Synthesis of monoalkenylated crown ethers and C-pivot cryptands

The synthesis of two N-(2-allyloxy)ethyl-substituted diaza-crowns and two C-pivot (allyloxy)methyl-substi-tuted cryptands is described. Controlled etherization of N,N-bis(2-hydroxyethyl)-4,13-diaza-18-crown-6 with allyl bromide and sodium hydride gave N-(2-allyloxy)ethyl-N-(2-hydroxyethyl)-4,13-diaza-18-crown-6 in a good yield. This macrocycle was reacted with sodium hydride and tetrahydrofurfuryl chloride or 3,3-dimeth-ylbutyl tosylate to give expected N-(2-allyloxy)ethyl-N'-tetrahydrofurfuryloxy)ethyl-[or (3,3-dimethylbutoxy)-ethyl]-substituted products 3 or 4 . 6,13-Dimethylenyl-14-crown-4 ( 9 ) and 9,19-dimethylenyl-20-crown-6 ( 10 ) were treated with mercuric acetate, followed by sodium borohydride in strong base to give macrocyclic diols 11 and 12 , respectively. These diols were reacted with sodium hydride and the ditosylate derivative of allyloxymethyl-substituted triethyleneglycol 13 to produce the C-pivot (allyloxy)methyl-substituted macrotri-cycles 6 and 7 .     

An unexpected preparation of 4-oxo-2H-1,3-benzothiazines

Treatment of compound N,N-(dithiobis(3-chloro-2,1-phenylene)dicarbonylbis (N-cyclopentylglycine)diethyl ester (3) with methanolic sodium hydroxide does not produce the expected hydrolysis product N,N-(dithiobis-(3-chloro-2,1-phenylene)dicarbonylbis (N-cylcopentylglycine) (4) but yields a mixture of compounds 8-chloro-3-cyclopentyl-3,4-dihydro-4-oxo-2H-1,3-benzothiazine-2-carboxylic acid (6) and N-(3-chloro-2-mercaptobenzoyl)-N-cyclopentylglycine (7). This unexpected observation has the potential of a new heterocyclic synthesis method for the 4-oxo-2H-1,3-benzothiazine class of compounds.     

Synthesis of 5-aryl-2-oxazolepropionic acids and analogs. Antiinflammatory agents

Condensation of 2-bromoacetophenones with sodium succinimide gave N-phenacylsuccinimides ( 1 ) which were opened with sodium hydroxide to N-phenacylsuccinamic acids ( 2 ). The latter were cyclized to 5-aryl-2-oxazolepropionic acids ( 3 ) in sulfuric acid. Similar cyclization of N-phenacylphthalamic acid ( 5 ) and succinic acid 2-benzoylhydrazide ( 7 ) gave o-(5-phenyl-2-oxazolyl)benzoic acid ( 6 ) and 5-phenyl-1,3,4-oxadiazole-2-propionic acid ( 8 ). The succinamic acids 2 and the phthalamic acid 5 were observed to recyclize to the corresponding imides ( 1 and 4 ) on heating, and the succinic acid hydrazide 7 was similarly cyclized to N-benzamidosuccinimide ( 9 ) with acetic anhydride. Antiinflammatory screening data are reported for 3 , 6 and 8 .     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

Synthesis of new carbamate derivatives of indole and their modification

Oximation of indoles having a methoxycarbonylamino group on C⁵ and an acyl group on C³ with hydroxylamine hydrochloride in the presence of pyridine gave the corresponding oximes. The reduction of the 3-C=O group with sodium tetrahydridoborate in the presence of sodium hydroxide was accompanied by removal of the methoxycarbonyl group at the pyrrole nitrogen atom with formation of racemic alcohols. 1,4-Addition of 1-(pyridin-3-yl)butane-1,3-dione to dimethyl 1,4-benzoquinone diimine N,N′-dicarboxylate in dioxane in the presence of sodium methoxide, followed by heating in boiling 22% hydrochloric acid, afforded methyl 2-methyl-5-(methoxycarbonylamino)-3-(pyridin-3-ylcarbonyl)-1H-indole-1-carboxylate. 3-(Dimethylamino)-1-(4-methyl-1,2,5-oxadiazol-3-yl)prop-2-en-1-one reacted with N,N′-bis(methoxycarbonyl)- and N,N′-bis(phenylsulfonyl)-1,4-benzoquinone diimines in methylene chloride and acetic acid, respectively, in the presence of BF₃ · Et₂O to produce indoles having a 1,2,5-oxadiazolylcarbonyl group on C₃.     

