Tartrate salts

R = N(CH2CH3 )2) (LSD-25, as the tartrate salt) could be absorbed through the skin with resulting inebriation. In a bold experiment, it was then demonstrated that oral ingestion resulted in symptoms characteristic of schizophrenia which, although temporary, were quite dramatic (64). 

Destmction of the aluminum complex with ammonia then permits hydrocarbon extraction of the alkaloid. The alkaloid is subsequently both isolated and used as its tartrate salt. This nonnarcotic dmg, for which tolerance may develop, is frequently used orally with caffeine (16) for treatment of migraine it acts to constrict cerebral blood vessels, thus reducing blood flow to the brain. 

Purified by recrystn from aqueous EtOH or MeOH or aqueous NH3 + EtOH or isoPrOH. Also recrystd from aqueous ammoniacal soln at pH 10.5 (lOOmg/mL) by diluting with 5 volumes of isopropanol and then adjusting to pH 6 with acetic acid. An aqueous soln buffered to pH 10 with Na2C03 can be stored in a refrigerator for 1 week without decomposition. UV Xma, 226nm (/ij 4.02). The tartrate salt has m 165-166° (dec), 166-168° (dec), and [ag -41° (c 0.7, H2O). [Stammer et al. J Am Chem Soc 79 3236 7959 UV Kuehl J Am Chem Soc 77 2344 7955.]... 

Resolution of racemorphan via the tartrate salt affords a very potent analgesic. The (-) isomer, is a narcotic... 

Condensation of piperazine with 2-methoxytropone gives the addition-elimination product 12 [2]. Alkylation of the remaining secondary amino group with bromoketone 13, itself the product from acylation of dimethyl catechol, gives aminoketone 14. Reduction of the carbonyl group with sodium borohydride leads to secondaiy alcohols 15 and 16. Resolution of these two enantiomers was achieved by recrystallization of their tartrate salts to give ciladopa (16) [3],... 

The tartrate salt is recrystallized by dissolving in hot methanol, filtering, adding hot ethanol to the filtrate and cooling. The product is collected and air-dried. MP 148°-150°C. A second crop is obtained from the filtrate for a total yield of 59%. The tartrate is then metathe-sized with pamoic acid (Merck Index 6867) to give pyrantel pamoate as the product. 

Sulfate, phosphate, chloride, acetate, and tartrate salts of 57/-dibcnz[6,/]a/cpine-5-carbox-amide have been described.182... 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

Chiral ethyl nipecotate L-tartrate salt 21 was not available on a large scale. 

C. (1S,2S)-(-)- and (1 R,2R)-(+)-1,2-Diphenyi-1,2-ethylenediamine (Note 11). A 1 -L, round-bottomed flask equipped with a mechanical stirrer is charged with 42.5 g (0.200 mol) of the racemic diamine and 230 mL of ethanol (Note 9). The solids are dissolved by heating the mixture to 70°C whereupon a hot (70°C), homogeneous solution, of 30.0 g (0.200 mol) of (L)-(+)-tartaric acid (Note 12) in 230 mL of ethanol is added (Note 13). The tartrate salts precipitate immediately, and after the mixture is cooled to ambient temperature, the crystals are collected by filtration, washed twice with 60 mL of ethanol, and dried under reduced pressure. The solids are dissolved in 230 mL of boiling water, 230 mL of ethanol is added and the homogeneous solution is allowed to cool slowly to room temperature. The crystals are collected by filtration, washed with 40 mL of ethanol and dried under reduced pressure. The recrystallization procedure is then repeated twice using the same volumes of solvents (230 mL of water and 230 mL of ethanol) to give 23-25 g (63-69%) of the tartrate salt... 

The resulting dry LSD base is chromatographed on basic alumina (activity grade 1) as previously described. The blue band is collected as before, evaporated and converted into the tartrate salt. The iso-LSD band may be collected and saved for further re-cycling. 

Crystal structures are available for many (N)4Co-amino acid complexes (Table I). Many of the diastereomers (AS, AS) in the bis-en series have been resolved using classic crystallization (usually via bromocamphor sulfonate, arsenyl-, or antimonyl-tartrate salts) or ion exchange methods (Table II). Reversed-phase ion-pair HPLC, using aryl phosphate or aryl/alkyl sulfonate ion pairing reagents in MeOH/ H20 eluent, has allowed diastereomer separations to be carried out on analytical amounts (28) (Table II). 

Metal oxides were also chirally modified and few of them showed a significant or at least useful e.s. Thus, while Al203/alkaloid [80] showed no enantiodifferentiation, Zn, Cu, and Cd tartrate salts were quite selective for a carbene addition (45% e.e.) [81] and for the nucleophilic ring opening of epoxides (up to 85% e.e.) [82], Recently, it was claimed that /(-zeolite, partially enriched in the chiral polymorph A, catalyzed the ring opening of an epoxide with low but significant e.s. (5% e.e.) [83], All these catalysts are notyet practically important but rather demonstrate that amorphous metal oxides can be modified successfully. 

