CN103539826A - Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose - Google Patents
Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose Download PDFInfo
- Publication number
- CN103539826A CN103539826A CN201310504508.0A CN201310504508A CN103539826A CN 103539826 A CN103539826 A CN 103539826A CN 201310504508 A CN201310504508 A CN 201310504508A CN 103539826 A CN103539826 A CN 103539826A
- Authority
- CN
- China
- Prior art keywords
- methyl
- benzoyl
- ribose
- tetra
- lactone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose. According to the synthesis method, by adopting D-fructose as a raw material, the 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose (compound d) is synthesized through four-step reaction of lactonization reaction, acylation, carbonyl reduction and reacylation, wherein the total yield is 10.60%. Structural characterization is performed on an intermediate product and a target product by the methods such as 1H-NMR (1 hydrogen-nuclear magnetic resonance), 13C-NMR (13 carbon-nuclear magnetic resonance) and MS (mass spectrometry). In the synthesis of 2-C-methyl-D-ribonic acid-1,4-lactone (a), the D-fructose and calcium oxide are determined as the best raw materials in combination with the reaction conditions; by comparing the reducing agents including sodium borohydride, lithium aluminum tetrahydride and sodium bis(2-methoxyethoxy)aluminum hydride, the sodium bis(2-methoxyethoxy)aluminum hydride is determined as the best reducing agent for synthesizing the intermediate 2,3,5-tribenzoyloxy-2-C-methyl-beta-D-ribofuranose (c), wherein the reducing yield can reach 96.20%; moreover, triethylamine is determined as an acid-binding agent for the acylation reaction through single-factor study, and the acylation yield can reach 75.84%.
Description
Technical field
The present invention relates to a kind ofly 1,2, the synthetic method of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, belongs to medicine intermediate chemical field.
Background technology
Hepatitis C, be defined as at first NANB-PTH, referred to as hepatitis C (hepatitis C), the third liver, Choo in 1989 etc. successfully clone HCV cDNA from infected chimpanzee blood, thereby confirm that its pathogenic agent is hepatitis C virus (hepatitis C virus, HCV).Hepatitis C is a kind of viral hepatitis causing that infected by hepatitis C virus (Hepatitis C virus, HCV), mainly through blood transfusion, acupuncture, the propagation such as drug abuse.Some data presentation, infect relevant mortality ratio (death that liver failure and hepatocellular carcinoma cause) to HCV in following 20 years and will continue to increase, very harmful to patient's health and lives, have become serious society and public health problem.
Hepatitis C virus (HCV) is the Etiological that causes chronic hepatic diseases.The target for the treatment of hepatitis C is to remove HCV infect and stop HCV to infect the generation of complication.To the treatment of Acute Hepatitis C Patients, should fully estimate the Best Times of viral spontaneous clearance rate and treatment; The standard scheme for the treatment of patients with chronic hepatitis C is coupling long-acting interferon and ribavirin (ribavirin, RBV), but that its persistence is replied is undesirable, and the untoward reaction of medicine is obvious.The major cause for the treatment of hepatitis c difficulty is the height variation of HCV and lacks desirable cell culture model and animal model, seriously hindered the research and development of HCV vaccine.Hepatitis C there is no effective vaccine at present, and therefore, the anti-HCV medicine of Improvement becomes the task of top priority.The improvement of in recent years treating hepatitis C medicine has obtained more achievement, along with HCV virus respectively being copied to the further investigation of link, found some promising drug targets, and studied the compound of having found to become novel drugs, some has entered the clinical front and clinical study stage.
The nucleosides that 2-C-methyl-β-D-RIBOSE is derived and nucleotide analog are widely used aspect pharmacy, can disturb or directly act on the metabolic process of nucleic acid in vivo, the biosynthesizing of blocking protein, nucleic acid has very important status in antiviral and antineoplastic chemotherapy medicine.The people such as Stanley Chamberlain finds to take that the nucleoside analog that 2-C-methyl-β-D-RIBOSE is glycosyl can treat virus infection, is the HCV medicine having compared with high biological activity.The present invention study 1,2,3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE (compound d) is the intermediate of multiple anti-HCV medicament.At present domestic production producer is very few, causes it expensive, to take the industrial route exploitation that 2-C-methyl-β-D-RIBOSE is glycosyl nucleoside derivates, is therefore very significant.
