, pages 5064-5065, 1984; Journal of Organ Chemistry (J.
Org.Chem.), Volume 25, Page 1673, 1960] In order to suitably carry out the method for producing the compound of the general formula () of the present invention, the compound represented by the general formula () is mixed in an inert solvent, e.g. Dissolve in methanol, add an excess amount of sodium borohydroxide, and stir briefly at room temperature. Add an appropriate amount of water to the reaction solution,
This is added dropwise to dilute hydrochloric acid with vigorous stirring to decompose excess sodium borohydride. The target compound (Ia) is obtained by treatment and purification according to conventional methods.

Next, dissolve this in an inert organic solvent such as methanol, add this solution to freshly prepared zinc amalgam, add an appropriate amount of 2N-hydrochloric acid, and add 2N hydrochloric acid.
Heat to reflux for ~5 hours. After the reaction is completed, the 4-amino compound is obtained by treatment and purification according to conventional methods. The obtained compound is dissolved in an inert organic solvent, such as tetrahydrofuran, and the required amount to a slight excess amount of base,
For example, after adding triethylamine, add the necessary amount or slightly excess amount of halocarbonate, such as methyl chlorocarbonate, and add 0.5
Allow to react for ~5 hours. After completion of the reaction, treatment and purification are performed according to conventional methods to obtain the target compound of general formula (1b).

R ¹ or R ² in the compound of general formula () of the present invention
When producing a compound in which any one of the above is a formyl group, it is preferable to protect the formyl group in advance during the reaction. After the reaction is complete, the protecting group is removed according to a conventional method. Examples of such protecting groups include ethylene acetal and the like.

The compound of the general formula () of the present invention has a chemical structure of 2
However, in the present invention, the steric configuration is not particularly limited. Also,
There are no particular limitations on the structural isomerism of the E-form or Z-form due to the arrangement of the substituent on the double bond of the substituent at the 5-position, or the structural isomerism of the cis or trans configuration between the substituents at the 4-position and the 5-position. However, the arrangement of the substituents at the 4- and 5-positions is preferably in the trans form.

The compound of general formula () of the present invention can be easily converted into ergot alkaloids, particularly clavine-type alkaloids, in a short process. For example, by reducing a compound of the general formula () in which either R ¹ or R ² is a hydroxymethyl group and the other is a methyl group using an appropriate reducing agent, norcanoclavine or norcanoclavine can be obtained. Isokanoclavine, canoclavine, isokanoclavine, etc. can be produced. Furthermore, agroclavine, festuclavine, etc. can be produced by ring-closing canoclavine, isokanoclavine, etc. according to a conventional method. Others: Costa Klavin,
It can be easily converted into alkaloids such as isocetoclavine, setoclavine, erimoclavine, peniclavine, and isopeniclavine.

All of these alkaloids exhibit pharmacological actions specific to ergot alkaloids, such as prolactin secretion suppressing action and uterine contraction action, 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 promoting drug 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 and Reference Examples. Note that the melting points of the compounds in each Example and Reference Example are all uncorrected.

Reference 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 at 98 to 100°C for 3 hours in a sealed tube. After cooling, 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) IR (film) νmax 3460, 1648, 1084cm ^-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/e228 [M ⁺ -31 (OMe)] Reference 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 and stirred on an oil bath at 88°C 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 mixed solvent of methylene chloride and methanol, and both liquids were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution 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:
Purification was performed in step 5) to obtain an additional 27.8 mg of the desired product. Total yield 75.8 mg (92.3%).

Orange-red prism crystal Melting point: 164-165℃ (methanol) IR (KBr): νmax 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/e302 (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 Reference 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%).

