CN108840832A - A kind of preparation method of Gadobutrol intermediate - Google Patents
A kind of preparation method of Gadobutrol intermediate Download PDFInfo
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- CN108840832A CN108840832A CN201810699264.9A CN201810699264A CN108840832A CN 108840832 A CN108840832 A CN 108840832A CN 201810699264 A CN201810699264 A CN 201810699264A CN 108840832 A CN108840832 A CN 108840832A
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- gdb1
- preparation
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- cycleanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Abstract
The present invention relates to the preparation methods of Gadobutrol intermediate GDB1 a kind of; using cycleanine as starting material; three amino are protected using Boc acid anhydrides; then with 4; 4- dimethyl -3,5, the reaction of 8- trioxa two rings [5.1.0] octane; hydrochloric acid hydrolysis is added after the reaction was completed, obtains the GDB1 of higher degree and good yield.
Description
Technical field
The present invention relates to a kind of preparation method of Gadobutrol intermediate more particularly to the preparation sides of Gadobutrol intermediate GDB1
Method.
Background technique
Magnetic resonance imaging (MRI) technology has a wide range of applications in biology and medical domain, has become a kind of common
Medical diagnosis means.Currently the important research direction of magnetic resonance contrast agent is that development has organ, tissue-targeting in the world
Contrast agent, so that contrast agent is enriched in specific organ and tissue, to improve contrasting effects.GadobutrolIt is
A kind of novel potent magnetic resonance imaging contrast agent is approved for the Contrast enhanced magnetic resonance imaging (CE- at the multiple positions of human body
MRI it) diagnoses, including brain, spinal cord, blood vessel, liver and kidney.
Since the tolerance of Gadobutrol is good, toxicity is low, imaging effect is good, high concentrate formulation is in the magnetic for needing a large amount of contrast medium
Unique advantage in resonance image-forming.And clinical test proves, rate of adverse reactions is low, and therefore, Gadobutrol has good
Application prospect, exploitation more practicability synthesis technology also become especially urgent.
Described Gadobutrol intermediate GDB1 is the critical component for synthesizing Gadobutrol herein, Inorg.Chem.1997,
36,6086-6093 is developed first synthesizes Gadobutrol using GDB1.It and is also that original is ground among the key of patent CN103547573
Body.Patent CN107001294A directly uses GDB1 to synthesize the Gadobutrol of high-purity as crucial starting material.So exploitation
One cost is relatively low, and the technique of amplification production GDB1 is suitble to be particularly important.
Unprotected cycleanine and 4 are used in Inorg.Chem.1997,36,6086-6093 and CN 103547573,
4- dimethyl -3,5, the reaction of 8- trioxa two rings [5.1.0] octane, selectivity is not high, wherein two substitutions and polysubstituted impurity
It is difficult to be controlled, and feed stock conversion is lower, obtained intermediate purity is poor, and yield is lower.
Cycleanine is protected with boron-based compounds first in CN 103613557A patent, then again with dimethyl -3 4,4-,
The reaction of 5,8- trioxa, two rings [5.1.0] octane, although improving selectivity, boron-based compounds are very unstable, and boron tries
Agent costly, is not suitable for amplification production.
The cycleanine and 4,4- diformazan protected in DE 4009119 and US 2002176823 with three p-toluenesulfonyls
Base -3,5,8- trioxa two rings [5.1.0] octane reaction, since the reaction need to react at 170 DEG C.Reaction temperature is higher, no
Easily amplification production.And easily form single de- or double removing impurities matter.
DE 4237943, EP 0596586, using DMF acetal three amino of cycleanine are protected in CN 102933562
Shield, then again with 4,4- dimethyl -3,5,8- trioxa two rings [5.1.0] octane reaction, but due to using DMF acetal to protect
Cycleanine it is extremely unstable, be easy hydrolysis, be difficult to control subsequent derivative impurity.
Summary of the invention
The object of the present invention is to provide the preparation methods of high-purity Gadobutrol intermediate GDB1 a kind of.
The preparation method of Gadobutrol intermediate according to the present invention is protected using cycleanine as starting material using Boc acid anhydrides
Protect three amino, then in a solvent with 4,4- dimethyl -3,5,8- trioxa two rings [5.1.0] octane reaction, reaction complete
Hydrochloric acid hydrolysis is added afterwards, the GDB1 of higher degree and good yield can be obtained.
The present invention provides the preparation methods of high-purity Gadobutrol intermediate GDB1 a kind of, including：
(1) cycleanine 1 and Boc anhydride reaction obtain compound 2；
(2) compound 2 reacts to obtain intermediate GDB1 with 4,4- dimethyl -3,5,8- trioxa two ring [5.1.0] octane.
Wherein, in step (1), cycleanine 1 can be carried out with reacting for Boc acid anhydrides under conditions of organic base, be had
Triethylamine etc. can be used in machine alkali；Reaction can carry out at 10 DEG C of temperature below, preferably carry out at 0 DEG C of temperature below.
Use Boc2O Preservation tactics, can greatly improve the selectivity of reaction, and the complete of cycleanine 1 may be implemented
Full conversion.
In step (2), reaction carries out in the presence of solvent and lithium chloride, and the solvent can be isopropanol, ethyl alcohol, just
Butanol etc.；After the reaction was completed, concentrated hydrochloric acid hydrolysis is added, obtains the purity of the intermediate GDB1, GDB1 of high-purity and good yield
It can achieve 99% or more.
Preferably, step (2) further comprises crystallization process, and product is recrystallized to give the intermediate of high-purity with alcohol
GDB1, it is preferable to use alcoholic solvents, such as methanol for recrystallization solvent.
