JPH02200683A - Tetrabromocyclopenta(b)benzofuran derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I. USE:A key synthetic intermediate for 5,6,7-trinor-4,8-inter-m-phenylene PGI2 derivative useful as an antithrombotic agent, antiulcer agent and hypotensor. PREPARATION:The objective compound of formula I is produced by brominating 3a, 8b-cis-dihydro-3H-cyclopenta[b]benzofuran of formula II optionally in the presence of a Friedel-Crafts catalyst. The compound of formula II used as a starting raw material can be produced by dissolving the compound of formula III in a solvent, adding dried metallic magnesium to the solution and cyclizing the resultant di-Grignard reagent by the addition of a catalytic amount of a metal reagent.

Description

[Detailed description of the invention] [Industrial application field] The present invention is represented by formula (I) B" Tetrabromocyclopenta[b]benzofuran derivative.

(2) The present invention relates to a Br Br tetrabromocyclopenta(b) benzofuran derivative represented by formula (If) and a method for producing the same.

[Prior art] Formula (I) tetrabromocyclopenta(b) easily obtained by debrominating a benzofuran derivative (
m) Br 3a,8b-cis-dihydro-3H-cyclopenta[b
] Characteristic 3a, 8 brominating benzofuran
b-cissu dihydro-3H-5,7-dipromocyclopenta(b)benzofuran is a 5,6,7-4 linoleum-4,8-inter- m-phenylene PG12 derivative (■) (
JP-A-5636477, JP-A-58-12477
8, etc.), and is a key synthesis intermediate of
44277, etc.).

Conventionally, as a method for producing (m), 3,5-cisbis(2,
4,6-)ribromophenoxy)cyclopentene (v)
After reacting with a Grignard reagent to perform halogen metal exchange, a metal catalyst was added to cause a cyclization reaction (Japanese Patent Laid-Open No. 57144277).

0υ [Problem to be solved by the invention] This conventional technique has the following problems.

(1) (III) cannot be purified by distillation due to its high boiling point. In addition, recrystallization purification is difficult because the yield of the cyclization reaction is poor, so column chromatography is used to purify (■). Therefore, it takes a lot of time to purify (I[[), which causes an increase in the manufacturing cost of (III).

(2) The yield of the cyclization reaction and the reaction largely depend on the equivalent weight of the Grignard reagent used in the halogen metal exchange reaction, and a slight difference in the equivalent weight causes a decrease in the yield. In addition, the optimum equivalent amount varies depending on the purity of 3,5-cis-bis(2,4゜6-dribromophenoxy)cyclopentene (V),
Yields may not be reproducible.

[Means for Solving the Problems] The present inventors have overcome the drawbacks of the prior art (II
As a result of intensive study on the industrial production method of formula (II),
) 3a,8b-cis-dihydro-3H-cyclopenta(b
) We have discovered a method for obtaining the new compound (4) from benzofuran easily and in high yield with good reproducibility, leading to the present invention.

That is, the present invention is a tetrabromocyclopenta(b) benzofuran derivative represented by formula (I) and a method for producing the same.

The compound (I) of the present invention is represented by (IA) and (IB) of the following formula:
including.

Br Br Br
, Br(IA) (rB) Specifically, the present invention is usually carried out under the following conditions.

First, (Il,), which is a raw material of the present invention, can be easily obtained by the following method. That is, JP-A-57-144
(VI), which can be synthesized according to the reaction conditions of No. 233, is dissolved in a solvent and added to dry magnesium metal to generate a digrignard reagent. Thereafter, a catalytic amount of metal reagent is added and cyclization is performed to obtain (II). The cyclization reaction proceeds with high yield and good reproducibility, and since (Il,) can be distilled, it is easy to isolate and purify.

(VI) (fi) Compound (I) of the present invention can be produced by dissolving (II) in a solvent and adding bromine.

The solvent used is dichloromethane, chloroform,
Chlorinated solvents such as carbon tetrachloride, carbon disulfide, acetic acid, and cyclohexane are commonly used, and dichloromethane and chloroform are particularly preferred.

The equivalent amount of bromine varies depending on whether a Friedel-Craft catalyst is used or not. That is, when a catalyst is not used, the equivalent amount of bromine used is 3 to 10 equivalents, with 4 to 6 equivalents being particularly preferred. When using a catalyst, the equivalent amount of bromine used is 3 to 6 equivalents, especially 3 to 6 equivalents.
~3.2 equivalents are preferred. Free-sol cod fluoride catalysts include iron, ferric chloride, ferric bromide, aluminum chloride, aluminum bromide, zinc chloride, and antimony chloride (m).
etc. are commonly used, and among these, iron and aluminum bromide are preferred. As the equivalent of the catalyst, 00OO1 to 0.5 equivalent is used, and 0.007 to 0.015 equivalent is particularly preferred.

