Commercial Synthesis

Bis( -cyclopentadienyl)iron 1, called ferrocene to emphasize the benzene-analogous reactivity (e. g., electrophilic alkylation and acylation), is not only the pioneer compound of organometallic chemistry [3-5]. It is also a platform for a plethora of derivatives and an efficient fuel additive, predominantly used in diesel fuels. This commercial use is based on the property that ferrocene undergoes homolytic decomposition under the conditions of fuel combustion. Ferrocene lowers the formation of soot particles upon combustion of diesel and ordinary fuel. 

Ferrocene is a crystalline, largely air- and water-stable compound (mp. 172-173 °C and bp. 249 °C). It is oxidized chemically and electrochemically to the stable monocation [(C5H5)2Fe] , the ferrieinium cation containing trivalent iron this one-electron step is fiilly reversible. Ferrocene is the only organoiron compound which is soluble in mineral oil and gasoline. At the same time, it is inert to all components in the oil tank. 

For large amounts of ferrocene, none of the conventional laboratory-scale preparations was sufficient neither the iron-based eon version of dieyclopentadiene (eq. (1)) is technically feasible on a large scale, nor the more expensive two-step synthesis via sodium cyclopentadienide (eq. (2)). 

While eq. (1) works only under harsh temperature conditions with concomitant partial decomposition, the preparation of the sodium cyclopentadiene required by eq. (2) is too expensive, with the purification process demanding Soxhlet extraction of the ferrocene with hydrocarbons. The same applies to the otherwise convenient laboratory synthesis according to eq. (3), which avoids the step of the sensitive sodium cyclopentadienide. Here, the acidic hydrogen of cyclopentadiene is stripped off by A -bases such as diethylamine. 

A technical synthesis was developed from 1965 until 1989 at the Chemische Betriebe Pluto GmbH at Heme (Germany) [6]. Here, the divalent iron is first generated by synproportionation. The useless NaCI is again the major drawback of this approach. Also, elemental sodium is required. 

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Raphael has deyised a commercial synthesis using intermediates 365A and B to provide the two halves of the molecule. B is converted in aqueous add to an isomeric alcohol. Draw this. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

Sorbitol is a sweetener often substituted for cane sugar because it is better tolerated by dia betics It IS also an intermediate in the commercial synthesis of vitamin C Sorbitol is prepared by high pressure hydrogenation of glucose over a nickel catalyst What is the structure (including stereochemistry) of sorbitoP... 

Nitdles may be prepared by several methods (1). The first nitrile to be prepared was propionitdle, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelou2e reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl hahdes with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide appHcabiUty ... 

Hydrofluorocarbons are also prepared from acetylene or olefins and hydrogen fluoride (3), or from chlorocarbons and anhydrous hydrogen fluoride in the presence of various catalysts (3,15). A commercial synthesis of 1,1-difluoroethane, a CFG alternative and an intermediate to vinyl fluoride, is conducted in the vapor phase over an aluminum fluoride catalyst. 

Although the CFCs and HCFCs are not as stable as the PFCs, they still can be rather stable compounds (3,11)- Dichlorodifluoromethane, CCI2F2, is stable at 500°C in quartz CCl F and CHCIF2 begin to decompose at 450 and 290°C, respectively (7). The pyrolysis of CHCIF2 at 650—700°C in metal tubes is the basis of a commercial synthesis of tetrafluoroethylene ... 

The chlorofluorocarbons react with molten alkah metals and CCI2F2 reacts vigorously with molten aluminum, but with most metals they do not react below 200°C. An exception is the dechlorination of chlorofluorocarbons with two or more carbon atoms in the presence of Zn, Mg, or A1 in polar solvents. A commercial synthesis of chlorotriduoroethylene [79-38-9] employs this reaction ... 

Catalyst systems used in the commercial synthesis of aromatic petroleum resins are very similar to those systems used in the manufacture of C-5 and C-5—C-9 type resins. The principal catalysts are AlCl and BF and their respective complexes. BF catalysis usually yields resins with improved color over AlCl catalyzed systems. 

Commercial Synthesis ofR,S-Mahc Acid. The commercial synthesis of R%-mahc acid involves hydration of maleic acid [110-16-7] or fumaric acid [110-17-8] at elevated temperature and pressure. A Japanese patent (33) describing a manufacturing procedure for malic acid claims the direct hydration of maleic acid at 180°C and 1.03—1.21 MPa (150—175 psi). 

A process for the commercial synthesis of -phenylene diisocyanate using terephthalamide [3010-82-0] as a precursor and involving N-halo intermediates has been studied extensively (21). The synthesis of 1,4-diisocyanatocyclohexane from terephthaUc acid [100-21-0] also involves a nitrene intermediate (22). 