Presence of an N-6 acetate group shifts the alkylation site of the ambident nucleophile sodium 1-N-methylisoguanide

Inclusion of an N-6 acetate into the ambident nucleophile, sodium 1-N-methylisoguanide, resulted in a shift in alkylation preference from N-9 to N-3. The preparation of the N-6 acetate of 1-N-methylisoguanine, 9-N-acetyl-1-N-methylisoguanine (4) , and related acetate analogs are described and evidence presented for their structural determination. Analysis of long range ¹³C-¹H coupling data facilitated the structural elucidation of the predominant alkylation products and provided evidence for the unusual N-7 hydrogen tautomeric form in one of them, 3-N-benzyl-6-N-acetyl-1-N-methylisoguanine (8).     

Studies on imidazole derivatives and related compounds. I. Synthesis of novel antineoplastic derivatives of 4-carbamoylimidazolium-5-olate

Acylation of 4-carbamoylimidazolium-5-olate ( 2 ) with a variety of acid chlorides produced 4(5)-carbamoyl-1H-imidazol-5-(4)yl acid carboxylates ( 3a-j ). Treatment of esters 3a,c with sodium hydroxide gave imides, 4a,c . Methylation of 3a and 2 with diazomethane gave the N-3 methyl derivative ( 6 ) and a mixture of the N-3, O-dimethyl derivative ( 9 ), the N-1, N-3-dimethyl derivative ( 10 ) and the O-methyl derivative ( 11 ), respectively. 5-Carbamoyl-1-methylimidazolium-4-olate ( 7 ) and its 4-carbamoyl isomer ( 16 ) were prepared from 2-aminopropanediamides 8 and 15 , respectively. Treatment of the imidazolium compound ( 10 ) with aqueous potassium hydroxide gave the recyclized product, 1-methyl-5-methylcarbamoylimidazolium 4-olate ( 18 ). Methyl derivatives 6, 7 , and 9 except 16 demonstrated the complete lack of antitumor activity against Lewis lung carcinoma or sarcoma 180 in mice.     

N-(2-tetrahydrofuranyl)azole nucleoside analogs by reactions of azoles with dihalomethanes in tetrahydrofuran

The reactions of the mono-N-substituted bispyrazolylpyridine 2-(1-methyl-4,5,6,7-tetxahydroindazol-3-yl)-6-(2H-4,5,6,7-tetrahydroindazol-3-yl)pyridine, 3,5-dimethylpyrazole and benzimidazole with sodium hydride and diiodomethane or dibromomethane in tetrahydrofuran produced the unexpected N-tetrahydrofuran-2-yl adducts as well as the expected diazolylmethanes. These side-reactions are thought to involve the 2-halo tetrahydrofuran derivative resulting from a free-radical halogenation by the dihalomethane.     

Hydroxide-promoted redox reactions in water of α-Phenyl-4-nitro-benzenemethanol, α-(p-Nitrophenyl)-4-pyridinemethanol,and α-(p-Nitrophenyl)-4-Pyridinemethanol N-Oxide steric inhibition of resonance

