Maleate salt

The hydrochloride salt was neutralized with 10% sodium hydroxide solution and the free base so produced was dissolved in ether. The ether solution was dried over anhydrous magnesium sulfate. Addition of an excess of maleic acid in methanol to the solution yielded the acid maleate salt which melted at 188.5°-191°C. 

Pfizer s initial formulation of amlodipine relied on a maleate salt, but two problems were encountered "(1) the chemical instability of... 

CAS Registry No 65576-45-6(Free base) 85650-56-2(maleate salt) Molecular Weight 285.77 (Free base) 401.84 (maleate salt)... 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

Various carboxylic acid salts have also been reported. Gallardo35 produced the maleate salt of neomycin which, it was claimed, improved the aqueous stability of the antibiotic. A practically tasteless compound, the citrate salt,has been described by Szyszka3 . Neomycin mandelate has been claimed to be particularly useful in the treatment of urogenital infections3 while the di-hydroxy-dinaphthylmethane-dicarboxylate4(3 and the pamoate salts43,67,68 have a low intestinal absorption and are thus effective treatments for intestinal infections. 

Amlodipine maleate salt Drug Calcium channel blocker... 

Since LSD would be released as an aerosol if used in a military setting, we devoted considerable effort to estimating its relative potency by the inhalation route. Two forms of the drug the maleate salt (black circles) and the free base (white) were compared (Fig. 95). There appeared to be no difference between the two salts in their effects on NF performance. 

LSD Comparative Retention of Inhaled Free Base vs. Maleate Salt... 

The initial synthetic route employed by the medicinal chemistry group is straightforward a moderately diastereoselective reductive amination between ethyl-2-oxo-4-phenylbutyrate (13) and alanyl-proline (14) generated a 1.6 1 mixture of diastereomers favoring the desired (5,5,5)-enantiomer (Scheme 10.2). Fractional recrystallization afforded enalapril as the maleate salt (Harris et al., 1983 Wyvratt et al., 1984). Although requiring only one synthetic step, the diastereoselectivity of the process is poor, reducing the overall yield. 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

Introduction of the C2 sulfonamide is accomplished via sulfonylation with chlorosulfonic acid, conversion to the sulfonyl chloride using thionyl chloride, and amidation using concentrated ammonium hydroxide in tetrahydrofuran. Reduction of the 4-acetamido compound using borane-tetrahydrofuran complex provides the 4-ethylamino derivative. The 45,65-frans diastereomer is selectively crystallized as its maleate salt from acetone in the presence of the unwanted 4R,6S-cis diastereomer. Neutralization of the maleate salt and extraction of the free base in ethyl acetate, followed by formation of the hydrochloride salt, yields crude dorzolamide hydrochloride. 

Dorzolamide contains two chiral centers, and is therefore capable of existing in four diastereomers. The stereochemistry at the C-6 position of the starting material is preserved during the various chemical reactions which take place during the synthesis. The stereochemistry at the C-4 position (absolute configuration being 5) results from the Ritter substitution reaction (Scheme 1, Steps I-II) used to transform the alcohol to an acetamide. The Ritter reaction yields mostly the rra j-diastereomer, and the c/s-diastereomers are easily separated as their maleate salts. The potential sulfonamide positional isomer (3-sulfonamide) has not been observed at levels greater than 0.1% in HPLC analyses. 

Enalapril maleate is an orally active angiotensin converting enzyme (ACE) inhibitor, it lowers peripheral vascular resistance without causing an increase in heart rate. The maleate salt (enalapril) allows better absorption after oral administration. It is an ideal drug for hypertensive patients who are intolerant to beta-blocker therapy. It also shows promise in the treatment of congestive heart failure. Following oral adminishation, enalapril is rapidly absorbed and hydrolysed to... 

A solution of N-(4-pyridinyl)-lH-indol-l-amine (6 g) in 25 ml of dimethylformamide was slowly added to an ice-cooled suspension of NaH (1.3 g of 60% NaH dispersion in mineral oil was washed with hexanes, the liquid was decanted and the residual solid was dispersed in 5 ml of dimethylformamide). After anion formation, a solution of 1-bromopropane (4 g) in 5 ml of dimethylformamide was added. After one hour of stirring at ambient temperature, the reaction mixture was stirred with ice-water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, filtered and concentrated to 8 g of oil. This oil was purified by HPLC (silica, ethyl acetate) and thereafter by column chromatography (alumina, ether) to give 6.4 g oil. This oil was converted to the maleate salt and recrystallized from methanol/ether to give 6.8 g of crystals, m.p. 115-116°C. 

The ethyl acetate solution containing aminosulfonamide (ca. 27.9 g, 86 mmol 95 5 trans/cis) from step 5 was concentrated by distillation (1 atm) to a volume of 70 mL. Acetone (250 mL) was added and the concentration repeated to a volume of 70 mL. The operation was repeated, this time concentrating to a volume of 160 mL. Maleic acid (9.98 g, 86 mmol) was added. The mixture was stirred until the salt crystallized, and was then stirred for 12-18 h at 20°-22°C. The mixture was filtered, and the product cake washed with acetone (1 bed volume). The product was air-dried, then dried in vacuo (100 mBar, nitrogen sweep, 75°C) to constant weight. Yield 33.0 g (92%) of the maleate salt as a white crystalline solid. HPLC 99 1 trans/cis (above method). 

To a mechanically stirred mixture of ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate (120 mL) was added maleate salt (33.0 g, 75 mmol 99 1 trans/cis). The mixture was stirred at 20°-25°C until all of the solid dissolved, and the two phases became clear. The mixture was allowed to settle and the layers then separated. The aqueous (lower) phase was extracted with ethyl acetate (50 mL). The organic layers were combined and... 

Chemical Abstracts Registry No. 91-84-9 6036-95-9 (Hydrochloride salt) 59-33-6 (Maleate salt)... 

Dihydro-10,10-dioxo-l l-methyldibenzo[c,f][l,2]thiazepin-5-yloxy)tropane and the hydrogen maleate salt thereof. (This name was given by the authors of U. S. Patent No 3 700 633. It corresponds to endo-6,11-dihydro-6-methyl-ll-[(8-methyl-6-azabicyclo[3.2.1]oct-3-yl)oxy]dibenzo[c,f] [l,2]thiazepine 5,5-dioxide and 6,ll-dihydro-6-methyl-ll-(8-methyl-8-azabicyclo[3.2.1]octan-3a-yloxy)dibenzo[cf][l,2]thiazepin-5,5-dioxide). 

The base is converted to the hydrogen maleate salt by treatment in ethyl acetate solution with one molecular proportion of maleic acid. This material is recrystallized from ethanol, MP 215°C. 

Initial blood pressure lowering studies of compound 20 in rats and dogs have been summarized by Sweet, Gross and co-workers (123, 125). After thorough study of its in vivo properties, compound 20 as its maleate salt entered clinical studies as MK-421, with the generic name enalapril. 

E. Zannou, Q. Ji, A. Serajnddin, and Y. Joshi, Stabilization of maleate salt of a basic drug in solid dosage form by microenvrromental pH adjnstment. Inti. J. Pharmaceutics (Oct 2006), snbmitted. 

---