- Preparation method of remdesivir intermediate 2-ethyl-1-butanol
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The invention relates to a preparation method of a remdesivir intermediate 2-ethyl-1-butanol. The preparation method comprises a step of substitution reaction, namely a step of carrying out a substitution reaction on alkyl acetoacetate and halogenated ethane under an alkaline condition to obtain alkyl 2-ethyl-3-oxo-butyrate; a step of addition reduction, namely a step of carrying out an addition reduction reaction on the alkyl 2-ethyl-3-oxo-butyate to obtain alkyl 2-ethylbutyrate; a step of reduction, namely a step of subjecting the alkyl 2-ethylbutyrate to a reduction reaction to prepare 2-ethyl-1-butanol (I). According to the preparation method of the remdesivir intermediate 2-ethyl-1-butanol, the alkyl acetoacetate and halogenated ethane serve as main raw materials, the raw materials are simple and easy to obtain, the 2-ethyl-1-butanol (I) is prepared through substitution reaction, addition reduction and reduction reaction, the process is simple, economical and environmentally friendly, the product is convenient to obtain, and industrial production of remdesivir bulk drugs is facilitated.
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Paragraph 0051-0052
(2020/08/09)
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- Substituted quinolinone inhibitor
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The invention provides a substituted quinolinone inhibitor and relates to a compound as shown in a formula (II) which is described in the specification or a pharmaceutically acceptable salt, solvate,active metabolite, polymorphic substance, ester, isomer or prodrug thereof, a pharmaceutical composition containing the compound as shown in the formula (II), and application of the compound and the pharmaceutical composition to treatment of diseases related to abnormal TOPK activity.
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Paragraph 0150-0153
(2018/09/08)
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- Asymmetric Aza-Wacker-Type Cyclization of N-Ts Hydrazine-Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters
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We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.
- Kou, Xuezhen,Shao, Qihang,Ye, Chenghao,Yang, Guoqiang,Zhang, Wanbin
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supporting information
p. 7587 - 7597
(2018/06/04)
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- Tunable Aerobic Oxidative Hydroxylation/Dehydrogenative Homocoupling of Pyrazol-5-ones under Transition-Metal-Free Conditions
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A practical and tunable transition-metal-free aerobic oxidation of pyrazol-5-ones preparing either 4-hydroxypyrazoles (via C-H hydroxylation) or bispyrazoles (via dehydrogenative homocoupling) is described. The K2CO3/dioxane reagent system predominately promoted hydroxylation to deliver the α-hydroxylated pyrazoles. In contrast, the formation of bispyrazoles was overwhelmingly preferred with CH3CN as the reaction medium without any additives.
- Sheng, Xuguang,Zhang, Jinlong,Yang, Huameng,Jiang, Gaoxi
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supporting information
p. 2618 - 2621
(2017/05/24)
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- Highly crystalline poly(heptazine imides) by mechanochemical synthesis for photooxidation of various organic substrates using an intriguing electron acceptor – Elemental sulfur
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Low-defect potassium poly(heptazine imide) (PHIK-BM) was engineered for application in photocatalytic oxidation of organic substrates. Mechanochemical pretreatment of a mixture of 5-aminotetrazole in LiCl/KCl eutectics using high-energy ball milling afforded a highly homogeneous mixture that, upon sequential thermolysis at 600?°C, gave nanosized particles of PHIK–BM. The photocatalytic activity of the free-standing PHIK–BM plates was assessed in the oxidation of benzyl alcohol to benzaldehyde under visible light irradiation using elemental sulfur as an electron acceptor. Both quantitative conversion (>99%) of benzyl alcohol and selectivity (>98%) with respect to benzaldehyde were achieved. The developed method was extended to aliphatic alcohol oxidation coupled with multicomponent Hantzsch 1,4-dihydropyridine synthesis. These 1,4-dihydropyridines were also photocatalytically oxidized by PHIK–BM to the corresponding substituted pyridines, with very good yields and under mild metal-free conditions.
- Savateev, Aleksandr,Dontsova, Dariya,Kurpil, Bogdan,Antonietti, Markus
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p. 203 - 211
(2017/05/04)
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- Nano-K2CO3: Preparation, characterization and evaluation of reactive activities
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A novel base, nano-K2CO3, was easily prepared by ultrafine wet milling. The surface properties and the reactive activities of nano-K2CO3 were characterized. It was found that such a base showed higher basicity than normal K2CO3 and could replace sodium (or potassium) alkoxide to carry out monoalkylation and oximation of active methylene compounds. The nano-K2CO3 could be regenarated and reused 10 times without loss of its reactive activity.
- Li, Jun-Zhang,Fan, Shi-Ming,Sun, Xuan-Fei,Liu, Shouxin
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p. 1865 - 1869
(2016/01/20)
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- Synthesis of Potential Bioactive Novel 7-[2-Hydroxy-3-(1,2,3-triazol-1-yl) propyloxy]-3-alkyl-4-methylcoumarins
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A series of 50 novel 7-[2-hydroxy-3-(1,2,3-triazol-1-yl)propyloxy]-3-alkyl-4-methylcoumarins had been designed and synthesized in good to excellent yields via Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction "click chemistry" of 7-(3-azido-2-hydroxypropyloxy)-3-alkyl-4-methylcoumarins with variety of acetylene derivatives. In turn, the precursor compound, that is, 7-(3-azido-2-hydroxypropyloxy)-3-alkyl-4-methylcoumarin, was synthesized by condensation of epichlorohydrin with 7-hydroxy-3-alkyl-4-methylcoumarins followed by opening of the epoxide ring in the resulted 7-epoxymethoxy-3-alkyl-4-methylcoumarins with sodium azide. All the synthesized compounds were unambiguously identified on the basis of their spectral data analyses (IR, 1H-NMR, 13C-NMR spectra, and HRMS).
- Arya, Anu,Kumar, Vinod,Mathur, Divya,Singh, Sukhdev,Brahma, Raju,Singh, Rajpal,Singh, Seema,Sharma,Parmar, Virinder S.,Prasad, Ashok K.
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- Copper(II) triflate catalyzed amination and aziridination of 2-Alkyl substituted 1,3-dicarbonyl compounds
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A method to prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives efficiently from Cu(OTf)2 + 1,10-phenanthroline (1,10-phen)-catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhI=NTs is described. By taking advantage of the orthogonal modes of reactivity of the substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the iminoiodane, amination of the allylic C-H bond of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the amount of the nitrogen source from 1.2 to 2-3 equiv was discovered to result in preferential formal aziridination of the C-C bond of the 2-alkyl substituent of the starting material and formation of the aziridine product.
- Ton, Thi My Uyen,Tejo, Ciputra,Tiong, Diane Ling Ying,Chan, Philip Wai Hong
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experimental part
p. 7344 - 7350
(2012/06/16)
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- Enantioselective synthesis of α-alkyl-β-ketoesters: Asymmetric Roskamp reaction catalyzed by an oxazaborolidinium ion
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Breaking kamp: A catalytic route toward chiral α-alkyl-β- ketoesters using the title reaction of α-alkyl diazoester with aldehydes has been developed (see scheme). The reaction proceeds with high to excellent enantioselectivities and this methodology was applied to a concise two-step synthesis of the natural pheromone sitophilate. Copyright
- Gao, Lizhu,Kang, Byung Chul,Hwang, Geum-Sook,Ryu, Do Hyun
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supporting information; experimental part
p. 8322 - 8325
(2012/09/08)
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- Asymmetric synthesis of β2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives
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Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4- isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium β-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2′-alkylacryloyl)-4-isopropyl-5,5- dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of β-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of β-amino- β′-hydroxy N-acyl oxazolidinones. The Royal Society of Chemistry.
- Beddow, James E.,Davies, Stephen G.,Ling, Kenneth B.,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Thomson, James E.
