CN106349337A - Caspofungin preparing method - Google Patents
Caspofungin preparing method Download PDFInfo
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- CN106349337A CN106349337A CN201610753914.4A CN201610753914A CN106349337A CN 106349337 A CN106349337 A CN 106349337A CN 201610753914 A CN201610753914 A CN 201610753914A CN 106349337 A CN106349337 A CN 106349337A
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- caspofungin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
Abstract
The invention discloses a caspofungin preparing method, the method comprises the steps of 1, under the protection of nitrogen, mixing Newmoxon B0, phenylboronic acid and acetonitrile, ultrasonic dispersion, and then cooled, adding 4-Hydroxy thiophenol and trifluoromethanesulfonic acid to produce compound A; 2, under the protection of nitrogen, mixing compound A, phenylboronic acid and anhydrous tetrahydrofuran, ultrasonic dispersion, and reflux reaction for 20-30min, cooling to room temperature, then adding BSTFA and di-methylsulfide borane to produce compound B; 3, under the protection of nitrogen, the material obtained by compound B is dissolved in methanol, ethylenediamine is added at -15 - -10 oC, then heated to 10-15 oC, reacted for 5-6h, concentrated and dried to produce caspofungin. The preparing method has the advantages of short route, simple preparation process, mild reaction condition, simple post-treatment, short reaction time and high yield, and is favorable for industrial production.
Description
Technical field
The invention belongs to chemicalses synthesis technical field is and in particular to a kind of preparation method of Caspofungin.
Background technology
Caspofungin is that a kind of new semisynthetic echinocandin tires out (echinocandins) antifungal, its effect
Mechanism is to stop the formation of fungal cell wall, particularly can stop necessary part β-(1,3)-d- glucosan of fungal cell wall
Biosynthesiss, it is treated no for treating Neutrophilic granulocytopenia, the suspected fungal infection with fever patient and treatment
Effect or intolerable invasive aspergillosis.Caspofungin (includes Aspergillus fumigatus, Aspergillus flavus, aspergillus niger to Eurotium
Bacterium, aspergillus nidulanses, aspergillus terreus and aspergillus candidus) and Candida (include Candida albicans, Candida dubliniensis, smooth
Candidiasises, candida guilliermondi, such as wine candidiasises, candida krusei, candida lipolytica, Candida lusitaniae, closely smooth thought
Pearl bacterium, fold candidiasises and Oidium tropicale) there is external activity.
But the preparation method of existing Caspofungin, the response time is long, and yield is not high, is not suitable for industrialized production.
Content of the invention
For above-mentioned deficiency of the prior art, the invention provides a kind of preparation method of Caspofungin, can effectively solve
Certainly in prior art, reaction efficiency is low, the problem of response time length.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of Caspofungin, comprises the following steps:
(1) under nitrogen protection, by knob not Kangding b0, phenylboric acid and acetonitrile mixing, ultrasonic disperse 10 ~ 20min, be then cooled to-
35 ~ -25 DEG C, add 4- hydroxythiophenol, mix, then Deca trifluoromethanesulfonic acid, drip and finish, react 2 ~ 3h in -35 ~ -25 DEG C, instead
After should terminating, temperature is risen to 0 DEG C, then Deca sodium acetate solution, adjusting solution ph is 6.5 ~ 7, filters, then by filtrate temperature
Degree rises to 10 DEG C, filters, then filtrate is risen to 20 DEG C, filters, merging filtrate, merging filtrate is cooled to -35 ~ -25 DEG C, Deca
Concentration is the sodium acetate solution of 0.05g/ml, then temperature directly rises to 20 DEG C, continues Deca sodium acetate solution and adjusts solution
Ph value is 6.5, filters, and merges filter cake, washs filter cake with the mixed solution that acetonitrile and water volume ratio are 8:1, is then vacuum dried;
Wherein knob not Kangding b0Mol ratio with phenylboric acid is 1 ~ 2:3 ~ 5;Knob not Kangding b0Mol ratio with 4- hydroxythiophenol is 1 ~ 2:
3~5;Knob not Kangding b0Mol ratio with trifluoromethanesulfonic acid is 1 ~ 2:3 ~ 5;
(2), under nitrogen protection, step (1) gained material, phenylboric acid and anhydrous tetrahydro furan are mixed, ultrasonic disperse 10 ~
20min, is then refluxed for reacting 20 ~ 30min, is cooled to room temperature, is subsequently added into after bstfa reacts 2 ~ 3h and is cooled to -15 ~ -10 DEG C,
It is slowly added dropwise borane dimethyl sulphide, is warming up to 10 ~ 15 DEG C, react 1 ~ 2h, then add and borine two after being cooled to -15 ~ -10 DEG C
The hydrochloric acid of Dimethyl sulfide equimolar amountss, reacts 1 ~ 2h, and vacuum distillation removes anhydrous tetrahydro furan;Wherein step (1) gained material
Mol ratio with phenylboric acid is 1 ~ 2:3 ~ 5;The mol ratio of step (1) gained material and bstfa is 1 ~ 2:5 ~ 7;Deca borine two
The speed of Dimethyl sulfide is 15 ~ 20ml/min, and step (1) gained material is 1 with the mass volume ratio of borane dimethyl sulphide:
0.8g/ml;
(3), under nitrogen protection, step (2) gained material is dissolved in methanol, adds ethylenediamine at -15 ~ -10 DEG C, then heat up
To 10 ~ 15 DEG C, react 5 ~ 6h, then Deca glacial acetic acid, stir 1 ~ 2h, then plus ethyl acetate stir 1 ~ 2h, last concentrating under reduced pressure,
It is dried, obtain Caspofungin;The mol ratio of wherein step (2) gained material and ethylenediamine is 1 ~ 2:3 ~ 5.
Further, knob not Kangding b in step (1)0Mol ratio with phenylboric acid is 1:3.
Further, knob not Kangding b in step (1)0Mol ratio with 4- hydroxythiophenol is 2:5.
Further, knob not Kangding b in step (1)0Mol ratio with trifluoromethanesulfonic acid is 1:3.5.
Further, in step (2), the mol ratio of step (1) gained material and phenylboric acid is 2:5.
Further, in step (2), the mol ratio of step (1) gained material and bstfa is 2:7.
Further, in step (2), the speed of Deca borane dimethyl sulphide is 18ml/min.
Further, in step (3), the mol ratio of step (2) gained material and ethylenediamine is 1:3.
The preparation method of the Caspofungin that the present invention provides, has the advantages that
Preparation method of the present invention, it is short to have a route, and preparation process is simple, and reaction condition is gentle, and post processing is simple, the response time
Short, the advantages of high income, and be conducive to industrialized production.
Specific embodiment
Embodiment 1
A kind of preparation method of Caspofungin, comprises the following steps:
(1) under nitrogen protection, by 1mol knob not Kangding b0, 3mol phenylboric acid and 350ml acetonitrile mixing, ultrasonic disperse 20min, so
After be cooled to -35 DEG C, add 3mol 4- hydroxythiophenol, mix, then Deca 3mol trifluoromethanesulfonic acid, drip finish, in -35 DEG C
Temperature is risen to 0 DEG C after reaction terminating, then Deca sodium acetate solution by reaction 3h, and adjusting solution ph is 6.5, filters, then will
Filtrate temperature rises to 10 DEG C, filters, then filtrate is risen to 20 DEG C, filters, merging filtrate, merging filtrate is cooled to -35 DEG C, drips
Plus concentration is the sodium acetate solution of 0.05g/ml, then temperature is directly risen to 20 DEG C, continue the regulation of Deca sodium acetate solution molten
Liquid ph value is 6.5, filters, and merges filter cake, washs filter cake with the mixed solution that acetonitrile and water volume ratio are 8:1, then vacuum is done
Dry, obtain compound a, yield is 98.9%;
(2), under nitrogen protection, 1mol compound a, 3mol phenylboric acid are dissolved in anhydrous tetrahydro furan, ultrasonic disperse
20min, is then refluxed for reacting 30min, is cooled to room temperature, is cooled to -15 DEG C, slowly after being subsequently added into 5mol bstfa reaction 3h
Deca borane dimethyl sulphide, rate of addition is 15ml/min, and makes the mass volume ratio of compound a and borane dimethyl sulphide
For 1:0.8g/ml, then heat to 10 DEG C, react 1h, then add and borane dimethyl sulphide equimolar amountss after being cooled to -15 DEG C
Hydrochloric acid, react 1h, vacuum distillation remove anhydrous tetrahydro furan, separate obtain compound b, yield be 96.1%;
(3), under nitrogen protection, 1mol compound b is dissolved in methanol, adds 3mol ethylenediamine at -15 DEG C, then heat to 10
DEG C, react 6h, then Deca glacial acetic acid, stir 2h, then plus ethyl acetate stirring 2h, last concentrating under reduced pressure, be dried, must block pool sweet smell
Only, yield 93.5%.
