Mandelic acid, -, preparation

Mandelic acid. This preparation is an example of the synthesis of an a-hydroxy acid by the cyanohydrin method. To avoid the use of the very volatile and extremely poisonous hquid hydrogen cyanide, the cyanohydrin (mandelonitrile) is prepared by treatment of the so um bisulphite addition compound of benzaldehj de (not isolated) with sodium cyanide ... 

The ether extraction method (B) is quicker, especially when several runs are to be made. Mandelic acid is obtained in the same yield by this method. The benzene extraction may be better for small preparations, or when a single run is to be made. 

Mandelic acid is best prepared by the hydrolysis of mandeloni-trile with hydrochloric acid. The mandelonitrile has been prepared from amygdalin, by the action of hydrocyanic acid on benzaldehyde, and by the action of sodium or potassium cyanide on the sodium bisulfite addition product of benzaldehyde. ... 

Chlorophenylacetic acid has been prepared from mandeloni-trile and hydrochloric acid in a sealed tube, from mandelic acid and hydrochloric acid in a sealed tube/ from a-nitrostyrene and hydrochloric acid in a sealed tube, from phenylglycine, hydrochloric acid, and sodium nitrite, from mandelic acid and phosphorus pentachloride (to give the acid chloride which is then hydrolyzed), and, in poor yield, from mandelic acid and thionyl chloride. In the method described, ethyl mandelate is prepared according to Fischer and Speier. The conversion to the chloroester and the acid hydrolysis step are modifications of a preparation described by McKenzie and Barrow. ... 

It is preferably prepared by reacting mandelic acid ethyl ester with guanidine in boiling alcoholic solution whereby it is obtained as difficultly soluble precipitate with a yield of 90%. 

Ethyl benzoylformate has been prepared by the direct esterification of the acid 1 and by the action of oxides of nitrogen on an alcoholic suspension of indigo.2 The acid has been prepared by many different reactions but the most practical are the hydrolysis of benzoyl cyanide,3 the oxidation of acetophenone 4 and the oxidation of mandelic acid.5... 

The enantiomerically pure (/ )- and (iS )-ketones are prepared from the corresponding enantiomer of mandelic acid by catalytic hydrogenation, treatment of the resulting hexahydroman-delic acid with ethyllithium, and subsequent introduction of the silyl protecting group33. 

The chiral acetate reagent is readily prepared from methyl mandelate [methyl (A)-hydroxy-phenyl acetate] which is first converted by treatment with phcnylmagnesium bromide into the triphenylglycol783, c (see Section 1.3.4.2.2.2.) and subsequently transformed into the acetate by reaction with acetyl chloride in the presence of pyridine. Thereby, the secondary hydroxyl group of the glycol is esterified exclusively. Both enantiomers of the reagent are readily accessible since both (R)- and (5)-hydroxyphenylacelic acid (mandelic acids) arc industrial products. 

Benzoylformic acid can be prepared by the oxidation of acetophenone with potassium permanganate in alkaline solution,1 by the oxidation of mandelic acid with potassium perman-... 

In the flask are placed 240 g. (2 moles) of acetophenone and 1 1. of glacial acetic acid. The thermometer is adjusted so that it extends considerably below the surface of the solution, and chlorine is admitted at such a rate that the temperature does not exceed 60° (Note 1). Chlorination is continued until an excess of the halogen has been absorbed. This requires about five hours completion of the reaction is indicated by the development of a yellow color. The reaction mixture is poured over 6 1. of crushed ice in a 2-gal. jar. The mixture is stirred several times (Note 2) and allowed to stand until the ice has melted. The dichloroacetophenone, which separates as a heavy lachrymatory oil, is removed. The yield is 340-370 g. (90-97 per cent of the theoretical amount). This product, containing only a few per cent of water and acetic acid, is pure enough for the preparation of mandelic acid. It may be purified by adding about 100 cc. of benzene, removing the... 

Mandelic acid has been prepared by hydrolysis of mandeloni-trile (prepared in turn from benzaldehyde and hydrogen cyanide or from benzaldehyde, sodium bisulfite, and sodium cyanide) 3 by action of water at 180° upon trichloromethylphenylcarbinol by action of potassium carbonate upon a heated mixture of benzaldehyde and chloroform 7 by action of warm, dilute alkali upon dibromoacetophenone 8 and by action of warm, dilute sodium hydroxide upon phenylglyoxal. ... 

