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ボリコナゾール

ボリコナゾール 化学構造式
137234-62-9
CAS番号.
137234-62-9
化学名:
ボリコナゾール
别名:
ボリコナゾール;(2R,3S)-2-(2,4-ジフルオロフェニル)-3-(5-フルオロ-4-ピリミジニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール;ボリコナゾール 溶液;ボリコナゾール (JP17)
英語化学名:
Voriconazole
英語别名:
UK-10949;UK-109496;Voricozole;Vorionazole;Voriconzole;VORICONAZOLE;Voriconsrole;Voriconazole RS;Voriconazole tab;Voriconazole USP
CBNumber:
CB1160110
化学式:
C16H14F3N5O
分子量:
349.31
MOL File:
137234-62-9.mol

ボリコナゾール 物理性質

融点 :
127-130°C
比旋光度 :
D25 -62° (c = 1 in methanol)
沸点 :
508.6±60.0 °C(Predicted)
比重(密度) :
1.42±0.1 g/cm3(Predicted)
闪点 :
9℃
貯蔵温度 :
2-8°C
溶解性:
DMSO: >20mg/mL
酸解離定数(Pka):
11.54±0.29(Predicted)
外見 :
white powder
Merck :
14,10033
InChIKey:
BCEHBSKCWLPMDN-MGPLVRAMSA-N
CAS データベース:
137234-62-9(CAS DataBase Reference)
安全性情報
  • リスクと安全性に関する声明
  • 危険有害性情報のコード(GHS)
主な危険性  Xn,T,F
Rフレーズ  22-36/38-52/53-48/22-40-25-61-39/23/24/25-23/24/25-11
Sフレーズ  26-36-45-36/37-22-53-16
RIDADR  UN1230 - class 3 - PG 2 - Methanol, solution
WGK Germany  3
RTECS 番号 UV9145000
国連危険物分類  6.1
容器等級  III
HSコード  29335990
絵表示(GHS)
注意喚起語 Danger
危険有害性情報
コード 危険有害性情報 危険有害性クラス 区分 注意喚起語 シンボル P コード
H225 引火性の高い液体および蒸気 引火性液体 2 危険 P210,P233, P240, P241, P242, P243,P280, P303+ P361+P353, P370+P378,P403+P235, P501
H301 飲み込むと有毒 急性毒性、経口 3 危険 P264, P270, P301+P310, P321, P330,P405, P501
H351 発がんのおそれの疑い 発がん性 2 警告 P201, P202, P281, P308+P313, P405,P501
H361 生殖能または胎児への悪影響のおそれの疑い 生殖毒性 2 警告 P201, P202, P281, P308+P313, P405,P501
H370 臓器の障害 特定標的臓器有害性、単回暴露 1 危険 P260, P264, P270, P307+P311, P321,P405, P501
H373 長期にわたる、または反復暴露により臓器の障 害のおそれ 特定標的臓器有害性、単回暴露 2 警告 P260, P314, P501
H412 長期的影響により水生生物に有害 水生環境有害性、慢性毒性 3 P273, P501
注意書き
P210 熱/火花/裸火/高温のもののような着火源から遠ざ けること。-禁煙。
P260 粉じん/煙/ガス/ミスト/蒸気/スプレーを吸入しないこ と。
P273 環境への放出を避けること。
P280 保護手袋/保護衣/保護眼鏡/保護面を着用するこ と。
P281 指定された個人用保護具を使用すること。
P301+P310 飲み込んだ場合:直ちに医師に連絡すること。
P311 医師に連絡すること。

ボリコナゾール 価格 もっと(11)

メーカー 製品番号 製品説明 CAS番号 包装 価格 更新時間 購入
富士フイルム和光純薬株式会社(wako) W01TOC3760 ボリコナゾール
Voriconazole
137234-62-9 10mg ¥38000 2021-03-23 購入
東京化成工業 V0116 ボリコナゾール >98.0%(HPLC)
Voriconazole >98.0%(HPLC)
137234-62-9 100mg ¥6100 2021-03-23 購入
東京化成工業 V0116 ボリコナゾール >98.0%(HPLC)
Voriconazole >98.0%(HPLC)
137234-62-9 1g ¥30300 2021-03-23 購入
Sigma-Aldrich Japan Y0001395 European Pharmacopoeia (EP) Reference Standard
Voriconazole European Pharmacopoeia (EP) Reference Standard
137234-62-9 ¥35200 2021-03-23 購入
Sigma-Aldrich Japan PHR1892 ボリコナゾール Pharmaceutical Secondary Standard: Certified Reference Material
Voriconazole Pharmaceutical Secondary Standard: Certified Reference Material
137234-62-9 1g ¥35600 2021-03-23 購入