Both at home and abroad to 1,2,3, the synthetic method report of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE seldom, but for intermediate 2-C-methyl D-ribonic acid-1, the method of the synthetic existing bibliographical information of 4-lactone (compound a) has two kinds, and it is starting raw material that the first be take glucose, CaO, through isomery, lactonizing to obtain thick product; It two is with D-Fructose, Ca (OH)
2for raw material, react 45 ~ 60 days to obtain thick product.All there is long reaction time, the shortcoming of complex operation in these two kinds of synthetic methods.
Summary of the invention
The object of the present invention is to provide a pharmaceutical intermediate 1,2, the synthetic method of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE.
Of the present invention a kind of 1,2,3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, its compound structure is as follows:
The technical solution that realizes the object of the invention is: a kind of 1,2, the synthetic method of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, comprises the following steps:
Step
2, 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone and Benzoyl chloride generation acylation reaction generate 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone;
Step
3, 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone is hydroxyl by the carbonyl reduction of C1 position under the red aluminium of reductive agent exists, and generates 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE;
Step
4, 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE generates 1,2 with Benzoyl chloride generation acylation reaction again, 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE.
Mol ratio 1:1.5 ~ 1:2 of D-Fructose described in step 1 and CaO;
Step
2described in temperature of reaction be 25 ℃, the mol ratio of 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone and Benzoyl chloride is 1:3 ~ 1:6, described acid binding agent is triethylamine, pyridine or salt of wormwood;
Step
3described in 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone and red al mole ratio are 1:1, the temperature that drips reductive agent is 0 ℃ ~-15 ℃;
Step
4described in temperature of reaction be 5 ℃ ~ 15 ℃, at N
2protection is lower stirs 8 ~ 10 h, and the mol ratio of 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE and Benzoyl chloride is 1:3 ~ 1:6.
Synthesis route is as follows:
Compared with prior art, the present invention has the following advantages:
The first step of the present invention be take D-Fructose as raw material, and raw material is easy to get.By Ca of the prior art (OH)
2change CaO into, CaO is nontoxic easy to use, and good with D-Fructose, water Combination, and the reaction times greatly reduces, and yield increases, and is applicable to suitability for industrialized production.In the present invention, use red aluminium as reductive agent, compare Lithium Aluminium Hydride, sodium borohydride reducing power is moderate, has certain stereoselectivity, can be optionally by C
1the carbonyl reduction of position is hydroxyl, and solvability is good, more stable, easily preserves, to O
2insensitive, and easily process.The whole synthetic route of the present invention is from economy, safety and environmental angle consideration, and by product is less, is relatively applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is embodiment
12-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone
1h NMR.
Fig. 2 is embodiment
62,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone
1h NMR.
Fig. 3 is embodiment
11the ESI of 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE
+-MS spectrogram.
Fig. 4 is embodiment
131,2,3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE
1h NMR.
Fig. 5 is embodiment
131,2, the carbon spectrum of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE.
Embodiment
The object of the present invention is to provide a pharmaceutical intermediate 1,2, the synthetic method of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, this compound structure is as follows:
Below in conjunction with example in detail the present invention 1,2, the synthetic method of 3,5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE.
Synthesizing of the first step 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (a)
At N
2under protection, D-Fructose (20 g, 0.111 mol) is dissolved in 100 mL deionized waters, then slowly adds CaO (11.2g, 0.2 mol), react at normal temperatures 24 h.Pass into CO
2gas to solution is neutral, adds oxalic acid 5 g(0.056mol after filtration), solution becomes oyster white, at 45 ℃, stirs and spends the night.Reaction solution underpressure distillation, except anhydrating, adds NaCl, tetrahydrofuran (THF) at 25 ℃ of vigorous stirring 30 min, and separatory is got organic layer, merge organic phase, anhydrous magnesium sulfate drying, underpressure distillation obtains dark oil thing, washing with acetone filters to obtain white solid a 2.80 g, and yield is 16.87%.
Fig. 1 from accompanying drawing explanation can find out,
1hNMR (500MHz, DMSO-d
6) δ/ppm:5.6950 (s, 1H, OH), 5.4211 (s, 1H, OH), 5.0023 (s, 1H, OH), 4.1647 ~ 4.1344(m, 1H, C
4), 3.7525 ~ 3.7068 (m, 2H, CH
2), 3.5250 ~ 3.4898 (m, 1H, C
3), 1.2416(s, 3H, CH
3).