Melting point: 125.5-126.5℃ (ethyl acetate-n-hexane) IR (KBr): νmax 3350, 3250, 1545, 1336, 1049 cm ^-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 = 16.0
Hz), 6.87 (1H, brs), 6.95-7.20 (3H, m),
7.10 (1H, d, J = 16.0Hz), 9.10 (1H, br) MS: m/e304 (M ⁺ ) Elemental analysis value (as C ₁₃ 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 1 4,5-trans-5(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz [cd ]
Indole (Compound 1) 4,5-trans-5-(Z-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (Compound 2) 4,5-cis-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-
1,3,4,5-tetrahydrobenz [cd]
Indole (compound 3) 4-(3-hydroxymethyl-3-methoxy-
501.0 mg of 1-buten-1-yl)-3-(2-nitroethyl)indole was dissolved in 30 ml of methanol, and 636.4 mg of sodium borohydride was added thereto with stirring at room temperature. After stirring for about 5 minutes, 30 ml of water was added to the reaction mixture, and the solution was diluted with 1N hydrochloric acid 60 ml.
ml dropwise with vigorous stirring. After dropping, stir for another 2 minutes, then add 100ml of saturated saline.
Then, 200 ml of methylene chloride was added and shaken, and the organic layer was separated. Add 100% methylene chloride to the aqueous layer.
The extract was extracted twice in ml portions, combined with the organic layer, washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residual oil was subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 99.5:0.5).
Separate and purify compound 1, compound 2, compound 3
142.2 mg (31.7%), 24.3 mg (5.4%), respectively.
25.0 mg (5.6%) was obtained. The physical constants of each compound were as follows.

Compound 1 4,5-trans-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz [cd]
Indole colorless prism crystal Melting point: 156.0-156.5℃ (methylene chloride-n-hexane) IR (KBr): νmax 3520, 3250, 1540, 1345 cm ^-1 NMR (10% CD ₃ OD in CDCl ₃ ) δ: 1.81 (3H, d, J=1.5Hz), 3.53(2H, d,
J=7.4Hz), 4.09 (2H, s), 4.60 (1H, dd,
J=9.5and9.7Hz), 4.81(1H, dt, J=
9.7and7.4Hz), 5.48 (1H, dq, J=9.5and1.5
Hz), 6.64-7.34 (4H, m), 9.16 (1H, brs) MS: m/e272 (M ⁺ ) Elemental analysis value (as C ₁₅ H ₁₆ N ₂ O ₃ ) C% H% N% Calculated value 66.16 5.92 10.29 Actual value 65.97 5.86 10.04 Compound 2 4,5-trans-5-(Z-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz [cd ]
Indole colorless prism crystal Melting point: 179-180℃ (methanol) IR (KBr): νmax 3540, 3270, 1540, 1366, 1344cm ^-1 NMR (pyridine-d ₅ ) δ: 2.07 (3H, d, J = 1.5Hz) , 3.46-3.64
(2H, m), 4.51 (1H, d, J=12.5Hz),
4.74 (1H, d, 12.5Hz), 4.96~5.22 (2H,
m), 5.44 (1H, dq, J=8.5and1.5Hz), 6.88
~7.60 (4H, m), 11.84 (1H, brs) MS: m/e272 (M ⁺ ) Elemental analysis value (as C ₁₅ H ₁₆ N ₂ O ₃ ) C% H% N% Calculated value 66.16 5.92 10.29 Actual value 66.18 5.89 10.17 Compound 3 4,5-cis-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,
3,4,5-tetrahydrobenz [cd] indole colorless prismatic crystal Melting point: 134-135℃ (methylene chloride-n-hexane) IR (KBr): νmax 3480, 3250, 1535, 1368 cm ^-1 NMR (10% CD ₃ OD in CDCl ₃ ) δ: 1.79 (3H, d, J = 1.2Hz), 3.06 to 3.76
(2H, m), 3.80 (2H, s), 4.70 (1H, dd,
J=10and4.4Hz), 4.74~5.10 (1H, m),
5.36 (1H, J=10and1.2Hz), 6.60~6.90 (2H,
m), 6.90-7.30 (2H, m), 8.86 (1H, brs) MS: m/e272 (M ⁺ ) Elemental analysis value (as C ₁₅ H ₁₆ N ₂ O ₃ ) C% H% N% Calculated value 66.16 5.92 10.29 Actual value 66.05 5.91 10.08 Example 2 4,5-trans-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz [ cd] indole (compound 1) 3-[4,5-trans-4-nitro-1,3,
4,5-tetrahydrobenz[cd]indol-5-yl]methacrolein (compound 2) 5-(2-methyl-1-propen-1-yl)-
57.2 mg of 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole was dissolved in 10 ml of dioxane-water mixed solvent (4:1), 143.8 mg of gelene dioxide was added thereto, and the mixture was stirred for about 12 hours. However, it refluxed. After cooling, an appropriate amount of water was added and extracted with a mixed solvent of methylene chloride and methanol (95:5). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel preparative thin layer chromatography (developing solvent: methylene chloride: methanol = 98:2) to obtain compound 1 (Rf value 0.23-0.15) and compound 2
(Rf value 0.64-0.52), 21.6 mg (35.5%),
11.5 mg (19.1%) was obtained. The physical constants of Compound 1 all matched those of Compound 1 obtained in Example 1.

