CN109305992A - A kind of preparation method of azacitidine - Google Patents
A kind of preparation method of azacitidine Download PDFInfo
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- CN109305992A CN109305992A CN201710627067.1A CN201710627067A CN109305992A CN 109305992 A CN109305992 A CN 109305992A CN 201710627067 A CN201710627067 A CN 201710627067A CN 109305992 A CN109305992 A CN 109305992A
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- azacitidine
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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
- C07H19/12—Triazine radicals
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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
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The present invention relates to a kind of preparation method of azacitidine, this method avoids azacitidine from contacting water, reduces the degradation of azacitidine, not only easy to operate, yield and purity greatly improve.In addition, the present invention uses ethyl alcohol as brilliant solvent is turned during azacitidine is further purified, cost, industrial application preferably are greatly reduced.
Description
Technical field
The invention belongs to biomedicine fields, are related to a kind of preparation method of azacitidine.
Background technique
Azacitidine is white, needle-shaped crystals, chemical name are as follows: 4- amino -1- β-D-RIBOSE base -1,3,5-triazines -2
(1H) -one or 4- amino -1- β--2 (1H) -one of D-RIBOSE base-S- triazine or 4- amino -1- (3,4- dihydroxy -5-
Methylol-tetrahydrofuran -2- base) -1H- [1,3,5] triazine -2- ketone is the one of Pharmion drugmaker of U.S. development
Dnmt rna inhibitor (DMTI) drug of kind of hypomethylation, in May, 2004 be in the granted listing in the U.S., product name
VIDAZA (Victor bundle) is first, field marketed drug for the treatment of all hypotypes of myelodysplastic syndrome.Knot
Structure is as follows:
Yuan Yan house journal CN103619864A discloses a kind of preparation method of azacitidine, the following institute of synthetic route
Show:
The route second step are as follows: in the presence of metal Lewis acids, silylated 5- azepine cytimidine and acyl group are protected
After the β of shield-D-RIBOSE reaction, with water and at least one neutralization reagent quenching reaction, shielded 5-azacitidine is obtained.
Specifically used sodium carbonate/bicarbonate is post-processed as neutralizer in embodiment, and the method for taking washing extracting and demixing
It is purified.Our company inventor has found that azacitidine is unstable when meeting water in the course of the research, is easy to happen hydrolysis
Reaction, makes the triazine ring of 5-azacitidine degrade.Especially in weakly alkaline aqueous solution, the aquation of 5,6- imine double bonds
Can quickly it occur, then bond cleavage, so that formyl derivative N- (formoxyl amidino groups)-N '-β-D-RIBOSE base urea is generated, then
Deformylase irreversibly obtains 1- β-D-RIBOSE base -3- dicyandiamidines.The route is adopted to remove remaining metal salt
With first at the way of purification to dissociate after salt, cumbersome, yield is relatively low.And portion is being had in DMSO/ methanol Crystallization Process
Methanol solvate is divided to generate.Therefore, according to this method, the yield of azacitidine is generally lower, operates also very complicated, our company's invention
It is found after people's further investigation, changes the mode of operations, controls reaction condition, it can be with the effective solution above problem.
Technology contents
In order to overcome above-mentioned difficulties, the present invention provides a new azacitidine preparation method, specific steps are as follows:
A) step a: in organic solvent, compound A reacts under lewis acidic catalysis with 1,2,3,5-Tetra-O-Acetyl-D-Ribose；
B) step b: alcohols solvent will be added in step a reaction solution after reaction, the reacting metal salt with alcohol obtains
Azacitidine.
Wherein, organic solvent can be specifically as follows acetonitrile, methylene chloride, chloroform, four with polar organic solvent in step a
Chlorination carbon, tetrahydrofuran, toluene, acetone, one of methyl ethyl ketone or a variety of；Preferably acetonitrile, methylene chloride, tetrahydro furan
It mutters or one of toluene or a variety of, preferably one of acetonitrile, methylene chloride, tetrahydrofuran or toluene.