For continuing polymerization to occur, the ion pair must display reasonable stabiUty. Strongly nucleophilic anions, such as C/ , are not suitable, because the ion pair is unstable with respect to THE and the alkyl haUde. A counterion of relatively low nucleophilicity is required to achieve a controlled and continuing polymerization. Examples of anions of suitably low nucleophilicity are complex ions such as SbE , AsF , PF , SbCf, BE 4, or other anions that can reversibly coUapse to a covalent ester species CF SO, FSO, and CIO . In order to achieve reproducible and predictable results in the cationic polymerization of THE, it is necessary to use pure, dry reagents and dry conditions. High vacuum techniques are required for theoretical studies. Careful work in an inert atmosphere, such as dry nitrogen, is satisfactory for many purposes, including commercial synthesis. 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

Although all six possible toluenediamine isomers are made in the commercial synthesis, only two products are available commercially. The properties of the individual isomers are summarized in Table 1. Specifications for the commercial products, named by the relative position of the predominant groups, along with some physical properties, are shown in Table 2. 

Phytol [505-06-5] (111) and isophytol [150-86-7] (112) are important intermediates used in commercial synthesis of Vitamins E and K. There is a variety of synthetic methods for their manufacture. Chlorophyll [479-61-8] is a phytyl ester. 

The first commercial synthesis of a vitamin occurred ia 1933 when the Reichsteia approach was employed to manufacture vitamin C (6). AH 13 vitamins ate available ia commercial quantities, and their biological functions have largely been estabUshed (7). A Hst of Nobel prize winners associated with vitamin research is given ia Table 2. 

As practiced by Hoffmann-La Roche, the commercial synthesis of vitamin is outlined ia Figure 1. Oxidation of 2-methylnaphthalene (4) yields menadione (3). Catalytic reduction to the naphthohydroquinone (5) is followed by reaction with a ben2oating reagent to yield the bis-benzoate (6). Selective deprotection yields the less hindered ben2oate (7). Condensation of isophytol (8) (see Vitamins, vitamins) with (7) under acid-cataly2ed conditions yields the coupled product (9). Saponification followed by an air oxidation yields vitamin (1) (29). 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

Manufacture. The most widely employed method for the commercial synthesis of (H)-cinnamic acid uti1i2es ben2aldehyde, acetic anhydride, and anhydrous sodium or potassium acetate in a condensation reaction commonly referred to as the Perkin reaction (11). 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

The first methacrylic esters were prepared by dehydration of hydroxyisobutyric esters, prohibitively expensive starting points for commercial synthesis. In 1932 J. W. C. Crawford discovered a new route to the monomer using cheap and readily available chemicals—acetone, hydrocyanic acid, methanol and sulphuric acid— and it is his process which has been used, with minor modifications, throughout the world. Sheet poly(methyl methacrylate) became prominent during World War II for aircraft glazing, a use predicted by Hill in his early patents, and since then has found other applications in many fields. 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

The alkyne hydrogenation reaction has been explored extensively by the Hoffmann-La Roche pharmaceutical company, where it is used in the commercial synthesis of vitamin A. The cis isomer of vitamin A produced on hydrogenation is converted to the trans isomer by heating. 

How would you carry out the following transformation, a step used in the commercial synthesis of (S)-ibuprofen ... 

Note that the product acid has one more carbon than the starling alkyl halide. An example occurs in the commercial synthesis of fenoprofen, a nonsteroidal antiinflammatory drug, or NSAID, marketed under the trade name Nalton. (See Chapter 15 Focus On.)... 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Figure 23.9 This Robinson annulation reaction is used in the commercial synthesis of the steroid hormone estrone. The nucleophilic donor is a /3-diketone.

An early success story in the field of catalytic asymmetric synthesis is the Monsanto Process for the commercial synthesis of l-DOPA (4) (see Scheme 1), a rare amino acid that is effective in the treatment of Parkinson s disease.57 The Monsanto Process, the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex, was introduced by W. S. Knowles and coworkers and has been in operation since 1974. This large-scale process for the synthesis of l-DOPA (4) is based on catalytic asymmetric hydrogenation, and its development can be... 

Scheme 2. Anic and Enichem s commercial synthesis of aspartame (7) using catalytic asymmetric hydrogenation.

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

Scheme 3. The ARCO Chemical Company s commercial synthesis of the glycidols using the Sharpless asymmetric epoxidatlon reaction.

Scheme 4. The Sharpless asymmetric epoxidation in the J.T. Baker Company s commercial synthesis of (7/ ,8S)-disparlure (15).

Scheme 5. The Sumitomo Chemical Company s catalytic asymmetric synthesis of ethyl (+)-(1 S)-2,2-dimethylcyclopropanecarboxylate (18), an intermediate in Merck s commercial synthesis of cilastatin (19).

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

As safe nutrient ingredients in many food systems, as well as available from commercial synthesis, the combination of vitamins C and E represents very useful compounds for the nutritional inhibition of formation of tumorigenic N-nitroso compounds. 

Finally, it is appropriate to close this chapter with an example from the roots of fine chemicals the dyestuff, indigo. Manufacture of indigo involves chemistry (see Fig. 2.15) which has hardly changed from the time of the first commercial synthesis more than a hundred years ago (see earlier). Mitsui Toatsu has developed a two-step process in which indole is produced by vapour-phase reaction of ethylene glycol with aniline over a supported silver catalyst (Inoue et al., 1994). Subsequent liquid-phase oxidation of the indole, with an alkyl hydroperoxide in the presence of a soluble molybdenum catalyst, affords indigo. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

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