Alcohols process development

Until World War 1 acetone was manufactured commercially by the dry distillation of calcium acetate from lime and pyroligneous acid (wood distillate) (9). During the war processes for acetic acid from acetylene and by fermentation supplanted the pyroligneous acid (10). In turn these methods were displaced by the process developed for the bacterial fermentation of carbohydrates (cornstarch and molasses) to acetone and alcohols (11). At one time Pubhcker Industries, Commercial Solvents, and National Distillers had combined biofermentation capacity of 22,700 metric tons of acetone per year. Biofermentation became noncompetitive around 1960 because of the economics of scale of the isopropyl alcohol dehydrogenation and cumene hydroperoxide processes. 

A process developed in Israel (263) uses solvent extraction using a higher alcohol or other solvating solvent. This removes phosphoric acid and some hydrochloric acid from the system driving the equiHbrium of equation 42 to the right. The same principle can be appHed in other salt—acid reactions of the form... 

The alkalized zinc oxide—chromia process developed by SEHT was tested on a commercial scale between 1982 and 1987 in a renovated high pressure methanol synthesis plant in Italy. This plant produced 15,000 t/yr of methanol containing approximately 30% higher alcohols. A demonstration plant for the lEP copper—cobalt oxide process was built in China with a capacity of 670 t/yr, but other higher alcohol synthesis processes have been tested only at bench or pilot-plant scale (23). 

Vista has offered for ficense a stoichiometric process, which has not yet been commercialized, although the related primary alcohol process has been described (see Alcohols, higher aliphatic-synthetic processes). Other processes, including developments by Dow and Exxon, have been reported in the hterature. 

In some processes, development additives such as benzyl alcohol are added to the developer to increase the hydrophilic nature of the organic phase. More frequentiy, higher pX couplers are designed to have additional ionizable sites, such as carboxyl, sulfo, or phenoHc groups, to accomplish the same end (57). 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

A representative set of a- and -keto esters was also tested as substrates (total 11) for each purified fusion protein (Figure 8.13b,c) [9bj. The stereoselectivities of -keto ester reductions depended both on the identity of the enzyme and the substrate stmcture, and some reductases yielded both l- and o-alcohols with high stereoselectivities. While a-keto esters were generally reduced with lower enantioselec-tivities, it was possible to identify pairs of yeast reductases that delivered both alcohol antipodes in optically pure form. These results demonstrate the power of genomic fusion protein libraries to identify appropriate biocatalysts rapidly and expedite process development. 

Process development of the synthesis of iodoaniline 28 began with an improved synthesis of l-(4 -aminobenzyl)-l,2,4-triazole (6) (Scheme 4.7), which was prepared in the medicinal chemistry synthesis, albeit with poor regioselectivity (Scheme 4.1). We found that this aniline intermediate 6 could be readily prepared in three steps in >90% overall yield from 4-amino-l,2,4-triazole (30) and 4-nitrobenzyl bromide (4) based on a modified literature procedure [9]. The condensation of 30 and 4 in isopropyl alcohol followed by deamination gave the nitro... 

Synol A version of the Fischer-Tropsch process developed in Germany during World War II. It used a different catalyst and produced a larger fraction of alcohols and olefins. 

The electrochemical process developed using Pb electrodes in aqueous sulphuric acid yields a practical procedure for m-hydroxv-benzyl alcohol (14). Yields up to 88% of (16) were achieved using l,3-dimethyl-2-imidazolidinone... 

This transformation has been applied to several chiral production processes, the first being the synthesis of a pheromone (Disparlure) intermediate (S) albeit with low turnover numbers and only 91 % ee. Another industrial product is the epoxide of allyl alcohol as developed by PPG-Sipsy, to give a process where catalyst loading was decreased by molecular sieve addition and the safety factors involving peroxide contamination were overcome. These examples are shown in Figure 1.46. 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

A further development of this successful technology was achieved to take advantage of the available feedstock base of butene isomers (raffinate II) for the preparation of n-C5 products (n-valeraldehyde, n-isoamyl alcohol, and n-valeric acid). In December 1995 production of n-valeraldehyde was started up in a new plant at Hoechst/Ruhrchemie (138). Generally, there are strong restrictions in the application of the two-phase catalytic processes to higher alkenes (Section IV.B.l), but the adaptation to butenes was possible with little modification of the process developed for propene. 

