CN100457769C - Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method - Google Patents
Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method Download PDFInfo
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- CN100457769C CN100457769C CNB2007100539197A CN200710053919A CN100457769C CN 100457769 C CN100457769 C CN 100457769C CN B2007100539197 A CNB2007100539197 A CN B2007100539197A CN 200710053919 A CN200710053919 A CN 200710053919A CN 100457769 C CN100457769 C CN 100457769C
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- dichloropurine
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- chemical synthesis
- ribofuranose
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Abstract
The invention discloses a manufacturing method of 2, 6-dichloropurine nucleoside, which comprises the following steps: 1) placing beta-1, 2, 3, 5-tetraacetyl furan ribonucleic acid and organic solvent into reacting autoclave; stirring; adding 2, 6-dichloropurine and phenolic ester phosphate compound catalyst batch by batch; heating to reflux; removing solvent and reacted acetic acid in the vacuum; obtaining 2, 6-dichlorine-9-(beta-D-2', 3' 5'-triacetyl furan ribonucleic acid) purine; 2) placing 2, 6-dichlorine-9-(beta-D-2', 3' 5'-triacetyl furan ribonucleic acid) purine and carbinol into autoclave; dripping condensed alcaine under 0-5 deg.c; keeping the temperature; adding solid alkaline to adjust pH value to 6.5-7.5; decompressing; sucking; condensing; obtaining the product.
Description
Technical field:
The present invention relates to a kind of synthesis technique of organic compound, particularly a kind of chemical synthesis produces 2, the technology of 6-dichloropurine nucleosides.
Background technology:
2,6-dichloropurine nucleosides (2,6-dichloropurine riboside) self is a kind of good antitumor drug, and it still is a good intermediate antibiotic, antiviral, antitumor drug.For example with 2,6-dichloropurine nucleosides is the 2-chlorine adenosine that raw material is produced, and 2-amino-6-chloropurine nucleosides etc. all has good pharmaceutical use.Studies show that in recent years: 2-chlorine adenosine has the effect of anti-epileptic and potent coronary artery dilating, can be used for treating diseases such as stenocardia, myocardial infarction, coronary artery functional defect, arteriosclerosis, essential hypertension, cerebrovascular disorder, apoplexy sequela and the myocardial atrophy of carrying out property.Takuma; People such as JamesA studies show that: 2-ammonia-6-chloropurine nucleosides has the infection of inhibition, the DNA synthetic function that suppresses virus of AIDS HIV, and function cells itself do not influenced, curative effect than 2 '-3 '-dideoxyguanosine, 2 ', 3 '-dideoxyinosine also will get well.2,6-dichloropurine nucleosides produce and scientific research in all bringing into play important effect, along with to the going deep into of the research of nucleosides material, the purposes that it also can display update.At present, 2, the market demand of 6-dichloropurine nucleosides increases gradually, but because the bottleneck problem of Technology makes 2, the turnout of 6-dichloropurine nucleosides can not satisfy the demand in market far away, and costs an arm and a leg.Find one can reduce production costs, workable, and technology that can suitability for industrialized production is extremely urgent.By consulting nearly 40 years data at home and abroad, discovery relevant 2, the prepared in laboratory method of 6-dichloropurine nucleosides is exemplified below:
(1) JohnF.Gerster is dissolved in 2-amino-6-chloropurine nucleosides in 31% the concentrated hydrochloric acid, and low temperature drips NaNO2 solution down, makes 2 bit amino diazotization, and diazo is replaced by Cl-and makes 2 then, 6-dichloropurine nucleosides, and its reaction equation is as follows:
It itself is exactly that a kind of expensive 2-amino-6-chloropurine nucleosides of medicine intermediate is raw material that this method has been used, improved the cost of product, whole process all is to carry out below 0 ℃, also need in the aftertreatment repeatedly to extract with ethyl acetate, these all are that concrete operations have increased difficulty, and yield only has 43%, undoubtedly, this method is because productive rate is low, raw materials cost height, operation inconvenience and can't suitability for industrialized production.
