CN109836462A - A kind of preparation method of triacetyl deoxyribose αisomer - Google Patents
A kind of preparation method of triacetyl deoxyribose αisomer Download PDFInfo
- Publication number
- CN109836462A CN109836462A CN201711212880.9A CN201711212880A CN109836462A CN 109836462 A CN109836462 A CN 109836462A CN 201711212880 A CN201711212880 A CN 201711212880A CN 109836462 A CN109836462 A CN 109836462A
- Authority
- CN
- China
- Prior art keywords
- deoxyribose
- triacetyl
- αisomer
- preparation
- acetate
- 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.)
- Granted
Links
Landscapes
- Saccharide Compounds (AREA)
Abstract
The present invention discloses a kind of capecitabine intermediate impurities triacetyl deoxyribose αisomer: chemical name is the preparation method of 1 α -1,2,3- triacetoxyl group -5- deoxy-D-ribose.The preparation method obtains triacetyl deoxyribose αisomer crude product using 5- deoxy-D-ribose as synthesis material, through methylvinyl acetate/ferric trichloride acetylation, then obtains triacetyl deoxyribose αisomer sterling through column chromatographic purifying.The preparation method of triacetyl deoxyribose αisomer provided by the invention has easy to operate, the high advantage of product purity, lays a good foundation for the quality research of capecitabine intermediate and finished product.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to the preparation of anti-tumor drug intermediate impurities and separation method,
In particular to the preparation of capecitabine intermediate impurities triacetyl deoxyribose αisomer and separation method, the impurity chemical name
Referred to as 1 α -1,2,3- triacetoxyl group -5- deoxy-D-riboses, the impurity chemical structural formula are as follows:
。
Background technique
Capecitabine (Capecitabine) is a kind of fluoropyrimidine deoxyribonucleoside ammonia developed by Roche Holding Ag, Switzerland
Carbamate series antineoplastic medicament, chemical name are as follows: the fluoro- N- of 5'- deoxidation -5- [(amoxy) carbonyl] cytidine, chemical structure is such as
Under:
。
Triacetyl deoxyribose is the important intermediate for synthesizing capecitabine, passes through route (Chinese Medicine reported in the literature
Industrial magazine, 2011,42 (12), 887-888) through three steps can prepare to capecitabine bulk pharmaceutical chemicals.According to the report of document,
The synthesis of triacetyl deoxyribose mainly with following two method: first is that using 1- methyl -5- deoxyribose as intermediate, through two steps
Triacetyl deoxyribose is reacted to obtain, such as document EP2210896A1, Journal of Medicinal Chemistry, 2000,43
(13), 2566-2574；Second is that obtaining triacetyl deoxyribose, such as document through a step acetylation using 5- deoxy-D-ribose as intermediate
EP2241556, Carbohydrate Research, 2003,338 (4), 303 ~ 306, reactive chemistry formula is as follows:
。
Such as the synthetic method of above-mentioned report, the triacetyl deoxyribose of preparation is the mixture of α and beta isomer, beta isomer
Capecitabine can be prepared by participating in reaction in next step, and αisomer is the impurity generated, and αisomer ratio is that 3 ~ 30%, α is different
The ratio of structure body will not be higher.Beta isomer sterling can be obtained by chromatographing or recrystallizing by column under this isomer proportion.Due to
The isomers accounting of α is less, and in addition α and beta isomer polarity are approximate, and hardly possible separation is separated pure using above-mentioned isomer mixture
Change cannot obtain triacetyl deoxyribose αisomer sterling.The structure of triacetyl deoxyribose αisomer and beta isomer is as follows
It is shown:
。
The presence of impurity is directly related to the quality and safety of drug, and synthesis is carried out to it and identifies the matter final to product
Amount control has great significance.Triacetyl deoxyribose is difficult to avoid that generation αisomer, preparation α are different during preparation
Structure body sterling can carry out quantitative detection to the isomer impurities in triacetyl deoxyribose, this is to realization triacetyl deoxidation core
The accurate control and its necessity of the impurity in sugared intermediate.
