Methoxy-side-chains

Poly(methyl vinyl ether) (PMVE), which has the same composition as PPG except for its methoxy side chains, formed no complex with either a-CD or [S-CD, but complexed with y-CD at three monomer units to one CD. In other words, in this complex, six main chain atoms are included in one y-CD, differing from the complexation of PEG with a-CD. 

A. Matagne, J. Lamotte-Brasseur, G. Dive, J. M. Frere, Interaction between Active Site-Serine /3-Lactamases and Compounds Bearing a Methoxy Side Chain on the a-Face of the /3-Lactam Ring Kinetic and Molecular Modelling , Biochem. J. 1993, 293, 607-611. 

Quinidine consists of a quinolinic group attached through a secondary alcohol linkage to a quinuclidine ring. A methoxy side chain is attached to the quinoline... 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

It would appear that this type of addition may not be confined to the addition of NH2 in liquid ammonia, since it has been observed that treatment of 2-chloro-3-dichloromethyl-pyrazine with an excess of methoxide results in the introduction of a methoxy group into the 6-position of the pyrazine ring (Scheme 9) (68TL5931). This reaction is best rationalized in terms of addition of the methoxide ion at the 6-position, followed by loss of chloride ion from the dichloromethyl side chain. 

Another route to a certain class of 6a-methoxypenicillanates (77TL3831) also probably involves the intermediacy of a 6-imino species. As shown in Scheme 46, 6/3-ketenimino intermediates are readily formed with penicillins having this kind of side chain. Chlorination followed by treatment with methoxide affords the 6a-methoxy-6/3-ketimine, probably involving the intermediates shown. 

The side chain hydroxy group of 3-(2-hydroxyethyl)-2-methyl-9-methoxy-4//-pyrido[l,2-u]pyrimidin-4-one, and that of its 6,7,8,9-tetrahydro derivative was acylated with MeS02Cl in the presence of NEts in CH2CI2 at room temperature (95MIP4, 96MIP2). The hydroxy group of 2-[4-(4-hydro-xybenzoyl)benzyloxy]-3-methyl-4//-pyrido[l, 2-u]-pyrimidin-4-one, its 6-methyl derivative and 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4//-pyrido[l, 2-u]pyrimidin-4-one was alkylated with 4-(2-chloroethyl)morpholine hydrochloride and 4-picolyl chloride hydrochloride (96EUP733633). 

The sulfonium precursor route may also be applied to alkoxy-substituted PPVs, but a dehydrohalogenation-condensation polymerization route, pioneered by Gilch, is favored 37]. The polymerization again proceeds via a quinomethide intermediate, but die syndicsis of the conjugated polymer requires only two steps and proceeds often in improved yields. The synthesis of the much-studied poly 2-methoxy-5-(2-ethylhexyloxy)-l,4-phenylene vinylene], MEH-PPV 15 is outlined in Scheme 1-5 33, 35]. The solubility of MEH-PPV is believed to be enhanced by the branched nature of its side-chain. 

Monobromination of 4-methoxy-3-methyl-2,l-benzisoxazole occurred at C-7, but side-chain bromination was evident with excess reagent (74RTC139). 

The data in Table 191 show a large difference in entropy of activation for reaction of the 4-methoxy compound in the three acids. The difference in the data for perchloric and sulphuric acids was again thought to arise from a significant amount of reaction in the latter occurring via bisulphate anion. This anion was proposed as being insufficiently electrophilic to react except by coordination with the side chain, as in scheme (2S0)... 

Fig. 5.2 (Opposite) Examples of the side chain R in various penicillins (the numbers 1-19 correspond to those in Table 5.1). Numbers 20 (mecillinam) and 21 (pivmecillinam) are 6-/3-amidinopenicillanic acids (mecillinams). Number 11 (temocillin) has a methoxy (—OCH3) group at position 6a this confers high /3-lactamase stability on the molecule.

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

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