Embodiment 2
A kind of preparation method of Caspofungin, comprises the following steps:
(1) under nitrogen protection, by 2mol knob not Kangding b0, 5mol phenylboric acid and 380ml acetonitrile mixing, ultrasonic disperse 20min, so
After be cooled to -30 DEG C, add 5mol 4- hydroxythiophenol, mix, then Deca 5mol trifluoromethanesulfonic acid, drip finish, in -30 DEG C
Temperature is risen to 0 DEG C after reaction terminating, then Deca sodium acetate solution by reaction 2.5h, and adjusting solution ph is 6.5, filters, then
Filtrate temperature is risen to 10 DEG C, filters, then filtrate is risen to 20 DEG C, filter, merging filtrate, merging filtrate is cooled to -30 DEG C,
Deca concentration is the sodium acetate solution of 0.05g/ml, then temperature directly rises to 20 DEG C, continues Deca sodium acetate solution and adjusts
Solution ph is 6.5, filters, and merges filter cake, washs filter cake with the mixed solution that acetonitrile and water volume ratio are 8:1, then vacuum
It is dried, obtains compound a, yield is 98.8%;
(2), under nitrogen protection, 2mol compound a, 5mol phenylboric acid are dissolved in anhydrous tetrahydro furan, ultrasonic disperse
20min, is then refluxed for reacting 30min, is cooled to room temperature, is cooled to -10 DEG C, delays after being subsequently added into 7mol bstfa reaction 2.5h
Slow Deca borane dimethyl sulphide, rate of addition is 20ml/min, and makes the quality volume of compound a and borane dimethyl sulphide
Ratio for 1:0.8g/ml, then heats to 10 DEG C, reacts 1.5h, then adds after being cooled to -10 DEG C and rub with borane dimethyl sulphide etc.
The hydrochloric acid of your amount, reacts 1.5h, and vacuum distillation removes anhydrous tetrahydro furan, separates and obtains compound b, and yield is 96.8%;
(3), under nitrogen protection, 2mol compound b is dissolved in methanol, adds 5mol ethylenediamine at -10 DEG C, then heat to 10
DEG C, react 5.5h, then Deca glacial acetic acid, stir 2h, then plus ethyl acetate stirring 2h, last concentrating under reduced pressure, be dried, get Ka Bo
Fragrant net, yield 94.1%.
Embodiment 3
A kind of preparation method of Caspofungin, comprises the following steps:
(1) under nitrogen protection, by 1mol knob not Kangding b0, 3mol phenylboric acid and 360ml acetonitrile mixing, ultrasonic disperse 20min, so
After be cooled to -30 DEG C, add 2.5mol 4- hydroxythiophenol, mix, then Deca 3.5mol trifluoromethanesulfonic acid, drip finish, in -
Temperature is risen to 0 DEG C after reaction terminating, then Deca sodium acetate solution by 30 DEG C of reaction 2.5h, and adjusting solution ph is 6.5, mistake
Filter, then filtrate temperature is risen to 10 DEG C, filters, then filtrate is risen to 20 DEG C, filters, merging filtrate, merging filtrate is cooled to-
30 DEG C, Deca concentration is the sodium acetate solution of 0.05g/ml, then temperature directly rises to 20 DEG C, continues Deca sodium acetate solution
Adjusting solution ph is 6.5, filters, merges filter cake, washs filter cake with the mixed solution that acetonitrile and water volume ratio are 8:1, then
Vacuum drying, obtains compound a, and yield is 99.1%;
(2), under nitrogen protection, 2mol compound a, 5mol phenylboric acid are dissolved in anhydrous tetrahydro furan, ultrasonic disperse
20min, is then refluxed for reacting 30min, is cooled to room temperature, is cooled to -10 DEG C, slowly after being subsequently added into 7mol bstfa reaction 3h
Deca borane dimethyl sulphide, rate of addition is 28ml/min, and makes the mass volume ratio of compound a and borane dimethyl sulphide
For 1:0.8g/ml, then heat to 10 DEG C, react 2h, then add and borane dimethyl sulphide equimolar amountss after being cooled to -10 DEG C
Hydrochloric acid, react 2h, vacuum distillation remove anhydrous tetrahydro furan, separate obtain compound b, yield be 97.2%;
(3), under nitrogen protection, 1mol compound b is dissolved in methanol, adds 3mol ethylenediamine at -10 DEG C, then heat to 10
DEG C, react 6h, then Deca glacial acetic acid, stir 2h, then plus ethyl acetate stirring 2h, last concentrating under reduced pressure, be dried, must block pool sweet smell
Only, yield 95.1%.
Claims (8)
1. a kind of preparation method of Caspofungin is it is characterised in that comprise the following steps:
(1) under nitrogen protection, by knob not Kangding b0, phenylboric acid and acetonitrile mixing, ultrasonic disperse 10 ~ 20min, be then cooled to -35
~ -25 DEG C, add 4- hydroxythiophenol, mix, then Deca trifluoromethanesulfonic acid, drip and finish, react 2 ~ 3h, reaction in -35 ~ -25 DEG C
After termination, temperature is risen to 0 DEG C, then Deca sodium acetate solution, adjusting solution ph is 6.5 ~ 7, filters, then by filtrate temperature
Rise to 10 DEG C, filter, then filtrate is risen to 20 DEG C, filter, merging filtrate, merging filtrate is cooled to -35 ~ -25 DEG C, Deca is dense
Spend the sodium acetate solution for 0.05g/ml, then temperature is directly risen to 20 DEG C, continue Deca sodium acetate solution and adjust solution ph
It is worth for 6.5, filters, merge filter cake, wash filter cake with the mixed solution that acetonitrile and water volume ratio are 8:1, be then vacuum dried;Its
Middle knob not Kangding b0Mol ratio with phenylboric acid is 1 ~ 2:3 ~ 5;Knob not Kangding b0With the mol ratio of 4- hydroxythiophenol be 1 ~ 2:3 ~
5;Knob not Kangding b0Mol ratio with trifluoromethanesulfonic acid is 1 ~ 2:3 ~ 5;
(2), under nitrogen protection, step (1) gained material, phenylboric acid and anhydrous tetrahydro furan are mixed, ultrasonic disperse 10 ~
20min, is then refluxed for reacting 20 ~ 30min, is cooled to room temperature, is subsequently added into after bstfa reacts 2 ~ 3h and is cooled to -15 ~ -10 DEG C,
It is slowly added dropwise borane dimethyl sulphide, is warming up to 10 ~ 15 DEG C, react 1 ~ 2h, then add and borine two after being cooled to -15 ~ -10 DEG C
The hydrochloric acid of Dimethyl sulfide equimolar amountss, reacts 1 ~ 2h, and vacuum distillation removes anhydrous tetrahydro furan;Wherein step (1) gained material
Mol ratio with phenylboric acid is 1 ~ 2:3 ~ 5;The mol ratio of step (1) gained material and bstfa is 1 ~ 2:5 ~ 7;Deca borine two
The speed of Dimethyl sulfide is 15 ~ 20ml/min, and step (1) gained material is 1 with the mass volume ratio of borane dimethyl sulphide:
0.8g/ml;
(3), under nitrogen protection, step (2) gained material is dissolved in methanol, adds ethylenediamine at -15 ~ -10 DEG C, then heat up
To 10 ~ 15 DEG C, react 5 ~ 6h, then Deca glacial acetic acid, stir 1 ~ 2h, then plus ethyl acetate stir 1 ~ 2h, last concentrating under reduced pressure,
It is dried, obtain Caspofungin;The mol ratio of wherein step (2) gained material and ethylenediamine is 1 ~ 2:3 ~ 5.
2. the preparation method of Caspofungin according to claim 1 is it is characterised in that knob not Kangding b in step (1)0And benzene
The mol ratio of boric acid is 1:3.
3. the preparation method of Caspofungin according to claim 1 is it is characterised in that knob not Kangding b in step (1)0And 4-
The mol ratio of hydroxythiophenol is 2:5.
4. the preparation method of Caspofungin according to claim 1 is it is characterised in that knob not Kangding b in step (1)0With three
The mol ratio of fluorine methanesulfonic acid is 1:3.5.
5. the preparation method of Caspofungin according to claim 1 is it is characterised in that in step (2), step (1) gained
The mol ratio of material and phenylboric acid is 2:5.
6. the preparation method of Caspofungin according to claim 1 is it is characterised in that in step (2), step (1) gained
The mol ratio of material and bstfa is 2:7.
7. the preparation method of Caspofungin according to claim 1 is it is characterised in that Deca borine diformazan in step (2)
The speed of base thioether is 18ml/min.
8. the preparation method of Caspofungin according to claim 1 is it is characterised in that in step (3), step (2) gained
The mol ratio of material and ethylenediamine is 1:3.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111233981A (en) * | 2020-03-17 | 2020-06-05 | 湖南欧亚药业有限公司 | Preparation method of caspofungin |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102367267A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Preparation method of caspofungin |
CN102367269A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Caspofungin analogue, its preparation method and application |
CN105440109A (en) * | 2015-11-26 | 2016-03-30 | 成都摩尔生物医药有限公司 | Preparation method of caspofungin |
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- 2016-08-30 CN CN201610753914.4A patent/CN106349337A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102367267A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Preparation method of caspofungin |
CN102367269A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Caspofungin analogue, its preparation method and application |
CN105440109A (en) * | 2015-11-26 | 2016-03-30 | 成都摩尔生物医药有限公司 | Preparation method of caspofungin |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111233981A (en) * | 2020-03-17 | 2020-06-05 | 湖南欧亚药业有限公司 | Preparation method of caspofungin |
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