CN106986787A - A kind of synthetic method of posaconazole intermediate - Google Patents
A kind of synthetic method of posaconazole intermediate Download PDFInfo
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- CN106986787A CN106986787A CN201710204742.XA CN201710204742A CN106986787A CN 106986787 A CN106986787 A CN 106986787A CN 201710204742 A CN201710204742 A CN 201710204742A CN 106986787 A CN106986787 A CN 106986787A
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- synthetic method
- posaconazole
- posaconazole intermediate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/04—Preparation of hydrazides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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Abstract
The invention discloses a kind of synthetic method of posaconazole intermediate; the posaconazole intermediate is 2 [(1S; 2S) the benzyloxy propyl group of 1 ethyl 2] hydrazine formaldehyde (TM); condensation reaction is carried out in having solvent by using compound (A) and formoxyl, condensation reaction thing is carried out into purification processes is made solid chemical compound (B)；In organic solvent, at catalyst Rh [(I) (R, R) BDPCH]24In the presence of, the compound and reducing agent sodium borohydride carry out reduction reaction, and intermediate 2 [the benzyloxy propyl group of (1S, 2S) 1 ethyl 2] hydrazine formaldehyde (TM) is prepared into after reaction product is carried out into purification processes；A kind of synthetic method for posaconazole intermediate that the present invention is provided, uses enzymatic, mild condition, and step shortens, and 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 synthesis side of posaconazole intermediate
Method.
Background technology
Posaconazole (posaconazole) is the derivative of Itraconazole, the second generation three listed in 2006 in FDA
Triazole antifungal agent thing.Chemical entitled 4- [4- [4- [4- [[(3R, 5R) -5- (the 2,4- difluoros of posaconazole (posaconazole)
Phenyl) penta ring -3- bases of -5- (1,2,4- triazol-1-yls methyl) oxa-] 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 a variety of 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 that 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde is used as conjunction
Into the reactional equation of intermediate II.
Specifically, the technique of existing synthesis 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde needs ultralow temperature, no
It is easy to control, obtain, route is long, consume and discarded all higher through multistep reaction.Formula (2) is existing synthesis 2- [(1S, 2S) -1-
Ethyl -2- benzyloxies propyl group] hydrazine formaldehyde technique：
In formula (2), the corresponding compounds of label TM are 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde.
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, is obtained through multistep reaction, and route is long, is consumed and discarded all higher, it is therefore intended that provide in a kind of posaconazole
The synthetic method of mesosome, uses enzymatic, mild condition, and step shortens, and reduces supplies consumption, waste also relative reduction, reduction
Production cost, is conducive to industrialized production.
The present invention is achieved through the following technical solutions：
A kind of synthetic method of posaconazole intermediate, the posaconazole intermediate is 2- [(1S, 2S) -1- ethyls -2-
Benzyloxy propyl group] hydrazine formaldehyde (TM), condensation reaction is carried out in having solvent by using compound (A) and formoxyl, will be condensed
Reactant carries out purification processes and solid chemical compound (B) is made；In organic solvent, catalyst Rh- [(I)-(R, R)-
BDPCH]24In the presence of, the compound and reducing agent sodium borohydride carry out reduction reaction, and reaction product is carried out into purification processes
After be prepared into intermediate 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM)；Reaction equation is：
Wherein, catalyst Rh- [(I)-(R, R)-BDPCH]24For existing catalyst.
Preferably, the organic solvent is methanol, isopropanol, toluene or tetrahydrofuran.
Preferably, the volume of the organic solvent is 4~10 times of the volume of dissolved raw material.
Preferably, the volume of the organic solvent is 5~6 times of the volume of dissolved raw material.
Preferably, the temperature of the condensation reaction is 20~25 DEG C, and the reaction time is 4~6h.
Preferably, the temperature of the reduction reaction is -10~20 DEG C, and the reaction time is 3h.
Preferably, the temperature of the reduction reaction is 5~15 DEG C.
Preferably, the addition of the catalyst is the 1% of the amount of the material of starting compound (B).
Preferably, condensation reaction products progress purification processes step is included successively：
First solvent-free steam is concentrated under reduced pressure under less than 50 DEG C temperature conditionss；
Then ethyl acetate is added to the system after decompression, is stirred under 20~25 DEG C of temperature conditionss, suction filtration；Acetic acid is used again
Ethyl ester carries out washing operation, combined ethyl acetate filtrate；
The filtrate decompression is concentrated into ethyl acetate under less than 40 DEG C temperature conditionss to be evaporated；
Petroleum ether is added in system after concentration, is stirred under 20~25 DEG C of temperature conditionss, solid is separated out, suction filtration behaviour is carried out
Make, then use petroleum ether filter cake；
The filter cake is dried in vacuo, compound as white solid (B) is made.
Preferably, reduction reaction product progress purification processes step is included successively：
Produced first to reduction reaction in product and be added dropwise to acetone, pressurization is concentrated into solvent-free under less than 50 DEG C temperature conditionss
Steam；
Water and methyl tertiary butyl ether(MTBE) are added into the concentrate, is stirred under 10~20 DEG C of temperature conditionss, is treated point
Aqueous phase and organic phase are formed after liquid；
First add and be stirred under methyl tertiary butyl ether(MTBE) stirring, 10~20 DEG C of temperature conditionss to aqueous phase, treat further to divide liquid
Form aqueous phase and organic phase；
Merge organic phase, using anhydrous sodium sulfate drying, the oily that is concentrated under reduced pressure to obtain is carried out under less than 50 DEG C temperature conditionss
Thing intermediate 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM).
The present invention compared with prior art, has the following advantages and advantages：
A kind of synthetic method of posaconazole intermediate of the present invention, original synthetic intermediate 2- [(1S, 2S) -1- ethyls -2-
Benzyloxy propyl group] technique of hydrazine formaldehyde (TM) needs ultralow temperature, it is difficult to control, step is long, and spent material is more, and waste is also more.And
The new technology of the decorum of the present invention uses enzymatic, mild condition, and step shortens, and reduces supplies consumption, waste also relative reduction, has
Beneficial to industrialized production, production cost is reduced.In addition, the method that the present invention is provided can be additionally used in imines reduction hand-type control,
For the reduction hand-type control of hydrazone class formation.
Embodiment
For the object, technical solutions and advantages of the present invention are more clearly understood, with reference to embodiment, to present invention work
Further to describe in detail, exemplary embodiment and its explanation of the invention is only used for explaining the present invention, is not intended as to this
The restriction of invention.
Embodiment 1
A kind of synthetic method of posaconazole intermediate of the present invention, is comprised the following steps that：
(1) compound (B), the i.e. synthesis of 2- [2S-1- ethyl -2- benzyloxies propylidene] hydrazine formaldehyde are first synthesized；
8.2g formoxyls hydrazine is added in 60mL methanol and is stirred dissolving, 0~5 DEG C is cooled to；Then by 20g compounds
(A) 50mL dichloromethane is dissolved in, and the dichloromethane solution of compound (A) is added in the methanol solution of formoxyl hydrazine, is delayed
Slowly 20~25 DEG C are warming up to, keep 4~6h of this temperature, it is complete to reacting.It is concentrated under reduced pressure under the temperature conditionss less than 50 DEG C
It is solvent-free to steam, 45mL ethyl acetate is added into the system after concentration, 2h is stirred under 20~25 DEG C of temperature conditionss, is then taken out
Filter is handled, then carries out washing filter cake with 5mL ethyl acetate, finally merges the ethyl acetate filtrate after washing twice, 40 DEG C with
Under temperature conditionss under be concentrated under reduced pressure ethyl acetate to dry；50mL petroleum ethers are added into concentrate system, in 20~25 DEG C of temperature
2h is stirred under the conditions of degree, solid is separated out, suction filtration processing is then carried out, then with 10mL petroleum ether filter cakes, it is finally true at 30 DEG C
Sky is dried, and obtains 19.3g off-white powders compound (B), yield 79%, HPLC98%.
(2) intermediate 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine is prepared using the compound (B) of above-mentioned synthesis
Formaldehyde (TM)；
12g compounds (B) are added in 60mL isopropanol solvent and are stirred dissolving, 0.4g catalyst is added
Rh-[(Ⅰ)-(R,R)-BDPCH]24, 0~5 DEG C is cooled to, then the aqueous isopropanol dissolved with 2.45g sodium borohydrides is slowly added dropwise, control
Reaction temperature processed is 5~15 DEG C, and detection reaction is complete after reaction 3h.20mL acetone is slowly added dropwise into reacted system, controls
Temperature processed is less than 20 DEG C；Under the temperature conditionss less than 50 DEG C pressurization be concentrated into it is solvent-free steam, to concentrate add 100mL water
With 50mL methyl tertiary butyl ether(MTBE)s, 0.5h is stirred under 10~20 DEG C of temperature conditionss, liquid to be divided is aqueous phase and organic phase, then to aqueous phase
Middle addition 30mL methyl tertiary butyl ether(MTBE)s are stirred 0.5h, and after after point liquid formation aqueous phase and organic phase, merging divides liquid to be formed twice
Organic phase, be dried, be concentrated under reduced pressure under the temperature conditionss less than 50 DEG C using 5g anhydrous sodium sulfates, it is final to be made
9.1g grease is obtained for intermediate 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM), HPLC 95%,
EE98%.
Above-described 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 the embodiment that the foregoing is only the present invention, be not intended to limit the present invention
Protection domain, within the spirit and principles of the invention, any modification, equivalent substitution and improvements done etc. all should be included
Within protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of posaconazole intermediate, it is characterised in that the posaconazole intermediate be 2- [(1S, 2S)-
1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM), carry out in having solvent being condensed by using compound (A) and formoxyl anti-
Should, condensation reaction thing is subjected to purification processes solid chemical compound (B) is made；In organic solvent, catalyst Rh- [(I)-(R,
R)-BDPCH]24In the presence of, the compound and reducing agent sodium borohydride carry out reduction reaction, and reaction product is purified
Intermediate 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM) is prepared into after processing；Reaction equation is：
2. a kind of synthetic method of posaconazole intermediate according to claim 1, it is characterised in that the organic solvent
For methanol, isopropanol, toluene or tetrahydrofuran.
3. a kind of synthetic method of posaconazole intermediate according to claim 1, it is characterised in that the organic solvent
Volume be 4~10 times of volume of dissolved raw material.
4. a kind of synthetic method of posaconazole intermediate according to claim 3, it is characterised in that the organic solvent
Volume be 5~6 times of volume of dissolved raw material.
5. a kind of synthetic method of posaconazole intermediate according to claim 1, it is characterised in that the condensation reaction
Temperature be 20~25 DEG C, the reaction time be 4~6h.
6. a kind of synthetic method of posaconazole intermediate according to claim 1, it is characterised in that the reduction reaction
Temperature be -10~20 DEG C, the reaction time is 3h.
7. a kind of synthetic method of posaconazole intermediate according to claim 6, it is characterised in that the reduction reaction
Temperature be 5~15 DEG C.
8. the synthetic method of a kind of posaconazole intermediate according to claim 1, it is characterised in that the catalyst
Addition is the 1% of the amount of the material of starting compound (B).
9. the synthetic method of a kind of posaconazole intermediate according to claim 1, it is characterised in that the condensation is anti-
Answer product to carry out purification processes step includes successively：
First solvent-free steam is concentrated under reduced pressure under less than 50 DEG C temperature conditionss；
Then ethyl acetate is added to the system after decompression, is stirred under 20~25 DEG C of temperature conditionss, suction filtration；Ethyl acetate is used again
Carry out washing operation, combined ethyl acetate filtrate；
The filtrate decompression is concentrated into ethyl acetate under less than 40 DEG C temperature conditionss to be evaporated；
Petroleum ether is added in system after concentration, is stirred under 20~25 DEG C of temperature conditionss, solid is separated out, suction filtration operation is carried out,
Then petroleum ether filter cake is used；
The filter cake is dried in vacuo, compound as white solid (B) is made.
10. the synthetic method of a kind of posaconazole intermediate according to claim 1, it is characterised in that by the reduction
Reaction product carries out purification processes step to be included successively：
Produced first to reduction reaction in product and be added dropwise to acetone, pressurization is concentrated into solvent-free steaming under less than 50 DEG C temperature conditionss
Go out；
Water and methyl tertiary butyl ether(MTBE) are added into the concentrate, is stirred under 10~20 DEG C of temperature conditionss, after after point liquid
Form aqueous phase and organic phase；
First add and be stirred under methyl tertiary butyl ether(MTBE) stirring, 10~20 DEG C of temperature conditionss to aqueous phase, treat further to divide liquid to be formed
Aqueous phase and organic phase；
Merge organic phase, using anhydrous sodium sulfate drying, carry out being concentrated under reduced pressure under less than 50 DEG C temperature conditionss in grease
Mesosome 2- [(1S, 2S) -1- ethyl -2- benzyloxies propyl group] hydrazine formaldehyde (TM).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108341754A (en) * | 2018-03-12 | 2018-07-31 | 扬子江药业集团有限公司 | Posaconazole impurity and its preparation method and application |
| CN115260055A (en) * | 2022-09-13 | 2022-11-01 | 济南大学 | A kind of preparation method of posaconazole side chain intermediate chiral isomer |
| CN116874388A (en) * | 2023-06-09 | 2023-10-13 | 连云港贵科药业有限公司 | Preparation method of posaconazole intermediate |
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| CN108341754A (en) * | 2018-03-12 | 2018-07-31 | 扬子江药业集团有限公司 | Posaconazole impurity and its preparation method and application |
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| CN116874388A (en) * | 2023-06-09 | 2023-10-13 | 连云港贵科药业有限公司 | Preparation method of posaconazole intermediate |
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Application publication date: 20170728 |