Thionyl chloride, reaction + amino acids

In one synthetic approach (Veld 1990, 1992), alanine is first converted to the bromo derivative via the reaction of the diazonium salt of the amine with hydrogen bromide. In the next step the acid functionality is activated by converting it to the acid chloride using thionyl chloride. The activated acid is condensed with a protected a-amino acid to yield the dipeptide intermediate which is then cyclized by heating in presence of Celite (ion exchange resin) to yield the final product. However, the overall yield of this reaction is fairly low. A more elegant approach is shown in Scheme 5. In this approach, an a-amino acid wth a protected side chain (e.g., e-Z-lysine) is reacted with 2-bromo-propionyl bromide under Schotten-Bauman condidons (Fischer 1908) to yield the intermediate 5a, which is then cyclized under basic conditions to the depsipeptide 5b. 

One of the first examples of the grafting to approach was published by Sun et al. in 2001 [32]. In this work carboxylic acid groups on the nanotube surface were converted into acyl chlorides by refluxing the samples in thionyl chloride. Then the acid chloride functionalized carbon nanotubes were reacted with hydroxyl groups of dendritic PEG polymers via esterification reactions. Similarly, many polymers terminated with amino or hydroxyl moieties have been used in amidation and esterification reactions with acid chloride modified NTs poly(propionylethylenimine-co-ethylenimine) (PPEI-EI) [33], poly(styrene-co-aminomethylstyrene) (PSN) [34], poly-(amic acid) containing bithiazole rings [35], monoamine-terminated poly(ethylene oxide) (PEO) [36], poly(styrene-co-hydroxymethylstyrene) (PSA) [37], poly(styrene-co-p-[4-(4 -vinylphenyl)-3-oxabutanol]) (PSV) [38], poly(vinyl alcohol) (PVA) [39], poly(vinyl acetate-co-vinyl alcohol) (PVA-VA) [40] or poly[3-(2-hydroxyethyl)-2,5-thienylene] (PHET) [41]. 

FIGURE 7.18 Preparation of Fmoc-amino-acid chlorides by reaction (A) of thionyl chloride,47 phosgene from triphosgene,54 l-chloro-2,A7,A7-trimethyl-l-propene- 1-amine, [Schmidt et al., 1988] or oxalyl chloride, [Rodriguez, 1997] with the parent acid and (B) of hydrogen chloride with the mixed anhydride.51... 

The traditional use of phosgene in Scheme 4 can be avoided by substituting it with the less toxic triphosgene, which gives comparable yields of the M-car-boxyanhydrides. Diphosgene may also be used to form the NCA, but the reaction requires the use of charcoal and is not as reliable. Free amino acids have also been converted to their corresponding NCAs by the use of benzyl chloroforma-te with thionyl chloride. 

Nohira et al. treated N-acylamino acids 195 with thionyl chloride mixed anhydrides 196 were formed below 30°C. The latter compounds gave the first type of hexahydro-2//-3,l-benzoxazin-4-one 197 on triethylamine treatment [77H(7)301]. This reaction was also performed with diexo- and diendo-substituted j8-amino acids 198 yielded the 5,8-methano-2//-3,l-benzoxazin-4-ones 199 via the acyl derivatives 200 (84S345,84T2385). Further homologs were also prepared by the dehydration of N-acylamino acid derivatives (85MI1 88MI3). 

Procaine Procaine, the 2-diethylaminoethyl ester of 4-aminobenzoic acid (2.1.1), better known as novocaine, is synthesized in two ways. The first way consists of the direct reaction of the 4-aminobenzoic acid ethyl ester with 2-diethylaminoethanol in the presence of sodium ethoxide. The second way of synthesis is by reacting 4-nitrobenzoic acid with thionyl chloride, which gives the acid chloride (2.1.2), which is then esterified with iV,Ar-diethylaminoethanol. Subsequent reduction of the nitro group by hydrogenation of the resulting ester (2.1.3) into an amino group takes place in the presence of Raney nickel [ 1 ]. 

Diclofenac Diclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is synthesized from 2-chIorobenzoic acid and 2,6-dichloroaniline. The reaction of these in the presence of sodium hydroxide and copper gives iV-(2,6-dichlorophenyl)anthranyIic acid (3.2.38), the carboxylic group of which undergoes reduction by lithium aluminum hydride. The resulting 2-[(2,6-dicholorphenyl)-amino]-benzyl alcohol (3.2.39) undergoes further chlorination by thionyl chloride into 2-[(2,6-dichlorophenyl)-amino]-ben-zylchloride (3.2.40) and further, upon reaction with sodium cyanide converts into... 

Mesoionic 4-amino-l,2,3,5-thiatriazoles constitute the only class of mesoionic 1,2,3,5-thiatriazoles known. They are prepared by the reaction of l-amino-l-methyl-3-phenylguanidine with approximately 2 equivalents of thionyl chloride with pyridine as solvent (88ACS(B)63>. They are obtained as the yellow 1 1 pyridine complexes (17). The dark-violet mesoionic 1,2,3,5-thiatriazole (18) was liberated on treatment with aqueous potassium carbonate (Scheme 3). The structure is established on the basis of elemental analysis and spectroscopic data. In particular, the IR spectrum is devoid of NH absorptions. Compound (18) exhibits a long-wavelength absorption at 463 nm in methanol. When mixed with an equivalent amount of pyridinium chloride, complex (17) is formed and the absorption shifts to 350 mn. The mesoionic thiatriazoles are sensitive towards mineral acids and aqueous base and although reaction takes place with 1,3-dipolarophiles such as dimethyl acetylene-dicarboxylate, a mixture of products were obtained which were not identified. 

