Amines, viii

Could R-l-methyl-3-phenylpropylamine (R-amine, VIII) be sourced at low enough cost ... 

Would the likely dialkylation of R-amine (VIII) introduce new impurities which are difficult to remove ... 

Raw Materials Sourcing. There was relatively little problem in sourcing 5-bromoacetylsalicylamide (in-house) or dibenzoyl-(+)-tartaric acid (large tonnage Italian source). Although RS-l-methyl-3-phenylpropylamine was available at low cost ( 10-12/kg) in tonnage quantities (Germany and Holland) no supplier of the R-amine VIII was known. 

Scheme 11 Option. A great deal of work was carried out on the preparation of R-epoxides (XII) and their reaction with R-amine (VIII). It has long been known that styrene oxides react with primary amines at either of the epoxide carbons, and also that neat amines appear to favor the desired reaction, attack at the methylene carbon atom of XII.13...

It is clear from the conversion yield that the biological process was worthy of further development for potential use in the longer term. Work was especially needed to improve the concentration (8 g/liter at the time) and to deal with the slightly different impurity profile (total 0.3% with 0.1% identified as the R-amine VIII). Also, technologies (e.g. ultrafiltration) needed to be evaluated to ensure that proteinaceous material did not contaminate the product. 

Hinsberg procedure for the separation of primary, secondary and tertiary amines is given under (viii) above, and this method may be used. The following experimental details may, however, be found useful for the preparation of derivatives of primary and secondary amines. 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

The separation of a mixture of amines by means of benzenesulphonyl chloride or p-toluenesulphonyl chloride (Hinsberg s procedure) is described in Section IV,100,(viii). 

A suspension of sodium amide in 500 ml of anhydrous liquid artmonia was prepared from 18 g of sodium (see Chapter II, Exp. 11). To the suspension was added in 10 min with swirling a mixture of 0.30 mol of 1-chloro-l-ethynylcyclohexane (see VIII-2, Exp. 27) and 50 ml of diethyl ether. The reaction was very vigorous and a thick suspension was formed. The greater part of the ammonia was evaporated by placing the flask in a water bath at 50°C. After addition of 500 ml of ice-water the product was extracted three times with diethyl ether. The ethereal extracts were dried over anhydrous KjCOj and subsequently concentrated in a water-pum vacuum. Distillation of the residue afforded the amine, b.p. 54°C/15 mmHg, n 1.4345, in 87% yield. 

N-Amination of indazole affords a mixture of 60% (271) and 40% (272), which compares with the 55 45 ratio obtained in methylation (Section 4.04.2.1.3(viii)). A camphopyrazole derivative (a mixture of tautomers 275 and 276) when treated with hydroxylamine O-sulfonic acid yields exclusively the (4S,7i )-4,7-methano-2-amino-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-indazole (277) (79YZ699). 

HC(22)l). Other azopyrazoles (318) and (319) have been described in Section 4.04.2.1.4(viii). These compounds can be reduced to amines (zinc and acetic acid) or to arylhydrazines (zinc in alkaline medium) (67HC(22)l). 

The activation energy of substitution of an unactivated aromatic halide (e.g., fiuorobenzene and 2-chloronaphthalene ) is over 30 kcal while that of activated compounds is 5-20 kcal. For the tabulated reactions (Tables II-VIII) with alkoxide and with primary, secondary, or tertiary amines, resonance activation (cf. 278 and 279) by ortho or para nitrogens is found to be greater than inductive activation (cf. 251). This relation is qualitatively demonstrated in... 

Benzo-fusion onto halonitrobenzenes (Table VIII, p. 277) produces acceleration of aminations or alkoxylations (Tables XII and XIII) except for 3-halo-2-nitronaphthalenes which are analogous to 3-haloisoquinolines. 

Studies of Trifluoroacetic Acid. Part VIII. Diazotisations of Aromatic Amines in Aqueous Trifluo-roacetic Acid and Other Perhalogeno-carboxylic Acids, M. R. Pettit, M. Stacey, and J. C. Tatlow, / Chem. Soc., (1953) 3081-3084. 

The relative rates of reaction of the silene Me2Si=C(SiMe3)2 with a series of amines, alcohols, phenols, thiophenols, dienes, and alkenes were obtained174 and are reported in Table VIII Section IV.C. 

Supported Co, Ni, Ru, Rh, Pd and Pt as well as Raney Ni and Co catalysts were used for the hydrogenation of dodecanenitrile to amines in stirred SS autoclaves both in cyclohexane and without a solvent. The reaction temperature and the hydrogen pressure were varied between 90-140 °C and 10-80 bar, respectively. Over Ni catalysts NH3 and/or a base modifier suppressed the formation of secondary amine. High selectivity (93-98 %) to primary amine was obtained on Raney nickel, Ni/Al203 and Ru/A1203 catalysts at complete nitrile conversion. With respect to the effect of metal supported on alumina the selectivity of dodecylamine decreased in the order Co Ni Ru>Rh>Pd>Pt. The difference between Group VIII metals in selectivity can be explained by the electronic properties of d-band of metals. High selectivity to primary amine was achieved on base modified Raney Ni even in the absence of NH3. 

While the desired product of the hydrogenation of nitriles is often the primary amines, the proportion of primaiy/secondary/tertiary amines in the product is strongly affected by the nature of metal. In the hydrogenation of nitriles on Group VIII metals, the selectivity of primary amine decreases in the order Co>Ni>Ru>Rh>Pd>Pt [1], The difference between Group VIII metals in selectivity to primary amine is explained by the difference in the electronic... 

The selectivity of RNH2 on M/A1203 and Raney catalysts decreased in the order Co Ni Ru>Rh>Pd>Pt. This order corresponds to the opposite sequence of reducibility of metal-oxides [8] and standard reduction potentials of metalions [9], The difference between Group VIII metals in selectivity to amines can probably been explained by the difference in the electronic properties of d-bands of metals [3], It is interacting to note that the formation of secondary amine, i.e. the nucleophilic addition of primary amine on the intermediate imine can also take place on the Group VIII metal itself. Therefore, the properties of the metal d-band could affect the reactivity of the imine and its interaction with the amine. One could expect that an electron enrichment of the metal d-band will decrease the electron donation from the unsaturated -C=NH system, and the nucleophilic attack at the C atom by the amine [3], Correlation between selectivity of metals in nitrile hydrogenation and their electronic properties will be published elsewhere. 

Osmium(VIII) tetraoxide (0s04) is an effective reagent for the cis hydroxylation of olefins under stoichiometric conditions as well as in a variety of catalytic variants.213 Under both catalytic and stoichiometric conditions, the critical step is the formation of an osmium(VI) cycloadduct, the formation of which is dramatically accelerated in the presence of amine bases such as pyridine,214 i.e.,... 

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