CN104119344B - The method that one kind prepares the glyoxalidine of 6,7 dichloro- 1,5 simultaneously [2,1 b] quinazoline 2 (3H) ketone - Google Patents
The method that one kind prepares the glyoxalidine of 6,7 dichloro- 1,5 simultaneously [2,1 b] quinazoline 2 (3H) ketone Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
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Abstract
The present invention provides one kind and prepares 6,7 dichloro-s 1,5 glyoxalidine simultaneously [2,1 b] quinazoline 2 (3H) ketone new method, specifically, the present invention has the compound of the structure as shown in formula (IV) by preparing, then with formula (IV) compound is as intermediate and then prepares anagrelide.The reaction has simple to operate, and reaction condition is gentle, overall low cost, the advantages of high income and purity high, therefore suitable for industrialized production.
Description
Technical field
The present invention relates to medical industry technical field, in particular it relates to a kind of new oral drop blood platelet medicine Ah
The preparation method of that Gray.
Background technology
Anagrelide (Anagrelide AG) is new oral drop blood platelet medicine, belongs to imidazoquinolie chemical classes medicine, is used
In treatment piastrenemia, including polycythemia vera, PMF, chronic granulocyte is from blood
All bone marrow proliferative diseases such as disease, primary thrombocytosis.
AG is that what is be uniquely approved by the FDA in the United States in the world can treat the medicine of primary thrombocytosis, its effect
Be it is very surprising, it is efficient up to more than 80%.Medicine selectivity is strong, without Neuroleptic Leukocytopenia, anaemia and suspicious leukemogenic tight
Many superiority such as side effect again, evident in efficacy and Small side effects and can with long-term use (3-5) the characteristics of, so
After it goes through listing for 1997, the choice drug of all kinds of piastrenemias is just turned at once.
According to the literature, the synthetic route of anagrelide (I) is prepared just like following：
Circuit one：
This is a synthetic route for the anagrelide of US4146718 patent reports (I).The reaction is to be with m-chloroaniline
Raw material, by condensation, cyclisation, chlorination, open loop simultaneously reduces, and replaces, amination and cyclisation totally seven steps, prepares anagrelide
Reaction.The synthetic route yield is low, and generation impurity is more, and product is difficult to purify, and production cost is high, and supplementary material employs pole
The shortcomings of poison and property active cyanogen bromide, therefore it is not suitable for industrialized production.
Circuit two：
The route be Kang Ying et al. [Chinese Journal of Pharmaceuticals, 2001,32 (2), 51-52] to patent US4146718 Ah
The synthetic route of that Gray (I) is improved.The reaction prepares anagrelide still through m-chloroaniline for initiation material,
Avoid using toxicity to be similar to the cyanogen bromide reagent of hydrogen cyanide in reaction, but increased organic deadly poisonous compound bromoacetate and do auxiliary
Material is reacted, while the step of also increasing reaction, operate it is also increasingly complex, therefore, it is difficult to carry out industrialized production.
Circuit three：
Above route is the route that report prepares anagrelide on patent US3932407, and with 1,2,3- benzotrichlorides are original
Material, by nitrification, substitution, reduction then replaces and reduces, cyclization totally seven steps, completes the synthesis of anagrelide.With circuit one
It is similar with circuit two, using organic deadly poisonous compound bromoacetate and the active cyanogen bromide of extremely toxic and property as preparation
Supplementary material, and a large amount of spent acid that the first step is produced are unfavorable for environmental protection, and second step is easily generated more than accessory substance and miscellaneous, total receipts
Rate only has 12.8%, the shortcomings of yield is relatively low, is still not suitable for industrialized production.
In sum, this area needs a kind of high income, low cost, is adapted to the anagrelide preparation side of industrialized production
Method.
The content of the invention
The present invention overcomes the weak point of above-mentioned technical problem, a kind of new anagrelide synthetic route of research and design.
The route has simple to operate a, low production cost, and reaction condition is gentle, and total recovery is high, and it is excellent that the target product purity of synthesis is high etc.
Point, therefore it is adapted to industrialized production.
A kind of the first aspect of the present invention, there is provided compound as shown in formula (IV)：
A kind of the second aspect of the present invention, there is provided the preparation side of formula (IV) compound as shown in first aspect present invention
Method, methods described includes step：
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate and triphosgene, obtain formula (IV)
Compound.
In another preference, described step (2) includes：
(2-1) is reacted with formula III compound with ethyl aminoacetate, obtains formula (III ') compound；
(2-2) is reacted with formula (III ') compound with triphosgene, obtains formula (IV) compound；
In another preference, described (2-2) step includes：
In another preference, after described step (2-1) terminates, product is not separated, directly carry out step (2-
2)。
In another preference, the step (2) is carried out in the presence of base catalyst.
