CN103288906A - A 3,5 - bis-O-benzoyl-2-C-methyl-C-methyl C-4 - (1,2,4 - triazolyl) uridine and a synthesis method thereof - Google Patents
A 3,5 - bis-O-benzoyl-2-C-methyl-C-methyl C-4 - (1,2,4 - triazolyl) uridine and a synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a 3,5 - bis-O-benzoyl-2-C-methyl-C-methyl C-4 - (1,2,4 - triazolyl) uridine and a synthesis method thereof, and further discloses intermediates thereof and a synthesis method for the intermediates. The method for the 3,5 - bis-O-benzoyl-2-C-methyl-C-methyl C-4 - (1,2,4 - triazolyl) uridine comprises firstly reaction between uracil and hydroxyl protected ribofuranose, then deprotection the hydroxyl, reaction with an acid anhydride at a strictly controlled proper temperature to give 3'-and 5'-hydroxyl-protected uridine, the reaction with triazole to give the compound of the invention. According to the invention, the uracil and the triazole as raw materials are easy to get and cheap, the cost is low, operations are easy, industrial production can be achieved to meet the need for intermediates in research and development of important anti-viral medicines.
Description
Technical field
The invention belongs to the synthetic field of pharmaceutical chemistry, be specifically related to 3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine and synthetic method thereof.
Background technology
Virus disease is a kind of important diseases of serious harm human health and life, different with tumour, cardiovascular and neural disease, virus disease has the infectivity of height, and is the cause of disease of many other diseases (from tumour to cardiovascular, internal secretion, autoimmune disorder and nervous system disorders etc.).Acquired immune deficiency syndrome (AIDS) due to the HIV (human immunodeficiency virus) of finding the eighties in 20th century (HIV) is the transmissible disease that hazardness is very big, mortality ratio is high.The whole world was found severe acute respiratory syndrome that a kind of new coronavirus causes first (severe acute respiratory syndrome SARS), was had hyperinfection, the lethality rate height beginning of this century.
The research of antiviral still is in the early development stage at present, and the kind of clinical use is few, and the antiviral of selling in market exists certain toxicity and resistance before the more number, is unfavorable for further promotion and application.To some serious virus disease, as hepatitis B, acquired immune deficiency syndrome (AIDS) etc., but lack effective medicine, become the serious Community health in all parts of the world and hygienic issues.Therefore, the research of antiviral and find that new and effective, low toxicity, the antiviral drug that selectivity is high become one of focus of current international the world of medicine research.
The ucleosides antiviral is the choice drug for the treatment of virus diseases such as acquired immune deficiency syndrome (AIDS), bleb, hepatitis at present clinically.And the research field of drug discovery is having the basis of darker understanding to concentrate on the nucleoside compound that nucleic acid is carried out structural modification to the virus replication cycle.Approved is used for the treatment of that the overwhelming majority is nucleoside compound in the medicine of various viruses, and the part transformed of nucleotide monomer has the configuration of base, ribose and glycosidic link, and the phosphoric acid part.Thereby change medicine tire, absorb, the character of aspects such as distribution, metabolism, toxicity, stability and solvability, reach orientation to be transported to target tissue, avoid taking place untoward reaction.To the transformation of Nucleotide modification property, reduce the genotoxic potential to human body, can reach and develop the novel high-efficiency low-toxicity of a class and the high antiviral drug of selectivity.
Of the present invention 3,5-is two-O-benzoyl-2-C-methyl
C-methyl-4-(1; 2,4-triazolyl) uridine (I) and derivative thereof, its principal feature are protected and the not protection of hydroxyl on the 2' position of 3' position and 5' position hydroxyl; this is the important intermediate of a class ucleosides antiviral newly developed, and the derivative that replaces on the synthetic all kinds of 2' position can be provided.Ucleosides intermediate in the US Patent No. 7781576 is exactly that hydroxyl on the 2' position obtains halo by reactions such as a few step replacements, and 3' position and 5' position hydroxyl are protected always.Document (H. J. Thomas et. al., Nucleosides Nucleotides, 1994,13 (1/3), 309-323) reported the one antiviral nucleoside derivate that 2' position hydroxyl is replaced by fluorine.Document (S. F. Jenkinson et. al.; Tetrahedron Letters 2007; 48; 4441-4444.) to have delivered relevant 3' position and 5' position hydroxyl protected and 2' position hydroxyl does not have the synthetic method of the uracil derivative of protection; corresponding initiator obtains with the open loop of tosic acid reflux in acetonitrile; but initiator synthesizes the cost height, is unfavorable for promoting amplifying producing, and its reaction formula is:
Summary of the invention
At the deficiencies in the prior art and defective, the purpose of this invention is to provide a kind of new nucleoside derivate: 3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine, shown in structural formula (I), and the synthetic method that this nucleoside derivate is provided.
In order to realize the foregoing invention purpose, the technical solution used in the present invention is:
3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine, its structure is shown in following structural formula (I):
。
A kind of 3,5-is two-O-benzoyl-2-C-methyl
CThe synthetic method of-methyl-4-(1,2,4-triazolyl) uridine, this method comprises: the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection carries out substitution reaction with triazole, obtains 3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine (I), reaction formula is as follows:
Concrete synthesis technique comprises following operation: the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection is dissolved in the pyridine with triazole; add dewatering agent; stirring reaction at room temperature; TLC point plate determines that reaction finishes, and the pressure reducing and steaming pyridine adds 3 ~ 8 ml methanol; cross filter solid methyl alcohol hot breakdown; remove excessive triazole, filter the back solid and once filter with the acetone making beating again, get finished product triazolyl ribofuranoside uridylic.
As further scheme, the dewatering agent that uses is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or 4-chloro-phenyl-dichloro phosphoric acid ester.
As further scheme; the ribofuranoside uridylic (II) of described 3' position and 5' position hydroxyl protection makes as follows: ribofuranoside uridylic (III) and benzoyl oxide generation part reactive esterify hydroxy; make the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection, its reaction formula is:
；
Concrete synthesis technique comprises following operation: (III), triethylamine and acid binding agent alkali is dissolved among the DMF, be cooled to about 0oC, drip the DMF solution of benzoyl oxide, stirring reaction, the point plate tracks to reaction and finishes, reaction solution is poured in the water, filters the ribofuranoside uridylic (II) that obtains 3' position and 5' position hydroxyl protection; The temperature of reaction is 10 ~ 50oC, and the time of reaction is 1 ~ 6 hour.
As further scheme, the acid binding agent alkali that uses as triethylamine, pyridine, piperidines, 4-Dimethylamino pyridine, aniline,
N,
N-xylidene(s),
N,
N-Diethyl Aniline,
N,
N-diisopropylethylamine, tri-isopropyl amine or tri-n-butylamine.
As further scheme, described ribofuranoside uridylic (III) makes as follows: under alkaline condition, the ribofuranoside uridylic (IV) of hydroxyl protection is sloughed protecting group, obtains ribofuranoside uridylic (III), and its reaction formula is:
Concrete synthesis technique comprises following operation: (IV) is dissolved in the methyl alcohol, is cooled to 0oC, feed ammonia and reach supersaturation, and stirring reaction, the some plate is followed the tracks of reaction extremely fully; Revolving inspissation is reduced to dried; Cross silica gel column chromatography, flow out 10% methanol/ethyl acetate mutually, obtain ribofuranoside uridylic (III); The temperature of reaction is-10 ~ 10oC, and the time of reaction is 36 ~ 72 hours.
As further scheme, the ribofuranoside uridylic (IV) of described hydroxyl protection makes as follows: the ribofuranose of hydroxyl protection and uridylic generation substitution reaction, obtain the ribofuranoside uridylic (IV) of hydroxyl protection, and its reaction formula is:
；
Concrete synthesis technique comprises following operation: uridylic is dissolved in acetonitrile, add two silica-based ethanamides of front three, reflux, be cooled to room temperature then, the acetonitrile and the tin tetrachloride mixing solutions that add the ribofuranose of hydroxyl protection, reflux, TLC point plate determines that reaction finishes, cooling back ethyl acetate and saturated sodium bicarbonate solution extracting and demixing, organic phase is washed with salt, anhydrous sodium sulfate drying, revolve and steam to doing, cross the silica gel column chromatography column purification, flow out 10% ethyl acetate/dichloromethane mutually, obtain the ribofuranoside uridylic (IV) of hydroxyl protection; The time of reaction is 1 ~ 6 hour.
Beneficial effect: nucleoside derivate of the present invention has novel particular structure, as the intermediate of novel potential antiviral thing.The synthetic route of nucleoside derivate of the present invention and method have the reaction conditions gentleness, and operating procedure is simplified, and the yield height is fit to amplification quantity production and satisfies demand clinical and research.
Embodiment
In order to make technique means of the present invention, creation characteristic, workflow, using method reach purpose and effect is easy to understand, below further set forth the present invention.
Embodiment
(1) 1-(2,3,5-three-
O-benzoyl-2-
C-methyl-β-D-ribofuranoside) preparation of uridylic (IV):
4 gram (35.7mmol) uridylics are dissolved in 120 milliliters of acetonitriles, add 18 milliliters of two silica-based ethanamides of front three, and reflux 30 minutes is cooled to room temperature then.10 gram (17.2mmol) 1,2,3,5-four-
O-benzoyl-2-
C-methyl-β-D-ribofuranose is dissolved in 120 milliliters of acetonitriles and 7 milliliters of tin tetrachloride, is added in the reaction solution, and reflux 4 hours, reaction finishes.Be cooled to 0oC, under this temperature, with 200 milliliters of ethyl acetate and 100 milliliters of saturated sodium bicarbonate solution extracting and demixing, tell organic phase, with 100 milliliters of salt washings, anhydrous sodium sulfate drying, revolve and steam to doing, cross silica gel column chromatography (flowing out 10% ethyl acetate/dichloromethane mutually) purifying, obtain 1-(2,3,5-three-
O-benzoyl-2-
C-methyl-β-D-ribofuranoside) uridylic (IV), white solid powder 8.5 grams, yield 86%.
(2) 1-(2-
C-methyl-β-D-ribofuranoside) preparation of uridylic (III):
8.5 the 1-of gram (14.9mmol) (2,3,5-three-
O-benzoyl-2-
C-methyl-β-D-ribofuranoside) uridylic is dissolved in 700 ml methanol, bathes with cryosel and is cooled to 0oC, and the feeding ammonia reaches supersaturation, and stirring reaction is 48 hours under 0oC, and the some plate is followed the tracks of reaction to complete.Revolving inspissation is reduced to dried.Cross silica gel column chromatography, flow out 10% methanol/ethyl acetate mutually, obtain 1-(2-
C-methyl-β-D-ribofuranoside) uridylic (III), white solid powder 3.5 grams, yield 91%.
(3) 1-(3,5-is two-
O-benzoyl-2-
C-methyl-β-D-ribofuranoside) preparation of uridylic (II):
；
1-(2-
C-methyl-β-D-ribofuranoside) uridylic (1.032g, 4mmol, 1eq), triethylamine (1.67mL, 3eq), (50mg 0.1eq) is dissolved among 5 milliliters of DMF DMAP, ice-water bath stirred 5 minutes, drip benzoyl oxide (1.81g, 8mmol, DMF 2eq) (2mL) solution, stirring at room reaction 3 hours, the some plate tracks to reaction and finishes.Reaction solution is poured in 60 ml waters, filter white solid, solid is added in 25 milliliters of acetonitriles, reflux 40 minutes, cold filtration gets (II), white solid 1.5 gram, yield 80%.
(4) 3,5-pairs-O-benzoyl-2-C-methyl
CThe preparation of-methyl-4-(1,2,4-triazolyl) uridine (I):
(II) (255mg, 0.55mmol, 1eq), (380mg 10eq) is dissolved in 4 milliliters of pyridines triazole, adds phosphorus oxychloride (100uL, 2eq), stir 2h, the pressure reducing and steaming pyridine, add 5 ml methanol, cross filter solid with 10 ml methanol hot breakdowns, remove excessive triazole, filter the back solid and once filter with 6 milliliters of acetone making beating again, get 3', 5'-pair-
O-benzoyl-2'-
C-methyl-4-(1,2,4-triazolyl) uridine (I), 0.18 gram off-white color solid, yield 63%, purity〉96%; Fusing point: 244 ~ 252oC.1H?NMR?(CDCl3)，δ：1.29(s,?3H,?CH3),?4.40(s,?1H,?-OH),?4.66-4.78(m,?2H,?CH2),?4.84-4.90(m,?1H,?CH),?5.32-5.35(m,?1H,?CH),?6.11(s,?1H,?CH),?7.18(m,?1H,?pyrimidine?ring),?7.44-7.52(m,?4H,?phenyl),?7.58-7.65(m,?2H,?triazole?ring),?8.03-8.15(m,?5H,?phenyl),?8.30(m,?1H,?phenyl),?9.26(s,?1H,?pyrimidine?ring)。
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1.3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine is characterized in that its structure is shown in following structural formula (I):
。
2. one kind 3,5-pair-O-benzoyl-2-C-methyl
CThe synthetic method of-methyl-4-(1,2,4-triazolyl) uridine is characterized in that this method comprises: the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection carries out substitution reaction with triazole, obtains 3,5-pair-O-benzoyl-2-C-methyl
C-methyl-4-(1,2,4-triazolyl) uridine (I), reaction formula is as follows:
；
Concrete synthesis technique comprises following operation: the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection is dissolved in the pyridine with triazole; add dewatering agent; stirring reaction at room temperature; TLC point plate determines that reaction finishes, and the pressure reducing and steaming pyridine adds 3 ~ 8 ml methanol; cross filter solid methyl alcohol hot breakdown; remove excessive triazole, filter the back solid and once filter with the acetone making beating again, get finished product triazolyl ribofuranoside uridylic.