The incorporation of complex side chains at the 7 position based on alkyloximes of 2-amino-thiazole-5-gyloxylamides has provided drugs with very wide antibacterial activity that extend to hitherto resistant species such as pseudomonas. The preparation of one of the simpler side chains involves, first, the formation of the methyl ether from the oxime obtained by the nitrosation of methyl acetoacetate. Chlorination of the product, for example with sulfuryl chloride, gives the intermediate (21-1). The aminothiazole ring is then formed by reaction of that with thiourea to give (21-2). The free acid (21-3) is obtained by saponification of the product. The protected acid chloride (21-5) is obtained by sequential acylation of the amino group with chloroacetyl chloride and then reaction with thionyl chloride. 

The hydroxy groups of pyrrolizidine amino-alcohols are readily replaced by chlorine atoms upon treatment with thionyl chloride (see, e.g., refs. 101 and 103). In this reaction, the allylic hydroxyl group is more reactive and can be selectively replaced by chlorine.79 In some particular cases, methoxyl groups can also be substituted for halogen e.g., l/3-methoxymethyl-8a-pyrrolizidine, when treated with hydro-bromic acid, gives rise to the corresponding bromo derivative.104... 

Symmetrical anhydrides (SAs) of protein amino acids are conveniently prepared in situ, whereas the more stable SAs from OMetrasubstituted a-amino acids generally give better results in coupling reactions when they are isolated beforehand. Only SAs of the least sterically hindered Ca-tetrasubstituted a-amino acids, e.g. Aib, can be prepared in good yields upon treatment of the urethane N-protected amino acid with half an equivalent of carbodiimide or thionyl chloride. In most of the other cases a mixture of SA and oxazol-5(4//)-one is obtained 14 however, SAs can be obtained in satisfactory yields by reacting one equivalent of preformed oxazol-5(4/7)-one with one equivalent of the corresponding free acid (Scheme 3)J49 50 ... 

If benzyl carbamate is used as the amide component in the reaction with a-oxo acids 23 then the Na-benzyloxycarbonyl-DHA 24 is obtained directly (Scheme 8). Shin and et al.[77 84l widely exploited the above method in the synthesis of various a, 3-didehydropeptides (Table 3). In presence of 3 M thionyl chloride and acetyl chloride, 24 gave the A-carboxy-DHA anhydride ANCA 25, which could be conveniently converted into dehydropeptides.[77 84 Compared with the common saturated A-carboxy-a-amino acid anhydrides (NCAs), ANCAs were found to be stable at room temperature for several months. 

The reaction of Tentagel-bound carboxylic esters with amidooximes has been used to prepare oxadiazoles (Entry 11, Table 15.20). Thiadiazoles have been prepared from support-bound iV-sulfonylhydrazones by treatment with thionyl chloride. Thiadiazole formation and cleavage from the support occurred simultaneously (Entry 12, Table 15.20). Perhydro-l-thia-2,5-diazole-2,2-dioxides (sulfahydantoins) have been prepared by aminosulfonylation of amino acids esterified with Wang resin, followed by ring-closure with simultaneous cleavage from the support [257]. 

Reaction of 4-(hydroxyl methylphosphinyl)butanoic acid (154) with thionyl chloride followed by successive treatment with copper powder, potassium iodide, and potassium carbonate affords l-methyl-2-oxophospholane 1-oxide (155) in 65% yield. 3-Bromo-, 3-amino-, 3-acethylamino-l-methyl-2-oxophospholanes (156-158) are prepared by substitution of the 3-methylene position (Scheme 51) [64]. 

Omeprazole is obtained [15] by the reaction of acetyl ethyl propionate 1 with ammonia to give ethyl -3-amino-2,3-dimethyl acrylate 2. Compound 2 was converted to to 2,4-dihydroxy-3,5,6-trimethyl pyridine 3 by treatment with methyl diethylmalonate. Treatment of compound 3 with phosphorous oxychloride produced 2,4-dichloro-3,5/6-trimethyl pyridine 4. 4-Chloro-3/5,6-trimethyl pyridine 5 was obtained by treatment of compound 4 with hydrogen. On treatment of compound 5 with hydrogen peroxide and acetic acid, 4-chloro-3,5,6-trimethyl-pyridine-N-oxide 6 was produced. Treatment of compound 6 with acetic anhydride gave 4-chloro-2-hydroxymethyl-3,5-dimethyl pyridine 7 which was converted to 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine 8 by treatment with sodium methoxide. Compound 8 was treated with thionyl chloride to produce 2-chloromethyl-3,5-dimethyl-4-methoxypyridinc 9. Compound 9 interacts with 5-methoxy-2-mercaptobenzimidazole to give 5-methoxy 2-[((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-lH-bcnzimidazole 10 which is oxidized to omeprazole 11. 

Substituted l,2,3,5-thiatriazolium+-aminides 9 constitute the only known class of mesoionic 1,2,3,5-thiatriazoles <1988ACB63>. They are formed in the reaction of l-amino-l,3-disubstituted guanidines with approximately 2 equiv of thionyl chloride in pyridine as the solvent. The mesoionic compounds 9 are sensitive toward acids and bases (Scheme 2) <1988ACB63>. 

Step 4 A solution of 20 grams of the above amino alcohol is dissolved in 50 ml of dry chloroform and treated with dry hydrogen chloride until acid. Then a solution of 9 grams of thionyl chloride in 50 ml of dry chloroform is added and the reaction mixture is heated on a water bath at 50°-60°C for 2 hours. Most of the chloroform is removed by distillation under reduced pressure. Addition of ether to the residue causes the product to crystallize. After recrystallization from a mixture of alcohol and ether, the N-(phenoxyisopropyl)-N-benzyl-p-chloroethylamine hydrochloride melts at 137.5°-140°C. 

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