Ethyl Chloroformate mixed anhydrides

Nucleophilic aromatic substitution of the anion from ary lace ton itrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

Example 1 ot-AzidobenzylpenicWin via the Mixed Anhydride — A solution of o-azido-phenylacetic acid (8.9 grams, 0.05 mol) of triethylamine (5.1 grams, 0.05 mol) in 50 ml of dry dimethylformamide was stirred and chilled below -5°C. At this temperature ethyl chloroformate (4.7 ml) was added in portions so that the temperature was never above -5°C. After the mixture had been stirred for 20 minutes, dry acetone (100 ml), chilled to -5°C, was added in one portion, immediately followed by an ice-cold solution of 6-aminopenicillanic acid (10.8 grams, 0.05 mol) and triethylamine (5.1 grams, 0.05 mol) in 100 ml of water, and the stirring was continued for VA hours at 0°C. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

Ethyl chloroformate obtained from Aldrich Chemical Company, Inc., was distilled, b.p. 93°. The progress of the reaction may be followed by proton magnetic resonance spectroscopy. Aliquots are partitioned between dichloromethane and water, the organic layer is concentrated, and the spectrum is recorded. A quartet from the ethoxy group of the mixed anhydride appears at 8 4.2. Ethyl chloroformate, which exhibits a quartet at 6 4.3, is removed in the concentration step. 

The acyl azide intermediates are prepared either by reaction of sodium azide with a reactive acylating agent or by diazotization of an acyl hydrazide. An especially convenient version of the former process is treatment of the carboxylic acid with ethyl chloroformate to form a mixed anhydride, which then reacts with azide ion.265... 

The title compound 188, currently under development for the treatment of acne, psoriasis and photoaging via a topical application, has been synthesized161 in two steps by reacting carboxyl-[14C]vitamin A, 189, with ethyl chloroformate and subsequent treatment of the mixed anhydride 190 with acetamidophenol in the presence of a catalytic amount of 4-dimethylaminopyridine (equation 68), Carbon- 14-labelled compound was needed to investigate its metabolism and the extent of systematic adsorption of 188 after dermal application. 

Mixed anhydrides. Ethyl chloroformate and isobutyl chloroformate are the reagents most often used. 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chloroformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

Cefoperazone Cefoperazone, (6/ ,7/ )-7-[(/ )-2-(4-ethyl-2,3-dioxo-l-piperazincarboxam-ido)-2-(p-hydroxyphenyl)acetamido]-3-[[(l-methyl-l//-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.84), is synthesized by acylating 7-amino-3-(l-methyl-l,2,3,4-tetrazol-5-yl)-thiomethyl-3-cefem-4-carboxylic acid (32.1.2.24) with a mixed anhydride synthesized from ethyl chloroformate and a-(4-ethylpiperazin-2,... 

Diazomethane is generated by the reaction of aqueous NaOH with N-methyl-N-nitroso-p-toluenesulfonamide (Diazald ) in DMSO. The diazomethane is generated quantitatively and is removed by a stream of N2 into a packed column containing a stream of mixed anhydride formed from an N-protected (BOC or CBZ) amino acid and ethyl chloroformate. The diazoketone is converted to the chloroketone using HCI, as shown in Scheme 11.10. The chiral epoxide can then be formed via diastereoselective reduction with NaBH4 and treatment with base. 

The synthesis of the peptide-based triazole 63 is shown in Scheme 19J102l Coupling of Boc-Ser(Bzl)-OH (61) with ethyl ox am i drazon ate11131141 proceeded under mixed anhydride conditions177 using ethyl chloroformate as the activating reagent. The product acylamidrazone 62 thus formed was simply heated in xylenes under Dean-Stark conditions to form the desired triazole 63. 

A number of 2,3-fused chromones have been prepared from ethyl chloroformate and acetylsalicylic acid, a source of the mixed anhydride of formic and salicylic acids, and piperidinocycloalkenes (69JCS(C)935). A plausible mechanism is outlined in Scheme 165. It has not proved possible to isolate the chromanone (460) but the formation of 3-acetyl-2-methylchromone from 2-pyrrolidinopropene lends support to the intermediacy of the chromanone. The migration of the acyl group from oxygen to carbon is supported by the synthesis of 3-benzoyl-2-methylchromone rather than 3-acetylflavone from benzoylsalicylic acid and the pyrrolidinopropene. 

Peptide bond formation. The process requires that the derivative (42), a carboxylic acid, should be caused to acylate the free base liberated from the hydrochloride (43). Activation of the carboxyl group is effected by conversion into a type of acid anhydride the mixed carbonic anhydride (44) is used here, and is prepared by reaction of the acid (42) with ethyl chloroformate. 

The mercapto group of 9-mercapto-4//-pyrido[ 1,2-a]pyrimidin-4-ones 513 was alkylated with (het)aralkyl bromides and chlorides in the presence of potassium carbonate in dimethylformamide at ambient temperature for several hours. It also was acylated with carboxyl chlorides in the presence of potassium carbonate in acetone at room temperature or with mixed anhydride, prepared from aryl carboxylic acid and ethyl chloroformate,... 

The reaction of phthalic anhydride with 1,3,4,6-tetra-0-acetyl-2-amino-2-deoxy-D-glucose leads to the formation of the expected A-phthaloyl amide or phthalamic acid. Furthermore, intramolecular condensation occurs, presumably by way of a mixed anhydride intermediate, on treating this with ethyl chloroformate, thereby forming an A,A-phthaloyl imide, 1,3,4,6-tetra-0-acetyl-2-deoxy-2-phthalimido-D-glucose.105 106 The 2-amino-2-deoxy-D-glucose derivative can be regenerated by the action of hydrazine.69 107... 

To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in methyl isobutylketone (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 min at room temperature. To the formed mixed anhydride was then added l-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65°C and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding benzamide, 4-amino-5-chloro-N-(l-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy-, monohydrate, cis- (Cisapride) having a cis/trans ratio higher than 99/1. 

The amino group in Z-Ala is protected as the nonnucleophilic amide half of a carbamate ester. The carboxyl group can be activated without reacting with the protected amino group. Treatment with ethyl chloroformate converts the carboxyl group to a mixed anhydride of the amino acid and carbonic acid. It is strongly activated toward nucleophilic attack. 

---