The reaction temperature is 20 to 10 when no catalyst is used.
0°C is used, with 20-60°C being preferred. When a catalyst is used, a temperature of 0 to 30°C is used.

The reaction time is 1 when carried out without using a catalyst.
0 minutes to 1 week are used, especially for 4 equivalents of bromine, 12
1 hour to 1 day is preferable, and if the amount of bromine is 5 equivalents or more, 10 minutes to 3 hours is preferable.
time is preferable. When a catalyst is used, a time of 1 minute to 1 week is used, and a time of 30 minutes to 1 day is particularly preferred.

As for other reaction conditions, it is preferable to carry out the reaction under light shielding, but the conditions are not limited thereto.

Recrystallization and silica gel column chromatography are used to isolate (I), but since the reaction proceeds quantitatively, it is also possible to use it in the next reaction in an unpurified state.

The compound (I) of the present invention can be easily converted to (m) by reductive debromination with a debrominating agent such as sodium thiosulfate, sodium sulfide or zinc; From compounds, for example, JP-A-57-144
No. 277, JP-A No. 58-124778, etc., the formula (TV) useful as a pharmaceutical is prepared by the method described in 5.
6.7-) dinor-4,8-inter.

[Examples] Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Reference example 1 Dry magnesium 1. 3g (53.5m
After adding 10 ml of dry THF to mol), 10 g of 3.5-cisbis(2-bromophenoxy)cyclopentene
(24.4 mmol) dissolved in 70 ml of THF was added. After heating this to cause a Grignard reaction, the remaining THF solution was added and stirred at room temperature. Next, 65.2 g of dried magnesium (2.
Add the above reaction solution to 68 river o1) and add dry THF.
After adding 0.5ff, 500g (1.22mol) of 3,5bis(2-bromophenoxy)cyclopentene
) dissolved in THF3.5α was gradually added.

After the addition was completed, the mixture was heated at 50° C. for 1 hour and then cooled with water.

Next, Cu11 1, 6g (60. 9+n+n
ol) was added, heated at 40°C for 1 hour, and then cooled with water. 0.9α of a 3N NaOH aqueous solution was added to the reaction solution, and the mixture was filtered using Hyfloth Parcel. After washing the filtered solid with THF2.5Q, the P solution was concentrated. The concentrated solution was extracted 4 times with 1 u of cyclohexane, and the organic layer was extracted with 2N NaOH aqueous solution 0.
．． After washing with 2i twice and three times with saturated saline 0.1α, it was dried over anhydrous magnesium sulfate. If the interface was unclear during extraction and washing, t-filtration was performed using Hyfloth Purcel as appropriate. Then, magnesium sulfate was added to P and the organic layer of the P solution was concentrated.

Further, the same operation was carried out using 816 g (1.99 mol) of 3,5-cis-bis(2-bromophenoxy)cyclopentene, and the two were distilled together.

Yield: 377.0g Yield: 73.7%b. p.
77, 8-78.8°C 10.1% HgNMR (
CDC13) δ: 2.80 (IHS dd, J=2.2.0.5t
(z), 2.82 (IHS dd, J=5.2.
0, 5Hz), 4. 35 (IH, d, J=
7゜8Hz), 5.43 (IH, dddS J
=7°8.5.2.2. 2Hz), 5. 71
(2H.

s), 6. 95 (4HS m) IR (liquid film method) νcm"-1: 3060.1602.1582 Mass: 158 (M") Example 1 3a,8b-cis-dihydro-3H-cyclopenta[b
]Benzofuran 2.0156g (12゜7mg+ol
) was dissolved in 20 ml of dichloromethane and cooled on ice, and 3. 9 ml (76, 2 mmol) was added slowly. After stirring at room temperature for 1 hour, the reaction solution was added to 100 ml of ice-cooled saturated aqueous sodium hydrogen carbonate solution. While stirring, 4.7 g of sodium thiosulfate dissolved in 10 ml of water was gradually added.

After confirming that the bromine color has disappeared, add 50ml of ethyl acetate.
Extracted twice. The organic layer was washed with 50 ml of saturated brine and dried over anhydrous sodium sulfate. sodium sulfate
Separately, it was concentrated to dryness and dried under reduced pressure to obtain a brown viscous liquid.

Yield: 6.2725g Yield: 103.8% 10.1mg of it was taken and the diastereomers were separated by thin layer chromatography preparative separation, and as a low polar fraction (I
A) 6.4mg, and (IB) 3.9mg as a highly polar fraction were obtained.

