AU633171B2 - Process - Google Patents
ProcessInfo
- Publication number
- AU633171B2 AU633171B2 AU68939/91A AU6893991A AU633171B2 AU 633171 B2 AU633171 B2 AU 633171B2 AU 68939/91 A AU68939/91 A AU 68939/91A AU 6893991 A AU6893991 A AU 6893991A AU 633171 B2 AU633171 B2 AU 633171B2
- Authority
- AU
- Australia
- Prior art keywords
- methyl methacrylate
- reaction
- reaction mixture
- methacrylate
- stabiliser
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
- C07C69/653—Acrylic acid esters; Methacrylic acid esters; Haloacrylic acid esters; Halomethacrylic acid esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Glass Compositions (AREA)
- Iron Core Of Rotating Electric Machines (AREA)
Description
PROCESS
The present invention relates to a process for preparing haloal yl methacrylate monomers which are useful in the preparation of certain polymers, in particular, which are useful in therapy in the lowering of serum cholesterol levels.
Haloalkyl methacrylate monomers can be prepared by processes known in the art, for example chloro or bromoalkyl methacrylates can be prepared by reaction of the corresponding chloro or bromoalkanol and methacrylic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in a suitable solvent such as pyridine, or by reaction of the corresponding chloro or bromo alkanol with methacryloyl chloride in the presence of a base in a suitable solvent - suitable combinations of bases and solvents include, for example, sodium bicarbonate in petroleum spirit as a solvent, and pyridine as a base in toluene as a solvent (cf. method described in Polymer, (1987), 28., 325-331, and Br. Polymer Journal (1984) 16, 39-45) .
However, these methods are not without problems, for example it has been found that reaction of methacrylic anhydride with, for example, 11-bromoundecanol in pyridine in the presence of DMAP, gives the required product and unreacted methacrylic anhydride both of which are difficult to separate from the product mixture. In addition reaction of methacryloyl chloride with, for example, 11-bromoundecanol using sodium bicarbonate as the base gives a reaction product comprising residual ll-bromoundecanol, unreacted methacryloyl chloride and an additional byproduct formed from the addition of hydrogen chloride across the double bond of the desired product,
11-bromoundecyl methacrylate. Such a mixture is again difficult to separate and the reaction inefficient. When preparing synthetic intermediates on an industrial scale, yields are of course critical and, in view of the foregoing inefficiency and difficulties with the prior art methods, there is clearly a need for new methods for the preparation of haloalkyl methacrylate monomers which proceed in high yields without producing undesirable mixtures of reaction products/unreacted starting materials.
The present invention therefore provides, in a first aspect, a process for preparing a compound of structure (I):
in which R is C-j^ lkyl, n is l to 20, and X is halogen, which comprises transesterification of a C1_4alkyl methacrylate, with a haloalkanol of structure HO(CH2)nX in which n and X are as described for structure (I) , in the presence of a titanium tetraC-j^alkoxide or a dialkyltin oxide catalyst, and a stabiliser.
Preferably, the reaction can be used to prepare bromoalkyl methacrylates, i.e. compounds of structure (I) in which R is methyl and X is bromo. Such compounds serve as intermediates in the preparation of the methacrylate polymers described in EP-A-373852 which themselves are useful in therapy as bile acid seguestrants for the treatment of hypercholesterolaemia.
A particular intermediate preparable by the presently claimed process is 11-bromoundecyl methacrylate ((I), R=methyl, n=ll, X=Br) .
The finding that the present process is effective is surprising since it has been found that a range of catalysts known in the art to be useful in transesterification reactions, e.g. zinc chloride, sodium ethoxide, 4-dimethylaminopyridine and p-toluenesulphonic acid, are not effective in reactions of this type.
However, the transesterification of for example methyl methacrylate with ll-bromoundecanol can be successfully carried out, in high yield, using a titanium tetraC1_4alkoxide or a dialkyltin oxide catalyst in the presence of a suitable stabiliser.
Particular titanium catalysts include titanium tetra ethoxide and titanium tetraisopropoxide.
Particular dialkyltin oxide catalysts include, for example, di-n-butyltin oxide, dimethyltin oxide and dioctyltin oxide. Other dialkyltin oxides can be prepared by standard techniques from the corresponding dialkyltin halides which are commercially available such as diethyltin dibromide, dicyclohexyltin dibromide or dibenzyltin dichloride.
Particular stabilisers include 2,6-di-t-butyl-4- ethylphenol (BHT) , butylated hydroxyanisole (BHA) , t-butylhydroxyquinone (TBHQ) and phenothiazine.
Preferably, titanium tetraisopropoxide in the presence of BHT or di-n-butyltin oxide in the presence of BHT is used to carry out the reaction.
Examples ;
(i) Preparation of 11-bromoundeσanol
11-Bromoundecanol can be prepared using either of the following methods :
(a) Sodium Borohydride (28.8 g, 0.76 mole) was dissolved in diglyme (700 ml) and THF (300 ml) and the solution cooled to 20° (dissolution of the NaBH4 is slightly exothermic). BF3OEt2 (145 g, 1.02 mole) was then added dropwise, with external cooling, at such a rate to keep the temperature of the mixture below 15°. After the addition was complete the mixture was stirred for 0.5 hour at 10°. This reducing agent was then added slowly to a solution of 11-bromoundecanoic acid (200 g, 0.76 mole) in THF (400 ml) keeping the temperature below 20°. After the addition was complete, the reaction was stirred at room temperature for 1.5 hours then quenched by pouring onto water (3 L) and concentrated HCl (100 ml) . The quenched mixture was stirred for 0.5 hour at room temperature then cooled to 5°. The crystalline product was filtered off, washed with water (3 x 1 L) and dried under vacuum to give 11-bromoundecanol (189.2 g, 99.2%).
(b) Sodium Borohydride (16.32 g, 0.43 mole) was dissolved in diglyme (350 ml) . To this was added a solution of aluminium trichloride (19.2 g, 0.14 mole) in diglyme (250 ml) maintaining the temperature below 20°. After the addition was complete, the mixture was stirred for 0.5 hour at room temperature. The reducing agent was then added dropwise to a solution of methyl 11-bromoundecanoate* (120 g, 0.43 mole) in diglyme (200 ml) maintaining the temperature at 10°. After the addition was complete the reaction was stirred at 20° for 3 hours and
then quenched by pouring onto water (2 L) and concentrated HCl (100 ml) . The quenched mixture was stirred for 1 hour then cooled to 15°. The product was filtered off, washed with water (2 x 500 ml) and dried under vacuum to give ll-bromoundecanol (106.8 g, 98.9%).
* This methyl ester can be produced in quantitative yield by esterifying 11-bromoundecanoic acid with MeOH/H2S04
(ii) Preparation of 11-Chloroundecanol
The procedure used follows the method reported by I. Bidd and M.C. Whiting, Tetrahedron Letters (1984), 25, 5949.
1,2-Dichloroethane (750 ml), ll-bromoundecanol (30g, 0.12 ol) , and tetrabutylammonium bromide (3.32g, 0.01 mol) were mixed and heated to reflux. After 24 hours at reflux the solvent was removed under reduced pressure, and the residue treated with n-hexane (600ml) . The resultant cloudy mixture was washed with water (2x150ml) , and the organic solution dried (MgS04) and filtered. The filter cake was washed with petroleum ether (100ml) and the combined filtrates concentrated under reduced pressure. The product, 11-chloroundecanol crystallised from the solvent and was dried to give 24g (97% yield) of a cream coloured solid.
Example 1
Preparation of 11-bromoundecylmethacrylate
(a) Usinσ titanium tetraisopropoxide as catalyst/BHT as stabiliser
Methyl methacrylate (1.15 L, stabilised with 50 ppm
of BHT), ll-bromoundecanol (200 g, 0.8 mole) and titanium tetraisopropoxide (11.4 g, 0.04 mole) were mixed together. A constant slow stream of dry air was bubbled through the reaction mixture during the reaction. The reaction mixture was heated under gentle reflux for 1 hour (internal temperature 90°). After this reflux period the methyl methacrylate/methanol azeotrope was removed under atmospheric distillation. During this time the internal temperature rose to 104° and the temperature at the still head rose from 65° to 101° (a total of 550 ml of distillate was collected) . The reaction mixture was cooled to 40° and quenched with water (1.5 ml, 2 equiv. based on titanium tetraisopropoxide) . The resulting mixture was then stirred for 3 hours and treated with celite (20 g) . After stirring for a further 10 minutes the reaction mixture was filtered through a pad of celite. The filter pad was washed with methyl methacrylate (50 ml) . The filtrate and wash were combined and distilled under vacuum (4-10 mmHg) at room temperature, then at 50-60° to remove last traces of methyl methacrylate. During distillation a slow stream of dry air was bubbled through the residue in the distillation vessel. The product, 11-bromoundecyl methacrylate (233 g, 91% yield) was obtained as a pale yellow oil.