The physical constants of Compound 2 were as follows.

3-[4,5-trans-4-nitro-1,
3.4,5-tetrahydrobenz[cd]indol-5-yl]methacrolein colorless prismatic crystal Melting point: 192-194℃ (decomp.) (methanol) IR (KBr): νmax 3400, 1676, 1540, 1365, ^{1340cm -1} NMR (10% DMSO- _d6 in _CDCl3 ) δ: 1.90 (3H, d=1.2Hz), 3.53 (2H, brd, J
=6Hz), 4.58~5.02 (2H, m), 6.17~6.67
(2H, m), 6.81-7.40 (3H, m), 9.32 (1H,
s), 10.02 (1H, brs) MS: m/e272 (M ⁺ ) Example 3 4,5-trans-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro- 1,3,4,5-tetrahydrobenz[cd]indole 3-[4,5-trans-4-nitro-1,3,
4,5-tetrahydrobenz[cd]indol-5-yl]methanol 24.1 mg of acrolein was dissolved in 10 ml of methanol, 4.3 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for about 0.5 hour. After the reaction was completed, 10 ml of purified water was added to the reaction solution, the solution was poured into 1N hydrochloric acid, and extracted with ethyl acetate.
The extract was washed with saturated brine until the liquid became neutral, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel preparative thin layer chromatography (developing solvent: methylene chloride: methanol = 98:2 and diethyl ether: n-hexane = 2:1) to obtain the desired product. 22.6mg
(93.0%). The physical constants of this compound were all consistent with those of Compound 1 obtained in Example 1.

Example 4 4,5-trans-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-methoxycarbonylamino-1,3,4,5-tetrahydrobenz[cd]indole[( ±)-6
-methoxycarbonyl-6-norcanoclavine-] 4,5-trans-5-(E-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz [cd ]
50.8 mg of indole was dissolved in 12 ml of methanol.
On the other hand, 2N of 353 mg of zinc powder and 54.5 mg of mercuric chloride
- After adding to 4 ml of hydrochloric acid and stirring for about 5 minutes, the aqueous layer was decanted and a zinc amalgam was prepared. After adding the above solution and 4 ml of 2N hydrochloric acid, the mixture was stirred and refluxed for about 2 hours. Insoluble zinc amalgam was filtered off with a cotton plug, and methanol was distilled off under reduced pressure. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and extracted with a mixed solvent of methylene chloride and methanol (95:5). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from methanol-methylene chloride to give 4,5-trans-4-amino-5-(E-2-hydroxymethyl-1-propen-1-yl)-1,3,4,5- 35.0 mg of tetrahydrobenz[cd]indole[(±)-norcanoclavine-] was obtained. The recrystallized mother liquor was separated and purified by preparative thin layer chromatography (developing solvent: chloroform: methanol: aqueous ammonia = 90:10:1) to further obtain 9.5 mg of the desired product. Total yield 44.5 mg (98.4%).

Colorless prism crystal Melting point: 182-183℃ (methylene chloride-methanol) IR (KBr): νmax 3230, 1585, 1446, 1066 cm ^-1 NMR (pyridine-d ₅ ) δ: 2.03 (3H, d, J = 1.2Hz) , 2.95 (1H, dd,
J=15.4and10.3Hz), 3.18~3.50 (2H, m),
4.00 (1H, dd, J=9.8and6.5Hz), 4.45 (2H,
s), 5.85 (1H, dq, J=9.9and1.2Hz), 6.98
(1H, d, J = 6.6Hz), 7.06~7.48 (3H,
m), 11.50 (1H, brs) MS: m/e242 (M ⁺ ) Elemental analysis value (as C ₁₅ H ₁₈ N ₂ O・1/8H ₂ O) C% H% N% Calculated value 73.66 7.52 11.46 Actual value 73.67 7.51 11.42 Dissolve 51.0 mg of (±)-norcanoclavine in 3.0 ml of tetrahydrofuran, add 0.15 ml of triethyleneamine, and add methyl chlorocarbonate.
After adding 0.065 ml, the mixture was stirred at room temperature for about 1 hour.
After the reaction was completed, an appropriate amount of saturated saline was added and the mixture was extracted with a methylene chloride-methanol mixed solvent (95:5).
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 subjected to silica gel preparative thin layer chromatography (developing solvent: chloroform: methanol: aqueous ammonia =
90:10:1; Rf value 0.52-0.35) to separate and purify the colorless oil (±)-6-methoxycarbonyl-6.
-Norcanoclavine-58.4 mg (92.4%) was obtained.

Colorless oil IR (film): νmax 3380, 1690, 1510 cm ^-1 NMR (CDCl ₃ ) δ: 1.63 (1H, s), 1.92 (3H, d, J = 1.4
Hz), 2.84 (1H, dd, J=15.7and5.4Hz),
3.25 (1H, ddd, J=15.7, 3.9and1.2Hz),
3.62 (3H, s), 4.03 (2H, s), 3.85-4.37
(2H, m), 4.75 (1H, brd, J=8.0Hz),
5.38 (1H, dq, J=9.2and1.4Hz), 6.80 (1H,
dd, J=5.9and2.0Hz), 6.90 (1H, brs),
7.02-7.28 (2H, m), 8.02 (1H, brs) High MS: Calculated value (as C ₁₇ H ₂₀ N ₂ O ₃ ): 300.1472 Actual value: 300.1464 Example 5 4,5-trans-5-[Z -2-hydroxymethyl-1-propen-1-yl)-4-methoxycarbonylamino-1,3,4,5-tetrahydrobenz[cd]indole[(±)-6
-methoxycarbonyl-6-norisocanoclavine-) 4,5-trans-5-[Z-2-hydroxymethyl-1-propen-1-yl)-4-nitro-1,3,4,5- Tetrahydrobenz [cd]
50.4 mg of indole was dissolved in 12 ml of methanol.
On the other hand, 349.1 mg of zinc powder and 53.8 mg of mercuric chloride
After adding the mixture to 4 ml of 2N hydrochloric acid and stirring at room temperature for about 5 minutes, the aqueous layer was decanted and a zinc amalgam was prepared. The above solution was added to this, and 4 ml of 2N hydrochloric acid was added thereto, followed by refluxing with stirring for about 2.5 hours. After removing the insoluble zinc amalgam through a cotton plug and distilling off the methanol under reduced pressure, an appropriate amount of saturated saline was added, and a methylene chloride-methanol mixed solvent (95:
5). Wash the extract with saturated saline,
It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from methylene chloride-methanol to give colorless prismatic crystals of 4,5-trans-4-amino-5-(Z-2-hydroxymethyl-1-propen-1-yl)-1,3, 4,5-
Tetrahydrobenz [cd] indole [(±)−
18.7 mg of norcanoclavine was obtained. The recrystallized mother liquor was separated and purified using silica gel preparative thin layer chromatography (developing solvent: chloroform: methanol: aqueous ammonia = 90:10:1) to obtain an additional 24.1 mg.
Obtained the desired object. Total yield 42.8 mg (95.7%).

