CN107722017A - A kind of preparation method of anagrelide derivative - Google Patents
A kind of preparation method of anagrelide derivative Download PDFInfo
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- CN107722017A CN107722017A CN201711068717.XA CN201711068717A CN107722017A CN 107722017 A CN107722017 A CN 107722017A CN 201711068717 A CN201711068717 A CN 201711068717A CN 107722017 A CN107722017 A CN 107722017A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The invention discloses a kind of preparation method of anagrelide derivative, belong to pharmaceutical synthesis field, this method technological design is reasonable, workable, and reaction condition is gentleer, and yield is high, and industrialized production can be achieved.The present invention is with 1,2,3,4 tetrachlorobenzenes are raw material, pass through six-step process, realize the synthesis of anagrelide derivative, the anagrelide derivative that the present invention is prepared, carry out quality, security and efficiency scientific evaluation for anagrelide and provide important evidence, and anagrelide derivative pharmacological activity is good, the medicine for treating thrombocythemia caused by a variety of causes can be developed, there is important application value.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, more particularly to a kind of preparation method of anagrelide derivative.
Background technology
Platelet aggregation inhibitor anagrelide is a kind of oral antidiabetic aggregation medicine, is ring phosphorus gland former times (cMAP) phosphorus
Sour two cruel enzyme (PDE) inhibitor, chemical name 6, bis- chloro- l of 7-, 2,3,5- imidazolidines simultaneously [2,1-b] quinazoline -2- (3H) -one,
Trade name Agrylin, developed by Robergts Phnaajeeutieals companies of the U.S., be approved in July, 1997 to list in the U.S..
The medical instrument is selective strong, no Neuroleptic Leukocytopenia, the advantages that anaemia and leukemogenic serious side effects.Currently used for treatment
Thrombocythemia caused by primary thrombocytosis and myeloproliferative disease, Platelet quantity is set to subtract in one week
Few 50%, effective percentage more than 80%, it might even be possible to which treatment is through the invalid patient of hydroxycarbamide treatment.In the range of therapeutic dose, no
The quantity of human leukocytes and red blood cell can be changed, will not the serious adverse reaction such as leukemogenesis, be first and go through to use
In the medicine of essential thrombocythemia, at least 100,000,000 dollars of the market potential in the U.S. is estimated.
With the progress in epoch, the raising of scientific and technological level, people to medicine before marketing drugs to that must carry out quality, safety
Property and the importance of efficiency scientific evaluation etc., which have, more fully to be recognized, wherein with drug quality it is closely related be medicine institute
Impure control.Impurity is often relevant with drug safety, and also relevant with efficiency in a few cases.Therefore, control miscellaneous
Matter level is increasingly paid attention to during drug development by medical personal.
Anagrelide derivative synthesizes and carries out related pharmacology, pharmacokinetic study to anagrelide derivative, can
There is provided test sample with the research for anagrelide and quality test, and anagrelide derivative also have it is medicinal well before
Scape, but the research on the synthetic method of anagrelide derivative not yet has been reported that.
The content of the invention
The invention provides a kind of preparation method of anagrelide derivative, this method technological design is reasonable, and yield is high, behaviour
Facilitate as process controllable.
