JPH0216318B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a lower alkyl group, and X is -CO- or -NR ₂
When X is -CO-, Y means -NR ₂ - and Z means -CH ₂ -, and when X is -NR ₂ -, Y means -CO- and Z means -O-. means. where R ₂
means a hydrogen atom, a lower alkyl group, a phenyl group or an aralkyl group. ) 7-oxa-2-azabicyclo[2,2,1]hepter
This invention relates to 2-ene derivatives and their production methods. More specifically, the present invention produces 7-oxa-2-azabicyclo[2,2,
1] A method for producing hept-2-ene derivatives and a novel compound obtained in this manner. Conventionally, 7-oxa-2-azabicyclo[2,
2,1] A known method for producing hept-2-ene derivatives is to cause an intermolecular reaction between oxazoles and dienophiles. However, in this method, the reaction occurs only when the reactivity of the oxazole and the dienophile is strong, and the target product cannot be obtained when the reactivity of the oxazole and the dienophile is small. For example, even if oxazole-5-carboxylic acid ester is reacted with N-allylaniline through an intermolecular reaction, no addition reaction occurs. Also, oxazole-5
-Even if a carbamate ester is reacted with crotonyl alcohol intermolecularly, 7-oxa-2-azabicyclo[2,2,1]hept-2-enes cannot be obtained at all. As a result of intensive study on the method for producing 7-oxa-2-azabicyclo[2,2,1]hept-2-ene derivatives, the present inventors have found that by bonding olefin to oxazole molecules through an acid amide bond, The present invention was completed based on the discovery that the desired product could be obtained extremely easily and in high yield by fixing the compound to In other words, in the case of oxazole-5-carboxylic acid aryl ester, in which an oxazole molecule and an olefin are bonded through an ester bond, no addition reaction occurs even when heated, but simply fixing the oxazole and olefin within the molecule does not cause any addition reaction. Rather, the object of the present invention can only be obtained by combining the two through an acid amide bond. Although the reaction proceeds even if the acid amide is a secondary amide, a tertiary amide in which an alkyl group, phenyl group, or aralkyl group is introduced into the amino group of the acid amide is preferable. The compound () of the present invention is produced by the method of the following formula. (In the formula, R ₁ , R ₃ , X, Y and Z are the same as above.) That is, the reaction of the present invention involves using an oxazole represented by the formula () in a solvent generally used in the Diers-Alder reaction. This process proceeds by heating the solvent to its boiling point, but it can also be carried out without a solvent. Examples of solvents used include benzene,
Examples include hydrocarbons such as toluene and xylene, ethers such as dioxane and ispropyl ether, amides such as dimethylformamide, as well as acetonitrile and chloroform. In addition, in order to isolate the target product of formula () from the reaction solution, the solvent used can be distilled off and the precipitated crystals can be collected by filtration, but in some cases, decolorization, recrystallization, chromatography, etc. Purification may be carried out using conventional methods. Note that the raw material compound () used in the present invention can be easily synthesized by bonding oxazole and olefin through an acid amide bond. For example, oxazole-5-carboxylic acid alkenylamide can be obtained by reacting oxazole-5-carboxylic acid chloride with alkenylamine. Further, oxazole-5-carbamic acid alkenyl ester can be obtained by reacting oxazole-5-isocyanate and alkenyl alcohol. Furthermore, this product can be converted to the corresponding N-
It can be derived into an alkyloxazole-5-carbamic acid alkenyl ester. Oxazole-5-carboxylic acid alkenylamide, N-alkyloxazole-5-carbamic acid alkenyl ester, etc. synthesized in this manner are generally colorless oils. The 7-oxer of the compound of the present invention thus produced