Embodiment 2
Synthesizing of the first step 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (a)
At N
2under protection, D-Fructose (20 g, 0.111 mol) is dissolved in 100 mL deionized waters, then slowly adds CaO (11.2g, 0.2 mol), react at normal temperatures 24h.Pass into CO
2gas to solution is neutral, adds oxalic acid (5 g, 0.056mol) after filtration, and solution becomes oyster white, at 25 ℃, stirs and spends the night.Reaction solution underpressure distillation, except anhydrating, adds NaCl, tetrahydrofuran (THF) at 25 ℃ of vigorous stirring 30 min, and separatory is got organic layer, merge organic phase, anhydrous magnesium sulfate drying, underpressure distillation obtains dark oil thing, washing with acetone filters to obtain white solid a 2.20 g, and yield is 13.22%.
Embodiment 3
Synthesizing of the first step 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (a)
At N
2under protection, D-Fructose (20 g, 0.111 mol) is dissolved in 100 mL deionized waters, then slowly adds CaO (11.2 g, 0.2 mol), react at normal temperatures 24h.Pass into CO
2gas to solution is neutral, adds oxalic acid (5 g, 0.056mol) after filtration, and solution becomes oyster white, at 65 ℃, stirs and spends the night.Reaction solution underpressure distillation, except anhydrating, adds NaCl, tetrahydrofuran (THF) at 25 ℃ of vigorous stirring 30 min, and separatory is got organic layer, merge organic phase, with anhydrous magnesium sulfate drying, after filtering, filtrate decompression distillation obtains dark oil thing, washing with acetone filters to obtain white solid a 2.68 g, and yield is 16.13%.
Embodiment 4
Synthesizing of the first step 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (a)
At N
2under protection, D-Fructose (20 g, 0.111 mol) is dissolved in 100 mL deionized waters, then adds CaO (12.5 g, 0.223 mol), react at normal temperatures 24h.Pass into CO
2gas to solution is neutral, adds oxalic acid (5 g, 0.056mol) after filtration, and solution becomes oyster white, at 45 ℃, stirs and spends the night.Reaction solution underpressure distillation, except anhydrating, adds NaCl, tetrahydrofuran (THF) at 25 ℃ of vigorous stirring 30 min, and separatory is got organic layer, merge organic phase, with anhydrous magnesium sulfate drying, after filtering, filtrate decompression distillation obtains dark oil thing, washing with acetone filters to obtain white solid a 1.73g, and yield is 10.41%.
Synthesizing of the first step 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (a)
At N
2under protection, D-Fructose (20 g, 0.111 mol) is dissolved in 100 mL deionized waters, then slowly adds CaO (8.7g, 0.155 mol), react at normal temperatures 24h.Pass into CO
2gas to solution is neutral, adds oxalic acid (5 g, 0.056mol) after filtration, and solution becomes oyster white, at 45 ℃, stirs and spends the night.Reaction solution underpressure distillation, except anhydrating, adds NaCl, tetrahydrofuran (THF) at 25 ℃ of vigorous stirring 30 min, and separatory is got organic layer, merge organic phase, with anhydrous magnesium sulfate drying, after filtering, filtrate decompression distillation obtains dark oil thing, washing with acetone filters to obtain white solid a 1.58g, and yield is 9.52%.
Embodiment 6
Second step 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone (b) synthetic
Material a(1.5 g, 9.25 mmol), DMAP (0.225 g, 1.86 mmol), triethylamine (12.64 g, 124.88 mmol) join in 25 mL glycol dimethyl ethers, reacts at normal temperatures 30 min(N
2protection).White suspension thing solution is cooled to 5 ℃, add Benzoyl chloride (5.8 g, 41.63 mmol), finish, at 25 ℃, continue to stir, continue to add ice cube 50 g after 2 h, continue stirring reaction 0.5h, solid after filtration washs to obtain white solid b 3.75 g with methyl tertiary butyl ether, and yield is 85.3 %.
