Chloroformate synthesis

This method useful for chloromethyl chloroformate synthesis gives poor yields and bad quality in the case of... 

Sigurdsson, S.T., Seeger, B., Kutzke, U. and Eckstein, F. (1996) A mild and simple method for the preparation of isocyanates from aliphatic amines using trichloromethyl chloroformate. Synthesis of an isocyanate containing an activated disulfide. The Journal of Organic Chemistry, 61, 3883-3884. 

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

Cyclizine Hydrochloride. l-(Diphenylmethyl)-4-methylpipera2ine monohydrochloride [303-25-3] (Mare2ine) (17) is a white crystalline powder, or small colorless crystals, that is odorless or nearly so and has a bitter taste. It melts indistinctly and with decomposition at ca 285°C. One gram of cycli2ine hydrochloride [303-25-3] is soluble in 115 mL water, 115 mL ethanol, and 5 mL chloroform it is insoluble in diethyl ether. It may be made by the synthesis shown in Reference 15. 

Meclizine Hydrochloride. Pipera2ine Antivert, and Bonine are trade names for mech2ine dihydrochloride monohydrate [31884-77-2] (20). It is a white or slightly yellowish crystalline powder with a slight odor, no taste, and a melting point of 217—224°C. The hydrochloride is practically insoluble in water and ether. It is freely soluble in chloroform, pyridine, methylacetamide, and mild acid alcohol—water mixtures, and is slightly soluble in dilute acids or alcohol. See Reference 16 for synthesis. 

The synthesis of phenoxaphosphine-containing PODs by the cyclodehydration of polyhydra2ides obtained from 2,8-dichloroformyl-lO-phenylphenoxaphosphine-lO-oxide and aUphatic and aromatic dihydra2ides has been described (60). All polymers are soluble in formic acid, y -cresol, and cone H2SO4, but insoluble or partially soluble in ben2ene, chloroform, and hexamethylphosphoric triamide. 

Resorcinol carboxylation with carbon dioxide leads to a mixture of 2,4-dihydroxyben2oic acid [89-86-1] (26) and 2,6-dihydroxyben2oic acid [303-07-1] (27) (116). The condensation of resorcinol with chloroform under basic conditions, in the presence of cyclodextrins, leads exclusively to 2,4-dihydroxyben2aldehyde [95-01-2] (28) (117). Finally, the synthesis of l,3-bis(2-hydroxyethoxy)ben2ene [102-40-9] (29) has been described with ethylene glycol carbonate in basic medium (118), in the presence of phosphines (119). Ethylene oxide, instead of ethyl glycol carbonate, can also be used (120). 

Tris(2,4-pentanedionato)iron(III) [14024-18-1], Fe(C H202)3 or Fe(acac)3, forms mby red rhombic crystals that melt at 184°C. This high spin complex is obtained by reaction of iron(III) hydroxide and excess ligand. It is only slightly soluble in water, but is soluble in alcohol, acetone, chloroform, or benzene. The stmcture has a near-octahedral arrangement of the six oxygen atoms. Related complexes can be formed with other P-diketones by either direct synthesis or exchange of the diketone into Fe(acac)3. The complex is used as a catalyst in oxidation and polymerization reactions. 

Pyrrohdinone (2-pyrrohdone, butyrolactam or 2-Pyrol) (27) was first reported in 1889 as a product of the dehydration of 4-aminobutanoic acid (49). The synthesis used for commercial manufacture, ie, condensation of butyrolactone with ammonia at high temperatures, was first described in 1936 (50). Other synthetic routes include carbon monoxide insertion into allylamine (51,52), hydrolytic hydrogenation of succinonitnle (53,54), and hydrogenation of ammoniacal solutions of maleic or succinic acids (55—57). Properties of 2-pyrrohdinone are Hsted in Table 2. 2-Pyrrohdinone is completely miscible with water, lower alcohols, lower ketones, ether, ethyl acetate, chloroform, and benzene. It is soluble to ca 1 wt % in aUphatic hydrocarbons. 

Org inic Esters. An unlimited number of organic esters can be prepared by reactions of poly(vinyl alcohol) employing standard synthesis (82,84). Chloroformate esters react with poly(vinyl alcohol) to yield poly(vinyl carbonates) (118). 

Methods for synthesis of the thia olium ring also have matured technically based on the cost, throughput, and waste disposal issues of production. In earlier syntheses, the 2-carbon and the sulfur atom were suppHed as potassium dithioformate, made from chloroform and potassium sulfide. 

From Boron Halides. Using boron haUdes is not economically desirable because boron haUdes are made from boric acid. However, this method does provide a convenient laboratory synthesis of boric acid esters. The esterification of boron haUdes with alcohol is analogous to the classical conversion of carboxyUc acid haUdes to carboxyUc esters. Simple mixing of the reactants at room temperature or below ia a solvent such as methylene chloride, chloroform, pentane, etc, yields hydrogen haUde and the borate ia high yield. 

