Efficient method for the asymmetric reduction of α- and β-ketophosphonates

An efficient and versatile method for the asymmetric reduction of α- and β-ketophosphonates using chiral reactant derived from sodium borohydride and l-(+)- or d-(−)-tartaric acid is developed. The methodology was used for the preparation of a number of biologically interesting enantiomerically pure products: including 2,3-epoxypropylphosphonate 11, 2-hydroxy-3-aminopropylphosphonic acid 14 (phospho-GABOB), phospho-carnitine 19, and others in multigram scale.     

New method for the asymmetric hydroboration of ketophosphonates and the synthesis of phospho-carnitine

The reduction of α- or β-ketophosphonates with a chiral reactant 1, prepared from sodium borohydride and (R)- or (S)-tartaric acids, led to the formation of both (S)- and (R)-α- or β-hydroxyphosphonates in high yields. The stereoselectivity of the reaction depended on the absolute configurations of 1 and the ketophosphonates. The reduction of di(1R,2S,5R)-menthyl ketophosphonates with (R)-1 proceeded with matched double asymmetric induction to give high diastereomeric excesses of hydroxyphosphonates (up to 96% de). This methodology was used for the preparation of enantiomerically pure phosphonate modified carnitine on a multigram scale.     

Enantioselective reduction of ketophosphonates using chiral acid adducts with sodium borohydride

A method for asymmetric reduction of α-and β-ketophosphonates using a chiral complex prepared from sodium borohydride and D-or L-tartaric acid is developed. Reduction of α-or β-ketophosphonates by these reagents led to formation of corresponding (S)-or (R)-hydroxyphosphonates. Reduction of chiral di(1R,2S,5R)-menthylketophosphonates by the chiral complex NaBH₄/(R,R)-tartaric acid due to the dual compliant asymmetric induction resulted in increased stereoselectivity of the reaction and led to formation of the hydroxyphosphonates with ee 90% or higher. On the other hand, reduction of di(1R,2S,5R)-methylketophosphonates by the chiral complex NaBH₄/(S,S)-tartaric acid proceeded as non-compliant dual asymmetric induction and resulted in decreased reaction stereoselectivity leading to formation of hydroxyphosphonates with ～45–60% ee. The developed methodology was applied to the synthesis of (R)-phosphocarnitine in multigram amounts.     

Reaction of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succininc anhydride

Reactions of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succinic anhydride in organic solvents at room temperature gave the corresponding 4-(2-aroylhydrazinyl)-4-oxobutanoic acids. The reactions in boiling acetic acid afforded N-(2,5-dioxopyrrolidin-1-yl)benzamide or N-(2,5-dioxopyrrolidin-1-yl)pyridine-3-carboxamide.     

Solvent-free reduction of aldehydes and ketones using solid acid-activated sodium borohydride

A simple and convenient procedure for the reduction of aldehydes and ketones with sodium borohydride activated by solid acids such as boric acid, benzoic acid, and p-toluenesulfonic acid monohydrate under solvent-free conditions is described.     

Stereoselective synthesis of substituted piperazines

The treatment of allylarylamines with mercury(II) acetate in tetrahydrofuran followed by a double decomposition reaction with potassium bromide leads to trans-2,5-bis(bromomercuriomethyl)-1,4-diarylpiperazines (2). The stereochemistry of the reaction products has been elucidated by an ¹H-nmr spectroscopic study of the trans-2,5-dimethyl-1,4-diarylpiperazines (3) obtained by sodium borohydride reduction of 2 in alkaline media. The course of the reaction strongly depends on the steric demand of the groups attached to either the allylic group or the ortho-position in the aromatic ring of the starting amine (1).     

A practical synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid—the key precursor toward imatinib

A simple and efficient in situ synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid through direct reductive alkylation of 1-methylpiperazine in the presence of triacetoxy sodium borohydride in 95-99% yields is elaborated. The process is easy to scale-up for the large-scale synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid as the key synthetic intermediate of imatinib. This method was used for the synthesis of benzyl derivatives of heterocyclic amines in 87-90% yields.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

Syntheses of Key Monomers for Advanced Polymer Materials Using Cyclodextrin as Catalyst

Terephthalic acid was synthesized by the carboxylation of benzoic acid with carbon tetrachloride in aqueous sodium hydroxide solution in the presence of cyclodextrin (CyD) and copper powder as catalyst. By the use of β-CyD at the initial molar ratio to benzoic acid of 0.5, the carboxylation at 60 °C for 7 hours produced terephthalic acid in 75 mol% yield with 87% selectivity. The selective synthesis of 4,4'-biphenyldicarboxylic acid in 70 mol% yield was achieved by the carboxylation of 4-biphenylcarboxylic acid with carbon tetrachloride in the presence of β-Cyd under similar conditions. The carboxylation of 2-naphthalene carboxylic acid with carbon tetrachloride using β-Cyd under similar conditions produced 2,6-naphthalenedicarboxylic acid in 67 mol% yield with 84% selectivity. When α-CyD and γ-CyD were used in place of β-Cyd, both the yields and the selectivities of the dicarboxylic acids were markedly small. In the absence of CyD, carboxylation did not proceed. Inclusion complex formations between β-Cyd and aromatic monocarboxylic acids were indicated by the ¹H chemical shifts of the β-Cyd. The reaction mechanism was discussed on the basis of inclusion complex formation.     

2,6-二取代苯并二噁唑的合成方法研究

文献报道合成2,6-二芳基取代苯并[1,2-d;4,5-d']二(口恶)唑有两种方法,其一是2,5-二氨基对苯醌与芳香醛缩合,然后氧化,关环;其二是2,5-二氨基对苯二酚盐酸盐与酰氯缩合关环.     

Synthese und Reaktionen 8-gliedriger Heterocyclen aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und Saccharin bzw. Phthalimid

Synthesis and Reactions of 8-membered Heterocycles from 3-Dimethylamino-2,2-dimethyl-2H-azirine and Saccharin or Phthalimide 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts at 0-20° with the NH-acidic compounds saccharin ( 2 ) and phthalimide ( 8 ) to give the 8-membered heterocycles 3-dimethylamino-4,4-dimethyl-5,6-dihydro-4 H-1,2,5-benzothiadiazocin-6-one-1,1-dioxide ( 3a ) and 4-dimethylamino-3,3-dimethyl-1,2,3,6-tetrahydro-2,5-benzodiazocin-1,6-dione ( 9 ), respectively. The structure of 3a has been established by X-ray (chap. 2). A possible mechanism for the formation of 3a and 9 is given in Schemes 1 and 4. Reduction of 3a with sodium borohydride yields the 2-sulfamoylbenzamide derivative 4 (Scheme 2); in methanolic solution 3a undergoes a rearrangement to give the methyl 2-sulfamoyl-benzoate 5 . The mechanism for this reaction as suggested in Scheme 2 involves a ring contraction/ring opening sequence. Again a ring contraction is postulated to explain the formation of the 4H-imidazole derivative 7 during thermolysis of 3a at 180° (Scheme 3). The 2,5-benzodiazocine derivative 9 rearranges in alcoholic solvents to 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl) benzoates ( 10 , 11 ), in water to the corresponding benzoic acid 12 , and in alcoholic solutions containing dimethylamine or pyrrolidine to the benzamides 13 and 14 , respectively (Scheme 5). The reaction with amines takes place only in very polar solvents like alcohols or formamide, but not in acetonitrile. Possible mechanisms of these rearrangements are given in Scheme 5. Sodium borohydride reduction of 9 in 2-propanol yields 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl)benzyl alcohol ( 15 , Scheme 6) which is easily converted to the O-acetate 16 . Hydrolysis of 15 with 3N HCl at 50° leads to an imidazolinone derivative 17a or 17b , whereas hydrolysis with 1N NaOH yields a mixture of phthalide ( 18 ) and 2-hydroxymethyl-benzoic acid ( 19 , Scheme 6). The zwitterionic compound 20 (Scheme 7) results from the hydrolysis of the phthalimide-adduct 9 or the esters 11 and 12 . Interestingly, compound 9 is thermally converted to the amide 13 and N-(1′-carbamoyl-1′-methylethyl)phthalimide ( 21 , Scheme 7) whose structure has been established by an independent synthesis starting with phthalic anhydride and 2-amino-isobutyric acid. However, the reaction mechanism is not clear at this stage.     

Investigation of acylation of β-cyclodextrin and its silyl derivative with benzoyl and acetylsalicyloyl chlorides

Acylation of β-cyclodextrin and its silyl derivative with benzoic and acetylsalicylic acid chlorides results in formation of the conjugates containing rests of benzoic and acetylsalicylic acids interesting in pharmacological aspect. It is found that heating slightly increases conversion at this reaction but effect of the solvent nature on the conversion is complicated. Thus, acylation of free β-cyclodextrin in pyridine and DMF proceeds at the primary hydroxyl groups, but after its treatment with sodium hydride in DMF this process carries out with formation of the products due to substitution at the secondary hydroxyls in not high yield. The inclusion complex of “guest-host” type of acetylsalicylic acid with β-cyclodextrin which composition is determined as 1:1 is prepared. On the whole, the conjugation and formation of the inclusion compound lead to increase in its solubility in water compared to acetylsalicylic acid.     

Regio- and stereoselective double alkylation of β-enamino esters with organolithium reagents followed by one-pot reduction: convenient method for the synthesis of tertiary γ-amino alcohols

An easy, high yielding and stereoselective procedure for the preparation of tertiary γ-amino alcohols starting from β-enamino esters is presented. In this procedure, the double alkylation of β-enamino esters with organolithium reagents is followed by one-pot reduction with sodium borohydride in methanol/acetic acid. A hypothesis of mechanism is given, explaining the observed diastereoselectivity through molecular modeling. The configuration of the products was determined by ¹H NMR spectroscopy coupled with conformational analysis.     

An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes

On the basis of our Pd enolate chemistry, we have succeeded in developing an efficient catalytic enantioselective fluorination of β-ketophosphonates. In the presence of chiral Pd complexes 1 (1-10 mol %), various substrates including cyclic and acyclic β-ketophosphonates underwent the reaction with N-fluorobenzenesulfonimide (NFSI) in EtOH to give the corresponding fluorinated products in a highly enantioselective manner (94-98% ee).     

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 .     

Heteroatomic derivatives of aziridine. 12. Reaction of 1-(carbomethoxyalkyl)aziridines with thiols and mercapto acids

The reaction of 1-(carbomethoxyalkyl)aziridines with thiols and mercapto acids, which leads to the formation of the corresponding sulfides and esters of S-substituted N-(2-mercaptoethyl)amino acids, was studied. The acid hydrolysis of o-[(N-carbomethoxyethyl)-2-aminoethylthio]benzoic acid and o-[(N-cyanoethyl)-2-aminoethylthio]benzoic acid leads to o-[N-(carboxyethyl)-2-aminoethylthio]benzoic acid hydrochloride. The cyclization of 1-[(N-carbomethoxyethyl)-2-aminoethylthio]benzoic acid in the presence of PCl₃ gives 5-oxo-4-(carbomethoxyethyl)-6,7-benzoperhydro-1,4-thiazepine.See [1] for communication 11.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 921–923, July, 1981.     

Theoretical studies of inclusion complexes of β-cyclodextrin with methylated benzoic acids

AM1 semiempirical molecular orbital calculations have been performed on the inclusion complexes of β-cyclodextrin (β-CD) with methylated benzoic acids in two orientations, the “head-first” and “tail-first” positions. In the former, the CO₂H group points toward the primary hydroxyls of the CD. In the latter, it points away from them. Out of 30 possible inclusion complexes, AM1 results predict only three clearly stable inclusion complexes. These are β-CD with 4-methyl benzoic acid in the head-first position, β-CD with 2,4-dimethyl benzoic acid in the head-first position, and β-CD with 3,5-dimethyl benzoic acid in the tail-first position. The orientations of the stable inclusion complexes correlate with the total number of intramolecular hydrogen bonds and intermolecular hydrogen bonds. The stability of a complex also correlates with the closeness of the host and guest geometries in the complex to their isolated molecule geometries. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 64 : 711–719, 1997     

胶束电动毛细管色谱法测定板蓝根中苯甲酸、水杨酸和邻氨基苯甲酸

采用胶束电动毛细管色谱法对板蓝根中芳香酸类化合物苯甲酸、水杨酸和邻氨基苯甲酸进行了分离测定。电泳介质(pH 9.8)为20 mmol.L-1硼砂、30 mmol.L-1十二烷基硫酸钠、2 mmol.L-1β-环糊精和4%(体积分数)甲醇组成的混合溶液,以对-羟基苯甲酸为内标,分离电压为16 kV,检测波长为250 nm。在优化的试验条件下,苯甲酸、水杨酸和邻氨基苯甲酸的线性范围分别为40～240 mg.L-1,64～320 mg.L-1和40～400 mg.L-1,检出限(3S/N)依次为0.64,1.08,1.36 mg.L-1。应用此方法分析了板蓝根样品,测定回收率在93.3%～104.2%之间。     

A new direct synthesis of cinnamic acids from aromatic aldehydes and aliphatic carboxylic acids in the presence of sodium borohydride

Cinnamic acids have been prepared in 59-86% yields by a new direct synthesis from aromatic aldehydes and aliphatic carboxylic acids in the presence of sodium borohydride and N-methyl-2-pyrrolidinone (NMP) as solvent, at reflux (185-190°C), for 9-12 hours. Without sodium borohydride, this reaction is not possible.     

Stereoselective synthesis of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids

Enantiomerically pure δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids were stereoselectively synthesized starting from (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) and suitable β-heteroaryl-α,β-unsaturated aldehydes. The stereocontrolled addition gave a mixture of two diastereoisomers whose configurations were assigned on the basis of spectroscopic data and the accepted model for aldol condensation of the Schöllkopf’s reagent. Upon controlled hydrolysis the adducts were transformed into the corresponding methyl esters of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids.