2-乙氧基-N-（4-甲基-2-丙基-1H-咪唑基-1）-苯甲酰胺的合成

2-乙氧基苯甲酸甲酯与水合肼发生肼解反应生成2-甲氧基苯甲酰肼(1);1与丁亚氨酸乙酯盐酸盐进行二次肼解反应制得2-乙氧基-N'-(1-亚胺丁基)苯甲酰肼盐酸盐(3);3与氯丙酮环化合成了2-乙氧基-N-(4-甲基-2-丙基-1H-咪唑基-1-)苯甲酰胺(合成伐地那非的关键中间体),总收率48%,其结构经1H NMR和MS确证.     

2-氯甲基-3-甲基-4-[(3-甲氧基)丙氧基]-吡啶盐酸盐的合成

以2,3-二甲基吡啶为原料,经6步反应合成了雷贝拉唑的关键中间体--2-氯甲基-3-甲基-4-[(3-甲氧基)丙氧基]-吡啶盐酸盐,总收率14.1%.     

脂蛋白脂酶激活剂艾溴利平类似物的合成

合成了两个新型的艾溴利平类似物——N-2 -硝基-4-氯苯基-4-[(膦酸二乙酯基)甲基]苯甲酰肼(5,总收率28.1％)和N-2-四氮唑基-4-氯苯基-4-[(膦酸二乙酯基)甲基]苯甲酰胺(7,总收率30.5％).以对氯甲基苯甲酸为原料,经酯化、水解和酰氯反应制得中间体4-[(膦酸二乙酯基)甲基]苯甲酰氯(4);4与2-硝基-4-氯苯肼盐酸盐反应合成了5.4先与2-氨基-5-氯苯腈反应制得N-2-氰基-4-氯苯基-4-[(膦酸二乙酯基)甲基]苯甲酰胺(6);6再与叠氮化钠反应合成了7.其结构经1 H NMR和IR表征.     

5-甲基胞嘧啶锁核酸的合成新方法

设计了一种新的合成5-甲基胞嘧啶锁核酸{(1R,3R,4R,7S)-3-[(5-甲基-4-N-苯甲酰基胞嘧啶-1-基)-7-(2-氰基乙氧基)-(N,N-二异丙基)膦氧代]-1-(4,4’-二甲氧基三苯代甲基氧基甲基)-2,5-二氧杂二环-[2.2.1]庚烷(1)}的方法。以3-苄氧基-4-C-羟甲基-1,2-O-异亚丙基-α-D-呋喃核糖为起始原料,经取代、水解等12步反应合成了1,总收率21.0%,其结构经1H NMR和MS确证。     

α-葡萄糖苷酶抑制剂Radicamine B的合成

以D-阿拉伯糖为原料,依次合成了中间体(2R,3R,4R)-2,3,5-三-O-苄氧基-4-羟基-O-叔丁基二甲基硅基-戊醛肟(3),(2R,3S,4S)-2,3,5-三-O-苄氧基-4-碘-O-叔丁基二甲基硅基-戊醛肟(4)和(2R,3R,4R)-3,4-二-O-苄氧基-2-(苄氧甲基)-3,4-二氢-2H-吡咯-1-醇(5);5与芳基Grignard试剂进行高立体选择性的加成反应制得(2R,3R,4R,5R)-3,4-二-O-苄氧基-2-[4-(苄氧基)苯基)]-5-吡咯-1-醇(6);6经催化氢化合成Radicamine B,总收率18.5%。3和4为新化合物,其结构经1HNMR,MS和元素分析表征。     

(±)-亮氨酸的合成

以氨基丙二酸二乙酯盐酸盐(2)为原料通过一条全新路线合成了外消旋亮氨酸盐酸盐(1)。2的氨基经Boc保护制得Boc-氨基丙二酸二乙酯(3);3与甲代烯丙基氯发生取代反应制得Boc-氨基-(2-甲基-2-丙烯基)丙二酸二乙酯(4);4经Pd/C催化加氢制得Boc-氨基-(2-异丁基)丙二酸二乙酯(5);5在浓盐酸中回流反应,一步完成脱保护、脱羧、水解过程合成1。总收率55%,其结构经1H NMR和MS确证。     

(S)-(+)-2,2-二甲基环丙烷甲酰胺的不对称合成

以环己二胺作为手性源,与3,5-二叔丁基水杨醛经缩合反应制得Salen配体(R,R)-N,N'-二(3,5-二叔丁基水杨醛)-1,2-环己二胺(6);甘氨酸乙酯盐酸盐经重氮化和6与三氟甲烷磺酸亚铜催化的不对称环丙烷化反应制得(S)-(+)-2,2-二甲基环丙烷甲酸乙酯(9);9经水解、酰氯化和氨解反应合成了(S)-(+)-2,2-二甲基环丙烷甲酰胺,ee值82%,总收率55.4%,其结构经1H NMR和IR确证。     

3-[(2-二甲基氨甲基)环己基]苯基乙酸酯盐酸盐的合成

以盐酸曲马多为起始原料,通过脱羟基,去甲基和乙酰化反应合成了一种新化合物3-[(2-二甲基氨甲基)环己基]苯基乙酸酯盐酸盐,其结构经1H NMR, MS和元素分析表征.     

无催化剂条件下4-羟基烷基-2-炔酸乙酯与N-杂环芳基甲基-N-2,2-二氟乙基-1-胺的串联反应

开发了无催化剂条件下4-羟基烷基-2-炔酸乙酯与N-杂环芳基甲基-N-2,2-二氟乙基-1-胺的串联反应.应用该反应在甲醇中回流,以39%~83%的收率合成了一系列4-(N-(2,2-二氟乙基)(N-杂环芳基甲基)氨基)-5,5-二取代呋喃-2(5H)-酮,其结构经1H NMR,13C NMR和HR-ESI-MS表征,并进一步通过3-氯-4-(N-2,2-二氟乙基)(N-嘧啶-5-基甲基胺基)-5,5-螺(4-甲氧基环己基)呋喃-2(5H)-酮(8)的晶体衍射间接证实.测试了所合成化合物的生物活性,结果表明,在600μg·mL^-1浓度时4-(N-2,2-二氟乙基)(N-6-氯吡啶-3-基甲基胺基)-5,5-二甲基呋喃-2(5H)-酮(3a)和4-(N-2,2-二.氟乙基)(N-6-氟吡啶-3-基甲基胺基)-5,5-二甲基呋喃-2(5H)-酮(3c)对桃蚜的死亡率均为100%.     

无催化剂条件下4-羟基烷基-2-炔酸乙酯与N-杂环芳基甲基-N-2,2-二氟乙基-1-胺的串联反应（英文）

开发了无催化剂条件下4-羟基烷基-2-炔酸乙酯与N-杂环芳基甲基-N-2,2-二氟乙基-1-胺的串联反应.应用该反应在甲醇中回流,以39%～83%的收率合成了一系列4-(N-(2,2-二氟乙基)(N-杂环芳基甲基)氨基)-5,5-二取代呋喃-2(5H)-酮,其结构经~1H NMR, ~(13)C NMR和HR-ESI-MS表征,并进一步通过3-氯-4-((N-2,2-二氟乙基)(N-嘧啶-5-基甲基胺基)-5,5-螺(4-甲氧基环己基)呋喃-2(5H)-酮(8)的晶体衍射间接证实.测试了所合成化合物的生物活性,结果表明,在600μg·mL~(-1)浓度时4-((N-2,2-二氟乙基)(N-6-氯吡啶-3-基甲基胺基)-5,5-二甲基呋喃-2(5H)-酮(3a)和4-((N-2,2-二氟乙基)(N-6-氟吡啶-3-基甲基胺基)-5,5-二甲基呋喃-2(5H)-酮(3c)对桃蚜的死亡率均为100%.     

