CN108187636A - A kind of preparation method of gemcitabine hydrochloride purification material - Google Patents
A kind of preparation method of gemcitabine hydrochloride purification material Download PDFInfo
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- CN108187636A CN108187636A CN201711169090.7A CN201711169090A CN108187636A CN 108187636 A CN108187636 A CN 108187636A CN 201711169090 A CN201711169090 A CN 201711169090A CN 108187636 A CN108187636 A CN 108187636A
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- gemcitabine hydrochloride
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/264—Synthetic macromolecular compounds derived from different types of monomers, e.g. linear or branched copolymers, block copolymers, graft copolymers
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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
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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Abstract
The present invention relates to a kind of preparation methods of gemcitabine hydrochloride purification material.By weight, ABS resin is added in a kettle, 4 (trimethylsiloxy group) 3 amylene, 2 ketone, 1, 1, 3, 3, 3 five fluorine 2 (fluorine methoxyl group), 1 propylene, (E) 3 [3 methyl 5 (3 methyl fourth, 2 alkenyl) imidazoles, 4 bases], the third 2 e pioic acid methyl ester, benzoyl peroxide, hydroxymethyl cellulose N, N' bis- (2 hydroxyl 5 (ethylene beta carboxyls) benzyl) ethylenediamine N, N' oxalic acid, 9, 10 2 (allyloxys) 4, 4 diethoxies 3, 8, 11 trioxa, 4 sila, 14 carbon, 13 alkene, water, it heats up after stirring evenly, reaction, product is filtered after reaction, washing, gemcitabine hydrochloride purification material is obtained after drying.
Description
Technical field
The present invention relates to a kind of preparation method of adsorbent, especially a kind of preparation side of gemcitabine hydrochloride purification material
Method.
Background technology
Gemcitabine hydrochloride be suitable for treating inoperable late period or metastatic cancer of pancreas and treatment Local advancement or
Metastatic Nsclc, treatment Advanced non-small cell lung cancer, cancer of pancreas, carcinoma of urinary bladder, breast cancer and other entities swell
Knurl.
CN102659884B discloses a kind of method of purification of gemcitabine hydrochloride, and step is as follows：A) by gemcitabine hydrochloride he
After shore crude product is dissolved in water, adds in alkali and adjust pH value of solution to 8~9, after being stirred to react, suction filtration obtains gemcitabine；B) Jiang Jixi
He is dissolved in alcoholic solvent shore, a concentration of 0.1~0.2g/mL, adds in activated carbon, and filtrate is collected in filtering；C) filtrate is utilized
It prepares chromatographic column to be detached, the mobile phase that chromatographic column uses is acetone or acetonitrile and hydrochloric acid solution, acetone or acetonitrile and salt
The volume ratio of acid solution is 30~50:70~50；Fixed phase stuffing is silica gel or alundum (Al2O3), collects filtrate, dry, is obtained
Gemcitabine hydrochloride highly finished product.
CN101492482 discloses a kind of synthesis technology of industrial production of gemcitabine hydrochloride, belongs to chemical products synthesis
Technology field.It is using 2,3- oxygen-isopentylidene-D- glyceraldehyde as raw material, through addition, open loop, cyclization, then is used respectively
Intermediate is made in TBDPSCL and chlorobenzoyl chloride protection hydroxyl.Intermediate is through restoring, remove-insurance after being condensed after Mesylation with cytimidine
Shield, gemcitabine hydrochloride is made into salt.
Existing gemcitabine hydrochloride is purifying link, is mostly purified, grasped using the method for crystallization or activated carbon adsorption
Make relatively complicated, adsorption effect is poor.
Invention content
In order to solve the above technical problems, present invention employs following technical solutions：A kind of gemcitabine hydrochloride purification
The preparation method of material, includes the following steps：
By weight, ABS resin is added in a kettle, 4- (trimethylsiloxy group) -3- amylene -2- ketone, 1,1,3,3,3-
Five fluoro- 2- (fluorine methoxyl group) -1- propylene, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2- olefin(e) acids
Methyl esters, benzoyl peroxide, hydroxymethyl cellulose N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine N,
N'- oxalic acid, 9,10- bis- (allyloxy) -4,4- diethoxies -3,8,14 carbon -13- alkene of 11- trioxa -4- silas, water,
80-100 DEG C is warming up to after stirring evenly, reacts 6-12h, product is filtered after reaction, washing, and hydrochloric acid Ji is obtained after dry
His shore of west purifies material.
4- (trimethylsiloxy group) -3- amylene -2- ketone, quality dosage are the 1-3% of ABS resin.
Described 1,1,3,3,3- five fluoro- 2- (fluorine methoxyl group) -1- propylene, quality dosage are the 0.1- of ABS resin
0.5%。
Described (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] the propyl- 2- e pioic acid methyl esters, quality
Dosage is the 0.5-1% of ABS resin.
The benzoyl peroxide, quality dosage are the 0.5-1.5% of ABS resin.
Its quality dosage of the hydroxymethyl cellulose is the 0.2-0.8% of ABS resin.
The N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine N, N'- oxalic acid, quality
Dosage is the 0.1-0.3% of ABS resin.
The 14 carbon -13- of 9,10- bis- (allyloxy) -4,4- diethoxy -3,8,11- trioxa -4- silas
Alkene, quality dosage are the 0.01-0.1% of ABS resin.
The water, quality dosage are the 300-600% of ABS resin.
The ABS resin, 4- (trimethylsiloxy group) -3- amylene -2- ketone, 1,1,3,3,3- five fluoro- 2- (fluorine methoxies
Base) -1- propylene, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2- e pioic acid methyl esters, benzoyl peroxide
Formyl, hydroxymethyl cellulose N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine N, N'- oxalic acid, 9,
14 carbon -13- alkene of 10- bis- (allyloxy) -4,4- diethoxies -3,8,11- trioxa -4- silas, is commercial product.
Beneficial effects of the present invention：
（1）The adsorbent that the present invention is produced, endurance, heat resistance, impact resistance are strong, non-breakable, are easily isolated；
（2）Adsorbent product, adsorption capacity is strong, can save adsorption time, simplifies gemcitabine hydrochloride purifying products technique.
Specific embodiment
Embodiment 1
In a kettle, addition ABS resin 100Kg, 4- (trimethylsiloxy group) -3- amylene -2- ketone 2Kg, 1,1,3,3,3- five
Fluoro- 2- (fluorine methoxyl group) -1- propylene 0.3Kg, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2-
E pioic acid methyl ester 0.75Kg, benzoyl peroxide 1Kg, ammonium persulfate 0.5Kg, 9,10- bis- (allyloxy) -4,4- diethoxies -
3,8,11- trioxa -4- silas, 14 carbon -13- alkene 0.05Kg, N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl)
Ethylenediamine N, N'- oxalic acid 0.2Kg, water 450Kg are warming up to 90 DEG C after stirring evenly, react 9h, and product passes through after reaction
Filtering, washing obtain gemcitabine hydrochloride purification material after dry.
Embodiment 2
In a kettle, addition ABS resin 100Kg, 4- (trimethylsiloxy group) -3- amylene -2- ketone 1Kg, 1,1,3,3,3- five
Fluoro- 2- (fluorine methoxyl group) -1- propylene 0.1Kg, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2-
E pioic acid methyl ester 0.5Kg, benzoyl peroxide 0.5Kg, ammonium persulfate 0.2Kg, 9,10- bis- (allyloxy) -4,4- diethoxies -
3,8,11- trioxa -4- silas, 14 carbon -13- alkene 0.01Kg, N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl)
Ethylenediamine N, N'- oxalic acid 0.1Kg, water 300Kg are warming up to 80 DEG C after stirring evenly, react 6h, and product passes through after reaction
Filtering, washing obtain gemcitabine hydrochloride purification material after dry.
Embodiment 3
In a kettle, addition ABS resin 100Kg, 4- (trimethylsiloxy group) -3- amylene -2- ketone 3Kg, 1,1,3,3,3- five
Fluoro- 2- (fluorine methoxyl group) -1- propylene 0.5Kg, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2-
E pioic acid methyl ester 1Kg, benzoyl peroxide 1.5Kg, ammonium persulfate 0.8Kg, 9,10- bis- (allyloxy) -4,4- diethoxy -3,
8,11- trioxa -4- silas 14 carbon -13- alkene 0.1Kg, N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) second
Diamines N, N'- oxalic acid 0.3Kg, water 600Kg are warming up to 100 DEG C after stirring evenly, react 12h, and product passes through after reaction
Filtering, washing obtain gemcitabine hydrochloride purification material after dry.
Comparative example 1
1,1,3,3,3- five fluoro- 2- (fluorine methoxyl group) -1- propylene is added without, other conditions are the same as embodiment 1.
Comparative example 2
(E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2- e pioic acid methyl esters are added without, other conditions are same
Embodiment 1.
Comparative example 3
It is added without 9,10- bis- (allyloxy) -4,4- diethoxies -3,8,14 carbon -13- alkene of 11- trioxa -4- silas,
His condition is the same as embodiment 1.
Comparative example 4
It is added without N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine N, N'- oxalic acid, other conditions are same
Embodiment 1.
Embodiment 4
The thick gemcitabine hydrochloride that purity is 95% is passed through to the adsorbent made equipped with 500g embodiments 1-3 and comparative example 1-4 to produce
In the 1000mL exchange columns of product, 80 DEG C, flow velocity 1BV/h of temperature, under the conditions of adsorb purification, with the matter of gas chromatographic detection efflux
Percentage composition is measured, is shown in Table 1.
Table 1：Gemcitabine hydrochloride purity after the gemcitabine hydrochloride adsorbent absorption purification that different process is produced.
Claims (9)
1. a kind of preparation method of gemcitabine hydrochloride purification material, it is characterised in that include the following steps：
By weight, ABS resin is added in a kettle, 4- (trimethylsiloxy group) -3- amylene -2- ketone, 1,1,3,3,3-
Five fluoro- 2- (fluorine methoxyl group) -1- propylene, (E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2- olefin(e) acids
Methyl esters, benzoyl peroxide, hydroxymethyl cellulose, N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine
N, N'- oxalic acid, 9,10- bis- (allyloxy) -4,4- diethoxies -3,8,14 carbon -13- alkene of 11- trioxa -4- silas,
Water is warming up to 80-100 DEG C after stirring evenly, react 6-12h, and product is filtered after reaction, and washing obtains salt after dry
Sour gemcitabine purifies material.
2. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
4- (trimethylsiloxy group) -3- amylene -2- ketone, quality dosage are the 1-3% of ABS resin.
3. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
1,1,3,3,3- five fluoro- 2- (fluorine methoxyl group) -1- propylene, quality dosage are the 0.1-0.5% of ABS resin.
4. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
(E) -3- [3- methyl -5- (3- methyl but-2-enes base) imidazol-4 yl] propyl- 2- e pioic acid methyl esters, quality dosage are ABS resin
0.5-1%.
5. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
Benzoyl peroxide, quality dosage are the 0.5-1.5% of ABS resin.
6. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
Its quality dosage of hydroxymethyl cellulose is the 0.2-0.8% of ABS resin.
7. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
N, N'- bis- (2- hydroxyls -5- (ethylene-beta- carboxyls) benzyl) ethylenediamine N, N'- oxalic acid, quality dosage are ABS resin
0.1-0.3%.
8. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
9,10- bis- (allyloxy) -4,4- diethoxies -3,8,14 carbon -13- alkene of 11- trioxa -4- silas, quality dosage are
The 0.01-0.1% of ABS resin.
9. a kind of preparation method of gemcitabine hydrochloride purification material according to claim 1, it is characterised in that：Described
Water, quality dosage are the 300-600% of ABS resin.
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| CN201711169090.7A CN108187636A (en) | 2017-11-22 | 2017-11-22 | A kind of preparation method of gemcitabine hydrochloride purification material |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106215895A (en) * | 2016-08-21 | 2016-12-14 | 王琪宇 | A kind of preparation method of gemcitabine hydrochloride purification adsorbent |
| CN106311168A (en) * | 2016-08-21 | 2017-01-11 | 王琪宇 | Preparation method for adsorbent for purifying 2-imidazolidone |
| CN107082884A (en) * | 2017-06-04 | 2017-08-22 | 王金桢 | A kind of method for adsorbing purification dimethicone |
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- 2017-11-22 CN CN201711169090.7A patent/CN108187636A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106215895A (en) * | 2016-08-21 | 2016-12-14 | 王琪宇 | A kind of preparation method of gemcitabine hydrochloride purification adsorbent |
| CN106311168A (en) * | 2016-08-21 | 2017-01-11 | 王琪宇 | Preparation method for adsorbent for purifying 2-imidazolidone |
| CN107051395A (en) * | 2016-08-21 | 2017-08-18 | 王琪宇 | A kind of gemcitabine hydrochloride purifies the preparation method of auxiliary agent |
| CN107082884A (en) * | 2017-06-04 | 2017-08-22 | 王金桢 | A kind of method for adsorbing purification dimethicone |
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Application publication date: 20180622 |