CN101870695B - Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone - Google Patents
Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone Download PDFInfo
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- CN101870695B CN101870695B CN2009100499856A CN200910049985A CN101870695B CN 101870695 B CN101870695 B CN 101870695B CN 2009100499856 A CN2009100499856 A CN 2009100499856A CN 200910049985 A CN200910049985 A CN 200910049985A CN 101870695 B CN101870695 B CN 101870695B
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Abstract
The invention relates to a preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone, which adopts nucleophilicity organic small-molecular catalyst as a catalyst, 2 - amino -3-hydroxypyridine and 2 - acetyl pyridine have cyclization reaction according to a chemical measurement ratio to obtain 3 - (2 - hydroxyethyl) -9-- hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone, then the 3 - (2 - hydroxyethyl) -9-- hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone is catalyzed and hydrogenated to obtain diol intermediate 3 - (2 - hydroxyethyl) -6,7,8,9 - tetrahydro-9 - hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone, and then primary hydroxyl group is selectively chloridized to obtain Paliperidone intermediate: 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone. Compared with the prior art, the method has the advantages of low cost, small environmental pollution, high selectivity and the like.
Description
Technical field
The present invention relates to a kind of medicine intermediate, especially relate to a kind of RO 76477 midbody 3-(2-chloroethyl)-6,7,8, the preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.
Background technology
Compound 3-(2-chloroethyl)-6,7,8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one is the intermediate A of synthetic so-and-so medicine RO 76477, mainly containing two kinds of methods at present can synthesize.One) from the 2-amino-3-pyridone of benzyl protection, through cyclisation, chlorination and hydrogenation obtain.Two) from unprotected 2-amino-3-pyridone, through cyclisation, chlorination and hydrogenation obtain.These two kinds of methods are all inevitable must to generate by product C with chlorizate B over-hydrogenation.
With SiO
2, gac, Al
2O
3Deng the palladium metal that is carrier, perhaps with Al (OH)
3Be the metallic nickel of carrier, the compound of pyrido [1,2-α] pyrimidin-4-one structure can be hydrogenated and be 4-pyridinium hydroxide [1,2-α] pyrimidin-4-one (its reaction formula is following) also.Contain simultaneously alkyl chloride in the structure segmental the time, inevitable again the catalytic hydrogenation dechlorination reaction must take place.The use platinum carbon catalyst can suppress the generation of this side reaction, but the expensive price of platinum carbon catalyst makes this catalysts selective on suitability for industrialized production, not to be applied.
85% key intermediate A, 15% dechlorination by product
Also has a kind of method; Earlier the secondary hydroxyl in the starting raw material is got up with benzyl protection exactly, with post chlorization, hydrogenated pyridine also [1 again; 2-α] pyrimidin-4-one; Slough protection basic benzyl (its reaction formula is following) simultaneously, the advantage of this method is Polychlorinated problem can not take place in the chlorination process, but still can not solve the catalytic hydrogenation dechlorination side reaction in the hydrogenation process.
85% key intermediate A, 15% dechlorination by product
Summary of the invention
The object of the invention is exactly for the defective that overcomes above-mentioned prior art existence the 3-that a kind of cost is low, environmental pollution is little, selectivity is high (2-chloroethyl)-6 to be provided; 7; 8, the preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.
The object of the invention can be realized through following technical scheme: a kind of 3-(2-chloroethyl)-6,7,8; The preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one is characterized in that; This method is to be catalyzer with the nucleophilicity organic micromolecule catalyst, and 2-amino-3-pyridone and 2-acetylpyridine are obtained 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one by the stoichiometric ratio cyclization; Carry out catalytic hydrogenation then and obtain two alcohol intermediate 3-(2-hydroxyethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one, selective chlorination primary hydroxyl again; Promptly obtain RO 76477 key intermediate: 3-(2-chloroethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one, its reaction formula is following:
Described nucleophilicity organic micromolecule catalyst is dimethylamino pyridine (DMAP).
The catalyzer of described catalytic hydrogenation is a palladium-carbon catalyst.
The temperature of reaction of described catalytic hydrogenation is 40-60 ℃, and reaction pressure is that 0.1-0.2 atmospheric hydrogen excess pressure is 1.1-1.2 atmospheric interior the pressure.
The chlorination reagent that adopts in the described selective chlorination primary hydroxyl comprises POCl
3, PCl
5Or SOCl
2
The temperature of reaction of described selective chlorination primary hydroxyl is 50-70 ℃, and the reaction times is 5-7h.
Compared with prior art; The present invention is in the process of synthetic RO 76477 intermediate A; Developed the synthetic starting raw material 3-(2-hydroxyethyl) of the catalytic ring-closure reaction of nucleophilicity organic micromolecule catalyst DMAP (dimethylamino pyridine)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] novel method of pyrimidin-4-one, reaction formula is as follows.
