JPS6185361A - 1,3,4,5-tetrahydrobenz(cd)indole derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is H or lower alkoxycarbonyl). EXAMPLE:4,5-trans-4-Amino-5-[2-methylpropen-1-yl)-1,3,4,5-tetrahydrobe nz[cd]i-nd ole. USE:Intermediate of ergot alkaloid. PREPARATION:The compound of formula I can be prepared by reducing the compound of formula II with a reducing agent (e.g. zinc amalgam), and if necessary, N-alkoxycarbonylating the product.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) One aspect of the invention [Industrial application field] The first aspect of the present invention is to use the general formula of sodium bicarbonate as an intermediate for the production of ergot alkaloids and their analogues, which are useful as pharmaceuticals. (In the formula, 1 is a hydrogen atom f-, '< is a lower alkoxycarbonylno, (te, aru) -C...represents 1, 3.
4.5 To provide a tetrahydrobenz(c+I'l indole derivative and its production method) (11).

1. of the present invention. In the compound of general formula (1), R is lower alk,
Acroclavine (s+: cnagroclave+ne) is a compound that can be very easily converted into an ergot alkaloid by reducing it.
By ring-closing this, it can be converted to acroclavine. In addition, in the compound of the general formula (1), in which R is a hydrogen atom, the 4-position amino group is substituted with an arbitrary substituent and the ring is closed, so that analogous compounds of clavine-type alkaloids can be prepared. As described above, the compound of general formula (1) of the present invention is particularly useful as an intermediate in the production of pharmaceuticals.

[Conventional technology]

Ergot alkaloids are alkaloids contained in blue, and are widely used in ancient times due to their various pharmacological effects.For example, they are used to treat vascular 1/1 headaches ((++1i headaches), peripheral vascular disorders, etc. Treatment of uterus 11-blood, medium ((x treatment of brain dysfunction due to neurological effects, etc.)

Ergot alkaloids have an ergoline (er to aline) structure as their basic chemical structure, but the position of the 21fi bond in the D ring, the type of substituent at the 8th position, etc. The effects are different. For this reason, various derivatives (IJ
The first investigation has been carried out.

In addition, new alkaloids different from the conventional peptide-type alkaloids, such as ergometrine ((〕[KUN+m+!1. r i ne), ergotamine, and ergotoxine] alkaloids, have recently been discovered. [Journal 4 Agricultural Chemical Society (,1
, 8gr, Chem, Soc, ) Abe et al., vol. 25, p. 458 (1952)
classified as an id. Since some of its derivatives have been found to have therapeutic effects on senile brain dysfunction, there are expectations for the development of pharmaceuticals with even newer pharmacological effects. Acroclavine (agroclaνin) represented by the formula is a representative compound of this clavine-type alkaloid.
+:) can be given. (±)-6,7-secoacroclavine (s+
: [, (]agroclavine) can be easily ring-closed to obtain acroclavine, and is useful as an intermediate for producing clavine-type alkaloids.

The present inventor has already discovered and reported several methods for producing this compound [Chemistry Letters (Chemistry 1. [!ttcrS) 61
Pages 5-618 (1981)]. For example, as shown in the reaction formula, 4-(indol-4-yl)-3-buten-2-2-21-(5) was used as the starting material for 6 steps with a total yield of about 0.3% ( ±)-6,7-Secoagroclavine (4) or the same compound (5)
(±)-6,7-Secoab 1]clavine (4) is obtained using the starting material in 7 steps with a total yield of about 0.6%. The compound of formula (5) used as the raw Ico 1 in these reactions is a known compound, and is produced from commercially available 5-ditroisoquinoline in 3 steps with a total yield of about 9 to 10% in all steps. Ru. All of these production methods require a large number of steps, are time-consuming, and have several drawbacks to industrial application, such as low yields.

[Problem that the invention seeks to solve]

As mentioned above, in producing ergot alkaloids, particularly clavine-type alkaloids and related compounds, which have various pharmacological effects and are useful as pharmaceuticals, conventional production methods require a lot of labor, have low yields, and are ineffective. research and development was not possible. Therefore, in research and development in this field, an efficient method for producing clavine-type alkaloids and related compounds has been desired.

(2) Structure of the invention [Means and effects for solving the problem] As a result of our research to find an efficient method for producing ergot alkaloids, particularly clavine-type alkaloids, and their related compounds, the results are expressed by the formula 4, 5-trans-4-finished minnow 5-(2-
Methylpropen-1-yl) River, 3.4.5-tetrahydrobenz (cd) indole (1゛)! 1! ! By using it as a synthetic intermediate, (±)-6 can be produced in extremely high yield.
, 7-Secoagroclavine (4) can be produced, and furthermore, it has been found that various clavine-type alkaloid derivatives can be produced by using the compound of formula (BI). Therefore, as shown in the reaction formula (%) (4), using 3-formylindole (11) as a starting material, 4,5-transyl-4-amino-5
-(2-methylpropen-1-yl)-], 3.4.
5-tetrahydrobenz [cd: l indole (1°
), 7 steps, 11 steps in total!
Agroclavine (4) can be produced at a rate of about 36.4%.

According to this manufacturing method, the operation is carried out in the cylinder, and 1. Y
The yield is increased approximately 60 to 120 times compared to the conventional production method.
can do.

Genuine convexity 1: Compounds of formulas (bi) and (1''') in the culm are both new compounds that have not been described in literature, especially formula (bi)
By introducing various substitutions into the amino group at the 4-position of the compound, it is possible to easily produce analogues of clavine-type alkaloids.

Therefore, the compound represented by the general formula (1) of the present invention is extremely f1° as an intermediate for producing Clapin type r alkaloid.
It is for use.

As shown in the reaction formula -1-, the compound of general formula (1) of the present invention is 4.5-) lance-5-(2-methylpropen-1-yl)-4-di-Ul, -1, 3, 4,
5-Tetrahydrobenz((:Il)indole(9)
It can be obtained by reducing or after reduction, alkoxycarbonylation.

Formula (9) used as a starting material in the production method of the present invention
The compound is a known compound, and 1! ↑You can.

The reducing agent used in the production method of the present invention may be any agent as long as it does not hydrogenate the reflex and can reduce a nitro group to an amine group, and examples thereof include zinc, zinc amalgam, and the like. In this reduction reaction, it is necessary to proceed with steric retention, that is, the 2-methylpropen-1-yl group at the 5-position and the amino group at the 4-position of the product (1'') must be trans, When reduction is carried out using zinc in hydrochloric acid, the cis and trans isomers are obtained as a nearly 1:1 mixture, whereas when zinc amalgam in hydrochloric acid is used, only the trans isomer is obtained. Therefore,
The most preferred reducing agent is zinc amargano.

The alkoxycarbonylation reaction in the second step of the production method of the present invention can be carried out according to a conventional method. That is, the compound of general formula (1) is prepared by reacting the obtained compound of formula (1) with an alkyl halocarbonate (for example, in the presence of triethylamine) in a suitable inert organic solvent.
A compound in which is a lower alkoxycarbonyl group is obtained.

To suitably carry out the production method of the present invention, a solution of freshly prepared zinc amalgam and an appropriate amount of 2N-hydrochloric acid is added with 4
．． 5-) Add a methanol solution of lance-5-(2-methylpropen-1-yl)-4-nitro-1,3,4,5-tetrahydrobenz(cd)indole (9) and add about 1
Reflux for an hour. After refluxing, 2N hydrochloric acid is further added and refluxed for 2 to 5 hours to complete the reaction. After completion of the reaction, methanol as a solvent is distilled off, a 2N aqueous sodium chloride solution and saturated saline are added to make it alkaline, and the mixture is extracted with a suitable organic solvent, such as a 5% methanol-methylene chloride mixed solvent.

After washing the organic layer with saturated brine and drying, the solvent was distilled off under reduced pressure to obtain 4.5-h lance-4-amino-5-(2-methylpropen-1-yl)-1,3, 4,5-tetrahydrobenz[cd]indole (1') is obtained.

Next, the gamma compound (1゛) obtained in 11) is dissolved in a suitable inert organic solvent, such as methylene chloride, and a methylene chloride solution of /'%0 alkyl carbonate, such as methyl chlorocarbonate, and a base, such as triethylamine, are then added. In addition, stir at room temperature or under heating for 1 to 5 hours. After the reaction is completed, water and dilute hydrochloric acid are added to the reaction mixture to neutralize it, and the organic layer is separated. The aqueous layer was further extracted with methylene chloride and combined with the organic layer.
After washing with water and drying, the solvent is distilled off. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride) to obtain 4.5-) lance-4-methoxycarbonylamino-5-(2-methylpropen-1-yl),
3.4.5-Tetrahydrobenz(cd)indole (1″°) is obtained.

This carbamate (1'') is dissolved in a suitable organic solvent such as dry tetrahydrofuran, lithium aluminum hydride is added thereto, refluxed for 3 to 5 hours, and treated according to a conventional method to obtain (±)-6,7 - Secoagroclavine (4) is obtained in high yield.

〔Example〕

The present invention will be explained in more detail below using Examples. Note that the melting points of the compounds in each example are uncorrected.

Example 1 rnr lead powder [i 29 , :I mg and 62.2 mg of mercuric chloride were added to 3.0 ml of 2N-hydrochloric acid. and stirred for 5 minutes. After decanting the aqueous layer, add 2N-hydrochloric acid 5
4.5-. 1-Lance-5-(2-Methylpropenkan-yl)-4-Nito Nikkan, 3.4.5
-Tetrahydrobenz (cd) indole 64.0m
Add a solution of g dissolved in methanol lid at once to 1
Refluxed for an hour. After refluxing, 2N hydrochloric acid was further added and the mixture was refluxed for 4 hours. After the reaction, methanol was distilled off, and the residue was mixed with a methanol-methylene chloride mixed solvent (5:95 v/
v) A saturated saline solution and a 2N aqueous sodium hydroxide solution were added to make the mixture alkaline, and after shaking, the organic layer was separated.

