Novel Synthesis of 5-Amino-3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbonitrile: A Versatile Intermediate for the Preparation of 5-Amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.     

Preparation of halomethyl-1,3,4-thiadiazoles. Conversion to 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole,an important antimicrobial agent

A new route for the synthesis of 2-amino-5-(l-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole ( 1 ) is described. This route was based upon the preparation of 2-amino-5-halomethyl-1,3,4-thiadiazoles by condensation of haloacetic acids with thiosemicarbazide. One of these intermediates, 2-acetamido-5-dichloromethyl-1,3,4-thiadiazole ( 4 ), was hydrolyzed to the corresponding 5-amino-2-carboxaldehyde 6 , which was trapped as its oxime 5 . 5-Acetamido-1,3,4-thiadiazole-2-carbonitrile ( 7 ), formed upon dehydration of 5 , was then converted into 2-amino-5-(2-imidazolyl)-1,3,4-thiadiazole ( 11 ) by a route based on the Pinner amidine synthesis. Methylation and nitration of the imidazole moiety then completed the preparation of 1.     

Design and effective synthesis of the first 4-aza-2,3-didehydropodophyllotoxin rigid aminologue: a N-methyl-4-[(3,4,5-trimethoxyphenyl)amino)]-1,2-dihydroquinoline-lactone

The first N1-alkyl-4-amino-1,2-dihydroquinoline-lactone has been prepared by a five-step sequence in a 51% overall yield via the corresponding furo[3,4-b]quinolin-1(3H)-one. A new practical synthesis of this intermediate was carried out using versatile, commercially available starting materials and constitutes the shortest and highest yielding route. These synthetic pathways could be widened with a view toward the preparation of different substituted derivatives, which could be considered as rigid aminologues of 4-aza-2,3-didehydropodophyllotoxins.     

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.     

Photochemical and Acid-Catalyzed Rearrangements of 4-Carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one

The synthesis of 4-carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one (1) in 60% overall yield from benzaldehyde is described. Irradiation (366 nm) of 1 in benzene solution gave products of type A photorearrangement; e.g., diastereomers of the 4-(trimethylsilyl)- and 5-(trimethylsilyl)bicyclo[3.1.0]hex-3-en-2-ones 8 and 9. Bicyclohexenones 9a and 9b could not be isolated, but underwent acid-catalyzed protiodesilylative rearrangements on attempted chromatography (silica gel) to give a 1:1 mixture of (E)- and (Z)-4-(carbomethoxymethylmethylene)cyclopent-2-en-1-ones 12 and 13. Irradiation (366 nm) of either 12 or 13 resulted in photoisomerization to a photostationary state that was also a 1:1 mixture. Irradiation of 8a or 8b gave equivalent mixtures of phenols 14 and 15 by way of the type B oxyallyl zwitterion 17. The available experimental evidence suggests that both 9a and 9b undergo regiospecific photorearrangement to phenol 16 with no trace of 3-methyl-4-carbomethoxyphenol (19), the product of ipso substitution of the Me(3)Si group at C(4). Phenol 15 was isolated in 65% yield from the photoreaction of 1 in benzene with 20 equiv of CF(3)CO(2)H. The acid-catalyzed rearrangement of 1 to 3-carbomethoxy-4-methylphenol (21) occurs in 91% yield by way of CO(2)Me group rearrangement to C(3) to give the Me(3)Si-stabilized carbocation 23.     

Synthesis of 5-fluoro-2-methyl-3-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)-4(3H)-quinazolinone and related compounds with potential antiviral and anticancer activity

The synthesis of ten new substituted 1,3,4-thiadiazolyl-4(3H)-quinazolinones 8–11, 13, 17 , and 20–23 is reported. Compounds 8–11 were prepared by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7. Compound 13 was obtained by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) with DL-α-amino-?-caprolactam (12) . Compound 17 was synthesized by condensation of 6-bromo-2-methyl-3,1-benzoxazin-4-one (16) and 2-amino-5-t-butyl-1,3,4-thiadiazole (5) . Compounds 20–23 were obtained by condensation of 5-chloro-6,8-dibromo-2-methyl-3,1-benzoxazin-4-one (19) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7, respectively. The substituted 3,1-benzoxazin-4-ones 3, 16, and 19 were obtained in good yield by refluxing the appropriate anthranilic acid, 1,15 , and 18 with acetic anhydride (2) .     

(R)-3-叔丁基二甲基硅氧丁基苯硫醚的合成方法改进

以4-(二甲氨基)吡啶为催化剂,通过(R)-3-叔丁基二甲基硅氧丁醇与甲磺酰氯之间的改进烷基磺酰化反应得到(R)-3-叔丁基二甲基硅氧丁基甲磺酸酯(2b,收率98%),2b再与苯硫酚钠反应生成(R)-3-叔丁基二甲基硅氧丁基苯硫醚(3,总收率89%)。2和3的结构经1H NMR,IR和MS表征。     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

General pathway for a convenient one-pot synthesis of trifluoromethyl-containing 2-amino-7-alkyl(aryl/heteroaryl)-1,8-naphthyridines and fused cycloalkane analogues

A convenient and general method for the synthesis in 26-73% yields of a new series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines from direct cyclocondensation reactions of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones [CF?C(O)CH=C(R1)OR, where R1 = H, Me, Ph, 4-MePh, 4-OMePh, 4-FPh, 4-BrPh, 4-NO?Ph, 2-furyl, 2-thienyl and R = Me, Et] with 2,6-diaminopyridine (2,6-DAP), under mild conditions, is described. Another synthetic route also allowed the synthesis of 2-amino-5-trifluoromethyl-cycloalka[b][1,8]naphthyridines in 33-36% yields, from direct or indirect cyclo-condensation reactions of five-, six- and seven-membered 2-trifluoroacetyl-1-methoxy-cycloalkenes with 2,6-DAP.     

Zur Synthese sulfonierter Derivate von 4- und 5-Aminoindan

On the Synthesis of Sulfonated Derivatives of 4- and 5-Aminoindan Baking the hydrogensulfate salt of 4-aminoindan (1) and 5-aminoindan (2) led, respectively, to 4-aminoindan-7-sulfonic acid (3) and 5-aminoindan-6-sulfonic acid (4). Acid 4 was also obtained by direct sulfonation of 2. 4-Aminoindan-6-sulfonic acid (5) and 6-aminoindan-4-sulfonic acid (6) were prepared by sulfonation of 4-nitroindan (7) and 5-nitroindan (9) , respectively, to 4-nitroindan-6-sulfonic acid (8) and 6-nitroindan-4-sulfonic acid (10) , followed by a Béchamp-reduction. Treatment of 1 with amidosulfuric acid gave 3 , whereas the same reaction with 2 led to a mixture of 4 and 5-aminoindan-4-sulfonic acid (11). Independent synthesis of 11 was achieved by the following sequence of reactions: sulfur dioxide treatment of the diazonium chloride derived from 4-amino-5-nitrodan (13) gave 5-nitroindan-4-sulfonyl chloride (14) ; hydrolysis to 5-nitroindan-4-sulfonic acid (15) , and final reduction. The 4-aminoindan-5-sulfonic acid (16) was synthesized by treatment of 4-amino-7-bromoindan (18) with amidosulfuric acid to give 4-amino-7-bromoindan-5-sulfonic acid (19) followed by hydrogenolysis. Sulfonation of 4-acetyl-amino-7-bromoindan (17) with oleum followed by hydrolysis led to 7-amino-4-bromoindan-5-sulfonic acid (20) , the structure of which was confirmed by reductive dehalogenation to 5 .     

(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan+-4-yl][-2-hydroxyethylamm onium benzoate, a versatile building block for chiral 2-aminoalkanols: concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor

A concise synthesis of a versatile chiral C4 building block for 2-aminoalkanols, (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammo nium benzoate (1a), was described. 1 (1a and its enantiomer 1b) acted as four stereoisomers of optically active 2-amino-1,3,4-butanetriol. The versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of 2.     

Zur Synthese sulfonierter Derivate von 4-Amino-1,3-dimethylbenzol und 2-Amino-1,3-dimethylbenzol

Syntheses of Sulfonated Derivatives of 4-Amino-1, 3-dimethylbenzene and 2-Amino-1, 3-dimethylbenzene Direct sulfonation of 4-amino-1, 3-dimethylbenzene (1) and sulfonation of 4-nitro-1,3-dimethylbenzene ( 4 ) to 4-nitro-1,3-dimethylbenzene-6-sulfonic acid ( 3 ) followed by reduction yield 4-amino-1,3-dimethylbenzene-6-sulfonic acid ( 2 ). The isomeric 5-sulfonic acid ( 5 ) however is prepared solely by baking the acid sulfate salt of 1 . Reaction of sulfur dioxide with the diazonium chloride derived from 2-amino-4-nitro-1,3-dimethylbenzene ( 7 ) leads to 4-nitro-1,3-dimethylbenzene-2-sulfonyl chloride ( 8 ), which is successively hydrolyzed to 4-nitro-1,3-dimethylbenzene-2-sulfonic acid ( 9 ) and reduced to 4-amino-1, 3-dimethylbenzene-2-sulfonic acid ( 6 ). Treatment of 4-amino-6-bromo-1,3-dimethylbenzene ( 12 ) and 4-amino-6-chloro-1, 3-dimethylbenzene ( 13 ), the former obtained by reduction of 4-chloro-6-nitro-1,3-dimethyl-benzene ( 10 ) and the latter from 4-chloro-6-nitro-1, 3-dimethylbenzene ( 11 ), with oleum yield 4-amino-6-bromo-1,3-dimethylbenzene-2-sulfonic acid ( 14 ) and 4-amino-6-chloro-1,3-dimethylbenzene-2-sulfonic acid ( 15 ) respectively; subsequent carbon-halogen hydrogenolyses of 14 and 15 lead also to 6 (Scheme 1). Baking the acid sulfate salt of 2-amino-1, 3-dimethylbenzene ( 17 ) gives 2-amino-1, 3-dimethylbenzene-5-sulfonic acid ( 16 ), whereas the isomeric 4-sulfonic acid ( 18 ) can be prepared by either of the following three possible pathways: Sulfonation of 2-nitro-1,3-dimethylbenzene ( 20 ) to 2-nitro-1,3-dimethylbenzene-4-sulfonic acid ( 21 ) followed by reduction or sulfonation of 2-acetylamino-1,3-dimethylbenzene ( 19 ) to 2-acetylamino-1,3-dimethylbenzene-4-sulfonic acid ( 22 ) with subsequent hydrolysis or direct sulfonation of 17 . Further sulfonation of 18 yields 2-amino 1,3-dimethylbenzene-4,6-disulfonic acid ( 23 ), the structure of which is independently confirmed by reduction of unequivocally prepared 2-nitro- 1,:3-dimethylbenzene-4,6-disulfonic acid ( 24 )(Scheme 2).     

5-硝基-6-羟基-2-(对甲氧羰基苯基)苯并噁唑的合成

研究了以关键中间体4-氨基-6-硝基间苯二酚盐酸盐（ANR·HCl）和对苯二甲酸单甲酯（MTA）为原料,分别经酰氯化、缩合、环合分步或原位合成AB型新单体前体--4-（5-硝基-6-羟基-2-苯并噁唑基）苯甲酸甲酯（MNB）的技术。 反应优化条件：在甲基异丁基酮溶剂中,n(ANR·HCl)∶n(MTA)=1.00∶1.03,115 ℃缩合反应2.5 h;m(ANR·HCl)∶m(PPA)=1.00∶3.25的多聚磷酸(PPA),120 ℃环合8.5 h;MNB收率75.68%（以ANR·HCl计）,HPLC测定ω(MNB)=96.32%。 产物结构经¹H NMR和IR确证。     

2-Amino-4-aryl-6-(ω-carboxyalkyl)-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones. Preparation via a one-pot synthesis of 1-(ω-carboxyalkyl)-4-carbethoxy-2,3-dioxopyrrolidines

