| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 24, 1977 |
| PATENT TITLE |
Dehydrohalogenation of a 7-halodihydrocodeinone dialkyl ketal |
| PATENT ABSTRACT | A process for the dehydrohalogenation of a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): ##STR1## in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine which comprises subjecting the ketal to the action of a base in the presence of a polar aprotic solvent. The process has utility in facilitating the production of codeine |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 28, 1975 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Fieser et al, Reagents for Organic Synthesis, John Wiley & Sons, Inc., N. Y. (1967) pp. 279-281, 298-299. Rapoport et al., J. Am. Chem. Soc., 89,(8) pp. 1942-1947 (1967). |
| PATENT CLAIMS |
We claim: 1. A process for the dehydrohalogenation of a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): ##STR3## in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine which comprises subjecting the ketal to the action of an alkali metal hydroxide in the presence of a polar aprotic solvent which is not a proton donor and which has a dielectric constant .epsilon. > 15. 2. A process as claimed in claim 1 in which the base is sodium or potassium hydroxide. 3. A process as claimed in claim 1 in which the solvent is a lower dialkyl sulphoxide. 4. A process as claimed in claim 6 in which the dialkylsulphoxide is dimethylsulphoxide. 5. A process as claimed in claim 1 in which the solvent is a di(lower alkyl)formamide, a di(lower alkyl)acetamide, an alkyl phosphoramide, a glycol ether or polyglycol ether or a sulphone. 6. A process as claimed in claim 1 in which the dialkyl ketal is a dimethyl ketal. 7. A process as claimed in claim 1 in which X is hydrogen or bromine. 8. A process as claimed in claim 1 in which an alkali metal hydroxide is used as base, the solvent is dimethylsulphoxide and the reaction is carried out in the presence of up to 20% of water (v/v). 9. A process as claimed in claim 11 in which a molar ratio of alkali metal hydroxide to halo ketal of from 1.5:1 to 10:1 is used. 10. A process as claimed in claim 1 in which the reaction is effected at a temperature within the range of room temperature to the reflux temperature of the solvent. 11. A process for the dehydrobromination of 1:7-dibromodihydrocodeinone dimethyl ketal or 7-bromodihydrocodeinone dimethyl ketal, in which said ketal is contacted with an alkali metal hydroxide and dimethyl sulphoxide in the presence of up to 20% water (v/v) based on the dimethyl sulphoxide, the molar ratio of alkali metal hydroxide to dimethyl sulphoxide being from 1.5:1 to 10:1 at an elevated temperature. 12. A process as claimed in claim 11 in which a temperature within the range of 70.degree. to 120.degree. C. is used. 13. In a process for the preparation of codeine from dihydrothebaine by the steps of: (a) preparing a 7-halo- or 1,7-dihalodihydrocodeinone dialkyl ketal as defined in claim 1; (b) dehydrohalogenating said 7-halo- or 1,7-dihalodihydrocodeinone to produce the corresponding codeinone ketal; (c) hydrolysing said codeinone ketal or 1-halocodeinone ketal from step (b); (d) reducing the codeinone or 1-halocodeinone from step (c); and (e) recovering codeine, the improvement which consists of carrying out step (b) by dehydrohalogenating a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): ##STR4## in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine by subjecting the ketal to the action of an alkali metal hydroxide in the presence of a polar aprotic solvent which is not a proton donor and which has a dielectric constant .epsilon. > 15. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
This invention relates to a novel process for the dehydrohalogenation of certain .alpha.-halo ketals some of which are known intermediates in the synthesis of codeine from thebaine. It is known to prepare 7-bromodihydrocodeinone dimethyl ketal, by treating dihydrothebaine with N-bromoacetamide in methyl alcohol (Rapoport et al J. Amer. Chem. Soc., 1956, 78, 5128; 1967, 89, 1942-47). This .alpha.-bromoketal can be dehydrobrominated to the corresponding .alpha.:.beta. unsaturated compound, codeinone dimethyl ketal, which on treatment with diluted acetic acid yields codeinone. Codeinone itself is easily reduced to the important analgesic and anti-tussive codeine with a reducing agent, such as sodium borohydride, and it therefore follows that in the attempt to develop a commercially feasible synthetic route to codeine, particularly one which starts from the related opium alkaloid thebaine, the dehydrohalogenation of 7-halodihydrocodeinone dimethyl ketal may well prove to be a key step. The procedure for dehydrobromination described in the above reference comprises refluxing the .alpha.-bromo ketal with potassium tertiary amylate (2-methylbutan-2-oxide) in tertiary amyl alcohol (2-methyl butan-2-ol). This method suffers from certain disadvantages from the commercial point of view, in particular the slowness of the reaction which requires 24 hours to go to completion. Another factor which has to be considered is that the preparation of potassium tertiary amylate involves the use of metallic potassium which is expensive and which, on account of its highly reactive character, is a potentially dangerous substance to handle. We have found that the use of polar aprotic solvents such as dialkylsulphoxides e.g. dimethyl sulphoxide (DMSO), dialkylformamides, e.g. dimethylformamide (DMF), and cyclic amides, e.g. N-methyl pyrrolidone, dialkylacetamides, e.g. dimethylacetamide (DMA), alkyl phosphoramides e.g. hexamethylphosphoramide, ethers of glycol and polyglycols, such as diglyme (diethyleneglycol dimethyl ether) and sulphones such as sulpholane (tetrahydrothiophene-1,1-dioxide) as solvents for the base catalysed dehydrobromination described above leads to certain advantages. The term "polar aprotic solvent" means a solvent which is not a proton donor and which preferably has a dielectric constant .epsilon.