Methods for preparing fuel additives

Abstract

A method for preparing a substituted fuel additive d is provided. The method comprises carrying out the following reaction: (a) (b) (d), The fuel additive d may be used as an octane-boosting additive in a fuel for a spark-ignition internal combustion engine. ##STR00001##

Claims

1. A method for preparing a fuel additive having the formula: ##STR00029## where: R.sub.1 is hydrogen; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.11 and R.sub.12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups; R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups; X is selected from —O— or —NR.sub.10—, where R.sub.10 is selected from hydrogen and alkyl groups; and n is 0 or 1, provided that at least one of R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.11 and R.sub.12 is selected from a group other than hydrogen, said method comprising carrying out the following reaction: ##STR00030## where: R.sub.13 is selected from hydrogen and alkyl groups; and each L is independently selected from leaving groups, or both L groups together form the group —O—C(O)—O—.

2. A method according to claim 1, wherein reagent b is selected from: ##STR00031##

3. A method according to claim 1, wherein reagent b is used in an amount of from 0.5 to 4 molar equivalents as compared to starting material a.

4. A method according to claim 1, wherein the reaction comprises the following sub-steps: ##STR00032##

5. A method according to claim 4, wherein step (i) is conducted in the presence of a solvent selected from tetrahydrofuran, acetonitrile, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethylene carbonate, sulfolane, diphenyl ether, acetonitrile, 2-nitropropane, acetone, butan-2-one, butylformate, ethyl acetate, isobutyronitrile, methylacetate, methyformate, nitromethane, oxolane and propionitrile and water.

6. A method according to claim 4, wherein step (i) is conducted at a temperature of greater than 15° C.

7. A method according to claim 4, wherein step (ii) is conducted in the presence of a hydrogen halide.

8. A method according to claim 7, wherein hydrogen halide is used in an amount of at least 5 molar equivalents as compared to intermediate c.

9. A method according to claim 7, wherein step (ii) is conducted at a temperature of greater than 60° C.

10. A method according to claim 4, wherein the reaction in step (ii) is carried out using a base, where the base is selected from: inorganic bases selected from alkali metal hydroxides, alkali metal carbonates and aqueous ammonia; and organic bases.

11. A method according to claim 4, wherein step (ii) is conducted in the presence of a trihydrocarbyl phosphone, and an azo compound.

12. A method according to claim 11, wherein step (ii) is conducted in the presence of an aprotic solvent selected from tetrahydrofuran, acetonitrile, dimethoxyethane and dioxane.

13. A method according to claim 1, wherein the reaction comprises the following sub-steps: ##STR00033##

14. A method according to claim 1, wherein R.sub.13 is selected from hydrogen, methyl, ethyl, propyl and butyl.

15. A method according to claim 1, wherein each L is independently selected from: halides, substituted aryloxy groups, sulfonates and —XH.

16. A method according to claim 1, wherein the method is a batch process in which the fuel additive is produced in a batch quantity of greater than 100 kg.

17. A method according to claim 1, wherein the method is a continuous process.

Description

EXAMPLES

Example 1

Preparation of Intermediate c Via Route (i)

(1) Intermediate c was prepared according to the following scheme:

(2) ##STR00025##

(3) A solution of 5-methyl-2-aminophenol 1 (10.0 g, 81 mmol) and ethylene oxide (2.5 to 3.3 M solution in THF, 25 ml, ˜72 mmol) was heated in an autoclave to 100° C. for 2 hours and cooled to ambient. The solvent was evaporated to dryness and the resulting solid recrystallised from ethyl acetate to give 4.4 g (32% yield) of 2 as an off white solid.

Example 2

Preparation of Octane-Boosting Fuel Additive d Via Route (ii)

(4) Fuel additive f was prepared from intermediate c according to the following scheme:

(5) ##STR00026##

(6) In a first experiment, the fuel additive was prepared using triphenylphosphine and diisopropyl azodicarboxylate, in the presence of a tetrahydrofuran solvent.

(7) The compound 2 (1.0 g, 6 mmol) and triphenylphosphine (6.2 mmol) were sonicated in THF (5 ml) for 2 minutes and then a solution of DIAD (6.2 mmol) in THF (5 ml) added over 2 minutes and sonication continued for approximately 30 minutes. The reaction mixture was diluted with approximately 30 ml of hexane and decanted away from a dark oil. The solvent was evaporated and purified by column chromatography using 20 to 40% ethyl acetate/hexane. Product fractions evaporated to give 0.4 g (45% yield) of 3 as a colourless oil (measured by LCMS).

(8) In a second experiment, the fuel additive was prepared using aqueous hydrogen bromide.

(9) A solution of 2-((2-hydroxyethyl)amino)-5-methylphenol 2 (6.7 g, 0.04 mol) in 35 mL of concentrated hydrobromic acid 62% (0.88 mol) was stirred and refluxed for 3 hours. The reaction mixture was basified with concentrated ammonium hydroxide 28% (50 mL) and water was evaporated in vacuo. The residue was treated with ethyl acetate (200 mL), the mixture was stirred for 1 hour and then filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated in vacuo to give 4.47 g (75% yield) of 3.

Example 3

Preparation of Intermediate c′ Via Route (i′)

(10) ##STR00027##

(11) A solution of 2-amino-5-methylphenol 1 (500.0 g, 4.06 mol) and ethylene carbonate (554 g, 6.29 mol) in DMF (5 L) was treated with potassium carbonate (2244 g, 16.24 mol) and heated to 145° C. for 1 h. Once cooled to room temperature, DMF was removed under reduced pressure. The resulting residue was then partitioned between ethyl acetate (5 L) and water (4 L). The separated organic phase was washed with water (4 L) and brine (2 L) and concentrated. A further 500 g and 3×250 g of 2-amino-5-methylphenol 1 were processed to give crude product 2 (2051 g) as a dark brown oil. The crude product was purified by adding tent-butyl methyl ether (10 L) and stirred on a rotary evaporator for 20 mins. The resulting solid was collected by vacuum filtration, washed with test-butyl methyl ether (500 ml) and vacuum dried to give product 2 (596 g) as a brown solid, with a purity of 99.82% as measured by UPLC-MS (run time: 1.40 mins; solvents B) acetonitrile C) 10 mM NH.sub.4HCO.sub.3 at pH 10; gradient: 2-98% B with C in 1.2 mins, hold at 98% B 2% C to 1.40 min; flow rate of 0.8 ml/min at 40° C.).

(12) The filtrate was diluted with tent-butyl methyl ether (5 L), washed with water (4.5 L), dried over sodium sulphate and concentrated. The residue (1069 g) was triturated with tert-butyl methyl ether (3 L) to give a dark brown solid (232 g). The solid was further purified by recrystallisation from isopropanol (300 ml) to give a second crop of product 2 (117.5 g) as a tan solid. The filtrate from the tent-butyl methyl ether trituration was purified by concentrating to dryness (793 g) and passed through a plug of silica eluting with ethyl acetate to give 767 g of crude product 2. It was then recrystallised from ethyl acetate (500 ml) to give a third crop of product 2 (126.5 g) as a tan solid. The total amount of product 2 obtained was 840 g (35% yield).

Example 4

Preparation of Octane-Boosting Fuel Additive d Via Route (ii′)

(13) ##STR00028##

(14) Cyclisation reactions in the presence of a metal catalyst but in the absence of a base, hydrogen or other reaction components were carried out under a variety of conditions. As a general procedure, a mixture of compound 2′ and the catalyst were heated, optionally in the presence of a solvent, to the specified temperature. Heating was continued, before cooling to room temperature and sampling for UPLC analysis.

(15) The yields of compound 3′ under different conditions are shown in the following table:

(16) TABLE-US-00001 Catalyst Solvent Temp (° C.) Time (hours) Yield RuCl.sub.2(PPh.sub.3).sub.3 none 145 3 52%  (1.6 mol %) RuCl.sub.2(PPh.sub.3).sub.3 NMP 105 3.5 3% (2.2 mol %) 120 2 5% RuCl.sub.2(PPh.sub.3).sub.3 toluene 105 3.5 4% (1.7 mol %) 120 2 5%

(17) Further experiments were carried out. As a general procedure, a mixture of compound 2′, Raney Ni (50% in water) and mesitylene was heated. The crude reaction mixture was analysed by HPLC to determine conversion and selectivity

(18) The yields of compound 3′ obtained under different conditions are shown in the following table:

(19) TABLE-US-00002 Solvent Catalyst Temp Time volume (eq) amount (eq) (° C.) (h) Yield None 0.6 150 16.5 76% >21 84% 16 0.2 167 4 11% 1.6 0.6 150 21 80% 3.2 0.8 150 21 83% 3.2 0.6 150 21 88% 1.1 0.4 140 16.5 73% 40 78% 2.3 0.4 140 16.5 59% 40 77% 1.1 0.2 140 16.5 49% 40 70% 2.3 0.2 140 16.5 67% 40 63% 2.4 0.4 140 67 90% 91 91% 2.4 0.2 140 67 86% 91 86% 3.4 0.2 140 67 88% 91 78% 2.4 0.2 140 67 90% 91 90% 3.4 0.2 140 67 88% 91 87% 2.5 0.2 140 69 84% 93 86% 1.5 0.2 140 69 81% 93 83% 3.5 0.2 140 69 78% 93 81% 2.5 0.2 125 69 56% 93 63% 2.5 0.3 150 5.5 80% 21.5 91% 26.5 91% 2.5 0.3 150 5.5 75% 21.5 94% 26.5 95%

(20) Further experiments were carried out in the presence of a metal catalyst and hydrogen gas. As a general procedure, catalyst was added to an argon flushed stainless steel autoclave (300 mL). To this was added material 2′ (0.33 g, 2.0 mmol) followed by mesitylene (10 mL). The autoclave was sealed, charged to 7 bar with hydrogen and heated to 170° C., except in the cases of Experiments xxxii, xxxiii and xxxiv where the temperature was raised to 210° C. The reaction was held at this temperature for 20 hours, before cooling to room temperature and sampling for UPLC (MeCN) analysis.

(21) The yields of compound 3′ obtained under different conditions are shown in the following table:

(22) TABLE-US-00003 Entry Catalyst (amount) Yield i Raney Ni 53% (slurry in water) ii Ni(65% wp/Al.sub.2O.sub.3/SiO.sub.2 72% (10 mol %) iii Pd/C  5% (5 wt %) iv Pt/C  6% (5 wt %) v Ru/C 55% (5 wt %) vi Pd/Al.sub.2O.sub.3  9% (5 wt %) vii Ru(5% wt)/C 80% (5 wt %) viii Pt/C  9% (5 wt %) ix Pt/C 30% (5 wt %) x Raney Ni 75% (5 wt %) xi Raney Ni 54% (5 wt %) xii Ni(65% wt/Al.sub.2O.sub.3/SiO.sub.2 52% (5 wt %) xiii Ni(65 wt %)/Al.sub.2O.sub.3/SiO.sub.2 72% (10 mol %) xiv Ir(5% wt)/C 44% (5 wt %) xv Rh(5% wt)/C 11% (5 wt %) xvi Raney Co 64% (5 wt %) xvii Pt(5% wt)/Al.sub.2O.sub.3 14% (5 wt %) xviii Pt/Fe/C 43% (5 wt %) xix Pt/C/Cu(1% wt) 51% (5 wt %) xx Raney Cu  2% (5 wt %) xxi Rh(5 wt %)/Al.sub.2O.sub.3  8% (5 wt %) xxii Pd(5 wt %)/Al.sub.2O.sub.3 17% (5 wt %) xxiii Pd(5 wt %)/Lindlars 59% (5 wt %) xxiv Pt(5 wt %)/Al.sub.2O.sub.3 31% (5 wt %) xxv Pt/C(5 wt %) 14% (5 wt %) xxvi Pt(5 wt %)/SiO.sub.2 20% (5 wt %) xxvii CuO/ZnO(50 wt %)  5% (5 wt %) xxviii CuO(50 wt %)/Al.sub.2O.sub.3/MnO 12% (5 wt %) xxix Ru(5 wt %)/Al.sub.2O.sub.3 26% (5 wt %) xxx Pd/C(5 wt %)/ZnO 62% (5 wt %) xxxi Pt/CN(5 wt %) 18% (5 wt %) xxxii CuO/ZnO(50 wt %) 19% (5 wt %) xxxiii CuO(50 wt %)/Al.sub.2O.sub.3/MnO 17% (5 wt %) xxxiv Cu.sub.2Cr.sub.2O.sub.5  6% (5 wt %)

(23) The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “40 mm” is intended to mean “about 40 mm.”

(24) Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

(25) While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope and spirit of this invention.