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1.
J Org Chem ; 88(21): 15367-15373, 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37862607

RESUMO

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

2.
ACS Omega ; 8(19): 17288-17295, 2023 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-37214716

RESUMO

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl3/Al/BF3·OEt2.

3.
Chemistry ; 28(26): e202200474, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35293041

RESUMO

Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated in situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3-1.5 ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O-protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper-mediated ketone synthesis could be applied to the synthesis of not only gluconolactone-derived ketone 6, a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8, a valuable synthetic intermediate for (+)-biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh2 ]- (12), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C-S bond of thioesters to [CuPh2 ]- , while reductive elimination from the CuIII intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]- , the latter reacted with [CuPh]4 (11) to regenerate the reactive diphenylcuprate(I).


Assuntos
Cobre , Cetonas , Catálise , Cobre/química , Ésteres/química , Halogênios , Cetonas/química
5.
Org Lett ; 23(18): 7044-7048, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34432479

RESUMO

An allylic C-H acyloxylation of terminal alkenes with 4-nitrobenzoic acid was assisted by a bidentate-sulfoxide-ligated palladium catalyst combined with 1,4-benzoquinone and Ag2CO3 under mild reaction conditions. The catalytic activity was remarkably enhanced by Ag2CO3 as an additive and 4-nitrobenzoic acid as a carboxylate source; both components were essential to exhibiting high catalytic activity, high branch selectivity, and a wide substrate scope with low loading of the palladium catalyst. Branch-selective allylic acyloxylation of ethyl 7-octenoate (1a) gave the product which was led to ethyl 6,8-dihydroxyoctanoate (5), a useful synthetic intermediate of (R)-α-lipoic acid.

6.
J Org Chem ; 86(11): 7842-7848, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34038109

RESUMO

A catalytic system for regioselective C-H azidation of inactive anilines was developed. In the presence of CuSO4·5H2O, simultaneous addition of NaN3 and Na2S2O8 to aq. CH3CN solution of free anilines under weakly acidic conditions (pH 4.5) smoothly underwent C-H azidation to provide corresponding α-azidated products in high yields. Methyl α-azidoanthranilate obtained by this method was readily transformed via simple reduction followed by cyclization to methyl 2-ethoxybenzimidazol-7-carboxylate, a key intermediate for antihypertensive Candesartan Cilexetil.


Assuntos
Compostos de Anilina , Preparações Farmacêuticas , Anti-Hipertensivos , Catálise , Ciclização
7.
Sci Rep ; 11(1): 7816, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837250

RESUMO

We investigated the relationship between trunk muscle mass and spinal pathologies by gender. This multicenter cross-sectional study included patients aged ≥ 30 years who visited a spinal outpatient clinic. Trunk and appendicular muscle mass were measured using bioelectrical impedance analysis. The Oswestry Disability Index (ODI), visual analog scale (VAS) score for low back pain, sagittal vertical axis (SVA), and EuroQol 5 Dimension (EQ5D) score were investigated to evaluate spinal pathology. The association between trunk muscle mass and these parameters was analyzed by gender using a non-linear regression model adjusted for patients' demographics. We investigated the association between age and trunk muscle mass. We included 781 men and 957 women. Trunk muscle mass differed significantly between men and women, although it decreased with age after age 70 in both genders. Lower trunk muscle mass was significantly associated with ODI, SVA, and EQ5D score deterioration in both genders; its association with VAS was significant only in men. Most parameters deteriorated when trunk muscle mass was < 26 kg in men and < 19 kg in women. Lower trunk muscle mass was associated with lumbar disability, spinal imbalance, and poor quality of life in both genders, with significant difference in muscle mass.


Assuntos
Dor Crônica/epidemiologia , Dor Lombar/epidemiologia , Vértebras Lombares , Músculo Esquelético , Tronco , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Avaliação da Deficiência , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Fatores Sexuais , Escala Visual Analógica
8.
J Org Chem ; 85(19): 12382-12392, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32911934

RESUMO

Nickel- and palladium-catalyzed Fukuyama coupling reactions of a d-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2-bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.