(2) people such as M.Huang adopt 2 ', 3 ', 5 '-triacetyl 2-ammonia-6-chloropurine nucleosides is that raw material carries out diazotization, after diazotization and the chlorination, deacetylation gets the purpose product at normal temperatures again, the reaction equation of this method is as follows:
This method is with respect to the method for John.F, reaction principle is similar, just adopted 2 ', 3 ', 5 '-triacetyl 2-ammonia-6-chloropurine nucleosides is a raw material, temperature of reaction increases, improved operability, but because raw material is rare and cost an arm and a leg, and ammonia there is again by product to generate when separating, productive rate is on the low side (40%), and unsuitable suitability for industrialized production.
(3) people such as Howard J.Schaeffer utilizes 2, the mercury salt of 6-dichloropurine at normal temperatures with 1-chloro-2,3, the condensation of 5-tri-benzoyl ribose, condensation product is used sodium methylate deacylated tRNA base again, its reaction equation is as follows:
In this method, 1-chloro-2,3,4-tri-benzoyl ribose raw material is rare, and by product is many after the deacylated tRNA base, the aftertreatment difficulty.
(4) John.A.Wright, Norman.F utilizes 2,6-dichloropurine and 1,2,3-triacetyl-5-benzyloxy ribose carries out condensation reaction under the Catalyzed by p-Toluenesulfonic Acid effect, and the deacylated tRNA base gets product then, and reaction equation is as follows:
In this method 1,2,3-triacetyl-5-benzyloxy raw material is rare, the temperature of reaction height.These have all increased operational difficulty.The product after moreover this method ammonia is separated is not single, needs post to separate, so suitability for industrialized production is difficult to realize.
(5) people such as R.Marymoto with DMF be solvent utilize 2-chloro-6-hydroxyl-2 ', 3 ', 5 '-triacetyl-purine nucleoside SOCl2 reaction, generate-2,6-two chloro-2 ', 3 ', 5 '-triacetyl-purine nucleoside, and then with its principle of ammoniacal liquor deacylated tRNA base such as figure below:
The starting raw material of this method is rare and expensive nucleosides, and it is not single that the ammonia of final step is separated product, and separation difficulty is so this method also should not realize industrialization.
In sum, the international at present Synthetic 2 of being reported is in the method for 6-dichloropurine nucleosides; also do not have a kind of raw material to be easy to get, technology is reasonable, is suitable for the novel process of suitability for industrialized production; and most methods have all adopted alkaline condition when the deacylated tRNA base; so very easily cause product not single, thereby productive rate reduce separation difficulty; for these reasons; owing to the needs in market, we have developed a kind of Synthetic 2, the new process of production of 6-dichloropurine nucleosides again.
Summary of the invention:
The purpose of this invention is to provide a kind of raw material and be easy to get, synthetic route is short, and low and chemical synthesis friendly environment of cost produces 2, the technology of 6-dichloropurine nucleosides.Technical scheme of the present invention is that a kind of chemical synthesis produces 2, the technology of 6-dichloropurine nucleosides, it is characterized in that: following steps are arranged: 1) with β-1,2,3, tetra-acetylated ribofuranose of 5-and organic solvent are put into reactor, add 2 under stirring, 6-dichloropurine and biconjugate nitrophenol phosphoric acid ester or biconjugate fluorophenol phosphoric acid ester are heated to backflow under stirring in batches, after reaction is finished, vacuum shifts out solvent and the acetate that reaction generates, and vacuum is drained and obtained 2,6-two chloro-9-(β-D-2 ', 3 ', 5 '-the triacetyl ribofuranose) purine; 2) with above-mentioned 2; 6-two chloro-9-(β-D-2 '; 3 '; 5 '-the triacetyl ribofuranose) purine and methyl alcohol puts into reactor; under 0-5 ℃ of condition, drip concentrated hydrochloric acid and keep this thermotonus complete, under this temperature, add solid adjusting PH with base=6.5-7.5, decompress filter; be concentrated into and driedly obtain 2,6-dichloropurine