Fig. 2 from accompanying drawing explanation can find out
1h-NMR (500 MHz, CDCl
3), δ 8.1558 (d,
j=4.8,2H, Ar-H), 8.0441(d,
j=4.23,2H, Ar-H), 7.8462(d,
j=4.8,1H, Ar-H), 7.7143 ~ 7.6994(t, 1H, Ar-H), 7.6243 ~ 7.5114(m, 4H, Ar-H), 7.4529 ~ 7.4214(t, 2H, Ar-H), 7.3092 ~ 7.2776 (t, 2H, Ar-H), 5.6318 (m, 1H, C
4), 5.3009 ~ 5.2876 (d,
j=3.33,1H, C
3), 4.9468 ~ 4.7985 (d of an AB quarter, 2H, CH
2), 2.0732 (s, 3H, CH
3).
Embodiment 7
Second step 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone (b) synthetic
Material a(1.5 g, 9.25 mmol), DMAP (0.225 g, 1.86 mmol), pyridine (9.88g, 124.88 mmol) join in 25 mL glycol dimethyl ethers, reacts at normal temperatures 30 min(N
2protection).White suspension thing solution is cooled to 5 ℃, adds Benzoyl chloride (5.8 g, 41.63 mmol), finish, continue at 25 ℃ to stir, continue to add ice cube 50 g after 2 h, continue stirring reaction 0.5h, the solid after filtration washs to such an extent that white solid b 3.06 g yields are 69.5% with methyl tertiary butyl ether.
Second step 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone (b) synthetic
Material a(1.5 g, 9.25 mmol), DMAP (0.225 g, 1.86 mmol), salt of wormwood (17.23g, 124.88 mmol) join in 25 mL glycol dimethyl ethers, reacts at normal temperatures 30 min(N
2protection).White suspension thing solution is cooled to 5 ℃, adds Benzoyl chloride (5.8 g, 41.63 mmol), finish, continue at 25 ℃ to stir, continue to add ice cube 50 g after 2 h, continue stirring reaction 0.5h, the solid after filtration washs to obtain white solid b1.53 g with methyl tertiary butyl ether, and yield is 34.7%.
Second step 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone (b) synthetic
Material a(1.5 g, 9.25 mmol), DMAP (0.225 g, 1.86 mmol), triethylamine (12.64 g, 124.88 mmol) join in 25 mL glycol dimethyl ethers, reacts at normal temperatures 30 min(N
2protection).White suspension thing solution is cooled to 5 ℃, adds Benzoyl chloride (3.9g, 27.75 mmol), finish, continue at 25 ℃ to stir, continue to add ice cube 50 g after 2 h, continue stirring reaction 0.5h, the solid after filtration washs to obtain white solid b 2.96 g with methyl tertiary butyl ether, and yield is 67.3%.
Second step 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone (b) synthetic
Material a(1.5 g, 9.25 mmol), DMAP (0.225 g, 1.86 mmol), triethylamine (12.64 g, 124.88 mmol) join in 25 mL glycol dimethyl ethers, reacts at normal temperatures 30 min(N
2protection).Solution is cooled to 5 ℃, adds Benzoyl chloride (7.8 g, 55.5 mmol), reactant is continued at 25 ℃ stir 2 h, add ice cube 50 g, continue stirring reaction 30 min, solid after filtration washs to obtain white solid b 3.36 g with methyl tertiary butyl ether, and yield is 76.5%.
Embodiment 11
The 3rd step 2,3,5-thribenzoyl-2-C-methyl-β D-RIBOSE (c) synthetic
Produce reductive agent: the toluene solution of 4 mL dry toluenes and the red aluminium of 4 mL is joined in the there-necked flask of 25 mL, at 0 ℃, N
2protection is lower stirs, and the mixing solutions of 3.2 mL dry toluenes and 0.78 mL dehydrated alcohol is slowly splashed in reaction solution.Drip and finish, at 0 ℃, N
2lower protection continues to stir 0.5h, and the reductant solution making is standby.
2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (0.95g, 2.0 mmol) is added in 7.5 mL dry toluenes, at-10 ℃, N
2the lower stirring of protection 15min mixes, and gets above-mentioned reductive agent 2 mL and slowly splashes in reaction solution.Drip and finish, continue at normal temperatures stirring reaction 2 h.After reaction finishes, the HCl of 0.4mL acetone, 30 mL water and 30 mL 1 mol/L is added to cancellation in reaction solution, be extracted with ethyl acetate, merge organic phase, with strong brine, wash, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE 0.914 g, yield is 96.2 %.
Fig. 3 from accompanying drawing explanation can find out
1h NMR (500 MHz, CDCl
3), δ/ppm:1.38 (s, 9H, C (CH
3)
3), 2.86 (s, 3H, CH
3), 3.31 (d, 1H, CH
2(H)), 3.64 (t, 1H, CH
2(H)), 4.54 (d, 1H, CH), 5.28 (s, 2H, CH
2), 7.26-7.42 (m, 5H, C
5h
5). MS(m/z): 515.97 [M+K]
+; [498.98 M+Na]
+.
Embodiment 12
The 3rd step 2,3,5-thribenzoyl-2-C-methyl-β D-RIBOSE (c) synthetic
Reductive agent preparation is as example 11
2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (0.95g, 2.0 mmol) is added in 7.5 mL dry toluenes, at-5 ℃, N
2the lower stirring of protection 15min mixes, and gets above-mentioned reductive agent 2 mL and slowly splashes in reaction solution.Drip and finish, continue at normal temperatures stirring reaction 2 h.After reaction finishes, the HCl of 0.4mL acetone, 30 mL water and 30 mL 1 mol/L is added to cancellation in reaction solution, be extracted with ethyl acetate, merge organic phase, with strong brine, wash, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE 0.835 g, yield is 87.9 %.
Embodiment 13
The 3rd step 2,3,5-thribenzoyl-2-C-methyl-β D-RIBOSE (c) synthetic
Reductive agent preparation is as example 11
2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone (0.95g, 2.0 mmol) is added in 7.5 mL dry toluenes, at-15 ℃, N
2the lower stirring of protection 15min mixes, and gets above-mentioned reductive agent 2 mL and slowly splashes in reaction solution.Drip and finish, continue at normal temperatures stirring reaction 2 h.After reaction finishes, the HCl of 0.4mL acetone, 30 mL water and 30 mL 1 mol/L is added to cancellation in reaction solution, be extracted with ethyl acetate, merge organic phase, with strong brine, wash, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE 0.913 g, yield is 96.1 %.
Embodiment 13
Synthetic (d) of the 4th step 2-C-methyl-α-D-RIBOSE four benzoic ethers
By material c(2.4 g, 5 mmol), DMAP (0.061 g, 0.5 mmol), triethylamine (2.53 g, 25 mmol) add in the anhydrous tetrahydro furan of 25 mL, at 5 ℃, slowly add Benzoyl chloride (1.42 g, 10 mmol), finish, at 25 ℃, N
2lower 8 ~ 10 h that stir of protection.Add 50 g frozen water cancellation, be extracted with ethyl acetate, merge organic phase, water, strong brine washing successively, anhydrous sodium sulfate drying, underpressure distillation obtains crude product and is dissolved in 25 mL methyl tertiary butyl ethers, after add normal heptane 25 mL and 0.5 mL water, separate out white solid filtration drying and obtain d 1.75 g, yield is 75.8%.
Fig. 4 and Fig. 5 from accompanying drawing explanation can find out
1h-NMR (500 MHz, DMSO-d
6), δ/ppm:8.1649 ~ 8.1457 (m, 4H, Ar-H), 8.0512(d,
j=4.42,2H, Ar-H), 7.9213(d,
j=4.8,2H, Ar-H), 7.6346 ~ 7.6050(m, 3H, Ar-H) and, 7.5052 ~ 7.4047(m, 6H, Ar-H), 7.1676 ~ 7.1365(m, 3H, Ar-H), 7.0600 (s, 1H, Ar-H) 5.9523 (dd,
j=2.93,1H, C
4), 4.8076 ~ 4.7740 (m, 1H, C
2), 4.6985 ~ 4.5282 (d of an AB quarter, 2H, CH
2); 1.9506 (s, 1H, CH
3).
13c-NMR (500MHz, DMSO-d
6), δ ppm 166.11,165.64,164.82,164.57,133.81,133.67,133.51,132.98,130.27,129.94,129.78,129.63,129.43,129.22,128.89,128.65,128.58,128.18,97.85,86.69,78.60,77.30,77.05,76.80,76.19,75.29,63.88,16.90.