Assuntos
Paládio , Inibidores do Transportador 2 de Sódio-Glicose , Catálise , Ligantes , Níquel
9.
Rapid Commun Mass Spectrom ; 34(7): e8648, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715032

RESUMO

RATIONALE: 25-Hydroxylated vitamin D is the best marker for vitamin D (VD). Due to its low ionization efficiency, a Cookson-type reagent, 1,2,4-triazoline-3,5-dione (TAD), is used to improve the detection/quantification of VD metabolites by liquid chromatography/tandem mass spectrometry (LC/MS/MS). However, the high reactivity of TAD makes its solution stability low and inconvenient for practical use. We here describe the development of a novel caged Cookson-type reagent, and we assess its performances in the quantitative and differential detection of four VD metabolites in serum using LC/MS/MS. METHODS: Caged 4-(4'-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD) analogues were prepared from 4-(4'-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione. Their stability and reactivity were examined. The optimized caged DAPTAD (14-(4-(dimethylamino)phenyl)-9-phenyl-9,10-dihydro-9,10-[1,2]epitriazoloanthracene-13,15-dione, DAP-PA) was used for LC/MS/MS analyses of VD metabolites. RESULTS: The solution stability of DAP-PA in ethyl acetate dramatically improved compared with that of the non-caged one. We measured the thermal retro-Diels-Alder reaction enabling the release of DAPTAD and found that the derivatization reaction was temperature-dependent. We also determined the detection limit and the lower limit of quantifications for four VD metabolites with DAPTAD derivatization. CONCLUSIONS: DAP-PA was stable enough for mid- to long-term storage in solution. This advantage shall contribute to the detection and quantification of VD in clinical laboratories, and as such to the broader use of clinical mass spectrometry.


Assuntos
Compostos de Anilina/química , Espectrometria de Massas em Tandem/métodos , Triazóis/química , Vitamina D/sangue , Vitamina D/metabolismo , 25-Hidroxivitamina D 2/análise , 25-Hidroxivitamina D 2/sangue , 25-Hidroxivitamina D 2/metabolismo , Compostos de Anilina/síntese química , Calcifediol/análise , Calcifediol/sangue , Calcifediol/metabolismo , Cromatografia Líquida , Humanos , Indicadores e Reagentes , Limite de Detecção , Triazóis/síntese química , Vitamina D/análise
10.
Eur Spine J ; 28(5): 914-921, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30729293

RESUMO

STUDY DESIGN: A multicenter cross-sectional study. OBJECTIVES: To clarify the relationship of trunk muscle mass with low back pain, spinal sagittal balance, and quality of life. Few reports have investigated the relationship of trunk muscle mass with lumbar spine function and spinal balance, and the clinical significance of trunk muscle mass remains unclear. METHODS: Patients attending spinal outpatient clinics at 10 different medical institutions were enrolled in this study. Patient demographics, trunk muscle mass and appendicular skeletal muscle mass (ASM) measured by bioelectrical impedance analysis (BIA), body mass index (BMI), Charlson Comorbidity Index (CCI), the Oswestry Disability Index (ODI), visual analog scale (VAS) for low back pain, sagittal vertical axis (SVA), and EuroQol 5 Dimension (EQ5D) score were investigated. Multivariate nonlinear regression analysis was used to investigate the association of trunk muscle mass with the ODI, VAS score, SVA, and EQ5D score. RESULTS: Of 2551 eligible patients, 1738 (mean age 70.2 ± 11.0 years; 781 men and 957 women) were enrolled. Trunk muscle mass was significantly correlated with the ODI, VAS score, SVA, and EQ5D score (P < 0.001) when adjusted for age, sex, BMI, ASM, CCI, and history of lumbar surgery. Patient deterioration was associated with a decrease in trunk muscle mass, and the deterioration accelerated from approximately 23 kg. CONCLUSIONS: Trunk muscle mass was significantly associated with the ODI, VAS score, SVA, and EQ5D score. Trunk muscle mass may assume an important role to elucidate and treat lumbar spinal dysfunction and spinal imbalance. These slides can be retrieved under Electronic Supplementary Material.