C. (R,R)-N,N -Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. A 2-L, three-necked, round-bottomed flask equipped with a mechanical overhead stirrer, reflux condenser, and an addition funnel is charged with 29.7 g of (R,R)-1,2-diammoniumcyclohexane mono-(+)-tartrate salt (0.112 mol), 31.2 g of potassium carbonate (0.225 mol, 2 eq), and 150 mL of water. The mixture is stirred until dissolution is achieved, and 600 mL of ethanol is added. The cloudy mixture is heated to reflux with a heating mantle and a solution of 53.7 g (0.229 mol, 2.0 eq) of 3,5-di-tert-butylsalicylaldehyde in 250 mL of ethanol is then added in a slow stream over 30 min (Note 19). The addition funnel is rinsed with 50 mL of ethanol and the mixture is stirred at reflux for 2 hr before heating is discontinued. Water, 150 mL, is added and the stirred mixture is cooled to <5°C over 2 hr and maintained at that temperature for another hour. The yellow solid is collected by vacuum filtration and washed with 100 mL of ethanol. After the solid is air dried, it is dissolved in 500 mL of methylene chloride. The organic solution is washed with 2 x 300 mL of water, followed by 300 mL of saturated aqueous sodium chloride. The organic layer is dried over sodium sulfate, and filtered to remove the drying agent. The solvent is removed by rotary evaporation to yield the product as a yellow solid, mp 200-203°C (Notes 20 and 21). 

The aqueous filtrates may be combined and saved for isolation of (S,S)-1,2-diaminocyclohexane as the bis-(+)-tartrate salt using an alternate procedure.2 The methanol washes can be discarded. 

The (S.S)-diamine can be obtained as the mono-(-)-tartrate salt by using the same procedure with D-(-)-tartaric acid. 

More than 60 years later Darwish and co-workers (151,152) prepared a series of chiral trialkylsulfonium, dialkylarylsulfonium, and diarylalkylsulfonium perchlorates by resolution of the corresponding (-)-dibenzoyl hydrogen tartrate salts followed by replacement of the optically active acid anion by perchlorate. At the same time, 1-ada-mantylethylmethylsulfonium perchlorate 105 (153) and 1-adaman-tylethylpropenylsulfonium tetrafluoroborate 106 (154) were resolved... 

Navelbine administered as its tartrate salt vinblastine and vincristine administered as their sulfate salts. 

These chiral bishydroxamic acids 235a and 235b were synthesized starting from a readily available diamine tartrate salt as shown in Scheme 101. 

At least one group attempted to synthesize enantio-enriched 1 via as5munetric reduction of 8 with modest success (Krasik and Alper, 1992). The classical resolution of racemic 1 (via the bis-tartrate salt, for example) (Nabenhaur, 1942) remains as the simplest and most economical method for preparing chiral amphetamine (1) on a large scale. 

An efficient and simple kinetic resolution of the racemic Betti base 387 was achieved via its reaction with acetone in the presence of L-(- -)-tartaric acid. When a suspension of racemic 387 in acetone was treated with L-(- -)-tartaric acid, the (A)-enantiomer formed a crystalline L-tartrate salt 389 this was filtered off, and the (iJ)-enantiomer could be isolated as a naphth[l,2-< ]oxazine derivative 388 from the filtrate (Equation 41). Both enantiomers were obtained in excellent yields and ee s. The enantioseparation is presumed to take place via a kinetically controlled N,0-deketalization of the (3)-naphth[l,2-< ]oxazine derivative <2005JOC8617>. An improved method for the enantioseparation of 387 was developed by the reaction of the ring-chain tautomeric l,3-diphenyl-3,4-dihydro-2//-naphth[2,l-< ][l,3]oxazine (41 X, Y = H) and L-(-f)-tartaric acid, yielding the crystalline 389 in 85% yield <2007SL488>. 

Thus, treatment of the benzamide (35-1) from 2-phenethylamine with phosphorus oxychloride probably results in an initial formation of a transient enol chloride this then cycUzes to (35-2) under reaction conditions. The imine is then reduced with sodium borohydride. Resolution by means of the tartrate salt affords (35-3) in optically pure form. Acylation of that intermediate with ethyl chloroformate leads to carbamate (35-4). Reaction of this last with the anion from chiral quiniclidol (35-5) interestingly results in the equivalent of an ester interchange. There is thus obtained the anticholinergic agent solifenacin (35-6) [40]. 

S)-N-(tert-butoxycarbonyl)-hydroxymethylpiperidine (8) is a key intermediate in the synthesis of a potent tryptase inhibitor (Scheme 7.5). It was synthesized from (R,.S)-3-hydroxyrnethylpiperidine via fractional crystallization of the corresponding L(-)dibenzoyl tartrate salt followed by hydrolysis and acylation [17]. The lipase from Pseudomonas cepacia (PS-30) immobilized on polypropylene accurel PP catalyzed the esterification of racemic 6 with succinic anhydride and toluene, giving the (S)-hemisuccinate ester (7). This was easily separated and hydrolyzed by base to the (S)-Boc-protected 3-hydroxymethylpiperidine (8). Using this repeated esterification procedure gave a 32% yield (maximum theoretical yield = 50%) and 98.9% . 

DAL, N,N-Diallyllysergamide. As the tartrate salt, there is at best a touch of sparkle seen at 600 micrograms orally, but there is a sedation also reported. It is certainly an order of magnitude less potent than LSD itself. 

Pyrantel, the parent compound of morantel, is used against gastrointestinal parasites of sheep, goats, pigs, cattle, and deer at dosages in the range 15-20 mg/kg bw. Its tartrate salt is administered orally to animals in forms of a feed premix, pellets, or drench. 

The tartrate salt was then converted to the phosphate salt, the desired salt form of sitagliptin by free-basing first with KOH in aqueous THF, solvent-switching the organic phase to ethanol and adding phosphoric acid to crystallize the phosphate salt in 93% yield with high enantiomeric and chemical purities. 

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