DE1929963A1 - Process for the preparation of esters - Google Patents

Description

PATENT LAWYERS. M0NCHEN5 DR.-ING. H. FINCKE WOiAiiaaTB * 1 DIPL.-IN G. H. BOHR MULVtIlMIIl. 51 DlPL-ING. S. STAEGER 1929963

1 2nd JUN11969 Description

on the patent application of Imperial Chemical Industries Limited, London, S.V.1.,

concerning:
Process for the production of esters'

The priority of the application in Great Britain from 14 · .6.69 is used

The invention relates to a new chemical process for the preparation of heterocyclic derivatives with valuable anti-inflammatory, antioxidant and antipyretic properties.

According to the invention, a method for producing Esters of the general formula:

where Het has the meaning given below, W represents a hydrogen atom or a methyl radical, X represents a hydrogen atom or a Hethoxy radical, T represents a Pheny! radical, the optionally bit a trifluoromethyl radical or with one or two of fluorine, chlorine and Bromine atoms can be substituted halogen atoms selected, R represents a methyl or ethyl radical, R ^{2 represents} a hydrogen atom or a methyl! Radical and R * represents an alkyl! Radical with up to H C atoms, and where T and the group - CR ¹ R ² XO ₂ R ^ to non-adjacent ring

80 988 3/1681

Carbon atoms of the heterocyclic nucleus (Het) bonded are, as well as pharmaceutically acceptable acid addition salts thereof, proposed that one Compound of the general formula:

V ₁ · "

II

where Het has the meaning given below and Ί ρ

W, X, Γ, R and R have the meanings given above, where X and

12 *

the group -CHR ¹ R are bonded to non-adjacent carbon atoms of the heterocyclic nucleus (Het) to react with sodium or potassium or a hydride, amide or C ,, alkoxide thereof and a carbonate of the formula: CO. (OR *) ₂ , in which R ^ has the above meaning, is brought.

Ib for the purposes of the invention, the group -CHR R (in the Raw materials) and the group -CR R .CCWEP (in the products) only be bound to certain positions of the heterocyclic nucleus (Het). In the following definition of het,

Ί 2

For the sake of simplicity, reference is only made to -CHR R; of course, however, het has the corresponding meaning b # i the products according to the invention. The meaning of Het istί

a) a thiazole or oxazole nucleus with de.m -CHR ¹ R ² in the 2-position, or,.

b) a ^ yrimidine or I ^ rridine nucleus, in which -CHR ¹ H ² in

the 2-> 4- or 6-Stellun ^ is 909883 / a ^

R * can conveniently be, for example, a methyl or ethyl radical.

The acid addition salts can, for example, salts with inorganic or organic acids that give a pharmaceutically acceptable anion, for example a hydrochloride.

Certain compounds according to the invention Processes that can be produced are, for example, methyl α- (4-p-chlorophenylpyrimid-2-yl) propionate, Ethyl ot- (5-pchlorphenylpyrimid-2-yl) propionate, Xthyl-a- (4-p-chlorophenylpyrimid-2-yl) -a-methylbutyr & t, Methyl a- (4-p-bromophenylthiazol-2-yl) isobutyrate, Metbyl a- (4-p-bromophenylthiazol-2-yl) propionate, methyl a- (5-p-chlorophenyloxazol-2-yl) isobutyrate and methyl α- (5-p-chlorophenyl-6-methoxypyrid-2-yl) propionate.

The inventive method is preferably in one excess of the carbonate used as a reactant, an excess of carbonate of 5 to 20 mol. Optionally, an organic solvent, for example an aromatic Carbon hydrogen, for example xylene, may be present. the The reaction can be accelerated or brought to a conclusion by supplying heat.

The hydrogen atom becomes through the process according to the invention (H *) in the group -GH * R R by the group -CÖ ^ R ^ originating from the carbonate used as a reactant

2
replaced. However, if B represents a hydrogen atom, that

909883/1681 ... - 4 -

as a reaction participant related carbonate is dimethyl or diethyl carbonate and this carbonate is present in excess, then in addition to the process described can also

1 the alkylation of the carbon atom (C *) of the group -C * HR R by the alkyl radical originating from the carbonate used as the reactant. The latter process can can be represented as follows:

R ¹ R ¹

I CO (OAIk) ₀ I.

