JPS63218676A - Azabicyclo compound and its manufacturing method - Google Patents

Abstract

NEW MATERIAL:An azacyclo compound expressed by formula I (E is alkoxycarbonyl). EXAMPLE:8-Methoxycarbonyl-6,7-bis(phenylsulfonyl)-8-azabicyclo(3-,2,1) octene-2. USE:Useful as an intermediate for medicine and agricultural chemicals. The above-mentioned compound can be converted into compounds undescribed in literatures such as 8-methyl-8-azabicyclo(3,2,1)octa-2,6 diene, etc., and further into well-known and biologically active substance such as tropane, tropine, tropacocaine, etc., via these compounds. PREPARATION:2-Alkoxycarbonyl-2-azabicyclo[3,1,0]hexene-3 expressed by formula II is subjected to addition reaction reaction with bis(arylsulfonyl)ethylene expressed by formula III and the resultant product is reacted with an alkali metal amalgam to provided the compound expressed by formula I.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention relates to an azabicyclo compound represented by the formula (wherein E represents an alkoxycarbonyl group) useful as an intermediate for pharmaceuticals, agricultural chemicals, etc. Regarding the manufacturing method.

<Prior art and problems to be solved by the invention> The above general formula [! The azabicyclo compound represented by ] is a compound of Compound 1 that has not been described in any literature. Further, the following methods can be considered as the manufacturing method.

For example, ■Known compound, compound 8-alkoxycarbonyl-8-
Azabicyclo(3,2,1)octan-3-one (J
, 11++, 'Ches+, So'c,, 96.3
336 (1974)) by treating tosylhydrazone with methyllithium.

■2-Alkoxycarbonyl-2-azabicyclo(3,
1,O) By adding tosylacetylene to hexene-3, 8, which is not described in the literature, is expected to be obtained.
-Alkoxycarbonyl-6 (or 7)-tosyl-
A method for removing the tosyl group of 8-azabicyclo(3,2,1)oct-2,s-7ene.

■Known substance 2.6.7- Tri(alkoxycarbonyl)-8-azabicyclo(3,2,1)octa-2,6-
Diene (J, Org, Ches, 39.2715
(1974))) is decarboxylated by heating the 6,7-dicarboxylic acid obtained by hydrolyzing it with copper powder in quinoline.

However, when we actually examined these methods, we found that
In methods (1) and (2), the target product was not detected at all, and in method (2), no adduct, which was a precursor, was obtained.

<Means for solving the problem> The present inventors have discovered that the azabicyclo °
As a result of various studies on the production method of the compound, 8-alkoxycarbonyl-8-azabicyclo(3,2,1)octa-2,6-diene, we found the production route shown by the following formula, and the compound is suitable for pharmaceutical and agricultural purposes. Found to be useful as an intermediate etc. (II) (m)
(IV) That is, the present invention provides an azabicyclo compound represented by (wherein E represents an alkoxycarbonyl group) and (2) 2-alkoxycarbonyl-2-azabicyclo (
3,1,0) Hexene-3 [■] is added with bis(arylsulfonyl)ethylene (III) to form 8-alkoxycarbonyl-6,7-bis(arylsulfonyl)-8-azabicyclo(3,2,1 ) off \te, -2 [■], and a second step of treating (IV) with an alkali metal amalgam to eliminate the arylsulfonyl group.
The present invention provides a method for producing an azabicyclo compound shown in the following.

The azabicyclo compound (I) of the present invention is an alkoxylic
It has a bonyl group, and such substituents include, for example,
Examples include lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and heptoxycarbonyl.

Next, the method of the present invention will be explained.

2-alkoxycarbonyl-2-azabicyclo(3,1,0)hexene-3(II) which is the starting material for the process of the present invention
) can be produced by reacting G*N-alkoxycarbonylpyrrole with diazomethane (for example, J,
CheIl, Soc, 457(196'1)) - Here, examples of the alkoxycarbonyl group include the same substituents as in the above general formula (1).

One of the raw materials is bis(arylsulfonyl)ethylene (Ill), and examples of the aryl group include phenyl, tolyl, xylyl, and the like. Furthermore, either the cis isomer or the trans isomer or a mixture thereof can be used.

The above compounds (n) and (III) are reacted to form a compound (
In carrying out the first step to obtain IV), it is sufficient to simply mix and heat the compound [■°], (1113).The reaction temperature is usually 80 to 120°C.The molar ratio of both compounds is usually t: The range is O, a to o, s:i, and the reaction time is generally 2.5 to 3.5 hours.

The produced compound [IV] can also be purified by an appropriate method, such as recrystallization.

Further, the second step, the elimination reaction of the sulfonyl group, proceeds under the action of an alkali metal amalgam such as sodium or lithium. The amount used is usually 2 to 2
1O equivalent. pH 3 such as sodium dihydrogen phosphate
The reaction proceeds smoothly if carried out in the presence of agent II. Lower alcohols such as methanol and ethanol are usually used as the reaction solvent.

The reaction proceeds easily even at room temperature and is usually completed in 5 to 15 hours. The target product can also be purified by distillation, recrystallization, column chromatography, liquid chromatography, etc. <Effects of the Invention> The compound of the present invention represented by general formula (1) can be used for bioactive substances such as pharmaceuticals and agricultural chemicals or for the production thereof. For example, compounds of the present invention are useful as 8-methyl-8-
Can be induced into compounds not described in literature such as azabicyclo(3,2,1)octa-2,6 diene, and further induced into known physiologically active substances such as tropane, tropine, and tropacacocaine via these compounds. You can also.

Further, according to the method of the present invention, compounds having various uses as described above can be efficiently produced.

<Examples> Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited only to the Examples.