More recent research efforts have focused on the development of other possible catalysts such as promoted Raney copper,371,403 catalysts prepared from intermetal-lic precursors,362,371 386 404-406 and catalysts that tolerate high C02 content.407 Catalyst modifications allowed to shift the selectivity to the formation of higher alcohols.208,408 110 For example, in a process developed by IFP, a multicomponent oxide catalyst is applied with copper and chromium as the main components 410 By this method, 70-75% total alcohol selectivities and 30-50% of C2 and higher alcohol selectivities can be achieved at 12-18% conversion levels (260-320°C, 60-100 atm). 

Edta can also be obtained by catalytic oxidation of tetra(hydroxyethyl) ethylenediamine (2) by a process developed by the Carbide and Carbon Chemical Corporation (equation 5).8,9 The amino alcohol is heated at 220-230 °C for several hours with sodium or potassium hydroxide and cadmium oxide as a catalyst. Hydrogen is liberated and Na4edta is obtained. 

A simple mathematical model is used for quantitative description of the process and consists of a set of equations relating inputs, outputs, and key parameters of the system. The model for an alcoholic fermentation fed-batch process developed by Mayer (10) and adapted with the Ghose and Tyagi (11) linear inhibition term by the product was used as the starting point for the development of a model-based substrate sensor with product (ethanol) and biomass on-line measurements. 

The fourth process for the production of allyl alcohol was developed partly for the purpose of producing epichlorohydrin via allyl alcohol as the intermediate, using a palladium catalyst. 

The catalytic oxidation of cyclohexane is performed in the liquid phase with air as reactant and in the presence of a catalyst. The resulting product is a mixture of alcohol and ketone (Table 1, entry 12) [19]. To limit formation of side-products (adipic, glutaric, and succinic acids) conversion is limited to 10-12 %. In a process developed by To ray a gas mixture containing HC1 and nitrosyl chloride is reacted with cyclohexane, with initiation by light, forming the oxime directly (Table 1, entry 12). The corrosiveness of the nitrosyl chloride causes massive problems, however [20]. The nitration of alkanes (Table 1, entry 13) became important in a liquid-phase reaction producing nitrocyclohexane which was further catalytically hydrated forming the oxime. 

In many olefmic reactions activation of the C=C double bond occurs, although in many reactions at least one C-H bond is transformed. Established processes are summarized in Table 3. Examples of liquid-phase reactions are the synthesis of ethers, especially methyl tert-butyl ether by reacting olefins (isobutene) and alcohol (methanol) in the liquid phase at slightly elevated temperature and pressure (Table 3, entry 22). Different processes developed differ only slightly in feed composition and design, which is optimized for heat removal [2]. 

Aerobic oxidation of alcohols to the corresponding aldehydes, ketones, and carboxylic acids can be performed in aqueous solution by using noble metals as catalysts under mild conditions, but severe deactivation of the catalysts often occurs, seriously limiting process development [5b, c, e]. 

Methanol (methyl alcohol, CH3OH), an important solvent and precursor for many organic chemicals, is made by a process developed in the 1920s... 

The (ft)-4-phenyl-2-oxazolidinonc auxiliary was used in the process development and scale up of Novartis purine nucleoside phosphorylase inhibitor PNP405 (16) (Scheme 23.2).43 Asymmetric alkylation of 17 with bromoacetonitrile provided a 7 1 diastereoisomeric ratio of crude 18. Recrystallization afforded 18 in 80% yield and >99% de. Simple addition of sodium borohydride in tetrahydrofuran (THF)-water at room temperature44 resulted in the desired y-cyano alcohol 19 and recovery of the auxiliary. 

The investigation in a microreactor was initially hampered by the presence of an insoluble compound for the ester process [4]. Because this reactant had to be changed, a process development study had to be carried out. A model reaction, an ester hydrolysis yielding a stable alcohol, was used instead of the real one in order to facile the process development. Twelve different conditions were run. Having acquired the process know-how, the same kind of process development was done for the real reaction in only 2 h with success. 

---