Preparation of 7-hydroxy-2-oxoindolin-3-ylacetic acid and its [13C2], [5-n-3H], and [5-n-3H]-7-O-glucosyl analogues for use in the study of indol-3-ylacetic acid catabolism

An improved synthesis of 7-hydroxy-2-oxoindolin-3-ylacetic acid via the base-induced condensation reaction between oxalate esters and 7-benzyloxyindolin-2-one is described. 7-Benzyloxyindolin-2-one was prepared in four steps and 50% overall yield from 3-hydroxy-2-nitrotoluene. The yield of the title compound from 7-benzyloxyindolin-2-one was 56%. This route was used to prepare 7-hydroxy-2-oxoindolin-3-yl[13C2]acetic acid in 30% yield from [13C2]oxalic acid dihydrate. The method could not be extended to the preparation of the corresponding [14C2]-compound. However, an enzyme preparation from Zea mays roots catalysed the conversion of carrier-free [5-n-3H]indol-3-ylacetic acid with a specific activity of 16.7 Ci mmol-1 to a mixture of 7-hydroxy-2-oxo[5-n-3H]indolin-3-ylacetic acid and its [5-n-3H]-7-O-glucoside in ca. 3 and 40% radiochemical yield respectively. The glucoside was converted into the 7-hydroxy compound in 80% yield by means of beta-glucosidase.     

Studies on pyrazines. 13 . Chlorination of 1-hydroxy-2(1H)-pyrazinones with phosphoryl chloride. Formation of 2,5-dichloro-3-phenylpyrazine from 1-hydroxy-3-phenyl-2(1H)-pyrazinone

The chlorination of 1-hydroxy-3-phenyl-2(1H)-pyrazinone with phosphoryl chloride proceeded to 5-chloro-3-phenyl-2(H)-pyrazinone or 2,5-dichloro-3-phenylpyrazine on heating to elevated temperatures. To define the mechanism of the novel formation, reactions of the parent or methyl-substituted 1-hydroxy-2(1H)-pyraz-inones with the same reagent were investigated.     

Studies on the Synthesis of (2R,4′R,8′R)-α-Tocopherol Alternative Syntheses of 2-Chroman-acetic Acid Intermediates

As an extension of previous studies on the total synthesis of (2R,4′R,8′R)-α-tocopherol ( 1 ) [1] [2], (S)-(?)-2-(6-benzyloxy-2,5,7,8-tetramethylchroman)acetic acid ( 6 ), a pivotal intermediate, possessing the absolute configuration required for construction of 1 was prepared by optical resolution of the racemic modification 11 . the latter substance was obtained by two routes, one emanating from the hydroxy acetal 7 [1] and the other based upon the Lewis acid mediated cycloaddition of trimethylhydroquinone to rac.-3-hydroxy-3-methylpent-4-en-l-yl acetate ( 16 ) giving rac. ethyl 2-(6-hydroxy-2,5,7,8-tetramethyl-chroman)acetate ( 12 ).     

Synthesis and Chemical Behaviour of 4, 5-Dideoxy-4, 5-Epithio-2, 3-DI-0-Methanesulfonyl-L-Xylose Dimethyl Acetal

ABSTRACT

Selective substitution of the primary sulfonate group in 2, 3, 4, 5-tetra-0-methanesulfonyl-D-arabinose dimethyl acetal (1) gives 5-S-acetyl-2, 3, 4-tri-0-methanesulfonyl--5-thio-D-arabinose dimethyl acetal (2) which is further converted into the title compound (3). Reductive desul-furization of 3 afforded deoxy dimethyl acetal derivatives 5 and 6 in a low yield. Unsaturated monosaccharide derivative 7 was obtained as the only reaction product from 3 with triphenylphosphine. Catalytic hydrogenation of 7 gave dideoxy-sugar 6 in a satisfactory yield. Finally, epi-sulfide 3 with acetyl chloride afforded 4-chloro-4-deoxy derivative 4, which can be recycled into the starting 3.     

Herstellung von Dihydro-, Tetrahydro- und Hexahydrochelidamsäure-Derivaten

Preparation of dihydro-, tetrahydro- and hexahydro-chelidamic-acid derivatives. Three methods for the preparation of 4-oxo-2,6-piperidine-dicarboxylic acid ( 3 ) and derivatives, required as a synthon for betalaine pigments, were explored. The best method was found to be the catalytic hydrogenation of chclidamic acid ( 1 ) with 5% Rh/Alox in water under 2.7 atm. H₂ for 33 h at 70° and subsequent esterification with methanol which gave 42% of cis, cis-4-hydroxy-2,6-piperidine- ( 7 ) and 10% of 2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 8 ), readily separable by chromatography. Oxidation of 7 with dimethylsulfoxide and a carbodiimide attached to a polymer afforded 90% of 4-oxo-2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 19 ). Other methods of oxydizing 7 to 19 were less successful. The electrochemical reduction of 1 followed by esterification with methanol led in a low yield to a mixture of 4-oxo-0-2,6-trans-piperidine-dicarboxylic acid dimethylester ( 24 ), its dimethyl acetal 25 and presumably trans-4-hydroxy-r-2, cis-6-piperidine-dicarboxylic acid dimethyl ester ( 26 ). Reaction of 4-oxo-hepta-2E, 5E-dienoic acid ( 35 ) with aqueous ammonia gave a 98% yield of a 3 : 2 mixture of cis- and trans-ammonium-4-oxo-2, 6-piperidine-dicarboxylate ( 39 and 40 ). The above mentioned catalytic hydrogenation method was also applied to N-ethyl-chelidamic acid ( 16 ) to give a 4:6 mixture of the N-ethyl derivatives 17 and 18 . Furthermore, a number of functional derivatives of 5 , of 19 , of 39 and of 40 were prepared. Oxidation of the hydroxy-diester 7 with dimethylsulfoxide and a carbodiimidc derivative in the presence of trifluoroacetic acid afforded 4-oxo-1,2,3,4-tetrahydro-2, 6-pyridine-dicarboxylic acid dimethyl ester ( 50 ). This ester was also obtained under the same conditions from thc keto-diester 19 .     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

由2',4'-二氢-6'-甲氧基-3',5'-二甲基查耳酮合成新黄酮

在DMSO/ I2的氧化作用下,由2',4'-二氢-6'-甲氧基-3',5'-二甲基查耳酮可合成一种全新结构的黄酮:7-羟基-5-甲氧基-6,8-二甲基黄酮(产率91%),而在HCl/MeOH作用下则得到了两种黄烷酮:7-羟基-5-甲氧基-6,8-二甲基黄烷酮 (产率70%) 和 5,7-二羟基-6,8-二甲基黄烷酮 (产率20%).     

Synthesis of a novel 8-thia-1,4-diazacycl[3.3.2] azine

A unique covalently hydrated cyclazine adduct, 2-imino-6a-hydroxy-4,5,6,6a-tetrahydro-7H-8-thia-J, 4-diazacycl[3.3.2]azin-5-one hydrochloride was prepared by reacting ethyl 4-chloro-acetoacetate with 4,6-diamino-2-thiopyrimidine in neutral alcohol. Neutralization gave 2-imino-5,6a-dihydroxy-6,6a-dihydro-7H-8-thia-1,4-diazacycl[3.3.2]azine which decomposed to 4,6-diamino-2-acetonylthiopyrimidine upon heating in water. Warming the hydrated hydrochloride in concentrated hydrochloric acid caused dehydration to yield 2-imino-5-hydroxy-6H-8-thia-1,4-diazacycl[3.3.2]azine hydrochloride. Partial isomerization (20%) to 2-imino-5-hydroxy-7H-8-thia-1,4-diazacycl[3.3.2]azine hydrochloride occurred during recrystallization from aqueous acidic methanol. The free base, 2-imino-5-hydroxy-7H-8-thia-1,4-diazacycl[3.3.2]azine was obtained after neutralizing either of the tautomeric hydrochlorides. Treating the free base with trifluoroacetic acid produced a mixture of the trifluoroacetate salts of the two tautomeric bases. Isomerization of one trifluoroacetate salt into the other in trifluoroacetic acid was observed by pmr at room temperature. Both 2-amino-5-hydroxy-7-nitroso-8-thia-1,4-diazacycl[3.3.2]azine and 2-amino-5-hydroxy-6-nitroso-8-thia-1,4-diazacycl[3.3.2]azine were isolated after nitrosation of the hydrochloride mixture.     