The Practical Asymmetric Syntheses of Key Chiral Intermediates of Chiral Drug from Four-Carbon Chiral Pool

(S)-or (R)-2-Amino-4-phenylbutyric acid and (S)-or (R)-2-hydroxy-4-phenylbutyric acid and their ethyl esters are key chiral intermediates for the preparation of angiotensin converting enzyme inhibitors (ACEI) and other chiral drugs. Their practically asymmetric synthetic methods in large scale from four-carbon chiral pool, commercially available L-aspartic acid and L-malic acid, will be presented (as scheme). (S)-2-Amino-4-phenylbutyric acid and its ethyl ester hydrochloride were prepared from the easily available L-aspartic acid via activation by forming anhydride hydrochloride, Friedel-Crafts reaction with benzene, hydrogenolysis and esterification with ethanol in the presence of thionyl chloride in overall yield of 80% and 73.6% respectively with 99% ee. We first used amino acid anhydride hydrochloride as the acylating agent in Friedel-Crafts reaction without racemization. [1]     

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.     

一种制备盐酸西那卡塞的新方法

（R）-1-萘乙胺与丙烯酰氯发生亲核取代反应制得酰胺（2）; 2与3-三氟甲基碘苯经Heck偶联反应制得α,β-不饱和酰胺（3）; 3经两次还原反应后再与盐酸成盐合成了盐酸西那卡塞,总收率40%,纯度>99.5%, ee值>99.9%,其结构经¹H NMR和¹³C NMR确证。     

(R)-2-硫代四氢噻唑-4-羧酸及其酯的合成

L-半胱氨酸盐酸盐与二硫化碳, 氢氧化钠在硝酸铅存在下进行成环反应得到(R)-四氢噻唑-2-硫酮-4-羧酸产率76% , 后者与 醇在硫酸铁水合物催化下反应得到(R)-四氢噻唑-2-硫酮-4-羧酸酯, 产率40～82% .     

手性3,5-二甲基-2-芳基-2-吗啉醇盐酸盐的合成及其晶体结构

以(S)-2-氨基丙醇为手性源与α-溴-3-氯苯丙酮反应, (R)-2-氨基丙醇为手性源与6-甲氧基-2-(2-溴丙酰基)萘反应, 分别合成了手性纯化合物(2R,3R,5S)-3,5-二甲基-2-(3-氯苯基)-2-吗啉醇盐酸盐(4a)和(2S,3S,5R)-3,5-二甲基-2-(6-甲氧基-2-萘基)-2-吗啉醇盐酸盐(4b), 利用X射线单晶衍射仪测定了两化合物的晶体结构和两化合物的空间结构, 并初步分析两化合物空间结构, 化合物4a晶体属正交晶系, 空间群为P2₁2₁2, 晶胞参数为: a＝0.8718(2) nm, b＝0.7883(2) nm, c＝2.0247(6) nm, Z＝4, V＝1.3915(7) nm³, D_c＝1.328 g/cm³, F(000)＝584, R₁＝0.0399, wR₂＝0.0797, S＝1.042. 化合物4b晶体属正交晶系, 空间群为P2₁2₁2₁, 晶胞参数为: a＝0.71035 (9) nm, b＝0.77703(10) nm, c＝2.9820(4) nm, Z＝4, V＝1.6318(4) nm³, D_c＝1.318 g/cm³, F(000)＝688, R₁＝0.0520, wR₂＝0.1108, S＝0.994.     

