US3764604A

US3764604A - 4-pyridylcarbinolamine anti-malarials

Info

Publication number: US3764604A
Application number: US00150745A
Authority: US
Inventors: A Ash; C Stevens; A Markovac
Original assignee: US Department of Army
Current assignee: US Department of Army
Priority date: 1968-12-17
Filing date: 1971-06-07
Publication date: 1973-10-09
Anticipated expiration: 1990-10-09

Abstract

A series of 4-pyridylcarbinolamines is herein disclosed which has value in treatment of plasmodial infections. The compounds have substituted phenyl groups at positions 2- and 6- on the pyridine moiety, with the electronegative substituents (the same, or different) present on the phenyl nuclei. The syntheses of such series is described, together with a method for separation of racemates of a representative 4-pyridyl-carbinolamine type.

Description

United States Patent 1 3,764,604 Ash et al. Oct. 9, 1973 4-PYRIDYLCARBINOLAMINE [56] References Cited ANTI-MALARIALS inventors: Arthur B. Ash; Calvin L. Stevens, both of Detroit; Anica Markovac, Lathrup Village, all of Mich.

Assignee: The United States of America as represented by the Secretary of the Army, Washington, D.C.

Filed: June 7, 1971 Appl. No.: 150,745

Related Application Data Continuation-impart of Ser. No. 784,467, Dec. 17, 1968, Pat. No. 3,600,396.

US. Cl. 260/293.53, 260/293.69, 260/295 R, 260/296 R, 260/296 T, 260/999 Int. Cl c07d 39/06 Field of Search 260/293.53, 293.69, 260/296 R OTHER PUBLICATIONS Wiselogle, A Survey of Antimaleria Drugs 1941 to l- 945, Edwards, Ann Arbor, Mich. (1946).

Primary ExaminerHenry R. Jiles Assistant ExaminerG. Thomas Todd Attorney-Miller, Morriss, Pappas & McLeod 5 7 ABSTRACT type.

9 Claims, N0 Drawings l 4-PYRIDYLCARBINOLAM'INE ANTI MAILA R'I'A'LS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of Application Ser. No. 784,467, filed Dec. 17, I968, now US. Pat. No. 3,600,369.

BACKGROUND OF THE INVENTION The subject invention relates to 4- pyridinecarbinolamines having enhanced antimalarial activity, and to means for achieving the synthesis of such compounds. Specifically, the new products are fer structurally from those known'hitherto, and provide advantages in chemotherapeutic index and also in po-' tential for avoiding unwanted side effects such as phototoxicity.

DETAILED DESCRIPTION OF THE INVENTION The subject series of carbinolamine typesisconveniently represented by the Structure I, andto pharmaceutically-acceptable acid-addition salts thereof which also form basis for the invention. It is'in tended that there be included the several isomeric forms possible in Structure I, moreover.

The above (Structure I) establishes the new antimalarial agents as pyridine-4-carbinols bearinga basicallysubstituted unit in the alpha-position, and-the same or different substituted-phenyl groupings on the pyridine ring system. This comes from definition of terms, wherein,

=hydrogen, while R =hydrogen or (lower alkyl) and R =(lower alkyl), the same or differentfrom R R+R-,=(CI-I with R,=H;

III R1 N-Cg: CHN c (crrm cu,

R: CH)-CH and ther the same or different. The term lower alkyl as used herein means one to carbon atoms which can be straight, branched chain or cyclic with repeating methylene groups.

The patterns of worth for representatives of Structure l'have been established through use ofhighly standardized'tests in experimental mammals. The preferred mode for administering these compounds consists in use of non-toxic acid-addition salts, inclusive of. those formed from (I) and acids such as hydrochloric, hydrobromic, sulfamic, sulfuric, phosphoric, citric, tartaric, methanesulfonic, isethionic, aceturic, malic, fumaric, beta-resorcylic, or pamoic acid. Said salts may be administered orally in the formof tablets, capsules or dragees when admixed with solid excipients such as lactose, sucrose, starch, microcrystalline cellulose, magnesium stearate, or tale. The foregoing compositions are preferred means for oral administration over use of flavoredsyrups or tinctures containing the antimalarial drug. Under special circumstances, parenteral adrninistrationmay be indicated, employing an aqueous solutionof the agent or an Oleaginous formulation of' it. Aqueous solutions could be prepared in water, physiological saline, Ringers solution, or the like, either with or without buffers. Oleaginous formulations may be made innatural oils (as, peanut oil or olive oil), or in benzyl benzoate, for example. The several possible isomeric forms for Structure I are to be included among the preferred antimalarials, and advantage may accrue in the choice of'one or other of these.

This invention includes mode for the chemical synthesis of the series defined by Structure I. It represents an extension and'amp'lification of art which certain of the present Inventors have divulged in their copending Patent Application of Ser. No. 784,467 on Antimalarial Compounds and'Process for the Preparation Thereof, now US Pat. No. 3,600,396. Charts 1 through 3 have been used to outline the synthesis of the subject carbinolamines. As is apparent from the structure, such series occur in optically active form. A representative type, where two optical centers are present, has been separated into a pair of racemates, one of which has appreciable antimalarial activity. In another case, where only one optical center is present, the racemic pair resulting from synthesis, was subsequently separated into the dextrorotary and laevorotary forms with resulting significant antimalarial differences.

The course of synthesis of alpha- (dialkylaminomethyl)-2,6-diaryl 4-pyridinecarbinols (Structure 1, R,=H, having R and R as lower alkyl groupings, with (Ar) and (Ar),; as substituted phenyl groups) is outlined in Chart 1. The requisite products have Formula III. This method was applicable to types having (Ar) and (Ar)., either the same or differing aryl functions. The intermediate oxirane could be caused to react with various primary amines (R =I-I; R =alkyl) or secondary amines (R and R each, being alkyl groupings, the same or different. Said carbinolamines (Formula III) were most'satisfactorily administered in the (Ar)-,and (Ar) are Substituted-phenyl groupings, ei-

form of acid-addition salts.

The requisite alpha-( 2-piperidyl)-2,6-diaryl-4- pyridylcarbinols (Formula IV) were prepared from the intermediate 2, 6-diaryl-isonicotinic acids (Formula II) in the manner outlined in Chart 2. The same intermediate (viz., the isonicotinic acid type II) was employed in the synthesis of alpha-(Z-quinuclidinyl)-2,6-diaryl-4- pyridinecarbinols (Formula V), as shown in Chart 3. As in the instance of the less complex carbinolamines (Chart 1), so also the products (Formula IV and V) of transformations given in Chart 2 and Chart 3 were most conveniently used in the form of their acid-addition salts.

The Examples hereinafter given further illustrate the preparation of 4-pyridylcarbinolamines of Formula I, but in no way limit the scope of the lnvention to Formulas lll, 1V and V as representative thereof. Said representations are not to be viewed as restricted to a single stereoisomeric form. All temperatures are given in degrees Celsius (C.), and metric units are employed for weights and measures.

EXPERIMENTAL Synthetic paths leading to the Examples have been shown in Charts 1 through 3, and all are illustrative of the Invention relating to 4-pyridylcarbinolamines having Formula I. Alternative routes for acquiring certain intermediates are apparent to those skilled in the art, and certain of these are revealed in the examples. For convenience, the Examples have been separated into Sections to ensure clarity. Thus, the common intermediate 2,6-diaryl isonicotinic acids (Formula 11) have been illustrated in Examples 1 through 11. Examples 12 through 36 are illustrative of the modes for synthesis of the carbinolamines of Formula 111, and Example 37 relates to compound of Formula IV. Example 38 provides an illustration of the alpha-(2-quinuc1idinyl)-2,6- diaryl-4-pyridinecarbinol type of Formula V.

A. 2,6-DIARYL ISONlCOTINlC ACIDS I Example l. 2,6-bis(4-chlorophenyl)isonicotinic Acid 1. N-(4-chlorophenacyl) pyridinium Bromide To a solution of 12.3 g. (0.155 mole) pyridine in 70 ml. ethanol, there was added 35.2 g. (0.150 mole) 4- chlorophenacyl bromide. The mixture was refluxed for minutes, cooled, and then the salt caused to separate by gradual addition of ethanol-ether and ether. The resulting crude product was recrystallized from ethanol to give 45 g. (95 percent yield) of white solid mp. 208-210.

2. 3-(4-Chlorobenzoyl) acrylic acid.

This intermediate was produced by the interaction of chlorobenzene with maleic anhydride under Friedel- Crafts conditions, as described in the literature by Papa, et al. J. Amer. Chem. Soc., 70, 3356 (1948).

3. 2,6-bis(4-Clorophenyl) isonicotinic acid.

A stirred mixture comprised of 2.11 g. (10 mmole) 3-(4-chlorobenzoyl)acrylic acid, 3.13 g. (IOmmole) N-(4-chlorophenacyl) pyridinium bromide, 10 ml. of acetic acid, 1 ml. acetic anhydride, and 6 g. ammonium acetate was refluxed for 4 hours. The hot mixture was diluted with ca. 30 to 40 ml. water and allowed to cool, then filtered. The solid was washed (water) and dissolved in 150 ml. of hot 2 percent aqueous potassium carbonate solution. Unwanted substances were removed by multiple extractions with chloroform, then ether, and treatment with charcoal in the hot. The product was precipitated by acidification to pH2, collected, washed with water, and crystallized from ethanol. A 54 percent yield (1.85 g.) of 2,6-bis (4- chlorophenyl) isonicotinic acid, m.p. 266- 288, was obtained.

Anal. Calcd for C H CI NO C, 62.81; H, 3.22; N, 4.07. Found: C, 62.47; H, 3.53; N, 4.30.

the foregoing example were replaced with 16ml of methanol, and the mixture was refluxed for five hr.

. '65 Alternatively, the acetic acid and acetic anhydride in (Solid appeared after 30 min to 1 hr). The mixture was filtered, and the precipitate was washed with 10 ml. of cold methanol. The solid was then digested in 30 ml of glacial acetic acid until the fine precipitate became granular (10 15 min). The mixture was diluted with ml of water, cooled and filtered. The solid was washed with water and crystallized (x2) from propanol- 2 to yield 60 percent of product, mp 286 288. Example 2. 2,6-bis (Phenyl)isonicotinic Acid 1. N-(Phenacyl) pyridinium bromide Phenacyl bromide (10 g., 0.05 mole) was added to a solution of 4.1 g., (0.052 mole) pyridine in 20 ml. ethanol and the solution heated on the steam bath for 10 minutes. The cooled solution was diluted with ether, and the solid separted. Following washing with ether, the product was dried to obtain 13.8 g. (99 percent yield) of product which melted 192 194.

2. 2,6-bis -(Phenyl) isonicotinic acid Following the procedure described in example 1, N- (phenacyl-pyridinium bromide was interacted with 3- benzoyl acrylic acid, ammonium acetate, acetic acid, and acetic anhydride. The yield of 2,6-bis-(phenyl) isonicotinic acid was 63 percent following successive crystallizations from ethanol and propanol-2. The compound melted at 280 282.

Anal. Calcd for C I-1 N0 2 C,. 78.53; H, 4.76; N, 5.09. Found: C, 78.70; H, 4.80; N, 5.28. Example 3. 2,6-bis (4-Fluorophenyl) isonicotinic acid I. 4-(Fluorophenacyl)bromide A solution of 30 g. (0.190) bromine in 15 ml ether was added slowly with stirring to a cooled (5) solution of 4-fluoroacetophenone (25 g., 0.18 mole) in 25 nil ether and the reaction mixture was stirred at room temperature for 15 minutes. The ether solution was washed twice with water, then with sodium thiosulfate solution, I

and finally with water, prior to drying over sodium sulfate. The removal of solvent left 40.6 g. of crude oil which was then distilled to yield 31 g. of product boiling at 82 at 0.4 mm. pressure. This product was ap proximately 94 percent pure and contained small amounts of starting material and dibrominated material. It was, however, quite satisfactory for further use.

2. N- (4-Fluorophenacyl) pyridinium bromide The foregoing intermediate, 25 g. was interacted with 10 ml. of pyridine in 50 ml. ofethanol to produce 31 g., 92 percent yield, of the title quaternary salt having a melting point of 208 2l0.

3. 3-(4-Fluorobenzoyl)acrylic acid This intermediate was prepared according to the method described by Papa, et al. (loc. cit.).

4. 2,6-bis(4-Fluorophenyl) isonicotinic acid By the method described in method 1, N-(4- fluorophenacyl)pyridinium bromide and 3-(4- fluorobenzoyl)-acrylic acid were interacted in the presence of acetic acid, acetic anhydride and ammonium acetate. The desired product, mp 278-280, was obtained in 55 percent yield following crystallization from ethanol.

Anal. Calcd for C,,H,,N0,F,; C, 69.45; H, 3.57; N, 4.50; F, 12.21. Found: C, 69.28; H, 3.65; N, 4.63; F, 11.91.

Example 4. 2,6-bis(4-Bromophenyl) isonicotinic acid 1. N-(4-Bromophenacyl)pyridinium bromide This intermediate was prepared from 4- bromophenacyl bromide and pyridine after the manner indicatd in Example 1. Following crystallization, it melted at 242244. I

2. 2,6-bis(4-Bromophenyl)isonicotinic acid The foregoing intermediates and 3-(4-bromobenzoyl)acrylic acid (prepared according to Papa, et a1. loc. cit.) were interacted with ammonium acetate in methanol solution as described in Example 1. Follow ing a 4 hour relux period, the mixture was filtered and the residual material was digested in hot acetic acid for a short time. Upon dilution with water, cooling and filtering, a crystalline product resulted. This was collected by filtration, washed with water and then recrystallized twice from propanol-Z (with use of charcoal) to give a 53 percent yield of the title compound, mp 293 295.

Anal. Calcd for C H Br NO z C, 49.92; H, 2.56; Br, 36.90; Found: C, 49.92; H, 2.60; Br, 37.07. Example 5. 2,6-bis (3,4-Dichlorophenyl) isonicotinic Acid 1. N(3,4-dichlorophenacyl) pyridinium bromide A solution of 25 g. (0.09 mole) 3,4-dichlorophenacyl bromide in 150 ml ethanol at 65 was added to a solution of 8 g. (0.1 mole) pyridine in 450 ml ethanol at 90. The resulting solution was refluxed for ten minutes, then allowed to cool. The crystalline solid product was filterd to yield 20 g. of product which melted 232234. The treatment of the concentrated filtrates with pyridine gave an additional amount of product. The total yield amounted to 86 percent of that theoretically expected.

2. 3-(3,4-dichlorobenzoyl) acrylic acid A mixture of 125 ml of 1,2-di-chlorobenzene and 25 g. (0.26 mole) maleic anhydride was stirred well and there was added, portion-wise, 70 g. (0.51 mole) anhydrous aluminum chloride powder during a half-hour period, meanwhile maintaining the temperature at approximately 45. Thereafter, the mixture was warmed on a steam bath to maintain steady evolution of hydrogen chloride gas. After 4 hours, the reaction mixture was poured over ice and acidified with concentrated hydrochloric acid. There resulted a yellow, gummy solid which was extracted with hot benzene. Upon cooling of the extracts, a yellow crystalline solid formed which was recrystallized from benzene (with use of charcoal) to give a 54 percent yield (33 g) of the title acrylic acid, mp 142144. The melting point agrees with that reported by Papa, et al. (loc. cit.).

3. 2,6-bis (3,4-Dichloropheny1)isonicotinic acid N-(3,4-dichlorophenacyl) pyridinium bromide (1.73 g.), 3-(3,4-dichlorobenzoyl) acrylic acid (1.23 g.), ammonium acetate (4 g.), and methanol (10 ml) were refluxed together for 5 hours. Thereafter, the mixture was allowed to cool and the resulting beige solid was collected by filtration. This solid was slurried with methanol and then with dilute acetic acid, and washed with water. There resulted 1.6 g. (78 percent yield) of crude product which melted 330332. It was recystallized from a mixture of dimethylformamide and water with the use of charcoal to obtain 1.4 g. of product which had the same melting point but gave good analy- Anal. Calcd for C H Cl NO C, 52.33; H, 2.20; C]

5. The material was recrystallized from a mixture of ethanol and ether to give 95 percent yield of the desired compound, mp 208 209.

Anal. Calcd for C H Bro N; C, 54.56; H, 4.58; N, 4.55. Found: C, 54.65; H, 4.74; N, 4.38.

2. 3-(4-Methoxybenzoy1)acrylic acid This intermediate was prepared as described by Papa and coworkers (loc. cit.).

3. 2,6-bis(4-Methoxyphenyl)isonicotinic acid Interaction of the intermediate pyridinium salt with the acrylic acid derivative was carried out in a methanol solution with ammonium acetate as described in Example 5. The resultant isonicotinic acid mp 2l4-217, was obtained in 36 percent yield after recyrstalliaati n r asst oac dt Anal. Calcd for C H NO C, 71.63; H, 5.11; N, 4.18. Found: C, 71.73; H, 5.31; N, 4.25. Example 7. 2-(4-Chlorophenyl)-6-phenyl) isonicotinic acid A mixture of N-phenacylpyridinium bromide (10.8 g., 0.039 mole), 3-(4-chlorobenzoyl) acrylic acid (8.05 g., 0.039 mole), and ammonium acetate (20 g.) was refluxed in methanol ml) for 4 hours. Next, hot glacial acetic acid (38 ml.) was added and a few drops of water, additionally. The mixture was allowed to cool to room temperature, whereupon a gray crystalline precipitate formed. The solid was collected, washed with water, and then dried. It was recyrstallized from propanol-2 to obtain 7.2 g. (61 percent yield) of the title isonicotinic acid mp 254 258.

Anal. Calcd for c H ClNo z C, 69.79; H, 3.91; N, 4.52. Found: C, 69.49; H, 4.07; N, 4.44.

Example 8. 6-(4-Bromophenyl)-2-(4-chloropheny1) isonicotinic acid.

The interaction of N-(4-bromophenacyl) pyridinium bromide and 3-(4-chlorobenzoyl) acrylic acid with ammonium acetate was carried out in methanol afterthe manner described in Example 7. Following crystallization for propanol-2, a 77 percent yield of the title isonicotinic acid mp 285287 was obtained.

Anal. Calcd for C H Br Cl N0 C, 55.62; H, 2.85; Halogen (as Cl), 18.25; Found: C, 55.40; H, 2.77; Halogen, 18.39. Example 9. 2-(4-Chlorophenyl)-6-(4-methoxyphenyl- )isonicitinic acid The reaction of N-(4-chlorophenacyl pyridinium bromide and 3-(4-methoxybenzoyl) acrylic .acid with ammonium acetate in methanol solution was accomplished after the manner described in Example 7. The requisite, acid, mp 240-242, was obtained in 69 percent yield.

Anal. Calcd for C H NO Cl: C, 67.16; H, 4.15; N,

4.12; Cl, 10.43. Found: C, 67.34; H, 4.38; N, 4.02; C1,

10.63. Example 10. dichlorophenyl) isonicotinic acid. I

A mixture of N-(4-chlorophenacyl) pyridinium bromide 15.6 g.), 3-(3,4-dichlorobenzoyl)acrylic acid (12 g) and ammonium acetate (45 g) in 200 ml of methanol was refluxed for 3 hours. The ammonium salt of the title compound precipitated. Following chilling, the mixture was filtered. The solid was digested in hot 20 percent aqueous acetic acid for 15 min. This mixture was cooled, filtered and the crude product so obtained was suspended in 50 ml of hot ethanol, refluxed briefly, cooled and filtered. The solid which was collected amountedto an 81 percent yield (15 g) of produnsymmetrically-substituted isonicitonic 2-(4-Chlorophenyl)-6-(3 ,4-

not which melted at 297300. After crystallization from ethanol, the product melted at 300.

Anal. Calcd for c,,,i-i,,cl,No C, 57.10; H, 2.64; N, 3.71. Found: C, 56.91; H, 2.75; N, 3.65.

Example 1 1. 2-(3,4-Dichlorophenyl)-6-( 4- methoxyphenyl) isonicotinic Acid. The intermediate quaternary salt from Example 6 was caused to react with 3-(3,4-dichlorobenzoyl)acrylic acid from Example 5, essentially according to the procedure employed for Example 10. There resulted thereby an 83 percent yield of product which melted at 245-247.

Anal. Calcd for C H Cl NO C, 60.98; H, 3.50; N, 3.74. Found: C, 61.17; H, 3.75; N, 3.74.

B. alpha-(ALKYLAMlNOMETHYL)-and alpha-( DIALKYLAMINOMETHYL)-2,6-DlARYI .-4- PYRIDINECARBINOLS Example 12. alpha -(Diethylaminomethyl)-2,6-bis-(4- Chlorophenyl)-4-pyridinecarbinol 1. Bromomethyl 2,6-bis-(4-chlorophenyl-4-pyridyl ketone A mixture of 2,6-bis-(4-chlorophenyl) isonicotinic acid from Example 1 (5.3 g., 0.017 mole) and thionyl chloride (50 ml) was refluxed for 5 hours. The excess of thionyl chloride was largely removed under reduced pressure and the last traces of that reagent were then removed by azeotropic distillation with benzene under reduced pressure. A yellow, crystalline acid chloride resulted which was converted into the diazomethyl ketone by interaction with an ether solution of approximately 900 mg of diazomethane at The reaction was allowed to proceed at -l0 for 24 hours, and then the mixture evaporated by dryness. The crystallization of the crude product from a mixture of ether and petroleum ether gave an 80 percent yield of the desired intermediate which melted with decomposition at l40.142. N,

Anal. Calcd for C H N Cl O: C, 61.97; H, 3.01; N, 11.41. Found: C, 61.30; H, 3.20; N, 11.44.

The foregoing diazomethyl pyridyl ketone (g.; 0.011 mole) was suspended in ether (100 ml) and cooled; to it there was added ml of 48 percent hydrobromic acid meanwhile stirring and cooling in an ice bath. After 2 hours, the mixture was diluted with water, and the ether layer was separted. The aqueous layer was rendered alkaline with sodium carbonate and then extracted with ether, and neutralized with aqueous sodium carbonate solution. Thereafter, the ether solution was dried over potassium carbonate, filtered, charcoaled, filtered and then concentrated to give a crystalline solid. The crude bromomethyl ketone thus obtained was recrystallized from ethanol to give 4.9 g. (90 percent of product) which melted 147149.

2. alpha-(Diethylaminomethyl)-2,6-bis-(4-chlorophenyl)-4-pyridinecarbinol.

A solution of the foregoing bromomethyl ketone (4.9 g.) was prepared in .100 ml of ethylene glycol monoethylether and chilled to 5. Then there was added a solution of 700 mg. sodium bromohydride in about 2 m1 of water. After 4 hours, the stirred reaction mixture was treated with 200 ml of water. The mixture was extracted well with ether. The ether extracts were dried over sodium sulfate and the ether was evaporated to give the epoxide containing a little (10 percent) bromohydrin. This crude material was then refluxed with a solution of 7 ml diethylamine in 25 ml of ethanol for 3 hours. Following removal of the solvent and excess amine'under reduced pressure, the residue was taken up in ether. The ether solution was washed with water and dried. Ether solution of the desired free base was then treated with a solution of hydrogen chloride in propanol2. The precipitated hydrochloride salt was collected and recrystallized from a mixture of ethanol and ether. There was obtained a 42 percent yield of the title compound in the form of the hydrochloride salt, mp 236238.

Anal. Calcd for C H Cl N O: C, 61.14; H, 5.58; N, 6.20; Cl, 23.54. Found: C, 60.95; H, 5.71; N, 6.05; Cl, 23.41.

Example 13. alpha-(Dimethylaminomethyl)-2,6-bis(4- chlorophenyl)-4-pyridinecarbinol Crude epoxide (2.6 g), prepared as described in Example 12 was added to a solution of 2 ml of dimethylamine in 20 ml of ethanol and the solution was refluxed for 3 hours. It was necessary to add additional amine (12 ml) and the mixture was then refluxed for several hours further owing to the escape of the volatile dimethylamine from the reaction mixture. The reaction mixture was then worked up according to that procedure given in example 12 and converted into the hydrochloride salt, which was a brown solid. This was crystallized successively from a mixture of ethanol and ether and from acetone to give 900 mg (28 percent) of the title compound in the form of its hydrochloride salt, mp 222-223.

Anal. Calcd for C H Cl N O: C, 59.52; H, 5.00; N, 6.61. Found: C, 59.20; H, 5.19; N, 6.50. Example 14. alpha-(Di-n-propylaminomethyl)-2,6-bis (4-chlorophenyl) -4-pyridinecarbinol Crude epoxide (2.2 g), prepared according to Example l2, and 6 ml of di-n-propylamine in 25 ml of ethanol were refluxed for 10 hours. The procedure given in Example 12 was followed and the crude material was converted to the hydrochloride salt. Upon crystallization of this from ethanol, there was obtained 1.4 g (63 percent) of the desired salt, mp 250-25 2.

Anal. Calcd for C H Cl N O: C, 62.57; H, 6.09; N, 5.84; Cl, 22.17. Found: C, 62.56; H, 6.28; N, 5.86; Cl, 19.82.

Example 15. alpha-(n-Butylaminomethyl)-2,6-bis-(4- Chlorophenyl) -4-Pyridinecarbinol Crude epoxide (5.5 grams) from example 12 was refluxed in 200 ml of ethanol which contained 3 ml of nbutylamine for 18 hours. The solvent and excess amine were removed under reduced pressure. This residual solid was slurried in ether, then filtered, and finally recrystallized from propanol-2. There resulted 2.85 g. (42 percent) of the title compound as the free base, mp 169-171.

Anal. Calcd for C H ,Cl NO: C, 66.51; H, 5.82; N, 6.74; Cl, 17.07. Found: C, 66.72; H, 6,03; N, 6.84; Cl, 16.90.

Example 16. alpha-(sec. -Bu'tylaminomethyl)-2,6-bis- (4-Chlorophenyl) -4-Pyridinecarbinol I The epoxide prepared according to Example 12 was interacted in ethanol solution with sec. butylamine after the procedure described in Example 20. The product was crystallized from a mixture of acetonitrile and ethanol. A 61 percent yield of product which melted 224-225 resulted therefrom.

Anal. Calcd for C H N Cl O: C, 61.27; H, 5.37; N,

6.21. Found: C, 61.08; H, 5.52; N, 6.02.

Example 17. alpha-(1-Adamantylaminomethyl)-2,6- bis-( 4-Chlorophenyl) -4-Pyridinecarbinol l-Aminoadamantane and the requisite epoxide from example 12 were refluxed in ethanol solution for 18 hours. The resulting product was recrystallized from ethanol to give a 37 percent yield of product, mp l82l 83.

Anal. Calcd for C H N Cl O; C, 70.58; H, 6.13; N, 5.68; Cl, 14.37. Found: C, 70.56; H, 5.99; N, 5.48; CI, 14.32.

Example 18. alpha-(di-n-pentylaminomethyl)-2,6-bis- (4-Chlorophenyl) -4-Pyridinecarbinol The method described in Example 12 was applied to the use of di-n-pentylamine. The requisite compound in the form of its hydrochloride was obtained in 38 percent yield; it melted at 228230.

Anal. Calcd for C29H31Cl3N20: C, H, N, 5.23. Found: C, 64.98; H, 6.91; N, 4.96.

Example 19. alpha-(4-heptylaminomethyl)-2,6-bis-(4- Chlorophenyl) -4-Pyridinecarbinol 4-Heptylamine was caused to react with the crude epoxide as obtained from example 12. The desired compound was isolated in the form of its hydrochloride salt which, following recrystallization from a mixture of ethanol and acetonitrile, was obtained in a yield of 63 percent mp 196198.

Anal. Calcd for C H N Cl O: C, 63.22; H, 6.33; N, 5.67. Found: C, 63.19; H, 6.50; N, 5.48. Example 20. alpha-(Methyl-n-butylaminomethyl)-2,6- bis-(4-Chlorophenyl)-4-Pyridinecarbinol The crude epoxide described in Example 12 was interacted with methyl-n-butylamine in refluxing ethanol solution for 18 hours. The solution was evaporated and the free base was transformed into its hydrochloride salt. The salt was recrystallized from a mixture of acetp nitrile and ethanol. The yield of product, mp 223224, was 63 percent.

Anal. Calcd for C H N CL O: C, 61.88; H, 5.84; N, 6.01. Found: C, 61.55; H, 5,73; N, 5.86.

Example 21. alpha( Methyl-sec.-butylaminomethyl)- 2,6-bis-(4-Chlorophenyl)-4-Pyridinecarbinol Methyl-sec. -butylamine and the epoxide from Example 12 were reacted as described in Example 12. Following crystallization from a mixture of ethanol and ether, the pure product, as the hydrochloride salt, was obtained in 68 percent yield, mp l85-l88.

Anal. Calcd for C H N Cl O: C, 61:88; H, 5.84; N, 6.01. Found: C, 61.61; H, 6.20; N, 5.72.

Example 22. alpha-(Methyl-iso-butylaminomethyl)- 2,6-bis-(4-chlorophenyl)-4-pyridinecarbinol.

The epoxide from Example 12 and methyl isobutylamine'were refluxed in ethanol for 20 hours. The hydrochloride salt of the desired compound, mp 220-222, was isolated in 30 percent yield following crystallization from propanol-2. I

Anal. Calcd for C H N C L O: C, 61.88; H, 5.84; N, 6.01. Found: C, 62.07; H, 6.09; N, 5.92. i

Example 23. alpha-(Di-n-butylaminomethyl)-2,6-bis- (4-fluorophenyl) -4-pyridinecarbinol l. Bromomethyl 2,6-bis (4-fluorophenyl)-4-pyridyl ketone The procedure described in Example 12 was followed. 2,6-bis (4-Fluorophenyl) isonicotinic acid prepared in Example 3 was transformed into the acid chloride. Following crystallization from benzene, it had mp 180-l82. The acid chloride was then interacted with diazomethane in ether solution. There was obtained a 98 percent yield of crude diazoketone, mp 160-% i0 (wTli decomposition), after recrystallization from ether. Following the procedure employed in Example 1, the diazoketone was converted into the required intermediate bromomethyl ket oiie by treatment with hydrobromic acid. The crude product wasrecrystallized from propanol-2 to produce a 74 per-- A suspension of the foregoing bromomethyl ketone (5.0g, 0.013 mole) in 150 ml ethanol at 5 was treated with a solution of 500 mg. sodium borohydride in 20 ml of water. The suspension was stirred at room temperature for 2.5 hours. Most of the ethanol was removed under reduced pressure, water (ml) was added to the residue and the pH was adjusted to approximately 2 to 3 by the addition of dilute hydrochloric acid. The solid (4.1 g.) which resulted was collected and treated further with a solution of sodium methoxide in methanol to yield crude epoxide free from bromohydrin.

The resulting epoxide (3.5 g.) was added to di-nbutylamine (20 ml) ethanol ml) and the mixture was heated on a steam bath for 17 hours. Excess of solvent and reagent were removed under reduced pressure and the oily residue was taken up in ether, washed (water) and dried over sodium sulfate. The ether solution of the desired base was converted into the hydrochloride salt by bubbling hydrogen chloride gas into the solution. The crude product was crystallized from a mixture of methanol and water to give 2.4 g. (45 percent) of the hydrochloride salt mp 228-230.

Anal. Calcd for C H N OF Cl: C, 68.27; H, 7.00; N, 5.90; F, 8.00. Found: C, 68.42; H, 6.91; N, 5.94; F, 7.90. Example 24. alpha-(Di-n-heptylaminomethyl)-2,6-bis (4-Fluorophenyl) -4-Pyridinecarbinol The intermediate epoxide obtained in crude form ac cording to Example 23 was caused to react with di-nheptylamine in ethanol after the method employed in Example 12. Following work-up, there was obtained crude hydrochloride salt which melted at -190. Recrystallization from hot ethanol afforded the pure compound as a white crystalline solid, mp l93195.

N, 501; F, 6.80. Found: C, 70.76; H, 8.10; N, 4.91; F, 6.72.

Example 25. alpha-(Diethylaminomethyl)-2.6-bis- (4-Bromophenyl)-4-Pyridinecarbinol l. Bromomethyl 2,6-bis-(4-bromophenyl)4-pyridyl ketone 2,6-bis-(4-bromophenyl) isonicotinic acid (from Example 4) was converted to the acid-chloride by interaction with thionyl chloride asdescribed in Example 12. The product was crystallized from a mixture of benzene and petroleum ether. The yield of product, mp 156-**, was 96%. The acid chloride in methylene chloride solution was treated with an ether solution of excess diazomethane. Following the usual procedure, there was obtained a 70 percent yield of the diazomethyl ketone, mp l55l57(decomposition) following a crystallization from a mixture of methylene chloride and petroleum ether. The intermediate diazoketone was converted to the bromomethyl ketone intermediate by treatment with concentrated hydrobromic acid. The crude product, mp l69-l71 was obtained in 92 percent yield. Two crystallizations from a mixture of benzene and petroleum ether provided analytically pure material, mp l71172.

Anal. Calcd for C H Br No: C, 44.74; H, 2.37; Br 47.00. Found: C, 45.03; H, 2.67; Br, 46.81.

2. alpha-(Diethylaminomethyl)-2,6-bis-(4-bromophenyl)-4-pyridinecarbinol The foregoing bromoketone was reduced in ethanol solution at room temperature using sodium borohydride, much after the procedure described in Example 23. The resulting crude epoxide was interacted with diethylamine such as described for dibutylamine in Example 23. The desired compound was recrystallized thrice from a mixture of ethanol and ether to give pure compound, mp 232233.

Anal. Calcd for C H Br ClN O: C, 51.09; H, 4.66; N, 5.18. Found: C, 51.18; H, 4.88; N, 5.09.

Example 26. alpha-(Di-n-butylaminomethyl)-2,6- bis(4-bromophenyl) -4-pyridinecarbinol The method applied in Example 25 was used for the synthesis of this compound. The yield of product from the interaction of the requisite secondary amine with the intermediate expoxide was 66percent. The hydrochloride salt so obtained melted at 233234, following crystallization from a mixture of methanol and ethanol.

Anal. Calcd for C H Br ClN O: C, 54.33; H, 5.57; N, 4.69. Found: C, 54.34; H, 5.61; N, 4.63.

Example 27. alpha-(n-Heptylaminomethyl)-2,6- bis(4-bromophenyl) -4-pyridinecarbinol.

The procedure employed in the previous two examples was used for the interaction of the epoxide with the required secondary amine. The hydrochloride salt isolated had mp 208209.

Anal. Calcd for C H Br ClN O: C, 58.20; H, 6.66; N, 4.05. Found: C, 58.11; H, 6.70; N, 4.05.

Example 28. alpha-(Di-n-butylaminoethyl)-2,6-bis-(4- methoxyphenyl)-4-Pyridinecarbinol l. Bromomethyl 2,6-bis-(4-methoxyphenyl)-4- pyridyl ketone 2,6-bis-(4-methoxyphenyl) isonicotinic acid was synthesized as given in example 6, this was converted to its acid chloride by interaction with thionyl chloride. The crude acid chloride hydrochloride was used directly for reaction with diazomethane following the procedure described in Example 23. It was necessary to purify the resulting diazomethyl 2,6-bis(4 methoxy-phenyl)-4- pyridyl ketone by chromatography over silica gel. Elution with benzene gave some of the ethyl ester of the intermediate acid (mp 99-x); upon changing the eluant to benzene and propanol-2(in a ratio of 99:1 by volume) the diazoketone was obtained with mp 99-102 and acceptable ($0.3 percent) elemental analysis in carbon, hydrogen and nitrogen. This was used directly for conversion into crude bromomethyl ketone by refluxing with hydrobromic acid.

2. alpha-(Di-n-butylaminomethyl)-2,6-bis-(4- methoxyphenyl)4-pyridine-carbinol The above crude bromomethyl ketone was reduced inethoxyethanol with sodium borohydride much as described in Example 23. The crude epoxide was treated with di-n-butylamine in ethanol solution (cf. Example 23) to obtain a 32percent yield of the hydrochloride of the desired carbinolamine. The purified material, recrystallized from propanol-2, melted at 215-2l6.

Anal. Calcd for C H N O Cl; C, 69.79; H, 7.88; N, 5.61; CL, 7.10. Found: C, 69.88; H, 8.05; N, 5.64; Cl, 7.34.

Example 29. alpha-(Di-n-butylaminomethyl)-2,6-bis- (3 ,4-Dichlorophenyl)-4-Pyridinecarbinol l. 2,6-bis-(3,4-dichloropheny1)isonicotinic Chloride -2,6-bis-(3,4-dichlorophenyl) isonicotinic acid (4.4g. 11 mmole) from Example 5 was mixed with thionyl chloride (20ml) and refluxed for 4 hours. Excess thionyl chloride was removed by azeotropic distillation with benzene under reduced pressure. The resulting crude yellow solid was recrystallized from benzenepetroleum ether to give 4.0 g (88percent) of material, mp 196198, containing 40.70 percent chlorine vs. 41.08 percent calculated.

2. Diazomethyl 2,6-bis(3,4-dichlorophenyl)4-pyridyl Ketone The above acid chloride (7.4g, 0.017 mole) was added in small portions over a 30 min period to a cold (0-5) solution of diazomethane (5g, 0.12 mole) in ether (300 ml). The heterogeneous mixture was stirred for 5 hours at 0 and stored overnight in'an ice bath. Excess diazomethane and solvent were removed under reduced pressure. There was obtained 7.4g (98 percent of the title compound, mp 155-158(dec.).

3. Bromomethyl 2,6-bis-(3,4-dichlorophenyl)-4- pyridyl Ketone A solution of the above diazoketone (3.5 g, 7.8mmole) in methylene chloride (200 ml) was added dropwise to a mixture of hydrobromic acid (8ml, 48 percent) and methylene chloride (100 ml). The mixture was stirred for 1 hour and filtered. The filtratewas washed successively with water, dilute sodium bicarbonate and dried (Na SO Removal of the solvent under reduced pressure gave a brownish-yellow crystalline solid. After recrystallization from chloroformisopropanol, there was obtained 2.8 g (71 percent) of product, mp 189-191.

Anal. Calcd for C H BrChNo: C, 46.57; H, 2.06. Found: C,46.81; H, 2.30. V

4. alpha-( di-n-butylaminomethyl )-2,6-bis-( 3 ,4- dichlorophenyl)-4-pyridinecarbinol The above bromomethyl ketone (1 g, 2 mmole) was suspended in ethanol (40 ml). Sodium borohydride mg) was added and the mixture was stirred for 1 hour at room temperature. Dilute hydrochloric acid was added to decompose excess borohydride. The mixture was neutralized with sodium bicarbonate. Water (30 ml) was added and the mixture was filtered. The collected solid was washed with water (X2, 20ml) and dried under reduced pressure. There was obtained 800 mg (95 percent) of crude epoxide, mp l38-145, whlclic ontamed a5out 5 percent of the bromohydrin by analysis.

The crude oxide (1.5 g, 3.7 mmole) from two runs was added to a solution of di-n-butylamine (5 ml) and ethanol (25 ml). The mixture was refluxed for 3 hours. Solvent and excess amine were removed under reduced pressure. The residual oil was dissolved in ether and treated with a saturated solution of hydrogen chloride in isopropanol. The hydrochloride salt was collected by Acid 7 filtration, washed with ether and crystallized from ethanol to afford 1.5 g (71 percent) of the titled compound, mp 220222.

Anal. Calcd for C H Cl N O: C, 56.22; H, 5.41; N, 486; C1, 30.73. Found: C, 56.11; H, 5.72; N, 4.71; Cl, 30.92. g

5. alpha-N-Oxo-(di-n-butylaminomethyl)-2,6-bis- (3,4-dichlorophenyl)- 4-pyridinemethanol Hydrochloride To a solution of a -di-n-butylaminomethyl-2,6-bis 3,4-dichlorophenyl)-4-pyridinemethanol (2.4 g, 4.5 mmole) in ether 100 ml) was added 40 percent peracetic acid in acetic acid (Sml). The reaction mixture was stirred at room temperature for 2 hours. During this time, a precipitate formed/The mixture was filtered to yield a solid (1.8 g) which is believed to be the acetic acid salt of the N-oxide. The solid was slurried in methanol and a few drops of concentrated HCl was added. The solid dissolved and water was added until no more solid formed. The mixture was filtered and the solid product was recrystallized from ethanol to give the target compound (0.8 g, 33 percent), mp 174175.

Anal. Calcd for C 1-1 N O Cl C, 54.70;H, 5.27; N, 4.72; O, 5.40. Found: C, 54.68; H, 5.24; N, 4.67; O, 5.50.

6. Alternative Procedure Alternatively, 2,6-bis-(3,4-dichlorophenyl) isonicotinic acid can be converted to the active antimalarial agent, a-di-n-butylaminomethyl-Z,6-bis-3,4-dichlorophenyl)-4-pyridinecarbinol, by methods other than that described, and which avoids the use of diazomethane, a hazardous reagent not suitable for large scale preparations.

Diethyl ethoxymagnesiummalonate, prepared by the procedure of'l-LG. Walker and C. R. Hauser, J. Am. Chem. Soc., 68, 1386 (1964), was dissolved in tetrahydrofuran and added slowly to a refluxing slurry of 2,6- bis-(3,4-dichlorophenyl)isonicotinic acid chloride in ether. After 2 hours the mixture was poured into a slurry of ice and dilute sulfuric acid. The ether layer was removed and the aqueous layer was extracted further with ether. The combined ether extracts were washed with sodium bicarbonate, and with water and acid per gram of the malonate. After 25 minutes the,

product was poured over ice. The resulting yellow solid was extracted with chloroform and the chloroform removed to yield 32 percent of the bromoethyl 2,6-bis- (3,4-dichlorophenyl)-4-pyridyl ketone, mp 187 190 The latter bromoketone was then converted to alphadi-n-butylaminomethyl) -2,6-bis-( 3 ,4-dichlorophenyl)-4-pyridinecarbinol, the target antimalarial compound, in the same manner as described above in paragraph 4. Example 30. alpha-(Diethylaminomethyl)-2,6-bis-(3,4- dichlorophenyl)-4-Pyridinecarbinol This crude epoxide from Example 29 was interacted with a solution of diethylamine in ethanol in the same manner as in Example 29. There resulted 63 percent yield of the hydrochloride of the desired carbinolamine. This compound had mp 245247 following recrystallization from ethanol.

Anal. Calcd for C l-l Cl N O: C, 53.05; H, 4.45; N, 5.38,Cl, 34.05. Found: C, 52.86; H, 4.41; N, 5.47; Cl,

34.05. Example 31. alpha-(Di-n-heptylaminomethyl)-2,6-bis- (3 ,4-Dichlorophenyl )-4-Pyridinecarbinol The crude epoxide from Example 29 was interacted with di-n-heptylamine in ethanol solution in the usual manner. The hydrochloride of the carbinolamine product melted 210212 following recrystallization fro ethanol. The yield was 41 percent.

Anal. Calcd for C H CI N O: C, 59.96; H, 6.56; N, 4.24; Cl, 26.82. Found: C, 60.01; H, 6.61; N, 4.19; Cl,

. Example 32. alpha-(Di-n-butylaminomethyl)-2-(4- Chlorophenyl)-6-Phenyl-4-Pyridinecarbinol 1. Bromomethyl 2c4-chlorophenyl)-6-phenyl-4- pyridyl ketone 2-(4-chlorophenyl)-6-phenyl isonicotinic acid (from Example 7 was converted to its acid chloride in the standard way. This intermediate was obtained in 65 percent yield and had mp 112-ll5.. The crude acid chloride thus obtained was converted into the diazoke- 'tone by interaction in the usual manner with diazomethane, The crude yellow oil was identified and interacted, without purification, with hydrobromic acid to yield the intermediate bromomethyl ketone, mp 102l05, in 77 percent yield after recrystallization from ethanol. 7

Anal. Calcd for C l-l BrClNO: C, 59.01; H, 3.39; N, 3.62. Found: C, 58.85; H, 3.63; N, 3.70.

2. alpha-(Di-n-butylaminomethyl)-2-(4-chlorophenyl)- 6-phenyl-4-pyridinecarbinol.

The intermediate bromoethyl ketone was reduced with sodium borohydride in ethanol, to obtain crude epoxide contaminated with a small amount of bromohydrin. This was interacted with di-n-butyalmine in ethanol solution, thereby obtaining the desired compound which was transformed into'its hydrochloride salt. The yield of the salt was 59percent and had the mp of 230232 following crystallization from ethanol.

Anal. Calcd for C l-l Cl N O: C, 68.49; H, 7.24; N, 5,92; C1, 14.98;O, 3.38. Found: C, 67.86; H, 7.33; N, 5.80; Cl, 14.99; 0, 3.36.

Example 33. alpha-(Di-n-butylaminomethyl)-6-(4- Bromophenyl)-2-(4-Chlorophenyl)-4-Pyridinecarbinol I 1. Bromomethyl chlorophenyl)4-pyridyl ketone The intermediate isonicotinic acid from Example 8 was transformed in the usual way into the bromomethyl ketone. The intermediate acid chloride melted 141-144 after crystallization from a mixture of benzene and petroleum ether. The diazomethyl ketone ob-' tained therefrom was used directly without purification for interaction with hydrobromic acid. This intermediate melted 154156.

Anal. Calcd for C l-l Br C1NO: C, 49.01; H, 2.60; N, 3.01. Found: C, 49.20; H, 2.87; N, 3.09.

2; alpha-(Di-n-butylaminomethyl)-6-(4- bromophenyl)-2- (4-chlorophenyl)-4-pyridinecarbinol The bromoketone intermediate was transformed into the oxirane in the customary manner and used without purification in the reaction with di-n-butylamine in ethanol. The hydrochloride salt of the product was isolated. Following crystallization from ethanol, a 71 percent yield (based on bromomethyl ketone) of the title compound results, mp 236-238.

Anal. Calcd for C H BrCl N O: C, 58.70; H, 6.02; N, 5.07; halogen as Cl, 19.26. Found: C, 58.70; H, 6.02; N, 4.86; halogen as Cl, 19.35.

Example 34. alpha-(di-n-butylaminomethyl)-2-(4- chlorophenyl)-6-(4Methoxyphenyl)-4- Pyridinecarbinol 1. Bromomethyl 2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-pyridyl ketone.

The intermediate isonicotinic acid from Example 9 was converted in the usual manner to the acid chloride, mp 104106 and had acceptable (i0.3 percent) elemental analysis in carbon hydrogen nitrogen and chlorine. This was transformed into the diazomethyl ketone in the usual manner. The crude intermediate was relatively unstable. Accordingly, this was immediately transformed into the bromomethyl ketone by treatment with hydrobromic acid in chloroform solution. Crystallization of the bromomethyl ketone from propanol-2 afforded pure title compound, mp 138.5140.5.

Anal. Calcd for C H BrClNO C, 67.65; H, 3.63; N, 3.47; halogen as C1, 17.01. Found: C, 67.91; H, 3.84; N, 3.84; halogen as Cl, 16.73.

2. alpha-(Di-n-butylaminomethyl)-2-(4- chlorophenyl)6 -(4-methoxyphenyl)-4- pyridinecarbinol The intermediate bromomethyl ketone was converted into the epoxide in the usual manner and the resulting crude product was reacted directly with di-nbutylamine in ethanol. The resulting pyridinecarbinol was converted into the hydrochloride salt which was crystallized from propanol-2. The yield was 40 percent of product with mp 224224.5, with decomposition.

Anal. Calcd for C H Cl N O C, 66.79; H, 7.21; N, 5.56; C1, 14.08. Found: C, 66.75; H, 7.40; N, 5.56; Cl,

Example 35. alpha-(Di-n-butylaminomethyl)-2-(4- chlorophenyl-6- (3,4-dichlorophenyl)-4- pyridinecarbinol eld. The pure compound melted at 136-137 after recrystallization with methylene chloride-ethanol and had acceptable (:03 percent) elemental analysis in carbon, hydrogen and nitrogen. 1n the usual way, the bromomethyl ketone was converted into the epoxide and this was used in crude form for reaction with di-n butylamine. The hydrochloride of the desired compound was isolated and 51 percent yield from crude epoxide. The pure compound melted at 216-2l7 following recrystallization from propanol-Z.

Anal. Calcd for C27H32Cl4N O: C, H, N, 5,16; Cl, 26.15. Found: C, 59.72; H, 6.05; N, 5.12; Cl, 26.04.

Example 36. alpha-(Di-n-butylaminomethyl)-2-(3,4- dichlorophenyl)-6-(4-methoxyphenyl)-4- Pyridinecarbinol 2-( 3 ,4-dichlorophenyl )-6-( 4-methoxy-phenyl) isonicotinic acid was obtained from Example 11. This was converted to the acid chloride, and thence into the diazomethyl ketone. The purified diazomethyl ketone, mp l07-l08 following crystallization from a mixture of ether and petroleum ether was obtained in 84 percent yield. This intermediate was then treated with hydrobromic acid to give a 91 percent yield of the rec tire d intermediate bromomethfiketoneof trip 117- 118. Reduction of the foregoing intermediate with sodium borohydride gave the corresponding epoxide type which was treated with di-n-butylamine in the usual manner. This resulting' product was converted into the hydrochloride of the desired carbinolamine in 57 percent yield. The compound melted 209-210 following crystallization from propanol-2.

' Anal. Calcd for C H C1 -,N,O C, 62.51;H, 6.56; N, 5.21; Cl, 19.77. Found: C, 62.84; H, 6.76; N, 5.24; Cl, 19.76.

C. alpha-(Z-PIPERIDYL)-2,6-DlARYL-4- PYRIDINECARBINOLS Example 37. alpha-(2-Piperidyl)-2,6-bis-(4-Chlorophenyl)-4-Pyridinecarbinol 1. 2,6-bis-(4-Chloroplienyl)-4-Pyridyl 2-Pyridyl Ketone A hexane (64 ml) solution of n-butyl lithium (0.1 mole) was mixed with ether ml) and the solution was chilled to 60 and stirred well. That temperature was maintained while 2-bromopyridine (16.0 g., 0.1

mole) was added gradually, and then held at 60 for one hour longer. There was then added 2,6-bis-(4- chlorophenyl)isonicotinic acid (13.76 g., 0.02 mole, obtained according to Example 1), and the entire was stirred at 60 for 2 hours. Thereafter, the solution was poured into ice-water and the product was collected. A yield of 81 percent (13 g.) of the title ketone, mp 18 l-183 was obtained. Recrystallization from propanol-2gave pure product, mp l86l88.

Anal. Calcd for C H N OCl C, 68.16; H, 3.48; N, 6.91 Cl, 17.50. Found: C, 68.23; H, 3.73; N, 6.80;-Cl, 17.43.

2. alpha-(Z-Piperidyl)-2,6-bis-(4-Chlorophenyl)-4- Pyridinecarbinol The foregoing intermediate ketone (2.4 g.) was reduced in acidic ethanol ml ethanol containing 0.55 ml conc. hydrochloric acid), with platinum (formed by pre-reduction on 150 mg. of platinum oxide) under 40 psig hydrogen. After uptake of the requisite amount of hydrogen, the mixture was filtered and the filtrates was concentrated in vacuo. The base was liberated by'the addition of 10 percent sodium hydroxide, extracted into ether, the extracts dried, then the solvent removed. The residual base was chromatographed over silica gel using chloroform and methanol (3:1, v/v) as the eluant. The base was. isolated, then crystallized from a mixture of propanol-2 and water to give the pure product, mp 180l8l, in 50 percent yield.

Anal. Calcd for C H N Cl o: C, 66.83; H, 5.37; N, 6.78; Cl, 17.15. Found: C, 67.04; H, 5.56; N, 6.76; Cl, 17.02.

D. alpha-( 2-QU1NUCL1D1NYL)-2,6-DlARYL-4- PYRIDENECARBINOLS Example 38. alpha-(2-Quinuc1idinyl)-2,6-bis-(4- chlorophenyl)-4-Pyridinecarbinol l. Ethyl 2, 6-bis(4-chlorophenyl-isonicotinate A solution of 2,6-bis-(4-chlorophenyl) isonicotinic acid (15.0 g, 44 mole) in dry ethanol (150 ml) containing sulfuric acid (6 ml) was heated to reflux for 17 hours. The reaction mixture was poured into water (200 ml) containing sodium bicarbonate g). The solution was filtered and the resulting solid recrystallized from benzene to yield the title ester (11.3g, 70

I percent), mp l68-169.

245246(dec). The product can be recrystallized from absolute ethanol.

3. Ethyl N-Benzoyl-3-(4-piperidyl) propionate The title compound was prepared according to the procedure of Kleinman and Weinhouse, J. Org. Chem. 10, 562 (1945), bp 174 (0.2 mm), reported 184l85 (1mm). The yield was 70 percent.

4. 2-(4-Piperidyl)ethyl 2,6-bis-(4-chlorophenyl)-4- pyridyl Ketone Hydrochloride To a well-stirred suspension of sodium ethoxide (1.36 g, 0.02 mole) in dry toluene (50 ml), a solution prepared from ethyl 2,6-bis-4-chlorophenylisonicotinate (4.1 g, 0.011 mole), ethyl N-benzoyl-3-(4-piperidyl) propionate (2.89 g, 0.01 mole) and toluene (50 ml) was added in a steady stream. The red-brown reaction mixture was refluxed with stirring for 2 hours. The toluene, together with the ethanol formed during the reaction, were removed by distillation. Fresh, dry toluene (200 ml) was added to the reaction mixture which was refluxed for another 6 hours and azeotropic removal of ethanol was repeated. The solvent was removed by distillation and the residue was treated with 18 percent hydrochloric acid (100 ml) and gently refluxed for 10 hours. The hot suspension was filtered and the filtrate was concentrated and made alkaline with percent potassium hydroxide solution. The free base was extracted with chloroform and the solution was dried (1( CO The solvent was evaporated ty yield 1.76 g (41 percent) of free base. A sample was dissolved in ethanol and treated with ethanolhydrogen chloride to give a colorless crystalline precipitate of the title compound. The salt was recrystallized from ethanol to give mp 264-266. Conversion of the free base to the hydrochloride salt was quantitative.

Anal. Calcd for C H Cl N QH O: C, 60.80; H, 5.53; N, 5.67. Found: C, 60.63; H, 5.42; N, 5.76.

5. l-Bromo-2-(4-piperidyl)ethyl 2,6-bis-(4-ch1oropheny1)-4-pyridyl Ketone Hydrobromide To the warm solution of the preceding ketone (4.39 g, 0.01 mole) and hydrobromic acid (48 percent, 50

ml), an equivalent amount of bromine (1.6 g) in hydrobromic acid (16 ml) was added with stirring. The suspension was stirred and held at for 15 min. The hydrobromic acid was evaporated under reduced pressure and the residue was refluxed with acetone (50 ml). The solvent was evaporated and the residue was suspended in cold water. The precipitate was separated and recrystallized from ethanol, 5.3 g percent), mp 256258.

Anal. Calcd for C H Br Cl N O: C, 50.12; H, 4.03; N, 4.68.'Found: C, 50.39; H, 4.14; N, 4.68.

6. 2Quinuclidiny1 2,6-bis-(4-chlorophenyl)-4-pyridy1 Ketone Hydrochloride The preceding bromoketone (5 g) in chlorofrom ml) was shaken with aqueous sodium bicarbonate (8 g in 80 ml of water) for 5 hours. The chloroform layer was separated and the aqueous layer was extracted twice with fresh chloroform. The combined extracts were dried (K CO The chloroform was evaporated to leave 3.5 g (90 percent) of the free base. A sample of the free base (45 mg) was dissolved in chloroform and treated with ethereal hydrogen chloride to give the hydrochloride salt, 44 mg (91 percent), mp 306-308(dec). The salt was recrystallized from ethanol, mp 308310 (dec).

Anal. Calcd for C H Cl N O: C, 63.37; H, 4.89; N, 5.71. Found: C, 63.10; H, 4.87; N, 5.84.