nucleosides.With produced 2,6-dichloropurine nucleosides makes 2 with Virahol organic solvent recrystallization, 6-dichloropurine nucleosides elaboration.A kind of chemical synthesis produces 2, and the technology of 6-dichloropurine nucleosides is characterized in that: following steps are arranged: 1) with β-D-1,2,3, the tetra-acetylated ribofuranose of 5-is put into reactor and is heated to moltenly, under agitation adds 2 in batches, 6-dichloropurine and biconjugate nitrophenol phosphoric acid ester or biconjugate fluorophenol phosphoric acid ester, stir down and be heated to backflow, connect vacuum and will react the acetate of generation and shift out, make 2,6-two chloro-9-(β-D-2 ', 3 ', 5 '-the triacetyl ribofuranose) purine; 2) with above-mentioned 2; 6-two chloro-9-(β-D-2 '; 3 '; 5 '-the triacetyl ribofuranose) purine and methyl alcohol puts into reactor, drips concentrated hydrochloric acid under the 0-5 ℃ of condition, keeps this temperature to reacting completely; continue to keep this temperature; add solid adjusting PH with base=6.5-7.5, decompress filter is concentrated into and driedly obtains 2,6-dichloropurine nucleosides.Prepared 2,6-dichloropurine nucleosides makes 2,6-dichloropurine nucleosides elaboration after with Virahol organic solvent recrystallization.Described solvent be ethylene dichloride, methylene dichloride or with described ethylene dichloride, organic solvent that methylene dichloride polarity is close.Step 2) solid alkali described in is any of sodium bicarbonate, sodium hydroxide.The present invention is owing to adopted phosphoric acid phenolic ester class catalyzer and two step method synthesis technique, thereby have following remarkable advantage compared with the prior art: raw material is easy to get, the catalyst efficiency height of catalyst system therefor, synthetic route is short, simple to operate, easy control, steady quality, yield height, intermediates and the finished product configuration are single stable and controllable for quality, and used organic solvent kind is few, toxicity is little, byproduct and waste liquid all can rationally be recycled but friendly environment, and product price is low.
Chemical synthesis produces 2, and the technology of 6-dichloropurine nucleosides has following two:
Synthetic route 1 is:
Synthetic route 2 is:
Used catalyzer is phosphoric acid phenolic ester compounds or halo tin, halo titanium Lewis acid compounds in the above synthetic route, catalyst consumption is decided according to the kind of catalyzer, and its phenyl-phosphate class catalyzer can be that the mono phosphoric acid ester phenyl ester also can be the two phenyl esters (can be that one or more any functional groups replace at an arbitrary position on its phenyl ring) of phosphoric acid; Condensation reaction can solvent-freely be carried out, and also can use solvent, if use solvent, its reaction solvent can be that ethylene dichloride also can be similarly other organic solvent of polarity.
Embodiment:
Embodiment 1:
(1) in 10000 liters of stainless steel cauldrons that have a stirring, adds 500Kg; β-D-1; 2; 3; the tetra-acetylated ribofuranose of 5-(II) is heated to molten; add 189Kg 2 under stirring, 6-dichloropurine (I) and 1.6kg biconjugate nitrophenols phosphoric acid ester are heated to backflow under stirring in batches; the connection vacuum will be reacted the acetate that generates and in time be shifted out; after reaction finishes, remove vacuum, get 2; 6-two chloro-9-(β-D-2 '; 3 ', 5 '-the triacetyl ribofuranose) purine (III) 371-402Kg, its transformation efficiency is 83-90%.
(2) in 10000 liters of stainless steel cauldrons that have a stirring, add 371Kg (III) and 2200 liters of methyl alcohol, under 0 ℃ of-5 ℃ of condition, drip concentrated hydrochloric acid 4, keep this temperature to continue reaction, continue to maintain the temperature at 0 ℃-5 ℃, add solid NaHCO3 and transfer to pH=7 until react completely (1-4h).Decompress filter, filtrate decompression are concentrated into to do and promptly get 2,6-dichloropurine nucleosides crude product.With promptly getting 2 behind the Virahol recrystallization, elaboration (IV) 252-234Kg (yield 81-88%) of 6-dichloropurine nucleosides.This embodiment total recovery is 67-79%.