(b) Using titanium tetraisopropoxide as catalyst BHA as stabiliser
Methyl methacrylate (100ml, stabilised with 50 pp of BHA) and ll-bromoundecanol (16.7g, 0.066 mol) were mixed and methyl methacrylate distilled out until the temperature at the still head reached 100°C. To the cooled solution was added titanium tetraisopropoxide (0.95g, 0.003 mol). A constant stream of dry air was
bubbled through the reaction mixture during the reaction. The reaction mixture was heated under gentle reflux for 1 hour and then the methyl methacrylate/ methanol azeotrope removed under atmospheric distillation. During this time the internal temperature rose to 104°C and the temperature at the still head from 65 to 101°C. The reaction mixture was then cooled to 50°C and treated with wet celite. After 15 minutes the reaction mixture was filtered through wet celite (1.7g of a 1:1 mixture of celite:water) , and the filter cake washed with methyl methacrylate (25ml) . The filtrate and wash were combined and distilled under vacuum (4-lOmmHg) at room temperature, then at 50-60°C to remove last traces of methyl methacrylate. During distillation a slow stream of dry air was bubbled through the residue in the distillation vessel. The product, 11-bromoundecyl methacrylate (17.3g, 82% yield) was obtained as a pale yellow oil.
(c) Using titanium tetraisopropoxide as catalyst/TBHQ as stabiliser
Methyl methacrylate (100ml, stabilised with 50 ppm of TBHQ) and ll-bromoundecanol (16.7g, 0.066 mol) were mixed and methyl methacrylate distilled out until the temperature at the still head reached 100°C. To the cooled solution was added titanium tetraisopropoxide (0.95g, 0.003 mol). A constant stream of dry air was bubbled through the reaction mixture during the reaction. The reaction mixture was heated under gentle reflux for 1 hour and then the methyl methacrylate/methanol azeotrope was removed under atmospheric distillation. During this time the internal temperature rose to 104°C and the temperature at the still head from 65 to 101°C. The reaction mixture was then cooled to 50°C and treated with wet celite (1.7g of a 1:1 mixture of celite:water) .
After 15 minutes the reaction mixture was filtered through wet celite (1.7g) , and the filter cake washed with methyl methacrylate (25ml) . The filtrate and wash were combined and distilled under vacuum (4-lOmmHg) at room temperature, then at 50-60°C to remove last traces of methyl methacrylate. During distillation a slow stream of dry air was bubbled through the residue in the distillation vessel. The product, 11-bromoundecyl methacrylate (17.5g, 82% yield) was obtained as a pale yellow oil.
(d) Using di-n-butyltin oxide as catalyst
Methyl methacrylate (1.15L, stabilised with 50ppm of BHT), ll-bromoundecanol (200g, 0.8 mol), and di-n-butyltin oxide (lOg, 0.04 mol) were mixed together. A slow stream of dry air was bubbled through the reaction mixture during the reaction. The reaction mixture was heated under gentle reflux for 1 hour and then the methyl methacrylate/methanol azeotrope removed under atmospheric distillation. During this time the internal temperature rose to 105°C (a total of 500ml of distillate was collected) . The reaction mixture was cooled to room temperature and quenched with water (0.72 ml, 1 equiv based on di-n-butyltin oxide) . The reaction mixture was distilled under vacuum (4-10 mmHg) at room temperature, then at 50-60°C to remove last traces of methyl methacrylate. During distillation a slow stream of dry air was bubbled through the residue in the distillation vessel. The crude product, 11-bromoundecyl methacrylate (230g) was obtained as a viscous oil.
Example 2 Preparation of ll-chloroundecyl methacrylate
Methyl methacrylate (1.14L, stabilised with 50 ppm of BHT), 11-chloroundecanol (210g, 1.02 mol), and titanium tetraisopropoxide (14g, 0.05 mol) were mixed together. A constant stream of dry air was bubbled through the reaction mixture during the reaction. The reaction mixture was heated under gentle reflux for 1 hour and then the methyl methacrylate/methanol azeotrope removed under atmospheric distillation. During this time the internal temperature rose to 104°C and the temperature at the still head to 100°C (a total of 550 ml of distillate was collected) . The reaction mixture was then cooled to 40°C and quenched with water (3.2 ml, 3.6 equiv. based on titanium tetraisopropoxide) . The resulting mixture was then stirred for 3 hours and treated with celite (32g) . After stirring for a further 15 minutes the reaction mixture was filtered through a pad of celite. The filter pad was washed with methyl methacrylate (160 ml) . The filtrate and wash were combined and distilled under vacuum (4-10 mmHg) at room temperature, then at 50-55°C to remove last traces of methyl methacrylate. During distillation a slow stream of dry air was bubbled through the residue in the distillation vessel. The product ll-chloroundecyl methacrylate (260.5g, 93% yield) was obtained as a pale yellow oil.