Assuntos
Dor Lombar/fisiopatologia , Músculo Esquelético/fisiologia , Equilíbrio Postural/fisiologia , Qualidade de Vida , Coluna Vertebral/fisiologia , Tronco/fisiologia , Idoso , Composição Corporal/fisiologia , Estudos Transversais , Avaliação da Deficiência , Impedância Elétrica , Feminino , Humanos , Masculino , Radiografia , Coluna Vertebral/diagnóstico por imagem , Escala Visual Analógica
11.
Spine (Phila Pa 1976) ; 42(22): 1675-1679, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28422796

RESUMO

MINI: Fourteen hundred consecutive patients were investigated for evaluating the utility of waterless hand rub before orthopaedic surgery. The risk in the surgical site infection incidence was the same, but costs of liquids used for hand hygiene were cheaper and the hand hygiene time was shorter for waterless protocol, compared with traditional hand scrub. STUDY DESIGN: A retrospective cohort study with prospectively collected data. OBJECTIVE: The aim of this study was to compare SSI incidences, the cost of hand hygiene agents, and hand hygiene time between the traditional hand scrub and the waterless hand rub protocols before orthopedic surgery. SUMMARY OF BACKGROUND DATA: Surgical site infections (SSI) prolong hospitalization and are a leading nosocomial cause of morbidity and a source of excess cost. Recently, a waterless hand rub protocol comprising alcohol based chlorhexidine gluconate for use before surgery was developed, but no studies have yet examined its utility in orthopedic surgery. METHODS: Fourteen hundred consecutive patients who underwent orthopedic surgery (spine, joint replacement, hand, and trauma surgeries) in our hospital since April 1, 2012 were included. A total of 712 cases underwent following traditional hand scrub between April 1, 2012 and April 30, 2013 and 688 cases underwent following waterless hand rub between June 1, 2013 and April 30, 2014. We compared SSI incidences within all and each subcategory between two hand hygiene protocols. All patients were screened for SSI within 1 year after surgery. We compared the cost of hand hygiene agents and hand hygiene time between two groups. RESULTS: The SSI incidences were 1.3% (9 of 712) following the traditional protocol (2 deep and 7 superficial infections) and 1.1% (8 of 688) following the waterless protocol (all superficial infections). There were no significant differences between the two groups. The costs of liquids used for one hand hygiene were about $2 for traditional hand scrub and less than $1 for waterless hand rub. The mean hand hygiene time was 264 seconds with the traditional protocol and 160 seconds with the waterless protocol. CONCLUSION: Waterless hand rub with an alcohol based chlorhexidine gluconate solution can be a safe, quick, and cost-effective alternative to traditional hand scrub. LEVEL OF EVIDENCE: 3.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Desinfecção das Mãos/normas , Higienizadores de Mão/administração & dosagem , Procedimentos Ortopédicos/normas , Infecção da Ferida Cirúrgica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos Locais/economia , Economia Hospitalar/normas , Feminino , Desinfecção das Mãos/economia , Desinfecção das Mãos/métodos , Higienizadores de Mão/economia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/economia , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/economia , Infecção da Ferida Cirúrgica/epidemiologia
12.
J Neurosurg Spine ; 26(2): 257-259, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27740393

RESUMO

Chondromas are benign tumors that are rarely located in the spine. The authors present a rare occurrence of a spinal chondroma that developed as an intradural but extramedullary tumor in a 60-year-old woman. The location of the tumor at C4-5 was confirmed by MRI, with hyperintensity on T2-weighted images and isointensity on T1-weighted images. The tumor was completely contained intradurally, with no continuity to any vertebrae. It adhered to the anterior dura, indicative of its likely origin from the dura mater. The tumor was completely resected, with no sign of recurrence after 3 years postoperatively. Although reports of chondromas originating from the dura mater have been previously described, these have all been intracranial tumors. To the best of the authors' knowledge, this is the first report of an intradural chondroma located in the spine. Therefore, chondromas should be considered in the differential diagnosis of intradural spinal tumors.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Condroma/diagnóstico por imagem , Condroma/cirurgia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Dor do Câncer/diagnóstico por imagem , Dor do Câncer/patologia , Dor do Câncer/cirurgia , Vértebras Cervicais/patologia , Condroma/complicações , Condroma/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Cervicalgia/diagnóstico por imagem , Cervicalgia/etiologia , Cervicalgia/patologia , Cervicalgia/cirurgia , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/patologia
13.
J Org Chem ; 76(24): 10198-206, 2011 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-22035509