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p. 2812 - 2825
(2008/03/12)
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- The synthesis of novel crown ethers, part X*, 4-propyl-and 3-ethyl-4-methylchromenone-crown ethers
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Starting from ethyl propionylacetate, and ethyl 2-ethylacetoacetate we prepared 4-propyl-7,8-, 4-propyl-6,7-, 3-ethyl-4-methyl-7,8- and 3-ethyl-4-methyl-6,7-dihydroxy-2H-chromenones which were allowed to react with the bis-dihalides or ditosylates of glycols in DMF/Na2CO3 to afford the 6,7- and 7,8-chromenone derivatives of 12-crown-4, 15-crown-4 and 18-crown-6. The products were identified using ir, 13C and 1H nmr, ms and high resolution mass spectroscopy. The cation selectivities of chromenone crown ethers with Li+, Na+ and K+ cations were estimated from the steady state emission fluorescence spectra of free and cation complexed chromenone macrocyclic ethers in acetonitrile.
- Tiftikci, Esra,Erk, Cakil
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p. 867 - 871
(2007/10/03)
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- A facile synthesis of 3,4-disubstituted-1,2-dihydro-5H-pyrrol-2-ones
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A facile and efficient method for the synthesis of 3,4-disubstituted-1,2- dihydro-5H-pyrrol-2-ones 8a,c-f is reported. The method involves the hydrogenation of cyanohydrins of 2-alkyl-3-oxobutyric acid alkyl esters 1a-f, over Raney Ni at 50 psi to furnish hitherto unknown aminoacetyl intermediates 6a-f in quantitative yields which are cyclised to the targeted compounds.
- Bhandari, Kalpana,Sharma
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p. 2467 - 2470
(2007/10/03)
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- Asymmetric synthesis of 2-substituted butane-1,4-diols by hydrogenation of homochiral fumaramide derivatives
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Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2R)-Oppolzer's sultam was observed by analysis of the 1H NMR spectra of the succinamide mixtures with de's of 77-88%. Reduction of these succinamides using LiAlH4 gave the corresponding (2S)-butane-1,4- diols and established that addition of hydrogen takes place selectively on the re-face of fumaramides 1. The stereoselectivity was confirmed by estimating the ee's from the 19F NMR spectra of the Mosher's diesters of the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.
- Jawaid, Samaila,Farrugia, Louis J.,Robins, David J.
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p. 3979 - 3988
(2007/10/03)
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- Total synthesis of cis and trans-hydroxyglimepiride: Active metabolite of glimepiride
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Syntheses of trans-hydroxyglimepiride 2b, a human metabolite of the blood glucose lowering agent glimepiride 1 and its corresponding cis-stereoisomer 2a, are described.
- Gurjar, Mukund K.,Joshi, Ramesh A.,Chaudhuri, Siddhartha R.,Joshi, Shreerang V.,Barde, Anup R.,Gediya, Lalji K.,Ranade, Prasad V.,Kadam, Suresh M.,Naik, Sanjay J.
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p. 4853 - 4855
(2007/10/03)
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- Use of the Nonionic Superbase P(MeNCH2CH2)3N in the Selective Monoalkylation of Active-Methylene Compounds
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The symmetric active-methylene compounds CH2(CO2Et)2 and CH2[C(O)Me]2 are selectively monoalkylated in the presence of 1.1 equiv of a variety of alkyl halides and 1 equiv of the nonionic Superbase P(MeNCH2CH2)2N in 85-98% yields in 30 min at room temperature. The unsymmetrical active-methylene compound EtO2CCH2C(O)Me is selectively monoalkylated under the same conditions, except for the temperature, which is 0 °C, in 59-88% yields. The observation of selective C- rather than O-alkylation is rationalized in terms of the formation of an enolate whose negatively charged oxygen is sterically protected by a nearby HP(MeNCH2CH2)2N+ counterion in a tight ion pair.
- Arumugam, Subramaniam,McLeod, Dale,Verkade, John G.
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p. 3677 - 3679
(2007/10/03)
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- Diastereoselective Synthesis of Phycocyanobilin-Cysteine Adducts
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Methodology is presented for the synthesis of two diastereomers of a cysteine-linked phycocyanobilin derivative. The crucial reaction is a diastereoselective 1,6-Michael addition of cysteine methyl ester to an appropriate dihydropyrromethenone educt. The diastereomers so generated were then elaborated to two phycocyanobilin trimethyl esters. Definitive assignments of relative stereochemistry, double bond geometry, and solution conformation are accomplished by application of ROESY NMR experiments, while absolute stereochemical assignments are based on degradation to compounds of known chirality.