Amino Acids. Chloroformates play a most important role for the protection of the amino group of amino acids (qv) during peptide synthesis (32). The protective carbamate formed by the reaction of benzyl chloroformate and amino acid (33) can be cleaved by hydrogenolysis to free the amine after the carboxyl group has reacted further. The selectivity of the amino groups toward chloroformates results in amino-protected amino acids with the other reactive groups unprotected (34,35). Methods for the preparation of protected amino acids on an industrial scale have been developed (36,37). A wide variety of chloroformates have been used that give various carbamates that are stable or cleaved under different conditions. 

Chloroformates are versatile, synthetic intermediates, based on the affinity of the chlorine atoms for active hydrogen atoms. Chloroformates should be considered as intermediates for syntheses of pesticides, perfumes, dmgs, polymers, dyes, and other chemicals. Some of these products, eg, carbonates, are used as solvents, plastici2ers, or as intermediates for further synthesis. A significant use of chloroformates is for conversion to peroxydicarbonates, which serve as free-radical initiators for the polymeri2ation of vinyl chloride, ethylene, and other unsaturated monomers. The most widely used percarbonate initiators are diisopropyl peroxydicarbonate (IPP), di-2-ethyIhexylperoxydicarbonate (2-EHP), and di-j -butylperoxydicarbonate (SBP). The following Hst includes most of the commercially used percarbonates. 

Nearly all of the benzyl chloride [100-44-7], henzal chloride [98-87-3], and hen zotrichl oride /P< -(97-i manufactured is converted to other chemical intermediates or products by reactions involving the chlorine substituents of the side chain. Each of the compounds has a single primary use that consumes a large portion of the compound produced. Benzyl chloride is utilized in the manufacture of benzyl butyl phthalate, a vinyl resin plasticizer benzal chloride is hydrolyzed to benzaldehyde hen zotrichl oride is converted to benzoyl chloride. Benzyl chloride is also hydrolyzed to benzyl alcohol, which is used in the photographic industry, in perfumes (as esters), and in peptide synthesis by conversion to benzyl chloroformate [501-53-1] (see Benzyl ALCOHOL AND p-PHENETHYL ALCOHOL CARBONIC AND CARBONOCm ORIDIC ESTERS). 

Another appHcation of 4-chlorophenol is in the synthesis of a dmg, ethyl a, a-dimethyl-4-chlorophenoxy acetate [637-07-0] (60), used as a cholesterol-reducing agent. This synthesis involves reaction with acetone and chloroform, followed by ethanol esterification. 

TtM use of vinyl chloroformate tor N-dealkytatlon of tertiary amines, protection of amino groups, protection of hydroxyl groups or formation of Z-ketoimidazoles. Synthesis of vtnyl cartxjnates by means of fluoro or chiorofonnates. 

A benzyl carbonate was prepared in 83% yield from the sodium alkoxide of glycerol and benzyl chloroformate (20°, 24 h). It is cleaved by hydrogenolysis (H2/ Pd-C, EtOH, 20°, 2 h, 2 atm, 76% yield) and electrolytic reduction (-2.7 V, R4N X, DMF, 70% yield). A benzyl carbonate was used to protect the hy-droxyl group in lactic acid during a peptide synthesis. 

In an early synthesis a methyl carbonate, prepared by reaction of a phenol with methyl chloroformate, was cleaved selectively in the presence of a phenyl ester. ... 

We have noted above that benzocrowns may be nitrated quite readily. This approach was used in the formation of a photoresponsive bis-crown (see Sect. 3.8) wherein the nitrobenzo crowns reductively dimerize to the corresponding azobenzene. Kikukawa, Nagira and Matsuda have utilized 4-nitrobenzo-15-crown-5 in a somewhat different way during the synthesis of 4 -vinylbenzo-l 5-crown-5Nitration is effected using nitric acid in a mbcture of chloroform and acetic acid. 

This formula was confirmed hy Haworth and Perkin s synthesis of a-flZZocryptopine from herherine, the first application of a process, of which examples have heen given already in the syntheses of cryptopine (p. 298) and protopine (p. 301) hy the same authors. Anhydrotetrahydromethyl-herherine (I cf. hase (a), p. 346) in dry chloroform was added to a solution of perhenzoic acid in ether cooled helow 5°. The amine oxide, C21H23O5N (II), separated as an oil, which after shaking with sodium hydroxide solution, solidified and was crystallised from water in slender prisms, m.p. 135°. It was dissolved in acetic acid, hydrochloric acid added, the mixture heated in boiling water for an hour and the hase precipitated hy addition of potassium hydroxide. The precipitate was dissolved in methyl alcohol, ether added, the alcohol washed out with water and the ethereal... 

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