Lenvatinib的合成

目的制备lenvatinib,并对其工艺进行改进,以简化操作,提高收率。方法以4-氨基水杨酸(2)为原料,经甲基化,与麦氏酸缩合、高温环合、氯代、氨化,得到4-氯-7-甲氧基喹啉-6-甲酰胺(6)。以3-氯-4-氨基苯酚(7)为原料,经与氯甲酸苯酯及环丙胺反应得到1-(2-氯-4-羟基苯基)-3-环丙基脲(8)。最后中间体6和8在叔丁醇钾的作用下反应得到lenvatinib(1)。结果与结论目标化合物结构经核磁共振氢谱、红外、质谱确证,总收率为34.35%(以4-氨基水杨酸计),纯度99.50%。改进后的合成方法操作简便、收率较高。     

(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯的合成

L-门冬氨酸在氯化亚砜作用下选择性甲酯化生成L-门冬氨酸-4-甲酯盐酸盐,经二碳酸二叔丁酯保护氨基、与氯甲酸乙酯成混酐后经硼氢化钠还原得到(3S)-3-(叔丁氧羰基氨基)-4-羟基丁酸甲酯,最后经NaClO/TEMPO氧化得到西他列汀重要手性中间体(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯,总收率约41%。     

抗血吸虫病药物的研究 α,ω-双-(对氨基苯氧(硫)基)-烷类及其多羟基衍生物的合成

1.对乙酰氨基苯酚与1,7-二溴代庚烷,在乙醇钠液中缩合,得1,7-双(对乙酰氨基苯氧基)-庚烷,经稀盐酸水解制得1,7-双(对氨基苯氧基)-庚烷二盐酸盐.2.对乙酰氨基硫酚在硷醇中分别与1,3-二溴代丙烷,1,6-二溴代己烷和1,7-二溴代庚烷缩合,水解就可以分别得到相应的α,ω-双(对氨基苯硫基)-烷二盐酸盐.3.1-氯代甘油及1,3-二溴代甘油与对乙酰氨基苯酚或硫酚缩合,再行水解后,分别获得甘油的1-(对氨基苯基)及1,3-双(对氨基苯基)-醚或其硫代醚.4.1,6-二氯代-2,3-4,5-二亚甲基-D-甘露醇与对乙酰氨基苯酚钠盐,在封闭管中长期加热,可获得2,3-4,5-二亚甲基-D-甘露醇-1,6-双(对乙酰氨基苯)-醚.5.将D-甘露醇做成1,2-3,4-5,6-三异丙基-D-甘露醇,经部分水解成3,4-异丙基化合物,再制成1,6-双(对甲苯磺酰基)-2,5-二乙酰基-3,4-异丙基-D-甘露醇,在乙醇钠溶液中,分别与对乙酰氨基苯酚或硫酚缩合,再经水解,即分别得到D-甘露醇-1,6-双(对氨基苯基)-醚或D-甘露醇-1,6-双(对氨基苯基)硫代醚的双盐酸盐.6.对硝基苯酚与1,4-二溴代-2-丁烯缩合,生成1,4-双(对硝基苯氧基)-2-丁烯,于双键上进行双羟基化,并将硝基还原,得1,4-双(对氨基苯氧基)-2,3-threo-双羟基丁烷二盐酸盐.7.本文报导中的11个化合物,其中除Ⅰ、Ⅴ外,均为未知化合物,用作动物试验,初步结果表明,这些多羟基的氨苯氧(或硫)烷类化合物,对日本住血吸虫病都无效.     