7. alpha-(2-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)- 4-pyridinemethanol Hydrochloride The free base of the preceding ketone (2.2 g) was dissolved in hot ethanol (80 ml) and treated with an aqueous solution of sodium borohydride (500 mg in 15 m1 of water). The solution was stirred at room temperature for 2 hours. Most of the ethanol was evaporated under reduced pressure. The suspension was diluted with water (20 ml) and acidified with 10 percent hydrochloric acid. After cooling and scratching, a colorless precipitate separated which was collected by filtration, washed with cold water and dried at 100 overnight (3.2 g, 81 percent). The product, mp 200-215 was a mixture of the two possible racemates. The mixture contained little water as shown by the infrared spectrum.

The crude product was refluxed with acetonitrile (50 ml). The hot suspension was filtered to yield a solid. The motherliquor was saved for later suspension of the racemates. The solid (1.7 g, mp 260-265) was recrystallized (X3) from a mixture of isopropanol and acetonitrile. After the third recrystallization, the product has mp 268-275.

Anal. Calcd for C H Cl NO: C, 63.10; H, 5.30; N, 5.89. Found: C, 63.09; H, 5.44; N. 5.73.

8. alpha-(2-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)- 4-pyridine-methanol Hydrochloride (Racemate A) The foregoing mixture of racemates, mp 268-275, recrystallized (X2) from a mixture of ethanol and ether to give mp 295297 (dec), 1.15 g. Thin layer chromatography showed one major spot and the product was considered to be a pure diastereoisomeric pair (Racemate A).

Anal. Calcd for C ,,H Cl NO: C, 63.10; H, 5.30; N, 5.89. Found: C, 63.09; H, 5.20; N, 5.85.

Free Base of Racemate A:

Theabove hydrochloride salt (100 mg), was suspended in ether and treated with 30 percent aqueous potassium hydroxide. The organic layer was scparted, dried (K CO and the solvent was evaporated. The

19 colorless, crystalline base was recrystallized from petroleum ether (30-60), mp l30-133 (65 mg). The product was very soluble in ether and chloroform.

Anal. Calcd for C H Cl NO: C, 68,34; H, 5.51; N, 6.37; Found: C, 68.39; H, 5.64; N, 6.l4. 5

alpha-(Z-Quinuclidinyl)-2,6-bis-(4-chlorophenyl)-4- pyridinemethanol Hydrochloride (Racemate B).

The acetonitrile solution (mother liquor) from paragraph 7 above was evaporated to dryness. The residue was recrystallized from hot acetonitrile several times to a constant rn 25926l. A yield was 750 mg. Thin layer chromatography showed one major spot and the product was considered a pure diastereoisomeric pair (Racemate B).

Anal Calcd for C H cl NOz C, 63.10; H, 5.30; N, 5.89. Found: C, 63,26; H, 5.28; N, 6.03.

Free Base of Racemate B.

The hydrochloride salt (60 mg) was suspended in chloroform and shaken with 30 potassium hydroxide. The organic layer was separated, dried (K CO and the solvent was evaporated The residue was crystallized from chloroform-petroleum ether, mp 200-202. The product (40 mg) was essentially insoluble in ether and petroluem ether, but was very soluble in chloroform.

Anal. Calcd for C H Cl NO: N, 6.37. Found: N, 6.14.

Mother liquors from all the crystallizations were combined. Solvents were evaporated and the fractional crystallization procedures were repeated. Additional amounts of Racemates A and B were obtained (100 mg of A and 65 mg of B). Y

CHART 1 Alpha-(Dialkylaminomethyl)-2,6Diaryl-4-Pyridinecarbinols Bra pyridine (ArhCOCI-l; (ArhCOCPhBr (AT)5COCH=CHCO2H (ArhCOCHaNB e NILO Ac; MeOH S 0 Cl: CHiNa acid chloride CHzClz )o. 2

(ljocHNz (FOCHzBr i HBr m (Ar)a- (Ar): (Am \N/ (Ar):

CH-CH: CHCHIN R. NH l NaBHr plymc R2 (Ar)@- NJ-(Al'): (Ar)l- N, -(Ar):

Ill

CHART J Alpha-t2-Pipcridyl)-2.G-Diaryl-i-Pyiidylcarbinols Alpha-(241 uinuclidinyl)-2,6-Diuryl-4-Pyridinucarbinols and pharmaceutically acceptable acid addition salts thereof wherein CHzCH:

\NH R is hydrogen, while CHICH R is hydrogen or lower-alykl NaHCOa H01 1IBr- 5and R is lower-aklyl, the same or different than R or, wherein R R; is (Cl-1 where R is H;

or, wherein N-CH2 NaBHl HCl l-ICl and (Ar) and (Ar); are substituted phenyl groupings, either the same or different with a halogen or methoxy substituent in at least one of the phenyl rings, wherein the compounds are curative against Plasmedium berghei in mice at a dosage of 640 mg/kg or lower. 2. The compound according to claim 1 wherein (Ar) and (Ar); are the same or different functional groupings which are both halogen-substituted phenyl moieties, and salts thereof.

P. berghei screening test (mice) Phototoidcity Activity A MST; test (mice) b dose levels (mg./kg.) Cures, mgJkg. MED; mg./kg.

160 320 1.1;). Oral TABLE I.EVALUATION 0F i-PYRIDYLCARBINOLAMINES gym. 0.

Patent A Example 843cc 9 791302822629.6809593 O Q2 3L5 33 fi .&3 2 0 3 0 0 20 0 0 m A WQZ hly standardized procedure in which the P. bcrghei causes death of control mice at essentially 6.2 days. An increase in survival of mice by more than 2.5 found to be statistically significant. Mice W. E. Rothe and D. P. Jacobus,

3. The compound according to claim 1 wherein (Ar)- and (Ar) are the same or different functional group ings which are both chloroor bromo-substituted phen yl moieties, and salts thereof.

4. The compound according to claim 3 having (Ar) and (Ar) both as 4-chloro-phenyl groupings, and salts of said bases.

5. The compound, 2-4-(-bromophenyl)-6-(4- chlorophenyl)-4-alpha-(n-butylamino) methylpyridine carbinol and salts thereof.

as cured (c). Drugs which prolong the life of the (1 active (:1). y determined in mice by the method of J. Med. Chem., 11, 366 (1968).

I Test method described by T. S. Osdcne, I. B. Russell, and L. Rune, J. Med. Chem, 10,

days beyond this time has been b Phototoxicit We claim:

1. Compound of the formula 431 (1967). This test has been made as a hig which live more than 60 days are regarded mice beyond 14 days are considere 23 24 6. The compound 2,6-bis-(4-Chlorophenyl)-4-alpha- 2,6-bis-(4-fluorophenyl)-4-pyridinecarbinol. (2-piperidyl)pyridine carbino] and its salts. 9. The compound alpha-di-n-butylaminomethyl)-2,6-

7. The compound 2,6-bis-(4-chlorophenyl)-4-alphabis-(4-br0mophenyl-4-pyridinecarbinol. (2-quinuclidinyl)pyridine carbinol and its salts.

8. The compound alpha-(di-n-butylaminomethyl)- 5

Claims

2. The compound according to claim 1 wherein (Ar)2 and (Ar)6 are the same or different functional groupings which are both halogen-substituted phenyl moieties, and salts thereof.
3. The compound according to claim 1 wherein (Ar)2and (Ar)6 are the same or different functional groupings which are both chloro-or bromo-substituted phenyl moieties, and salts thereof.
4. The compound according to claim 3 having (Ar)2 and (Ar)6 both as 4-chloro-phenyl groupings, and salts of said bases.
5. The compound, 2-4-(-bromophenyl)-6-(4-trifluoromethylphenyl)-2-4(-bromophenyl)-6-(4 -chlorophenyl)-4-chlorophenyl)-4-alpha-(n-butylamine)methylpridine carbinol and salts thereof.
6. The compound 2,6-bis-(4-Chlorophenyl)-4-alpha-(2-piperidyl)pyridine carbinol and its salts.
7. The compound 2,6-bis-(4-chlorophenyl)-4-alpha-(2-quinuclidinyl)pyridine carbinol and its salts.
8. The compound alpha-(di-n-butylaminomethyl)-2,6-bis-(4-fluorophenyl)-4-pyridinecarbinol.
9. The compound alpha-di-n-butylaminomethyl)-2,6-bis-(4-bromophenyl-4-pyridinecarbinol.