In another preference, the step (2) includes：In atent solvent, with formula (III) compound and amion acetic acid
After ethyl ester reaction a period of time (1-5h), triphosgene and/or base catalyst are added.
In another preference, after being reacted with formula (III) compound and ethyl aminoacetate, TLC methods determine that previous step is anti-
Should complete, add triphosgene and/or base catalyst.
In another preference, described atent solvent is selected from the group：Tetrahydrofuran, dichloromethane, dioxane, first
Benzene, acetonitrile, normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), or its combination；Preferably tetrahydrofuran, dichloromethane, or its combination.
In another preference, described base catalyst is selected from the group：Potassium carbonate, sodium carbonate, sodium acid carbonate, calcium carbonate,
NaOH, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination.
In another preference, described base catalyst is selected from the group：Sodium carbonate, potassium carbonate, or its combination.
In another preference, in the course of reaction, described base catalyst is dividedly in some parts.
In another preference, described base catalyst and/or described triphosgene are added at -20~80 DEG C；Preferably
Ground is added at -10~40 DEG C.
In another preference, described reaction is carried out at -20~80 DEG C；Preferably carried out at -10~40 DEG C.
In another preference, described reaction is quenched with ammonium chloride solution.
In another preference, described formula (III) compound is prepared by the following method：
(1) in atent solvent, reacted with formula (II) compound and oxidising agent, obtain formula (III) compound.
In another preference, described oxidising agent is selected from the group：Osmium tetroxide, potassium permanganate, perchloric acid, ozone,
Sodium peroxide, hydrogen peroxide, metachloroperbenzoic acid, Dai Si-Martin's oxidant, IBX, sodium hypochlorite, or its combination；It is preferred that m-chloro
Benzoyl hydroperoxide, hydrogen peroxide.
In another preference, described atent solvent is selected from the group：Methyl tertiary butyl ether(MTBE), normal heptane, n-hexane, second
Ether, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, or its combination；Preferably dichloromethane.
In another preference, described reaction temperature is -20~50 DEG C, preferably 0~40 DEG C.
A kind of the third aspect of the present invention, there is provided the purposes of formula (IV) compound as described in the first aspect of the invention,
For preparing formula (I) compound (anagrelide).
A kind of the fourth aspect of the present invention, there is provided preparation method of formula (V) compound, methods described includes step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound.
In another preference, in described step (3), described go back original reagent is selected from the group：10% palladium carbon, cyano group
Sodium borohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, boron trifluoride tetrahydrofuran complex compound, sodium borohydride, or its combination；It is preferred that
Boron trifluoride tetrahydrofuran complex compound；And/or
In described step (3), described atent solvent is selected from the group：Methyl alcohol, ethanol, isopropanol, dichloromethane, tetrahydrochysene
Furans, toluene, dimethylbenzene, acetic acid, trifluoroacetic acid, formic acid, or its combination；Preferably tetrahydrofuran.
In another preference, described go back original reagent is dividedly in some parts.
In another preference, the reaction temperature of described step (3) is -20~100 DEG C, preferably -10~80 DEG C.
In another preference, described step (3) is quenched with sodium hydroxide solution.
The fifth aspect of the present invention, there is provided a kind of preparation method of formula (I) compound (anagrelide), methods described bag
Include step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound；
(4) in atent solvent, reacted with chlorination reagent with formula (V) compound, obtained formula (VI) compound；
(5) in atent solvent, reacted with formula (VI) compound and amination reagent, obtain formula (I) compound anagrelide.
In another preference, in the step (4), described chlorination reagent is selected from the group：Chlorine, NCS, protochloride
Sulfone, phosphorus trichloride, POCl3, phosphorus pentachloride, or its combination；It is preferred that phosphorus pentachloride, POCl3.
In another preference, in the step (4), described solvent is selected from the group：Dioxane, dichloromethane,
Tetrahydrofuran, toluene, dimethylbenzene, or its combination；It is preferred that toluene, dimethylbenzene, or its combination.
In another preference, the reaction temperature of described step (4) is 0~150 DEG C, preferably 80~130 DEG C.
In another preference, in the step (5), described amination reagent is selected from the group：Ammoniacal liquor, ammonia, chlorination
Ammonium, or its combination；Preferably ammonia.
In another preference, in the step (5), described amination reagent is the ethanol solution of ammonia.
In another preference, in the step (5), described reaction is carried out in pressure-resistant reactor.
In another preference, in the step (5), described atent solvent is selected from the group：Methyl alcohol, ethanol, isopropyl
Alcohol, ether, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, or its combination；It is preferred that methyl alcohol, ethanol, or its combination.