>15. Thus with potassium tertiary butoxide as base and DMSO as solvent the reaction proceeds rapidly at room temperature and is complete in about one-half hour, whereas with the same base in boiling tertiary butyl alcohol as solvent the reaction proceeds only to a very small extent (less than 10%) in 24 hours. Furthermore, with DMSO as solvent it is not essential to use potassium tertiary butoxide or potassium tertiary pentoxide for the dehydrobromination and excellent yields of codeinone dimethyl ketal are also obtained using other bases such as alkali metal hydroxides, alkali metal hydrides and alkoxides other than those mentioned above. We have also found that when using an alkali metal hydroxide, the addition of a small amount of water, e.g. up to 20% and particularly 1 to 20% (v/v) is advantageous regard being taken of the fact that some of the solvents specified may be subject to hydrolysis. It has also been found that the use of DMSO as solvent is similarly effective in promoting the dehydrobromination of 1:7-dibromodihydrocodeinone dimethyl ketal to 1-bromocodeinone dimethyl ketal. The latter can be hydrolysed with dilute acid to 1-bromocodeinone, reduction of which with lithium aluminium hydride yields codeine. The invention therefore provides a process for the dehydrohalogenation of a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): ##STR2## in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine which comprises subjecting the ketal to the action of a base in the presence of a polar aprotic solvent. The particularly preferred bases for the reaction according to the invention include alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal hydrides, such as sodium hydride, or alkali metal amides, such as sodamide, or sodium piperidide or alkali metal alkoxides containing 1 to 6 carbon atoms in particular sodium methoxide or ethoxide. Potassium alkoxides may also be used instead of sodium alkoxides, such as methoxide, ethoxide, butoxide or pentoxide, but these latter bases are less preferred, since the preparation of these reagents involves the use of metallic potassium, which is expensive and potentially dangerous to handle as mentioned above. Particularly, in the preparation of the lower alkoxides using potassium and lower alcohols, a very violent reaction may occur. The preferred polar aprotic solvent is a dialkyl sulphoxide, preferably a lower dialkyl sulphoxide, in particular dimethyl sulphoxide. Other suitable polar aprotic solvents include those specified above. Preferably the reaction is carried out under substantially anhydrous conditions or when the base is an alkali metal hydroxide the addition of a small amount of water, e.g. up to 20% (v/v) may be advantageous. In the above general formula I it is preferred that R represents methyl. It is also preferred that X represents hydrogen or bromine. The ketals in which X is hydrogen, Y is chlorine and R is an alkyl group containing 1 to 6 carbon atoms are novel and the invention includes such ketals as novel compounds. A preferred novel ketal of this type is described in Example 18, namely 7-chlorodihydrocodeinone dimethyl ketal. According to a preferred feature of the invention, therefore, there is provided a process for the dehydrobromination of 7-bromodihydrocodeinone dimethyl ketal or 1,7-dibromodihydrocodeinone dimethyl ketal which comprises treating said ketal with sodium or potassium hydroxide in the presence of dimethyl sulphoxide as solvent and under anhydrous conditions, or in the presence of a limited amount of water, e.g. up to 20% v/v based on the dimethyl sulphoxide, at a temperature from room temperature to reflux temperature of the solvent and isolating the dehydrobrominated product therefrom. Preferably a temperature of from 70.degree. to 120.degree. C. is used when an alkali metal hydroxide is utilized as base. In carrying out the process of the invention any convenient amount of base may be used but normally a molar excess based on the halo ketal is preferably utilized. In the case of sodium hydride which acts as a very strong base in solvents such as DMSO an excess is, however, preferably to be avoided since this may lead to side reactions. When utilizing an alkali metal hydroxide an excess of hydroxide based on the compound undergoing dehydrohalogenation is preferably used. Thus, the molar ratio of hydroxide to the halo ketal is preferably greater than 1:1 more particularly 1.5:1 to 10:1, and more particularly 1.5:1 to 4:1. The invention also provides in a process for the production of codeine from 7-bromodihydrocodeinone dimethyl ketal or 1:7-dibromodihydrocodeinone dimethyl ketal the step of dehydrobrominating said ketal by the method herein described. It is surprising that the dehydrobromination or dihydrochlorination of the halo ketal takes place with an alkali metal hydroxide and a small amount of water since under the conditions other reactions such as substitution would be expected to take place. In the production of codeine from dihydrothebaine utilizing the method of the invention there is no necessity to isolate the various intermediates and the process can be operated without such isolation. In particular this is the case using DMSO as solvent, an alkali metal hydroxide as base and utilizing a small amount of water as indicated. Although the process has in particular been described with relation to dehydrobromination it may also be used for dehydrochlorination. The ketals used as starting materials may be prepared by the methods generally indicated in Examples 16-18. |
| PATENT EXAMPLES | Available on request |
| PATENT PHOTOCOPY | Available on request |
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