- Bishop, John E.,Nagy, Jon O.,O'Connell, John F.,Rapoport, Henry
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p. 8024 - 8035
(2007/10/02)
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- Chemo-enzymatic alkylation of active methylene compounds
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Active methylene compounds undergo chemical condensation in water with aldehydes derived from yeast oxidation of the corresponding alcohols. Unsaturated compounds so obtained are then further reduced by yeast.
- Fuganti,Pedrocchi-Fantoni,Servi
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p. 4195 - 4198
(2007/10/02)
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- Photochemistry of 2-azido-2-alkyl-3-oxobutanoic esters and amides
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Photolysis of 2-alkyl-2-azido-3-oxobutanoic esters and amides gave products resulting from alkyl or acyl migration onto nitrogen.The resulting ketimines could be isolated in moderate purity, but the N-acyl imines were rapidly converted into solvation products or enamides (N-acylated dehydroamino acid esters) resulting from double bond migration.Mechanisms for formation of these products are discussed.The N-(2-azido-2-methyl-3-oxobutanoyl) derivative of the diketopiperazine from L-valyl-L-proline gave a stereoisomer of the cyclol tripeptide unit of ergovaline.
- Edwards, Oliver E.,Rank, Werner
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p. 1425 - 1436
(2007/10/02)
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- Stereochemical Control in Microbial Reduction. 9. Diastereoselective Reduction of 2-Alkyl-3-oxobutanoate with Bakers' Yeast
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Bakers' yeast reduces esters of 2-alkyl-3-oxobutanoic acid (CH3COCHRCO2R'; R=methyl, ethyl, propyl, propargyl, and allyl) into the corresponding (S)-hydroxy esters with exclusive stereoselectivity, while the configuration at the 2-position of the hydroxy esters is either S (anti) or R (syn) depending on the structure of the alkoxyl group in the carboalkoxyl moeity of the ester.Oftently, the stereoselectivity with respect to the 2-position is not satisfactory.In general, the reduction of t-butyl esters exerts predominancy in the products, whereas that of 1,1-dimethylpropyl esters exerts the syn predominancy.A marked difference between these two esters in diastereoselectivity is dicussed from the view point of plausible conformations of the esters.
- Nakamura, Kaoru,Miyai, Takehiko,Nagar, Ashish,Oka, Shinzaburo,Ohno, Atsuyoshi
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p. 1179 - 1187
(2007/10/02)
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- The efficiency of diphenylalkylsulfonium salts as alkylating agents
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A series of the title reagents have been used for the alkylation of a number of nucleophiles including iodide, cyanide, thiocyanate and fluoride ions as well as ethyl acetoacetate, phenylacetonitrile and a variety of nitrogen heterocyclic compounds.The results compared favorably with literature methods.
- Badet, Bernard,Julia, Marc,Lefebvre, Christian
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p. 431 - 434
(2007/10/02)
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- EFFET DE SOLVANT SUR SUPPORT SOLIDE: COMPARAISON DE POLYMERES PORTEURS DE MOTIFS HEXAMETHYLPHOSPHOROTRIAMIDE, N-PYRROLIDONE ET N-OXAZOLIDINONE SUR L'ALKYLATION DE L'ENOLATE DE L'ACETYLACETATE D'ETHYLE
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The rate of ethylation by Et2SO4 of potassium enolate of ethylacetoacetate is enhanced in the presence of polymers bearing N-pyrrolidone (P-N.P.) or N-oxazolidone (P-N.O.) moieties.It depends inter alia on the nature of the polymeric skeleton.The C/O alkylation as well as the ratio E/Z of the enol ethers gives an account of the interaction of the enolate with its associated cation inside the polymer: the efficiency is thus: P-HMPA > P-N.P. > P-N.O., although a different order is observed on the reaction rate: P-HMPA > P-N.O. > P-N.P..Thus, this test reaction gives more information on the different interactions involved than the study of rate enhancements of nucleophilic substitutions.