In another preference, the reaction temperature of described step (5) is 50~150 DEG C, preferably 80~130 DEG C.
In another preference, methods described also includes step：
(1) in atent solvent, with formula (II) compound and oxidant reaction, formula (III) compound is obtained；
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate, obtain formula (IV) compound.
In another preference, described oxidising agent is selected from the group：Osmium tetroxide, potassium permanganate, perchloric acid, ozone,
Sodium peroxide, hydrogen peroxide, metachloroperbenzoic acid, Dai Si-Martin's oxidant, IBX, sodium hypochlorite, or its combination；It is preferred that m-chloro
Benzoyl hydroperoxide, hydrogen peroxide.
In another preference, described atent solvent is selected from the group：Methyl tertiary butyl ether(MTBE), normal heptane, n-hexane, second
Ether, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, or its combination；Preferably dichloromethane.
In another preference, described reaction temperature is -20~80 DEG C, preferably -10~40 DEG C.
In another preference, described step (2) includes：
(2-1) is reacted with formula III compound with ethyl aminoacetate, obtains formula (III ') compound；
(2-2) is reacted with formula (III ') compound with triphosgene, obtains formula (IV) compound；
In another preference, described (2-2) step includes：
In another preference, after described step (2-1) terminates, product is not separated, directly carry out step (2-
2)。
In another preference, the step (2) is carried out in the presence of base catalyst.
In another preference, the step (2) includes：In atent solvent, with formula (III) compound and amion acetic acid
After ethyl ester reaction a period of time, triphosgene and/or base catalyst are added.
In another preference, described atent solvent is selected from the group：Tetrahydrofuran, dichloromethane, dioxane, first
Benzene, acetonitrile, normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), or its combination；Preferably tetrahydrofuran, dichloromethane, or its combination.
In another preference, described base catalyst is selected from the group：Potassium carbonate, sodium carbonate, sodium acid carbonate, calcium carbonate,
NaOH, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination.
In another preference, described base catalyst is selected from the group：Sodium carbonate, potassium carbonate, or its combination.
In another preference, in the course of reaction, described base catalyst is dividedly in some parts.
In another preference, described base catalyst and/or described triphosgene are added at -20~80 DEG C；Preferably
Ground is added at -10~40 DEG C.
In another preference, described reaction is carried out at -20~80 DEG C；Preferably carried out at -10~40 DEG C.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
Can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that, there is the structure as shown in formula (IV) by preparing
Compound, and as intermediate so as to prepare formula (I) compound anagrelide, can be with shorter route and higher
Yield obtains end-product anagrelide, and accessory substance is few, is not related to the compound bromoacetate that toxicity is stronger in preparation process
Or hydrogen bromide, thus it is highly suitable for industrialization large-scale production.Based on above-mentioned discovery, inventor completes the present invention.
Term
As used herein, term " anagrelide ", " formula (I) compound " or " 6,7- dichloro- -1,5- glyoxalidine is simultaneously
[2,1-b] quinazoline -2- (3H) -one " is used interchangeably, and refers both to the compound as shown in following formula (I)：
Formula (IV) compound
The invention provides compound of the one kind as shown in formula (IV)：
Described formula (IV) compound can be prepared by the following method：
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate and triphosgene, obtain formula (IV)
Compound.
In a preferred embodiment of the invention, the step (2) is including step：
(2-1) is reacted with formula III compound with ethyl aminoacetate, obtains formula (III ') compound；
(2-2) is reacted with formula (III ') compound with triphosgene, obtains formula (IV) compound；
In another preference, described (2-2) step includes：
In another preference, after described step (2-1) terminates, product is not separated, directly carry out step (2-
2)。
In another preference of the invention, described reaction is carried out in the presence of base catalyst.In another preference,
Described base catalyst is selected from the group：Potassium carbonate, sodium carbonate, sodium acid carbonate, calcium carbonate, NaOH, potassium hydroxide, hydroxide
Calcium, lithium hydroxide, or its combination.In another preference, described base catalyst is selected from the group：Sodium carbonate, potassium carbonate, or its
Combination.
Described each material can be added in reaction system in any way, in a kind of preferred embodiment of the invention
In, the step (2) includes：In atent solvent, after reacting a period of time with formula (III) compound and ethyl aminoacetate,
Add triphosgene and/or base catalyst.
In another preference, in the course of reaction, described base catalyst is dividedly in some parts.
Described atent solvent has no particular limits, and in another preference, described atent solvent is selected from the group：Four
Hydrogen furans, dichloromethane, dioxane, toluene, acetonitrile, normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), or its combination；Preferably
Tetrahydrofuran, dichloromethane, or its combination.