To realize object above, the present invention uses following scheme：
A kind of preparation method of anagrelide derivative, comprises the following steps：
(1) take 1,2,3,4- tetrachlorobenzenes to be suspended in solvent, the mixed solution of 65% concentrated nitric acid and the concentrated sulfuric acid is added, 20
3h is stirred under the conditions of DEG C -50 DEG C, obtains compound ii, structural formula is as follows：
(2) take compound ii to be dissolved in organic solvent, add cuprous cyanide, in 110 DEG C of -170 DEG C of heating stirring 4h, then pass through
Pillar layer separation obtains compound III, and structural formula is as follows：
(3) compound III is taken to be dissolved in tetrahydrofuran, under ice bath, addition sodium borohydride and lewis acid, 10 DEG C~70
DEG C reaction 0.5-8 hours, obtain compounds Ⅳ, structural formula is as follows：
(4) take compounds Ⅳ to be dissolved in organic solvent, add organic base, bromoacetate, 70 DEG C~130 DEG C reactions are 2 small
When, compound V is obtained through pillar layer separation, structural formula is as follows：
(5) take compound V to be suspended in concentrated hydrochloric acid, under condition of ice bath, add the concentrated hydrochloric acid solution of stannous chloride, 50 DEG C
Reaction 4 hours, obtains compound VI, structural formula is as follows through pillar layer separation：
(6) compound VI is suspended in 90% isopropanol water solution, under condition of ice bath, addition bromine cyanogen, 60 DEG C~120
DEG C reaction 6-30 hours, obtain compound VII, structural formula is as follows：
Solvent in above step described in step (1) is the concentrated sulfuric acid or the concentrated sulfuric acid and 1,2- dichloroethanes, described 1,2,
The ratio between amount of material of 3,4- tetrachlorobenzenes and concentrated nitric acid is 1:1~1:2, preferably described solvent is the concentrated sulfuric acid, described 1,2,
The ratio between amount of material of 3,4- tetrachlorobenzenes and concentrated nitric acid is 1:1.1, the reaction temperature is 35 DEG C；It is organic described in step (2)
Solvent is pyridine, 2,4,6- trimethylpyridines, DMF or DMA, and preferably described is organic
Solvent is DMA, and the reaction temperature is 145 DEG C, the amount of the material of the compound ii and stannous chloride it
Than for 1:1；Lewis acid described in step (3) is alchlor or boron trifluoride, the compound III, sodium borohydride and Louis
The ratio between this sour amount of material 1:0.5:0.5~1:5:5, the lewis acid described in preferred steps (3) is alchlor, describedization
The ratio between amount of compound III, sodium borohydride and lewis acidic material 1:2:2；Organic solvent described in step (4) is dioxane,
DMF or dimethyl sulfoxide (DMSO), the organic base are triethylamine, ethylenediamine or DIPEA, described
Compounds Ⅳ, the ratio between the amount of material 1 of organic base and bromoacetate:1:0.5~1:3:2, having described in preferred steps (4)
Solvent is dimethyl sulfoxide (DMSO), the organic base DIPEA, described compounds Ⅳ, organic base and bromoacetic acid second
The ratio between amount of material of ester 1:2:1.2, the reaction temperature is 90 DEG C；Reaction temperature described in step (6) is 90 DEG C, during reaction
Between be 22 hours, the ratio between amount of material of the compound VI and bromine cyanogen is 1:1.
The beneficial effects of the invention are as follows：The invention provides a kind of preparation method of anagrelide derivative, this method work
Skill is reasonable in design, and operating method is simple, raw material is easy to get, technique can amplify production, purity is high, course of reaction is controllable and environmental protection
Effect is good, and the anagrelide derivative that the present invention is prepared, and quality, security and efficiency science are carried out for anagrelide
Evaluation provides important evidence, can develop the medicine for treating piastrenemia, have important application value.
Brief description of the drawings
Fig. 1 is the flow chart of preparation method of the present invention.
Embodiment
The preparation of compound ii：1,2,3,4- tetrachlorobenzenes are taken to be suspended in the concentrated sulfuric acids of 40mL 98%, under the conditions of 25 DEG C,
The mixed solution of 65% concentrated nitric acid and the concentrated sulfuric acids of 9.17mL 98% is added, is stirred 3 hours at a certain temperature, reaction solution is by white
Color suspension is changed into yellow suspension.Reaction solution is directly poured into 200g ice, adds 200mL water, is extracted with 200mL ethyl acetate
Take twice, after organic phase merges, wash with 200mL water washings, then with 200mL saturated sodium bicarbonates, organic phase after drying, steaming
It is dry to obtain yellow solid compound II, the ratio between amount of material of 1,2,3,4- tetrachlorobenzene and concentrated nitric acid, the experimental data of reaction dissolvent
It is as follows：
The screening experiment data of optimal reaction temperature are as follows：