Embodiment 14
Synthetic (d) of the 4th step 2-C-methyl-α-D-RIBOSE four benzoic ethers
By material c(2.4 g, 5 mmol), DMAP (0.061 g, 0.5 mmol), triethylamine (2.53 g, 25 mmol) add in the anhydrous tetrahydro furan of 25 mL, at 5 ℃, slowly add Benzoyl chloride (0.71g, 5mmol), finish, at 25 ℃, N
2lower 8 ~ 10 h that stir of protection.Add 50 g frozen water cancellation, be extracted with ethyl acetate, merge organic phase, water, strong brine washing successively, anhydrous sodium sulfate drying, underpressure distillation obtains crude product and is dissolved in 25 mL methyl tertiary butyl ethers, after add normal heptane 25 mL and 0.5 mL water, separate out white solid filtration drying and obtain d 0.81 g, yield is 34.9%.
Embodiment 15
Synthetic (d) of the 4th step 2-C-methyl-α-D-RIBOSE four benzoic ethers
By material c(2.4 g, 5 mmol), DMAP (0.061 g, 0.5 mmol), triethylamine (2.53 g, 25 mmol) add in the anhydrous tetrahydro furan of 25 mL, at 5 ℃, slowly add Benzoyl chloride (2.13 g, 15 mmol), finish, at 25 ℃, N
2lower 8 ~ 10 h that stir of protection.Add 50 g frozen water cancellation, be extracted with ethyl acetate, merge organic phase, water, strong brine washing successively, anhydrous sodium sulfate drying, underpressure distillation obtains crude product and is dissolved in 25 mL methyl tertiary butyl ethers, after add normal heptane 25 mL and 0.5 mL water, separate out white solid filtration drying and obtain d 1.76 g, yield is 76.2%.
Embodiment 16
Synthetic (d) of the 4th step 2-C-methyl-α-D-RIBOSE four benzoic ethers
By material c(2.4 g, 5 mmol), DMAP (0.061 g, 0.5 mmol), triethylamine (2.53 g, 25 mmol) add in the anhydrous tetrahydro furan of 25 mL, at 5 ℃, slowly add Benzoyl chloride (1.42 g, 10 mmol), finish, at 15 ℃, N
2lower 8 ~ 10 h that stir of protection.Add 50 g frozen water cancellation, be extracted with ethyl acetate, merge organic phase, water, strong brine washing successively, anhydrous sodium sulfate drying, underpressure distillation obtains crude product and is dissolved in 25 mL methyl tertiary butyl ethers, after add normal heptane 25 mL and 0.5 mL water, separate out white solid filtration drying and obtain d 1.52 g, yield is 65.8 %.
Embodiment 17
Synthetic (d) of the 4th step 2-C-methyl-α-D-RIBOSE four benzoic ethers
By material c(2.4 g, 5 mmol), DMAP (0.061 g, 0.5 mmol), triethylamine (2.53 g, 25 mmol) add in the anhydrous tetrahydro furan of 25 mL, at 5 ℃, slowly add Benzoyl chloride (1.42 g, 10 mmol), finish, at 35 ℃, N
2lower 8 ~ 10 h that stir of protection.Add 50 g frozen water cancellation, be extracted with ethyl acetate, merge organic phase, water, strong brine washing successively, anhydrous sodium sulfate drying, underpressure distillation obtains crude product and is dissolved in 25 mL methyl tertiary butyl ethers, after add normal heptane 25 mL and 0.5 mL water, separate out white solid filtration drying and obtain d 1.55g, yield is 67.3 %.
Claims (5)
1. one kind 1,2,3, the synthetic method of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, is characterized in that comprising the following steps:
Step 1, N
2under protection, D-Fructose is soluble in water, slowly add CaO, react at normal temperatures 24h, pass into CO
2gas to solution is neutral, adds oxalic acid in filtrate, and at 25~65 ℃, stirring spends the night generates 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone;
Step 2,2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone and Benzoyl chloride generation acylation reaction generate 2,3,5-thribenzoyl-2-C-methyl D-ribonic acid Isosorbide-5-Nitrae-lactone;
Step 3,2,3,5-thribenzoyl-2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone is hydroxyl by the carbonyl reduction of C1 position under the red aluminium of reductive agent exists, and generates 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE;
Step 4,2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE generates 1,2,3,5-, tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE with Benzoyl chloride generation acylation reaction again.
2. according to claim 11,2,3, the synthetic method of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, is characterized in that mol ratio 1:1.5~1:2 of the D-Fructose described in step 1 and CaO.
3. according to claim 11; 2; 3; the synthetic method of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE; it is characterized in that the temperature of reaction described in step 2 is 25 ℃; the mol ratio of 2-C-methyl D-ribonic acid-Isosorbide-5-Nitrae-lactone and Benzoyl chloride is 1:3~1:6, and described acid binding agent is triethylamine, pyridine or salt of wormwood.
4. according to claim 11; 2; 3; the synthetic method of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE; it is characterized in that described in step 32,3,5-thribenzoyl-2-C-methyl D-ribonic acid-1; 4-lactone and red al mole ratio are 1:1, and the temperature that drips reductive agent is 0 ℃~-15 ℃.
5. according to claim 11,2,3, the synthetic method of 5-tetra--O-benzoyl-2-C-methyl-β-D-RIBOSE, is characterized in that the temperature of reaction described in step 4 is 5 ℃~15 ℃, at N
2protection is lower stirs 8~10h, and the mol ratio of 2,3,5-thribenzoyl-2-C-methyl-β-D-RIBOSE and Benzoyl chloride is 1:3~1:6.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310504508.0A CN103539826A (en) | 2013-10-23 | 2013-10-23 | Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310504508.0A CN103539826A (en) | 2013-10-23 | 2013-10-23 | Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103539826A true CN103539826A (en) | 2014-01-29 |
Family
ID=49963724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310504508.0A Pending CN103539826A (en) | 2013-10-23 | 2013-10-23 | Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103539826A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103992360A (en) * | 2014-04-21 | 2014-08-20 | 中美华世通生物医药科技(武汉)有限公司 | Reduction method suitable for industrialized production |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1744903A (en) * | 2002-12-12 | 2006-03-08 | 埃迪尼克斯(开曼)有限公司 | Process for the production of 2'-branched nucleosides |
-
2013
- 2013-10-23 CN CN201310504508.0A patent/CN103539826A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1744903A (en) * | 2002-12-12 | 2006-03-08 | 埃迪尼克斯(开曼)有限公司 | Process for the production of 2'-branched nucleosides |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103992360A (en) * | 2014-04-21 | 2014-08-20 | 中美华世通生物医药科技(武汉)有限公司 | Reduction method suitable for industrialized production |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022222994A1 (en) | Nucleoside compound and application thereof in the treatment of feline infectious peritonitis | |
CN101153012B (en) | Novel method of producing dronedarone key intermediate | |
CN103588757B (en) | N-substituted imidazole carboxylic ester compound with ultrashort-acting anesthetic effect, preparation method and use thereof | |
CN107163092A (en) | The preparation method of the diabetes inhibitor of SGLT 2 and its intermediate | |
CN101058535B (en) | Di(7-hydrxyl-2,3-dihydro-1-1H-indeno)ether and the like, synthetic method and application | |
CN108727460A (en) | Betulonic acid derivative and its synthetic method and application | |
CN102212095A (en) | Preparation methods of capecitabine and intermediate thereof | |
CN105237516A (en) | Preparation method of Ledipasvir | |
CN109824675A (en) | A kind of synthetic method of 4- chloropyrrolo [2,3-d | |
CN103539826A (en) | Synthesis method of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose | |
KR20100120973A (en) | Method for preparating ascorbic acid derivatives | |
CN106831397B (en) | A kind of anthraquinone analog compound and preparation method thereof and medical application | |
CN102516215B (en) | Preparation method of C-glucoside containing saturated cyclohexane structure | |
CN107235853B (en) | A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers | |
CN107011377B (en) | A kind of preparation method of β-oxo-phosphoric acid ester | |
CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
CN101654401A (en) | Asymmetrical biphenyl compounds, medicinal compositions containing same and application of medicinal compositions | |
CN109422788A (en) | A kind of preparation method of cytarabine hydrochloride | |
CN110272384B (en) | 12-quinoline substituted-andrographolide derivative and preparation method and application thereof | |
CN108137644A (en) | A kind of compound with antitumor action and its preparation method and application | |
CN103833635B (en) | A kind of preparation method of the Dimemorfan phosphate of cough medicine safely and effectively | |
CN104672136B (en) | 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof | |
CN102399197B (en) | 2-(2-hydroxy - substituted phenethyl sulfenyl]-3H-pyrimidin-4-ketone compounds and synthesis method and application thereof | |
CN102070577B (en) | 2-normal-butyl-3-(4-replaces propoxy-benzoyl)-5-substituted-amino cumarone and application thereof | |
CN101317845B (en) | Pharmaceutical use of 6-aryl substituted pyridine compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140129 |