Described base catalyst and/or triphosgene should be added at suitable temperature and reaction condition.Another preferred
In example, described base catalyst and/or described triphosgene are added at -20~80 DEG C；Preferably add at -10~40 DEG C
Enter.In another preference of the invention, after described formula (III) compound and ethyl aminoacetate react 0.5-8h, compared with
After good ground 1-5h, after more preferably 2-4h, described base catalyst and/or triphosgene is added.
In another preference, described reaction is carried out at -20~80 DEG C；Preferably carried out at -10~40 DEG C.
Each raw material can be bought by commercially available approach, or prepared by methods known in the art.At one of the invention preferably
In example, described formula (III) compound is prepared by the following method：
(1) in atent solvent, with formula (II) compound and oxidant reaction, formula (III) compound is obtained.
In another preference, described oxidising agent is selected from the group：Osmium tetroxide, potassium permanganate, perchloric acid, ozone,
Sodium peroxide, hydrogen peroxide, metachloroperbenzoic acid, Dai Si-Martin's oxidant, IBX, sodium hypochlorite, or its combination；It is preferred that m-chloro
Benzoyl hydroperoxide, hydrogen peroxide.
In another preference, described atent solvent is selected from the group：Methyl tertiary butyl ether(MTBE), normal heptane, n-hexane, second
Ether, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, or its combination；Preferably dichloromethane.
In another preference, described reaction temperature is -20~50 DEG C, preferably 0~40 DEG C.
Described formula (III) compound can be used for preparing formula (I) compound (anagrelide), or prepare formula (I) chemical combination
Intermediate in thing building-up process, for example, formula (V) compound or formula (VI) compound.
The preparation of formula (V) compound
The present invention provides a kind of preparation method of formula (V) compound, it is characterised in that including step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound.
In preference of the invention, in described step (3), described go back original reagent is selected from the group：10% palladium carbon,
Sodium cyanoborohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, boron trifluoride tetrahydrofuran complex compound, sodium borohydride, or its combination；
It is preferred that sodium borohydride；And/or
In described step (3), described atent solvent is selected from the group：Methyl alcohol, ethanol, isopropanol, dichloromethane, tetrahydrochysene
Furans, toluene, dimethylbenzene, acetic acid, trifluoroacetic acid, formic acid, or its combination；Preferably tetrahydrofuran.
In another preference, described go back original reagent is dividedly in some parts.
In another preference, the reaction temperature of described step (3) is -20~100 DEG C, preferably -10~80 DEG C.
The preparation of formula (I) compound (anagrelide)
Present invention also offers the preparation method of a kind of formula (I) compound (anagrelide), methods described includes step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound；
(4) in atent solvent, reacted with chlorination reagent with formula (V) compound, obtained formula (VII) compound；
(5) in atent solvent, reacted with formula (VI) compound and amination reagent, obtain formula (I) compound anagrelide.
In another preference, in the step (4), described chlorination reagent is selected from the group：Chlorine, NCS, protochloride
Sulfone, phosphorus trichloride, POCl3, phosphorus pentachloride, or its combination；It is preferred that phosphorus pentachloride, POCl3.
In another preference, in the step (4), described solvent is selected from the group：Dioxane, dichloromethane,
Tetrahydrofuran, toluene, dimethylbenzene, or its combination；It is preferred that toluene, dimethylbenzene, or its combination.
In another preference, the reaction temperature of described step (4) is 0~150 DEG C, preferably 80~130 DEG C.
In another preference, in the step (5), described amination reagent is selected from the group：Ammoniacal liquor, ammonia, chlorination
Ammonium, or its combination；Preferably ammonia.
In another preference, in the step (5), described reaction is carried out in pressure-resistant reactor.
In another preference, in the step (5), described atent solvent is selected from the group：Methyl alcohol, ethanol, isopropyl
Alcohol, ether, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, or its combination；It is preferred that methyl alcohol, ethanol, or its combination.
In another preference, the reaction temperature of described step (5) is 50~150 DEG C, preferably 80~130 DEG C.
In another preference of the invention, methods described also includes step：
(1) in atent solvent, with formula (II) compound and oxidant reaction, formula (III) compound is obtained；
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate, obtain formula (IV) compound.
A kind of method that particularly preferred present invention prepares anagrelide is with formula (II) compound and formula (III) compound
As initiation material, comprise the following steps：
The preparation of (1) 5,6- bis- chloroisatoic anhydride (III)：
By the chlorisatides of 4,5- bis- (II) dispersions in a suitable solvent, appropriate oxidant is added, at a suitable temperature
Aoxidized, reaction just can obtain the chloroisatoic anhydrides of 5,6- bis- (III) after completing through appropriate post processing.
