Benzhydryl ethers

The crude benzhydryl ether was a clear reddish oil. It was dissolved in 75 ml of 20% hydrochloric acid and the aqueous acid solution then washed three times with 50 ml portions each of ethyl ether. The aqueous acid solution was then decolorized with activated carbon and thereafter slowly admixed with 75 ml of 28% aqueous ammonia. The benzhydryl ether separated as an oily material and was removed from the aqueous mixture by extraction with three 50 ml portions of ethyl ether. 

On evaporation of the ethyl ether from the ethyl ether solution, the benzhydryl ether was recovered as a pale yellow oil. The benzhydryl ether was dissolved in 60 ml of isopropanol and the isopropanol solution acidified to a pH of 3 with dry hydrogen chloride-methanol solution. The acidic propanol solution was then diluted with ethyl ether until a faint turbidity was observed. In a short time, the crystalline hydrochloride salt of the benzhydryl ether separated from the propanol solution. The crystallized salt was recrystallized once from 75 ml of isopropanol with the aid of ethyl ether in order to further purify the material. A yield of the pure hydrochloride salt of 1-methylpiperidyl-4-benzhydryl ether of 24.5 grams was obtained. This was 39% of the theoretical yield. The pure material had a melting point of 206°C. 

Dimethylamino ethyl benzhydryl ether Dimenhyd rinate... 

Ethers are stable toward hydrolysis, yet are hydrolyzed under severe conditions of acidity and temperature. Furthermore, the presence of certain moieties can decrease the high stability of ethers. In the case of aminoalkyl benzhydryl ethers of the general structure (aryl)2CH-0-(CH2)n-NRR, the decrease in stability becomes marked enough to be of pharmaceutical and even pharmacological relevance. This structural motif is a component of various drugs, including some well-known antihistamines and anticholinergics, e.g., diphenhydramine, orphenadrine, and chlorphenoxamine. 

Fig. 11.2. Mechanism of proton-catalyzed, hydrolysis of aminoalkyl benzhydryl ethers 11.24, e.g., diphenhydramine (R = R = H), orphenadrine (R = 2-Me, R = H), and chlorphenoxamine...

A. M. de Roos, R. F. Rekker, W. T. Nauta, Investigation into the Stabihty of the Ether Bond in a Series of Benzhydryl Ethers. I. The Rate of Hydrolysis of Substituted Dimeth-ylaminoethylbenhydryl Ethers , Arzneim.-Forsch. 1963, 13, 534 - 537 A. M. de Roos, R. F. Rekker, W. T. Nauta, Investigation into the Stabihty of the Ether Bond in a Series of Benzhydryl Ethers. VI. The Rate of Hydrolysis in an Extended Series of Substituted 2-(Diphenylmethoxy)-V,A-Dimethylethylamines , Arzneim.-Forsch. 1971,21, 818 - 820. 

Thus, reaction of equimolar amounts of 2-phenyl-2,2"-spirobis(l,3,2-benzodioxaphosphole) (3a) 6) and benzhydrol under anhydrous conditions in boiling acetonitrile gave l-benzhy-drylacetamide (40%), bis(benzhydryl)ether (30%) and 2-phenyl-1,3, 2-benzodioxaphosphole (4) which was identified by spectroscopic comparison with an authentic sample prepared from phenylphosphonic dichloride and catechol (10). 

Equimolar quantities of benzhydrol and the phosphorane (3a) were also reacted in dimethyl sulphoxide solution. Apart from bis(benzhydryl) ether (18%) and catechol monobenzhydryl ether (39%), a small amount of benzophenone (17%) was obtained. It was shown that, in the absence of phosphorane, benzhydrol is not oxidised to benzophenone by dimethyl sulphoxide. Reaction similar to that outlined in Scheme 1 is a likely possibility. Again, the alcohol is activated by reaction with the phosphorane toward nucleophilic attack, in this case by dimethyl sulphoxide. Significantly, oxidation of alcohols by dimethyl sulphoxide is usually carried out using the Pfitzner-Moffatt reagent (dicyclohexyl carbodiimide and anhydrous phosphoric acid in dimethyl sulphoxide) (13) whereas the reaction using the phosphorane (3a) is carried out under neutral conditions. Unfortunately, however, attempts to improve the yield of benzophenone have hitherto failed. 

Benzhydryl ether Ph2Z(CH3)OCH2CH2N(C2H5)2 NH3C1 I C,Si 34... 

Because of the wide spectrum of activity shown by amines, definitive conclusions concerning structure-activity relationships cannot be made at this time. However, studies using single test systems reveal that the most active silylated amines contain the silicon atom in a y position relative to the nitrogen, as shown in partial structures 12 and 13 (55, 56). Some examples of compounds containing these groupings are found in Tables I and II. The silylated benzhydryl ethers (Section II,F) and sila-tranes (Section III,C) also contain this type of grouping. 

The benzhydryl ethers constitute a class of drugs that exhibit antihistamine activity and also find use in the treatment of tremors characteristic... 

Silylated benzhydryl ethers containing a quaternary nitrogen atom, such as 20, are reported to be anticholinergic agents of short duration (66). 

A mixture of 46 grams of l-methyl-4-piperidinol (0.4 mol), 49.4 grams of benzhydryl bromide (0.2 mol) and 100 ml of xylene was refluxed for approximately 24 hours. The reaction mixture separated into two phases with the upper phase containing the desired ether compound dissolved in xylene. The lower phase consisted of the hydrobromide salt of the excess l-methyl-4-piperidinol. The upper phase was separated from the lower phase and the desired benzhydryl ether recovered in the crude state by distilling off the xylene under reduced pressure. 

A mixture of 46 g of l-methyl-4-piperidinol (0.4 mol), 49.4 g of benzhydryl bromide (0.2 mol) and 100 ml of xylene was refluxed for approximately 24 hours. The reaction mixture separated into two phases with the upper phase containing the desired ether compound dissolved in xylene. The lower phase consisted of the hydro bromide salt of the excess l-methyl-4-piperidinol. The upper phase was separated from the lower phase and the desired benzhydryl ether recovered in the crude state by distilling off the xylene under reduced pressure. The crude benzhydryl ether was a clear reddish oil. It was dissolved in 75 ml of 20% hydrochloric acid and the aqueous acid solution then washed three times with 50 ml portions each of ethyl ether. The aqueous acid solution was then decolorized with activated carbon and thereafter slowly admixed with 75 ml of 28% aqueous ammonia. The benzhydryl ether separated as an oily material and was removed from the aqueous mixture by extraction with three 50 ml portions of ethylether. On evaporation of the ethyl ether from the ethyl ether solution, the benzhydryl ether was recovered as a pale yellow oil. The benzhydryl ether was dissolved in 60 ml of isopropanol and the isopropanol solution acidified to a PH of 3 with dry hydrogen chloride-methanol solution. The acidic propanol solution was then diluted with ethyl ether until a faint turbidity was observed. In a short time, the crystalline hydrochloride salt of the benzhydryl ether separated from the propanol solution. The crystallized salt was recrystallized once from 75 ml of isopropanol with the aid of ethyl ether in order to further purify the material. 

A yield 24.5 g of the pure hydrochloride salt l-methylpiperldyl-4-benzhydryl ether (diphenylpyraline) was obtained. This was 39% of the theoretical yield. The pure material had a melting point of 206°C. 

Besides the methods described above for the side-chain anchoring of Ser and Thr, the 3,4-dihydro-2//-pyran-2-functionalized-resin and handle 331 23,124] Table 3) allows the preparation of peptide alcohols by treatment with TEA in the presence of scavengers. Furthermore, the alkylation of Fmoc amino alcohols with a diphenyldiazomethane polymeric resin 34 gives rise to a benzhydryl ether, which can be cleaved with TFA/CH2CI2 (2 98) to give protected peptide alcohols. 

Lowe E, MacMillan R, Katser M. The antihistamine properties of Benadryl, beta-dimethyl-aminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946 86 229. 

Clemastine (SEDA-7,172) (SEDA-21,173) belongs to the benzhydryl ether group and was developed in the hope of lessening sedative effects. There was no significant difference compared with other first-generation antihistamines. 

In the absence of acid, diphenyldiazomethane, or DDM as it is conveniently abbreviated, decomposes unimolecularly with the loss of nitrogen, either on heating or on irradiation. In alcoholic solutions in the presence of oxygen the products of both thermal and photochemical decompositions have heen well established as the benzhydryl ether of the solvent, diphenylketazine, tetraphenylethane and benzophenone (Bethell et al., 1965 Kirmse, 1963 Bartlett and Traylor, 1962). All of these products can be visualized as coming from a diphenylcarbene intermediate. 

A more critical examination of scheme 5 and of the data for the DDM reaction suggests alternatives to the proposed paths to the products. Thus, the carbonium ion precursors of the benzhydryl ether might be formed not from dissociation of carbonium carboxylate ion pairs but by nitrogen loss from already dissociated diazonium ions. Whether or not... 

The proportion of ester (72) in the reaction products (benzhydryl ether and ester) was estimated for each reaction under a variety of conditions and some of the results are shown in Table 9. 

Harms, A. R, Nauta, W. T. The effects of alkyl substitution in drugs-1. Substituted dimethylaminoethyl benzhydryl ethers. J. Med. Pharm. Chem. 1960, 2, 57-77. 

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