抗血吸虫病药物的研究 α,ω-双-(对氨基苯氧(硫)基)-烷类及其多羟基衍生物的合成

1.对乙酰氨基苯酚与1,7-二溴代庚烷,在乙醇钠液中缩合,得1,7-双(对乙酰氨基苯氧基)-庚烷,经稀盐酸水解制得1,7-双(对氨基苯氧基)-庚烷二盐酸盐.2.对乙酰氨基硫酚在硷醇中分别与1,3-二溴代丙烷,1,6-二溴代己烷和1,7-二溴代庚烷缩合,水解就可以分别得到相应的α,ω-双(对氨基苯硫基)-烷二盐酸盐.3.1-氯代甘油及1,3-二溴代甘油与对乙酰氨基苯酚或硫酚缩合,再行水解后,分别获得甘油的1-(对氨基苯基)及1,3-双(对氨基苯基)-醚或其硫代醚.4.1,6-二氯代-2,3-4,5-二亚甲基-D-甘露醇与对乙酰氨基苯酚钠盐,在封闭管中长期加热,可获得2,3-4,5-二亚甲基-D-甘露醇-1,6-双(对乙酰氨基苯)-醚.5.将 D-甘露醇做成1,2-3,4-5,6-三异丙基-D-甘露醇,经部分水解成3,4-异丙基化合物,再制成1,6-双(对甲苯磺酰基)-2,5-二乙酰基-3,4-异丙基-D-甘露醇,在乙醇钠溶液中,分别与对乙酰氨基苯酚或硫酚缩合,再经水解,即分别得到 D-甘露醇-1,6-双(对氨基苯基)-醚或 D-甘露醇-1,6-双(对氨基苯基)硫代醚的双盐酸盐.6.对硝基苯酚与1,4-二溴代-2-丁烯缩合,生成1,4-双(对硝基苯氧基)-2-丁烯,于双键上进行双羟基化,并将硝基还原,得1,4-双(对氨基苯氧基)-2,3-threo-双羟基丁烷二盐酸盐.7.本文报导中的11个化合物,其中除Ⅰ、Ⅴ外,均为未知化合物,用作动物试验,初步结果表明,这些多羟基的氨苯氧(或硫)烷类化合物,对日本住血吸虫病都无效.     

氨噻肟酸乙酯的合成

4-氯-3-氧代丁酸乙酯经肟化、与硫脲环合制得2-（2-氨基-4-噻唑基）-2-羟基亚胺基乙酸乙酯，在相转移催化剂溴化四乙铵作用下用硫酸二甲酯醚化制得氨噻肟酸乙酯，总收率46％。     

半富马酸喹硫平的合成研究

2-氨基二苯硫醚和三光气反应得到的2-异氰酸基二苯硫醚在多聚磷酸中闭环后,经氯代、与哌嗪缩合得到11-哌嗪-1-基二苯并[b,f][1,4]硫氮杂革,由2-(2-氯乙氧基)乙醇进行哌嗪N4-位烷基化反应后与富马酸成盐,制得抗精神病药半富马酸喹硫平,总收率63.4%(以2-氨基二苯硫醚计).     

JAK1抑制剂 filgotinib 的合成工艺研究

目的对JAK抑制剂filgotinib的合成工艺进行优化。方法以2-氨基-6-溴吡啶为起始原料,经缩合、环合、酰化、Suzuki偶联和溴代反应得到关键中间体N-{5-[4-(溴甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶-2-基}环丙基乙酰胺(7);以硫代吗啉为另一起始原料,经Boc保护、氧化、脱Boc反应得到中间体硫代吗啉-1,1-二氧化物(11);中间体7与中间体11经亲核取代反应制得目标产物filgotinib。结果与结论 filgotinib的结构经~1H-NMR、~(13)C-NMR和MS确证。总收率为46.6%(以2-氨基-6-溴吡啶计),纯度达99.7%(HPLC法)。优化后的工艺路线所用原料廉价易得,操作简便,条件温和,收率较高,可为工业化生产提供参考。     

盐酸溴己新的合成

以2-氨基-3,5-二溴苯甲醛为原料,经硼氢化钠还原得2-氨基-3,5-二溴苄醇,经氯化亚砜氯代所得2,4-二溴-6-氯甲基苯胺,再与N-甲基环己胺进行氨化反应及成盐酸盐即可制得祛痰药盐酸溴己新,总收率约57％.     

5-氨基-4-氧代戊酸盐酸盐的制备

乙酰丙酸经酯化、溴化得到5-溴或3-溴-4-氧代戊酸甲酯混合物，无需分离，直接与邻苯二甲酰亚胺钾在DMF中反应得N-[（2-氧代-4-甲氧羰基）丁基]邻苯二甲酰亚胺，最后经稀盐酸酸解得到5-氨基-4-氧代戊酸盐酸盐，总收率接近44％。     

盐酸维拉唑酮的合成

以5-溴水杨醛和溴代丙二酸二乙酯为起始原料,经醚化、环合、酰胺化、取代及脱保护反应制得关键中间体5-(1-哌嗪基)苯并呋喃-2-甲酰胺(5).另用5-氰基吲哚和4-氯丁酰氯经酰化、还原制得3-(4-氯丁基)-5-氰基-1H-吲哚(7).5和7经缩合及与盐酸成盐制得盐酸维拉唑酮,总收率为36.3％(以5-溴水杨醛计).     

精氨酸加压素V2受体拮抗剂SR-121463的合成

用对乙氧基苯胺和间羟基苯甲酸为原料,分别拟得5′-乙氧基-4-[2-（4-吗啉基）乙氧基]螺[环己烷-1,3′-二氢吲哚]-2′-酮和4-叔丁氨甲酰基-2-甲氧基苯磺酰氯,二者缩合制得精氨酸加压素V2受体拮抗剂SR-121463.     

Newer substituted benzoxazepinyl-quinazolinones as potent antipsychotic and anticonvulsant agents

3-Amino-[2'-substitutedaryl-3'-substitutedarylaminomethylene-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 11-18 and 3-amino-[2'-substituted aryl-3'-substitutedaryl-azo-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 19-26 were synthesized from 3-amino-[2'-substitutedaryl-2',3'-dihydro-1',5'- benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 7-10 by Mannich's reaction and by diazotisation, respectively, on the 3rd position of the benzoxazepine ring of the compounds 7-10. The newly synthesized compounds showed potent antipsychotic and anticonvulsant activities.     

Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorophenyl)pentanoic acid.

(RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acidB (GABAB) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R, 5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12. HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABAA or GABAB receptor sites and was inactive as an agonist or an antagonist at GABAB receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABAA receptor sites, and in agreement with the findings for (S)-baclofen, 12 did not interact significantly with GABAB receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 microM), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 microM) as an inhibitor of GABAB binding. Accordingly, 11 (EC50 = 150 +/- 23 microM) was shown to be weaker than 2 (EC50 = 11 +/- 1 microM) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABAB antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 microM) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.     

Methotrexate analogues. 31. Meta and ortho isomers of aminopterin, compounds with a double bond in the side chain, and a novel analogue modified at the alpha-carbon: chemical and in vitro biological studies

Five heretofore undescribed analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized and tested as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. The meta isomer of AMT was obtained from 2,4-diamino-6-(bromomethyl)pteridine and m-(aminobenzoyl)-L-glutamic acid, while the ortho isomer was obtained via the same route by using alpha-methyl gamma-tert-butyl o-(aminobenzoyl)-L-glutamate instead of the free acid. Analogues of MTX and AMT containing a double bond in the side chain were prepared from dimethyl D,L-2-amino-4-hexenedioate and 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively. Finally, a positional isomer of MTX with the CH2CH2COOH moiety moved from the alpha-carbon to the adjacent carboxamide nitrogen was synthesized from 3-[N-(carboxymethyl)amino]propanoic acid diethyl ester and 4-amino-4-deoxy-N10-methylpteroic acid. The positional isomers of AMT were weak DHFR inhibitors and showed very little growth-inhibitory activity against L1210 murine leukemia cells or the MTX-resistant L1210/R81 mutant line in culture. The MTX and AMT analogues with the CH2CH2COOH moiety replaced by a CH2CH = CHCOOH side chain showed anti-DHFR activity similar to that of the previously described saturated compound N-(4-amino-4-deoxy-N10-methylpteroyl)-L-2-aminoadipic acid, but were less potent than the parent drugs. The MTX analogue with the CH2CH2COOH side chain displaced from C to N was weakly bound to DHFR, confirming the importance of an intact CONH moiety, and showed greatly diminished cell growth inhibitory potency relative to MTX. None of the compounds was a substrate for folylpolyglutamate synthetase (FPGS) from mouse liver. Furthermore, inhibition of folic acid polyglutamylation in vitro at equimolar 500 microM concentrations of drug and substrate was negligible. The structural changes embodied in these five novel compounds are therefore too great for binding to the FPGS active site.     

Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides

(+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.     

Folate analogues. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase

Five analogues of methotrextate (MTX), 10-deazaaminopterin (10-DAM), and 10-ethyl-10-deazaaminopterin (10-EDAM) in which the glutamate moiety was replaced by either a gamma-methyleneglutamate or beta-hydroxyglutamate were synthesized and evaluated for their antifolate activity. These analogous are 4-amino-4-deoxy-N10-methylpteroyl-beta-hydroxyglutamic acid (1), 4-amino-4-deoxy-10-deazapteroyl-beta-hydroxyglutamic acid (2), 4-amino-4-deoxy-N10-methylpteroyl-gamma-methyleneglutamic acid (3, MMTX), 4-amino-4-deoxy-10-deazapteroyl-gamma-methyleneglutamic acid (4, MDAM), and 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-gamma-methyleneglutamic acid (5, MEDAM). None of these compounds were metabolized to the respective polyglutamate derivative as judged by their inability to serve as substrates for CCRF-CEM human leukemia cell folylpolyglutamate synthetase (FPGS) in vitro. All compounds inhibited recombinant human-dihydrofolate reductase (DHFR) at nearly equivalent magnitude as MTX. Growth-inhibition studies with H35 hepatoma, Manca human lymphoma, and CCRF-CEM human leukemia cells established greater cytotoxic effects with compounds 3-5 than with compounds 1 and 2. gamma-Methyleneglutamate derivatives 3-5 were transported to H35 hepatoma cells better than MTX or beta-hydroxyglutamate derivatives 1 and 2. Compound 3 was 2.5 times better than MTX in competing with folinic acid transport in H35 hepatoma cells. Compound 1 did not have a significant inhibitory effect on folinic acid transport even at 50 microM under identical conditions. The IC50 for compound 1 against H35-hepatoma cell growth was 8.5-fold higher than MTX. Compounds with the gamma-methyleneglutamate moiety (3-5) exhibited almost equal or lower IC50 values than MTX against the growth of CCRF-CEM human leukemia cells. These studies show that on continuous exposure, the non-polyglutamylatable inhibitors DHFR (3-5) can exhibit superior antifolate activity compared to the polyglutamylatable methotrexate, presumably due to their enhanced transport to these cell lines. Compounds 3-5 appear to be excellent models to study the role of polyglutamylation of antifolates in antitumor activity and host toxicity.     

头孢克肟的合成

用7-氨基-3-乙烯基-3-头孢烯-4-羧酸和(Z)-2-(2-氨基噻唑-4-基)-2-甲氧羰基甲氧亚氨基硫代乙酸(S)-2-苯并噻唑酯在三乙胺催化下经酰化、水解反应,一锅法制得头孢克肟,收率约92%。     

Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents

2-Amino-5-acetyl-4-methyl-thiophene-3-carboxylic acid ethyl ester (1) and 5-acetyl-2-amino-4-methylthiophene-3-carbohydrazide (2) were synthesized and used as starting materials for the synthesis of new series of 1-(5-amino-4-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3a), 1-(5-amino-4-(4-chloro-3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3b), 1-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl)pyrazolidine-3,5-dione (4), (Z)-N'-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) formohydrazonic acid (5a), (Z)-ethyl-N'-4-methyl-2-amino-5-acetylthiophene-3-carbonylformo hydrazonate (5b), 6-acetyl-3-amino-2,5-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (8), 5-methyl-3-amino-2-mercapto-6-acetylthieno [2,3-d]pyrimidin-4(3H)-one (10) and 5-methyl-6-acetyl-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one (12) as potential antioxidant and antitumor agents. Pharmacological tests showed that compounds 6a, 6b, 8, 10 and 12 exhibited significant antitumor and antioxidant activity.     

Synthesis and antiviral activity of carbocyclic analogues of 2'-deoxyribofuranosides of 2-amino-6-substituted-purines and of 2-amino-6-substituted-8-azapurines

(+/-)-(1 alpha, 2 beta, 4 alpha)-4-[(2,5-Diamino-6-chloro-4-pyrimidinyl) amino]-2-hydroxycyclopentanemethanol (9) was synthesized by beginning with 2-amino-4,6-dichloropyrimidine and (+/-)-1 alpha, 2 beta, 4 alpha)-4-amino-2-hydroxycyclopentanemethanol, preparing the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine, and reducing the azo derivative. The carbocyclic analogue of 2-amino-6-chloropurine 2'-deoxyribofuranoside (10) was prepared from 9 and triethyl orthoformate, and the analogous 8-azapurine (11) was obtained by diazotizing 9. From 10 or 11, the carbocyclic analogues of 2'-deoxyguanosine, 2'-deoxythioguanosine, 2,6-diaminopurine 2'-deoxyribofuranoside, 2'-deoxy-8-azaguanosine, and 2,6-diamino-8-azapurine 2'-deoxyribofuranoside were prepared. All of these 2'-deoxyribofuranoside analogues were active against herpes simplex virus (types 1 and 2) replicating in cells in culture; some demonstrated potent activity.     

Synthesis, characterization and evaluation of benzylidene analogues as a new class of potential antioxidant agents

Seventeen analogues of benzylidene were synthesized and evaluated for in vitro hydrogen peroxide scavenging activity. The structure of the newly synthesized compounds were confirmed by elemental and spectral (IR, 1H-NMR, 13C-NMR) studies. The antioxidant activity of the titled compounds was evaluated. Compounds: 4h--N'-[2-amino-3-(morpholinomethyl)benzylidene]isonicotinohydrazide, 4p 7-(4-(2-amino-3-[(2-isonicotinoylhydrazono)methyl]benzyl}piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquino- line-3-carboxylic acid and 4q 7-(4-{2-amino-3-[(2 isonicotinoylhydrazono)methyl]benzyl} piperazin-1-yl)-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were the most active compounds with significant hydrogen peroxide scavenging activity.