Wherein：Suitable solvent is methyl tertiary butyl ether(MTBE), normal heptane, n-hexane, ether, dichloromethane, tetrahydrofuran, first
Benzene, dimethylbenzene etc., preferably dichloromethane；Oxidant is osmium tetroxide, potassium permanganate, perchloric acid, ozone, sodium peroxide, dioxygen
Water, metachloroperbenzoic acid, Dai Si-Martin's oxidant, IBX, sodium hypochlorite, preferably metachloroperbenzoic acid, hydrogen peroxide；Suitably
At a temperature of be dividedly in some parts；Reaction temperature is -20~50 DEG C, preferably 0~40 DEG C.
(2) preparation of compound (IV)：
5,6- bis- chloroisatoic anhydrides (III) in a suitable solvent, add ethyl aminoacetate, at a suitable temperature instead
After answering the suitable time, triphosgene and corresponding base catalyst are added, continue to react reasonable time, obtain compound
(Ⅳ)。
Wherein：Suitable solvent is tetrahydrofuran, dichloromethane, dioxane, toluene, acetonitrile, normal heptane, n-hexane,
Methyl tertiary butyl ether(MTBE) etc., preferably tetrahydrofuran, dichloromethane；Described catalyst is potassium carbonate, sodium carbonate, sodium acid carbonate, carbon
Sour calcium, NaOH, potassium hydroxide, calcium hydroxide, lithium hydroxide, preferably sodium carbonate, potassium carbonate；Add in batches under preference temperature
Enter；The described temperature of reaction is -20~80 DEG C, preferably -10~40 DEG C
(3) preparation of compound (V)
Appropriate reducing agent is dividedly in some parts in suitable solvent, compound (IV) is then slowly added into, in suitable temperature
Reduced under degree, through appropriate treatment, obtained compound (V).
Wherein：Suitable solvent is methyl alcohol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene, acetic acid,
Trifluoroacetic acid, formic acid etc., preferably trifluoroacetic acid；Go back original reagent is 10% palladium carbon, sodium cyanoborohydride, acetic acid sodium borohydride, hydrogen
Change aluminium lithium, preferably boron trifluoride tetrahydrofuran complex compound or sodium borohydride etc., boron trifluoride tetrahydrofuran complex compound；Preference temperature
Under be dividedly in some parts；Reaction temperature is -20~100 DEG C, preferably -10~80 DEG C.
(4) preparation of compound (VI)
Compound (V) is dissolved in suitable solvent, adds appropriate chlorination reagent, and chlorination is carried out at a suitable temperature
Reaction, reaction obtains compound (VI) after completing through appropriate treatment.
Wherein：Suitable solvent is dioxane, dichloromethane, tetrahydrofuran, toluene, dimethylbenzene etc., preferably toluene, two
Toluene；Chlorination reagent is chlorine, NCS, thionyl chloride, phosphorus trichloride, POCl3, phosphorus pentachloride, preferably phosphorus pentachloride, trichlorine
Oxygen phosphorus；It is dividedly in some parts under preference temperature；Reaction temperature is 0~150 DEG C, preferably 80~130 DEG C.
(5) preparation of anagrelide (I)：
Compound (VI) is dissolved in suitable solvent, appropriate amination reagent is added, in suitable pressure and suitable
At a temperature of complete amination and cyclization, can obtain target product anagrelide (I) through appropriate treatment.
Wherein：Described suitable solvent is methyl alcohol, ethanol, isopropanol, ether, dichloromethane, tetrahydrofuran, toluene, two
Toluene, preferably methyl alcohol, ethanol；The suitable amination reagent is ammoniacal liquor, ammonia, preferably ammonium chloride, ammonia；Reaction temperature is 50
~150 DEG C, preferably 80~130 DEG C.
Main advantages of the present invention include：
Compared with the synthetic method of previous literature report, the present invention reacts has simple to operate, low cost, high income,
Reaction condition is gentle and the advantages of target product purity of synthesis high, therefore is adapted to industrialized production.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number is calculated by weight.
Embodiment 1：
(1) preparation of the chloroisatoic anhydrides of 5,6- bis- (III)：
The chlorisatides of 4,5- bis- (II) (50.0g, 231.46mmol) is dissolved in dichloromethane (600ml), is divided at room temperature
Batch adds metachloroperbenzoic acid (79.89g, 462.92mmol), and stirring reaction 2h, TLC detection reaction is completed.Suction filtration is few
Amount dichloromethane washing, can obtain 5,6- bis- chloroisatoic anhydride (III) 51.02g, and yield is 95%.