The preparation of compound III：Take 0.07mol compound iis to be dissolved in 9.6mL solvents, add 0.07mol cuprous cyanides,
Heating stirring 4 hours, reaction solution is changed into black suspension from yellow solution, and reaction solution is cooled into room temperature, extracted with ethyl acetate
Take, organic phase merges, and concentration, is 50 with volume ratio after drying:1 petroleum ether and ethyl acetate as eluent, column chromatography point
From faint yellow solid compound III is obtained, reaction dissolvent, the screening experiment data of reaction temperature are as follows：
The preparation of compounds Ⅳ：Take compound III to be dissolved in 27mL tetrahydrofurans, under condition of ice bath, add sodium borohydride
And lewis acid, reaction solution are changed into light yellow suspension from yellow solution, 35 DEG C are reacted 1 hour, under ice bath cooling, use saturated carbon
Sour sodium regulation pH is 9 or so, and ethyl acetate extracts three times, and organic phase merges, and after drying, is evaporated to obtain yellowish-brown oily liquids
Compound IV, compound III, sodium borohydride and the screening experiment data of the ratio between the amount of lewis acidic optimisation substance are as follows：
The preparation of compound V：Take compounds Ⅳ to be dissolved in 15mL organic solvents, add organic base, add 0.02mol bromines
Ethyl acetate, 90 DEG C are reacted 2 hours, and reaction solution has brown solution to be changed into yellow-brown suspension.Room temperature is cooled to, adds 50mL
Water, it is extracted with ethyl acetate, is 10 with volume ratio after organic phase merging is dried:1.5 petroleum ether:Ethyl acetate as eluent,
Pillar layer separation obtains yellow solid compound V, organic base species, the screening experiment data of organic solvent species in reaction condition
It is as follows:
The screening experiment data of the ratio between reaction temperature, the amount of material of compounds Ⅳ, organic base and bromoacetate are as follows：
The preparation of compound VI：Take 0.005mol compounds V to be suspended in 4mL concentrated hydrochloric acids, under condition of ice bath, add
The 10mL concentrated hydrochloric acid solutions of 0.009mol stannous chlorides, 50 DEG C are reacted 4 hours, and reaction solution is changed into yellow suspension, ice bath cooling
Under, it is 8~9 with saturated aqueous sodium carbonate regulation pH, is extracted with ethyl acetate, organic phase merges, and after drying, uses volume ratio
For 10:1 petroleum ether：Ethyl acetate as eluent, pillar layer separation obtain 1.01g yellow solid compounds VI, and yield is
69.1%；
The preparation of compound VII：Compound VI is taken to be suspended in the isopropanol water solutions of 18mL 90%, under condition of ice bath,
0.003mol bromine cyanogen is added, reaction forms white suspension.Reaction solution is cooled to room temperature, it is water-soluble with sodium hydroxide under ice bath
Reacting liquid pH value is adjusted to 9 by liquid, is stirred at room temperature 1.5 hours, is filtered, and filter cake is washed with water three times, dry 0.85g white solids
The screening experiment data in compound VII, purity 99.70%HPLC, reaction temperature and reaction time are as follows：
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of anagrelide derivative, it is characterised in that comprise the following steps：
(1) take 1,2,3,4- tetrachlorobenzenes to be suspended in solvent, add the mixed solution of 65% concentrated nitric acid and the concentrated sulfuric acid, 20 DEG C-
3h is stirred under the conditions of 50 DEG C, obtains compound ii, structural formula is as follows：
(2) take compound ii to be dissolved in organic solvent, cuprous cyanide is added, in 110 DEG C of -170 DEG C of heating stirring 4h, then through post color
Isolated compound III is composed, structural formula is as follows：
(3) take compound III to be dissolved in tetrahydrofuran, under ice bath, add sodium borohydride and lewis acid, 10 DEG C~70 DEG C anti-
0.5-8 hours are answered, obtain compounds Ⅳ, structural formula is as follows：
(4) take compounds Ⅳ to be dissolved in organic solvent, add organic base, bromoacetate, 70 DEG C~130 DEG C are reacted 2 hours, warp
Pillar layer separation obtains compound V, and structural formula is as follows：
(5) take compound V to be suspended in concentrated hydrochloric acid, under condition of ice bath, add the concentrated hydrochloric acid solution of stannous chloride, 50 DEG C anti-
Answer 4 hours, obtain compound VI through pillar layer separation, structural formula is as follows：
(6) compound VI is suspended in 90% isopropanol water solution, under condition of ice bath, adds bromine cyanogen, 60 DEG C~120 DEG C anti-
6-30 hours are answered, obtain compound VII, structural formula is as follows：
2. the preparation method of anagrelide derivative according to claim 1, it is characterised in that molten described in step (1)
Agent is the concentrated sulfuric acid or the concentrated sulfuric acid and 1,2- dichloroethanes, described 1, the ratio between amount of material of 2,3,4- tetrachlorobenzenes and concentrated nitric acid is
1:1~1:2.
