- Preparation method of m-methoxyphenethylamine
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The invention discloses a preparation method of m-methoxyethylamine, and relates to the field of organic synthesis preparation chemistry. The preparation method comprises the following steps: adding M-methoxybenzyl chloride to an aqueous solution of cyanide, carrying out cyanation reaction at 60 - 95 °C DEG C, generating M-methoxycyanide, and then cooling and crystallizing in acetone to obtain m-methoxycyanide crystals. A proper amount of ammonia gas is introduced into the solvent, then a proper amount of ammonia gas is introduced, and then hydrogen is introduced to carry out catalytic hydrogenation reaction at a temperature 110 - 160 °C, and the hydrogenated product is distilled under reduced pressure to obtain m-methoxyethylamine. The preparation method of the meta-methoxyethylamine is simple, the raw materials are easily available, the process is easy to control, the cost is low, and the method has the characteristics of high yield, high purity, environmental friendliness and the like, and is suitable for industrial production.
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Paragraph 0018; 0025-0026; 0029-0032; 0035-0038; ...
(2021/11/14)
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- Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds
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Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
- Vara, Brandon A.,Levi, Samuel M.,Achab, Abdelghani,Candito, David A.,Fradera, Xavier,Lesburg, Charles A.,Kawamura, Shuhei,Lacey, Brian M.,Lim, Jongwon,Methot, Joey L.,Xu, Zangwei,Xu, Haiyan,Smith, Dustin M.,Piesvaux, Jennifer A.,Miller, J. Richard,Bittinger, Mark,Ranganath, Sheila H.,Bennett, David J.,Dimauro, Erin F.,Pasternak, Alexander
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supporting information
p. 653 - 661
(2021/04/12)
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- Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
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A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.
- Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
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p. 346 - 364
(2019/01/08)
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- Combined Photoredox/Enzymatic C?H Benzylic Hydroxylations
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Chemical transformations that install heteroatoms into C?H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C?H oxyfunctionalization, or the one step conversion of a C?H bond to a C?O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single-flask photoredox/enzymatic process for direct C?H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.
- Betori, Rick C.,May, Catherine M.,Scheidt, Karl A.
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p. 16490 - 16494
(2019/11/03)
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- One-pot chemoenzymatic synthesis of trolline and tetrahydroisoquinoline analogues
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Chemoenzymatic reaction cascades can provide access to chiral compounds from low-cost starting materials in one pot. Here we describe one-pot asymmetric routes to tetrahydroisoquinoline alkaloids (THIAs) using the Pictet-Spenglerase norcoclaurine synthase (NCS) followed by a cyclisation, to give alkaloids with two new heterocyclic rings. These reactions operated with a high atom economy to generate THIAs in high yields.
- Zhao, Jianxiong,Lichman, Benjamin R.,Ward, John M.,Hailes, Helen C.
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supporting information
p. 1323 - 1326
(2018/02/14)
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- Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes
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Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation-isomerization-amination for hydroamination and epoxidation-isomerization-reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (S)-amine and (S)-alcohol in 84-81% conversion with 97-92% ee, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O2, NH3, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols.
- Wu, Shuke,Liu, Ji,Li, Zhi
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p. 5225 - 5233
(2017/08/17)
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- Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
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Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
- Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 925 - 937
(2015/03/31)
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- 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Paragraph 0313
(2014/03/21)
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- SAR based design of nicotinamides as a novel class of androgen receptor antagonists for prostate cancer
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Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesized for H12 displacement. AR binding affinity and molecular basis of antiandrogenic effect establish the optimized derivatives, 7au and 7bb, as promising candidates of second generation AR antagonists for advanced prostate cancer.
- Yang, Su Hui,Song, Chin-Hee,Van, Hue Thi My,Park, Eunsook,Khadka, Daulat Bikram,Gong, Eun-Yeung,Lee, Keesook,Cho, Won-Jea
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p. 3414 - 3418
(2013/06/05)
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- Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands
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A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.
- Pignataro, Luca,Boghi, Michele,Civera, Monica,Carboni, Stefano,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 1383 - 1400
(2012/03/27)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Page/Page column 54
(2012/04/04)
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- 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indole-5-carbonitriles for SERT imaging: Chemical synthesis, evaluation in vitro and radiofluorination
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Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as 18F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful 18F-fluoroalkylation of one pair of compounds are described herein.