α-Phenyl-4-nitrobenzenemethanol ( 3 ) reacted with 1 M sodium hydroxide to yield 4, 4′-dibenzoyl-azoybenzene ( 5 ) (51%), 4-hydroxy-4′-benzoylazobenzene ( 6 ) and benzoic acid (12% each), and smaller amounts of 4-aminobenzophenone and 4-nitrobenzophenone. Both α-phenyl-2-nitrobenzenemethanol ( 9 ) and 3, 5-dimethyl-4-nitrobenzenemethanol ( 10a ) did not react with 1 M sodium hydroxide, presumably due to steric hindrance. α-(p-Nitrophenyl)-4-pyridinemethanol ( 14 ) and its N-oxide 11 with 1 M sodium hydroxide yielded 4,4′-diaroylazoxybenzenes 15a and 12a , respectively, 4,4′-diaroylazobenzenes 15b and 12b , respectively, as well as 4-hydroxy-4′-aroylazobenzenes 16 and 13 , respectively. The relative reaction rates were 11 > 14 > 3 . Studies with 11 showed that the nitro group is involved in the redox reaction in preference to the N-oxide group.     

1,6- and 1,7-naphthyridines. II. Synthesis from acyclic precursors

A number of 8-hydroxy-6-methyl-1,6-naphthyridin-5(6H)-one-7-carboxylic acid alkyl esters 3 and the isomeric 5-hydroxy-7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid alkyl esters 4 were synthesized from acyclic precursors obtained starting from quinolinic anhydride 5. Thus, methanolysis of 5 afforded the hemiester 6 which treated with oxalyl chloride and sarcosine ethyl ester gave 3-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-2-carboxylic acid methyl ester 8. Compound 8 was cyclized to naphthyridines 3a-e with sodium alkoxides. The isomeric naphthyridines 4a-c were obtained by cyclization of the open intermediary 2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-3-carboxylic acid methyl ester 9 obtained by a route that involves treatment of 5 with sarcosine ethyl ester and esterification with diazomethane. Spectroscopic properties (¹H nmr, uv, ir) of compounds 3 and 4 are discussed and confirmed the proposed structures.     

Synthesis and characterization of some new pyridines,thieno[2,3-b] pyridines and pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4(3H)-ones bearing styryl moiety

3-Cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridine-2(1H)-thione ( 3 ) was prepared by reaction of 2-cyano-5-phenylpenta-2,4-dienethioamide ( 2 ) with ethyl acetoacetate or by multicomponent reaction of cinnamaldehyde ( 1 ), cyanothioacetamide and ethyl acetoacetate in a moderate yield. Reaction of compound 3 with some N-aryl-2-chloroacetamides, in the presence of sodium acetate, gave the corresponding 2-(N-arylcarbamoylmethylsulfanyl)-3-cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridines 4a-f . When compounds 4a-f were subjected to Thorpe-Ziegler reaction conditions, they converted into the corresponding 3-amino-5-ethoxycarbonyl-2-(N-arylcarbamoyl)-6-methyl-4-styrylthieno[2,3-b]pyridines 5a-f . Compounds 5a,e,f were reacted, in turn, with 2,5-dimethoxytetrahydrofuran to furnish the corresponding 3-(pyrrol-1-yl)thieno-pyridines 6a,e,f . Reactions of 5a-f with triethyl orthoformate or nitrous acid were also carried out and their products were identified. Structural formulas of all synthesized compounds was characterized and confirmed on the basis of their elemental and spectral analyses.     

Glycosylidene Carbenes. Part 21. Synthesis of N-tosylglycono-1,4-lactone hydrazones as precursors of glycofuranosylidene carbenes

The N′-(glycofuranosylidene)toluene-4-sulfonohydrazides 5 and 10 (Scheme 1) were prepared in good yields by oxidation (1,3-dibromo-5,5-dimethylhydantoin/Et₃N) of the N′-glycosyltoluene-4-sulfonohydrazides 4 and 9 , which were obtained from 2,3,5-tri-O-benzyl-D -ribose ( 3 ) and 2,3,5-tri-O-benzyl-D -arabinose ( 8 ), respectively, and toluene-4-sulfonohydrazide. The analogous naphthalene-2-sulfonohydrazides 7 and 12 were similarly prepared from 3 and 8 via 6 and 11 . Photolysis in the presence of phenol of the sodium salt 15 (Scheme 2), best generated in situ, yielded the anomeric glycosides 16 , some 5 , and traces of the glycosides (1R)/(1S)- 17 . Photolysis of 15 in THF gave the sulfones α-D /β-D - 18 . Photolysis of 15 (quartz filter) and dimethyl fumarate led to a single cyclopropane 19 , the sulfones α-D /β-D - 18 , and the N-(ribofuranosyl)-N′-(ribofuranosylidene)toluene-4-sulfonohydrazide 20 . Similarly, N-phenylmaleimide afforded the cyclopropanes 21 and 22 . Photolysis of the sodium salt of 10 and phenol afforded the anomeric glycosides α-D /β-D - 23 , the C-glycoside 24 , and the sulfone 25 . Photolytic glycosidation of 15 with N⁶-benzyladenine gave the two nucleosides 26 and 27 (Scheme 3).     

