- Preparation method of posaconazole intermediate
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The invention discloses a preparation method of a posaconazole intermediate shown as a formula I. According to the method, p-brominated nitrobenzene and anhydrous piperazine are used as raw materials, and a target product is prepared through a condensation reaction, a reduction reaction, a monoacylation reaction, a cyclization reaction and a diazotization hydrolysis reaction. Compared with a synthesis method taking 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine as a starting material in the prior art, the preparation method provided by the invention has the advantages that the raw materials are easy to obtain, the reaction efficiency is high, the reaction conditions are mild, the yield of a target product is high, the operation is simple and convenient, the efficiency is high, and the cost is low.
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- Preparation method of posaconazole
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The invention discloses a preparation method of posaconazole. The preparation method comprises the following steps: in a reaction solvent acetonitrile, carrying out a cyclization reaction on SM1 and SM2 under the action of an organic base namely triethanolamine to generate an intermediate 1; in a reaction solvent dimethyl sulfoxide, carrying out a nucleophilic substitution reaction on the intermediate 1 and SM3 under the action of sodium hydroxide to generate an intermediate 2; and in a reaction solvent hydrochloric acid, removing benzyl from the intermediate 2 to obtain a posaconazole crude product: heating and dissolving the posaconazole crude product, crystallizing, filtering, and drying under reduced pressure to obtain posaconazole. The preparation method has the advantages that the reaction conditions are easy to control, the product yield reaches 98.6%, the product separation and purification are simple and convenient, and the method is suitable for industrial production.
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Paragraph 0057-0065
(2020/09/30)
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- A PROCESS FOR THE MANUFACTURE OF POSACONAZOLE
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The present invention discloses an improved process for the manufacture of Posaconazole, an anti-fungal agent belonging to the category of substituted Tetrahydrofuran Triazole compound. The present invention further describes preparation of formula A and formula B, the key intermediates in the preparation of Posaconazole. The invention also discloses novel intermediates that are useful in the synthesis of Posaconazole.
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Page/Page column 12; 22; 23
(2019/05/10)
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- Synthesis, Crystal Structure, Anti-Bone Cancer Activity and Molecular Docking Investigations of the Heterocyclic Compound 1-((2S,3S)-2-(Benzyloxy)Pentan-3-yl) -4-(4-(4-(4-Hydroxyphenyl)Piperazin-1-yl) Phenyl)-1H-1,2,4-Triazol-5(4H)-One
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Heterocyclic compound 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (1) designed using 4-(4-(4-aminophenyl)piperazin-1-yl)phenol (2) and (S)-N′-(2-(benzyloxy)propylidene)formohydrazide (3) as start materials is successfully obtained via a multistep synthesis and finally characterized by IR, 1H NMR, and single crystal X-ray diffraction. In addition, the in vitro anticancer activities of newly synthesized compound 1 are evaluated against three human bone cancer cell lines U2OS, Saos-2, and GC9811. In addition, the molecular docking is used to study the potential antiviral activity of 1 by calculating the binding sites for the 1AS0 protein.
- Lv,Zhang,Wang,Pan,Liu
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p. 1173 - 1179
(2019/08/12)
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- Intermediate for preparing posaconazole
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The invention discloses an intermediate POP for preparing posaconazole. A structure of the intermediate is as shown in the specification. By using the intermediate to prepare POB, the obtained POB hasa diastereomer content being smaller than or equal to 0.01%, and the total yield of the overall route is relatively high.
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- Preparation method of high-purity posaconazole
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The invention discloses a preparation method of posaconazole, comprising: subjecting BP004b04 and oxalic acid to salt forming to obtain POE; subjecting POE and di-tert-butyl decarbonate to reaction inthe presence of a base to obtain POP, and recrystallizing POP; subjecting POP and POK o reaction in the presence of a base to obtain POR, and removing tert-butyl carbonate protecting group from POR to obtain POS; subjecting the POS to ring closing to obtain POB; subjecting the POB and POA to reaction to obtain posaconazole. Posaconazole prepared via the preparation method has the content of diastereoisomers being /=0.01%, and the overall route has high total yield.
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Paragraph 0043; 0065; 0066; 0072; 0074; 0093; 0094
(2019/06/27)
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- Preparation method of posaconazole intermediate
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The invention discloses a preparation method of a key intermediate POB for preparing posaconazole. Firstly, BP004b04 and oxalic acid are salified to obtain POE; secondly, the POE reacts with di-tert-butyl dicarbonate in the presence of a base to obtain POP, and the POP is recrystallized; thirdly, the POP and POK react with each other in the presence of a base to obtain POR, and POS is obtained after a tert-butyl carbonate protecting group of the POR is removed; finally, the POS is subjected to ring closure to obtain the POB. By means of the method, in the obtained POB, the content of diastereomers is smaller than or equal to 0.01%, and the total yield of the entire route is high.
