CN106866459A - A kind of preparation method of antifungal drug intermediate - Google Patents
A kind of preparation method of antifungal drug intermediate Download PDFInfo
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- CN106866459A CN106866459A CN201710204769.9A CN201710204769A CN106866459A CN 106866459 A CN106866459 A CN 106866459A CN 201710204769 A CN201710204769 A CN 201710204769A CN 106866459 A CN106866459 A CN 106866459A
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- preparation
- hydrazine
- ethyl
- benzyloxies
- antifungal drug
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/76—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
Abstract
It is that raw material carries out condensation reaction with formoxyl hydrazine with compound (A) in organic solvent the invention discloses a kind of preparation method of antifungal drug intermediate；The reactant of the condensation reaction is carried out into purification and is prepared into 2 [the benzyloxy propylidene of 1 ethyls of 2S 2] hydrazine formaldehyde (B) intermediates.Reaction condition is gentle, is conducive to step to shorten, reduces supplies consumption, waste also relative reduction, reduces production cost, is conducive to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, and in particular to a kind of preparation of antifungal drug intermediate
Method.
Background technology
Posaconazole (posaconazole) was the derivative of Itraconazole, in the second generation three in FDA listings in 2006
Triazole antifungal agent thing.Chemical entitled 4- [4- [4- [4- [[(3R, 5R) -5- (the 2,4- difluoros of posaconazole (posaconazole)
Phenyl) ring -3- bases of -5- (1,2,4- triazol-1-yls methyl) oxa- penta] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2-
[the amyl- 3- yls of (2S, 3S) -2- hydroxyls] -1,2,4- triazole -3- ketone, has a broad antifungal spectrum, for Mycotoruloides, Histoplasma capsulatum,
Fill in many pityrosporion ovales, bipolar bacterium zygomycete, sickle-like bacteria, saccharomycete.Non-white beads bacterial strain including resistance to Fluconazole, Cryptococcus neoformans
There is powerful inhibitory activity with Aspergillus；Especially to relatively rarer but life-threatening fungal disease (zygomycosis, sickle
Knife bacterium disease and coccidioidomycosis etc.) it is also effective.Therefore be mainly used in it is various anphotericin is not resistant to or it is intractable adult invade
The treatment and prevention of attacking property fungal infection.
It is main in the prior art to be synthesized using intermediate I and intermediate II, the chemistry side of the intermediate I and intermediate II
Formula is as follows：
Wherein, 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde is important as one of synthetic intermediate II
Intermediate, occupies significant cost, and formula (1) is 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde as conjunction
Into the reactional equation of intermediate II.
The technique of existing synthesis 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde needs ultralow temperature, is difficult to control,
Obtained through multistep reaction, route is long, consumed and discarded all higher.Formula (2) is existing synthesis 2- [(1S, 2S) -1- ethyls -2-
Benzyloxy propyl group] hydrazine formaldehyde technique：
The content of the invention
The technical problems to be solved by the invention are existing synthesis 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine first
The technique of aldehyde, obtains through multistep reaction, and route is long, consumes and discarded all higher, it is therefore intended that provide a kind of antifungal drug
The preparation method of intermediate, a kind of centre for preparing 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde of synthesis
Body, reaction condition is gentle, is conducive to step to shorten, reduces supplies consumption, waste also relative reduction, reduces production cost, favorably
In industrialized production.
The present invention is achieved through the following technical solutions：
A kind of preparation method of antifungal drug intermediate, in organic solvent, with compound (A) as raw material and formoxyl
Hydrazine carries out condensation reaction；The reactant of the condensation reaction is carried out into purification and is prepared into 2- [2S-1- ethyl -2- benzyloxies Asias third
Base] hydrazine formaldehyde (B) intermediate；The condensation reaction equation is：
Preferably, the temperature of the condensation reaction is 20~25 DEG C, and the reaction time is 4~6h.
Preferably, the purification step specifically includes successively：
Carry out being concentrated under reduced pressure into solvent-free steaming under the temperature conditionss less than 50 DEG C；
Ethyl acetate is added in concentrate to the step 1, after being stirred 2h under 20~25 DEG C of temperature conditionss
Carry out suction filtration treatment；
Filter cake is washed with ethyl acetate again, it is then that the filtrate after the suction filtration and the ethyl acetate of cleaning solution is molten
Liquid is merged, and carries out being concentrated under reduced pressure into ethyl acetate being evaporated under the temperature conditionss less than 40 DEG C；
Then to petroleum ether is added in concentrate system, 2h is stirred under 20~25 DEG C of temperature conditionss and separates out solid
Afterwards, suction filtration treatment is carried out；
Using petroleum ether filter cake, then it is vacuum dried, is prepared into 2- [2S-1- ethyl -2- benzyloxies Asias third
Base] hydrazine formaldehyde (B) intermediate.
Preferably, the organic solvent is methyl alcohol, isopropanol, toluene or tetrahydrofuran.
Preferably, 2- [2S-1- ethyl -2- benzyloxies propylidene] the hydrazine formaldehyde (B) is used to synthesize by reduction reaction
2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM) intermediate.Reaction equation is：
Preferably, the reduction reaction step includes：In organic solvent, catalyst Rh- [(I)-(R, R)-BDPCH] 24
In the presence of, 2- [2S-1- ethyl -2- benzyloxies propylidene] the hydrazine formaldehyde (B) and sodium borohydride carry out reduction reaction；By institute
State reduction reaction product and carry out purification and be prepared into 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM) intermediate.
Specifically, 2- [2S-1- ethyl -2- benzyloxies propylidene] the hydrazine formaldehyde (B) is used to synthesize by reduction reaction
The step of 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM) intermediate, includes following：
The reduction reaction temperature is -10~20 DEG C, and the reaction time is 3h；It is preferred that reduction reaction temperature is 5~15 DEG C；
The purification step specifically includes successively：
To the organic solution that sodium borohydride is added dropwise in the reduction reaction product, pressurizeed under the temperature conditionss less than 50 DEG C
It is concentrated into solvent-free steaming；
To water and methyl tertiary butyl ether(MTBE) is added in the concentrate, it is stirred under 10~20 DEG C of temperature conditionss, is treated
Liquid is divided to form water phase and organic phase；
To methyl tertiary butyl ether(MTBE) stir process is added in the water phase, treat to divide liquid to form water phase and organic phase again；
After the organic phase divided twice after liquid treatment is merged, it is dried using anhydrous sodium sulfate；
Then prepared grease 2- [(1S, 2S) -1- ethyls -2- concentrated under reduced pressure are carried out under the temperature conditionss less than 50 DEG C
Benzyloxy propyl group] hydrazine formaldehyde (TM) intermediate.
The present invention compared with prior art, has the following advantages and advantages：
A kind of preparation method of antifungal drug intermediate of the present invention, existing synthesis 2- [(1S, 2S) -1- ethyl -2- benzyloxies
Base propyl group] hydrazine formaldehyde technique, obtained through multistep reaction, route is long, consumption and discarded all higher, it is therefore intended that provide a kind of
The preparation method of antifungal drug intermediate, synthesis is a kind of for preparing 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine
The intermediate of formaldehyde, reaction condition is gentle, is conducive to step to shorten, reduces supplies consumption, waste also relative reduction, reduces production
Cost, is conducive to industrialized production.
Specific embodiment
To make the object, technical solutions and advantages of the present invention become more apparent, with reference to embodiment, the present invention is made
Further to describe in detail, exemplary embodiment of the invention and its explanation are only used for explaining the present invention, are not intended as to this
The restriction of invention.
Embodiment 1
A kind of preparation method of antifungal drug intermediate of the present invention, synthesis 2- [2S-1- ethyl -2- benzyloxies propylidene]
Hydrazine formaldehyde (B's) concretely comprises the following steps：
Dissolving is stirred during 8.2g formoxyls hydrazine first is added into 60mL methyl alcohol, 0~5 DEG C is cooled to, by 20g compounds
(A) it is dissolved in 50mL dichloromethane and is then added in the methanol solution system of formoxyl hydrazine, be to slowly warm up to 20~25 DEG C, protects
4~6h of reaction temperature is held, it is complete to reacting.Reaction solution is carried out under the temperature conditionss less than 50 DEG C be concentrated under reduced pressure into solvent-free
Steam；To 45mL ethyl acetate is added in concentrate system, 2h is stirred under 20~25 DEG C of temperature conditionss；Suction filtration treatment is carried out, then
Filter cake is washed with 5mL ethyl acetate, finally by the ethyl acetate washing after ethyl acetate concentrate after concentration and washing
After liquid is closed, the ethyl acetate that is concentrated under reduced pressure under the temperature conditionss less than 40 DEG C is to dry；Again to adding 50mL in concentrate system
Petroleum ether, stirs 2h, solid to be separated out under 20~25 DEG C of temperature conditionss, then carries out suction filtration treatment, finally uses 10mL petroleum ethers
Washing filter cake, the filter cake after washing is vacuum dried under 30 DEG C of temperature conditionss, is prepared into 19.3g off-white powder 2- [2S-1-
Ethyl -2- benzyloxies propylidene] hydrazine formaldehyde (B), yield 79%, HPLC 98%.
2- [2S-1- ethyl -2- benzyloxies propylidene] hydrazine formaldehyde (B) be used for synthetic intermediate 2- [(1S, 2S) -1- ethyls -
2- benzyloxies propyl group] hydrazine formaldehyde (TM) the step of be specially；
12g 2- [2S-1- ethyl -2- benzyloxies propylidene] hydrazine formaldehyde (B) is weighed to be stirred in being added to 60mL isopropanols
Dissolving is mixed, 0.4g catalyst Rh- [(I)-(R, R)-BDPCH] 24 is added；It is subsequently cooled under the conditions of 0~5 DEG C, is slowly added dropwise
Dissolved with the aqueous isopropanol of 2.45g sodium borohydrides, controlling reaction temperature is 5~15 DEG C, detects that reaction is complete after reaction 3h.To institute
State and be slowly added dropwise in reaction system 20mL acetone, control temperature is less than 20 DEG C；Then pressurizeed under the temperature conditionss less than 50 DEG C
Concentration is steamed to solvent-free；To addition 100mL water and 50mL methyl tertiary butyl ether(MTBE)s in concentrate in 10~20 DEG C of temperature strips
0.5h is stirred under part, 30mL methyl tertiary butyl ether(MTBE)s stirring 0.5h is added after point liquid forms water phase and organic phase, in Xiang Shuixiang, then
Secondary point of liquid forms water phase and organic opposite；The organic phase that merging divides after liquid treatment twice, is dried using 5g anhydrous sodium sulfates,
Be concentrated under reduced pressure to obtain 9.1g grease 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde under less than 50 DEG C of temperature conditionss
(TM), HPLC 95%, EE98%.
Above-described specific embodiment, has been carried out further to the purpose of the present invention, technical scheme and beneficial effect
Describe in detail, should be understood that and the foregoing is only specific embodiment of the invention, be not intended to limit the present invention
Protection domain, all any modification, equivalent substitution and improvements within the spirit and principles in the present invention, done etc. all should include
Within protection scope of the present invention.
Claims (6)
1. a kind of preparation method of antifungal drug intermediate, it is characterised in that in organic solvent, is original with compound (A)
Material carries out condensation reaction with formoxyl hydrazine；The reactant of the condensation reaction is carried out into purification and is prepared into 2- [2S-1- ethyls -2-
Benzyloxy propylidene] hydrazine formaldehyde (B) intermediate；The condensation reaction equation is：
2. the preparation method of a kind of antifungal drug intermediate according to claim 1, it is characterised in that the condensation is anti-
The temperature answered is 20~25 DEG C, and the reaction time is 4~6h.
3. a kind of preparation method of antifungal drug intermediate according to claim 1, it is characterised in that the purification step
Suddenly specifically include successively：
Carry out being concentrated under reduced pressure into solvent-free steaming under the temperature conditionss less than 50 DEG C；
Ethyl acetate is added in concentrate to the step 1, is carried out after being stirred 2h under 20~25 DEG C of temperature conditionss
Suction filtration treatment；
Filter cake is washed with ethyl acetate again, then enters the filtrate after the suction filtration and the ethyl acetate solution of cleaning solution
Row merges, and carries out being concentrated under reduced pressure into ethyl acetate being evaporated under the temperature conditionss less than 40 DEG C；
Then to petroleum ether is added in concentrate system, after 2h precipitation solids are stirred under 20~25 DEG C of temperature conditionss, enter
The treatment of row suction filtration；
Using petroleum ether filter cake, then it is vacuum dried, is prepared into 2- [2S-1- ethyl -2- benzyloxies propylidene] hydrazine
Formaldehyde (B) intermediate.
4. the preparation method of a kind of antifungal drug intermediate according to claim 1, it is characterised in that described organic molten
Agent is methyl alcohol, isopropanol, toluene or tetrahydrofuran.
5. a kind of preparation method of antifungal drug intermediate according to claim 1, it is characterised in that the 2- [2S-
1- ethyl -2- benzyloxies propylidene] hydrazine formaldehyde (B) be used for by reduction reaction synthesis 2- [(1S, 2S) -1- ethyl -2- benzyloxies
Propyl group] hydrazine formaldehyde (TM) intermediate.
6. the preparation method of a kind of antifungal drug intermediate according to claim 5, it is characterised in that the reduction is anti-
Answering step includes：In organic solvent, in the presence of catalyst Rh- [(I)-(R, R)-BDPCH] 24,2- [the 2S-1- second
Base -2- benzyloxies propylidene] hydrazine formaldehyde (B) and sodium borohydride carry out reduction reaction；The reduction reaction product is purified
It is prepared into 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM) intermediate.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5625064A (en) * | 1995-04-19 | 1997-04-29 | Schering Corporation | Process for the preparation of triazolones |
| JP2001064244A (en) * | 1999-08-30 | 2001-03-13 | Mitsubishi Chemicals Corp | Reduction of optically active imine derivative |
| CN1073109C (en) * | 1995-06-02 | 2001-10-17 | 先灵公司 | Tetrahydrofuran antifungals |
| WO2013155218A1 (en) * | 2012-04-11 | 2013-10-17 | The Johns Hopkins University School Of Medicine | Chirally pure isomers of itraconazole for use as angiogenesis inhibitors |
| CN105392364A (en) * | 2013-06-07 | 2016-03-09 | 加州生物医学研究所 | Small molecule inhibitors of fibrosis |
| CN105461644A (en) * | 2014-09-05 | 2016-04-06 | 上海欣生源药业有限公司 | Preparation and separation purification methods of drug intermediate |
-
2017
- 2017-03-30 CN CN201710204769.9A patent/CN106866459A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5625064A (en) * | 1995-04-19 | 1997-04-29 | Schering Corporation | Process for the preparation of triazolones |
| CN1073109C (en) * | 1995-06-02 | 2001-10-17 | 先灵公司 | Tetrahydrofuran antifungals |
| JP2001064244A (en) * | 1999-08-30 | 2001-03-13 | Mitsubishi Chemicals Corp | Reduction of optically active imine derivative |
| WO2013155218A1 (en) * | 2012-04-11 | 2013-10-17 | The Johns Hopkins University School Of Medicine | Chirally pure isomers of itraconazole for use as angiogenesis inhibitors |
| CN105392364A (en) * | 2013-06-07 | 2016-03-09 | 加州生物医学研究所 | Small molecule inhibitors of fibrosis |
| CN105461644A (en) * | 2014-09-05 | 2016-04-06 | 上海欣生源药业有限公司 | Preparation and separation purification methods of drug intermediate |
Non-Patent Citations (2)
| Title |
|---|
| VITALI I.TARAROV等: "Phosphines versus phosphinites as ligands in the rhodium catalyzed asymmetric hydrogenation of imines: a systematic study", 《TETRAHEDRON: ASYMMETRY》 * |
| 靳凤民，张静: "泊沙康唑的合成", 《中国新药杂志》 * |
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Application publication date: 20170620 |