3. the preparation method of anagrelide derivative according to claim 1 or 2, it is characterised in that described in step (1)
Solvent is the concentrated sulfuric acid, described 1, the ratio between amount of material of 2,3,4- tetrachlorobenzenes and concentrated nitric acid is 1:1.1, the reaction temperature is
35℃。
4. the preparation method of anagrelide derivative according to claim 1, it is characterised in that having described in step (2)
Solvent is pyridine, 2,4,6- trimethylpyridines, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.
5. the preparation method of the anagrelide derivative according to claim 1 or 4, it is characterised in that described in step (2)
Organic solvent is DMA, and the reaction temperature is 145 DEG C, the material of the compound ii and stannous chloride
The ratio between amount is 1:1.
6. the preparation method of anagrelide derivative according to claim 1, it is characterised in that the road described in step (3)
Lewis acid is the ratio between alchlor or boron trifluoride, the amount of the compound III, sodium borohydride and lewis acidic material 1:
0.5:0.5~1:5:5.
7. the preparation method of the anagrelide derivative according to claim 1 or 6, it is characterised in that described in step (3)
Lewis acid is alchlor, the ratio between amount of the compound III, sodium borohydride and lewis acidic material 1:2:2.
8. the preparation method of anagrelide derivative according to claim 1, it is characterised in that having described in step (4)
Solvent is dioxane, DMF or dimethyl sulfoxide (DMSO), and the organic base is triethylamine, ethylenediamine or N, N-
The ratio between diisopropylethylamine, the amount of material of described compounds Ⅳ, organic base and bromoacetate 1:1:0.5~1:3:2.
9. the preparation method of the anagrelide derivative according to claim 1 or 8, it is characterised in that described in step (4)
Organic solvent is dimethyl sulfoxide (DMSO), the organic base DIPEA, described compounds Ⅳ, organic base and bromoacetic acid
The ratio between amount of material of ethyl ester 1:2:1.2, the reaction temperature is 90 DEG C.
10. the preparation method of anagrelide derivative according to claim 1, it is characterised in that anti-described in step (6)
It is 90 DEG C to answer temperature, and the reaction time is 22 hours, and the ratio between amount of material of the compound VI and bromine cyanogen is 1:1.
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| CN201711068717.XA CN107722017A (en) | 2017-11-03 | 2017-11-03 | A kind of preparation method of anagrelide derivative |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041232A (en) * | 2019-04-10 | 2019-07-23 | 丽珠集团新北江制药股份有限公司 | A method of preparing GnRHR key intermediate of medicament compound |
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|---|---|---|---|---|
| US3932407A (en) * | 1973-11-19 | 1976-01-13 | Bristol-Myers Company | Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones |
| WO2009087673A1 (en) * | 2007-12-19 | 2009-07-16 | Watson Pharma Private Limited | Improved process for the manufacture of anagrelide hidrochloride monhydrate |
| CN103254197A (en) * | 2013-05-29 | 2013-08-21 | 黑龙江大学 | Preparation method of anagrelide hydrochloride |
| CN105801429A (en) * | 2014-12-31 | 2016-07-27 | 上海北卡医药技术有限公司 | Preparation method for 3,5,-dichloro-2,4,-difluoroaniline |
-
2017
- 2017-11-03 CN CN201711068717.XA patent/CN107722017A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3932407A (en) * | 1973-11-19 | 1976-01-13 | Bristol-Myers Company | Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones |
| WO2009087673A1 (en) * | 2007-12-19 | 2009-07-16 | Watson Pharma Private Limited | Improved process for the manufacture of anagrelide hidrochloride monhydrate |
| CN103254197A (en) * | 2013-05-29 | 2013-08-21 | 黑龙江大学 | Preparation method of anagrelide hydrochloride |
| CN105801429A (en) * | 2014-12-31 | 2016-07-27 | 上海北卡医药技术有限公司 | Preparation method for 3,5,-dichloro-2,4,-difluoroaniline |
Non-Patent Citations (1)
| Title |
|---|
| P. TRINKA等: "A Simple Synthesis of 2,3-Dichloro-6- nitrobenzonitri", 《J. PRAKT. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041232A (en) * | 2019-04-10 | 2019-07-23 | 丽珠集团新北江制药股份有限公司 | A method of preparing GnRHR key intermediate of medicament compound |
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Application publication date: 20180223 |