(2) preparation of compound (IV)：
In 5,6- bis- chloroisatoic anhydride (III) (50.0g, 215.50mmol) tetrahydrofurans (450ml), amino second is added
Acetoacetic ester (24.4g, 237.05mmol), stirs 3h at room temperature, adds triphosgene (63.95g, 215.50mmol) and carbonic acid
Sodium (45.68g, 431.0mmol), continues to stir 8h, and TLC detection reactions are completed.Ammonium chloride reaction solution is added dropwise to be quenched, reclaims
Tetrahydrofuran, ethyl acetate (3x200ml) is extracted, and merges organic phase, successively with water (2x100ml) and salt solution (100ml)
Washing, anhydrous sodium sulfate drying is spin-dried for, second alcohol and water (10:1) recrystallize, compound (IV) 58.1g can be obtained, yield is 85%.
1HNMR(400MHz；CDCl3):δ 8.22 (s, 1H), 7.72 (s, 1H), 4.53 (s, 2H), 4.13 (d, J=4.8Hz,
2H),1.22(m,3H).C12H11Cl2N2O4(M+H)+Calcd:317.0096,found:317.0106.
(3) preparation of compound (V)
500ml three neck round bottom is taken, BH is added3THF (191.1mL, 1M), is cooled to 0 DEG C, is slowly added into 0 DEG C
Compound (IV) (20.0g, 63.7mmol) solution of THF (150ml) is dissolved in, 15min is stirred at such a temperature, be subsequently placed in oil
The 1h that flows back is heated in bath, TLC detection reactions are completed.It is cooled to 0 DEG C, 2.0M NaOH (70mL) is added dropwise reaction solution is quenched
Go out.Rotation goes THF, Liquid Residue to be extracted with dichloromethane (3x70mL), merges organic phase, with water (70mL) and saturated aqueous common salt
(70mL) is washed successively, anhydrous sodium sulfate drying, suction filtration, is spin-dried for compound (V) 16.61g, and yield is 86%.
(4) preparation of compound (VI)
Compound (V) (15.0g, 49.48mmol) is dissolved in the solvent of toluene (150ml), phosphorus pentachloride is added
(20.57g, 98.96mmol) and it is heated with stirring to 100 DEG C, reaction 5h, TLC detection reaction completion.Carried out with water (150ml) dilute
Release, reclaim toluene, Liquid Residue extracted (3x100ml) with dichloromethane, 5% sodium carbonate (200ml) and saturated aqueous common salt
(100ml) is washed successively, anhydrous sodium sulfate drying, is spin-dried for obtaining compound (VI) 14.0g, and yield is 88%.
(5) preparation of anagrelide (I)：
The ethanol solution (50ml) of compound (VI) (5.0g, 15.55mmol) and 10% ammonia is put into closed pressure-resistant anti-
In answering kettle, and heat and rise to 120 DEG C, react 10h, reaction is completed, and is cooled to room temperature, is filtered, and a small amount of ethanol washing, drying can be obtained
Shallow white solid product anagrelide (I) 3.74g, yield is 94%.
Embodiment 2：
(1) preparation of the chloroisatoic anhydrides of 5,6- bis- (III)：
The chlorisatides of 4,5- bis- (II) (50.0g, 231.46mmol) is dissolved in dichloromethane (600ml), is divided at room temperature
Batch adds metachloroperbenzoic acid (59.91g, 347.19mmol), and stirring reaction 2.5h, TLC detection reaction is completed.Suction filtration,
A small amount of dichloromethane washing, can obtain 5,6- bis- chloroisatoic anhydride (III) 49.95g, and yield is 93%.
(2) preparation of compound (IV)：
In 5,6- bis- chloroisatoic anhydride (III) (40.0g, 172.40mmol) tetrahydrofurans (350ml), amino second is added
Acetoacetic ester (19.52g, 189.64mmol), stirs 3h at room temperature, adds triphosgene (51.16g, 172.40mmol) and carbon
Sour sodium (27.41g, 258.60mmol), continues to stir 8h, and TLC detection reactions are completed.Ammonium chloride reaction solution is added dropwise to be quenched,
Tetrahydrofuran is reclaimed, ethyl acetate (3x150ml) is extracted, merge organic phase, successively with water (2x80ml) and salt solution
(80ml) is washed, and anhydrous sodium sulfate drying is spin-dried for, second alcohol and water (10:1) recrystallize, compound (IV) 42.65g, yield can be obtained
It is 78%.
(3) preparation of compound (V)
500ml three neck round bottom is taken, BH is added3THF (191.1mL, 1M), is cooled to 0 DEG C, is slowly added into 0 DEG C
Compound (IV) (20.0g, 63.7mmol) solution of THF (150ml) is dissolved in, 15min is stirred at such a temperature, be subsequently placed in oil
The 1h that flows back is heated in bath, TLC detection reactions are completed.It is cooled to 0 DEG C, 2.0M NaOH (70mL) is added dropwise reaction solution is quenched
Go out.Rotation goes THF, Liquid Residue to be extracted with dichloromethane (3x70mL), merges organic phase, with water (70mL) and saturated aqueous common salt
(70mL) is washed successively, anhydrous sodium sulfate drying, suction filtration, is spin-dried for compound (V) 16.99g, and yield is 88%..