Embodiment 2:
(1) in 10000 liters of stainless steel cauldrons that have a stirring, adds 321Kg; β-D-1; 2; 3; the tetra-acetylated ribofuranose of 5-(II) and 600 liters of ethylene dichloride; add 189Kg2 under stirring, 6-dichloropurine (I) and 1.6kg biconjugate nitrophenols phosphonic acid ester are heated to backflow under stirring in batches; after reaction finishes; connect vacuum solvent and the acetate that reaction generates are shifted out, after vacuum is drained, get 2; 6-two chloro-9-(β-D-2 '; 3 ', 5 '-the triacetyl ribofuranose) purine (III) 304-344Kg, its transformation efficiency is 68-77%.
(2) in 10000 liters of stainless steel cauldrons that have a stirring, add 304Kg (III) and 2000 liters of methyl alcohol, under 0 ℃ of-5 ℃ of condition, drip concentrated hydrochloric acid 4, keep this temperature to continue reaction, continue to maintain the temperature at 0 ℃-5 ℃, add solid NaHCO3 and transfer to pH=7 until react completely (1-4h).Decompress filter, filtrate decompression are concentrated into to do and promptly get off-white color 2,6-dichloropurine nucleosides crude product.Promptly get 2 with the Virahol recrystallization, 6-dichloropurine nucleosides elaboration (IV) 174-194Kg (yield 80-89%).This embodiment total recovery is 54-68.5%.
Embodiment 3:
(1) in 10000 liters of stainless steel cauldrons that have a stirring, adds 500Kg; β-D-1; 2; 3; the tetra-acetylated ribofuranose of 5-(II) is heated to molten; add 189Kg2 under stirring, 6-dichloropurine (I) and 1.8kg biconjugate fluorophenol phosphoric acid ester are heated to backflow under stirring in batches; vacuumizing the acetate that reaction is generated in time shifts out; after reaction finishes, remove vacuum, get 2; 6-two chloro-9-(β-D-2 '; 3 ', 5 '-the triacetyl ribofuranose) purine (III) 286-344Kg, its transformation efficiency is 64-77%.
(2) in 10000 liters of stainless steel cauldrons that have a stirring, add 286Kg (III) and 1900 liters of methyl alcohol, under 0 ℃ of-5 ℃ of condition, drip concentrated hydrochloric acid 4, keep this temperature to continue reaction, continue to maintain the temperature at 0 ℃-5 ℃, add solid NaHCO3 and transfer to pH=7 until react completely (1-4h).Decompress filter, filtrate decompression are concentrated into to do and promptly get off-white color 2,6-dichloropurine nucleosides crude product.Promptly get 2 with the Virahol recrystallization, 6-dichloropurine nucleosides elaboration (IV) 164-180.4Kg (yield 80-88%).This embodiment total recovery is 51-68%.
Embodiment 4:
(1) in 10000 liters of stainless steel cauldrons that have a stirring, adds 321Kg; β-D-1; 2; 3; the tetra-acetylated ribofuranose of 5-(II) and 600 liters of ethylene dichloride; add 189Kg 2 under stirring, 6-dichloropurine (I) and 1.6kg biconjugate fluorophenol phosphonic acid ester are heated to backflow under stirring in batches; after reaction finishes; connect vacuum solvent and the acetate that reaction generates are shifted out, after vacuum is drained, get 2; 6-two chloro-9-(β-D-2 '; 3 ', 5 '-the triacetyl ribofuranose) purine (III) 263-295Kg, its transformation efficiency is 59-66%.
(2) in 10000 liters of stainless steel cauldrons that have a stirring, add 295Kg (III) and 1800 liters of methyl alcohol, under 0 ℃ of-5 ℃ of condition, drip concentrated hydrochloric acid 4, keep this temperature to continue reaction, continue to maintain the temperature at 0 ℃-5 ℃, add solid NaHCO3 and transfer to pH=7 until react completely (about 1-4h).Decompress filter, filtrate decompression are concentrated into to do and promptly get 2,6-dichloropurine nucleosides crude product.With promptly getting 2 behind the Virahol recrystallization, 6-dichloropurine nucleosides elaboration (IV) 149-166Kg (yield 79-88%).This embodiment total recovery is 46.6-58%.
