CN107325133A - A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 - Google Patents
A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 Download PDFInfo
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- CN107325133A CN107325133A CN201710683469.3A CN201710683469A CN107325133A CN 107325133 A CN107325133 A CN 107325133A CN 201710683469 A CN201710683469 A CN 201710683469A CN 107325133 A CN107325133 A CN 107325133A
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- 0 CCC[C@]1OC(C)(C)O[C@@]1[C@](*)CC Chemical compound CCC[C@]1OC(C)(C)O[C@@]1[C@](*)CC 0.000 description 2
- JSALOLMKSZVCAM-CKYFFXLPSA-N CC(C)O[C@]1(C2)O[C@H](C)[C@@H]2OC(C)(C)OC1 Chemical compound CC(C)O[C@]1(C2)O[C@H](C)[C@@H]2OC(C)(C)OC1 JSALOLMKSZVCAM-CKYFFXLPSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a kind of synthetic method of the deoxidation D ribose of 1,2,3 three O acetyl group 5, using D ribose as initiation material; 1 of D ribose is protected with isopropyl, and 2,3 are protected with propylidene, after removing 5 hydroxyls through reduction; 2,3 deprotections, then obtain target product through acetylation.The route total recovery is 64%, is significantly better than traditional handicraft, particularly final product for pure beta isomer, it is easy to which recrystallization purification is mass produced.
Description
Technical field
The invention belongs to sugar compounds synthesis technical field, more particularly to a kind of-O- of capecitabine intermediate 1,2,3- tri-
The synthetic method of acetyl group -5- desoxy-D-riboses.
Background technology
Capecitabine is a kind of oral fluoropyrimidine nucleoside analogue, itself no cytotoxicity, but is selected by intra-tumor
Selecting property activation can preferentially make to produce 5 FU 5 fluorouracil in tumor tissues, and targeting plays the effect for suppressing tumour, the market development
Have a extensive future.The chemical name of capecitabine is the fluoro- N- of 5 '-deoxidation -5- [(amoxy) carbonyl] cytidine, and chemical constitution is as follows：
Capecitabine is main in 5 FU 5 fluorouracil and-O- acetyl group -5- desoxy-D-riboses the two keys of 1,2,3- tri-
Mesosome is synthesized.5 FU 5 fluorouracil is as marketed drug, and industrialized route is ripe, and 1,2,3- tri--O- acetyl group -5- is de-
Oxygen-D ribose synthetic routes are relatively complicated, and as the key obstacle of reduction capecitabine production of raw medicine cost.
The synthetic route of 1,2,3- tri--O- acetyl group -5- desoxy-D-riboses of existing literature report mainly has two, first
Bar route is that, using inosine as initiation material, the synthetic route is related to skeleton nickel catalyzed hydrogenation intermediate 5- iodo -5- deoxidation fleshes
Glycosides, the operation of its technique productions and security have many unfavorable factors.Another route is that, using D ribose as initiation material, its is main
Problem be final step acetylization reaction obtain be 1 anomeric carbon α and beta isomer, pure β target products yield is relatively low,
So as to cause to recrystallize purification difficult.
The content of the invention
For 1,2,3- tri--O- acetyl group -5- desoxy-D-riboses of pure beta configurations low yield the problem of, the present invention is carried
A kind of synthetic method of 1,2,3- tri--O- acetyl group -5- desoxy-D-riboses has been supplied, has been comprised the following steps：
(1) the addition compound D ribose of formula 1 in the mixed solution of isopropanol and the concentrated sulfuric acid, reaction generation 1-O- isopropyls-
D ribose, carries out isopropylation to 1-O- isopropyl-D ribose with acetone, the concentrated sulfuric acid and anhydrous cupric sulfate, obtains the compound of formula 2；
(2) compound of formula 2 is dissolved in the mixed solution of dichloromethane and triethylamine, added wherein to toluene after cooling
Sulfonic acid chloride, by the compound sulfonylation of formula 2, obtains the compound of formula 3；
(3) compound of formula 3 is dissolved in the in the mixed solvent of ethyl acetate and dimethyl sulfoxide (DMSO), potassium borohydride is added at room temperature
Deprotection base, obtains the compound of formula 4；
(4) 35% hydrochloric acid solution and water are added dropwise into the compound of formula 4, temperature reaction obtains the compound of formula 5；
(5) compound of formula 5 is dissolved in acetic acid and acetic anhydride, adds perchloric acid and make catalyst, carry out acetylization reaction, obtain
To-O- acetyl group -5- the desoxy-D-riboses of 6 compound 1,2,3- of formula tri-；
Alternatively, in step (1), the mol ratio of D ribose, isopropanol and the concentrated sulfuric acid is 1：20.6：0.125；1-O- isopropyls
Base-D ribose, acetone, the mol ratio of the concentrated sulfuric acid and anhydrous cupric sulfate are 1：10.8：0.32：0.38.
Alternatively, in step (2), the compound of formula 2, dichloromethane, the mol ratio of triethylamine and paratoluensulfonyl chloride are 1：
7.5：2.48：1.05.
Alternatively, in step (3), the compound of formula 3, ethyl acetate, the mol ratio of dimethyl sulfoxide (DMSO) and potassium borohydride are 1：
8.4：5.7：1.55.
Alternatively, in step (5), the compound of formula 5, acetic acid, the mol ratio of acetic anhydride and perchloric acid are 1：2.1：3.85：
0.03。
Preferably, in step (1), the compound D ribose of formula 1, reaction are added in the mixed solution of isopropanol and the concentrated sulfuric acid
Obtain the compound 1-O- isopropyl-D ribose of formula 7；The compound of substep synthesis type 2, is favorably improved the yield of the compound of formula 2, enters
And improve the yield of final product；
The present invention has advantages below：
The synthetic method for-O- acetyl group -5- the desoxy-D-riboses of 1,2,3- tri- that the present invention is provided is with cheap D ribose
For initiation material, 1, D ribose is protected with isopropyl, and 2,3 are protected with propylidene, after removing 5 hydroxyls through reduction, 2,3 remove-insurances
Shield, then obtain target product through acetylation.In step (1) of the present invention, after 1 isopropyl protection, thick purification directly carries out 2,3
The propylidene protection of position；In step (4) of the present invention, hydrochloric acid water takes off the propylidene protection group of 2,3, retains the isopropyl on 1, has
The target product of beta comfiguration is obtained beneficial to next step；In step (5) of the present invention, acetylization reaction makees solvent with acetic acid, uses catalytic amount
Perchloric acid catalysis, reduces reaction temperature, reduces accessory substance, it is to avoid ɑ anomeric products, improves the yield of beta comfiguration product.
The route total recovery is 64%, is significantly better than traditional handicraft, particularly final product for pure beta isomer, it is easy to recrystallization purification
Mass produced.
It should be appreciated that the general description of the above and detailed description hereinafter are only exemplary and explanatory, not
Can the limitation present invention.
Embodiment
With reference to embodiment, the present invention is described further, but the present invention is not limited by following embodiments.
Embodiment
The synthetic method of-O- acetyl group -5- the desoxy-D-riboses of 1,2,3- of one kind tri-, comprises the following steps：
(1) toward the compound D ribose of addition 120g formulas 1 in the mixed solution of 1L isopropanols and the 10mL concentrated sulfuric acids, stir at room temperature
Mix 24 hours, after HPLC detection reactions completely, plus sodium bicarbonate solid is adjusted to neutrality, and suction filtration, filtrate revolving obtains light yellow oil
Shape thing, as the compound 1-O- isopropyl-D ribose of formula 7.
The compound 0.5L acetone solutions of formula 7, are added dropwise system L temperature to 45 after concentrated sulfuric acid 25mL, completion of dropping at room temperature
DEG C, add and be stirred overnight at anhydrous cupric sulfate 50g, 45 DEG C, after HPLC detection reactions completely, is added portionwise in sodium bicarbonate solid
With, filtering, filter cake elutes with acetone, filtrate revolving, obtains oily compound, the i.e. compound of formula 2, is directly used in step (2)
Reaction.
Synthetic line is as follows：
(2) compound of formula 2 that step (1) is obtained is dissolved in 0.5L dichloromethane and 200mL triethylamines, system is cooled to
0 DEG C, 160g paratoluensulfonyl chlorides are added portionwise, after charging is finished, system is risen again to being stirred overnight at room temperature naturally, and HPLC detections are anti-
Should completely after, plus 500mL water be sufficiently stirred for after point liquid, organic phase is concentrated under reduced pressure, and residue methanol is crystallized at -10 DEG C, is obtained
To 261g white solid products, the as compound of formula 3.The yield of the compound of formula 3 is 261g, step (1) and the production of the step of step (2) two
Rate is 91%.
Synthetic route is as follows：
(3) compound of 261g formulas 3 is dissolved in 500mL ethyl acetate and 300mLDMSO in the mixed solvent, at room temperature in batches
Potassium borohydride 100g is added, after charging is finished, is heated to reflux 3 hours, after reaction completely, 0 DEG C is cooled to system, is added dropwise to 1L
After water, completion of dropping, aqueous phase is extracted with ethyl acetate twice, and combined ethyl acetate phase, vacuum distillation obtains oily compound,
The as compound of formula 4.The yield of the compound of formula 4 is 137g, yield 86%.The compound of formula 4 is not purified further, is directly thrown
Enter step (4).
Synthetic route is as follows：
(4) the 78mL 35%HCl aqueous solution and 500mL water are added dropwise into the compound of 137g formulas 4, by system L temperature to 50 DEG C instead
Answer 7 hours, reaction terminates rear vacuum distillation and obtains oily compound, as the compound of formula 5, is not purified further, directly throwing
Enter step (5).
Synthetic route is as follows：
(5) compound of formula 5 is dissolved in 80mL acetic acid and 250mL acetic anhydride, adds 2g perchloric acid and make catalyst, charging is finished
Afterwards, by system L temperature to 40 DEG C react 8 hours, filter after completion of the reaction, filter cake with 100mL methanol elute, filtrate decompression distillation,
Residue adds methanol and water mixed solvent crystallization, and it is that-O- acetyl group-the 5- of final product 1,2,3- tri- takes off to obtain white solid
Oxygen-D ribose, the compound of formula 6.The yield of final product is 161g, is pure beta configurations, HPLC purity 98.9%, step (4) and
The step yield 82% of step (5) two.
Synthetic route is as follows：
Those skilled in the art will readily occur to its of the present invention after the disclosure that specification and practice are invented here is considered
Its embodiment.It is contemplated that cover the present invention any modification, purposes or adaptations, these modifications, purposes or
Person's adaptations follow the general principle of the present invention and including undocumented common knowledge in the art of the invention
Or conventional techniques.Description and embodiments be considered only as it is exemplary, true scope and spirit of the invention by right will
Ask and point out.