RESUMO

A highly efficient catalytic system for C-H activation has been worked out that involves inexpensive RuCl(3)·xH(2)O and a specific amount of PPh(3). This procedure has been successfully applied to a practical synthesis of angiotensin II receptor blockers (ARBs). The residual ruthenium that existed in the reaction mixture was thoroughly removed by treatment with properly selected metal scavengers. The new process permits ready access to the important class of drugs in a highly atom-economical and sustainable manner.


Assuntos
Antagonistas de Receptores de Angiotensina/síntese química , Anti-Hipertensivos/síntese química , Losartan/síntese química , Tetrazóis/síntese química , Sais de Tetrazólio/síntese química , Valina/análogos & derivados , Compostos de Bifenilo/química , Catálise , Quelantes/química , Humanos , Espectroscopia de Ressonância Magnética , Rutênio , Valina/síntese química , Valsartana
14.
Spine (Phila Pa 1976) ; 33(16): E573-5, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18628701

RESUMO

STUDY DESIGN: A case report. OBJECTIVE: To describe an unusual case of acute hematoma in the lumbar ligamentum flavum causing foot drop. SUMMARY OF BACKGROUND DATA: There have been several reports of hematoma in the lumbar ligamentum flavum causing compression of the cauda equina and/or nerve root. However, the majority of these cases were chronic hematomas, based on clinical history and histologic findings. METHODS: A 64-year-old man presented with right foot drop of sudden onset and severe sciatica. Magnetic resonance imaging (MRI) on the 10th day after the onset of symptoms revealed spinal stenosis at L4/5 caused by a posterior mass that was isointense on T1-weighted images and hyperintense on T2-weighted images, but was hyperintense on T1-weighted images and hypointense on T2-weighted images 5 days later. Because of these neurologic findings, surgical exploration and excision of the intraspinal mass were performed on the 18th day after onset. RESULTS: Surgical treatment was uneventful, and the severe sciatica improved immediately after surgical treatment. Histologic examination revealed recent extravasation of blood in the degenerated ligamentum flavum. These findings were supported by the 2 consecutive preoperative MRI examinations. At 1 year after surgery, manual muscle testing of the tibialis anterior on the affected side had recovered to grade 4. CONCLUSION: Consecutive MRI examinations performed 5 days apart in the early stage after the onset of symptoms clearly demonstrated intensity change, indicating acute hematoma of ligamentum flavum as a cause of foot drop of sudden onset.


Assuntos
Transtornos Neurológicos da Marcha/diagnóstico , Hematoma/diagnóstico , Ligamento Amarelo/patologia , Vértebras Lombares/patologia , Doença Aguda , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/cirurgia , Hematoma/complicações , Hematoma/cirurgia , Humanos , Ligamento Amarelo/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade
15.
J Clin Neurosci ; 13(6): 694-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16797993

RESUMO

We report a post-traumatic lumbar facet cyst in which results of magnetic resonance imaging (MRI) performed at the time of injury were available. The patient was a 59-year-old man who presented with severe low back and right leg pain immediately after injury of his sacroiliac region in a traffic accident. MRI at the time of injury revealed high intensity signal change in the right facet joint at L4/5. Re-examination 5 months after the injury with MRI revealed a cyst, which was continuous with the facet joint. Surgical resection of the cyst yielded satisfactory results. We describe detailed MRI findings for this case and review the literature on traumatic juxta-facet cyst in the lumbar spine.


