JPS5888385A - 7-oxa-2-azabicyclo(2,2,1)hept-2-ene derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The comound of formulaI[R1 and R3 are H or lower alkyl; when X is -CO-, then Y is -NR2- (R2 is H, lower alkyl, phenyl, or aralkyl) and Z is -CH2-, and when X is -NR2-, then Y is -CO- and Z is -O-]. EXAMPLE:10-Methyl-2-oxo-3-phenyl -11- oxa-3, 9-diazatricyclo[6,2,1,0<1>,<6>]-undec- 9-ene. USE:Synthetic intermediates for pharmaceuticals, dyes, etc. PROCESS:The compound of formulaIcan be prepared by heating the oxazole derivative of formula II[e.g. N-(3-butenyl)-4-methyloxazole-5-carboxylic acid anilide]in a solvent such as o-xylene at the boiling point of the solvent.

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (Formula Nakajima and Kame each independently represent a hydrogen atom or a lower alkyl group, X means -CO- or -NR1-, and x represents - When co-no, Y means -N%-teZ means -CHz-, and when X is -NRz-, Y means -CO- and 2 means 10-.Here, crow is a hydrogen atom, 7-oxa-8-azabicyclo (2,!, l means lower alkyl group, 7!nyl group or aralkyl group)
) Hebut-2-ene derivatives and their production methods.

More specifically, 1 the present invention produces 7-oxa-
The present invention relates to a method for producing 2-azabisic'("*s+1) but-2-ene derivatives and to novel compounds thus obtained.

Conventionally, 7-oxa-! -Azabicyclo(B, 2.1) To produce a but-2-ene derivative, a method is known in which oxazoles and Genophile are reacted intermolecularly. However, in this method, the reaction occurs only when the reactivity of the oxazole and Genophile is strong, and the target product cannot be obtained when the reactivity of the oxazole and Genophile is small.

For example, oxazole-5-carboxylic acid ester is
Even if it reacts with allylaniline through an intermolecular reaction, no addition reaction occurs. Furthermore, even if oxazo-/L'-6-1 rubamate ester is reacted intermolecularly with crotonyl alcohol, no but-2-enes can be obtained from 7-oxa-2-azabicyclo(Z,!,1). do not have.

The present inventors have discovered that 7-oxa-2-azabicyclo (1,2,
1) As a result of intensive studies on the method for producing H2$-@-ene derivatives, we found that the desired product could be obtained extremely easily and in high yield by bonding an olefin to an oxazole molecule through an acid amide bond and fixing it within the oxazole molecule. They found that it can be obtained and completed the present invention.

In other words, in the case of oxazole-5-carboxylic acid aryl ester, in which an oxazole molecule and an olefin are bonded together through an ester bond, no addition reaction occurs at all even when heated; 1. The object of the present invention can only be obtained by bonding both of them 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, 78yl group, or aralkyl group is introduced into the amino group of the acid amide is preferable.

The compound (1) of the present invention is produced by the method of the following formula.

(In the formula, R1, R3, X, Y and 2 are the same as above.)
That is, the reaction of the present invention generally proceeds by heating the oxazole represented by formula (1) in a solvent used in the Diels-Alder reaction to a point in the solvent used, but it can also be carried out without a solvent. can. Examples of solvents used include hydrocarbons such as benzene, toluene, and xylene.

Ethers such as dioxane and isopropyl ether, amides such as dimethylformamide, acetonitrile,
Examples include chloroform.

In addition, in order to isolate the target product of the formula (9) from the reaction solution, the solvent used can be distilled off and the precipitated crystals can be collected by filtration, but depending on the case, decolorization, recrystallization, lipomatography, etc. Purification may be carried out by the following method.

Note that the raw material compound (1) used in the present invention can be easily synthesized by bonding an oxazole and an olefin through an acid amide bond. For example, oxazole-
Oxazole-5-carboxylic acid alkenylamide is obtained by reacting 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 compound can be converted into the corresponding N-alkyloxazole-carbamic acid alkenyl ester in a conventional manner using, for example, an alkylating agent. Oxazole-5-cardanoic acid alkenylamide synthesized in this way, N-alkyloxazole-5
- Carbamic acid alkenyl esters etc. are generally colorless oils.