Claims (6)
1. one kind 1,2, the synthetic method of-O- acetyl group -5- desoxy-D-riboses of 3- tri-, it is characterised in that comprise the following steps：
(1) the compound D ribose of formula 1, reaction generation 1-O- isopropyl-D cores are added in the mixed solution of isopropanol and the concentrated sulfuric acid
Sugar, carries out isopropylidene to 1-O- isopropyl-D ribose with acetone, the concentrated sulfuric acid and anhydrous cupric sulfate, obtains the compound of formula 2；
(2) compound of formula 2 is dissolved in the mixed solution of dichloromethane and triethylamine, adds tolysulfonyl after cooling wherein
Chlorine, by the compound sulfonylation of formula 2, obtains the compound of formula 3；
(3) compound of formula 3 is dissolved in the in the mixed solvent of ethyl acetate and dimethyl sulfoxide (DMSO), potassium borohydride removing is added at room temperature
Protection group, obtains the compound of formula 4；
(4) 35% hydrochloric acid solution and water are added dropwise into the compound of formula 4, temperature reaction obtains the compound of formula 5；
(5) compound of formula 5 is dissolved in acetic acid and acetic anhydride, adds perchloric acid and make catalyst, carry out acetylization reaction, obtain formula
- O- acetyl group -5- the desoxy-D-riboses of 6 compound 1,2,3- tri-；
2. synthetic method according to claim 1, it is characterised in that in step (1), D ribose, isopropanol and the concentrated sulfuric acid
Mol ratio is 1：20.6：0.125；1-O- isopropyl-D ribose, acetone, the mol ratio of the concentrated sulfuric acid and anhydrous cupric sulfate are 1：
10.8：0.32：0.38.
3. synthetic method according to claim 1, it is characterised in that in step (2), the compound of formula 2, dichloromethane, three
The mol ratio of ethamine and paratoluensulfonyl chloride is 1：7.5：2.48：1.05.
4. synthetic method according to claim 1, it is characterised in that in step (3), the compound of formula 3, ethyl acetate, two
The mol ratio of methyl sulfoxide and potassium borohydride is 1：8.4：5.7：1.55.
5. synthetic method according to claim 1, it is characterised in that in step (5), the compound of formula 5, acetic acid, acetic anhydride
Mol ratio with perchloric acid is 1：2.1：3.85：0.03.
6. synthetic method according to claim 2, it is characterised in that in step (1), in the mixing of isopropanol and the concentrated sulfuric acid
The compound D ribose of formula 1 is added in solution, reaction obtains the compound 1-O- isopropyl-D ribose of formula 7；
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| CN201710683469.3A CN107325133A (en) | 2017-08-11 | 2017-08-11 | A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526950A (en) * | 2019-09-23 | 2019-12-03 | 济南山目生物医药科技有限公司 | A kind of preparation method of five-O- acetylmannosamine sugar of alpha- |
| CN111647028A (en) * | 2020-06-23 | 2020-09-11 | 苏州华鑫医药科技有限公司 | Industrial large-scale production method of capecitabine intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB878060A (en) * | 1958-05-20 | 1961-09-27 | Hoffmann La Roche | Novel nucleotides and salts thereof and a process for the manufacture of same |
| CN101239998A (en) * | 2008-02-03 | 2008-08-13 | 王效山 | Method of synthesizing 1,2,3-tri-acetyl-5-deoxy-D-ribose |
| CN102199176A (en) * | 2011-04-12 | 2011-09-28 | 江苏澳新生物工程有限公司 | Preparation method for 2-amino-2-deoxy-D-glucose and salt thereof |
-
2017
- 2017-08-11 CN CN201710683469.3A patent/CN107325133A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB878060A (en) * | 1958-05-20 | 1961-09-27 | Hoffmann La Roche | Novel nucleotides and salts thereof and a process for the manufacture of same |
| CN101239998A (en) * | 2008-02-03 | 2008-08-13 | 王效山 | Method of synthesizing 1,2,3-tri-acetyl-5-deoxy-D-ribose |
| CN102199176A (en) * | 2011-04-12 | 2011-09-28 | 江苏澳新生物工程有限公司 | Preparation method for 2-amino-2-deoxy-D-glucose and salt thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526950A (en) * | 2019-09-23 | 2019-12-03 | 济南山目生物医药科技有限公司 | A kind of preparation method of five-O- acetylmannosamine sugar of alpha- |
| CN110526950B (en) * | 2019-09-23 | 2023-08-04 | 济南山目生物医药科技有限公司 | Preparation method of alpha-five-O-acetyl mannose |
| CN111647028A (en) * | 2020-06-23 | 2020-09-11 | 苏州华鑫医药科技有限公司 | Industrial large-scale production method of capecitabine intermediate |
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