GB2185978A

GB2185978A - Amino-oxazolylalkenes

Info

Publication number: GB2185978A
Application number: GB08617590A
Authority: GB
Inventors: Graham S Poindexter; Jr Davis L Temple
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1983-05-11
Filing date: 1986-07-18
Publication date: 1987-08-05
Also published as: GB2185978B; GB8617590D0

Abstract

An intermediate for preparation of an imidate ester which intermediate has the formula: <IMAGE> wherein R and R<1> are independently selected from lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups; R<2> is lower alkyl, phenyl or thienyl; R<5> is lower alkyl or aryl; m is 0 or 1; and n is 0, 1, or 2, is prepared by reacting a substituted metalated methyl heterocycle with a cyanide R<2>CN and quenching with ammonium chloride.

Description

SPECIFICATION Amino-oxazolylalkenes This invention relates to amino-oxazolylalkenes and their preparation.

In Specification 2,139,21 2Athere is described the preparation of dihydropyridyl cyclic imidate esters of Formula I

and the acid addition salts of these substances. In the foregoing structural formula, the symbols R, R1, R2, R3, R4, R5, m and n havethefollowing meanings.Rand R1 are independently selected from hydrogen ower alkyl oralkoxyalkyi groups, ower alkyl meaning C1 to C4andalkoxyalkyl referring to a C1 to C4 alkylene chain and a C1 to Alkyl group, connected byan oxygen atom; R2is loweralkyl, phenyl, orthienyl; R3 iscycloalkyl of 5to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, hetaryl such as furanyl, indolyl, pyridyl, thienyl, and the like, aryl meaning phenyl, naphthyi, or substituted phenyl withthe substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, and methylsulfonyl and the like;; R4 is lower alkyl or alkoxyalkyl as defined above, aminoalkyl, haloalkyl, or dialkylaminoalkyl referring to a C1 to C4 alkylene chain and Ci to C4 alkyl groups connected by a nitrogen atom; R5 is lower alkyl or aryl; m isOor1; and n isO, 1, or2.

These compounds are prepared by a process according to the following reaction sequence:

In the foregoing scheme, R, R1, R2, R3, R4, R5, m and n are as defined in Formula I. The preferred method for making compounds of Formula I consists of refluxing the intermediate adducts II and Ill in ethanol solution for 18 to 24 hours. Removal of the solvent gives a material which if it is a solid, is purified byrecrystallisation and, if it is an oil, is converted to an acid addition salt and then purified. This facile reaction takes place in ordinary laboratory or plant equipment under convenient operating conditions. Preparation of compounds of Formula I according to the process of the invention generally comprises heating II and Ill neat or in the presence of a wide variety of reaction inert organic solvents.Suitable solvents include but are not limited two benzene, toluene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethane, ethyleneglycol, etc. Suitable reaction temperatures are from about 60 to 1 50"C. No catalyst or condensation agent is required.

The intermediate cyclic imidate ester enamines (II) are conveniently prepared by reacting an appropriately substituted metalated methyl heterocycle (lV) with an appropriate nitrilefollowed by quenching the reaction with ammonium chloride solution.

The intermediate acetylcinnamate compounds of structure Ill are prepared utilizing known Knoevenagel condensation reaction conditions. In general, appropriately substituted aldehydes and acetoacetates were condensed to give Ill.

According to the invention there are provided compounds of Formula

wherein Rand R1 are independently selected from lower (C1 -C4) alkyl or lower alkoxy-lower alkyl groups; R2is loweralkyl, phenyl,orthienyl; R5is loweralkyl oraryl; misOor1;and nis0,1or2, In another aspect of the invention the said compounds are prepared by a process which comprises reacting a substituted metalated methyl heterocycle of Formula IV,

wherein R, R1, R5, m and n are as defined above, M is a metal, with R2CaN, wherein R2 is as defined above, and then quenching the reaction with ammonium chloride solution to give compounds of Formula II.

The products and process of the invention will appear more fully from a consideration ofthefollowing examples and appended claims which are given forthe purpose of illustration only and are notto be construed as limiting the invention in sphere or scope. In examples which follow, used to illustratethe foregoing processes,temperatures are expressed in degrees centrigrade and melting points are uncorrected.

Intermediates ofFormula II Example 1 2-Amino- l-(4,5-dihydro-2-oxazolyl)- 1-butene A solution of 2-methyl-2-oxazoline (8.5 g; 0.10 mole) in 100 ml drytetrahydrofuran (THF) was added via syringe two a stirred suspension offreshly prepared lithium diisopropylamide in 50 mLTHF. The suspension was kept stirred under a nitrogen atmosphere at -78 Cfor an additional hour after the addition was completed. At this point propionitrile (10 mL; 0.14 mole) was added to the stirred suspension which was then allowed to warm to room temperature with continued stirring. The reaction was then quenched with 25 mL saturated NH4Cl solution. The organic layer was separated and washed with water.The water wash was back extracted with ether and the organic portions combined and washed with brine. The organic solution was dried over K2CO3, filtered, and concentrated to 13 g of yellow liquid. Distillation (90-95"C at 1 mm Hg)yielded 6.5 g clear liquid as product (70% yield).

Example 2 2-Amino- 1-64,5-dihydro-4,4dimethyl-2-(oxazolyl- 1-propene A solution of4,5-dihydro-2,4,4-trimethyl-2-oxazoline (25 g; 0.22 mole) andtetramethylethylenediamine (25.5 g; 0.22 mole) was added to a stirred mixture of lithium diisopropylamide (freshly prepared from 0.23 mole diisopropylamine and 0.23 mole ofn-butyl lithium in 100 mL dry THF) kept undera nitrogen atmosphere at-78 C. The resultantwhitish suspension was stirred at-78 Cforan additional 2.5 hr. Asolution of acetonitrile (15 g; 0.35 mole) in 50 m L TH F was added to the stirred reaction mixture which was then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution and water added in a quantity sufficientto dissolve all solids in the mixture.A 100 mL portion of ether was added and the resulting layers separated. The organic layer was washed with brine and dired (K2CO3), filtered and concentrated in vacuo to yield 24.9 g yellow liquid. Distillation afforded a 10% yield of product enamino oxazoline, b.p. 102-105"C at 4 mm Hg.

Example 3 2-Amino- (5, 6-dihydro-4,4, 6-trimethyl-4H- 1, 3-oxazine-2-yl)- 1-butene To a solution of 11.0 mmoles of lithium diisopropylamide (11.1 g diisopropylamine; 50 mL of 2.4M n-butyl lithium in n-hexane) in 100 mLTHF, kept at 78"C u n der a nitrogen atmosphere, was added a solution of 5,6-dihydro-4,4,6-trimethyl-411-1 3-oxazine (14.1 g; 0.10 mole) in 100 mL THF. The reaction mixture wasthen allowed to stirat-78 Cfor2 additional hours at which time a solution of propionitrile (8.3 g; 0.15 mole) in 50 mL THF was added. The reaction mixture was allowed to warm to room temperature and was quenched with 75 mL saturated NH4CI solution.A 100 mL portion of ether ways added, the organic layer was separated, washed with brine, and dried (K2CO3). After the K2CO3 was removed by filtration, the filtrate was concentrated in vacuo to give 21.2 g of a yellow liquid which was distilled to yield 15.5 g (79% yield) of product as a pale yellowoil, b.p.140 Cat4mm Hg.

Example 4 2-Amino- 1-(4, 5-dihydro-4methoxymethyl-4-methyl-2-oxazolyJ- 1-butene Asolution of 4,5-dihydro-2,4-dimethyl-4-hydroxymethyl-oxazole [10.0 g; 0.78 mole. For synthesis ofthis hydroxyoxazoline, cf: H. Witte and W. Seeliger,Angew. Chem.,lnt Ed. Vol 11,287(1972); J. Nys and J.

Libeer, Bull. Soc. Chim. Belges., Vol.65,377(1956)] in 100 mLTHFwas added dropwise to a stirred suspension of sodium hydride (3.6 g of a 57% suspension in mineral oil) in 40 mL dry THF underthe nitrogen atomosphere at room temperature. The resulting suspension was stirred for 3 hr underthe nitrogen atmosphere and then a solution of methyl iodide (12.1 g; 0.08 mole) in 25 mLTHFwas added and the mixture allowed to continue stirring overnight. A 100 mL portion of ether ways added following which the layers were separated and the organic layer was washed twice with water and then with brine.The organic layerwas dried (K2CO3), filtered, and concentrated in vacuo to 8.4g yellow residual iiquorwhich on distillation afforded 4.4 g (39% yield) of clear liquid product, b.p. 90"C at 10 mm Hg.

To a stirred, chilled (-78"C) mixture of lithium diisopropylamide (27 mmoles, prepared from 2.7 g ofthe amine, 11.3 mLof2.4M n-butyllithium in n-hexane) in 10 mLTHFwasadded a solution oftheoxazoline intermediate (3.6 g; 25 mm) prepared above. The resulting yellow mixture was stirred at -780C for 1.5 hrat which time propionitrile (2.8 g; 0.05 mole) in 10 mLTHFwas added. This mixture was allowed to warm to room temperature and was then quenched with a saturated NH4CI solution. The reaction mixture was then worked up as in the above examples and distillation yielded 1.2 g (25% yield) of the product enamino oxazoline, b.p. 120" at 1 mm Hg.

Some additional examples of intermediates of Formula II which can be prepared using the procedure followed in theforegoing examples are given in Table 1.

Table 1 Additional Formula II Intermediates

Ex. R R1 R2 m R5 n bp( CIO. lmm) mp C 5 Me- Me Et O - 1 70-72 6 Me H Et 0 - 1 - 7 H H Et 0 - 2 - 8 H H Et 1 Et 1 - 9 MeOCH2 Me Me 0 - 2 10 H Me Ph 0 - 1 - - 11 Me Me CHMe2 0 - 1 80 58-61 12 Me Me CMe3 0 - 1 - 132-133 13 Me Me Ph O - 1 - 74-75 14 Me Me 2-thienyl 0 - 1 107 69-70 15 H H Et 1 Ph 1 175(at2.5mm) -

Claims

CLAIMS 1. Compounds of Formula II wherein Rand R1 are independently selected from lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups; R2 is lower alkyl, phenyl orthienyl; R5 is lower alkyl oraryl; misOor1;and nisO,1 or2. 2. A compounds as claimed in claim 1 substantially as hereinbefore described specifically in the Examples. 3. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a substituted metaiated methyl heterocycle of Formula IV wherein R, R1, R5, m and n are as defined above, M is a metal, with R2C-N, wherein R2 is as defined above,and then quenching the reaction with ammonium chloride solution to give compounds of Formula II. 4. A process according to claim 3 substantially as described in Examples 1 -4. 5. A compound when produced buy a process as claimed in eitherof claims 3 and 4. Amendments to the claims have been filed, and have the following effect: (a) Claims 1 to 5 above have been deleted ortextuallyamended. (b) New ortextually amended claims have been filed asfollows: Claims 1 to 8.

1. Compounds of Formula II

wherein Rand R1 are independently selected from hydrogen, lower (Cn -C4) alkyl or lower alkoxy-lower alkyl groups; R2 is loweralkyl, phenyl orthienyl; R5 is lower alkyl oraryl; m is O orl; and nisO,1 or2.

2. A compound according to claim 1 wherein both Rand R1 are otherthan hydrogen.

3. A compound as claimed in claim 1 substantially as hereinbefore described specifically in the Examples.

4. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a substituted metalated methyl heterocycle of Formula IV

wherein R, R1, R5, m and n are as defined above in claim 1, Mis a metal, with R2C=N,wherein R2is as defined above, and then quenching the reaction with ammonium chloride solution to give compounds of Formula II.

5. A process according to claim 4wherein Rand R1 are both not hydrogen.

6. A process according to claim 4 substantially described in Examples 1 to 15.

7. A process according to claim 5 substantially as described in Examples 2 - 5,9 and 11 to 14.

8. A compound according to claim 1 when produced by a process as claimed in any one of claims 4to 7.