The 7-oxa-2-□azabicyclo(t, 2.1)hebut-2-ene derivative of the present compound thus produced is:
Heating in the presence of water alone or water and acid gives a 7-ran derivative; heating in the presence of acid alone gives a phenol derivative;
Alternatively, it can be easily converted into a pyridine derivative by heating in an inert solvent, making it useful as a synthetic intermediate for pharmaceuticals, dyes, and others.

The present invention will be explained below with reference to Examples and Reference Examples.

°Example 1 N-(8-butenyl)-4-methyloxazole-5-
0-xylene 170- is added to 5.09 g of carboxylic acid anilide and heated under reflux for 34 hours.

After distilling off the solvent from the reaction solution, it was subjected to alumina column chromatography and eluted with ethyl acetate.

Purification yields 10-methyl-2-oxo-8-phenyl-11-oxa-8,9-diazatricyclo(e, L I?'cylo) undec-9-ene 1 as a colorless oil.
．． Obtaining B 89 (25,6%). Note that 1.629 (82.4%) of raw material oxazole was recovered.

IRy""cm-': 1 6 5 0. 1
6 20x NMR (CDC13) δ: s-1s (s Hl g + -N-CCah)1
．． 60~L@0 (5H,ya, -0HzCklG
Hx-)8.70 (@H, *, -N-0danzOHt
-) 5.85 (IH, 6, J-8, 0H1, -〇-'
pa>? , 80 (5H,ss, arom, I(
) Example 2 N-(8-butenyl)-2,4-dimethyloxazole-5-carboxylic acid anilide 6.4- in 0-xylene
After heating under reflux for one day, the same treatment as in Example 1 was carried out, and 8.10-
Dimethyl-2-oxo-8-7! Nyl-11-oxa-
3,9-diazatridicry(6,Ll,0)undec-9-ene 4.111 (64.1%) is obtained as colorless fine needles.

Melting point 1@6-186°C0 Example 3 0-xylene 200- was added to domethyl-4-methyloxazole-5-lupamic acid z-propenyl ester IJ69 (0.01 mol) and heated under reflux for 34 hours. The solvent was distilled off under reduced pressure, an appropriate amount of isopropyl ether was added to the residual liquid, and the precipitated crystals were collected by filtration to give z,10-dimethyl-3-oxo-4,11-dioxa-3,9-diazatricyclo(6,111,O'+' ) undec-e-ent, e
Obtain sp (88 attacks). Melting point: 114°C.

Example 4 N-benzyl-4-methyloxazole-5-carpamine 1I2-p (benyl ester 1.7110, oxol) was reacted and treated in the same manner as in Example 3 to give 2-benzyl-1O-methyl-8 -oxo-4,11-dioxa-2
,9-diazatricyclo(6,2,1,g''-)undec-9-ene LSO 181%), melting point 170°C.

Example 5 N-benzyl-4-methyloxazole-5-carbamic acid z-butenyl ester 1.4B9 (0,005 mol) was heated under reflux for 71 hours under the same conditions as in Example 3, and the same procedure as in Example B was carried out. Upon treatment, 2-benzyl-7,lO-dimethyl-8-oxo-4,11-dioxa-2,9-diazatricyclo(612,1,O1w@)undec-9-
0.609 (42%). Melting point 15! 'C0 Example 6 N-benzyl-2,4-dimethyloxazole-b-rubamic acid z-propenyl ester 3.86 (0,0
1 mol) was treated in the same manner as in Example 5 to give 3-benzyl-8
,lO-dimethyl-3-oxo-4,11-dioxa-
3,9-diazatridyl o (6J, l, O”-:l
undeca-Q −x >Z, yielding II9 (74%).