Colorless prism crystal Melting point: 196-197℃ (methanol-methylene chloride) IR (KBr): νmax 3170, 1588, 1445, 1343, 1093, 1030
cm ^-1 NMR (pyridine-d ₅ ) δ: 2.15 (3H, d, J = 1.5Hz), 2.91 (1H,
ddd, J=15.3, 10.8and1.5Hz), 3.12~3.48
(2H, m), 4.11 (1H, dd, J=9.8and7.3
Hz), 4.51 (1H, d, J = 12.0Hz), 4.70 (1H,
d, J = 12.0Hz), 5.47 (1H, brd, J = 9.8
Hz), 7.01 (1H, dt, J=6.6and1Hz), 7.08~
7.47 (3H, m), 11.51 (1H, brs) MS: m/e242 (M ⁺ ) (±)-Norisocanoclavine - 43.1 mg was dissolved in 4.0 ml of tetrahydrofuran, and triethylamine 0.13 ml was added thereto. Next, 0.055 ml of methyl chlorocarbonate was added and stirred at room temperature for about 30 minutes. Appropriate amounts of saturated saline and methylene chloride-methanol mixed solvent (95:5) were added and shaken, and the organic layer was separated. The aqueous layer was further extracted with a methylene chloride-methanol mixed solvent, combined with the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel preparative thin layer chromatography (developing solvent: methylene chloride: methanol = 95:5; Rf value 0.35-0.23) to obtain a colorless oil ( ±)-6-methoxycarbonyl-6-norcanoclavine-46.8 mg (87.6
%) was obtained.

Colorless oil IR (Flim): νmax 3470, 1690, 1510, 1444cm ^-1 NMR (CDC1 ₃ ) δ: 1.83 (3H, d, J = 1.4Hz), 2.56 (1H,
brs), 2.72 (1H, dd, 15.2and4.8Hz), 3.26
(1H, dd, J=15.2and4.0Hz), 3.55 (3H,
s), 3.80-4.25 (2H, m), 4.08 (1H, d,
J = 11.2Hz), 4.42 (1H, d, J = 11.2Hz),
4.89~5.46 (2H, m), 6.52~6.87 (2H, m),
6.94-7.22 (2H, m), 8.00 (1H, brs) MS: m/e282 (M ⁺ -H ₂ O) Reference example 4 (±)-Canoclavine- (±)-6-methoxycarbonyl-6-norcanoclavine- Dissolve 353.2 mg in anhydrous tetrafuran and add 542.8 mg of lithium aluminum hydride.
mg was added thereto, and the mixture was refluxed with stirring for about 1 hour. After the reaction is complete, methanol is added to decompose the excess lithium aluminum hydride, a Rothsiel salt aqueous solution is added, and a methylene chloride-methanol mixed solvent (95:
5). Wash the extract with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from methanol to give colorless prismatic crystals of (±)-kanoclavine-182.7 mg.
I got it. The recrystallization mother liquor was concentrated and separated and purified using silica gel preparative thin layer chromatography (developing solvent: chloroform: methanol: aqueous ammonia = 90:10:1) to further obtain 105.5 mg of the target product in prism crystals.
I got it. Total yield 288.2 mg (95.8%).

Colorless prism crystal Melting point: 194-195℃ (decomp.) (methanol) IR (KBr): νmax 3230, 1600, 1435, 1074, 743 cm ^-1 NMR (pyridine-d ₅ ) δ: 2.03 (3H, d, J= 1.5Hz), 2.40(3H,
s), 2.70-3.15 (2H, m), 3.41 (1H, dd,
J=18.8and8.3Hz), 4.03~4.29 (1H, m),
4.41 (2H, s), 5.85 (1H, dq, J=
10.0and1.5Hz), 6.97 (1H, d, J=66.6Hz),
7.06-7.47 (3H, m), 11.49 (1H, brs) MS: m/e256 (M ⁺ ) Elemental analysis value (as C ₁₆ H ₂₀ N ₂ O) C% H% N% Calculated value 74.96 7.86 10.93 Actual value 74.91 7.99 10.96 Reference example 5 (±)-isocanoclavine- (±)-6-methoxycarbonyl-6-norisocanoclavine (-19.2 mg was dissolved in 2 ml of anhydrous tetrahydrofuran, and 28.1 mg of lithium aluminum hydride was dissolved in it. In addition, the mixture was refluxed for about 1 hour with stirring. After the reaction was completed, an appropriate amount of methanol was added to decompose the excess lithium aluminum hydride, an aqueous solution of Rothsiel's salt was added, and the mixture was diluted with a methylene chloride-methanol mixed solvent (95:5). The extract was washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel (developing solvent: chloroform: methanol: aqueous ammonia = 90:10:1;
(Rf value 0.29-0.17) and separated and purified into colorless prismatic crystals of (±)-isocanoclavine-12.7 mg (77.5
%) was obtained.

