- Convergent Synthesis of Immune Inhibitor IMMH002
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A convergent synthesis of IMMH002 in 36% overall yield starting from bromobenzene is described with a key Suzuki-Miyaura cross-coupling reaction used to provide a crucial intermediate. The route does not require column chromatography and solves the most intractable quality problem caused by a homologue by-product in the original linear synthesis. Furthermore, reducing the use of Lewis acid mediated reactions improves the environmental impact of the synthesis and reduces overall waste. The new route described herein is more efficient, convenient, reliable, and economically more viable when compared to the previously reported linear route.
- Chen, Si,Shi, Zeyu,Xiao, Qiong,Yin, Dali
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p. 1174 - 1180
(2020/10/30)
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- Preparation method of pusaimode (Chinese name)
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The invention discloses a preparation method of pusaimode. Bromo-benzene is used as an initial raw material to prepare pusaimode by adopting a convergent synthesis route. The yield of the preparationmethod is high, the cost is low, the amount of generated waste water, waste gas, and waste solids is low, the operation is convenient, and the application value is high.
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Paragraph 0058-0061
(2020/05/29)
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- Preparation method of aituomode
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The invention discloses a preparation method of aituomode. Bromo-benzene is used as an initial raw material to prepare aituomode by adopting a convergent synthesis route. The yield of the preparationmethod is high, the cost is low, the amount of generated waste water, waste gas, and waste solids is low, the operation is convenient, and the application value is high.
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Paragraph 0058-0061
(2020/05/29)
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- Preparation method of aituomode
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The invention discloses a preparation method of aituomode. Bromo-benzene and benzene are used as initial raw materials to prepare aituomode by adopting a convergent synthesis route. The yield of the preparation method is high, the cost is low, the amount of generated waste water, waste gas, and waste solids is low, the operation is convenient, and the application value is high.
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Paragraph 0050-0053
(2020/05/29)
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- Migratory Hydrogenation of Terminal Alkynes by Base/Cobalt Relay Catalysis
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Migratory functionalization of alkenes has emerged as a powerful strategy to achieve functionalization at a distal position to the original reactive site on a hydrocarbon chain. However, an analogous protocol for alkyne substrates is yet to be developed. Herein, a base and cobalt relay catalytic process for the selective synthesis of (Z)-2-alkenes and conjugated E alkenes by migratory hydrogenation of terminal alkynes is disclosed. Mechanistic studies support a relay catalytic process involving a sequential base-catalyzed isomerization of terminal alkynes and cobalt-catalyzed hydrogenation of either 2-alkynes or conjugated diene intermediates. Notably, this practical non-noble metal catalytic system enables efficient control of the chemo-, regio-, and stereoselectivity of this transformation.
- Liu, Bingxue,Liu, Qiang,Liu, Xufang
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supporting information
p. 6750 - 6755
(2020/03/13)
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- Preparation method of pusaimode (Chinese name)
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The invention discloses a preparation method of pusaimode. Bromo-benzene and benzene are used as initial raw materials to prepare pusaimode by adopting a convergent synthesis route. The yield of the preparation method is high, the cost is low, the amount of generated waste water, waste gas, and waste solids is low, the operation is convenient, and the application value is high.
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Paragraph 0049; 0050; 0052
(2020/05/29)
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- Transition-Metal-Free Borylation of Alkyl Iodides via a Radical Mechanism
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We describe an operationally simple transition-metal-free borylation of alkyl iodides. This method uses commercially available diboron reagents as the boron source and exhibits excellent functional group compatibility. Furthermore, a diverse range of prim
- Liu, Qianyi,Hong, Junting,Sun, Beiqi,Bai, Guangcan,Li, Feng,Liu, Guoquan,Yang, Yang,Mo, Fanyang
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supporting information
(2019/07/08)
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- Selective C(sp3)?H and C(sp2)?H Fluorination of Alcohols Using Practical Auxiliaries
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Selective introduction of fluorine into molecules by the cleavage of inert C?H bonds is of central academic and synthetic interest, yet remains challenging. Given the central role of alcohols in organic chemistry as the most ubiquitous building blocks, a
- Mao, Yang-Jie,Lou, Shao-Jie,Hao, Hong-Yan,Xu, Dan-Qian
-
supporting information
p. 14085 - 14089
(2018/10/15)
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- Ni-Catalyzed Enantioselective Conjunctive Coupling with C(sp3) Electrophiles: A Radical-Ionic Mechanistic Dichotomy
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The catalytic enantioselective conjunctive coupling of C(sp3) electrophiles can be accomplished with Ni catalysis. The enantioselectivity of the reaction is dependent on reaction mechanism with many substrates able to engage in an asymmetric process with Pybox-Ni complexes, whereas other substrates provide racemic product mixtures. The link between substrate structure and selectivity is addressed.