, Example 1 (1-1) 8-methoxycarbonyl-6,7-bis(phenylsulfonyl)-8-7zabicyclo[3°2.
1] Production of octene-2 2-methoxycarbonyl-2-7zabicyclo(3,1,
0) Hexene-3480-g (3,45 mmol) and cis-bis(phenylsulfonyl)ethylene i, 06 g
(3.45 mmol) at 100"C.
Heated for 5 hours.

After cooling, the resulting yellow solid was recrystallized from chloroform to obtain 1.14 g (2.55 mmol) of the desired product.

Yield 4%, colorless crystals, melting point 268-270''C (decomposed).

Elemental analysis (Cm+Hg+NJSt) HNS Calculated value (%) 56,36 4.73 3.13 1
4.33 Actual measurement I (%) 56.58 4. [io
2.88 14.45 mass analysis (13,5eV1.10
0 "C) m/e 306 (M" -5o, Ph, b
ase), 165 (58%) I R (KBr) 1700.1340, 1310.1155, 690.6
00 am-''H-NMR (90 MIIz, δ,
,,)1.03-1.48(IH,s),2.30-2
．． 62 (III, d, J proverb 1B, OH,) 3.63
(3H,S), 4.10(2)1. *), 4.62-4
．． 80 (2B, Otori).

5.38-5.62 (ill, d, J=9.5 H,
).

5.62-5.85 (II (, d, J earthquake 9.5 II
,).

7.37-7.80 (611, m), 7.80-8.0
6(411,5)(1-2) 2.29 g of diphenylsulfonyl compound obtained by the method for producing 8-methoxycarbonyl-8-azabicyclo(3,2,1)octa2,6-diene (1-1) (5.12 mmol) and 13.7 g of sodium dihydrogen phosphate dihydrate were dissolved in 125 m of methanol, and nitrogen gas was blown into the solution for 30 minutes.

After adding 62 g (8 equivalents) of sodium amalgam (1.5%) to this and stirring at room temperature for 9 hours, the generated mercury and insoluble matter were filtered off and extracted with n-hexane (50 m
After drying the n-hexane layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 782 mg of a colorless oil. This oily substance is the target product and 8-methoxycarbonyl-
It was a mixture of 8-azabicyclo(3,2,1)octene-2 (19:1).

・ From this oily substance, pour medium pressure liquid and mouthwash (1,25
% ethyl acetate/n-hexane), the target product 612m
g was separated.

Yield 72.3%, colorless oil, boiling point 90"C (1.5m
m1g) Elemental analysis (C*Il++NO-rich) HN Calculated value (%) 65,44 6.71 8.48 Actual value (%) 65,15 6.92 8.60 Mass analysis (13,5eV, 80″C) m/e I65 (
M+, base) +150 (19%, 161
(31%) I R (oil) 1700, 1445.13 & 0.1290.1405c
m-''II-NMR (90M11 friend, et
':? 2 >1.76 (111, ddd, J=Il1
1.3. 2.0. 3.7 ++*).

2.73 (LH, d, J, 18.3n,).

3.69 (38,s), 4.50 (Ill, fog, Js
2.3 Rm).

4.62(IH,m,J-2,'7H*)+5.29(
IH, m, J-9,411m) + 5.87 (LH, dd
, J Fable 6.0.2, 311. ).

6.12 (1'11.m, J-9,411,).

6.40 (LH, dd, J=6.0.2.3+1.)U
V (cyclohexane) λ (g
°)=218(610)n+m Reference Example 1 8-Methyl-8-azabicyclo(3,2,1)octa-
8-Methoxycarbonyl derivative 31 obtained in Production Example 1-2 of 2,6-diene
2 mg (1,89 mmol) was dissolved in anhydrous ether 1011, and this was dissolved in lithium aluminum hydride 20
It was added dropwise to 50 if of an anhydrous ether suspension containing 0 mg (5.27 mmol) at room temperature, and the mixture was further heated under reflux for 30 minutes. After cooling, 101d of ethyl acetate was gradually added to decompose the excess reducing reagent, and insoluble matter was filtered off. The obtained growth layer was concentrated under reduced pressure to obtain 226 s*q of colorless oily substance.Next, vacuum distillation was performed to obtain 221 mg of the target product.

Yield 96.3%, boiling point 60°C (10 mml 1 g) Elemental analysis (C@HIIN) HN Calculated value (%) 79,29 9.15 1r, 56 Actual value (%) 78.92 9.18 11.33 mass Analysis ('13.5eV, 80℃) m/e 121 (
M”, base) +120 (45%), 94
(73%) I R(oll) 2920.1438.1315.12B5.1105;
770c'm-'' HNMR (90Mll wealth *
6'pc's) 1.70 (Ill,
+w, J-18,3H,), 2.27 (38,s).

2.49 < 111. m, J-18,311,), 3
．． 45C2H, ei).

5.30 (IH, -8J・7.8.3.011
g).

5.72 (111,, dd, J.5.4.2.011.
).

5.80 (111, dddd, J, 7.8.5.3, 1
．． 2.1.2. H,).

Claims (2)

[Claims] (1) Azabicyclo compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, E represents an alkoxycarbonyl group.) (2) 2-alkoxycarbonyl-2-azabicyclo [
3.1.0] Adding bis(arylsulfonyl)ethylene to hexene-3 to form 8-alkoxycarbonyl-
A first step of producing 6,7-bis(arylsulfonyl)-8-azabicyclo[3.2.1]octene-2,
and a second step in which the adduct is treated with an alkali metal amalgam to remove the arylsulfonyl group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where E is an alkoxycarbonyl group) A method for producing an azabicyclo compound represented by