CN106117290A - A kind of preparation method of cancer therapy drug decitabine - Google Patents
A kind of preparation method of cancer therapy drug decitabine Download PDFInfo
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- CN106117290A CN106117290A CN201610479449.XA CN201610479449A CN106117290A CN 106117290 A CN106117290 A CN 106117290A CN 201610479449 A CN201610479449 A CN 201610479449A CN 106117290 A CN106117290 A CN 106117290A
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- 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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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses the preparation method of cancer therapy drug decitabine, the method includes: 1) by 1 chlorine 2 deoxidation D ribofuranose, palladium chloride, (S) () 1,1 ' dinaphthalene 2,2 ' double two (3,5 xylyls) phosphine joins in DMF, 45～60 DEG C of stirring mixing 12 hours, it is then cooled to room temperature, filter, obtain the mixture M containing 1 chlorine 2 deoxidation D ribofuranose coordination compound；2) in the presence of triethylamine, by 2, the 4 pairs of trimethyl silica-based S triazines add steps 1) 30 40 DEG C of stirring reactions 68 hours in the mixture M that obtains, being poured in water, dichloromethane extracts, dilute hydrochloric acid washing, saturated sodium bicarbonate washing, concentrating, ethyl alcohol recrystallization obtains decitabine.The method preparing decitabine of the present invention is effectively increased the yield of β selectivity of product and decitabine, provides new approach for preparing decitabine.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to the preparation method of a kind of cancer therapy drug decitabine.
Background technology
Decitabine (Decitabine), chemical entitled 4-amino-1-(2-deoxidation-β-D-erythro ribofuranose)-1,3,
5-triazine-2-(1H)-one, concrete structure such as following formula is
Decitabine is a kind of specific DNA methylated transferase inhibitor, SuperGen company of the U.S. develop, later
Change company and whole world research, production and sales development rights are transferred MGI drug company, within 2006, be approved for treating bone in the U.S.
Marrow hypertrophy abnormal syndrome (MDS).In JIUYUE, 2012, EU Committee's approval decitabine examines constitutional or Secondary cases for newly
The treatment of acute myeloid leukemia (AML) gerontal patient (>=65 years old).
Study of synthesis method currently, with respect to decitabine is more, CN103739636B disclose one synthetically west he
The route of shore, although this technique is simple, easy and simple to handle, but the method there is also poor selectivity, β-low asking of isomer yield
Topic, concrete route is as follows:
And, CN101821278B discloses the preparation method of a kind of cancer therapy drug decitabine, the method with 2-deoxidation-
D-RIBOSE is that initiation material synthesizes decitabine through multistep, owing to have employed catalyst, and glycosyl and base direct reaction, but
It is, the method αisomer more (α: β >=3:2) that additionally overall yield is extremely low, only about 15%.Concrete synthetic route is such as
Under:
Although the synthetic method of decitabine began to from 1964 report, but still do not have a kind of selectivity good, receipts
The method that rate is high.Therefore, the method that this area still needs to the synthesis decitabine that a kind of selectivity is good and yield is high.
Summary of the invention
It is an object of the invention to overcome in the existing method preparing decitabine that yield is low and β selectivity of product is poor
Defect, it is provided that the preparation method of the decitabine that a kind of selectivity is good and yield is high.
Inventor has been surprisingly found that under study for action, by chloro-for 1-2-deoxy-D-ribofuranose, palladium chloride, (S)-(-)-1,
1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine mix in DMF by formed 1-chloro-2-deoxy-D-ribofuranose join
Compound, thus complete next with 2, the stereoselective reaction of the double trimethyl silica-based-S-triazine nucleophilic of 4-, thus improve β product
Selectivity and the yield of decitabine.
To achieve these goals, the present invention provides the preparation method of a kind of cancer therapy drug decitabine, and the method includes:
1) by chloro-for 1-2-deoxy-D-ribofuranose, palladium chloride, (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-
Xylyl) phosphine joins in DMF, 45～60 DEG C of stirring mixing 1-2 hour, and it is then cooled to room temperature, filters, obtain containing 1-
The mixture M of chloro-2-deoxy-D-ribofuranose coordination compound；
2) in the presence of triethylamine, by 2, the double trimethyl silica-based-S-triazine of 4-adds step 1) in the mixture M that obtains
30-40 DEG C of stirring is reacted 6-8 hour, is poured in water, and dichloromethane extracts, and dilute hydrochloric acid washs, and saturated sodium bicarbonate washs, dense
Contracting, ethyl alcohol recrystallization obtains decitabine.