(4) preparation of compound (VI)
Compound (V) (10.0g, 32.99mmol) is dissolved in the solvent of toluene (150ml), phosphorus pentachloride is added
(10.30g, 49.48mmol) and it is heated with stirring to 100 DEG C, reaction 5h, TLC detection reaction completion.Carried out with water (100ml) dilute
Release, reclaim toluene, Liquid Residue extracted (3x80ml) with dichloromethane, 5% sodium carbonate (150ml) and saturated aqueous common salt
(80ml) is washed successively, anhydrous sodium sulfate drying, is spin-dried for obtaining compound (VI) 9.02g, and yield is 85%.
(5) preparation of anagrelide (I)：
The ethanol solution (50ml) of compound (VI) (5.0g, 15.55mmol) and 10% ammonia is put into closed pressure-resistant
In reactor, and heating rises to 120 DEG C, reacts 10h, and reaction is completed, and is cooled to room temperature, is filtered, and a small amount of ethanol is washed, and drying can
Shallow white solid anagrelide (I) 3.58g is obtained, yield is 90%.
Embodiment 3：
(1) preparation of the chloroisatoic anhydrides of 5,6- bis- (III)：
The chlorisatides of 4,5- bis- (II) (50.0g, 231.46mmol) is dissolved in tetrahydrofuran (600ml), is divided at room temperature
Batch adds metachloroperbenzoic acid (59.91g, 347.19mmol), and stirring reaction 2.5h, TLC detection reaction is completed.Suction filtration,
A small amount of tetrahydrofuran washing, can obtain 5,6- bis- chloroisatoic anhydride (III) 44.04g, and yield is 82%.
(2) preparation of compound (IV)：
In 5,6- bis- chloroisatoic anhydride (III) (30.0g, 129.30mmol) tetrahydrofurans (300ml), amino second is added
Acetoacetic ester (14.64g, 189.64mmol), stirs 2.5h at room temperature, add triphosgene (38.37g, 129.30mmol) and
Potassium carbonate (26.81g, 193.95mmol), continues to stir 6h, and TLC detection reactions are completed.Ammonium chloride reaction solution is added dropwise to be quenched
Go out, reclaim tetrahydrofuran, ethyl acetate (3x150ml) is extracted, merge organic phase, successively with water (2x80ml) and salt solution
(80ml) is washed, and anhydrous sodium sulfate drying is spin-dried for, second alcohol and water (10:1) recrystallize, compound (IV) 35.67g, yield can be obtained
It is 87%.
(3) preparation of compound (V)
500ml three neck round bottom is taken, BH3THF (191.1mL, 1M) is added, is cooled to 0 DEG C, be slowly added into 0 DEG C
Compound (IV) (20.0g, 63.7mmol) solution of THF (150ml) is dissolved in, 15min is stirred at such a temperature, be subsequently placed in oil
The 1h that flows back is heated in bath, TLC detection reactions are completed.It is cooled to 0 DEG C, 2.0M NaOH (70mL) is added dropwise reaction solution is quenched
Go out.Rotation goes THF, Liquid Residue to be extracted with dichloromethane (3x70mL), merges organic phase, with water (70mL) and saturated aqueous common salt
(70mL) is washed successively, anhydrous sodium sulfate drying, suction filtration, is spin-dried for compound (V) 16.22g, and yield is 84%..
(4) preparation of compound (VI)
Compound (V) (15.0g, 49.48mmol) is dissolved in the solvent of toluene (150ml), phosphorus pentachloride is added
(20.57g, 98.96mmol) and it is heated with stirring to 100 DEG C, reaction 5h, TLC detection reaction completion.Carried out with water (150ml) dilute
Release, reclaim toluene, Liquid Residue extracted (3x100ml) with dichloromethane, 5% sodium carbonate (200ml) and saturated aqueous common salt
(100ml) is washed successively, anhydrous sodium sulfate drying, is spin-dried for obtaining compound (VI) 13.68g, and yield is 86%.
(5) preparation of anagrelide (I)：
The ethanol solution (50ml) of compound (VI) (10.0g, 31.10mmol) and 15% ammonia is put into closed pressure-resistant anti-
In answering kettle, and heat and rise to 120 DEG C, react 10h, reaction is completed, and is cooled to room temperature, is filtered, and a small amount of ethanol washing, drying can be obtained
Shallow white solid product anagrelide (I) 7.65g, yield is 95%.
