Pharmaceutical industry amines

Alicyclic amines are used as pesticides, plasticizers, explosives, inhibitors of metal corrosion and sweetening agents as well as having uses in the pharmaceuticals industry. Aniline hydrogenation has been studied in the literature with the main reaction products cyclohexylamine, dicyclohexylamine, A-phenylcyclohexylamine, diphenylamine, ammonia, benzene, cyclohexane, cyclohexanol and cyclohexanone [1-9], The products formed depend on the catalyst used, reaction temperature, solvent and whether the reaction is performed in gas or liquid phase. For example high temperature, gas-phase aniline hydrogenation over Rh/Al203 produced cyclohexylamine and dicyclohexylamine as the main products [1],... 

The removal of carbobenzyloxy (Cbz or Z) groups from amines or alcohols is of high interest in the fine chemicals, agricultural and pharmaceutical industry. Palladium on activated carbon is the catalyst of choice for these deprotection reactions. Nitrogen containing modifiers are known to influence the selectivity for certain deprotection reactions. In this paper we show the rate accelerating effect of certain N-containing modifiers on the deprotection of carbobenzyloxy protected amino acids in the presence of palladium on activated carbon catalysts. The experiments show that certain modifiers like pyridine and ethylenediamine increase the reaction rate and therefore shorten the reaction times compared to non-modified palladium catalysts. Triethylamine does not have an influence on the rate of deprotection. 

Although secondary amines are common building blocks in the pharmaceutical industry, there are few examples of the resolution of secondary amines in the hterature. Preparation of substituted phenyl allylcarbonates allowed the resolution of 1-methyl-tetrahydroisoqui-noline (1-MTQ) to proceed with excellent enantioselectivity and recovery (Figure 3.1). 

What is the reason for the overwhelming acceptance of stationary phases based on high-purity silicas in the pharmaceutical industry The answer is simple superior peak shapes for analytes with basic functional groups, which has been a problem with older phases. The older, low-purity silicas contain metal ions buried in the matrix of the silica. These contaminants acidify the surface silanols, and the consequence is a strong and non-uniform interaction with basic analytes. This in turn results in tailing peaks, which is an impediment for accurate peak integration and peak resolution. Of course, adding appropriate additives, such as amine modifiers, to the mobile phase can solve these difficulties. But this is an unnecessary and undesired complication in methods development. Therefore, silicas that are free from this complication are much preferred. 

In 1956, glycidol was only used for research purposes (Hine et al., 1956), but by 1978 it was used in the preparation of glycerol, glycidyl ethers, esters and amines in the pharmaceutical industry (Proctor Hughes, 1978) and as a sterilant in pharmaceuticals (Ivashkiv Dunham, 1973). 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

Production of enantiomerically pure a-arylpropanoic acids, also known as profens, is of critical importance to the pharmaceutical industry because they constitute a major class of antiinflammatory agents. One of the most practical approaches to preparing optically pure a-arylpropanoic acids is by resolution with chiral amines. Notable examples include brucine, quinidine, cinchonidine, morphine, ephedrine, and a-(l-naphthyl)ethylamine. For instance, (.Sj-a-methylbenzylaminc and... 

One of the most known formulation reaction in the pharmaceutical industry is the reaction between an amine (primary or secondary) and a carbohydrate (e.g., sugar) is known as the Maillard reaction (the browning reaction due to mixing of a reduced sugar and an amine) [13]. One of the examples of the Maillard reaction is fluoxetine HCl [14] Figure A15-6. The details of how to avoid this reaction in the formulation is outlined in Section 15.5 [Impact of excipients on Degradation products of API(s)]. 

Shono [25] pointed out that the microsomal oxidation of tertiary amines and amides occurs via the same intermediates as the anodic oxidation in methanol solution. The dealkylation of 7V-methyl-7V,7V-dialkyl amines by both methods results in almost the same A -demethylation/A/ -dealkylation ratio. This method has been used in the pharmaceutical industry for the easy supply of metabolites of pharmaceuticals. 

Light amines are important intermediates in chemistry and in the pharmaceutical industry. The substituted light amines are prepared from alcohol, ammonia and/or monosubstituted amine in the presence of a solid catalyst (1-4). 

Aliphatic amines are amongst the most important bulk and fine chemicals in the chemical and pharmaceutical industry [13]. Hydroaminomethylation of alkenes to amines presents an atom-economic, efficient and elegant synthetic pathway towards this class of compounds. In hydroaminomethylation a reaction sequence of hydroformylation of an alkene to an aldehyde with subsequent reductive amina-tion proceeds in a domino reaction (see Eq. 4) [14]. Recently, the highly selective hydroamination of alkenes with ammonia to form linear primary and secondary aliphatic amines with a new Rh/Ir catalytic system (] Rh(cod)Cl 2], ] Ir(cod)Cl 2], aqueous TPPTS solution) has been described (see Scheme 2) [15]. The method is of particular importance for the production of industrially relevant, low molecular weight amines. 

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

The amination reaction, forming primary, secondary, and tertiary amines, can be between alcohols, aldehydes, or ketones, and ammonia and hydrogen. Sabatier and Mailhe in 1909 [1] first reported the synthesis of amines from alcohols. Over the course of the 20 century the in jortance of these compounds has increased and amines are key intermediates and final products within the fine chemical, agrochemical, and pharmaceutical industries. The amination of alcohols to form amines has been the subject of a number of mechanistic studies [2-8] proposing a variety of mechanisms. In this study we have investigated the... 

Finally, the strategy should be of interest because it only requires two reactions steps. This is possible because ketimine isolation is not required, and while rarely discussed can be time consuming, may provide mediocre yield, and unnecessarily lengthens the synthesis of amines. Furthermore, all the reagents are already in use by the pharmaceutical industry, a broad range of ketone substrates are suitable (even aliphatic ketones), either enantiomeric form of the a-chiral amine product can be produced, and the process has been demonstrated on a 20 g scale. The method is compatible with acetonides, ethers, silyl ethers, bulky esters, secondary amides, tertiary amides, carbamates, urethanes, etc. With these beneficial qualities noted, the method suffers when non-branched 2-alkanones are used (product des <75%). In these cases, HCl salt formation allows further enrichment via crystallization, alternatively stoichiometric Yb(OAc)3 can be used during the reductive amination to allow enhanced de. Both of these solutions require additional processing time and/or cost and require consideration before scale-up. 

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