In the present invention, in order to preferably form coordination compound, improving nucleophilic selectivity, under preferable case, the chloro-2-of 1-takes off
Oxygen-D-RIBOSE and palladium chloride, (S)-(-) consumption mole of-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine
Ratio is 1:0.5～0.8:0.5～1.It is further preferred that 1-chloro-2-deoxy-D-ribofuranose and palladium chloride, (S)-(-)-
1,1 '-dinaphthalene-2,2 ' the consumption mol ratio of-bis-two (3,5-xylyl) phosphine is 1:0.6～0.8:0.5～0.6.
In step 2) in, in order to improve yield and the stability of protection cooperation thing of reaction, it is preferable that 2,4-double front threes
Base silica-based-S-triazine is 1:1.05～1.2:1.5～2 with 1-chloro-2-deoxy-D-ribofuranose, the amount ratio of triethylamine.
In order to avoid air etc. to obtain impact to reacting, improve reaction yield and efficiency, described step 1 further) reaction
Carrying out in the presence of protective gas, described protective gas is nitrogen, helium or argon.
In the present invention, it is also possible to include the step that the decitabine obtaining said method is purified, described purification
Method is not particularly limited, and the means that this area can be used conventional are purified, such as recrystallization in methanol/ethanol
Or then be dissolved in dichloromethane uses the stirrings such as petroleum ether to separate out product.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS,
GCMS etc., react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue be less than
2%.
Decitabine prepared by the method for the present invention, can be prepared as various required crystal according to this area conventional method.
The concrete route of the preparation method of decitabine of the present invention is as follows:
Compared with prior art, use the method preparing decitabine that the present invention provides, use and generate Pd coordination compound side
Formula, the preparation of position decitabine provides new approach, is effectively increased the yield of β selectivity of product and decitabine, with
1-chloro-2-deoxy-D-ribofuranose is initiation material, and decitabine yield reaches more than 87%；The method is simple, locates afterwards
Reason is simple.
Why obtain above-mentioned beneficial effect, inventor guess 1-chloro-2-deoxy-D-ribofuranose and palladium chloride,
(S)-(-)-1,1 '-dinaphthalene-2, the coordination compound that 2 '-bis-two (3,5-xylyl) phosphine (S-BINAP) are formed, by the chloro-2-of 1-
Deoxy-D-ribofuranose hydroxyl, copper ion and naphthols occupy the space of furan nucleus α so that 2,4-double silica-based-S-of trimethyl
Triazine from the attack of β direction, thus can only complete the present invention.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to illustrate the present invention and not
It it is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of preparation method of cancer therapy drug decitabine, the method includes:
1) under nitrogen protection, by chloro-for 1-2-deoxy-D-ribofuranose 15.3g (100mmol), palladium chloride 6.2g
(35mmol), (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine 43.6g (70mmol) join 150ml
In DMF, 60 DEG C of stirrings mix 1-2 hour, are then cooled to room temperature, and filter, obtain containing 1-chloro-2-deoxy-D-ribofuranose
The mixture M of coordination compound；
2) double to triethylamine 11.1g (110mmol), 2,4-trimethyls silica-based-S-triazine 51.2g (200mmol) are added successively
Enter step 1) 40 DEG C of stirring reactions 6 hours in the mixture M that obtains, it is poured in water, dichloromethane extracts, 2M HCl washing three
Secondary, saturated sodium bicarbonate washs, and concentrates, and ethyl alcohol recrystallization obtains decitabine 19.8g, and yield is 86.7%, purity 99.61%.
Embodiment 2
A kind of preparation method of cancer therapy drug decitabine, the method includes:
1) under nitrogen protection, by chloro-for 1-2-deoxy-D-ribofuranose 15.3g (100mmol), palladium chloride 5.3g
(30mmol), (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine 49.8g (80mmol) join 150ml
In DMF, 45 DEG C of stirrings mix 1-2 hour, are then cooled to room temperature, and filter, obtain containing 1-chloro-2-deoxy-D-ribofuranose
The mixture M of coordination compound；
2) in the presence of, by triethylamine 12.1g (120mmol), 2, double trimethyl silica-based-S-triazine 38.5g of 4-
(150mmol) it is sequentially added into step 1) 30-40 DEG C of stirring reaction 6-8 hour in the mixture M that obtains, it is poured in water, dichloromethane
Alkane extracts, and 2MHCl washs three times, and saturated sodium bicarbonate washs, and concentrates, and ethyl alcohol recrystallization obtains decitabine 19.7g, and yield is
86.5%, purity 99.49%.