The all documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after above-mentioned instruction content of the invention has been read, those skilled in the art can
Made various changes or modifications with to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (11)
1. compound of the one kind as shown in formula (IV)：
2. the preparation method of formula (IV) compound as shown in claim 1, it is characterised in that including step：
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate and triphosgene, obtain formula (IV) chemical combination
Thing.
3. method as claimed in claim 2, it is characterised in that the step (2) is carried out in the presence of base catalyst.
4. method as claimed in claim 3, it is characterised in that described base catalyst is selected from the group：Potassium carbonate, sodium carbonate,
Sodium acid carbonate, NaOH, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination.
5. method as claimed in claim 2, it is characterised in that described formula (III) compound is to be prepared by the following method
's：
(1) in atent solvent, reacted with formula (II) compound and oxidising agent, obtain formula (III) compound.
6. the purposes of formula (IV) compound as claimed in claim 1, it is characterised in that for preparing formula (I) compound：
7. a kind of preparation method of formula (V) compound, it is characterised in that including step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound.
8. preparation method as claimed in claim 7, it is characterised in that in described step (3), described go back original reagent choosing
From the following group：10% palladium carbon, sodium cyanoborohydride, acetic acid sodium borohydride, lithium aluminium hydride reduction, boron trifluoride tetrahydrofuran complex compound, boron
Sodium hydride, or its combination；And/or
In described step (3), described atent solvent is selected from the group：Methyl alcohol, ethanol, isopropanol, dichloromethane, tetrahydrochysene furan
Mutter, toluene, dimethylbenzene, acetic acid, trifluoroacetic acid, formic acid, or its combination.
9. preparation method as claimed in claim 8, it is characterised in that in described step (3), described go back original reagent is
Boron trifluoride tetrahydrofuran complex compound；And/or
In described step (3), described atent solvent is tetrahydrofuran.
10. a kind of preparation method of formula (I) compound, it is characterised in that including step：
(3) in atent solvent, reacted with go back original reagent with formula (IV) compound, obtained formula (V) compound；
(4) in atent solvent, reacted with chlorination reagent with formula (V) compound, obtained formula (VI) compound；
(5) in atent solvent, reacted with formula (VI) compound and amination reagent, obtain formula (I) compound anagrelide.
The preparation method of 11. formula (I) compounds as claimed in claim 10, it is characterised in that methods described also includes step：
(1) in atent solvent, with formula (II) compound and oxidant reaction, formula (III) compound is obtained；
(2) in atent solvent, reacted with formula (III) compound and ethyl aminoacetate, obtain formula (IV) compound.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0456835A1 (en) * | 1989-12-11 | 1991-11-21 | Kyorin Pharmaceutical Co., Ltd. | Quinazoline-3-alkanoic acid derivative, salt thereof, and production thereof |
| WO2011114160A1 (en) * | 2010-03-18 | 2011-09-22 | Shire Llc | Anagrelide derivatives (imidazo [2, 1-b] quinazolin - 2 - ones ) as pde iii inhibitors useful as antithrombotic agents |
| CN103333078A (en) * | 2013-06-14 | 2013-10-02 | 苏州汇和药业有限公司 | Synthesis method for key intermediate, analogue or salt of ticlopidine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5679675A (en) * | 1979-12-03 | 1981-06-30 | Dai Ichi Seiyaku Co Ltd | Production of 2-halogeno-3-substituted 3,4- dihydroquinazoline |
| JPS56110678A (en) * | 1980-02-07 | 1981-09-01 | Dai Ichi Seiyaku Co Ltd | Preparation of alkoxycarbonylmethyl-substituted condensed pyrimidine compound |
-
2014
- 2014-05-30 CN CN201410241179.XA patent/CN104119344B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0456835A1 (en) * | 1989-12-11 | 1991-11-21 | Kyorin Pharmaceutical Co., Ltd. | Quinazoline-3-alkanoic acid derivative, salt thereof, and production thereof |
| WO2011114160A1 (en) * | 2010-03-18 | 2011-09-22 | Shire Llc | Anagrelide derivatives (imidazo [2, 1-b] quinazolin - 2 - ones ) as pde iii inhibitors useful as antithrombotic agents |
| CN103333078A (en) * | 2013-06-14 | 2013-10-02 | 苏州汇和药业有限公司 | Synthesis method for key intermediate, analogue or salt of ticlopidine |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸阿那格雷的合成;翁志洁，等;《中国医药工业杂志》;20121231;第43卷(第6期);第405-408页 * |
| 血小板凝聚抑制剂阿那格雷的合成;康影，等;《中国医药工业杂志》;20011231;第32卷(第2期);第51-52页 * |
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