Colorless prism crystal Melting point: 200-201℃ (decomp.) (methanol-water) IR (KBr): νmax 3470, 3380, 1605, 1438, 1338, 1023,
752cm ^-1 NMR (pyridine-d ₅ ) δ: 2.13 (3H, d, J = 1.2Hz), 2.43 (3H,
s), 2.62-3.05 (2H, m), 3.41 (1H, dd,
J=19.2and8.2Hz), 4.11~4.38 (1H, m),
4.51 (1H, d, J = 12.2Hz), 4.71 (1H, d,
J = 12.2Hz), 5.46 (1H, brd, J = 10.3Hz),
6.99 (1H, dt, J=6.8and1.1Hz), 7.13~7.48
(3H, m), 11.51 (1H, brs) MS: m/e256 (M ⁺ ) Elemental analysis value (as C ₁₆ H ₂₀ N ₂ O) C% H% N% Calculated value 74.96 7.86 10.93 Actual value 74.76 7.97 10.90 Reference example 6 (±)-agroclavine (±)-isocanoclavine - 28.8 mg was dissolved in 10 ml of freshly distilled dioxane, a solution of 571.1 mg of thionyl chloride dissolved in 1 ml of dioxane was added, and the mixture was heated with N ₂ gas at room temperature. The mixture was stirred for about 15 minutes under a stream of air. The reaction mixture was made alkaline by adding an aqueous sodium bicarbonate solution, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel preparative thin layer chromatography (developing solvent: chloroform: methanol: aqueous ammonia: n-hexane = 93:10:1:35). )-17.3 mg (64.3%) of agroclavine was obtained.

Colorless needle crystal Melting point: 189-191℃ (decomp.) (acetone) IR (KBr): νmax 3230, 1605, 1458, 1440, 1351, 1213,
743cm ^-1 NMR (CDCl ₃ ) δ: 1.78 (3H, brs), 2.50 (3H, s), 2.51 (1H,
ddd, J=10.9, 8.8and3.7Hz), 2.78 (1H,
ddd, J=13.2, 10.9and2.0Hz), 2.92 (1H,
brd, J=15.9Hz), 3.28 (1H, brd, J=15.9
Hz), 3.33 (1H, dd, J=13.2and3.7Hz),
3.75 (1H, brd, J=8.8Hz), 6.18 (1H,
brs), 6.88 (1H, brs), 6.95-7.24 (3H, m),
8.00 (1H, brs) MS: m/e238 (M ⁺ ) [Effects of the Invention] The compound of the general formula () of the present invention has α-receptor blocking action, anti-serotonin action, etc., and is used as a migraine treatment drug. It is also useful as a drug for treating hypertension.

In addition, the compound of the general formula () of the present invention can be easily converted into various ergot alkaloids in a short process, such as norcanoclavine, norisocanoclavine, canoclavine, isokanoclavine, agroclavine, festuclavine, costaclavine, setoclavine,
It can lead to isosetoclavine, erimoclavine, peniclavine, isopeniclavine, etc.

All of the ergot alkaloids derived from the compound of the general formula () of the present invention exhibit pharmacological effects specific to ergot alkaloids, such as prolactin inhibitory action and uterine contraction action, 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 promoting drug because it exhibits a strong uterine contraction effect.

Therefore, the compound of the general formula () of the present invention is also extremely useful as an intermediate for the production of pharmaceuticals having an ergot alkaloid skeleton.

Claims (1)

[Claims] 1. General formula (In the formula, either R ¹ or R ² is substituted with a hydroxyl group or a lower alkoxy group, and has 1 to 1 carbon atoms.
3 is an alkyl group or formyl group, the other is an alkyl group having 1 to 6 carbon atoms, and R ³ is a nitro group or a lower alkoxycarbonylamino group). -Tetrahydrobenz[cd]indole derivative.