Efficient enantioselective hetero-Diels-Alder reaction of Brassard's diene with aliphatic aldehydes: a one-step synthesis of (R)-(+)-kavain and (S)-(+)-dihydrokavain

An efficient catalytic asymmetric hetero-Diels-Alder reaction of Brassard's diene with aliphatic aldehydes was reported. The catalyst, which was generated from (R)-BINOL, Ti(i-PrO)4, and 4-picolyl chloride hydrochloride, promoted the reaction smoothly to afford the corresponding alpha,beta-unsaturated delta-lactone derivatives in moderate-to-good yields (46-79%) with high enantioselectivities (up to 88% ee). Natural products (R)-(+)-kavain (70% ee, >99% ee after single recrystallization) and (S)-(+)-dihydrokavain (84% ee) were also prepared in one step by using this methodology.     

A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.     

Synthesis and Some Chemical Properties of 2,2-Dimethyl-4-R-1-oxa-4-aza-2-sila-5-benzocycloheptanones

One-pot synthesis of 2,2-dimethyl-4-R-1-oxa-4-aza-2-sila-5-benzocycloheptanones (R = Me, CH₂SiMe₂Cl) from the N-methylamide of salicylic acid and salicylamide, respectively, by treatment of these amides with a mixture of hexamethyldisilazane and dimethylchloromethylchlorosilane was developed. The hydrolysis and other nucleophilic substitution reactions of the resultant seven-membered silacyclanes were studied. In the case of the silacyclane with R = Me, hydrolysis leads to the corresponding disiloxane, while the silacyclane with R = CH₂SiMe₂Cl gives either 2,2,6,6-tetramethyl-4-(2-hydroxybenzoyl)-2,6-disilamorpholine or its hydrochloride, depending on the reaction conditions. The chlorine atom was replaced by fluorine in the silacyclane with R = CH₂SiMe₂Cl. The structures of 2,2,6,6-tetramethyl-4-(2-hydroxybenzoyl)-2,6-disilamorpholine and its hydrochloride as well as 2,2-dimethyl-4-R-1-oxa-4-az! a-2-sila-5-benzocycloheptanones (R = CH₂SiMe₂Cl, CH₂SiMe₂F) were confirmed by X-ray diffraction.     

Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine

Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (<1 %). The purity of erlotinib hydrochloride was >99.9 %.     

Asymmetric Synthesis and DNA Intercalation of (-)-6-[[(Aminoalkyl)oxy]methyl]-4-demethoxy-6,7- dideoxydaunomycinones(1)(,)

The BF(3).Et(2)O-promoted Diels-Alder addition of 1-acetylvinyl RADO(Et)-ate (RADO(Et)-ate = 3-ethyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate) to 1-(dimethoxymethyl)-2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane led to one major monoadduct that added to 1,2-didehydrobenzene and was converted into (-)-4-demethoxy-7-deoxydaunomycinone and (2R)-12-acetoxy-2-acetyl-5-(bromomethyl)-1,2,3,4-tetrahydronaphthacen-2-yl RADO(Et)-ate. The latter compound was used to construct (8R)-8-acetyl-6,8-dihydroxy-11-[[(3'-[(aminopropyl)oxy]-, -4'-[(aminobutyl)oxy], and -5'-[(aminopentyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride (-)-8, (-)-9, (-)-10, respectively, as well as (8R)-8-acetyl-6,8-dihydroxy-11- [[[2'-[(3"-aminopropyl)amino]ethyl]oxy]- ((-)-11) and -[[3'-[(3"-aminopropyl)amino]propyl]oxy]methyl]-7,8,9, 10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-12). (8R)-8-Acetyl-6,8-dihydroxy-11-[[(alpha-L-daunosaminyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-13), a mimic of idarubicin, was also prepared. Absorbance and fluorescence titration experiments showed (-)-8, (-)-9, and (-)-10 to intercalate calf thymus DNA whereas (-)-11, (-)-12, and (-)-13 did not. The best intercalator was (-)-9 (K(b) = (1.1 +/- 0.1) x 10(5) M(-)(1)) with the [(4'-aminobutyl)oxy]methyl chain. Inhibition of topoisomerase II-induced DNA strand religation was observed for (-)-8 at a concentration of 50 &mgr;M.