- Lovinger, Gabriel J.,Morken, James P.
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supporting information
p. 17293 - 17296
(2017/12/15)
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- One-pot preparation of alkyl iodides from esters by indium-catalyzed reductive cleavage of a carbon-oxygen bond
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We describe the indium-catalyzed reductive iodination of aliphatic and aromatic esters with iodine and 1,1,3,3- tetramethyldisiloxane (TMDS). This reducing procedure accommodates a variety of esters, including esters containing alkyl groups, halogens, a hydroxy group, a thioether, and an alkene moiety. Also, this procedure was applied to the cleavage of carbon-oxygen bonds in acrylate polymers.
- Sakai, Norio,Matsushita, Yohei,Konakahara, Takeo,Ogiwara, Yohei,Hirano, Keisuke
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supporting information
p. 1591 - 1595
(2015/03/04)
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- ANTIBACTERIAL AGENTS
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Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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Page/Page column 105
(2013/12/03)
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- Indium(III)-catalyzed reductive bromination and iodination of carboxylic acids to alkyl bromides and iodides: Scope, mechanism, and one-pot transformation to alkyl halides and amine derivatives
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Highly effective indium(III)-catalyzed reductive bromination or iodination of a variety of carboxylic acids with 1,1,3,3-tetramethyldisiloxane (TMDS) and a source of bromine or iodine is described. This functional group interconversion has high tolerance for several functional groups, such as halogens, a hydroxy group, a nitro group, an olefin part, and a sulfide moiety. This indium catalytic system is also applicable to the reductive iodination of aldehyded, acyl chlorides, and esters. Furthermore, this reducing system can be applied to the one-pot synthesis of alkyl halides and amine derivatives via the addition of nucleophiles. Insight into the reaction mechanism was gained via the time course of 1H and 13C NMR monitoring experiments and the corresponding stepwise reactions.
- Moriya, Toshimitsu,Yoneda, Shinichiro,Kawana, Keita,Ikeda, Reiko,Konakahara, Takeo,Sakai, Norio
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p. 10642 - 10650
(2013/11/19)
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- Indium(III)-catalyzed one-pot synthesis of alkyl cyanides from carboxylic Acids
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The one-pot preparation of alkyl cyanides from carboxylic acids via alkyl iodides or alkyl bromides, which were in situ generated either by indium(III)-catalyzed reductive iodination or bromination of carboxylic acids, is described. Georg Thieme Verlag Stuttgart New York.
- Moriya, Toshimitsu,Shoji, Kohei,Yoneda, Shinichiro,Ikeda, Reiko,Konakahara, Takeo,Sakai, Norio
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p. 3233 - 3238
(2013/12/04)
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- C-LINKED HYDROXAMIC ACID DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS
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The present invention is directed to a new class of hydroxamic acid derivatives, their use as LpxC inhibitors, and more specifically their use to treat bacterial infections.
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Page/Page column 29
(2011/05/05)
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- Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer
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G-quadruplexes are non-canonical DNA secondary structures putatively present in the promoter regions of oncogenes in the human genome. The targeting of promoter G-quadruplex structures to repress oncogene transcription represents a potential anticancer st
- Chan, Daniel Shiu-Hin,Yang, Hui,Kwan, Maria Hiu-Tung,Cheng, Zhen,Lee, Paul,Bai, Li-Ping,Jiang, Zhi-Hong,Wong, Chun-Yuen,Fong, Wang-Fun,Leung, Chung-Hang,Ma, Dik-Lung
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scheme or table
p. 1055 - 1064
(2012/03/22)
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- Removal of sphingosine 1-phosphate receptor-3 (S1P3) agonism is essential, but inadequate to obtain immunomodulating 2-aminopropane-1,3-diol S1P1 agonists with reduced effect on heart rate
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A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P1) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P1 but no agonism at S1P3, which had been reported to be a receptor responsible for heart rate reduction. Although high S1P1/S1P 3 selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P 3 agonism should be responsible for the heart rate reduction caused by S1P1 agonists. Only 2-amino-2-[2-[2′-fluoro-4′-(4- methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P1 receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
- Hamada, Maiko,Nakamura, Mitsuharu,Kiuchi, Masatoshi,Marukawa, Kaoru,Tomatsu, Ayumi,Shimano, Kyoko,Sato, Noriko,Sugahara, Kunio,Asayama, Mahoko,Takagi, Kan,Adachi, Kunitomo
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experimental part
p. 3154 - 3168
(2010/10/03)
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- 2-AMINOBUTANOL COMPOUND AND USE THEREOF FOR MEDICAL PURPOSES
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The present invention provides a novel compound having few side effects such as bradycardia and the like and having superior peripheral blood lymphocyte-decreasing effect. The present invention provides a 2-aminobutanol compound represented by the following formula (I) wherein R1 is a hydrogen atom or P(=O)(OH)2, R2 is an alkyl having 1 to 4 carbon atoms optionally substituted by hydroxyl group(s) or optionally substituted by halogen atom(s), R3 is a hydrogen atom; a halogen atom; cyano; an alkyl having 1 to 4 carbon atoms optionally substituted by halogen atom(s); or an acyl having 2 to 5 carbon atoms optionally substituted by halogen atom(s), X is an oxygen atom, a sulfur atom, carbonyl or NR4 wherein R4 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, Ar1 is an optionally substituted arylene or an optionally substituted heteroarylene, and Ar2 is an optionally substituted aryl or an optionally substituted heteroaryl, provided that when X is an oxygen atom, Ar1 is phenylene and Ar2 is phenyl, then the phenyl for Ar2 should be substituted, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof, as well as a production method of the above-mentioned 2-aminobutanol compound.
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Page/Page column 16-17
(2009/02/10)
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- Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinaseγ
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The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci. 2003, 24, 366]. Of the four type 1 PI3Ks, the γ-isoform, which is expressed almost exclusively in leukocytes [Curr. Biol., 1997, 7, R470], is of particular interest with respect to its role in inflammatory diseases such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) [Mol. Med. Today, 2000, 6, 347]. Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kγ, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration.
- Lanni Jr., Thomas B.,Greene, Keri L.,Kolz, Christine N.,Para, Kimberly S.,Visnick, Melean,Mobley, James L.,Dudley, David T.,Baginski, Theodore J.,Liimatta, Marya B.
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p. 756 - 760
(2007/10/03)
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- BI-ARYL COMPOUND HAVING IMMUNOSUPPRESSIVE ACTIVITY
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The invention is directed to a bi-aryl compound having a unique immunomodulating activity, a process for a preparation thereof, a pharmaceutical composition containing the same, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound to a subject in need of treatment.
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Page/Page column 43; 44
(2010/02/10)
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- 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability
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In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
- Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Kennedy, Joseph H.,Wright, Rebecca A.,Johnson, Bryan G.,Tizzano, Joseph P.,Helton, David R.,Kallman, Mary Jeanne,Schoepp, Darryle D.,Hérin, Marc
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p. 358 - 378
(2007/10/03)
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- Synthesis of (+/-)--9-halogeno-2-methyl-1,2,3,4,4a,5,6,10b,11,12,12a-dodecahydronaphthoisoquinolines
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Treatment of 5-(2-arylethyl)-1,2,3,4,5,6,7,8-octahydroisoquinolines with 48percent HBr resulted in isomerisation of the double bond and subsequent cyclisation at position 6 of the octahydroisoquinoline ring system to give (+/-)--9-halogeno-2-methyl-1,2,3,4,4a,4b,5,6,10b,11,12,12a-dodecahydronaphtho2,1-f>isoquinolines.The products obtained represent novel analogues of aza-D-homoestranes.No reaction was observed with the corresponding 5,5-disubstituted octahydroisoquinolines.An X-ray crystallographic study of compound 10 (X = Br) is described.
- Patrick, Graham L.
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p. 1273 - 1280
(2007/10/02)
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