Lewis acid used in step a is that can be metal Lewis acids catalyst, is also possible to nonmetallic Louis
Acid catalyst, metal Lewis acids catalyst has stannic chloride, aluminium chloride, titanium chloride, iron chloride, copper chloride, zinc chloride, nonmetallic
Lewis acid catalyst has one of trifluoromethanesulfonic acid trimethyl silicone grease, trifluoromethanesulfanhydride anhydride or a variety of；Preferably fluoroform
One of sulfonic acid trimethyl silicone grease, trifluoromethanesulfanhydride anhydride, stannic chloride, aluminium chloride, titanium tetrachloride, copper chloride, iron chloride are more
Kind；More preferably trifluoromethanesulfonic acid trimethyl silicone grease, trifluoromethanesulfanhydride anhydride, stannic chloride, aluminium chloride, titanium tetrachloride, copper chloride, chlorine
Change one of iron.
The temperature of step a is 40~75 DEG C, preferably 60~75 DEG C.
Alcohols solvent can be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, ring in step b
One of hexanol, n-hexyl alcohol are a variety of；Preferably one of methanol, ethyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol
Or it is a variety of；More preferably one of methanol, ethyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, cyclohexanol.
The metal salt of alcohol can be one of the lithium of alcohol, sodium, potassium, calcium, magnesium, zinc, iron, mantoquita or a variety of in step b；It is excellent
It is selected as one of potassium alcoholate, sodium alkoxide, alcohol calcium or a variety of, preferably one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or a variety of,
Preferably one of potassium alcoholate, sodium alkoxide, alcohol calcium or a variety of, preferably one of sodium methoxide, sodium ethoxide, potassium tert-butoxide.
The temperature of step b is 0~60 DEG C, preferably 0~30 DEG C.
PH is 12~14 after the metal salt of alcohol is added in step b.
Further, the azacitidine that step b is obtained can be purified further by following step:
C) step c: dissolving step b obtained azacitidine crude product 1, with DMSO and recrystallizing methanol, (DMSO dissolves, rear to add
Enter methanol, solid be precipitated), obtain azacitidine crude product 2；
D) step d: azacitidine crude product is mixed with ethyl alcohol, stirs 1~6h, and filtering obtains azacitidine.
The crystal form of azacitidine prepared by step d is detected as US20130059810A1 crystal form I.
Original is cleverly ground the second step of patent preparation method for preparation method provided by the invention and third step merges, thus
It avoids azacitidine from contacting water, reduces the degradation of azacitidine.Modified preparation method is easy to operate, and yield and purity are significantly
It improves.In addition, the present invention uses ethyl alcohol as brilliant solvent is turned during azacitidine is further purified, methanol solvate can be made
It is converted into crystal form I.This method is compared with original grinds patent preparation method, industrial application preferably.
Specific embodiment
The embodiment of the invention discloses the new preparation methods of azacitidine.Those skilled in the art can use for reference in this paper
Hold, is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are to those skilled in the art
For be it will be apparent that they are considered as being included in the present invention.Method of the invention is carried out by preferred embodiment
Description, related personnel can obviously not depart from the content of present invention, be modified to method described herein in spirit and scope
Or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
Embodiment 1
5- nitrogen cytosine (10g), hexamethyldisilazane (50g) and ammonium sulfate (0.4g) are mixed, it is heated to 120~
150 DEG C of reactions；It is further continued for heating reaction 2~3 hours after reaction to solid all dissolution, is cooled to 15~25 DEG C, solid is precipitated,
The solid was filtered, and vacuum drying obtains compound A (21.9g).Yield: 95.7%.
Embodiment 2
By compound A (20g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (20.2g), trifluoromethanesulfonic acid trimethyl silicone grease (0.15g) and acetonitrile
(60ml) is mixed in three-necked flask, is warming up to 60~75 DEG C, is stirred to react 6~7 hours, after complete reaction, is cooled to 10
~40 DEG C, be filtered to remove insoluble matter, 300ml methanol be added, be added dropwise at 10~30 DEG C sodium methoxide methanol solution (25ml,
30% (weight)), be added dropwise sodium methoxide solution after reacting liquid pH value be 12~14, drip off 3~4h of stirring, be filtered under diminished pressure, obtain Ah
It pricks to dry at 0~50 DEG C of cytidine crude product Isosorbide-5-Nitrae to constant weight and obtains 17.8g.Yield: 93.4%.