Pseudoephedrine hydrochloride is prepared by a Welsh rearrangement10 of -ephedrine hydrochloride with acetic anhydride followed by deacetylation with hydrochloric acid.11 -Ephedrine can be resolved from d -ephedrine with -mandelic acid.12 -Ephedrine occurs naturally in certain plants of the Ma Huang species. 

Mandelamide has been prepared by treating the ethyl ester with concentrated aqueous ammonia,12 and a saturated alcoholic solution of ammonia has been used to effect ammonolysis of the methyl ester.1 3 Esters of mandelic acid were treated with liquid... 

The next step was, therefore, to develop chiral enolates which show high diastereoselectivities (>100 1) in single asymmetric reactions. Of the many chiral (Z)-enolates which were prepared and studied by Masamune and his associates, those shown (74) in Scheme 9.24 -prepared from optically pure (S)- and R)-mandelic acid- meet the requirements set for a chiral reagent [22c]. Thus, the chiral... 

J )-Mandelic acid 3 is a useful chiral synthon for the production of pharmaceuticals such as semi-synthetic penecillins, cephalosporins and antiobesity agents and many methods have been reported for the preparation of the optically pure material. A method to deracemize the racemate which is readily available on a large scale was developed by Ohta et al. using a combination of two biotransformations. The method consists of enantioselective oxidation of (S)-... 

The pyridine subcycle unit has been introduced into a wide range of 18-crown-6 derivatives. For example, reaction of 2,6-pyridinedicarbonyl chloride with the dimethyl substituted tetraethylene glycol (SS)-84, derived from (S)-lactic acid, afforded (126) the chiral macrocyclic polyether diester (5S)-184. A similar preparative approach (127) gave (SS)-185, where the source of the chirality is (5)-mandelic acid. 

The diamine (99) was prepared from (S)-proline90b) or (S)-glutamic acid I15) maintaining the asymmetric center. Racemic 2-(anilinomethyl)pyrrolidine, prepared from (RS)-5-oxopyrrolidine-2-carboxylic acid, was effectively resolved into a pair of enantiomers by fractional crystallization of its mandelic acid salt U6). Moreover, the preferential crystallization of its 4-hydrobenzoic acid salt was found to produce both enantiomers in high optical purities by alternate seeding116). 

The original Sanofi synthesis of ( )-clopidogrel (2) began with the formation of the methyl ester 13. Thus methyl mandelate 13 was prepared by refluxing chlorinated mandelic acid 12 with methanol in the presence of concentrated HCl. Chlorination of... 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

The P-cyanodiester 4 was prepared by condensation of isovaleraldehyde with diethyl malonate followed by the addihon of potassium cyanide. The cyanodiester 4 was hydrolyzed and decarboxylated to give the P-cyano acid 5. Reduction with Raney nickel gave racemic pregabalin (6), which was resolved with (S)-mandelic acid. The diastereomeric salt was split with wet TH F under neutral conditions to give pregabalin, which was recrystallized from isopropanol (IPA) to give the final Active Pharmaceutical Ingredient (API). 

Enantioselective aldol condensation. Masamtinc et al. have prepared optically pure /Miydroxy-a-methyl carboxylic acids by aldol condensation with the (S)- and (RHsomers of the ethyl ketone I, prepared in three steps from commercially available (S)- and (R>mandelic acid. For example, (SH is converted into the (Z)-boron cnolatc (2), which condenses with propionaldehyde to form a single aldol... 

S-(0-Methyl)mandelic acid chloride was prepared (14-h reflux in 5 mL of benzene) from the S-(0-methyl)mandelic acid (0.33 g, 2.0 mmol) and oxalyl chloride (0.34 mL, 4.0 mmol). The chloride was added to a solution of 3 (0.56 g, 2.0 mmol) and dry pyridine (0.33 mL, 4.0 mmol) in dry toluene (20 mL) at — 10°C. The mixture was then allowed to attain 0°C. After 14 h, toluene was added, and the mixture was washed with water (20 mL). Toluene solution was dried (MgS04) and concentrated to dryness to yield 4 (0.84, 98%), which was used in the next step without purification. 

---