(IA) White crystal m, p, 117.0-119.0° CNMR (C
DC13) δ: 2.69-2.78 (IH, m), 3.11-3.
22 (IHSm), 4.37~4°43 (IH,
m), 4.43-4.51 (IHSm), 4.55
~4.62 (IH.

m), 5.52-5.60 (IHSm), 7.32
~7.41 (IHSm), 7.49 (IHS
dS J=1.95Hz) I R(KB r) νcm
': 2970.1452.1258.1187.1135.
1058.992.804.7Mass (EI method, m/
e): 472 (M”) High-resolution mass spectrum calculation value (CHOB r 4 , M”): 471.
7309 Actual value (M”): 471.7323 (IB) White crystal m, p, 110.0-112.0°C NMR (C
DCI3) δ: 2.59-2.70 (IHSm), 2.97 (I
HSddd, J=15.13.5°37.3.42Hz
), 4.35 (IHSt.

J=7.82Hz), 4.40 (IHSt.

J=5.86Hz), 4.57~4.64(IHSm
), 5.46-5.53 (IH.

m), 7. 34 (IH,s), 7. 50(
LH, d,, J=1.95Hz) IR(KB r) νctn-”: 2970.1455.1263.1161.1013.
867.812 Mass (EI method, m/e): 472 (M”)
High-resolution mass spectrum calculation value (CILH80Br 4, M”): 471
．． 7309 Actual value (M+): 471.7349 B[ Br (IA) Br Br (IB) Example 2 Cyclopenta(b) Benzofuran 3a,8b-cis-dihydro-3H-cyclopenta(b
) Benzofuran 100g (0,632m.

1) in dichloromethane 02, 353 mg of iron (6
, 32 mmol) and then cooled with water. Bromine 100ml
(1,96 mol) was slowly added and stirred at room temperature for 21 hours, the reaction solution was cooled with ice, and 160 g (1,90 mol) of sodium hydrogen carbonate and water IQ were added. While stirring, add 7°8 g of sodium thiosulfate (0.03
141101), the aqueous layer and organic layer were separated.

The aqueous layer was extracted with ethyl acetate 2α, and the organic layer was washed with water IQ and 1 u of saturated brine, and then dried over anhydrous magnesium sulfate. Magnesium sulfate was concentrated to dryness using P and dried under reduced pressure.

Yield: 298.7g Yield: 99.7% GC purity
93% Reference Example 2 3a,8b-cis-2,3,3a,8b-tetrahydro-IH-1,2,5,7-tetrabromocyclopenta[
b] 3.00 g (6°31 mmol) of benzofuran was dissolved in a mixed solvent of THFloml and acetic acid 10 ml, and 0.8657 g (13.2 ml IIol) of zinc was added and stirred at room temperature for 1 hour. The solvent of the liquid was distilled off. 20 ml of water and 20 ml of ethyl acetate were added to the residue for extraction.The aqueous layer was further extracted twice with 20 ml of ethyl acetate, and the organic layer was washed with 20 ml of water and 20 ml of saturated brine, then anhydrous. It was dried with magnesium sulfate.The magnesium sulfate was separated from P and concentrated to dryness.

Yield 1. 95g Yield 97.5% GC Purity 96.6% m, p, 108.0-109.0℃ NMR (C
DC1a) δ: 2.90 (2HSm), 4.48 (IH.

m), 5.60 (IHSm), 5.80 (2H
Sm), 7.25 (IHSdS J-2,0Hz)
7.40 (IHS d, J-2,0Hz) I R (K
B r) cm-': 3070.2980.2920.1595, 1570.
865.830.740.720Mass: 314 (M+), 316 (M++2), 3
18 (M” +4) [Effect of the invention] According to the present invention, 3a,8b-cis-dihydro-3H-
5,7-dibromocyclopenta[b]benzofuran (m
) is 3a,8b-cis-dihydro-3H-cyclopenta (b) benzofuran (II) to the compound of the present invention, tetrabromocyclopenta [b) benzofuran derivative (I)
can be easily produced in high yield and with good reproducibility. Therefore, isolation and purification of (III) by recrystallization became possible, and large-scale synthesis of (m) on an industrial scale became extremely easy.

Claims (2)

[Claims] (1) Expressed by formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) Tetrabromocyclopenta[b]benzofuran derivative. (2) Shown by formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) 3a,8b-cis-dihydro-3H-cyclopenta[b
] A method for producing a tetrabromocyclopenta[b]benzofuran derivative represented by formula (I) according to claim (1), which comprises brominating benzofuran.