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- A method of preparing intermediates of posaconazole (by machine translation)
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The invention relates to the field of pharmaceutical chemistry, and in particular relates to a kind of posaconazole intermediate (formula II compound) of the preparation method, the compound is represented by formula III compounds by the reaction of the compound of formula IV, and further explore ways to optimize the preparation method and the purification process, to obtain a simple technology, the product has high purity, high yield, easy industrialization of formula II shown in the preparation method of posaconazole. (by machine translation)
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Paragraph 0043-0082
(2019/01/21)
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- Preparation method of posaconazole important intermediate
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The invention provides a preparation method of a posaconazole important intermediate. A synthesis route is as follows: a formula is shown in the description. The preparation method comprises the specific preparation steps: (1) adding a compound III into an aprotic solvent; in the presence of an acid binding agent, dropwise adding benzyl chloroformate at 0 to 5 DEG C; reacting at 20 DEG C to 25 DEGC for 1h to 8h; after reacting, adding 1 to 5 times of purified water into a reaction system; crystallizing in an ice water bath for 3h to 5h; filtering and drying to obtain a compound II; (2) underthe protection of nitrogen gas, adding the compound II into toluene or ethylene glycol dimethyl ether; then adding the acid binding agent and a compound IV in sequence; carrying out reflowing reactionfor 12h to 48h; after reacting, filtering while the product is hot; crystallizing at 0 to 10 DEG C for 1h to 5h; filtering and drying to obtain the intermediate I.
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Paragraph 0016; 0018
(2018/03/28)
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- Preparation method of posaconazole
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The invention discloses preparation methods of antifungal drug posaconazole shown in the formula as shown in the specification. A first preparation method comprises the following steps: by taking a compound 1 as a raw material, performing amino protection so as to obtain a compound 2, performing reaction on alcohol 3 with a sulfonylation reagent in the presence of alkali to protect hydroxyl so as to obtain a compound 4, performing reaction on an intermediate 2 with triazole under a strong alkali condition so as to obtain an intermediate 5, performing condensation and cyclization with a formylhydrazine derivative 6 under an organic alkali condition so as to obtain a posaconazole key intermediate compound 7, and removing a protection group R2, thereby obtaining posaconazole; a second preparation method comprises the following steps: performing cyclization reaction on the compound 2 with the compound 6 in the presence of organic alkali so as to obtain a compound 8, performing nucleophilic substitution reaction on the compound 8 and the compound 4 under the action of strong alkali so as to obtain a compound 7, and removing the protection group R2, thereby obtaining posaconazole.
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- Preparation method of posaconazole
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The invention discloses a preparation method of posaconazole. The preparation method of the posaconazole provided by the invention comprises the following steps: in the presence of inorganic protonic acid, performing hydrolysis reaction on a compound II to obtain posaconazole I. The preparation method provided by the invention is easy and safe to operate, does not need any special equipment, is free from heavy metal residues, produces less reaction side products, and has high yield; a prepared product has high purity (chiral purity is larger than 99.90 percent, related substance purity is larger than 99.50 percent, all impurities are less than 0.1 percent, and raw materials meet the standard), is low in production cost, is environmentally friendly, and is suitable for industrial production. The formula of the posaconazole is shown in the description.
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- Preparation and separation purification methods of drug intermediate
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The invention provides a preparation method of 1-((2S,3S)-2-(benzyloxy) amyl-3-)-4-(4-(4-(4-hydroxyphenyl) piperazine-1-yl)-1H-1,2,4-triazole-5-(4H) ketone. The preparation method comprises: adding substituted or unsubstituted phenyl chloroformate into a reaction solution of a compound II for reaction for 12 hours at a temperature of -10 to 30 DEG C; and then adding a compound III and an alkali into the reaction system, and heating to 80 to 120 DEG C to continuously carry out reflux reaction for 5-24 hours. In comparison with the prior art, according to the preparation method provided by the invention, the process time is greatly saved, the total yield is improved by 10-15%, the discharge of three wastes is reduced, the energy source and cost are saved, and certain contributions can be generated for reduction of the synthetic cost of an important drug intermediate.
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Paragraph 0072-0078
(2017/03/23)
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- Process for the Preparation of Triazole Antifungal Drug, Its Intermediates and Polymorphs Thereof
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A process for the preparation of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one compound of formula-1, its intermediates and polymorphs thereof. (I)
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Paragraph 0340; 0341; 0342
(2014/12/09)
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- PROCESS FOR PREPARING POSACONAZOLE AND INTERMEDIATES THEREOF
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The present invention relates to an industrially advantageous process for the preparation of tetrahydrofuran antifungals preferably posaconazole of formula I. The present invention further relates to improved processes for preparing key and novel intermediates useful in the preparation of posaconazole. The present invention further relates to improved processes for preparing the compound of formula II, a key intermediate in the preparation of posaconazole.
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Page/Page column 18
(2009/12/27)
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