Summary of the invention
The present invention provides a kind of preparation method for preparing triacetyl deoxyribose αisomer.Specific method is with 5- deoxidation-D-
Ribose is starting material, and acetylation obtains triacetyl deoxyribose isomers under the action of acetoxyacrylic acid ester/ferric trichloride
Triacetyl deoxyribose αisomer sterling is further purified in mixture, the mixture.Reaction raw materials 5- deoxy-D-ribose is
The acquisition of known compound, sample can be by the synthetic method of patent WO2008/105593, with methyl -5- deoxidation -2,3-
O- isopropylidene-β-D- nucleosides (V) is prepared into sample through sulfuric acid heating hydrolysis for raw material.Starting material compound 5- deoxidation-D-
The synthetic route of ribose is as follows:
Triacetyl deoxyribose αisomer synthetic route is as follows:
。
αisomer is primary product in the mixture, and ratio is 85 ~ 95%.Acidic catalyst is added in reaction system, such as
Acid cation exchange resin, polyphosphoric acids, methanesulfonic acid, sulfuric acid etc. can accelerate the progress of reaction.Reaction dissolvent is acetic acid esters
Class solvent, such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate etc..Reaction temperature is 60 ~ 100
℃.By the available triacetyl deoxyribose αisomer sterling of column chromatography for separation once or twice, purity is 99% or more.Column
Solvent system is methylene chloride: hexamethylene=1:10.Chromatography process is monitored by thin layer point plate, with solvent methylene chloride: hexamethylene
Alkane=1:4, single are climbed plate and cannot be separated, and need to climb plate repeatedly can separate α and beta isomer three times.
The structure determination of triacetyl deoxyribose αisomer mainly by hydrogen compose determine, characteristic peak be 6.262 ~
6.257ppm's is bimodal, coupling constant 4.8Hz, is 1 proton of saccharide ring；Corresponding beta isomer saccharide ring 1 be proton be it is unimodal,
Appearance is in 6.078 ppm.Nucleus magnetic hydrogen spectrum (the equal deuterated chloroform of solvent, 800M) contrast table of α and beta isomer is as follows:
。
Present invention simultaneously discloses the methods with liquid phase detection triacetyl deoxyribose isomers:
Mobile phase: acetonitrile: water=1:1
Chromatographic column: moon rising sun C18 4.6*250mm
Flow velocity: 1.0mL/min
Column temperature: 30 DEG C
Evaporation photodetector: 45 DEG C of detector temperature, air pressure 350kpa
Sample takes dissolved in right amount with acetonitrile after sample introduction.
Detailed description of the invention
Fig. 1 ~ Fig. 4 is the nucleus magnetic hydrogen spectrum map of triacetyl deoxyribose αisomer
Fig. 5 is the nucleus magnetic hydrogen spectrum map of triacetyl deoxyribose beta isomer
Fig. 6 is embodiment 2-1 triacetyl deoxyribose αisomer crude product liquid phase figure
Fig. 7 is embodiment 2-3 triacetyl deoxyribose αisomer crude product liquid phase figure
Fig. 8 is the liquid phase figure that 3 triacetyl deoxyribose αisomer of embodiment crosses column sterling
The present invention provides a method for preparing triacetyl deoxyribose αisomer, has easy to operate, high excellent of product purity
Point.The quality research for being prepared as capecitabine and its intermediate and control of triacetyl deoxyribose αisomer are established good
Basis.
Specific embodiment
The present invention will be further described by the following examples, but in addition to following embodiment, according to the common skill in this field
The various replacements or change that art knowledge and customary means are made, are included in the scope of the invention.
The preparation of 1 5- deoxy-D-ribose of embodiment
Embodiment 1-1 is by compound V 70g (0.37mol) plus water 700mL, concentrated sulfuric acid 2.0mL, after mixing evenly, heating 80 ~ 90
DEG C reaction 4h, thin-layer chromatography show raw material it is reacted it is complete (EA: n-hexane=1:10, KMnO4 colour developing).Processing: it is cooled to room
Temperature filters resin, 80 DEG C of evaporated under reduced pressure of filtrate with 717 strongly basic anionic resin tune pH=6 ~ 7.It is evaporated residue toluene
150mL band water is primary, and acetonitrile 600mL is added, and dissolved clarification, anhydrous magnesium sulfate is dry, is concentrated under reduced pressure and does to obtain 5- deoxy-D-ribose oily
Object 37.5g, yield 75.2%.
Embodiment 1-2 is by compound V 100g (0.53mol) plus 0.04M sulfuric acid 500mL, after mixing evenly, heating 80 ~ 90
DEG C reaction 2h, thin-layer chromatography show raw material it is reacted it is complete (EA: n-hexane=1:10, KMnO4 colour developing).Processing: it is cooled to room
Temperature, with sodium carbonate solid tune pH6 ~ 7,80 DEG C of evaporated under reduced pressure.It is primary to be evaporated residue toluene 150mL band water, acetonitrile is added
600mL disperses, and anhydrous magnesium sulfate drying is added, filters, and filtrate decompression concentration is done to obtain 5- deoxy-D-ribose grease 57.4g, receives
Rate 80.7%.