-CH *> -C-CO ₀ AIk

I NaH (e.g.) \ ^d

H Alk

where R ^{1 represents} a methyl radical and Alk represents a methyl or ethyl radical.

As starting materials for the process according to the invention Compounds used can be prepared by known chemical methods.

The invention is explained in more detail below with the aid of examples.

example 1

Sodium hydride (2.5 g) would become a mixture of dry Added xylene (40 ml) and dimethyl carbonate (30 ml). The mixture was left in a nitrogen atmosphere for 10 minutes touched. Then 4 ^ p-chlorophenyl-2-ethyIpyrimidine (5 g) was added and the mixture was refluxed for 13 hours while stirring and then over

909883/1681

Left to stand at room temperature overnight. The solid material was filtered off, washed with dry benzene (100 ml), suspended in dry benzene (30 ml) and cooled to 5 ° G, whereupon glacial acetic acid (30 ml) is added to the suspension

quickly.
Stir / was added. After 5 minutes, water (50 ml) was added and the organic phase was separated. The aqueous phase was extracted 3 times with benzene (50 ml). The organic phases were mixed together and washed with a saturated sodium bicarbonate solution (3 × 30 ml) and then with water (30 ml), dried and evaporated. The oily residue was purified by preparative thin layer chromatography on silica plates with a 1: purified were eluted 4 mixture of acetone and petroleum ether (b.p. 60-80 ⁰ O.). The purified material was recovered from the silica by elution with chloroform. The chloroform solution was evaporated to dryness. Thus, methyl α- (4-p-chlorophenylpyrimid-2-yl) propionate was obtained as an oil with the following nuclear magnetic resonance results; f 1.1 O ^H i ^d »pyrimidine proton at Cg), 1.9 (2H, d, phenyl protons ortho to the connection point with the pyrimidine ring), 2.45 (IH, d, pyrimidine proton at C-), 2.58 (2H , d, phenyl protons), 5.84 (1H, quartet, CH), 6.27 (3H, s, CH ₅ from the ester) and 8.3 (3H, d, CH, next to CH).

The 4-p-chlorophenyl-2- ethylpyrimidine used as starting material was shown as follows?

Propionamidine hydrochloride (21.7 g) was added to a solution of sodium (4.6 g) in dry ethanol (100 ml) . The mixture was stirred for 30 minutes and filtered. That

. 909883/1681

Filtrate was stirred and cooled to 10 ⁰ C. Then a solution of p-chlorophenyl-β-chloroviny! Ketone (10 g) in dry ethanol (50 ml) was added dropwise while maintaining the temperature at 10 ⁹ C. After the addition, the mixture was left to stand at room temperature overnight. Then the ethanol was evaporated. A 2N hydrochloric acid solution (200 ml) was added to the residual oil, and the precipitated hydrochloride was filtered off and added to an excess of 2N sodium hydroxide solution. The resulting mixture was extracted with ether. The ethereal solution was washed with water, dried and evaporated. The residual oil slowly crystallized. Thus one obtained ^ -p-chlorophenyl ^ -ethylpyrimidine, m.p. 33'-35 ° 0.

Example 2

The procedure of Example 1 was repeated using 5-p-chlorophenyl ~ 2-ethylpyrimidine instead of 4-p-chlorophenyl-2-ethylpyrimidine, diethyl carbonate instead of dimethyl carbonate and a reflux time of -J hours instead of 13 hours. The product was purified in this case by recrystallization from petroleum ether (bp. 60-80 ⁰ C). Thus, ethyl a- (5-p-chlorophenylpyrimid-2-yl) propionate was obtained, Sep. ^;

The S-ppyrimidine used as the starting material was represented as follows:

Propionaimine hydrochloride (4.34 g) was added to a solution of Added sodium (0.92 g) in dry ethanol (50 ml). the

909883/1681

• ■

Mixture was stirred for 30 minutes and then filtered. Ap -chlorophenyl-ß-dimethylaminoacrolein (2.1 g) was added to the filtrate and the mixture was refluxed for 3 hours. The ethanol was evaporated and the residue was triturated with water. The solid was filtered and recrystallized from petroleum ether (bp. 60-80 ⁰ C). This gave 5-p-chlorophenyl-2-ethylpyrimidine, m.p. 92-93 »5 * 0

Example 3

Sodium hydride (2 g) was added to diethyl carbonate (30 ml), and the mixture was left in a nitrogen atmosphere for 10 minutes touched. Then ^ -p-chlorophenyl - ^ - ethylpyrimidine (4g) was added and the mixture was refluxed in a nitrogen atmosphere for 6 hours. the The mixture was cooled and the solid was filtered off and washed with benzene (30 ml). The filtrate was with a saturated sodium bicarbonate solution and then washed with water and then dried and evaporated. The oily residue was purified by preparation Thin-layer chromatography on silica plates, eluting with a 10; 90 gel from ethyl acetate and benzene were cleaned. The purified material was recovered from the silica by elution with chloroform. The chloroform solution was evaporated to dryness. Thus one obtained Xthyl-a- (4-p-chlorophenurlpyrimid-2 «» - yl) -a-methylbutyrate, M.p. 40-4-5 ° C.

Example 4-

A mixture of ^ - p-bromophenyl-S-ethylthiazole (1.0

«09883/1681. _Q

Sodium hydride (0.5 g) and dimethyl carbonate (10 ml) were refluxed for 3 hours while stirring. The mixture was then cooled and added to a cold mixture of ether (100 ml) and acetic acid (5 ml) with about -40 ⁰ C. After the excess sodium hydride was decomposed, the mixture was washed with water and then with a saturated sodium bicarbonate solution and then dried (with anhydrous K ₂ CO-) and evaporated. The residue was umkrisfcallislert from petroleum ether (bp. 60-80 ⁰ C) to remove almost completely to the starting material, after which the components of the residue by preparative thin layer chromatography using Eieselgel CF and a mixture of 95 # petroleum ether (Sdp.60-80 ° C) and 5 # ethyl acetate were separated from each other.

The material with an R ^ value of 0.5 was the starting material. The material with an R - value of 0.35 was ^{recrystallized from petroleum ether (bp. 60-80 0} C) and gave me thy 1 * κχ- (4 - p-bromophenylthiazol-2-yl) isobutyraty mp. 73- 74 "5 ° C. The material having a Rp value of 0.2 was recrystallized from petroleum ether (bp. 60-80 ⁰ C) to give Metfayl-a- (4-pbromphenylthiazol-2-yl) propionate _f mp. 59 -61 ⁰ C.

The used as starting material ^ -p-bromophenyl ^ -äthyl-

thiazole was represented as follows:

A mixture of p-bromophenacyl bromide (8.4 g) and thio-

propionamide (2.7 g) in acetone (100 ml) was left overnight stirred at room temperature. The mixture was then filtered, and the solid residue was washed with acetone. Consequently

909883/1681

to give 4-p-bromophenyl-2-ethyl-4 - hydro: xythiazolin · - hydröbromid, m.p. · 225-230 ⁰ C with softening at 200 ° 0th

This hydrobromide (26.2 g) was added with stirring and external cooling added to concentrated sulfuric acid (80 ml) in such a way that the internal temperature did not exceed 15 ° C. After the addition was complete, the solution was stirred at room temperature for 2 hours and then poured onto ice. The mixture was diluted to about 1 liter with water, whereupon the solid was filtered off, washed thoroughly with water and was finally recrystallized from methanol. This gave /i-p-bromophenyl-2-ethylthiazole, m.p. 82-8 * ° 0.