Boc anhydride group steric hindrance is very big, and the present invention effectively overcomes its steric hindrance, makes itself and 4,4- dimethyl -3,5, tri- oxygen of 8-
Miscellaneous two ring [5.1.0] octane goes on smoothly reaction, improves conversion ratio.
The present invention protects cycleanine than using boron-based compounds, the cycleanine of DMF acetal protection steady using Boc acid anhydrides
Determine, subsequent and 4,4- dimethyl -3,5, will not be decomposed in two ring of 8- trioxa [5.1.0] octane reaction process.Use Boc acid anhydrides
Protection cycleanine is compared with using tolysulfonyl based compound to protect cycleanine, appearance when step takes off protecting group below
Easily, the condition of high-temperature high concentration acid is not needed.
Beneficial effects of the present invention：
(1) since cycleanine price is higher, synthetic route of the invention can make raw material convert completely, and cost is substantially
It reduces.
(2) Boc is used2The strategy of O protection, substantially increases selectivity, avoids the life of two substitutions and polysubstituted impurity
At.
(3) process of second step hydrolysising protection base is easy, and crystallization process is high-efficient, can directly be obtained using methanol primary crystallization
Purity to the product of higher degree, GDB1 can achieve 99% or more.
(4) reaction condition is mild, convenient for amplification production；Yield greatly improves, and greatly reduces production cost.
Specific embodiment
Hereinafter, the preparation method for the Gadobutrol intermediate GDB1 that invention will be described in conjunction with the embodiments.
Embodiment
The preparation method of Gadobutrol intermediate GDB1 according to the present invention is as follows：
The first step：The synthesis of compound 2
40mL CH is added under stirring into reaction vessel2Cl2, 12.0g cycleanine and 30mL triethylamine, be added dropwise at 0 DEG C
The 20mL CH of 4.6g Boc acid anhydrides2Cl2Solution.After completion of the reaction, it separates organic phase and is concentrated to get 29.6g compound 2, yield
90%.
Compound 2:1HNMR(400MHz,CDCl3,ppm):0.87 (s, 27H), 2.82 (s, 4H), 3.26~3.37 (m,
8H), 3.60~3.64 (m, 4H), 3.15 (s, 2H), 3.20 (s, 2H), 3.35~3.42 (m, 4H), 7.92 (s, 1H)
Second step：The synthesis of intermediate GDB1
80mL isopropanol, 1.80 grams lithium chlorides, 40.0g compound 2 and 18.30g 4 is added under stirring into reaction vessel,
4- dimethyl -3,5, two ring of 8- trioxa [5.1.0] octane react 20 hours at a reflux temperature；After completion of the reaction, it is cooled to
66.90g concentrated hydrochloric acid is added dropwise in room temperature, and 60 DEG C are warming up to after being added dropwise and is reacted 2 hours.Then it is concentrated under reduced pressure, methanol is added dropwise,
It is stirred 2 hours at 60 DEG C.Cooling filtering, vacuum drying obtain 30.30g white powder, yield 85%.
HPLC-CAD analysis, intermediate GDB1 purity >=99%, cycleanine content≤0.2%.
GDB1:13CNMR(400MHz,D2O,ppm):41.50(2C),43.07(2C),44.01(2C),45.83(2C),
58.18(1C),59.97(1C),63.45(1C),69.88(1C)。
Preparation method according to the present invention, reaction step is simple, and reaction condition is mild, and selectivity is high, can be obtained more high-purity
The GDB1 of degree and good yield.
Claims (8)
1. a kind of preparation method of high-purity Gadobutrol intermediate GDB1, including：
(1) cycleanine 1 and Boc anhydride reaction obtain compound 2；
(2) compound 2 reacts to obtain intermediate GDB1 with 4,4- dimethyl -3,5,8- trioxa two ring [5.1.0] octane.
2. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 1, wherein
In step (1), cycleanine 1 carries out under conditions of organic base with reacting for Boc acid anhydrides.
3. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 2, wherein
The organic base is triethylamine.
4. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 1, wherein
In step (1), reaction carries out at 10 DEG C of temperature below.
5. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 1, wherein
In step (2), reaction carries out in the presence of solvent and lithium chloride, is hydrolyzed after the reaction was completed with concentrated hydrochloric acid.
6. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 5, wherein
The solvent is isopropanol, ethyl alcohol, n-butanol.
7. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 1, wherein
Step (2) further comprises crystallization process.
8. the preparation method of high-purity Gadobutrol intermediate GDB1 according to claim 7, wherein
The solvent of crystallization process is methanol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810699264.9A CN108840832A (en) | 2018-06-29 | 2018-06-29 | A kind of preparation method of Gadobutrol intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1528763A (en) * | 2003-10-14 | 2004-09-15 | 四川大学 | Binuclear macrocyclic polyamine metal complex and its use |
| CN103547573A (en) * | 2011-04-21 | 2014-01-29 | 拜耳知识产权有限责任公司 | Preparation of high-purity gadobutrol |
-
2018
- 2018-06-29 CN CN201810699264.9A patent/CN108840832A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1528763A (en) * | 2003-10-14 | 2004-09-15 | 四川大学 | Binuclear macrocyclic polyamine metal complex and its use |
| CN103547573A (en) * | 2011-04-21 | 2014-01-29 | 拜耳知识产权有限责任公司 | Preparation of high-purity gadobutrol |
Non-Patent Citations (2)
| Title |
|---|
| J. PLATZEK ET AL.: "Synthesis and Structure of a New Macrocyclic Polyhydroxylated Gadolinium Chelate Used as a Contrast Agent for Magnetic Resonance Imaging", 《INORG. CHEM.》 * |
| THOMAS WALENZYK ET AL.: "Immobilised zinc(II) cyclen complexes as catalytic reagents for phosphodiester hydrolysis", 《INORGANICA CHIMICA ACTA》 * |
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