The lab scale result shows, nucleophilicity organic micromolecule catalyst DMAP (dimethylamino pyridine) is the ring-closure reaction of catalysis 2-amino-3-pyridone and 2-ethanoyl GBL effectively, and productive rate reaches 75% (the use tosic acid is made catalyzer, productive rate 74%).This step is different from the Catalyzed by p-Toluenesulfonic Acid system of having reported, reaction can not re-use expensive, and the chlorobenzene that toxicity is big is a solvent, adopts cheap toluene to get final product.Can effectively reduce big production cost, alleviate environmental pollution.
Simultaneously, in new synthesis route, with 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] pyrimidin-4-one is the hydrogenation starting raw material; Owing to no longer contain the alkyl chloride fragment in the structure, in hydrogenation process, catalytic hydrogenation dechlorination side reaction common in the prior art can not take place again.And the hydroxyl in the structure can be by POCl in afterreaction
3, PCl
5, SOCl
2Etc. the common chlorination reagent chlorination that cheaply is easy to get, obtain target compound RO 76477 key intermediate A.Through the appropriate design reactions step, select gentleness, reaction reagent and reaction conditions that selectivity is high, reach efficient, environmental protection, economy must be synthesized RO 76477 key intermediate A.
100% key intermediate A
Embodiment
Below in conjunction with accompanying drawing and specific embodiment the present invention is elaborated.
RO 76477 midbody 3-of the present invention (2-chloroethyl)-6; 7; 8, the preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one; Be that cyclization with nucleophilicity organic micromolecule catalyst DMAP (dimethylamino pyridine) catalysis 2-amino-3-pyridone and 2-acetylpyridine obtains 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.Shown in reaction mechanism can be descended.
Carry out catalytic hydrogenation subsequently and obtain two alcohol intermediate 3-(2-hydroxyethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one, the selective chlorination primary hydroxyl; Can obtain RO 76477 key intermediate A, 3-(2-chloroethyl)-6,7; 8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.The reaction formula of this technological process is as follows:
Embodiment 1
A kind of RO 76477 intermediates preparation, this method may further comprise the steps:
(1) cyclization
Reaction flask is installed water trap, and tap funnel adds 1200 milliliters of toluene, adds 110.12 gram 2-amino-3-pyridones.Drip 2-ethanoyl GBL 134.53 grams then under the stirring at room.Tap funnel drips in the reaction flask with 200 milliliters of toluene wash, adds dimethylamino pyridine 3 grams then and makees catalyzer, reaction system heating reflux reaction (beginning to reflux at 115 degree).Reflux and (in this process, will divide water) after 18 hours, be as cold as 80 degree, adds 200 milliliters of Virahols, 25 gram gacs are then with being heated to backflow (100 spend backflow) in 30 minutes.Spend in 85 degree 80 then and filter, filter cake is with 100 milliliters of toluene (80 degree temperature) washing, the filtrating cool to room temperature of merging; In the 40-45 degree, begin to separate out product, continue to leave standstill 18 hours (under the room temperature) and separate out solid collected by filtration up to product fully; 100 milliliters of chlorobenzene washings; 50 to 60 degree vacuum-dryings 24 hours obtain 167 gram products 75%, fusing point 150 degree.Purity is higher than 98%.
(2) catalytic hydrogenation
5 litre bottle, the first step product of adding 250 grams, gac 40 grams, 2 liters of methyl alcohol.Mixture heating up to 50 degree stirred 1 hour, filtered then.Filter cake washs with 200 ml methanol.Methanol solution then and 55 gram palladium charcoals (10%, moisture 50%) add the hydrogenation still.Vacuumize displacement hydrogen three times.Be heated to 50 degree, 0.15 atmospheric hydrogen excess pressure (pressing just is 1.15 normal atmosphere) hydrogenation.After 5 hours, cold filtration, filter cake washs with 300 ml methanol.Boil off methyl alcohol then and obtain heavy-gravity oily matter.80 degree added 900 gram water in following 20 minutes, were cooled to 25 degree then, were added dropwise to the Potassium ethanoate aqueous solution (180 gram Potassium ethanoates, 180 ml waters), dripped in 1 hour.5 degree stirred 2 hours down then.Filtration obtains crystal, washes twice (each 250 milliliters), and vacuum 40 degree dryings obtain product 198.6 grams, 78% productive rate.Purity 99.0%.
(3) selective chlorination primary hydroxyl
250 milliliters of three-necked bottles add 50 milliliters of chloroforms, add 25 gram thionyl chlorides, drip 2 DMF, add reflux condensing tube, tap funnel.11 gram alcohol (the second step product) are dissolved in 50 milliliters of chloroforms, are added in the tap funnel.Dropwise half a hour, is heated to 60 degree then, stirred 6 hours.Cooling feeds hydrochloric acid gas, decompression and solvent recovery (absorption of tail gas alkali lye).Residuum obtains 11.2 grams with MTBE crystallization deposition, productive rate 94%, and purity is greater than 99.0%.