1-(ω-Carboxyalkyl)-4-carboethoxy-2,3-dioxopyrrolidines were prepared by a one-pot synthesis from β-alanine or γ-aminobutyric acid, ethyl acrylate and diethyl oxalate. In a second one-pot process these products were hydrolyzed, decarboxylated and condensed with aromatic aldehydes under the influence of hydrochloric acid to yield 1-(ω-carboxyalkyl)-4-arylidene-2,3-dioxo-pyrolidines, which yielded 2-amino-4-aryl-6-(ω-carboxyalkyl)-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)-ones upon treatment with guanidine. It was shown that 3,4-dihydro derivatives of certain 2-amino-4-aryl-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones, formed initially in the guanidine reaction, readily undergo conversion to 5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones.     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.     

A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid,an antirheumatic agent (part 1)

An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.     

Syntheses and Crystal Structures of Methyl 2-（4,5-Dibromo- 1-methylpyrrole-2-carbonylamino）-3-phenyl propanoate and 4,5-Dibromo-1-methyl-2-trichloroacetylpyrrole

1 INTRODUCTION Pyrrole and its derivatives have attracted much attention due to their chemical properties as well as biological activities[1]. They have been widely used as the materials to produce pharmaceutical, essences, biochemicals, etc. It has been found that a great deal of pyrrole derivatives present bioactivities, such as antitumor and antiviral activities[2~5]. Thus, due to the interest in exploring the syntheses of potential bioactive materials which contain pyrrole ring andna…     

Synthesis of 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one

The synthesis of two new acyclic nucleoside analogs, 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one (1) and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one (2), is reported. The first compound, 1, was obtained by reaction of 3-chloro-1,2-propanediol with the sodium salt of 5-amino-2H-1,2,4-thiadiazol-3-one (3) in anhydrous dimethylformamide. Similarly, 5-amino-3H-1,3,4-thiadiazol-2-one (4) reacted with 3-chloro-1,2-propanediol to give 2. The thiadiazole 4 was prepared by condensation-cyclization of hydrazothiodicarbonamide (9).     

Conversion of 2-deoxy-D-ribose into 2-amino-5-(2-deoxy-beta-D-ribofuranosyl)pyridine, 2'-deoxypseudouridine, and other C-(2'-deoxyribonucleosides)

The synthesis of 2-amino-5-(2-deoxy-beta-D-ribofuranosyl)pyridine 2a, 2-amino-5-(2-deoxy-alpha-D-ribofuranosyl)-pyridine 23, 2-amino-5-(2-deoxy-beta-D-ribofuranosyl)-3-methylpyridine 2b, 2-amino-5-(2-deoxy-alpha-D-ribofuranosyl)-3-methylpyridine 29 and 5-(2-deoxy-beta-D-ribofuranosyl)-2,4-dioxopyrimidine [2'-deoxypseudouridine] 30a is described. These C-nucleosides are prepared either from 2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)-D-ribofuranose 15 or from 2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)-D-ribono-1,4-lactone 16, which are themselves prepared from 2-deoxy-D-ribose 13. The sugar derivatives are first allowed to react with the appropriate 5-lithio-pyridine or 5-lithio-pyrimidine derivatives, which are prepared from 5-bromo-2-(dibenzylamino)pyridine 12a, 5-bromo-2-[bis(4-methoxybenzyl)amino]pyridine 12b, 5-bromo-2-dibenzylamino-3-methylpyridine 25 and 5-bromo-2,4-bis(4-methoxybenzyloxy)pyrimidine 33. The products from the reactions between the lithio-derivatives and the lactol 15 are cyclized under Mitsunobu conditions; the products from the reactions between the lithio-derivatives and the lactone 16 are first reduced with L-Selectride before cyclization, also under Mitsunobu conditions. In all cases, the beta-anomers of the protected C-nucleosides are the predominant products. Finally, the separation of the alpha- and beta-anomers and the removal of all of the protecting groups are described.     

Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4- pyrrolidinyl]benzamide (TKS159) and its optical isomers

Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans-4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of the benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]GR113808). The activities of 25-27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl]benzamide (1).