- Funke, Uta,Fischer, Steffen,Hiller, Achim,Scheunemann, Matthias,Deuther-Conrad, Winnie,Brust, Peter,Steinbach, Joerg
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scheme or table
p. 4727 - 4730
(2009/04/08)
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- A very mild access to 3,4-dihydroisoquinolines using triphenyl phosphite-bromine-mediated bischler-napieralski-type cyclization
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Substituted β-phenylethylamides undergo smooth intramolecular cyclization to 3,4-dihydroisoquinolines in good to excellent yields when treated with bromotriphenoxyphosphonium bromide at -60°C in dichloromethane in the presence of triethylamine. The reaction proceeds under the mildest conditions ever reported for Bischler-Napieralski-type cyclizations. When chlorotriphenoxyphosphonium choride is used, low yields are obtained instead. Georg Thieme Verlag Stuttgart.
- Vaccari, Daniele,Davoli, Paolo,Ori, Claudia,Spaggiari, Alberto,Prati, Fabio
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experimental part
p. 2807 - 2810
(2009/05/07)
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- Novel High Energy Intermediate Analogues with Triazasterol-Related Structures as Potential Inhibitors of the Ergosterol Biosynthesis II [1]. Optimization of the Synthesis of 1,6,7,11b-Tetrahydro-2H-pyrimido[4,3-a] isoquinolin-4-amines as Parent Compounds of Novel 8,13,15-Triazasteroids
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Summary. Various routes for an effective synthesis of 1,6,7,11b-tetrahydro- 2H-pyrimido[4,3-a]isoquinolin-4-amine and its 9-methoxy derivative, which were designed as tricyclic triaza-analogues with stable positive charge to mimic carbocationic high energy intermediates (HEI) of the ergosterol biosynthesis, were investigated. Starting from β-phenylethylamines the corresponding 3-chloro-N-phenethylpropionamides were prepared and transformed into N-phenethyl-3-phthalimidopropionamides. These amides were cyclized via Bischler-Napieralski reaction to yield after hydrolytic deprotection 1-(aminoethyl)tetrahydroisoquinolines. The 1,6,7,11b-tetrahydro-2H-pyrimido[4,3- a]isoquinoline ring system was then built up by condensation of the bicyclic diamines with various carbonic acid derivatives (carbon disulfide, nitroguanidine, tetraethyl orthocarbonate). Along with the applied reaction sequences unexpected side reactions took place. The structures of all isolated compounds were proven and completely assigned on the basis of homo- and heteronuclear correlated 1D and 2D NMR experiments. The in vitro antifungal susceptibility tests with a standard panel of eight pathogenic fungi revealed only weak antimycotic effects of the pyrimidoisoquinolinamine salts, but strong inhibitory activity of the intermediate 1-(aminoethyl)-3,4-dihydroisoquinoline.
- Goessnitzer, Edith,Punkenhofer, Asbjoern
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p. 909 - 927
(2007/10/03)
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- The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT1A/5-HT2A receptor activities of its 1-adamantoyloaminoalkyl derivatives
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Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT1A ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT1A and 5-HT2A receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that modification reduced the binding affinity for 5-HT1A receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT1A ligands (Ki = 4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT1A receptors. At the same time, their 5-HT2A receptor affinity was slightly increased (Ki = 40-1475 nM), which resulted in a loss of 5-HT2A/5-HT1A selectivity. 5-Br,8-OCH3 derivative - the most potent, mixed 5-HT1A/5-HT2A ligand - produced activation of presynaptic 5-HT1A receptors and showed properties of a 5-HT2A receptor antagonist. Copyright
- Bojarski, Andrzej J,Mokrosz, Maria J,Minol, Sijka Charakchieva,Koziol, Aneta,Wesolowska, Anna,Tatarczynska, Ewa,Klodzinska, Aleksandra,Chojnacka-Wojcik, Ewa
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- Regioselective synthesis of 6-fluorodopamine, 6-fluoro-m-tyramine and 4-fluoro-m-tyramine using elemental fluorine, oxygen difluoride and acetyl hypofluorite
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6-Fluorodopamine was regioselectively synthesized in good yields from N-(trifluoroacetyl)-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)phenylethylamine (6) via a fluorodestannylation reaction using F2, OF2 or CH3COOF followed by acid hydrolysis.Similarly, 6-fluoro-m-tyramine (14) and 4-fluoro-m-tyramine (20) were prepared from their corresponding trimethylstannyl derivatives.All precursors and products were fully characterized by multinuclear NMR spectroscopy and high resolution mass spectrometry. - Keywords: Dopamine neurotransmission; Norepinephrine synthesis; Dopamine agonist; 6-fluorodopamine; Fluorodestannylation
- Namavari, Mohammad,Satyamurthy, N.,Barrio, Jorge R.