3. according to claim 23,5-is two-O-benzoyl-2-C-methyl
CThe synthetic method of-methyl-4-(1,2,4-triazolyl) uridine is characterized in that, the dewatering agent that uses is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or 4-chloro-phenyl-dichloro phosphoric acid ester.
4. according to claim 23,5-is two-O-benzoyl-2-C-methyl
C-methyl-4-(1; 2; the 4-triazolyl) synthetic method of uridine; it is characterized in that; the ribofuranoside uridylic (II) of described 3' position and 5' position hydroxyl protection makes as follows: ribofuranoside uridylic (III) and benzoyl oxide generation part reactive esterify hydroxy; make the ribofuranoside uridylic (II) of 3' position and 5' position hydroxyl protection, its reaction formula is:
Concrete synthesis technique comprises following operation: (III), triethylamine and acid binding agent alkali is dissolved among the DMF, be cooled to about 0oC, drip the DMF solution of benzoyl oxide, stirring reaction, the point plate tracks to reaction and finishes, reaction solution is poured in the water, filters the ribofuranoside uridylic (II) that obtains 3' position and 5' position hydroxyl protection; The temperature of reaction is 10 ~ 50oC, and the time of reaction is 1 ~ 6 hour.
5. according to claim 43,5-is two-O-benzoyl-2-C-methyl
CThe synthetic method of-methyl-4-(1,2,4-triazolyl) uridine is characterized in that, the acid binding agent alkali that uses as triethylamine, pyridine, piperidines, 4-Dimethylamino pyridine, aniline,
N,
N-xylidene(s),
N,
N-Diethyl Aniline,
N,
N-diisopropylethylamine, tri-isopropyl amine or tri-n-butylamine.
6. according to claim 43,5-is two-O-benzoyl-2-C-methyl
C-methyl-4-(1; 2; the 4-triazolyl) synthetic method of uridine; it is characterized in that; described ribofuranoside uridylic (III) makes as follows: under alkaline condition; the ribofuranoside uridylic (IV) of hydroxyl protection is sloughed protecting group, obtains ribofuranoside uridylic (III), and its reaction formula is:
Concrete synthesis technique comprises following operation: (IV) is dissolved in the methyl alcohol, is cooled to 0oC, feed ammonia and reach supersaturation, and stirring reaction, the some plate is followed the tracks of reaction extremely fully; Revolving inspissation is reduced to dried; Cross silica gel column chromatography, flow out 10% methanol/ethyl acetate mutually, obtain ribofuranoside uridylic (III); The temperature of reaction is-10 ~ 10oC, and the time of reaction is 36 ~ 72 hours.
7. according to claim 63,5-is two-O-benzoyl-2-C-methyl
C-methyl-4-(1; 2; the 4-triazolyl) synthetic method of uridine; it is characterized in that; the ribofuranoside uridylic (IV) of described hydroxyl protection makes as follows: the ribofuranose of hydroxyl protection and uridylic generation substitution reaction; obtain the ribofuranoside uridylic (IV) of hydroxyl protection, its reaction formula is:
Concrete synthesis technique comprises following operation: uridylic is dissolved in acetonitrile, add two silica-based ethanamides of front three, reflux, be cooled to room temperature then, the acetonitrile and the tin tetrachloride mixing solutions that add the ribofuranose of hydroxyl protection, reflux, TLC point plate determines that reaction finishes, cooling back ethyl acetate and saturated sodium bicarbonate solution extracting and demixing, organic phase is washed with salt, anhydrous sodium sulfate drying, revolve and steam to doing, cross the silica gel column chromatography column purification, flow out 10% ethyl acetate/dichloromethane mutually, obtain the ribofuranoside uridylic (IV) of hydroxyl protection; The time of reaction is 1 ~ 6 hour.
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Cited By (2)
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| CN103467509A (en) * | 2013-09-27 | 2013-12-25 | 成都爱博协诺化学技术有限公司 | Antitumor drug intermediate synthesis method |
| CN113621009A (en) * | 2021-06-25 | 2021-11-09 | 北大方正集团有限公司 | Chemical synthesis method of beta-nicotinamide mononucleotide |
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| CN113621009A (en) * | 2021-06-25 | 2021-11-09 | 北大方正集团有限公司 | Chemical synthesis method of beta-nicotinamide mononucleotide |
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