On the structure of thromboxane A2

The reactions of the 2-alkoxyoxetane 5 with sodium azide and methanol yield the α-azidoether 7 and the dimethyl acetal 8, respectively, paralleling reactions reported for TXA₂. The hydrolysis of 5 reported by Bruice to involve general acid catalysis proceeds at a rate similar to that reported for TXA₂. All these cleavage reactions are most likely to proceed by the same mechanism. These findings support structure 1 for TXA₂.     

A favorski reaction using iodosobenzene

Iodosobenzene or iodobenzene diacetate and excess base when reacted with 17β-hydroxy-5α-androstane-3-one (1a) unexpectedly gave a good yield of Favorski acid (3a) and some (3b). 17β-hydroxy-5α-19-norandrostan-3-one (1b) gave mainly the expected dimethylketal of the 2α-hydroxy-3-keto steroid (5).     

Synthesis of N-[4-[2-(2,4-Diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-ethylamino]benzoyl]-L-glutamic acid. An acyclic analogue of 5,6,7,8-tetrahydrofolic acid

The synthesis of N-[4-[2-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamic acid ( 2 ), a two carbon analogue of 5-DACTHF ( 1 ) and an acyclic analogue of 5,6,7,8-tetrahydrofolic acid, is reported. The pyrimidinylacetaldehyde diethyl acetal 3 , which was prepared in 2-steps from 2-chloro acetaldehyde diethyl acetal, was converted to 2 in four steps. Compound 2 was less cytotoxic toward Detroit 98 or L cells than 5-DACTHF ( 1 ).     

3-氨基-2-羟基-4-苯基丁酸的合成

3-氨基-2-羟基-4-苯基丁酸的合成;乌苯美司;氨基羟基苯基丁酸;合成     

内型2—（3,3—二甲基—2—降冰片基）丁醛及其衍生物的合成

以内型３，３－二甲基－２－降冰片基乙醛（１）与叔丁胺反应制得醛亚胺（２），依次和溴化乙基镁，碘乙烷反应制得内型２－（３，３－二甲基－２－降冰片基）丁醛的亚胺（４），再经水解得内型２－（３，３－二甲基－２－降冰片基）丁醛（５）。后者经与乙二醇缩醛化及氧化分别制得该醛的缩醛（６）及羧酸（７）。这些化合物均为新化合物，经纯化后进行了结构分析，并对其质谱进行了讨论。     

Asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside,methyl N-Boc-2-deoxy-2-amino-d-threoside and methyl N-Boc-2,3-dideoxy-3-amino-l-arabinopyranoside

The asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside and methyl N-Boc-2-deoxy-2-amino-d-threoside have been achieved from sorbic acid, in six and eight steps, and in 35 and 13% overall yield, respectively. Diastereoselective aminohydroxylation of tert-butyl sorbate gives access to two diastereoisomeric α-hydroxy-β-amino-γ,δ-unsaturated esters. Reduction of the ester functionality and ozonolysis of the double bond gives the corresponding aldehyde, which exists exclusively in the ring-closed (furanose) form. An alternative synthesis of methyl N-Boc-2-deoxy-2-amino-l-erythroside was also developed, reliant on aminohydroxylation of an α,β-unsaturated ester bearing an acetal functionality at the γ-position, and this synthesis proceeded in five steps and 54% overall yield from acrolein diethyl acetal. This approach was extended to permit the synthesis of methyl N-Boc-2,3-dideoxy-3-amino-l-arabinopyranoside in six steps and 58% overall yield from ethyl 3,3-diethoxypropanote.     

Use of 3–(2′-formyl-1′-chlorovinyl)coumarin in the syntheses of pyrazol,salicylaldazine and pyrimidine derivatives

3–(Pyrazol-5-yl)coumarin (3) was prepared from condensation of 3–(2′-formyl-l-chlorovinyl)-coumarin (1) with hydrazine hydrate at room temperature, followed by cyclyzation with base. Salicylaldazine was prepared from methoxylation of 1 to give acetal 7 , followed by condensation of 7 with hydrazine hydrate at 80°C: Treatment of acetal 7 with thiourea yielded the corresponding 4-substituted-2-thioxo-2H-pyrimidine[3, 4-b]-coumarin (12).     