Convenient synthesis of 6-substituted-2-chloro-5,12-dihydro-5-oxobenzoxazolo[3,2-a]quinolines and N-acylated-3-chlorodibenz[b,e][1,4]oxazepin-11(5H)-ones

Convenient synthesis of variously substituted 2-chloro-5,12-dihydro-5-oxobenzoxazolo[3,2-a]quinolines at the 6-position and N-acylated-3-chlorodibenz[b,e][1,4]oxazepin-11(5H)-ones are reported. The former compounds were obtained in 65–93% yield by simply heating N-acyl-4-chloro-N-(2-hydroxyphenyl)-anthranilic acids in acetic anhydride for 4 hours, and the latter by heating sodium salt of N-acyl-4-chloro-N-(2-hydroxyphenyl)anthranilic acids with acetic anhydride.     

Synthesis of potential impurities of cloxacillin sodium drug substance

The present work describes the synthesis and characterization of six related compounds of cloxacillin sodium ( 1 ) viz penicilloic acid of cloxacillin (2) , (3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl) glycine (Glycine analogue of cloxacillin) (3), CMICAA adduct of cloxacillin (4) , (4S)-2-(carboxy(3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido) methyl)-3-(2-ethylhexanoyl)-5,5-dimethylthiazolidine-4-carboxylic acid (N-2-ethylhexanoyl penicilloic acid of cloxacillin) ( 5 ), N-Acetylated penicilloic acid of cloxacillin ( 6 ), and Cloxacillin Penicillamide (7) . These related compounds are very essential in the process development of cloxacillin sodium and are used as reference standards to determine the quality of the drug substance.     

Synthesis and characterization of some nitrogen heterocycles from d-galactose derivatives

The tetrazoles 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′-di-O-isopropylidene-D-glycero-α-D-galactohexopyranos-6′-yl)tetrazole ( 1 ) and 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′–di-O-isopropylidene-L-glycero-α-D-galacto-hexopyranos-6′-yl)-tetrazole ( 2 ) were synthesized by the 1,3-dipolar cycloaddition reaction of the epimeric α-acetamidonitriles 5 and 6 , respectively, with sodium azide. Reaction of tetrazole 1 with acetic anhydride in the presence of pyridine afforded the N-acetyl-1,3,4-oxadiazole derivative 3 and the N-acetylacetamido-1,3,4-oxadiazole derivative 7 . The N-acetylacetamido-1,3,4-oxadiazole derivative ( 8 ) was isolated when the tetrazole 2 was allowed to react under the same conditions. The physical and spectroscopic data of the five new compounds 1, 2, 3, 7 and 8 are presented.     