Claims (6)
1. A process for preparing a compound of structure (I):
in which R is C-j^alkyl, n is 1 to 20, and X is halogen, which comprises transesterification of a C-j^alkyl methacrylate, with a haloalkanol of structure H0(CH )nX in which n and X are as described for structure (I) , in the presence of a titanium tetraC1_4alkoxide or a dialkyltin oxide catalyst, and a stabiliser.
2. A process according to claim 1 in which the stabiliser is selected from 2,6-di-t-butyl-4-methylphenol (BHT) , butylated hydroxyanisole (BHA) and t-butylhydroxy- quinone (TBHQ) .
3. A process according to claim 2 in which in structure (I) , R is methyl, n is 11 and X is bromo or chloro.
4. A process according to claim 2 in which in structure (I) R is methyl, n is 11 and X is bromo.
5. A process according to claim 4 in which the catalyst is titanium tetraisopropoxide, and the stabiliser is 2,6-di-t-butyl-4-methylphenol (BHT) .
6. A process according to claim 4 in which the catalyst is di-n-butyltin oxide and the stabiliser is 2,6-di-t-butyl-4-methylphenol (BHT) .
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44901389A | 1989-12-11 | 1989-12-11 | |
US449013 | 1999-11-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU6893991A AU6893991A (en) | 1991-07-18 |
AU633171B2 true AU633171B2 (en) | 1993-01-21 |
Family
ID=23782518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU68939/91A Ceased AU633171B2 (en) | 1989-12-11 | 1990-12-10 | Process |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0505406A1 (en) |
JP (1) | JPH05502666A (en) |
KR (1) | KR927003505A (en) |
AU (1) | AU633171B2 (en) |
CA (1) | CA2073007A1 (en) |
IE (1) | IE904440A1 (en) |
NZ (1) | NZ236409A (en) |
PT (1) | PT96146A (en) |
WO (1) | WO1991009005A1 (en) |
ZA (1) | ZA909888B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2707291B1 (en) * | 1993-07-06 | 1995-09-01 | Atochem Elf Sa | Process for the preparation of an ester of an unsaturated carboxylic acid by a reaction catalyzed by an organic tin compound. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US368268A (en) * | 1887-08-16 | Shingle beveling machine |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3686268A (en) * | 1970-02-24 | 1972-08-22 | Ugine Kuhlmann | Process of manufacture of acrylic and methacrylic higher esters |
SU789508A1 (en) * | 1974-12-30 | 1980-12-23 | Предприятие П/Я В-8585 | Method of producing beta-chloro- or beta-bromoethylmethacrylate |
JPS63196544A (en) * | 1987-02-10 | 1988-08-15 | Osaka Yuki Kagaku Kogyo Kk | Production of fluorinated alkyl (meth)acrylates |
-
1990
- 1990-12-10 ZA ZA909888A patent/ZA909888B/en unknown
- 1990-12-10 KR KR1019920701211A patent/KR927003505A/en not_active Application Discontinuation
- 1990-12-10 CA CA002073007A patent/CA2073007A1/en not_active Abandoned
- 1990-12-10 PT PT96146A patent/PT96146A/en not_active Application Discontinuation
- 1990-12-10 WO PCT/GB1990/001922 patent/WO1991009005A1/en not_active Application Discontinuation
- 1990-12-10 EP EP91900279A patent/EP0505406A1/en not_active Ceased
- 1990-12-10 IE IE444090A patent/IE904440A1/en unknown
- 1990-12-10 AU AU68939/91A patent/AU633171B2/en not_active Ceased
- 1990-12-10 NZ NZ236409A patent/NZ236409A/en unknown
- 1990-12-10 JP JP3500991A patent/JPH05502666A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US368268A (en) * | 1887-08-16 | Shingle beveling machine |
Also Published As
Publication number | Publication date |
---|---|
CA2073007A1 (en) | 1991-06-12 |
EP0505406A1 (en) | 1992-09-30 |
KR927003505A (en) | 1992-12-18 |
AU6893991A (en) | 1991-07-18 |
IE904440A1 (en) | 1991-06-19 |
JPH05502666A (en) | 1993-05-13 |
ZA909888B (en) | 1992-07-29 |
WO1991009005A1 (en) | 1991-06-27 |
PT96146A (en) | 1991-09-30 |
NZ236409A (en) | 1992-04-28 |
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