The preparation of 2 triacetyl deoxyribose αisomer of embodiment
Embodiment 2-1
5- deoxidation D-ribose prepared by embodiment 1-1 is taken into 10g(74.6mmol) isopropyl acetate 100mL, isopropyl acetate is added
Enester 19.0g(0.19mol), anhydrous ferric trichloride 1.6g(10mmol), sulfuric acid 2.9g(30mmol) and cold it is warming up to 60 DEG C of reactions
8h, reaction are diluted with water, and layering, organic layer crosses diatomite, and anhydrous sodium sulfate is dry, 35 DEG C be concentrated under reduced pressure be evaporated triacetyl is de-
Oxygen ribose αisomer crude product, 18.6g, yield 95.9%, α: β=87:13 of liquid phase ratio.
Embodiment 2-2
5- deoxidation D-ribose prepared by embodiment 1-1 is taken into 10g(74.6mmol) butyl acetate 100mL, isopropyl acetate alkene is added
Ester 19.0g(0.19mol), anhydrous ferric trichloride 1.6g(10mol), 732 storng-acid cation exchange resin 5g are warming up to 100
DEG C reaction 3h, reaction is diluted with water, and is layered, and organic layer crosses diatomite, and anhydrous sodium sulfate is dry, 45 DEG C be concentrated under reduced pressure be evaporated three
Acetyl deoxyribose αisomer crude product, 19.0g, yield 97.9%, α: β=91:9 of liquid phase ratio.
Embodiment 2-3
5- deoxidation D-ribose prepared by embodiment 1-1 is taken into 10g(74.6mmol) n-propyl acetate 100mL, isopropyl acetate is added
Enester 19.0g(0.19mol), anhydrous ferric trichloride 1.6g(10mol), methanesulfonic acid (30mmol) is cold to be warming up to 75 DEG C of reaction 3h,
Reaction is diluted with water, layering, and organic layer crosses diatomite, and anhydrous sodium sulfate is dry, and 35 DEG C of reduced pressures are evaporated to obtain triacetyl deoxidation
Ribose αisomer crude product, 18.9g, yield 97.4%, α: β=95:5 of liquid phase ratio.
The purifying of 3 triacetyl deoxyribose αisomer of embodiment
Column chromatographic purifying: Example 2-1 crude product 18.0g, eluant dichloromethane: hexamethylene=1:10 crosses column, collects purity
Higher efflux is concentrated and is evaporated, triacetyl deoxyribose αisomer sterling, and 13.5g crosses column yield 75%, HPLC purity
100%, HRMS (ESI+): [M+Na] +=283.0778.1H NMR (800M, CDCl3): δ 6.262 ~ 6.257 (1H, d, J=
4.8Hz), 5.162 ~ 5.148 (1H, dd, J1=6.4Hz, J2=4.8Hz), 4.858 ~ 4.844 (1H, dd, J1=7.2Hz, J2=
4.0Hz), 4.235 ~ 4.210 (1H, m), 1.266 ~ 1.258 (1H, d, J=6.4Hz), 2.017 (3H, s), 2.005 (3H,
S), 1.970 (3H, s).
Claims (7)
1. a kind of preparation method of triacetyl deoxyribose αisomer, comprises the following steps:
5- deoxy-D-ribose obtains triacetyl deoxyribose αisomer crude product by acetylization reaction,
(b) triacetyl deoxyribose αisomer crude product column chromatographic purifying is obtained into triacetyl deoxyribose αisomer sterling；
It is characterized in that acetylation reagent used in the acetylization reaction is isopropyl acetate/ferric trichloride system, it is described
Triacetyl deoxyribose αisomer crude product purity be 85~95%.
2. the preparation method of triacetyl deoxyribose αisomer as described in claim 1, it is characterised in that the acetylation
Acid is added in reaction, reaction can be accelerated and carried out.
3. the preparation method of triacetyl deoxyribose αisomer as claimed in claim 2, it is characterised in that the quickening is anti-
The acid that should be carried out is one of acid cation exchange resin, polyphosphoric acids, methanesulfonic acid, p-methyl benzenesulfonic acid, sulfuric acid.
4. the preparation method of triacetyl deoxyribose αisomer as described in claim 1, it is characterised in that the acetylation
Reaction temperature is 60~100 DEG C.
5. the preparation method of triacetyl deoxyribose αisomer as described in claim 1, it is characterised in that the acetylation is anti-
The solvent used in answering is acetate esters solvents.
6. the preparation method of triacetyl deoxyribose αisomer as claimed in claim 5, it is characterised in that the acetate esters
Solvent is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, one of butyl acetate.