- Nee, Gerard,Seyden-Penne, Jacqueline
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p. 3485 - 3488
(2007/10/02)
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- EFFET DE SOLVANT SUR SUPPORT SOLIDE: REGIOSELECTIVITE DE L'ALKYLATION DES ENOLATES DE L'ACETYLACETATE D'ETHYLE PAR LE SULFATE D'ETHYLE EN PRESENCE DE "HMPT SOLIDE"
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The reaction of Li, Na, K enolates of ethylaceto acetate with diethylsulfate in THF at room temperature gives 60-70percent O-alkylation when performed in presence of one molar equivalent of solid HMPA.Without HMPA, in the same conditions, Li enolate does not react, Na enolate only gives C-alkylation while K enolate leads to 90percent C-alkylation, the reactions being quite slower in the two latter cases.The effects of one molar equivalent of solid and liquid HMPA are compared: for the K enolate the reaction is faster and the degree of O-alkylation higher with solid HMPA; practically no difference is seen for Na enolate, while the reverse is observed with the Li enolate.The cooperative effect of the polymer should thus only work for a sufficiently large cation, as the Li enolate is fixed on the solid HMPA in a larger amount than the K enolate.The study of this reaction is proposed to test the efficiency of other "solid solvents" interacting strongly with cations.
- Nee, Gerard,Leroux, Yves,Seyden-Penne, Jacqueline
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p. 1541 - 1546
(2007/10/02)
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- INFLUENCE DE LA SOLVATATION PAR LE TERT-BUTANOL SUR LA STRUCTURE ET LA REACTIVE DE L'ENOLATE DE POTASSIUM DE L'ACETYLACETATE D'ETHYLE EN PRESENCE DE COURONNE OU DE CRYPTAND. ETUDE PAR SPECTROMETRIE INFRA-ROUGE ET CINETIQE.
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The structure and the nucleophilic reactivity of crowned (18-crown-6) or crypted potassium ethyl acetoacetate enolate have been compared in tert-butanol and in DME (or THF).In the protic solvent tert-butanol, the crowned and the cryptated potassium enolate species both exist as loose ion pairs in which the enolate anion, strongly hidrogen-bonded to the solvent, is in a "transoid" (non chelating) conformation.Both species show similar reactivities towards alkylating agents but completely different reactivities are observed in aprotic weakly dissociating media (THF, DME).In contrast to what is observed in tert-bu tanol, the cryptated species and the crowned species have very different nucleophilic reactivities in THF or DME: in those solvents only the cryptated species retains a loose ion pair structure; the crowned species is a contact ion pair in which the enolate anion chelates the potassium cation.The solvatation of this crowned chelate species by tert-butanol has been demonstrated in binary mixtures of solvents (C6D6-t-BuOH, THF-t-BuOH).The oxygen basicity of the enolate anion is very different in the crowned chelated ion pair compared with the cryptand separated ion pair.
- Sarthou, P.,Bram, G.,Guibe, F.,Corset, J.
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p. 1043 - 1050
(2007/10/02)
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- Regioselectivity of the Alkylation of Ambident Anionic Species on Alumina or in the Presence of 'Solid Hexamethylphosphoric Triamide'
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C-Alkylation of the acetoacetate anions and of sodium naphthoxide is highly favoured on alumina, while O-alkylation of the acetoacetate anion predominates in tetrahydrofuran in the presence of solid hexamethylphosphoric triamide.
- Bram, Georges,Geraghty, Niall,Nee, Gerard,Seyden-Penne, Jacqueline
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p. 325 - 326
(2007/10/02)
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The alkylation of alkali metal and N+Bu4 ethylacetoacetate enolates by means of ethyl iodide, bromide and tosylate has been studied in dimethoxyethane, in order to measure the reactivity of the associated forms. C/O alkylation ratios
- Guibe,Sarthou,Bram
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p. 3139 - 3151
(2007/10/05)
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