- One-Pot Preparation of C1-Homologated Aliphatic Nitriles from Aldehydes through a Wittig Reaction under Metal-Cyanide-Free Conditions
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A one-pot protocol to obtain C1-homologated aliphatic nitriles was achieved by treating aromatic and aliphatic aldehydes with the (methoxymethyl)triphenylphosphonium ylide followed by hydrolysis of the resulting methyl vinyl ethers with pTsOH (Ts = para-toluenesulfonyl) and treatment with molecular iodine and aqueous ammonia under metal cyanide free conditions. Neopentyl-type nitriles, which could not be obtained by conventional methods that involved conversion of the neopentyl alcohol into a tosylate and treatment with metal cyanide, were successfully obtained by using the present method.
- Ezawa, Masatoshi,Togo, Hideo
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p. 2379 - 2384
(2017/05/01)
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- A 2, 4, 6-Trimethylbenzene acetyl chloride synthesis process
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The invention relates to a synthesis technology for 2, 4, 6-trimethylbenzene acetyl chloride, comprising the following steps of: putting thionyl chloride, a catalyst and 2, 4, 6-trimethylbenzene acetic acid into a reaction kettle in batches, and controlling temperature to carry out reaction; and after the reaction, distilling (high vacuum) in a heating way in the reaction kettle, and acquiring a final product. The preparation method of the 2, 4, 6-trimethylbenzene acetic acid can comprise the following steps of: carrying out chloromethylation reaction by taking trimethylbenzene, formaldehyde and concentrated hydrochloric acid as raw materials, adding toluene to extract after reacting, and washing to obtain a toluene solution of 2, 4, 6-trimethyl benzyl chloride; taking the toluene solution of 2, 4, 6-trimethyl benzyl chloride and the sodium cyanide as raw materials, adding a phase transfer catalyst, reflowing in a heating way to carry out cyanation reaction, washing by adding water after reacting, distilling oil phase to recover toluene and mesitylene, and rectifying to obtain 2, 4, 6-trimethylbenzene acetonitrile; and hydrolyzing the 2, 4, 6-trimethylbenzene acetonitrile, centrifuging to obtain a 2, 4, 6-trimethylbenzeneacetic acid crude product, and optionally selecting and carrying out the aftertreatment to obtain the 2, 4, 6-trimethylbenzeneacetic acid. The content of the 2, 4, 6-trimethylbenzene acetyl chloride synthesized by the method disclosed by the invention is more than or equal to 98.0%, and the content of the 2, 4, 6-trimethylbenzene acetonitrile is less than or equal to 0.5%.
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Paragraph 0064
(2017/02/09)
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- Copper-catalyzed cyanation of benzyl chlorides with non-toxic K 4[Fe(CN)6]
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Copper-based catalysts were firstly introduced into the cyanation of benzyl chlorides with non-toxic K4[Fe(CN)6]. The presented method avoids the use of extremely poisonous alkali cyanides and precious palladium catalysts. No other reagent apart from CuI, K4[Fe(CN) 6] and toluene was used in the cyanation, showing that the presented protocol is simple and practical. A series of benzyl chlorides were smoothly cyanated in up to 85% yield under the optimal conditions.
- Ren, Yunlai,Dong, Chuanhua,Zhao, Shuang,Sun, Yanpei,Wang, Jianji,Ma, Junying,Hou, Chaodong
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supporting information; experimental part
p. 2825 - 2827
(2012/07/17)
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- Pd-catalyzed cyanation of benzyl chlorides with nontoxic K 4[Fe(CN)6]
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Non-toxic K4[Fe(CN)6] was demonstrated to be effective as a green cyanating agent for the cyanation of alkyl halides using PPh3/Pd(OAc)2 as a catalyst system. The presented method allowed a series of benzyl chlorides to be smoothly cyanated in up to 88% yield. In order to avoid or suppress the deactivation of the catalyst, the reaction was required to be performed in a stringent inert ambiance.
- Ren, Yunlai,Yan, Mengjie,Zhao, Shuang,Sun, Yanpei,Wang, Jianji,Yin, Weiping,Liu, Zhifei
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scheme or table
p. 5107 - 5109
(2011/10/05)
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- Palladium-catalyzed cyanomethylation of aryl halides through domino Suzuki coupling-isoxazole fragmentation
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A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester was developed. Mechanistically, the reaction proceeds through (1) Suzuki coupling, (2) base-induced fragmentation, and (3) deformylation as shown by characterization of all postulated intermediates. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 °C) a broad spectrum of aryl bromides could be converted into arylacetonitriles with up to 88% yield.
- Velcicky, Juraj,Soicke, Arne,Steiner, Roland,Schmalz, Hans-Guenther
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supporting information; experimental part
p. 6948 - 6951
(2011/06/19)
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- NOVEL BETA MIMETICS WITH EXTENDED DURATION OF ACTION, METHOD FOR PRODUCTION AND USE THEREOF AS MEDICAMENTS
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The invention relates to compounds of general formula (I), where the groups R1, R2 and R3 can have the meanings given in the claims and the description, method for production and use thereof as medicaments, in particular for the treatment of inflammatory and obstructive bronchial diseases.
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Page/Page column 9
(2010/02/06)
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- Spirodiclofen and spiromesifen - Novel acaricidal and insecticidal tetronic acid derivatives with a new mode of action
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The broad spectrum acaricides spirodiclofen (BAJ2740, trade name: Envidor) and spiromesifen (BSN2060, trade name: Oberon) with an additional excellent activity against whiteflies, both belong to the new chemical class of tetronic acid derivatives discovered at Bayer CropScience during the 1990s. The discovery process starting from herbicidal PPO (protoporphyrinogen oxidase) chemistry, the synthetic routes leading to the products, and some insight into process development of central intermediates is given. Spirodiclofen and spiromesifen have a new mode of action (interference with lipid biosynthesis), show no cross-resistance to any resistant mite or whitefly field population and are therefore valuable tools for resistance management.
- Bretschneider, Thomas,Benet-Buchholz, Jordi,Fischer, Reiner,Nauen, Ralf
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p. 697 - 701
(2007/10/03)
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- N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin
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Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit the activity of endothelin are also provided.
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- Endothelin antagonists: Substituted mesitylcarboxamides with high potency and selectivity for ET(A) receptors
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We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. 3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. 2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ETA selectivity by ~10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has ~10- fold higher ETA binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.
- Wu, Chengde,Decker, E. Radford,Blok, Natalie,Bui, Huong,Chen, Qi,Raju,Bourgoyne, Andree R.,Knowles, Vippra,Biediger, Ronald J.,Market, Robert V.,Lin, Shuqun,Dupré, Brian,Kogan, Timothy P.,Holland, George W.,Brock, Tommy A.,Dixon, Richard A. F.
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p. 4485 - 4499
(2007/10/03)
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- Benzylimidazolines as h5-HT(1B/1D) serotonin receptor ligands: A structure-affinity investigation
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Benzylimidazolines may represent a class of 5-HT(1D) ligands that has yet to be exploited. On the basis of a previous report that the 2- (substituted-benzyl)imidazoline α-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT(1D) receptors, we explored the structure-affinity relationships of a series of related derivatives. Each of the aromatic substituents was removed and then reinstated in a systematic manner to determine the influence of the individual substituents on binding. It was found that all of the aromatic substituents of 8 act in concert to impart high affinity. However, although the 3-hydroxy group could be removed without significantly reducing affinity for h5-HT(1D) (i.e., human 5- HT(1Dα)) receptors, this modification reduced h5-HT(1B) (i.e., human 5- HT(1Dβ)) receptor affinity by nearly 50-fold. The 2,6-dimethyl groups also contribute to binding but seem to play a greater role for h5-HT(1B) binding than h5-HT(1D) binding. With the appropriate structural modifications, several compounds were identified that display 20- to > 100-fold selectivity for h5-HT(1D) versus h5-HT(1B) receptors. Preliminary functional data suggest that these compounds behave as agonists. Given that 5-HT(1D) agonists are currently being explored for their antimigraine action and that activation of h5-HT(1B) receptors might be associated with cardiovascular side effects, h5- HT(1D)selective agents may offer a new lead for the development of therapeutically efficacious agents.
- Law, Ho,Dukat, Malgorzata,Teitler, Milt,Lee, David K. H.,Mazzocco, Lucia,Kamboj, Raj,Rampersad, Vik,Prisinzano, Thomas,Glennon, Richard A.
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p. 2243 - 2251
(2007/10/03)
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- Process for preparing substituted phenylacetic acid derivatives and novel intermediates
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Description here is a novel process for preparing phenyl acetic acid derivatives of the formula (I) in which Ar and R1 are as defined in the description by reaction of sulfonyloxy-activated hydroxyacetic acid derivatives of the formula (II) in which R3 is as defined in the description. with aromatics of the formula (III) has been found. The intermediates of the formula (II), some of which are novel, are obtained from hydroxyacetic acid derivatives by reaction with sulfonyl halides or sulfonic anhydrides. The phenylacetic acid derivatives are important starting materials for preparing pesticides.
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- Diverse photochemistry of sterically congested α-arylacetophenones: ground-state conformational control of reactivity
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The effects of α and ortho substituents on the photoreactivity of various α-(o-tolyl)- and α-mesitylacetophenones have been measured. In general, both types of substitution lower the efficiency of cyclization to 2-indanol derivatives in solution. 1,3-Rearrangement of an α-mesityl group to group to form enol ethers and α-cleavage to radicals compete to various degrees, in some cases becoming dominant. Quenching studies in solution show that all three reactions occur from the same n,π* triplet state; α-substitution lowers rate constants for δ-hydrogen abstraction and increases those for α-cleavage and 1,3-rearrangement. X-ray crystal analysis and MMX calculations both show that any additional substitution at the α-carbon of α-aryl (phenyl, tolyl, or mesityl) ketones favors conformers in which the α-aryl group have rotated 120° away from eclipsing the carbonyl. In agreement with this, α-phenyl and α-(o-tolyl) ketones undergo γ-hydrogen abstraction (Norrish type II reaction) with rate constants almost as large as those of the nonarylated ketones. NMR line-broadening studies show that, in most of the α-mesityl ketones, the rate constants for rotation around the mesityl-α-carbon bond (104-106 s-1) are much slower than triplet decay. The same is true for rotations around the carbonyl-α-carbon bond in the α-arylisobutyrophenones. Considered of the spectroscopic evidence, triplet lifetimes, and calculated rotational barriers indicates that ground-state conformational preferences determine which excited-state reactions can occur in most of these ketones. Many of the ketones that cyclize in low yield in solution do so in much higher yield when irradiated as solids, presumably because α-cleavage to radicals becomes mostly revertible. The solid-state reactivity demonstrates that hydrogen abstraction can occur from what are supposedly nonideal geometries; in particular, large values (60-70°) for the dihedral angle and rate constants for hydrogen abstraction in solution plane of the carbonyl π system. The relationship between this angle and rate constants for hydrogen abstraction in solution is discussed. Rate constants for α-cleavage reveal the separate influences of steric congestion and conjugation of the developing benzyl radicals. The 1,3-aryl migration to oxygen appears to arise from initial CT complexation of the α-aryl to the carbonyl; subsequent bonding of oxygen to the benzene ring apparently relieves steric congestion. The 50:50 initial mixture of Z and E enol ethers suggests that the rearrangement is adiabatic, generating enol ether in its twisted triplet state. A large enhancement of indanol yields by alcoholic solvents is suggested to involve protonation of the same CT complex.
- Wagner, Peter J.,Zhou, Boli,Hasegawa, Tadashi,Ward, Donald L.
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p. 9640 - 9654
(2007/10/02)
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- Antihypertensive Activity of 6-Arylpyridopyrimidin-7-amine Derivatives
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A series of 51 6-arylpyridopyrimidin-7-amine derivatives was prepared and evaluated for antihypertensive activity in the conscious spontaneously hypertensive rat.A number of these compounds, notably 6-(2,6-dichlorophenyl)-2-methylpyridopyrimidin-7-amine (36), lowered blood pressure in these rats in a gradual and sustained manner to normotensive levels at oral doses of 10-50 mg/kg.Normalized blood pressure levels could then be maintained by single daily oral doses.The effect of structural variation in the 6-aryl group and in the 2 and 4 positions of the pyridopyrimidine ring on activity is reported and discussed.
- Bennett, Lawrence R.,Blankley, C. John,Fleming, Robert W.,Smith, Ronald D.,Tessman, Deirdre K.
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p. 382 - 389
(2007/10/02)
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