7. the preparation method of triacetyl deoxyribose αisomer as described in claim 1~6 any one, it is characterised in that column
Chromatography is with eluant, eluent DCM: hexamethylene=1:10 purifies to obtain triacetyl deoxyribose αisomer sterling.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711212880.9A CN109836462B (en) | 2017-11-28 | 2017-11-28 | Preparation method of triacetyl deoxyribose alpha isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711212880.9A CN109836462B (en) | 2017-11-28 | 2017-11-28 | Preparation method of triacetyl deoxyribose alpha isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109836462A true CN109836462A (en) | 2019-06-04 |
| CN109836462B CN109836462B (en) | 2021-12-28 |
Family
ID=66879550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711212880.9A Active CN109836462B (en) | 2017-11-28 | 2017-11-28 | Preparation method of triacetyl deoxyribose alpha isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109836462B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0725892A (en) * | 1993-05-13 | 1995-01-27 | Ono Pharmaceut Co Ltd | Production of 2-chloro-4-nitrophenyl-(peracetyl)-alpha-d-maltotrioside |
| CN1305486A (en) * | 1998-06-24 | 2001-07-25 | 弗尼亚工业和卫生 | Novel compounds derived from alpha-D-xylose, preparation method and therapeutic use |
| CN103242386A (en) * | 2013-04-11 | 2013-08-14 | 中国中化股份有限公司 | Method for preparing alpha-1-methoxy-2-deoxyribofuranose derivatives |
| CN104926890A (en) * | 2015-06-04 | 2015-09-23 | 新乡学院 | Method for synthesizing 1,2-O-diacetyl-3,5-O-dibenzoyl ribose |
| CN105968156A (en) * | 2016-05-15 | 2016-09-28 | 南京海融医药科技有限公司 | Alpha isomer impurity of regadenoson and preparation method and use thereof |
-
2017
- 2017-11-28 CN CN201711212880.9A patent/CN109836462B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0725892A (en) * | 1993-05-13 | 1995-01-27 | Ono Pharmaceut Co Ltd | Production of 2-chloro-4-nitrophenyl-(peracetyl)-alpha-d-maltotrioside |
| CN1305486A (en) * | 1998-06-24 | 2001-07-25 | 弗尼亚工业和卫生 | Novel compounds derived from alpha-D-xylose, preparation method and therapeutic use |
| CN103242386A (en) * | 2013-04-11 | 2013-08-14 | 中国中化股份有限公司 | Method for preparing alpha-1-methoxy-2-deoxyribofuranose derivatives |
| CN104926890A (en) * | 2015-06-04 | 2015-09-23 | 新乡学院 | Method for synthesizing 1,2-O-diacetyl-3,5-O-dibenzoyl ribose |
| CN105968156A (en) * | 2016-05-15 | 2016-09-28 | 南京海融医药科技有限公司 | Alpha isomer impurity of regadenoson and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| HENRY M.KISSMAN，等: "The Synthesis of Certain 5-Deoxy-D-ribofuranosylpurines", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| HIDEO TSUTSUMI, 等: "Synthesis of 1,2-0-isopropylidene-α-D-ribofuranose from D-ribose", 《CARBOHYDRATE RESEARCH》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109836462B (en) | 2021-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN102219817A (en) | Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent | |
| CN107245045A (en) | A kind of preparation method for the ground ostelin that ends | |
| CN102348706A (en) | Process for producing pyripyropene derivative | |
| CN104151243B (en) | Prepare the method for polysubstituted Acridine derivatives | |
| CN112441952B (en) | Cannabidiol-3-sulfonic acid, preparation method and application thereof, and cannabidiol derivative | |
| JP2018532718A (en) | Phosphoramidate compound, production method thereof and crystal | |
| CN101585840A (en) | Optically pure alpha-ketoacyl harringtonine and preparing and purifying method thereof | |
| CN112110897B (en) | Preparation method of deuterated crizotinib and derivative thereof | |
| CN101735220B (en) | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof | |
| CN109836462A (en) | A kind of preparation method of triacetyl deoxyribose αisomer | |
| CN105481913B (en) | A method of synthesis azithromycin | |
| CN103342707B (en) | For the preparation of the preparation method of A Sainaping intermediate | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN104513241B (en) | New regadenoson intermediate, preparation method and application thereof | |
| CN101993464B (en) | Preparation method of capecitabine | |
| CN111285876A (en) | Linagliptin intermediate isomer impurity, preparation method and application thereof | |
| CN101883486B (en) | Process for preparing r-gossypol l-phenylalaninol dienamine | |
| CN110872305B (en) | Fluorocamptothecin medicament derivative and preparation and application thereof | |
| CN112321642A (en) | Ruidexiwei related substance and preparation method and application thereof | |
| CN107089942B (en) | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB | |
| CN106632393A (en) | Preparation method for antituberculous candidate drug namely PA-824 | |
| CN108822171B (en) | Anthraquinone triazole antibiotic nucleoside analogues, synthesis method and application thereof in preparation of anti-tumor or anti-virus drugs | |
| CN112500441A (en) | Preparation process of high-purity glycosyl phosphate | |
| CN108912018B (en) | Preparation method and application of impurity compound in key intermediate for synthesizing sulpiride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |