4（R）—（6—氨基—9—嘌呤基）—2（R）—（羟甲基）四氢呋喃—3（R）—醇的合成

为寻找抗免疫缺陷病毒化合物,以D－核糖为原料,经甲基化、硅烷基化、还原裂解反应制得重要中间体1－脱氧核糖（5）,再通过形成环状亚砜化合物,与NaN3发生反应后,经过还原、缩合、环合、氨化、脱保护基反应制得异脱氧腺嘌呤核苷（1）,各步反应收率均超过70％。     

5—氨基—1环丙基6,7,8—三氟—1,4—二氢—4—氧代—3—喹啉羧酸 …

由６－硝基－２,３,４,５＝四氟苯甲酸为原料,经酰氯化后与β－环丙基氨基丙烯酸乙酯反应,再经环合,还原得标题化合物（１）,总收率５１．６％,由五氟苯甲酸依同法可制得１－环丙基－５,６,７,８－四氯－１,４－二氢－４－氧代－３－喹啉羧酸乙酯（６ｂ）,总收率为４８．７％。     

N—（四氢呋喃—2—甲酰）哌嗪的合成

Ｎ－（四氢呋喃－２－甲酰）哌嗪（１）是治疗良性前列腺增生药特拉唑嗪（ｔｅｒａｚｏｓｉｎ）［１］的重要中间体。文献［２］报道将糠酰氯与哌嗪缩合，制成氢溴酸盐后再催化加氢制得１；或以四氢糠醇为原料，经氧化、氯化、酰化得到１［３］。本文以呋喃－２－甲酸甲酯（２）为原料，经还原、酰化制得１。两步总收率为６２％（以２）计。实验部分四氢呋喃－２－甲酸甲酯（３）依次加入２（１２６ｇ，１ｍｏｌ）、甲醇（６００ｍｌ）和雷内镍（１０ｇ，６８ｍｍｏｌ，含镍４０％），通入氢气，在１０００ｋＰａ下于７０°Ｃ反应８ｈ后，抽…     

（S）—（＋）—2—氨基丙醇合成工艺改进

对（S）－（＋）－2－氨基丙醇的合成工艺进行了改进。以L－丙氨酸为起始原料，经缩合、KBH4还原两步反应，制得本品，工艺简单、易操作，收率82％。     

1—（2—吡啶基）哌嗪的合成

用工业品2－氨基吡啶在Br2-HBr体系中重氮化,制得2－溴吡啶,收率73．5％;2－溴吡啶与工业无水哌秦直接反应,制得1－（2－吡啶基）哌嗪,收率60％。     

4—氨基—5—咪唑甲酰胺盐酸盐的合成

４－氨基－５－咪唑甲酰胺盐酸盐（１）是重要医药中间体。文献［１］以氰乙酸乙酯（５）为原料,经酯化、氨解和偶联反应制得２－脒基－２－苯偶氮基乙酰胺盐酸盐（２）,再还原制得２－脒基－２－甲酰胺基乙酰胺盐酸盐,在此步反应中使用大量无水乙醚和９５％乙醇,然后在１７０°Ｃ油浴上直接加热环合制备１。该法成本高,纯化困难。文献［２］以２为原料经还原和环合反应制得４－甲酰胺基－５－咪唑甲酰胺盐酸盐,然后酸性水解,用乙醇－乙醚精制得１,收率为２７％。本文参照文献［１～５］,以价廉易得的氯乙酸为起始原料,经氰解、酯…     

5-氯-3-（2-噻吩甲酰）-1-甲酰胺-2-羟基吲哚钠盐的合成

目的：合成具抗炎活性的5－氯－3（2－噻吩甲酰）－1－甲酰胺－2－羟基吲哚钠盐。方法：以对氯苯胺为起始原料,经四步反应制得关键中间体5－氯－2－羟基吲哚,收率75％,然后与三氯乙酰异腈酸酯和2－噻吩甲酰氯反应,最后经NaHCO3处理,制得标题化合物。结果：总有收率可达45％以上,标题化合物经红外光谱、核磁共振谱、质谱及元素分析确证了结构,结论：该实验方法条件温和,操作简单、收率高,适合大规模合成。     

富马酸替诺福韦酯的合成工艺改进（英文）

目的合成抗病毒药物富马酸替诺福韦酯并进行工艺改进。方法以亚磷酸二乙酯和多聚甲醛为原料,经缩合、酯化反应制得对甲苯磺酰氧甲基膦酸二乙酯(4);再以(S)-缩水甘油为起始物,经氢化还原、缩合反应制得(R)-碳酸丙烯酯(7),7与腺嘌呤反应合成(R)-9-(2-羟丙基)腺嘌呤(8),8经醚化、水解反应得到替诺福韦(10),再经氯甲基碳酸异丙酯酯化、与富马酸成盐得到目标化合物。结果与结论目标化合物的结构经MS、1H-NMR谱予以确证,该合成路线的总收率提高到30.4%(文献报道的最高收率为21%)。     

2－（2－甲氧苯氧）乙胺的合成

２－（２－甲氧苯氧）乙胺是合成某些β－受体阻断剂的重要中间体。我们探讨了几种不同的制备途径，发现将愈创木酚与１，２－二氯乙烷（或１，２－二溴乙烷）反应的单取代卤代物转化为叠氮化物，通过催化氢化，可以获得产率高，纯度好的伯胺。目标物也可以通过Ｇａｂｒｉｅｌ反应或通过相应睛的还原制得，但是叠氮化合物途径是一条经济而安全的路线。     

二氢吡咯并吡嗪酮衍生物的合成和抗炎镇痛作用

目的 研究3，4，－二氢吡咯并[1,2-a]吡嗪－1－酮（Ⅱ）类化合物的抗炎镇痛作用构效关系。方法 通过2－吡咯甲酸甲酯与N－氯乙腈的烃基化反应，制得N－氢甲基吡咯－2－甲酸甲酯（Ⅳ），Ⅳ经还原，环合，Friedel-Crafts酰基化反应，生成6－芳酰基－2－甲基－3，4－二氢吡咯并[1,2-a]吡嗪－1－酮类化合物；用小鼠测试了所合成化合物的抗炎镇痛活性。结果与结论 合成了13个目标化合物；小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用，其中，ZP163的作用活性与对照药布洛芬相似。     

Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-alkenyl-, -N-alkynyl-, and -N-cyanoalkyl-5, 9-dimethyl-2'-hydroxy-6,7-benzomorphan homologues

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED(50) = 0.05 mg/kg), and (-)-(1R,5R, 9R)-N-but-2-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan ((-)-(1R, 5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa-opioid receptor than the mu-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for delta-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective sigma(1)-ligands (K(i) = 2 nM, sigma(2)/sigma(1) = 1250, and 1 nM, sigma(2)/sigma(1) = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at sigma(1), and its sigma(1)/sigma(2) ratio was <100.     

Synthesis and antiviral activity of 9-alkoxypurines. 2. 9-(2,3-Dihydroxypropoxy)-, 9-(3,4-dihydroxybutoxy)-, and 9-(1,4-dihydroxybut-2-oxy)purines.

Reaction of alkenoxyamines (3,5) or (R,S)-, (R)-, and (S)-hydroxy-protected derivatives of hydroxyalkoxyamines (20a,b, 37a-c) with 4,6-dichloro-2,5-diformamidopyrimidine (4) and cyclization of the resultant 6-[(alkenoxy)amino]-and 6-(alkoxyamino)pyrimidines (6,7,21a,b, 38a,b,c) by heating with diethoxymethyl acetate afforded 9-alkenoxy- and 9-alkoxy-6-chloropurines (9,10,22a,b, 39a-c, 40a). These were subsequently converted to 9-(2,3-dihydroxypropoxy), 9-(3,4-dihydroxybutoxy), and 9-(1,4-dihydroxybut-2-oxy) derivatives of guanine and 2-aminopurine (13-16, 25-28, 41a-c, 42a). A 2-amino-6-methoxypurine derivative (17) was also prepared. The racemic guanine derivative 13 showed potent and selective activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), but was less active against varicella zoster virus (VZV). Its antiviral activity is attributable to the S isomer (28), which was found to be more active than acyclovir against HSV-1 and HSV-2 and about 4 times less active than acyclovir against VZV. The S enantiomer of 9-(1,4-dihydroxybut-2-oxy)guanine (41c) also showed noteworthy antiviral activity in cell culture. Although this acyclonucleoside (41c) is only weakly active against HSV-1 and inactive against HSV-2, it is about twice as active as acyclovir against VZV.     

Preparation and properties of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl- (R)-(+)-alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha- (4-[125I]iodophenyl)-alpha-phenyl acetate as potential radiopharmaceuticals

rac-4-Nitrobenzilic acid was synthesized and resolved with quinidine and quinine to give the corresponding (R)- and (S)-salts. The resolved diastereomeric salts were converted to (R)- and (S)-4-nitrobenzilic acids and subsequent esterification gave their corresponding ethyl esters. Transesterification with (R)-(-)-3-quinuclidinol afforded (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha- (4-nitrophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-nitrophenyl)-alpha-phenyl acetate. After hydrogenation, the (R,R)- and (R,S)-amines were converted to the respective triazene derivatives. The triazene derivatives reacted with sodium [125I]iodide to give (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)- alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate. The evaluation of their affinities to muscarinic acetylcholine receptors (MAcChR) shows that (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate exhibits an affinity for the MAcChR from corpus striatum that is approximately threefold lower than that of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate.     

Enantio-selective inhibition of (1R,9S)- and (1S,9R)-beta-hydrastines on dopamine biosynthesis in PC12 cells

The inhibitory effects of (1R,9S)- and (1S,9R)-enantiomers of beta-hydrastine (BHS) on dopamine biosynthesis in PC12 cells were investigated. (1R,9S)-BHS decreased the intracellular dopamine content with the IC50 value of 14.3 microM at 24 h, but (1S,9R)-BHS did not. (1R,9S)-BHS was not cytotoxic at concentrations up to 250 microM towards PC12 cells. In these conditions, (1R,9S)-BHS inhibited tyrosine hydroxylase (TH) activity mainly in a concentration-dependent manner (33% inhibition at 20 microM) and decreased TH mRNA level in PC12 cells. The inhibitory patterns of dopamine content and TH activity by (1R,9S)-BHS showed similar behavioral curves. (1R,9S)-BHS at 10-50 microM also reduced the intracellular cyclic AMP level and Ca2+ concentration. In addition, treatment of L-DOPA at 20-50 microM for 24 h increased the intracellular dopamine content to 198-251% compared with the control in PC12 cells. However, the increase in dopamine levels induced by L-DOPA (20-50 microM) was reduced when L-DOPA was combined with (1R,9S)-BHS (10-50 microM). These results indicate that (1R,9S)-BHS, but not (1S,9R)-BHS, reduced dopamine content and L-DOPA-induced increase in dopamine content, in part, through the inhibition of TH activity and TH gene expression in PC12 cells: thus, (1R,9S)-BHS proved to have a function to regulate dopamine biosynthesis.     

Synthesis and absolute configuration of the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid and comparison with its enantiomer

The synthesis of (3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid (Bay u 3405), a new, enantiomerically pure antagonist of thromboxane A2, is described. The determination of the absolute configuration of Bay u 3405 was performed by an X-ray analysis of compound 7 ([3((2S)-acetylamido)-3-phenylpropionamido]-1,2,3,4- tetrahydro-carbazol). Bay u 3405 is in vitro 1 to 2 orders of magnitude more active than its (-)-enantiomer Bay u 3406.     

GABA agonists and uptake inhibitors. Synthesis, absolute stereochemistry, and enantioselectivity of (R)-(-)- and (S)-(+)-homo-beta-proline

The cyclic analogue of 4-aminobutyric acid (GABA), 3-pyrrolidineacetic acid (homo-beta-proline), is a potent agonist at GABAA receptors, it interacts effectively with GABA-uptake mechanisms, and it is a moderately potent inhibitor of GABAB receptor binding. (R)-(-)- (10) and (S)-(+)-homo-beta-proline (15) were synthesized via methyl (3S)-1-[(R)-1-phenylethyl]-5-oxo-3-pyrrolidinecarboxylate (5) and its 3R diastereomer (4), respectively. The mixture 3 consisting of 4 and 5 was synthesized via addition-cyclization reactions between (R)-1-phenylethylamine and itaconic acid (1). The diastereomers 5 and 4, which were separated chromatographically, were converted into (R)- (10) and (S)-homo-beta-proline (15), respectively. The absolute stereochemistry of 10 and 15 was established on the basis of an X-ray analysis of compound 5. The enantiomers 10 and 15 were shown to bind to GABAA and GABAB receptor sites with opposite stereoselectivity. Thus, (R)-homo-beta-proline (10) proved to be more than 1 order of magnitude more potent than the S enantiomer (15) as an inhibitor of GABAA receptor binding, whereas the GABAB receptor affinity of homo-beta-proline was shown to reside exclusively in (S)-homo-beta-proline (15). In contrast to the stereoselective receptor affinities of 10 and 15, these enantiomers were approximately equieffective as inhibitors of synaptosomal GABA uptake.     

Synthesis and antiviral activity of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine

The synthesis of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine (3), starting from (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4), is described. Alkylation of trityl derivative 7 with (diethylphosphono)methyl triflate provided phosphonate 8, which was readily converted to mesylate 12 in three steps. Nucleophilic substitution of the mesylate group of 12 by 2-amino-6-chloropurine sodium salt led to (S)-2-amino-6-chloro-9-[3-[(diethyl-phosphono)methoxy]-4-(tetrahydro- 2H-pyran-2-yloxy)butyl]purine (13). Sequential treatment of 13 with trimethylsilyl bromide and then with 2 N HCl furnished 3. Preliminary in vitro screening indicated that 3 exhibited a potent activity against human cytomegalovirus (HCMV) but was not active against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The adenine and cytosine derivatives (14 and 15) did not exhibit activity against HSV-1 and -2 and HCMV.     

Action of the novel selective thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid on vascular smooth muscle preparations

The action of the thromboxane A2-receptor-antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) on vascular smooth muscle preparations was investigated in vitro. In rabbit aortic rings Bay u 3405 is a potent inhibitor of vasoconstriction produced by thromboxane A2 (TXA2)/PG endoperoxides generated by stimulated human platelets (EC50 1.3 x 10(-6) mol/l), (+/-)-cTA2 (Carbocyclic thromboxane A2 [2 beta(Z),3 alpha-(1E,3R*)-3- (3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid]) (EC50 3.3 x 10(-7) mol/l) and U 46619 (EC50 3.8 x 10(-7) mol/l). In pig circumflex coronary arteries Bay u 3405 was 150 times more potent (EC50 2.6 x 10(-9) mol/l) than in rabbit aorta. In rabbit and rat aorta the concentration-response curves for U 46619 were shifted to the right in a parallel manner and the maximum responses were not suppressed. The Schild-plot yielded a straight line with a slope of 1.14 (rabbit) or 1.29 (rat) and pA2 values of 7.43 and 8.59, respectively. The vasoconstrictive action of other agonists such as KCl, serotonin, histamine, epinephrine, norepinephrine, acetylcholine and angiotensin were not affected. In human platelets inhibition of the TXA2-synthase was seen only at concentrations of Bay u 3405 of 2.4 x 10(-5) mol/l and above. From these findings it is concluded that Bay u 3405 is a potent, competitive TXA2/endoperoxide receptor antagonist in vascular smooth muscle.     

(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.