2-Azabicyclo[2,2,1]hept-2-ene derivatives are converted into furan derivatives when heated in the presence of water alone or water and an acid, and into phenol derivatives when heated in the presence of an acid alone, or heated in an inert solvent. This can easily lead to pyridine derivatives, which can have nicotinic effects or vitamin _B6
It is useful as a compound with a similar effect, a dye, and other synthetic intermediates. The present invention will be explained below with reference to Examples and Reference Examples. Example 1 170 ml of 0-xylene was added to 5.0 g of N-(3-butenyl)-4-methyloxazole-5-carboxylic acid anilide, and the mixture was heated under reflux for 24 hours. After distilling off the solvent from the reaction solution, it was subjected to alumina column chromatography, eluted with ethyl acetate, and purified to give 10-methyl-2-oxo-3-phenyl-11-oxa-3,9- as a colorless oil. Diazatricyclo[6,2,1,0 ^1,6 ]undec-9-ene 1.28g
(25.6%). In addition, raw material oxazole 1.62g
(32.4%). IRν ^neat _nax cm ^-1 : 1650, 1620 NMR (CDCl ₃ ) δ: 2.15 (3H, s,

[Formula]) 1.60~2.20 (5H, m, -C H ₂ C H C H ₂ -) 3.70 (2H, m, -N-C H ₂ CH ₂ -) 5.85 (1H, d, J = 3.0Hz, -OC H ) 7.30 (5H, s, arom.H) Example 2 6.4 g of N-(3-butenyl)-2,4-dimethyloxazole-5-carboxylic acid anilide was dissolved in 0-
After heating under reflux in xylene for 6 days, the same treatment as in Example 1 was carried out to obtain 8,10-dimethyl-2-oxo-3-phenyl-11-oxa-3,9-diazatricyclo[6,2,1,0 ^{1, 6} ] Undekar-9-ene 4.1g
(64.1%). Colorless fine needle crystals, melting point 135~
136℃. Example 3 N-methyl-4-methyloxazole-5-carbamic acid 2-propenyl ester 1.96 g (0.01
Add 200 ml of 0-xylene to the mixture and heat under reflux for 24 hours. The solvent was distilled off under reduced pressure, an appropriate amount of isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 2.
10-dimethyl-3-oxo-4,11-dioxer
2,9-diazatricyclo[6,2,1,0 ^1,6 ]
1.63 g (83%) of undec-9-ene is obtained. melting point
114℃. Example 4 N-benzyl-4-methyloxazole-5-
Carbamic acid 2-propenyl ester 2.72g
(0.01 mol) was reacted and treated in the same manner as in Example 3, and 2-benzyl-10-methyl-3-oxo-
2.20 g of 4,11-dioxa-2,9-diazatricyclo[6,2,1,0 ^1,6 ]undec-9-ene
(81%). Melting point 170℃. Example 5 N-benzyl-4-methyloxazole-5-
Carbamic acid 2-butenyl ester 1.43g
(0.005 mol) was heated under reflux for 72 hours under the same conditions as in Example 3, and then treated in the same manner as in Example 3. Diazatricyclo[6,2,
1,0 ^1,6 ] 0.60 g (42%) of undec-9-ene was obtained. Melting point 152℃. Example 6 N-benzyl-2,4-dimethyloxazole-5-carbamic acid 2-propenyl ester 2.86
g (0.01 mol) was treated in the same manner as in Example 5 to obtain 2-
benzyl-8,10-dimethyl-3-oxo-4,
11-dioxa-2,9-diazatricyclo[6,
2,1,0 ^1,6 ] Undec-9-ene 2.12g (74%)
get. Melting point: 112℃. Example 7 N-benzyl-2,4-dimethyloxazole-5-carbamic acid 2-butenyl ester was treated in the same manner as in Example 5 to give 2-benzyl-7,8,10
-Trimethyl-3-oxo-4,11-dioxer-
2,9-diazatricyclo[6,2,1,0 ^1,6 ]
Obtain Undekar-9-en. Melting point: 132℃. Reference example 1 100 ml of thionyl chloride in 6.43 g (45.6 mmol) of 2,4-dimethyloxazole-5-carboxylic acid
and heated under reflux for 4 hours. Excess thionyl chloride was distilled off under reduced pressure, and the resulting residue was dissolved in benzene 30
Dissolve in ml. N-(3-butenyl)aniline
Dissolve 6.73g (45.7mmol) in 100ml of pyridine,
Add the acid chloride dropwise while cooling on ice. Pyridine is distilled off under reduced pressure, and the residue is dissolved in chloroform, washed with a saturated aqueous copper sulfate solution, a 1N aqueous hydrochloric acid solution, and a 5% aqueous sodium chloride solution, and dried over magnesium sulfate.
The residue obtained by distilling off chloroform is purified by column chromatography using silica gel. N-(3-butenyl)-2,4 as oil
12.09 g (98.2%) of -dimethyloxazole-5-carboxylic acid anilide is obtained. Reference example 2 4-methyloxazole-5-isocyanate
Dissolve 12.4g in 20ml of toluene, gradually add 10g of allyl alcohol, and heat the mixture at 100℃ to 110℃ for 2 hours.
Heat it up. After the reaction was completed, the solvent was distilled off, and the residue was purified by column chromatography using silica gel to obtain 4-methyloxazole-5 with a melting point of 80°C.
-Carbamic acid 2-propenyl ester 15.5g
(85%). After dissolving this in a mixture of 2.0 g of sodium metal and 100 ml of methanol, the solvent was concentrated to dryness under reduced pressure. Add 50 ml of dimethylformamide to the concentrated residue, add 12.0 ml of benzyl chloride, and heat at 60°C to 80°C for 30 minutes. After cooling, water is added to the reaction mixture and extracted with ether. The ether layer is washed with water, dried, the solvent is distilled off, and the residue is purified by column chromatography using silica gel. N-
Benzyl-4-methyloxazole-5-carbamic acid 2-propenyl ester 18.5g (77.4%)
is obtained as an oil. Reference example 3 10-methyl-2-oxo-3-phenyl-11-
Oxa-3,9-diazatricyclo[6,2,
1,0 ^1,6 ] Undec-9-ene 1.5g (5.5mmol)
Dissolve in a mixture of 40 ml of dioxane and 40 ml of water and heat under reflux for 1.5 hours. After cooling, the solvent was distilled off from the reaction solution,
The resulting residue was poured into water and extracted with chloroform. After drying the chloroform layer, the solvent was distilled off and 2
16.4 g (quantitative) of a mixture of α and β forms of -hydroxy-7a-acetyl-6-phenyl-3aH-dihydrofuro[2,3-C]piperidin-7-one is obtained as a pale yellow oil. IRν ^neat _nax cm ^-1 : 3390, 1705, 1650, 1630 MS: 275 (7%, M ⁺ ), 257 (15%) 233 (57%), 232 (100%) NMR (CDCl ₃ ) δ: 1.50 ~ 2.50 (5H, m,

[Formula] ~ O H ) 2.29, 2.50 (total 3H, each s, ~ COC H ₃ ) 3.50 ~ 4.00 (3H, m,

[Formula]) 5.70, 5.76 (total 1H, each d, J = 4.0Hz, -
C H ~OH) 7.25 (5H, s, aroma.H) Reference example 4 8,10-dimethyl-2-oxo-3-phenyl-11-oxa-3,9-diazatricyclo[6,
2,1,0 ^1,6 ] 1.5 g of undec-9-ene is heated under reflux in 0-xylene for 5 days. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography using silica gel to obtain 8-methyl-1-oxo-2-
Phenylpiperidino[3,4-C]pyridine 0.98
g (70.3%). Colorless fine needle crystals, melting point 128
~130℃.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a lower alkyl group, and X is -CO- or -NR ₂
When X is -CO-, Y means -NR ₂ - and Z means -CH ₂ -, and when X is -NR ₂ -, Y means -CO- and Z means -O-. means. where R ₂
means a hydrogen atom, a lower alkyl group, a phenyl group or an aralkyl group. ) A general formula characterized by heating the oxazole derivative represented by (In the formula, R ₁ , R ₃ , X, Y and Z are the same as above.)
A method for producing a 7-oxa-2-azabicyclo[2,2,1]hept-2-ene derivative represented by 2 General formula (In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a lower alkyl group, and X is -CO- or -NR ₂
When X is -CO-, Y means -NR ₂ - and Z means -CH ₂ -, and when X is -NR ₂ -, Y means -CO- and Z means -O-. means. where R ₂
means a hydrogen atom, a lower alkyl group, a phenyl group or an aralkyl group. ) 7-oxa-2-azabicyclo[2,2,1]hepter
2-ene derivative.