ボリコナゾール 化学特性,用途語,生産方法

外観

白色~ほとんど白色粉末~結晶

用途

カンジダ菌に対し強力な作用を示します。トリアゾール系抗真菌薬作用を示します。

用途

カンジダ属に対し強力な作用を示します。トリアゾール系抗真菌薬作用を示します。

効能

抗真菌薬, エルゴステロール合成阻害薬

商品名

ブイフェンド (ファイザー); ブイフェンド (ファイザー); ブイフェンド (ファイザー)

説明

Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis, candidosis and other emerging fungal infections seen in immuno compromised patients. It can be synthesized in 3 steps by reaction of readily available 6-( 1 -bromoethyl)-4-chloro-5 fluoropyrimidine with I-(2,4-difluorophenyl)-2-(1,2,4-triazol-I-yl) ethanone in the presence of zinc metal. The resulting racemic mixture was submitted to a reductive dechlorination step followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurally related to fluconazole (Pfizer, diflucan?) and acts by inhibiting the cytochrome P450- dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole. In clinical trials, voriconazole was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis and HIV patients with oropharyngeal candidiasis. Voriconazole is available as oral or intravenous formulations. Following oral administration, absorption is rapid and the bioavailability is greater than 80%. Voriconazole exhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and a relatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450 and has a drug interactions potential similar to itraconazole. Voriconazole was generally well tolerated, the most common treatment-related adverse events were transient visual disturbances.

化学的特性

Cyrstalline Solid

Originator

Pfizer (UK)

使用

An antifungal. An Ergosterol Biosynthesis inhibitor

使用

An antifungal (systemic). An ergosterol biosynthesis inhibitor.

使用

antibacterial

使用

Voriconazole is a triazole, antifungal agent that inhibits a broad range of pathogenic yeasts, including Candida (MIC = 0.03-8 μg/ml), and filamentous fungi such as Aspergillus, Scedosporium, and Fusarium. Its inhibitory action results from its ability to inhibit the synthesis of ergosterol, the major sterol of the fungal cell membrane.

定義

ChEBI: A triazole-based antifungal agent used for the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. It is an inhibitor of cytochr me P450 2C9 (CYP2C9) and CYP3A4.

適応症

Voriconazole (Vfend), a derivative of fluconazole, is a second-generation triazole that has improved antifungal activity against Aspergillus and Fusarium spp., P. boydii, Penicillium marneffei, and fluconazole-resistant Candida spp. Like fluconazole, voriconazole has high oral bioavailability and good cerebrospinal fluid penetration, but unlike fluconazole, it undergoes extensive hepatic metabolism and is highly protein bound. No significant amount of bioactive drug is excreted into the urine. Dosage reduction is necessary with severe hepatic insufficiency but not with renal insufficiency.

Manufacturing Process

A solution of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H- 1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (0.307 g, 0.8 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (30 mg) and sodium acetate (0.082 g, 1 mmol). After 5 hours a further 10 mg of 10% palladium-on-charcoal was added and hydrogenation was continued for an additional 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. 'Flash' chromatography of the residue on silica using 97:3 ethyl acetate/methanol as the eluent provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the 2- (2,4-difluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-I-yl)butan- 2-ol enantiomeric pair B, (0.249 g, 89%), m.p. 127°C.
2-(2,4-DifluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol enantiomeric pair A was prepared by a similar method using 3- (4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol, enantiomeric pair A as a starting material. This gave the product with m.p. 137°C.

brand name

Vfend (Pfizer).

Therapeutic Function

Antifungal

抗菌性

The spectrum includes most fungi that cause human disease: dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Pen. marneffei and Spor. schenckii), molds (Aspergillus spp., Fusarium spp. and Scedosporium spp.), dematiaceous fungi and yeasts (Candida spp., Cryptococcus spp. and Trichosporon spp.).

獲得抵抗性

Some fluconazole- and itraconazole-resistant strains of Candida and Aspergillus spp. show reduced susceptibility to voriconazole.