Embodiment 3
Azacitidine crude product 1 (19.8g) and DMSO (80ml) mixing, are heated to about 30~35 degree, stir 1~2 hour, Gu
Body dissolved clarification is filtered under diminished pressure removing insoluble matter while hot, in 30~35 DEG C of dropwise addition methanol (200ml) crystallizations, stirs 1~5h and depressurized
Filter, 40~50 DEG C of vacuum drying obtain azacitidine crude product 2 (15g).Yield: 75.8%.
Embodiment 4
Azacitidine crude product 2 (15g) is added in dehydrated alcohol (150ml), 10~30 DEG C are stirred 1~6 hour, are depressurized
Filter, 40-50 DEG C of dry get A Zha born of the same parents' highly finished product 13.5g.HPLC purity 99.98%.Yield: 90%.
Embodiment 5
Compound A (10g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (10.1g), trifluoromethanesulfanhydride anhydride (0.10g) and acetonitrile (30ml) are mixed
In three-necked flask, 40~60 DEG C are warming up to, is stirred to react 6~7 hours, after complete reaction, is cooled to 10~40 DEG C, filtering
Insoluble matter is removed, 150ml methanol is added, the methanol solution (13ml, 30% (weight)) of sodium methoxide, drop are added dropwise at 30~60 DEG C
Adding reacting liquid pH value after sodium methoxide solution is 13, drips off 5~6h of stirring, is filtered under diminished pressure, obtains azacitidine crude product Isosorbide-5-Nitrae 0~50
It dries at DEG C to constant weight and obtains 9.2g, yield 96.6%.
Embodiment 6
Compound A (5g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (5.1g), titanium tetrachloride (0.05g) and acetonitrile (15ml) are mixed in three mouthfuls
In flask, 55~75 DEG C are warming up to, is stirred to react 6~7 hours, after complete reaction, is cooled to 10~40 DEG C, is filtered to remove not
100ml methanol is added in molten object, and the methanol solution (13ml, 30% (weight ratio)) of sodium methoxide is added dropwise at 30~60 DEG C, and first is added dropwise
Reacting liquid pH value is 14 after alcohol sodium solution, drips off 3~4h of stirring, is filtered under diminished pressure, obtains at 0~50 DEG C of azacitidine crude product Isosorbide-5-Nitrae
Drying to constant weight obtains 4.2g, yield 88.2%.
Embodiment 7
By compound A (10g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (10.1g), trifluoromethanesulfonic acid trimethyl silicone grease (0.10g) and toluene
(30ml) is mixed in three-necked flask, is warming up to 40~60 DEG C, is stirred to react 6~7 hours, after complete reaction, is cooled to 10
It~20 DEG C, is filtered to remove insoluble matter, 150ml methanol is added, lithium ethoxide (0.2g) is added dropwise at 30~60 DEG C, add anti-after lithium ethoxide
Answering liquid pH value is 13, drips off 5~6h of stirring, is filtered under diminished pressure, and obtains drying to constant weight at 0~50 DEG C of azacitidine crude product Isosorbide-5-Nitrae and obtains
7.68g, yield: 80.6%.
Embodiment 8
Compound A (5g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (5.1g), stannic chloride (0.15g) and methylene chloride (15ml) are mixed in three
In mouth flask, it is warming up to 45-65 DEG C, is stirred to react 6~7 hours, after complete reaction, is cooled to 10~40 DEG C, is filtered to remove
100ml n-hexyl alcohol is added in insoluble matter, and sodium methoxide (0.39g) is added dropwise at 30~60 DEG C, and reacting liquid pH value is after sodium methoxide is added
14,3~4h of stirring is dripped off, is filtered under diminished pressure, drying to constant weight at 0~50 DEG C of azacitidine crude product Isosorbide-5-Nitrae is obtained and obtains 4.1g, yield:
86.1%.
Embodiment 9
Compound A (5g) and 1,2,3,5-Tetra-O-Acetyl-D-Ribose (5.1g), trifluoromethanesulfonic acid (0.05g) and acetonitrile (15ml) are mixed in three
In mouth flask, 55~75 DEG C are warming up to, is stirred to react 6~7 hours, after complete reaction, is cooled to 10~40 DEG C, is filtered to remove
100ml isopropanol is added in insoluble matter, and potassium tert-butoxide (0.24g) is added dropwise at 30~60 DEG C, and reaction solution pH after potassium tert-butoxide is added
Value is 13, drips off 3~4h of stirring, is filtered under diminished pressure, and obtains drying to constant weight at 0~50 DEG C of azacitidine crude product Isosorbide-5-Nitrae and obtains 3.6g, receives
Rate 75.6%.
