- PYRIMIDINE-FUSED CYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
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Disclosed in the present disclosure are a pyrimidine-fused cyclic compound or a pharmaceutically acceptable salt, hydrate, prodrug, stereoisomer, solvate or isotope labeled compound thereof. Also provided in the present disclosure are a preparation method for the compound, a composition comprising the compound and a use of the compound for the preparation of a medicament for the prevention and/or treatment of a disease or condition associated with abnormal SHP2 activity.
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Paragraph 0363; 0366-0369
(2021/02/26)
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- Design of a mesoscale continuous-flow route toward lithiated methoxyallene
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The unique nucleophilic properties of lithiated methoxyallene allow for C C bond formation with a wide variety of electro-philes, thus introducing an allenic group for further functionali-zation. This approach has yielded a tremendously broad range of (hetero)cyclic scaffolds, including precursors to active pharmaceutical ingredients. To date, however, its valorization at scale is hampered by the batch synthesis procedure, which suf- fers from serious safety issues. Hence, the attractive heat-and mass-transfer properties of flow technology were exploited to establish a mesoscale continuous-flow route toward lithiated methoxyallene. An excellent conversion of 94 % was obtained, corresponding to a methoxyallene throughput of 8.2 g h1. The process is characterized by short reaction times, mild reaction conditions and a stoichiometric use of reagents.
- Seghers, Sofie,Heugebaert, Thomas S. A.,Moens, Matthias,Sonck, Jolien,Thybaut, Joris W.,Stevens, Christian V.
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- Versatile PdTe/C catalyst for liquid-phase oxidations of 1,3-butadiene
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A commercial Pd catalyst based on Sibunit carbon support was treated with H6TeO6 in a reducing media to obtain a Te coating on the surface of Pd particles. The PdTe/C catalyst prepared in this way showed the ability to control the radical chain oxidation of 1,3-butadiene by promoting the selective formation of 2-butene-1,4-diol, 4-hydroxybut-2-enal and furan in DMA (total selectivity of 61% and yield of 7%). At the same time, the catalyst induced oxidation of 1,3-butadiene by a non-radical heterolytic mechanism involving the formation of two groups of primary products: (1) crotonaldehyde and methyl vinyl ketone and (2) the products of oxygenation at the 1,4-positions. The compounds of the second group including 1,4-dimethoxy-2-butene and maleic acid dimethyl ester were formed on PdTe centers in MeOH. Increasing the Te concentration in the PdTe/C catalyst forced the conversion of 1,3-butadiene toward 1,4-oxygenation and simultaneously decreased the intensity of secondary oxidation, resulting in the selective formation of derivatives of the 1,4-oxygenation - 1,4-dimethoxy-2-butene and allenic alcohol methyl ether (total selectivity of 84% and yield of 48%).
- Kuznetsova,Zudin,Kuznetsova,Zaikovskii,Kajitani,Utsunomiya,Takahashi
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- Water freezing as a regiocontrol element in the multicomponent assembly of cyclic enones
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Regioselective synthesis of dialkoxy 2-cyclopentenones and 2-cyclohexenones with novel substitution patterns has been accomplished by the one-pot combination of three simple starting materials (chromium carbene complex, Weinreb acetamide lithium enolate a
- De la Campa, Raquel,Flrez, Josefa
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supporting information
p. 1854 - 1859
(2015/01/30)
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- Routes for the synthesis of (2S)-2-methyltetrahydropyran-4-one from simple optically pure building blocks
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Routes to (2S)-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of (S)-5-hydroxyhex-1-en-3-one, derived either from an alkyl (S)-3-hydroxybutyrate or (S)-propylene oxide. Formation of the tetrahydropyran ring directly via an intramolecular oxy-Michael reaction under acid-catalysed conditions resulted in loss of optical purity, whereas proceeding through the intermediate (2S)-2-methyl-2,3-dihydropyran-4-one, via an oxidative Pd-catalysed ring closure, followed by hydrogenation of the alkenyl bond, preserved the optical purity. An alternative approach to (2S)-2-methyl-2,3-dihydropyran-4-one is also reported, again starting from an alkyl (S)-3-hydroxybutyrate by elaboration to a carbonyl-protected (6S)-6-methyl-5,6-dihydropyran-2,4-dione derivative, followed by partial reduction and dehydration. Alternatively, the carbonyl group can be reduced out completely in one step to furnish (2S)-2-methyltetrahydropyran-4-one directly after deprotection.
- Anderson, Kevin R.,Atkinson, Stephanie L. G.,Fujiwara, Takahiro,Giles, Melvyn E.,Matsumoto, Takaji,Merifield, Eric,Singleton, John T.,Saito, Takao,Sotoguchi, Tsukasa,Tornos, James A.,Way, Edward L.
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experimental part
p. 58 - 71
(2010/05/18)
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- Modified copolymers of bifunctional vinyl ethers with methyl vinyl sulfide as active matrices of solid superbases
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Reactive linear and crosslinked copolymers of diethylene glycol divinyl ether and ethylene glycol vinyl glycidyl ether with methyl vinyl sulfide have been synthesized in the presence of 2,2′-azobis(isobutyronitrile) (2%, 60 °C, 45-55 h) in ~53% yield. The hydrolyzed at the residual vinyloxy and epoxy groups and oxidized at the methylthio groups copolymers upon treatment with KOH afford alkoxide (complex) and crown-like superbases. They are capable of catalyzing the acetone ethynylation, as well as the prototropic isomerization of methyl propargyl ether to allenyl methyl ether and vinylation of ethylene and diethylene glycols with acetylene.
- Trofimov,Morozova,Mikhaleva,Markova,Tatarinova,Henkelmann
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experimental part
p. 2111 - 2116
(2010/05/02)
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- ALDOSTERONE RECEPTOR ANTAGONISTS
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Compounds of the formula (I), (R1 is one of a wide range of substituents; R2 = H, halogen and R3 = H, hydroxymethyl or CR2R3 = cyclopropyl ring; CR4R5 is one of formula (II), formula (III) and formula (IV) Ra and Rb are a bond between carbons 9 and 11 or an -O-, -S-, -CH2- or -CF2- bridge; R6 is H, alkyl, -CH2ORx, -CH2SRx, -CH2SO-alkyl, -CH2SO2-alkyl, -CH2NHRx, -CH2N(alkyl)(Rx), -C(=O)O-alkyl, -C(=O)-alkyl, -C(=O)NHRx or -C(=O)N(alkyl)(Rx); R7 = R8 = H or CR7R8 is a cyclopropyl ring; R9 and R9’ are H, halogen, alkyl or alkoxycarbonyl or a bond between carbons 22 and 23; R10 is H or -C(=O)ORx; Rx is H, alkyl or acyl; Ry is H, alkyl; Rz is H, alkyl) are provided. They are aldosterone receptor antagonists, useful for the treatment of aldosteronism including hypertension, cardiovascular disease, renal dysfunction, edema, cerebrovascular disease and insulinopathies.
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Page/Page column 118
(2010/11/26)
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- LAULIMALIDE ANALOGS AND USES THEREOF
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The present invention provides compounds having formula 1: (I) and pharmaceutically acceptable derivatives thereof, wherein R1-R10, q, t, X0, X1, A, B, D, E, G, J, K, L, M and Z are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders associated with cellular hyperproliferation.
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Page/Page column 138-139
(2010/02/11)
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- The methoxyallene approach to oxacycles, part 2: Stereoselective synthesis of 2,3-disubstituted oxepanes
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2,3-Disubstituted oxepanes 3 and 4 were stereoselectively synthesized from methoxyallene (1) and iodide 2. The trans stereochemistry of diol 3 was established by NMR studies of the bicyclic precursor 10, while the cis stereochemistry of 4 was secured by using the highly diastereoselective reducing agent L-Selectride. Georg Thieme Verlag Stuttgart.
- Perez, Manuel,Canoa, Pilar,Gomez, Generosa,Teijeira, Marta,Fall, Yagamare
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p. 411 - 414
(2007/10/03)
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- 2-CYANOPYRROLOPYRIMIDINES AND PHARMACEUTICAL USES THEREOF
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The invention relates to pyrrolo pyrimidines of formula (I), wherein Y represents -(CH2)t-O- or -(CH2)r-S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, or Y is -(CH2)j- or -CH=CH-, j is 1 or 2; p is 1 or 2, or Y is -(CH2)f-, f is 1 or 2, p is 1, and the further radicals and symbols have the meaning as defined herein; their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such a compound for the manufacture of a pharmaceutical preparation for the treatment of neuropathic pain and to a method for the treatment of such a disease in animals, especially in humans.
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Page/Page column 34
(2010/02/08)
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- Palladium-mediated intramolecular C-N bond formation involving allyl substituted pyridines. Application to a novel strategy for the synthesis of the skeleton of berberinium derivatives
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The insertion of allenes in the Pd-C σ bond of cyclopalladated pyridine derivatives afforded (η3-allyl) Pd complexes. The ideally located imine unit reacted selectively with the allyl functionality to yield a series of new cationic heterocycles. The process opened the route to a novel strategy for the synthesis of berberiniums, a class of molecules of pharmacological interest.
- Chengebroyen, Jaganaiden,Linke, Myriam,Robitzer, Mike,Sirlin, Claude,Pfeffer, Michel
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p. 313 - 321
(2007/10/03)
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- Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
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Biaromatic compounds connected by a propynylene or ailenylene bond, corresponding to the formula (I).
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Page column 15
(2010/02/04)
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- Analogues of the potent nonpolyglutamatable antifolate N(α)-(4-amino-4- deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity
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Seven N(α)-(4-amino-4-deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. In growth assa
- Rosowsky, Andre,Wright, Joel E.,Vaidya, Chitra M.,Forsch, Ronald A.,Bader, Henry
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p. 1620 - 1634
(2007/10/03)
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- Propynyl or dienyl biaromatic compounds
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PCT No. PCT/FR97/00390 Sec. 371 Date Jan. 26, 1998 Sec. 102(e) Date Jan. 26, 1998 PCT Filed Mar. 5, 1997 PCT Pub. No. WO97/33856 PCT Pub. Date Sep. 18, 1997The invention relates to novel propynyl or dienyl biaromatic compounds which have the general formula (I) as well as to the use of these compounds in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmological complaints in particular), or alternatively in cosmetic compositions.
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- Bi-aromatic compounds and pharmaceutical and cosmetic compositions containing same
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PCT No. PCT/FR98/01238 Sec. 371 Date Mar. 23, 1999 Sec. 102(e) Date Mar. 23, 1999 PCT Filed Jun. 12, 1998 PCT Pub. No. WO98/56783 PCT Pub. Date Dec. 17, 1998The invention concerns bi-aromatic compounds of formula (I) in which Ar represents (a), Z being O or S, R1 is -CH3, -CH2-O-R6, -OR6 or -COR7; R2 is -OR8, -SR8 or a polyether radical if in the latter case R4 is C1-C20 alkyl and is in ortho or meta position relative to X-Ar; R3 is alkyl or R2 and R3 together form a cycle optionally interrupted by O or S; R4 is aryl radical; R5 is H, halogen, C1-C20 alkyl or -OR8; R6 is H, alkyl or -COR9; R7 is H, alkyl, -N(r')(r'') or -OR10; R8 is H, alkyl or -COR9; R9 is alkyl; R10 is H, C1-C20 alkyl, alkenyl, monohydroxyalkyl or polyhydroxyalkyl, aryl or aralkyl or a sugar residue, r' and r'' are H, alkyl mono- or polyhydroxyalkyl, aryl, an amino acid or sugar residue or together form a heterocycle, X represents a radical of formula (d) or (e) in which R11 is H or -OR6; R12 is H or alkyl; or R11 and R12 form an oxo radical, and the salts, optical and geometrical isomers of the compounds of formula (I).
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- Methoxyallene, a building block for the synthesis of seven-membered oxacycles
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An efficient new approach for the synthesis of seven-membered oxacycles is described.
- Fall, Yagamare,Gomez, Generosa,Fernandez, Carlos
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p. 8307 - 8308
(2007/10/03)
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- Substituted alkenoic acid and its derivatives
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The new substituted alkenoic acid derivatives can be prepared by reacting the appropriate aldehyde with a phosphonium compound. The compounds have leukotriene antagonistic properties and can be incorporated into pharmaceutical compositions.
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- Vibrational spectrum and molecular structure of methoxyallene
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Infrared and Raman spectra of methoxyallene and its deuteroderivative CD3OCH=C=CH2 were analysed on the basis of a scaled ab initio force field (4-21G basis set).Scaling factors were transfered from calculations of allene and dimethyl ether molecules in the same basis set.The ab initio force field scaled in this way provides a good agreement of calculated frequencies with experimental ones.Infrared intensities were calculated and compared with experiment.Contrary to vinyl group CH2 stretching vibration intensities, the intensity of νsCH2 of allenyl group is higher than of νasCH2.This relation is reproduced by ab initio intensities.Both experimental spectra and ab initio calculations show that the local asymmetry of CH3 group in methoxyallene is the same as in methoxyethene.
- Eroshchenko, S. V.,Sinegovskaya, L. M.,Tarasova, O. A.,Frolov, Yu. L.,Trofimov, B. A.,Ignatyev, I. S.
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p. 1505 - 1512
(2007/10/02)
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- ALLENE ETHERS FOR THE CATIONIC CYCLOPENTANNELATION
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Only allene ethers having a group which is capable of departing as a stable cation participate successfully in the cationic cyclopentannelation reaction.
- Tius, Marcus A.,Ousset, J-B.,Astrab, Donald P.,Fauq, Abdul H.,Trehan, Sanjay
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p. 923 - 924
(2007/10/02)
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- MEDICINAL PLANTS OF SOUTHERN AFRICA. PART 2. SYNTHESIS OF 1,3-BIS-(4-METHOXYPHENYL)PENTA-1,4-DIENE, A STEREOISOMER OF DIMETHYLHINOKIRESINOL, AND ITS 4-MONOMETHOXY ANALOGUE
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A six-step synthesis of the title compounds (6) and (7) from prop-2-yn-1-ol, and proceeding via 3-(4-methoxyphenyl)prop-1-yne, is described.Detailed 1H n.m.r. spectral analysis (500 MHz) suggests that the synthetic compounds have a 1,2-E stereochemistry in contrast to the Z-configuration present in the naturally occurring hinokiresinol (3).By utilizing a different, and much less efficient route, a small quantity of (Z)-3-(4-methoxyphenyl)-1-phenylpenta-1,4-diene (5) was obtained.
- Ameer, Farouk,Drewes, Siegfried E.,Drewes, Mark W.,Roos, Gregory H. P.,Watson, Martin C.
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p. 1425 - 1430
(2007/10/02)
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- Tandem Alkylation-Reduction. Highly Stereoselective Synthesis of (E)-1-Hydroxymethyl Methyl Propenyl Ethers from Aldehydes Using 1-Lithio-1-methoxyallene
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Tandem alkylation-reduction of a series of aldehydes, by alkylating with 1-lithio-1-methoxyallene followed by reducing with lithium-ammonia, regiospecifically and highly stereoselectively affords the 1-hydroxymethyl methyl propenyl ether in which the alkene geometry is exclusively E.Aldehydes that have been subjected to this convenient procedure include aromatic, aliphatic, and heterocyclic aldehydes.Subsequent hydrolysis, in the aromatic and aliphatic cases, affords the corresponding α-hydroxy ethyl ketones.The stereochemistry of the propenyl ethers was established by 13C NMR spectroscopy.A mechanism for the selective reduction of the methoxyallene system is proposed.
- Weiberth, Franz J.,Hall, Stan S.
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p. 5308 - 5314
(2007/10/02)
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- 10-Alkyl-10-deazaminopterins
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A process and composition are provided employing 10-deazaminopterin and 10-alkyl derivatives thereof for the treatment of leukemia, as well as other tumor systems including those of ascitic character, and also a process for preparing 10-deazaminopterin compounds.
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- Process and composition for treatment of leukemia and process for preparing the same
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A process and composition are provided employing 10-deazaminopterin for treating leukemia and ascites tumor.
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