Example 5

A mixture of 4- ~ p-bromophenyl-2-isopropylthiazole (0.5 g), Sodium hydride (0.5 g), dimethyl carbonate (5 ml) and tert-butanol (2 drops) was refluxed for 16 hours and stirred at the same time. The mixture was then worked up as in Example 4.

The material with an R ^ value of 0.5 was the starting material. The material having a R "value of 0.35 was umkrietallisiert from Fetroläther (bp. 60-80 ⁰ O) to give methyl a- (4-p" bromphenylthiazol-2-yl) isobutyrate, mp. 73-74- »5 ° 0 ·

Example 6 A mixture of 2-ethyl-5-p- © chlorophenyloxazole (15 g), Sodium hydride (50% by weight dispersion in mineral oil; 15 g)

and dimethyl carbonate (150 ml) was refluxed for 20 hours

8098837 168t

heated. The mixture was cooled and poured into a stirred mixture of ether (200 ml), water (200 ml) and glacial acetic acid (15 ml). The ethereal layer was separated from the mixture and washed with water (100 ml) and then evaporated to dryness in vacuo. The oily residue was washed successively with petroleum ether, shaken, methanol (50 ml) and water (5 ml) (bp 40-60 ⁰ G 50 ml.). The methanol layer was evaporated to dryness in vacuo and the oily residue was subjected to fractional distillation on a 0.2 mm Hg column. The fraction boiling at 131-133 ° C was collected. Thus, methyl α- (5-p-chlorophenyloxazol-2-yl) isobutyrate was obtained as an oil with the following nuclear magnetic resonance values: one singlet each at 2.75T, 6.25T and 8.3T.

The oxazole derivative used as the starting material was represented as follows:

Ethyl propionate (77.5 g), sodium hydride (50% by weight dispersion in mineral oil; 50 g) and ether (250 ml) were mixed together, and p-chloroacetophenone (80 g) was slowly added to the mixture while cooling was poured into a stirred mixture of water (200 ml), ice (200 g) and acetic acid (50 ml). The oil was extracted with ether (400 ml). The obtained oil was subjected to fractional distillation in vacuo and the fraction boiling at 93-1OO ° C / 0.05 mm was collected. The distillate was 3 volumes of petroleum ether (bp. 40-60 ⁰ G) at -70 0 recrystallized *. This gave 1-p-chlorophenylpentane-1,3-dione, m.p. 13-15 ⁰ G.

909883/1681. - 11 -

Sodium azide (30 g) was added in small portions within hours to a stirred Nisohung of concentrated sulfuric acid (300 ml) and IP Chlorphenylpentan-i ^ -dione (60 g) at 0-10 ⁰ C. After 16 hours at room temperature, the solution was poured on ice (1 300 g) and the resulting mixture was filtered and alkali wobbles with a 2n-Hatriumhydroxydlöeung to pH 11, keeping the temperature below 30 ⁰ C was maintained by addition of ice. The resulting oil was extracted with chloroform (500 ml) and the chloroform solution was evaporated to dryness in vacuo. The oily solid obtained as residue was extracted twice with petroleum ether (boiling point 40-60 ° C., 100 ml), and the extracts were filtered off

Petroleum ether in a vacuum, the oil was subjected to a fractional distillation, the fraction boiling at 93-95 ° C./0.1 mm being collected. Bas distillate was recrystallized from ether at -70 ⁰ C. Thus, 2-ethyl-5-p-chlorophenyloxazole, Sap was obtained. 40-41 ⁰ C.

Example 7

5-p-Chloropbenyl-2-ethyl-6-aethoxypyridine (Sap. 22-25 ° C; 75 "β) and sodium hydride (0.1 g) were stirred under reflux together with dimethyl carbonate (2 ml) for 6 hours. the The mixture was then cooled and added to a solution of acetic acid (1 ml) in Xther (20 ml). From the emerging Solution was the excess acetic acid by Vaechen with a 2N sodium carbonate solution removed. The organic one Solvent was then evaporated, and the residual products were separated from one another by preparative thin-film

909883/1681

Chromatography on silica gel, which was eluted with a 1: 4 vol. Mixture of ethyl acetate and petroleum ether (bp 60-80 ° C.), separated. The tape with the desired product was off ¹ separates, and the product was eluted with ether, evaporated after which the solvent. The residue was recrystallized from petroleum ether (Sdp.60-90 ⁰ C). This gave methyl α- (5-p-chlorohenyl-6-methoxypyrid-2-yl) propionate, m.p. 56-58 ° 0.