Claims (6)
1, a kind of chemical synthesis produces 2, the technology of 6-dichloropurine nucleosides, it is characterized in that: following steps are arranged: 1) with β-1,2,3, tetra-acetylated ribofuranose of 5-and organic solvent are put into reactor, add 2 under stirring, 6-dichloropurine and biconjugate nitrophenol phosphoric acid ester or biconjugate fluorophenol phosphoric acid ester are heated to backflow under stirring in batches, after reaction is finished, vacuum shifts out solvent and the acetate that reaction generates, and vacuum is drained and obtained 2,6-two chloro-9-(β-D-2 ', 3 ', 5 '-the triacetyl ribofuranose) purine; 2) with above-mentioned 2; 6-two chloro-9-(β-D-2 '; 3 '; 5 '-the triacetyl ribofuranose) purine and methyl alcohol puts into reactor; under 0-5 ℃ of condition, drip concentrated hydrochloric acid and keep this thermotonus complete, under this temperature, add solid adjusting PH with base=6.5-7.5, decompress filter; be concentrated into and driedly obtain 2,6-dichloropurine nucleosides.
2, chemical synthesis as claimed in claim 1 produces 2, and the technology of 6-dichloropurine nucleosides is characterized in that: with produced 2,6-dichloropurine nucleosides makes 2 with Virahol organic solvent recrystallization, 6-dichloropurine nucleosides elaboration.
3, a kind of chemical synthesis produces 2, and the technology of 6-dichloropurine nucleosides is characterized in that: following steps are arranged: 1) with β-D-1,2,3, the tetra-acetylated ribofuranose of 5-is put into reactor and is heated to moltenly, under agitation adds 2 in batches, 6-dichloropurine and biconjugate nitrophenol phosphoric acid ester or biconjugate fluorophenol phosphoric acid ester, stir down and be heated to backflow, connect vacuum and will react the acetate of generation and shift out, make 2,6-two chloro-9-(β-D-2 ', 3 ', 5 '-the triacetyl ribofuranose) purine; 2) with above-mentioned 2; 6-two chloro-9-(β-D-2 '; 3 '; 5 '-the triacetyl ribofuranose) purine and methyl alcohol puts into reactor, drips concentrated hydrochloric acid under the 0-5 ℃ of condition, keeps this temperature to reacting completely; continue to keep this temperature; add solid adjusting PH with base=6.5-7.5, decompress filter is concentrated into and driedly obtains 2,6-dichloropurine nucleosides.
4, chemical synthesis as claimed in claim 3 produces 2, and the technology of 6-dichloropurine nucleosides is characterized in that: prepared 2,6-dichloropurine nucleosides makes 2,6-dichloropurine nucleosides elaboration after with Virahol organic solvent recrystallization.
5, chemical synthesis as claimed in claim 1 produces 2, and the technology of 6-dichloropurine nucleosides is characterized in that: described solvent is ethylene dichloride or methylene dichloride.
6, produce 2 as the chemical synthesis of claim 1 or 3, the technology of 6-dichloropurine nucleosides is characterized in that: step 2) described in solid alkali be any of sodium bicarbonate, sodium hydroxide.
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US9580457B2 (en) | 2012-10-29 | 2017-02-28 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for the preparation of (1-{9-[(4S, 2R, 3R, 5R)-3, 4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide |
CN105085595B (en) * | 2015-09-15 | 2017-12-29 | 安阳工学院 | A kind of method of deacylation base protection 2,6 halosubstituted purine nucleosides of synthesis |
CN105418710B (en) * | 2015-09-28 | 2018-04-27 | 新乡学院 | A kind of method using inosine as Material synthesis 2,6- dichloropurine nucleosides |
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CN1408720A (en) * | 2001-09-30 | 2003-04-09 | 河南师范大学 | Process for producing adenosin by chemical synthesis |
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CN1408720A (en) * | 2001-09-30 | 2003-04-09 | 河南师范大学 | Process for producing adenosin by chemical synthesis |
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