Claims (9)
1. a kind of preparation method of azacitidine, specific steps are as follows:
A) step a: in organic solvent, compound A reacts under lewis acidic catalysis with 1,2,3,5-Tetra-O-Acetyl-D-Ribose；
B) step b: alcohols solvent will be added in step a reaction solution after reaction, the reacting metal salt with alcohol obtains A Zha
Cytidine.
2. preparation method as described in claim 1, it is characterised in that: organic solvent can be acetonitrile, dichloromethane in step a
One of alkane, tetrahydrofuran or toluene are a variety of.
3. preparation method as described in claim 1, it is characterised in that: lewis acid used in step a is trifluoromethanesulfonic acid
One of trimethyl silicone grease, trifluoromethanesulfanhydride anhydride, stannic chloride, aluminium chloride, titanium tetrachloride, copper chloride, iron chloride are a variety of.
4. preparation method as described in claim 1, it is characterised in that: the temperature of step a be 40~75 DEG C, preferably 60~75
℃。
5. preparation method as described in claim 1, it is characterised in that: in step b alcohols solvent be methanol, ethyl alcohol, isopropanol,
One of n-butanol, the tert-butyl alcohol, cyclohexanol are a variety of.
6. preparation method as described in claim 1, it is characterised in that: the metal salt of alcohol is potassium alcoholate, sodium alkoxide, alcohol calcium in step b
One of or a variety of, preferably one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or a variety of.
7. preparation method as described in claim 1, it is characterised in that: the temperature of step b is 0~60 DEG C, preferably 0~30 DEG C.
8. preparation method as described in claim 1, it is characterised in that: pH is 12~14 after the metal salt of alcohol is added in step b.
9. preparation method as described in claim 1, which is characterized in that under the azacitidine that step b is obtained can further pass through
State step purifying:
C) step c: dissolving step b obtained azacitidine crude product 1 obtains azacitidine crude product 2 with DMSO and recrystallizing methanol；
D) step d: azacitidine crude product is mixed with ethyl alcohol, stirs 1~6h, and filtering obtains azacitidine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642901A (en) * | 2019-11-11 | 2020-01-03 | 扬子江药业集团有限公司 | Azacitidine methanolate, preparation method thereof, pharmaceutical composition and application |
| CN112279881A (en) * | 2020-10-12 | 2021-01-29 | 福建南方制药股份有限公司 | Method for preparing antitumor drug azacitidine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101010329A (en) * | 2004-12-30 | 2007-08-01 | 韩美药品株式会社 | Method for the preparation of 2'-deoxy-2',2'-difluoro cytidine |
| CN102702292A (en) * | 2012-05-20 | 2012-10-03 | 湖州展望药业有限公司 | Preparation method of azacitidine |
| CN103619864A (en) * | 2011-03-31 | 2014-03-05 | 细胞基因国际有限公司 | Systhesis of 5-azacytidine |
-
2017
- 2017-07-28 CN CN201710627067.1A patent/CN109305992A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101010329A (en) * | 2004-12-30 | 2007-08-01 | 韩美药品株式会社 | Method for the preparation of 2'-deoxy-2',2'-difluoro cytidine |
| CN103619864A (en) * | 2011-03-31 | 2014-03-05 | 细胞基因国际有限公司 | Systhesis of 5-azacytidine |
| CN102702292A (en) * | 2012-05-20 | 2012-10-03 | 湖州展望药业有限公司 | Preparation method of azacitidine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642901A (en) * | 2019-11-11 | 2020-01-03 | 扬子江药业集团有限公司 | Azacitidine methanolate, preparation method thereof, pharmaceutical composition and application |
| CN112279881A (en) * | 2020-10-12 | 2021-01-29 | 福建南方制药股份有限公司 | Method for preparing antitumor drug azacitidine |
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Address after: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant after: SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |
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Application publication date: 20190205 |