Rearrangement reactions of aziridinylbenzaldoximes

Reactions of 2,2-dimethylaziridine with benzohydroximoyl chlorides [ArC(Cl)?NOH] give aziridinylbenzaldoximes 1 . It has been found that the aziridine ring in these compounds undergoes ring opening in hydrogen chloride-dioxane solution to give (Z)-N-hydroxy-N′-(2-chloro-2-methylpropyl)benzenecarboximidamides [ArC(NHCH₂CR¹R²Cl)?NOH, 4 ]. Treatment of 1 with hydrochloric acid followed by neutralization with aqueous sodium hydroxide gave 6,6-dimethyl-3-aryl-1,2,4-oxadiazines 2. Reaction of 4 with sodium hydride in dioxane gave 5-isopropyl-3-aryl-4,5-dihydro-1,2,4-oxadiazoles 5. Reaction of the 4,5-dihydro-1,2,4-oxadiazoles 5 with N-chlorosuccinimide gave the heteroaromatic 1,2,4-oxadiazoles 6 . It is suggested that reactions of 4 with sodium hydride in dioxane solution involve the conjugate base of 4 which undergoes a 1,2-hydride shift that is concerted with loss of chloride ion. In aqueous sodium hydroxide solution it is suggested that the conjugate base of 4 undergoes ionization of the chlorine atom followed by nucleophilic attack by the oximate anion.     

Synthesis of isonipecotinoyl analogues of aminopterin and folic acid

The preparation of isonipecotinoyl analogues of aminopterin and methotrexate is described. Condensation of diethyl N-isonipecotinoyl-L-glutamate 4 with 2-amino-5-bromomethyl-3-cyanopyrazine 5 afforded diethyl N-(N-[(2-amino-3-cyanopyrazin-5-yl)methyl]isonipecotinoyl)-L-glutamate 6 . Cyclisation of 6 with guanidine followed by blocking group hydrolysis afforded N-([N-(2,4-diaminopteridin-6-yl)methyl]isonipecotinoyl)-L-glutamic acid 8 . Coupling of N-(2-amino-4(3H)ioxopteridin-6-yl]methyl)isonipecotinic acid 11 with diethyl L-glutamate gave diethyl N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamate 12 . Blocking group hydrolysis afforded N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamic acid 13 .     

A novel and facile reaction to N6‐alkylated adenosine via benzotriazole as a synthetic auxiliary

The reaction of benzotriazole with aliphatic, aromatic or heteroaromatic aldehyde and adenosine leads to a benzotriazole adduct which is reduced with sodium borohydride to the corresponding N⁶‐alkylated adenosine derivatives. This procedure is also utilized in a new route to N⁶‐(3‐iodobenzyl)adenosine‐5′‐N‐methyluronamide (IB‐MECA) which is considered an important adenosine agonist at A₃ adenosine receptors.     

New reaction pathway of dialkyl phosphorochloridites with salts of α-benzylideneaminocarboxylic acids. Direct synthesis of α-aminophosphonates from isostructural α-benzylideneaminocarboxylic acids

The reaction of sodium N-benzylidenevalinate with dialkyl phosphorochloridites is accompanied by decarboxylation and yields diastereomeric N-(1-dialkoxyphosphoryl-2-methylpropyl)-N-(1-dialkoxyphosphorylbenzyl)amines. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1449–1452, June, 2005.     

Sulfonylcarbamimidic azides from sulfonyl chlorides and 5-aminotetrazole

Treatment of o-nitrobenzenesulfonyl chloride ( 3 ) with 5-aminotetrazole (5-AT) gave [(2-nitrophenyl)-sulfonyl]carbamimidic azide ( 6 ), a ring-opened isomer of the expected N-(1H-tetrazol-5-yl)-2-nitrobenzenesulfonamide ( 4 ). Sulfonylcarbamimidic azide 6 was converted to 2-amino-N-(aminoiminomethyl)benzene-sulfonamide ( 7 ) with ethanolic stannous chloride, and to 3-amino-1,2,4-thiadiazine 1,1-dioxide ( 8 ) with sodium dithionite. Methanesulfonyl chloride ( 9 ) and 5-AT gave 2-(methylsulfonyl)carbamimidic azide ( 10 ), which isomerized to 5-[(methylsulfonyl)amino]-1H-tetrazole ( 11 ) in warm ethanol. Attempted cycloaddition of 2-(phenylsulfonyl)carbamimidic azide ( 13 ) and ethyl vinyl ether led only to alkylated tetrazole products. In addition, other tetrazole-alkylating reactions are described. Isomers produced from these alkylations were differentiated with ¹³C nmr spectroscopy.