Embodiment 2
A kind of RO 76477 intermediates preparation, this method are with nucleophilicity organic micromolecule catalyst dimethylamino pyridine (DMAP), and 2-amino-3-pyridone and 2-acetylpyridine are obtained 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1 by the stoichiometric ratio cyclization; 2-α] pyrimidin-4-one; In the presence of palladium-carbon catalyst, carry out catalytic hydrogenation then and obtain two alcohol intermediate 3-(2-hydroxyethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] pyrimidin-4-one, temperature of reaction is 40 ℃, reaction pressure is i.e. 1.2 atmospheric interior pressures of 0.2 atmospheric hydrogen excess pressure; Adopt POCl again
3Be chlorination reagent, in 50 ℃, the reaction times is 7h, and the selective chlorination primary hydroxyl promptly obtains RO 76477 key intermediate: 3-(2-chloroethyl)-6,7,8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.
Embodiment 3
A kind of RO 76477 intermediates preparation, this method are with nucleophilicity organic micromolecule catalyst dimethylamino pyridine (DMAP), and 2-amino-3-pyridone and 2-acetylpyridine are obtained 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1 by the stoichiometric ratio cyclization; 2-α] pyrimidin-4-one; In the presence of palladium-carbon catalyst, carry out catalytic hydrogenation then and obtain two alcohol intermediate 3-(2-hydroxyethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] pyrimidin-4-one, temperature of reaction is 60 ℃, reaction pressure is i.e. 1.1 atmospheric interior pressures of 0.1 atmospheric hydrogen excess pressure; Adopt POCl again
3Be chlorination reagent, in 70 ℃, the reaction times is 7h, and the selective chlorination primary hydroxyl promptly obtains RO 76477 key intermediate: 3-(2-chloroethyl)-6,7,8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one.
Claims (5)
1. a 3-(2-chloroethyl)-6,7,8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] preparation method of pyrimidin-4-one, it is characterized in that this method is to be catalyzer with the nucleophilicity organic micromolecule catalyst, and 2-amino-3-pyridone and 2-acetylpyridine are obtained 3-(2-hydroxyethyl)-9-hydroxy-2-methyl tetrahydrochysene-pyridine [1 by the stoichiometric ratio cyclization; 2-α] pyrimidin-4-one, carry out catalytic hydrogenation then and obtain two alcohol intermediate 3-(2-hydroxyethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one, selective chlorination primary hydroxyl again; Promptly obtain RO 76477 key intermediate: 3-(2-chloroethyl)-6,7,8; 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one, its reaction formula is following:
Described nucleophilicity organic micromolecule catalyst is dimethylamino pyridine (DMAP).
2. a kind of 3-according to claim 1 (2-chloroethyl)-6,7,8, the preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one is characterized in that the catalyzer of described catalytic hydrogenation is a palladium-carbon catalyst.
3. a kind of 3-according to claim 1 (2-chloroethyl)-6; 7,8,9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1; 2-α] preparation method of pyrimidin-4-one; It is characterized in that the temperature of reaction of described catalytic hydrogenation is 40-60 ℃, reaction pressure is that 0.1-0.2 atmospheric hydrogen excess pressure is 1.1-1.2 atmospheric interior the pressure.
4. a kind of 3-according to claim 1 (2-chloroethyl)-6,7,8, the preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one is characterized in that the chlorination reagent that adopts in the described selective chlorination primary hydroxyl comprises POCl
3, PCl
5Or SOCl
2
5. a kind of 3-according to claim 1 (2-chloroethyl)-6,7,8; The preparation method of 9-tetrahydrochysene 9-hydroxy-2-methyl tetrahydrochysene-pyridine [1,2-α] pyrimidin-4-one is characterized in that; The temperature of reaction of described selective chlorination primary hydroxyl is 50-70 ℃, and the reaction times is 5-7h.
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| CN2009100499856A CN101870695B (en) | 2009-04-24 | 2009-04-24 | Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone |
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| CN106220622A (en) * | 2016-06-30 | 2016-12-14 | 广州仁恒医药科技有限公司 | A kind of preparation method of Palmic acid 9-hydroxy-risperidone |
| CN117777131B (en) * | 2024-02-27 | 2024-06-11 | 合肥华方医药科技有限公司 | Synthesis method of paliperidone and key intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008024415A2 (en) * | 2006-08-23 | 2008-02-28 | Teva Pharmaceutical Insustries Ltd. | Process for the synthesis of cmhtp and intermediates thereof |
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| WO2008024415A2 (en) * | 2006-08-23 | 2008-02-28 | Teva Pharmaceutical Insustries Ltd. | Process for the synthesis of cmhtp and intermediates thereof |
| US20080214809A1 (en) * | 2006-08-23 | 2008-09-04 | Ben-Zion Dolitzky | Process for the synthesis of CMHTP and intermediates thereof |
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