CN109369679A - A kind of refining methd of rapamycin - Google Patents
A kind of refining methd of rapamycin Download PDFInfo
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- CN109369679A CN109369679A CN201811582081.5A CN201811582081A CN109369679A CN 109369679 A CN109369679 A CN 109369679A CN 201811582081 A CN201811582081 A CN 201811582081A CN 109369679 A CN109369679 A CN 109369679A
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- rapamycin
- silicon ether
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- structural formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of refining methds of rapamycin, comprising the following steps: S1: structural formula rapamycin crude product as shown in formula (1) reacts to obtain structural formula rapamycin silicon ether as shown in formula (2) through the protection of silicon ether；S2: rapamycin silicon ether obtained in step S1 is obtained into rapamycin silicon ether crystal through alcohols solvent dissolving-recrystallization；S3: rapamycin silicon ether crystal deprotection reaction obtained in step S2 is generated into structural formula target product rapamycin fine work as shown in formula (3).Rapamycin obtained by refining methd using a kind of disclosed rapamycin can reach ion-exchange column effect by simple chemical method, and the period is short, and product stability is good.
Description
Technical field
The invention belongs to medical production technical fields, specifically relate to a kind of refining methd of rapamycin.
Background technique
Rapamycin (Rapamycin, RAPA) is a kind of novel macrolide antibiotics.Originally RAPA is studied makees
For the antifungal drug of hypotoxicity, discovery RAPA in 1977 has immunosuppressive action, and 1989 start using RAPA as treatment
The new drug of the rejection of organ transplant is tried out.RAPA is conducted by different cytokine receptor disabling signals, blocks T
Lymphocyte and other cells are by the G1 phase to the process of S phase, to play immunosuppressive effect.From the point of view of current clinical application,
RAPA has good anti-repulsive interaction, and has good synergistic effect with immunosuppressor such as Ciclosporin A (CsA) and FK506,
It is a kind of good effect, low toxicity, the neotype immunosuppressant of no renal toxicity.Current research discovery, RAPA is a kind of effective autophagy
Inducer mitigates inflammatory reaction by induction autophagy, it may be possible to which it plays one of immunosuppressive mechanism.
RAPA not only itself as medicinal application in the starting material of multiple medicine preparations such as clinical treatment or everolimus
Material, but RAPA generates a large amount of impurity in fermentation preparation process, and prior art uses ion-exchange column chromatography for separation substantially, and the period is long,
Product purity is poor, it is necessary to develop new refining methd to solve the purity problem of rapamycin.
Summary of the invention
It is an object of the invention to disclose a kind of refining methd of rapamycin, this method does not use ion-exchange column, overcomes
In the prior art using at high cost caused by ion-exchange column, the period is long, the problem of stable product quality difference, the present invention passes through simple
Chemical method i.e. can reach ion-exchange column effect, the period is short, and product stability is good.
To achieve the above object, the present invention provides a kind of refining methds of rapamycin, comprising the following steps:
S1: structural formula rapamycin crude product as shown in formula (1) through silicon ether protection react structural formula as shown in formula (2)
Rapamycin silicon ether；
S2: rapamycin silicon ether obtained in step S1 is obtained into rapamycin silicon ether crystalline substance through alcohols solvent dissolving-recrystallization
Body；
S3: rapamycin silicon ether crystal deprotection reaction obtained in step S2 is generated into structural formula as shown in formula (3)
The equation of target product rapamycin fine work, reaction is as follows:
As a further improvement of the present invention, the catalyst in the silicon ether protection reaction of step S1 is imidazoles, pyridine, hydrogen
The mixture of one or more of sodium oxide molybdena, potassium hydroxide or triethylamine arbitrary proportion.
As a further improvement of the present invention, the R in formula (2) includes methyl, ethyl or isopropyl.
As a further improvement of the present invention, alcohols solvent described in step S2 is methanol, ethyl alcohol, isopropanol, tetrahydro furan
It mutters, one of acetone, acetonitrile, methylene chloride, methyl tertiary butyl ether(MTBE), ethyl acetate, hexamethylene, dioxane or water or two
The mixture of kind any of the above ratio.
As a further improvement of the present invention, alcohols solvent is the mixture of methyl tertiary butyl ether(MTBE) and tetrahydrofuran.
As a further improvement of the present invention, deprotection reaction described in step S3 are as follows: be added in step S2 in reaction flask
Rapamycin silicon ether crystal silica gel column chromatography obtained is added eluant, eluent and is eluted, and collects corresponding eluent concentration, and residue is true
Empty dry rapamycin fine work.
As a further improvement of the present invention, silica gel column chromatography is the silica gel column chromatography of 200-300 mesh.
As a further improvement of the present invention, eluant, eluent is that the mixing of ethyl acetate and ethyl alcohol that volume ratio is 20:1 is molten
Liquid.
Compared with prior art, the beneficial effects of the present invention are: the refining methd of rapamycin disclosed herein is only
It is that can reach the effect for using ion-exchange column in the prior art, and the period is shorter by simple chemical method, product stability is good.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure
Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
The present invention provides a kind of refining methds of rapamycin, comprising the following steps:
S1: structural formula rapamycin crude product as shown in formula (1) through silicon ether protection react structural formula as shown in formula (2)
Rapamycin silicon ether；
S2: rapamycin silicon ether obtained in step S1 is obtained into rapamycin silicon ether crystalline substance through alcohols solvent dissolving-recrystallization
Body；
S3: rapamycin silicon ether crystal deprotection reaction obtained in step S2 is generated into structural formula as shown in formula (3)
The equation of target product rapamycin fine work, reaction is as follows:
Embodiment one
The present embodiment is obtained rapamycin according to the method described above, the specific steps are as follows:
100m anhydrous methylene chloride, 9.5g rapamycin, 4g imidazoles and 6.4g tri- are sequentially added in S1:250ml reaction flask
Methylchlorosilane, magnetic agitation react at room temperature 12h, and TLC judgement reaction terminates, is concentrated, obtains rapamycin silicon ether 11.5g.
Rapamycin silicon ether 10g is added in S2:250ml round-bottomed flask, is added methyl tertiary butyl ether(MTBE)/tetrahydrofuran (10/1)
135ml is heated to reflux 1h, and heat filters, and filtrate is cooled to room temperature 0 DEG C naturally and is stirred overnight crystallization, filters, and a small amount of ethyl alcohol of filter cake is washed
It washs, obtains white crystal 8.8g.
11.3 rapamycin silicon ether crystal silica gel column chromatographies are added in S3:250ml reaction flask, and silica gel column chromatography is 200-300
Corresponding eluent concentration, residue dried under vacuum get Lei Pa are collected in purpose silica gel column chromatography, ethyl acetate/ethyl alcohol (20:1) elution
Mycin fine work 8.1g.
Rapamycin fine work purity made from the method according to embodiment one is measured with chemical analysis method to reach
99.72%.
Embodiment first is that rapamycin when using R as methyl refining methd, R is the rapamycin of ethyl or isopropyl
Refining methd it is identical as the method for embodiment one, will not repeat them here.
The refining methd of rapamycin disclosed herein, being only through simple chemical method can reach the prior art
The middle effect using ion-exchange column, and the period is shorter, product stability is more preferable.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (8)
1. a kind of refining methd of rapamycin, which comprises the following steps:
S1: structural formula rapamycin crude product as shown in formula (1) reacts to obtain structural formula thunder pa as shown in formula (2) through the protection of silicon ether
Mycin silicon ether；
S2: rapamycin silicon ether obtained in step S1 is obtained into rapamycin silicon ether crystal through alcohols solvent dissolving-recrystallization；
S3: rapamycin silicon ether crystal deprotection reaction obtained in step S2 is generated into structural formula target as shown in formula (3)
The equation of product rapamycin fine work, reaction is as follows:
2. preparation method according to claim 1, which is characterized in that urging in the silicon ether protection reaction of the step S1
Agent is the mixing of one or more of imidazoles, pyridine, sodium hydroxide, potassium hydroxide or triethylamine arbitrary proportion
Object.
3. preparation method according to claim 1, which is characterized in that the R in the formula (2) includes methyl, second
Base or isopropyl.
4. preparation method according to claim 1, which is characterized in that alcohols solvent described in the step S2 be methanol,
Ethyl alcohol, isopropanol, tetrahydrofuran, acetone, acetonitrile, methylene chloride, methyl tertiary butyl ether(MTBE), ethyl acetate, hexamethylene, dioxane
Or the mixture of one or more of water arbitrary proportion.
5. the preparation method according to claim 4, which is characterized in that the alcohols solvent is methyl tertiary butyl ether(MTBE) and tetrahydro
The mixture of furans.
6. preparation method according to claim 1, which is characterized in that deprotection reaction described in the step S3 are as follows: anti-
It answers and rapamycin silicon ether crystal silica gel column chromatography obtained in step S2 is added in bottle, eluant, eluent is added and is eluted, phase is collected
Eluent is answered to be concentrated, residue dried under vacuum obtains rapamycin fine work.
7. preparation method according to claim 6, which is characterized in that the silica gel column chromatography is the silica gel of 200-300 mesh
Chromatographic column.
8. preparation method according to claim 6, which is characterized in that the eluant, eluent is the acetic acid second that volume ratio is 20:1
The mixed solution of ester and ethyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201811582081.5A CN109369679A (en) | 2018-12-24 | 2018-12-24 | A kind of refining methd of rapamycin |
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| CN201811582081.5A CN109369679A (en) | 2018-12-24 | 2018-12-24 | A kind of refining methd of rapamycin |
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| CN201811582081.5A Pending CN109369679A (en) | 2018-12-24 | 2018-12-24 | A kind of refining methd of rapamycin |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| CN101133065A (en) * | 2005-03-02 | 2008-02-27 | 惠氏公司 | Purification of rapamycin |
| CN104844620A (en) * | 2015-04-10 | 2015-08-19 | 鲁南新时代生物技术有限公司 | Separation and purification method for rapamycin |
| CN107619413A (en) * | 2017-09-25 | 2018-01-23 | 四川摩尔生物制药有限公司 | A kind of isolation and purification method of rapamycin |
-
2018
- 2018-12-24 CN CN201811582081.5A patent/CN109369679A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| CN101133065A (en) * | 2005-03-02 | 2008-02-27 | 惠氏公司 | Purification of rapamycin |
| CN104844620A (en) * | 2015-04-10 | 2015-08-19 | 鲁南新时代生物技术有限公司 | Separation and purification method for rapamycin |
| CN107619413A (en) * | 2017-09-25 | 2018-01-23 | 四川摩尔生物制药有限公司 | A kind of isolation and purification method of rapamycin |
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Application publication date: 20190222 |
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