脓疱疮治疗药Altabax

葛兰素制药公司研发的retapamulin（瑞他帕林）凝胶剂（商品名：Altabax）于2007年4月获得美国FDA批准，用于治疗金葡菌或化脓性链球菌感染引起的脓疱疮。Retapamulin属于半合成的截短侧耳素类抗生素，其化学名为[[（3-外型）-8-甲基-8-氮杂双环[3．2．1]辛-3-基]硫代]-（3d，4R，5S，6S，8R，9aR，10R）-6-乙烯基十氢-5-羟基-4，6，9，10-四甲基-1-氧代-3α，9-丙醇-3αH-环戊基环辛基-8-乙酸酯。其分子式为C30H47NO4S；化学结构式：     

瑞他妙林的合成

α-托品醇(4)经甲磺酰化、与乙基黄原酸钾进行亲核取代反应、水解、与盐酸成盐得外-8-甲基-8-氮杂二环[3.2.1]辛烷-3-硫醇盐酸盐(7)。另用截短侧耳素经甲磺酰化后与7发生亲核取代反应制得瑞他妙林,总收率为43%(以4计)。     

替加环素的合成

盐酸米诺环素经硝化和还原得9-氨基米诺环素二硫酸盐(8),经盐酸和氨水处理得9-氨基米诺环素盐酸盐(9);另以溴乙酸叔丁酯为原料,经缩合、酸水解和氯化得N-叔丁基甘氨酰氯盐酸盐(5).5和,反应后经乙醇-丙酮(1:1)及丁醇重结晶,制得抗生素替加环素,总收率约28%(以盐酸米诺环素计),纯度99.8%.     

头孢匹胺的合成

目的 研究头孢匹胺的合成工艺。 方法 (R)2-(6-甲基-4-羟基吡啶-3-羰基)-氨基]-2-(4-羟基苯基)乙酸乙酯(NPA-Et)经水解、成盐得到(R)2-(6-甲基-4-羟基吡啶-3-羰基)-氨基]-2-(4-羟基苯基)乙酸钠( NPA-Na)。NPA-Na与7-TMCA,即：(6R,7R)3-(1-甲基-1H-四唑-5-硫代甲基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸)缩合得头孢匹胺粗品,再成三乙胺盐,转酸,得到头孢匹胺成品。结果 第一步收率84.6%,第二步收率69.3%。结论     

硼替佐米的合成

L-苯丙氨酸甲酯盐酸盐与吡嗪-2-甲酸经酰胺化、酯解得到(S)-3-苯基-2-(吡嗪-2-甲酰胺基)丙酸,再与(R)-(1-氨基-3-甲基)丁基硼酸-(1S,2S,3R,5S)-蒎烷二醇酯三氟乙酸盐(6)缩合、脱保护得到硼替佐米,总收率约27%(以6计)。     

尼罗替尼的合成

5-溴-3-三氟甲基苯胺和4-甲基-1H-咪唑在碳酸铯和碘化亚铜作用下缩合,得到3-三氟甲基-5-(4-甲基-1H-咪唑-1-基)苯胺(4).另用3-氨基-4-甲基苯甲酸乙酯(5)与氨腈成胍6,6与3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮环合得4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯(8),8经叔丁氧羰摹保护、水解,再与4经酰胺化、脱保护后得到尼罗替尼,总收率40%(以5计).     

盐酸贝那普利的合成

以L-苹果酸为手性源,经成酐活化、傅-克反应、常压氢化和酯化反应制得(S)-2-羟基-4-苯基丁酸乙酯(8),8经甲磺酰化活化后经与丙酸钾反应和水解制得构型反转的(R)-2-羟基4-苯基丁酸乙酯(3).3经磺酰化活化后与(3S)-3-氨基-2,3,4,5-四氢-2-氧代-1H-1-苯并氮(革)-1-乙酸叔丁酯(2)反应后水解、成盐制得盐酸贝那普利,总收率约32％.     

美罗培南三水合物的合成

目的合成碳青霉烯类抗生素美罗培南.方法以羟脯氨酸为起始原料,经5步反应合成得到侧链(2S,4S)-二甲氨基甲酰基-4-巯基-1-(4-硝基苯甲氧羰基)吡咯烷(V),V与(1R,5R,6S)-2-(二苯氧基磷酰氧基)-6-[(R)-1-羟乙基]-1-甲基碳青霉-2-烯-3-羧酸对硝基苄酯(Ⅵ)经取代、氢化、大孔吸附树脂柱色谱纯化得到美罗培南三水合物,总收率为13.9%(以羟脯氨酸计).结果与结论合成了美罗培南三水合物,其结构经质谱、核磁共振氢谱和热重分析确证.     

头孢米诺有关物质的合成及结构鉴定

在头孢米诺钠无菌粉质量研究中,通过HPLC-MS解析鉴定出一个新杂质,推测其结构为:(6R,7S)-7-[[[(2S)-2-氨基-2-羧乙基]硫基]乙酰胺基]-3-[[(1-甲基-1H-四唑-5-基)硫基]甲基]-7-甲硫基-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸钠.并以(6R,7S)-7-氨基-7-甲氧基-3-[[(1-甲基-1H-四唑-5-基)硫基]甲基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸二苯甲酯和甲硫醇为原料,经取代、酰化、脱保护及取代反应得到该杂质,经1H NMR和MS确证结构,而且与头孢米诺钠新杂质HPLC保留时间相同.     

盐酸帕唑帕尼的合成

3-甲基-6-硝基-2H-吲唑(3)经甲基化、还原、单甲基化后,与2,4-二氯嘧啶缩合制得2,3-二甲基-N-(2-氯嘧啶-4-基)-N-甲基-2H-吲唑-6-胺,再与2-甲基-5-氨基苯磺酰胺经缩合、成盐酸盐制得抗肿瘤药盐酸帕唑帕尼,总收率约为37%。     

杜仲叶中倍半萜及降碳倍半萜的分离与鉴定

目的 研究植物杜仲(Eucommia ulmoides Oliver)叶中的化学成分.方法 综合运用硅胶柱色谱、反相硅胶柱色谱和Sephadex LH-20凝胶柱色谱以及制备型高效液相色谱等方法进行系统分离,根据化合物的理化性质及其波谱数据确定化合物的结构.结果 从杜仲叶80％(体积分数)乙醇提取物中分离得到了12个倍...     

Norsesquiterpenoid glucosides and a rhamnoside of pyrrolizidine alkaloid from Tephroseris kirilowii

Four new glycosylated compounds have been isolated from the whole plant of Tephroseris kirilowii, including (-)-(1R,5R,6S,7R,8S)-8-O-beta-D-glucopyranosyloxy-7-hydroxy-6-(2-hydroxypropan-2-yl)-9-methylenebicyclo[4.3.0]non-3-one (tephroside A, 1), (-)-(1R,5R,6R,8R)-6-(2-O-beta-D-glucopyranosyloxypropan-2-yl)-8-hydroxy-9-methylenebicyclo[4.3.0]non-3-one (tephroside B, 2), thesinine-4'-O-alpha-L-rhamnoside (3), and p-coumaric acid 4-O-alpha-L-rhamnoside (4), together with the known roseoside. The structures of the new compounds were established by means of spectroscopic analysis.     

Lignans from the flower buds of Magnolia liliflora Desr

Six new lignans, 1- 6, along with six known compounds were obtained from the flower buds of Magnolia liliflora Desr. The new lignans were elucidated as (1 S*,2 R*,5 S*,6 S*)-2-(3,5-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (1), (1 R*,2 R*,5 R*,6 S*)-2-(3,5-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (2), (1 R*,?2 R*,5 R*,6 S*)-2,6-bis (3,5-dimethoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (3), (1 R*,2 S*,5 R*,6 R*)-2-(3,4-methylenedioxyphenyl)-6-(3,5-dimethoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane ( 4), (7' S*,8 R*,8' R*)-3,5'-dimethoxy-3',4,9'-trihydroxy-7',9-epoxy-8,8'-lignan (5), and (7' R*,8' S*)-3,3',4,5'-tetramethoxy-7-en-7',9-epoxy-8,8'-lignan (6), by the analysis of 1D and 2D-NMR as well as HRESIMS data. The capacity of compound 1 to protect against damages to the DNA of rat lymphocyte cells induced by UV irradiation was assessed by the comet assay. It showed stronger antigenotoxicity than ascorbic acid from 6×10(-3)?mmol·L(-1) to 6×10(-6)?mmol·L(-1).     

鸡血藤化学成分的分离与结构鉴定

目的对中药鸡血藤(Spatholobus suberectus Dunn)中化学成分进行分离及结构鉴定。方法采用正相硅胶、反相ODS、Sephadex LH-20等柱色谱及高效液相色谱等手段进行分离纯化,并通过理化性质与波谱分析方法鉴定了化合物的结构。结果从鸡血藤体积分数为95%的乙醇提取物中分离鉴定了9个单体成分,分别为blumenol A(1)、(6S,7E,9R)-roseoside(2)、(6S,7E,9R)-6,9-dihydroxy-4,7-megastigman-3-one-9-O-[α-L-arabinopyranosyl-(1→6)-(β-D-glucopyranoside](3)、7S,8R-erythro-4,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-7-O-β-D-glucopyranoside(4)、(7S,8R)-dihydrodehydrodiconiferyl alcohol-4-O-(β-D-glucopyranoside(5)、(7S,8R)-3,3',5-trimethoxy-4',7-epoxy-8,5'-neolignan-4,9,9'-triol(6)、次黄苷(hypoxanthine-9-β-D-ribofuranoside,7)、烟酸(nicotinic acid,8)和丁二酸(amber acid,9)。结论其中2-8均为首次从密花豆属中分离得到的化合物。     

中药北刘寄奴中化学成分的分离与鉴定

目的研究中药北刘寄奴(Siphonostegia chinensis Benth.)的化学成分。方法采用正相硅胶、反相ODS、Sephadex LH-20等柱色谱及高效液相色谱等手段进行分离纯化,并通过理化性质与光谱分析方法鉴定化合物的结构。结果从北刘寄奴体积分数95%乙醇提取物中分离鉴定10个单体化合物,分别为反式对羟基肉桂酸((E)-p-hydroxycinnamic acid,1)、咖啡酸(caffeic acid,2)、syring-in(3)、(7S,8R)-dehydrodiconiferyl alcohol 9'-β-glucopyranoside(4)、vanillyl alcohol-4-O-β-D-gluco-pyranoside(5)、2,6-二甲氧基-4-羟基苯酚-1-O-葡萄糖苷(2,6-dimethoxy-4-hydroxyphenol 1-O-glu-copyranoside,6)、3,5-dimethoxy-4-hydroxybenzyl alcohol 4-O-β-D-glucopyranoside(7)、rubinaphthinA(8)、rel-5-(3S,8S-dihydroxy-1R,5S-dimethyl-7-oxa-6-oxobicyclo[3,2,1]-oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid(9)、(6S,9R)-roseoside(10)。结论化合物2～10为首次从阴行草属植物中分离得到。     

从D-葡萄糖合成(3S,4S,5R)-4-O-苄基-3-表莽草酸甲酯

本文报道用D-葡萄糖为原料,经九步反应,对映选择地合成了标题化合物(10),从而为制备新抗生素二(口恶)霉素及类似物提供了对映选择合成的途径。     

Chemical constituents of Saxifraga stolonifera (L.) Meeb

To study the chemical constituents of Saxifraga stolonifera (L.) Meeb., chromatographic techniques were applied to separate and purify the compounds, and their structures were confirmed on the basis of physicochemical properties and spectral data. Ten compounds were isolated and identified as 5-O-methylnorbergenin (1), 3, 4-dihydroxyallylbenzene-4-O-beta-D-glucopyranoside (2), (7R, 8S)-4, 9, 9'-trihydroxyl-3-methoxyl-7, 8-dihydrobenzofuran-1'-propylneolignan-3'-O-beta-D-glucopyranoside (3), quercetin-3-O-beta-D-xylopyranosyl-(1 --> 2)-beta-D-galactopyranoside (4), kaempferol-3-O-alpha-L-rhamnopyranoside (5), (3S, 5R, 6R, 7E, 9R)-3, 5, 6, 9-tetrahydroxy-7-megastigmane (6), benzyl-O-alpha-L-rhamnopyranosyl-(1 --> 6)-beta-D-glucopyranoside (7), p-hydroxyacetophenone (8), pyrogallic acid (9) and p-hydroxyphenol (10). Compound 1 is a new compound. Compounds 2-10 were isolated from this plant for the first time.     

(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.     

Sesquiterpene lactones from Inula hookeri

Four new sesquiterpene lactones, (1 S,5 R,6 S,7 S,8 R,9 R,10 S,11 S)-6-acetoxy-9-hydroxy-4-oxo-pseudoguai-2(3)-en-12,8-olide, (1 S,2 R,5 R,6 S,7 R,8 S,10 R)-6-acetoxy-2-ethoxy-4-oxo-pseudoguai-11(13)-en-12,8-olide, (1 S,2 R,5 R,6 S,7 R,8 S,10 R)-6-acetoxy-2-hydroxy-4-oxo-pseudoguai-11(13)-en-12,8-olide, and 14-acetoxy-1 β,5 α,7 αH-4 β-hydroxy-guai-9(10),11(13)-dien-12,8 α-olide, along with 26 known sesquiterpene lactones, were isolated from the whole plants of Inula hookeri C. B. Clarke. Their structures were established based on spectroscopic methods including HRESIMS, 1D and 2D NMR, and CD techniques. All compounds were evaluated for their cytotoxic activities against HepG2, HeLa, PC-3, and MGC-803 cell lines by CCK-8 assay. Some of the isolates, especiallly pseudoguaianolides and guaianolides, exhibited significant cytotoxicities against these four examined cell lines.     

Synthesis and in vivo antitumor activity of 2-amino-9H-purine-6-sulfenamide, -sulfinamide, and -sulfonamide and related purine ribonucleosides

A number of 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide derivatives of 2-aminopurine and certain related purine ribonucleosides have been synthesized and evaluated for antileukemic activity in mice. Amination of 6-mercaptopurine ribonucleoside (7a) and 6-thioguanosine (7b) with chloramine solution gave 9-beta-D-ribofuranosylpurine-6-sulfenamide (8a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide (sulfenosine, 8b), respectively. Selective oxidation of 8a and 8b with 3-chloroperoxybenzoic acid (MCPBA) gave (R,S)-9-beta-D-ribofuranosylpurine-6-sulfinamide (9a) and (R,S)-2-amino-9-beta-D-ribofuranosylpurine-6-sulfinamide (sulfinosine, 9b), respectively. However, oxidation of 8a and 8b with excess of MCPBA gave 9-beta-D-ribofuranosylpurine-6-sulfonamide (10a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfonamide (sulfonosine, 10b), respectively. Similarly, amination of 5'-deoxy-6-thioguanosine (7c) afforded the 6-sulfenamide derivative (8c), which on controlled oxidation gave (R,S)-2-amino-9-(5-deoxy-beta-D-ribofuranosyl)purine-6-sulfinamide (9c) and the corresponding 6-sulfonamide derivative (10c). Treatment of 6-thioguanine (12) with aqueous chloramine solution gave 2-amino-9H-purine-6-sulfenamide (13). Oxidation of 13 with 1 molar equiv of MCPBA afforded (R,S)-2-amino-9H-purine-6-sulfinamide (14), whereas the use of 4 molar equiv of MCPBA furnished 2-amino-9H-purine-6-sulfonamide (15). The resolution of R and S diastereomers of sulfinosine (9b) was accomplished by HPLC techniques. The structures of (R)-9b and 10b were assigned by single-crystal X-ray diffraction studies. (R)-9b exists in the crystal structure in four crystallographically independent conformations. Of the 18 compounds evaluated, 13 exhibited very significant anti-L1210 activity in mice. Sulfenosine (8b) at 22 mg/kg per day X 1 showed a T/C of 170, whereas sulfinosine (9b) at 173 mg/kg per day X 1 showed a T/C of 167 against L1210 leukemia. The 5'-deoxy analogue of sulfinosine (9c) at 104 mg/kg per day also showed a T/C of 172. A single treatment with 8b, 9b, and 9c reduced body burdens of viable L1210 cells by more than 99.8%.