一般的な説明

Voriconazole is a synthetically prepared, broad-spectrum triazole derivative of fluconazole, which shows in vitro activity against many yeasts and a broad-spectrum of mold and dermatophyte isolates. Its mode of action involves the inhibition of cytochrome P450 (CYP)-dependent enzyme, 14-α-sterol demethylase, and hence it is involved in disrupting the cell membrane and terminate the fungal growth.

応用例(製薬)

A synthetic triazole formulated for oral and parenteral use.

生物活性

Triazole antifungal agent. Displays potent activity against Candida , Cryptococcus and Aspergillus species.

Biochem/physiol Actions

Voriconazole is an antifungal used to treat serious fungal infections. Voriconazole inhibits ergosterol synthesis by inhibiting CYP450-dependent 14-α sterol demethylase resulting in a depletion of ergosterol in fungal cell membranes.

薬物動態学

Oral absorption: 96%
Cmax 400 mg oral: c. 2 mg/L after 2 h
Plasma half-life: c. 6 h
Volume of distribution: 4.6 L/kg
Plasma protein binding: 58%
Absorption
Oral absorption is rapid and almost complete, and is unaffected by intragastric pH. In adults, there is a disproportionate increase in blood concentrations with increasing oral and parenteral dosage, due to partial saturation of first-pass metabolism. In children given low dosages of the drug, proportional changes in drug levels are seen.
Distribution
It is widely distributed into body tissues and fluids, including brain and CSF.
Metabolism and excretion
It is extensively metabolized by the liver. More than 80% of a dose appears in the urine, but less than 2% is excreted in unchanged form. It is metabolized by several different hepatic cytochrome P450 enzymes. Some people with point mutations in the genes encoding these enzymes are poor metabolizers while others are extensive metabolizers. Drug levels are as much as four-fold lower in individuals who metabolize the drug more extensively.

臨床応用

Acute and chronic invasive aspergillosis
Serious invasive Candida infections
Serious infections caused by Scedosporium and Fusarium spp.

副作用

Unwanted effects include mild to moderate visual disturbance, rashes, and transient abnormalities of liver enzymes. Rare side effects include life-threatening hepatitis.

Chemical Synthesis

The synthesis of voriconazole is an excellent example of process research. As depicted in the scheme, 5-fluorouracil (229) was chlorinated in both the 2- and 4- positions using a mixture of phosphorus oxychloride and N,N-dimethylaniline at 95° C to afford 230 in 95% yield. Dichloro pyrimidine 230 was reacted with ethyl magnesium bromide to give dihydropyrimidine adduct 231. Adduct 231 was oxidized prior to quenching using a mixture of iodine and TEA in THF to give 2,4-dichloro-6-ethyl-5-fluoro pyrimidine (232) in 75% yield. Reaction of 232 with two equiv of aqueous NaOH at reflux gave selective displacement of the chloro functionality at 4-position. Acidification of the reaction and extraction with DCM gave 2-chloro-6-ethyl-5-fluoro-4(3H)- pyrimidine which was conveniently isolated as its ammonia salt 233. Dechlorination of 233 was achieved using catalytic hydrogenation at 50℃ to provide 234 in 80% yield. Alternatively, 4-fluoro-6-ethyl-5-fluoropyrimidine (234) was prepared in a two-pot process in which methyl 3- oxopentanoate (235) was fluorinated with fluorine gas to give methyl 2-fluoro-3-oxopentanoate (236) in 80-90% yield. This ester was then cyclized with formamidine acetate in the presence of NaOMe to give 234 in a moderate yield (50-70%). Reaction of 234 with phosphorus oxychloride and TEA afforded 4-chloro-6-methyl-5- fluoropyrimidine (237) in 90% yield. Reaction of 237 with NBS in the presence of AIBN initiator provided bromide 238 in 95% yield. A Reformatsky protocol was employed in the condensation of 238 with ketone 239 which was an intermediate in the commercial synthesis of Diflucan. A solution of iodine in THF was added to a slurry of zinc and lead at rt and then a mixture of bromide 238 and ketone 239 were added to the above mixture at 5°C for 30 min. This provided the best diastereomeric selectivity and the ratio of 241 and 240 enantiomeric pair reached approximately 10 to 1. Adduct 241 was de-chlorinated using standard hydrogenation condition (5% w/w Pd on carbon /15 psi hydrogen) to give the racemate of voriconazole. The racemic voriconazole was resolved using (1R)-10-camphorsulfonic acid (242) and crystallization of the required diastereomeric salt provided optically pure voriconazole (28) in 80% yield.