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p. 113 - 122
(2007/10/03)
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- 3,10-Dimethoxyprotoberberines
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Protoberberines with the unusual 3,10-dimethoxy substitution are synthesized by photocyclization of E- and Z-1-ethylidene-1,2,3,4-tetrahydro-6-methoxy-2-(3-methoxybenzoyl)isoquinolines.
- Chinnasamy, Pennamuthiriar,Iwasa, Kinuko,Angerer, Silvia von,Weimar, Christian,Wiegrebe, Wolfgang
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p. 790 - 798
(2007/10/02)
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- Diazaestrones and analogs. I. Pharmacological study and synthesis of heterosteroid analogs to establish structure-analgesic activity relationships
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With the intention of showing the effect, about pharmacological properties, in replacing two estron asymetric carbon by nitrogen atoms and removal of angular methyl from steroid, stereospecific synthesis of 8,13-diazaestron and several substituted similar compounds was realized from β-1-(succinimidoethyl)-dihydroisoquinolines, precursors of a C open ring synthesis. The splitting of the 2-methoxydiazaestron methyl ester was carried out by mean of binaphthylphosphoric acid, and synthesis of several modified analogs of heterosteroid, was carried out to determine the effect of aromatic ring reduction, lactamic carbonyl reduction, and distance between 8 and 13 nitrogen atoms, about pharmacological activity. Hormonal, spasmolytic and analgesic activities were studied, good results were observed in analgesic activity.
- Hocquaux,Marcot,Redeuilh,et al.
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p. 319 - 329
(2007/10/02)
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- Synthesis of 1,2,3,4-Tetrahydroisoquinolines
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Several aspects of 1,2,3,4-tetrahydroisoquinoline synthesis have been examined.An improved synthesis of 2-(m-methoxyphenyl)ethylamine (4) is reported. m-Anisaldehyde (5) was treated with potassium cyanide and ethyl chloroformate to yield O-(ethoxycarbonyl)-3-methoxymandelonitrile (7).Hydrogenation afforded 2-(m-methoxyphenyl)ethylamine (4) in 87percent yield overall.Some observations have been made regarding the reduction of 3,4-dihydroisoquinolines derived from the Bischler-Napieralski reaction.Amides 3a and 3c were cyclized with phosphorus oxychloride, followed by reduction to the corresponding tetrahydroisoquinolines 1a and 1c.It was shown that 1a and 1c were contaminated with 4percent of 2a and 3percent of 2c, respectively.Both 2a and 2c were independently synthesized by routes with general applicability to 8-alkoxy-1,2,3,4-tetrahydroisoquinolines.
- Kashdan, David S.,Schwartz, John A.,Rapoport, Henry
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p. 2638 - 2643
(2007/10/02)
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- Total Synthesis of (+/-)-3-Deoxy-7,8-dihydromorphinone
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The total synthesis of (+/-)-3-deoxy-7,8-dihydromorphinone (1), starting from readily available acetic acid (4) is described.The amide 6, obtained from acid 4 and m-methoxyphenethylamine was converted by Bischler-Napieralski cyclization to the dihydroisoquinoline hydrochloride 7.Birch reduction of 7 gave the dihydroxydihydroanisole 8, which was acid cyclized in situ and then converted to (+/-)-2,4-bis-17-(methoxycarbonyl)morphinan-6-one (10).The conversion of 7 to 10 was carried out without isolation of intermediates.Hydrolysis with THF/Et2NH gave the 4-hydroxy compound 14.Reaction of 14 with cupric bromide followed by treatment with NaOH/CHCl3 and hydrolysis gave 4,5-epoxy-2-hydroxymorphinan-6-one (16).The 2-oxygen function was removed by Li/NH3 reduction of the phosphate ester 18 obtained by acylation of the ketal 17 with diethyl chlorophosphate.LAH reduction of the ketal 19 followed by acid hydrolysis gave the title compound (+/-)-3-deoxy-7,8-dihydromorphinone (1) in an overall yield (from 4) of 27percent.
- Manmade, Awinash,Marshall, John L.,Minns, Richard A.,Dalzell, Haldean,Razdan, Raj K.
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p. 1717 - 1721
(2007/10/02)
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