809883/1681 - 13 -

Claims (7)

Claims 1. Process for the preparation of esters of the general formula: IR ¹ V * ν wherein Het a) a thiazole or oxazole nucleus, in which the Group -CR ¹ R .COgR 'is in the 2-position, or b) a fyrimidine or pyridine nucleus, in which the group -CR ¹ R .CO ^ R * in the 2-, 4- or 6-position lies, represents, as well as pharmaceutically acceptable acid addition salts thereof, characterized in that a compound the general formula: C-H in which Het ' a) a thiazole or oxazole nucleus, in which the Group -CHR ¹ R ^{2 is} in the 2-position, or b) a fyrimidine or fyridine nucleus, in which the λ ο ■ Group -OHR R in the 2-, * - or 6-position lies, represents, to react with sodium or potassium or a 909883/1681 Hydride, amide or C ,. "-Alkoxide thereof and a carbonate of the formula: CO. (OR *)" is brought, where W represents a hydrogen atom or a methyl radical, Z represents a hydrogen atom or a methoxy radical, Y represents a phenyl radical, which optionally with a trifluoromethyl radical or can be substituted by one or two halogen atoms selected from fluorine, chlorine and bromine atoms, R represents a methyl or ethyl radical, R represents a hydrogen atom or a methyl radical and R * represents an alkyl radical with up to 4 carbon atoms, and where Y and the group -CR ¹ R .COgR ^ or -CHR ¹ R are bonded to non-adjacent carbon ring atoms of the core Het. 2. Process for the preparation of esters of the general formula I, wherein Het has a thiazole, Qxazole, lyrimidine or lyridine nucleus, in which the group -CR R .COgR * in the 2-position is, and of pharmaceutically acceptable acid addition salts thereof, characterized in that a Compound of the general formula II, wherein Het is a thiazole, Qxalol, lyrimidine or lyridine nucleus in which the group -CHR R is in the 2-position, is caused to react with sodium or potassium or a hydride, amide or C ^ »alkoxide thereof and a carbonate of the formula: 00. (OiP) ₂ , where W and Σ, respectively represent a hydrogen atom, T represents a phenyl, fluorophenyl, chlorophenyl or bromophenyl radical, R and R, which may be the same or different, each represent a methyl or ethyl radical and R represents a hydrogen atom or a methyl radical, and where Y and the group or -CHR ¹ H ² are bonded to non-adjacent carbon ring atoms of the core Het. 3. The method according to claim 1 or 2 for the preparation of methyl-α (4-p-chlorophenylpyrimid-2-yl) propionate, ethyl a »(5-chlorophenylpyrimid-2-yl) propionate, ethyl a- (i |.-P-chlorophenylpyrimid-2-yl) -a-methylbutyrate, Methyl a- (4-p-bromophenylthiazol-2-yl) isobutyrate or methyl a- (4-p-bromophenylthiarol-2-yl) propionate. 4. The method according to claim 1 or 2 for the preparation of methyl (5-p-chlorophenyloxazol-2-yl) isobutyrate or methyl-a- (5-p-chlorophenyl-e-methoxypyrid ^ -yl) propionate 5. The method according to any one of claims 1 to 4, characterized in that it is carried out in an excess of the carbonate used as the reactant. 6. The method according to any one of claims 1 to 5t, characterized in that it is carried out in the presence of an organic solvent which is an aromatic hydrocarbon. 7. A compound of the general formula I according to claim 1, characterized in that it is according to a method any one of claims 1 to 6 was produced. »8.-1H · η w '! Μ.-ΙΝβ S. Π * »« 90988 3/1 6 8 1