Veterinary Drugs and Treatments

Voriconazole may be a useful treatment for a variety of fungal infections in veterinary patients, particularly against Blastomyces, Cryptococcus, and Aspergillus. It has high oral bioavailability in a variety of species and can cross into the CNS. Currently available human dosage forms are extremely expensive, however, and little clinical experience has occurred using voriconazole in veterinary patients. There is considerable interest in using voriconazole for treating aspergillosis in pet birds as their relative small size may allow the drug to be affordable; additional research must be performed before dosing regimens are available.

予防処置

Significant drug interactions include cyclosporins(increased cyclosporine levels), phenytoin, rifampin,and rifabutin (decreased voriconazole levels). Becauseof its low toxicity profile, this drug may gain importancein the chronic treatment of infections with invasive dimorphicfungi and resistant Candida spp.

ボリコナゾール 上流と下流の製品情報

原材料

準備製品


ボリコナゾール 生産企業

Global( 509)Suppliers
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HubeiwidelychemicaltechnologyCo.,Ltd
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Joyochem Co.,Ltd
+8613290333633 +86-0531-82687558
0531-82687996 sales@joyochem.com;sales@jychem.cc China 28 58
Capot Chemical Co.,Ltd.
+86(0)13336195806 +86-571-85586718
+86-571-85864795 sales@capotchem.com China 20012 60
Beijing Cooperate Pharmaceutical Co.,Ltd
010-60279497
010-60279497 sales01@cooperate-pharm.com CHINA 1817 55
Henan Tianfu Chemical Co.,Ltd.
0371-55170693
0371-55170693 info@tianfuchem.com China 22607 55
Hangzhou FandaChem Co.,Ltd.
008615858145714
+86-571-56059825 fandachem@gmail.com China 9156 55
Nanjing ChemLin Chemical Industry Co., Ltd.
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Hubei XinRunde Chemical Co., Ltd.
+8615102730682
02783214688 bruce@xrdchem.cn CHINA 567 55
Shanxi Naipu Import and Export Co.,Ltd
+8613734021967
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Shanghai Zheyan Biotech Co., Ltd.
18017610038
zheyansh@163.com CHINA 3623 58

137234-62-9(ボリコナゾール)キーワード:


  • 137234-62-9
  • Voriconazole 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
  • Voriconazole solution
  • (2R,3S)-2-(2,4-Difluorophenyl)-3
  • 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan-2-ol
  • 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol
  • Voriconazole, >=98.5%
  • (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
  • Voriconazole(UK 109496)
  • Voriconazole, 98%, a potent and broad-spectrum anti-fungal agent
  • Voriconazole USP
  • Voriconazole tab
  • Voriconazole - Vfend | UK 109496
  • (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-((1H)-1,2,4-triazol-1-yl)-butan-2-
  • Voriconazole≥ 99.9% (HPLC, Dried basis)
  • Voricozole
  • 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl)butan-2-ol
  • VORICONAZOLE
  • (2R,3S/2S,3R)-3-(5-FLUORO-4-PYRIMIDINYL)-2-(2,4-DIFLUOROPHENYL)-1-(1H-1,2,4-TRIA
  • (aR,bS)-a-(2,4-Difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol
  • UK-10949
  • (2R,3S)-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL)BUTAN-2-OL
  • (aR,S)-a-(2,4-Difluorophenyl)-5-fluoro--methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol
  • UK-109496
  • Vorionazole
  • (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol
  • (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-((1H)-1,2,4-triazol-1-yl)-butan-2-ol
  • (R*,S*)-α-(2,4-Difluorophenyl)-5-fluoro-β-Methyl-α-(1H- 1,2,4-triazol-1-ylMethyl)-4-pyriMidineethanol
  • (αR,βS)-α-(2,4-Difluorophenyl)-5-fluoro-β-Methyl-α-(1H-1,2,4-triazol-1-ylMethyl)-4-pyriMidineethanol
  • Voriconazole RS
  • Voriconazole CRS
  • ボリコナゾール
  • (2R,3S)-2-(2,4-ジフルオロフェニル)-3-(5-フルオロ-4-ピリミジニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
  • ボリコナゾール 溶液
  • ボリコナゾール (JP17)
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