The aqueous layer was further added to a methanol-methylene chloride mixed solvent (5:9).
5 v/v), combined with the above-prepared organic layer, 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 methylene chloride to give a colorless prismatic product of 4.5-)U/su-4-amino-5-(2
~Methylpropen-1-yl)-L 3.4.5-Tetrahydrobenz[cd]indole 5L 3mg to 11
)is.

(Yield 96%) Melting point 121.5 - 123°C Infrared absorption spectrum (Kllr) 3400 (br), 3100 (br), 159
3. 1444 1m-') nuclear magnetic resonance spectrum (C
fl[:ll3)δ:], 81(311,d, J=]
1lz), 1.85 (311, +J.

J・1llz), 1.65~2.28 (211,f
]r), 2.58-3.35 (311, m), 3
．． G] (III, dd, J=911z.

711z), 5.10(IIl, br-d, ,
I=911z).

6.55-6.88 (211, m), 6.91
~7.21 (211゜m), 7.84 (Ill b
rs) Mass spectrometry spectrum m/e: 226 (M”) Example 2 4.5-trans-4-reminor-5-(2-methylpropen-1-yl)-1,3,4,5- 101.0 mg of tetrahydrobenz (cd) indole was dissolved in methylene chloride 5
To this was added a solution of 165.0 mg of methyl chlorocarbonate dissolved in methylene chloride, 0.3 ni of triethylamine was added, and the mixture was stirred at room temperature for -62.5 hours. The reaction mixture was made neutral by adding an appropriate amount of water and IN-hydrochloric acid, and after shaking, the organic layer was separated. The aqueous layer was further extracted with methylene chloride, combined with the separated organic layer, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride) to obtain colorless viscose oil of 4.5-)ransul 4-methoxycarbonylamino-5-(2-methylpropene-yl)-1, 3,
12.6 mg of 4,5-tetrahydrobenz['cd:1 indole I was obtained. (Yield 93%) Infrared absorption spectrum (KBr) 3410, 3325. 169? , 1512 (cm
') Nuclear magnetic resonance spectrum (CflC1,)δ: ],
73 (311, d, , l1llz), 1.86 (3
11,d.

, I=]ll), 2.76(III, dd, J=
I5.511z, 5Hz).

3.22(Ill, dd, , I=15.511z,
411z).

3, 56 (311s), 3.69-4.32 (
211, m).

4.46-4.82 (III, br-s), 5.0
1 (II, br-d.

, J=IOllz), 6.5! ']-6,89(21
1, m), 6.96-7, 19 (211 m), 7
．． 89 (III, b"-s) Mass spectrometry spectrum m/e: 284 (M") (3) Effects of the invention As described above, the compound represented by the general formula (1) of the present invention is used as a production intermediate. By using this, clavine-type alkaloids and their analogues can be produced extremely efficiently.

The compound represented by the general formula (1) of the present invention has a much wider range of applications than the various intermediates used in conventional production methods, and can be easily produced and obtained in good yield.

Therefore, the compound (1) of the present invention is extremely important as an intermediate for the production of ergot alkaloids useful as pharmaceuticals, particularly clavine-type alkaloids and their analogues.

〔Effect of the invention〕

(±)-6,7-Secoagroclavine (4) Ata) J, 4.5-) Lance-5-(2-methylpropen-1-yl)-4-nitro-1,3 ,4,5-tetrahydridepenz[t:d]indole (9) as a starting material, in the conventional production method, it is oxidized in two steps with a total yield of about 3.4%. , the method using the compound of general formula (1) of the present invention involves 3 steps, all steps JJI! It was obtained with a calculated yield of about 87.5%, which is an increase of about 25 times. Furthermore, when comparing the conventional production method and the production method using the general formula (1) of the present invention using generally commercially available and easily manipulable compounds as starting materials, the conventional production method produces 5-nitro Using isoquinoline as a starting material, 9 to 1O steps, total yield of about 0.03 to I), f
lfi% (:I-)-6,7-secoacroclavine is 111, whereas in the method of preparing the compound of general formula (1) of the present invention, 3-formylindole is used as the starting material. Used as Nemi), for about 7 years, all culms Nj:
IIM thousand: lfi, ij) at 11%, about 600-1
This means that the yield is 200 times higher than that of l:y+'.

patent applicant Kissei Kuwahina 1: Business Co., Ltd. -C Niri-

Claims (5)

[Claims] (1) 1,3,4,5-tetrahydrobenz[cd]indole derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R in the formula is a hydrogen atom or a lower alkoxycarbonyl group) . (2) The 1,3,4,5-tetrahydrobenz[cd]indole derivative according to claim 1, wherein R is a hydrogen atom. (3) The 1,3,4,5-tetrahydrobenz[cd]indole derivative according to claim 1, wherein R is a lower alkoxycarbonyl group. (4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A general formula characterized by reducing the compound represented by with a reducing agent and then N-alkoxycarbonylation as necessary ▲ Numerical formulas, chemical formulas, tables, etc. There is a method for producing a 1,3,4,5-tetrahydrobenz[cd]indole derivative represented by ▼ (in the formula, R is a hydrogen atom or a lower alkoxycarbonyl group). (5) The manufacturing method according to claim 4, wherein the reducing agent is zinc amalgam.