Assuntos
Cistos/etiologia , Ferimentos e Lesões/complicações , Articulação Zigapofisária/patologia , Humanos , Região Lombossacral/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Literatura de Revisão como Assunto , Tomografia Computadorizada por Raios X/métodos
16.
Med Res Rev ; 26(4): 434-82, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16676358

RESUMO

Biotin (1), a water-soluble B series vitamin, distributes widely in microorganisms, plants, and animals. Biosynthesis of 1 involves five steps sequence starting from pimelic acid. The last step, a transformation from dethiobiotin (DTB) to 1, includes an iron clusters-mediated radical process. The compound 1 is a cofactor of carboxylation enzymes and plays crucial roles in the metabolism of fatty acids, sugars, and alpha-amino acids. In addition to the increasing application to feed additives, recent reports have revealed that 1 enhances insulin secretion in animals, suggesting it for a promising therapeutic candidate for an anti-diabetes drug. The remarkably strong affinity of 1 with avidin and streptavidin has been extensively applied for such technologies as photoaffinity labeling. Among the number of approaches to 1 so far developed in 50 years, a synthesis using L-cysteine and thiolactone as a starting material and a key intermediate, respectively, represents one of the best routes leading to 1, because of short steps, high yield, use of inexpensive reagents, and ease of operation.


Assuntos
Biotina/química , Biotina/síntese química , Animais , Avidina/química , Biotina/análogos & derivados , Biotina/metabolismo , Catálise , Cisteína/química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ferro/química , Lactonas/química , Modelos Biológicos , Modelos Químicos , Ácidos Pimélicos/química , Rhizobium/metabolismo
17.
Chemistry ; 10(23): 6102-10, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15515067

RESUMO

Alpha-amino aldehyde 4, which is readily derived from L-cysteine through cyclization and elaboration of the carboxy group, was subjected to the Strecker reaction, which, via sodium bisulfite adduct 16, afforded alpha-amino nitrile 5 with high diastereoselectivity (syn/anti=11:1) and in high yield. Amide 6, derived from 5, was converted to thiolactone 8, a key intermediate in the synthesis of (+)-biotin (1), by a novel S,N-carbonyl migration and cyclization reaction. The Fukuyama coupling reaction of 8 with the zinc reagent 21, which has an ester group, in the presence of a heterogeneous Pd/C catalyst allowed the efficient installation of the 4-carboxybutyl chain to provide 9. Compound 9 was hydrogenated and the protecting groups removed to furnish 1 in 10 steps and in 34 % overall yield from L-cysteine.


Assuntos
Biotina/síntese química , Cisteína/química , Biotina/química , Estrutura Molecular , Complexo Vitamínico B/síntese química , Complexo Vitamínico B/química
18.
J Spinal Disord Tech ; 17(4): 343-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15280769

RESUMO

We report a rare case of hemangioblastoma existing in the intradural extramedullary location diagnosed by magnetic resonance imaging (MRI) examination alone. A 46-year-old man gradually developed numbness in his lower extremities. MR images revealed a tumor shadow located posterior to the spinal cord at C5-C7. Small signal void shadows were continuously observed from C1 to C5 in the region cranial to the tumor, indicating the presence of enlarged vessels. Under microscopic observation, the tumor with accompanying vessels was resected totally via hemilaminectomy. The postoperative course was uneventful, and MR images obtained 4 months after the operative procedure demonstrated total removal of the tumor and the abnormal vessels. In this case, recognizing the abnormally enlarged vessels outside the tumor mass preoperatively led us to the correct diagnosis on MR images.


Assuntos
Vértebras Cervicais , Hemangioblastoma/patologia , Imageamento por Ressonância Magnética , Neoplasias da Medula Espinal/patologia , Hemangioblastoma/cirurgia , Humanos , Laminectomia , Masculino , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/cirurgia
19.
J Org Chem ; 69(12): 4216-26, 2004 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-15176851

RESUMO

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.

20.
J Org Chem ; 68(4): 1571-4, 2003 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-12585906

RESUMO

Treatment of thiol esters 1 with zinc reagent 2 in the presence of a small amount (

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