Melting point 11S"C0 Example 7 N-benzyl-2,4-dimethyloxazole-5-carbamic acid@-futhynyl ester was treated in the same manner as in Example 6 to give !-benzyl?, 8.10-trimethyl-8-
Oxo-4,11-diox-3,9-diazatridi9
0 (e, z, i, os+s)undec-9-ene is obtained. Melting point 18fi'C6 Reference example 1 3.4-dimethyloxazole-5-carboxylic acid 6.4
89 (45,6 gaol) with thionyl chloride lo
Add ogt and heat under reflux for 4 hours. Excess thionyl chloride is distilled off under reduced pressure, and the resulting residue is dissolved in 80% of benzene. N-(3-butenyl)aniline 6.789
(45,7101) is dissolved in pyridine 100-, and -chloride is added dropwise while cooling with water. Pyridine was distilled off under reduced pressure, 1p4 moat was dissolved in chloroform, and a saturated aqueous copper sulfate solution was added.

Wash with IN hydrochloric acid aqueous solution and 5% sodium chloride aqueous solution, and dry with magnesium sulfate. The Oa form is distilled off, and the resulting residue is purified by column chromatography using silica gel. 12.099 (98.2%) of oil are obtained.

Reference Example 2 So-4-methyloxazole-5-isacyane) 11.4
Dissolve F in 20@l of toluene and add allyl alcohol IO
g is gradually added and the mixture is heated at 100°C to 110°C for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by column chromatography using silica gel to obtain a melting point of 80.
15.51 (855G) of 4-methyloxazole-5-carbamic acid 2-propenyl ester are obtained. After dissolving this in a mixed solution of metallic sodium 2.0 F and methanol 100 m/l, the solvent was concentrated to dryness under reduced pressure. Dimethylformamide 50- is added to the concentrated residue, benzyl chloride 11.0- is added thereto, and the mixture is heated at 60°C to 80°C for 80 minutes δ. After cooling, water was added to the reaction solution 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 3-propenyl ester/I/18.5F (77,4 doses) is obtained as an oily eyelid.

Reference example 8 1G-methyl-Z-ox/-1%-7,=ru-11-oxa-8,9-diazatricyclo(6,2°101-)
Undec-9-ene L, S 9 (5.5 mmol) was dissolved in a mixture of 40 g of dioxane and 40@t of water, and heated under reflux for 1.5 hours. After cooling, the solvent is distilled off from the reaction mixture, and the resulting residual liquid is poured into water and extracted with chloroform. After drying the chloroform layer, the solvent was distilled off and 2-hydroxy-
7a-acetyl-6-7* nyl-8aH-dihydro7
16.4F (quantitative) of mixed α and β forms of o(Z, 21-C]piperidin-7-one is obtained as a pale yellow oil.

n5nt -1 1RI/c discussion: @89Cj, 1705,165
0,1680m&X Ms175 (7%, M"), 25'1l (ischi)!,
RB (67%), 282 (100%) NMR (C
DOlj) δ knee 1.50~g, s o (5H, vs, -a, !l!
20Hgh-, -disruption) II9. II0 (total 8H, each ks, ~C0CHa) 8.50-4. oo (8
H, II, -NC enemy C-61 equipment-) 5.70.5.76
(Total IH, each d, J-4, 0Hz, -Cji-
OH)'j, B S (5H,s, arose, H
) Reference Example 4 8.10-dimethyl-2-oxo-8-phenyl-11
-oxa-8,9-diazatricyclo(6,!, 1.O
',.]]Undec-9-ene 1.5 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.
Methyl-1-oxo-! -7X Nylpiperidino (8,4
-(3) 0.989 (70.8%) of pyridine is obtained. Colorless fine needle crystals, melting point 118-180°C.

Claims (1)

[Claims] (1) General formula (in the formula, R, and R3 each independently represent a hydrogen atom or a lower alkyl group, X means -GO- or -N1%-, and X is 100-(7) When Y is -N%- and 2 is -OH
,-, and when X is -NR,-, Y is -CO-
te 2 means 10-. Here & is a hydrogen atom, a lower alkyl group, 7! It means a nyl group or an aralkyl group. ) 7-oxa-2-azabicyclo (S, 2
．． 1) Method for producing hebut-2-ene derivatives. (z) General formula (in the formula, R and - each independently represent a hydrogen atom or a lower alkyl group, X means -CO- or -N%-,
When X is -cO-, Y is -NR2- and 2 means -CH2-, and when X is -NR', Y is -CO- and 2 means 10-.Here, the island is hydrogen atom, lower alkyl group, phenyl group or aralkyl group).