Synthesis of methyl 3-bromomethylbut-3-enoate and its reactions with aldehydes and tributylchlorostannane in the presence of zinc

Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β-methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3-enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.     

Reaktionen des 4,6-Dichlor-5-formylpyrimidins

Zusammenfassung Bei der Methanolyse des 4,6-Dichlor-5-formylpyrimidins (I) tritt neben dem 4,6-Dimethoxy-5-formylpyrimidin (III) auch das 4-Methoxy-6-hydroxy-5-formylpyrimidin (IV) als Reaktionsprodukt [in Verhältnis 11] auf. Das Aldoxim V des 4,6-Dichlor-5-formylpyrimidins ist instabil und geht in das 4-Chlor-5-cyano-6-hydroxypyrimidin (VI) über. Beide Reaktionen werden mit Hilfe möglicher Zwischenprodukte erklärt. Hingegen führt Methanolyse des Dimethylacetals von I in guter Ausbeute zum 4,6-Dimethoxy-5-formylpyrimidin (III). Das 4,6-Dichlordimethylacetal (II) wird durch aufeinanderfolgende Sulfanilamidolyse, Methanolyse und Hydrolyse in das Acetal des 4-Sulfanilamido-6-methoxy-5-formylpyrimidins (IX) verwandelt. Die gleiche Reaktionsfolge wird auch mit dem cyclischen Acetal 5-(2-Dioxolano)-4,6-dichlorpyrimidin zu XII durchgeführt.

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During methanolysis of 4.6-dichloro-5-formylpyrimidine (I) 4-methoxy-6-hydroxy-5-formylpyrimidine (IV) is formed as well as 4,6-dimethoxy-5-formylpyrimidine (III) in a ratio of 11. The aldoxime V of 4,6-dichloro-5-formylpyrimidine is not stable and is converted into 4-chloro-5-cyano-6-hydroxypyrimidine (VI). Both reactions are interpreted by considering possible intermediates. On the other hand, methanolysis of the dimethylacetal of I affords a good yield of 4,6-dimethoxy-5-formylpyrimidine (III). The 4,6-dichlorodimethylacetal (II) is converted into the acetal of 4-sulfanilamido-6-methoxy-5-formylpyrimidine (IX) by sulfanilamidolysis followed by methanolysis and hydrolysis. The same series of reactions has also been applied to the cyclic acetal of 5-(2-dioxolano)-4,6-dichloropyrimidine to give XII.

     

Synthesis and application of novel degradable crosslinkers

A novel divinyl ether was synthesized by a convenient method with high yield.Then the divinyl ether was combined with 2- hydroxyethyl methacrylate and acrylic acid,respectively,generating difunctional polymeric crosslinkers with(hemi)acetal structure that was labile in acid.The chemical structures of the divinyl ether and crosslinkers were confirmed by ~1H NMR and elemental analysis.The crosslinkers were employed in free-radical polymerization to prepare polymer gel and gel particles. Due to the(hemi)acetal structure in the crosslinking segment,the polymer gel and particles exhibited degradable ability in strong acid.     

Synthesis of 6,7,8,9-tetrahydro-N,N-di-n-propyl-1H-benz[g] indol-7-amine,a potential dopamine receptor agonist

In this work, the synthesis of 6,7,8,9-tetrahydro-N,N-di -n-propyl-1H-benz[g]indol-7-amine (1) is described. This compound was designed as an indole bioisostere to the known dopamine receptor agonist 5-OH-aminotetraline 2 . The key step of the synthesis was a Mukaiyama type aldol condensation between the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ) and 4-di-n-propylamino-1-trimethylsilyloxycyclohexene ( 8 ) followed by cycloaromatization to afford 1-p-toluenesulfonyl-6,7,8,9-tetrahydro-N,N-di-n- propyl-1H-benz[g]indol-7-amine ( 10 ). Scission of the sulfonamide bond in 10 gave the target compound 1 . A byproduct which was isolated was assigned to the structure of 1-(p-toluenesul-fonyl)-6-[3-[1-(p-toluenesulfonyl)]pyrrolyl]indole ( 11 ). This compound was also synthesized in good yield by an acid catalyzed dimerization of the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ). Preliminary screening of 1 indicated that it possesses central dopamine receptor agonist properties.