Embodiment 3
A kind of preparation method of cancer therapy drug decitabine, the method includes:
1) under nitrogen protection, by chloro-for 1-2-deoxy-D-ribofuranose 15.3g (100mmol), palladium chloride 7.1g
(40mmol), (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine 37.3g (60mmol) join 100ml
In DMF, 50 DEG C of stirrings mix 1-2 hour, are then cooled to room temperature, and filter, obtain containing 1-chloro-2-deoxy-D-ribofuranose
The mixture M of coordination compound；
2) in the presence of, by triethylamine 10.6g (105mmol), 2, double trimethyl silica-based-S-triazine 38.5g of 4-
(150mmol) it is sequentially added into step 1) 40 DEG C of stirring reactions 6 hours in the mixture M that obtains, it is poured in water, dichloromethane extracts
Taking, 2M HCl washs three times, and saturated sodium bicarbonate washs, and concentrates, and ethyl alcohol recrystallization obtains decitabine 19.9g, and yield is
87.1%, purity 99.61%.
Embodiment 4
A kind of preparation method of cancer therapy drug decitabine, the method includes:
1) under nitrogen protection, by chloro-for 1-2-deoxy-D-ribofuranose 15.3g (100mmol), palladium chloride 8.9g
(50mmol), (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine 62.2g (100mmol) join 200ml
In DMF, 60 DEG C of stirrings mix 1-2 hour, are then cooled to room temperature, and filter, obtain containing 1-chloro-2-deoxy-D-ribofuranose
The mixture M of coordination compound；
2) in the presence of, by triethylamine 12.1g (120mmol), 2, double trimethyl silica-based-S-triazine 51.2g of 4-
(200mmol) it is sequentially added into step 1) 30 DEG C of stirring reactions 8 hours in the mixture M that obtains, it is poured in water, dichloromethane extracts
Taking, 2M HCl washs three times, and saturated sodium bicarbonate washs, and concentrates, and ethyl alcohol recrystallization obtains decitabine 18.3g, and yield is
80.6%, purity 99.41%.
Embodiment 5
A kind of preparation method of cancer therapy drug decitabine, the method includes:
1) under nitrogen protection, by chloro-for 1-2-deoxy-D-ribofuranose 15.3g (100mmol), palladium chloride 10.6g
(60mmol), (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine 22.9g (50mmol) join 100ml
In DMF, 70 DEG C of stirrings mix 1-2 hour, are then cooled to room temperature, and filter, obtain containing 1-chloro-2-deoxy-D-ribofuranose
The mixture M of coordination compound；
2) in the presence of, by triethylamine 10.6g (105mmol), 2, double trimethyl silica-based-S-triazine 38.5g of 4-
(150mmol) it is sequentially added into step 1) 30-40 DEG C of stirring reaction 6 hours in the mixture M that obtains, it is poured in water, dichloromethane
Extraction, 2M HCl washs three times, and saturated sodium bicarbonate washs, and concentrates, and ethyl alcohol recrystallization obtains decitabine 18.1g, and yield is
79.4%, purity 99.40%.
Embodiment 6
Such as the preparation method of the decitabine in embodiment 1, except that, the consumption of palladium chloride is 0.9g, obtains ground
His shore 14.3g of west, yield is 62.8%, purity 99.35%.
Embodiment 7
Such as the preparation method of the decitabine in embodiment 1, except that, the consumption of palladium chloride is 17.7g, obtains ground
His shore 19.9g of west, yield is 87.2%, purity 96.48%.
Embodiment 8
Such as the preparation method of the decitabine in embodiment 1, except that, (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-
The consumption of two (3,5-xylyl) phosphine is 2.8g, obtains decitabine 11.6g, and yield is 50.7%, purity 98.95%.
Comparative example 1
Such as the preparation method of the decitabine of embodiment 1, except that, substitute dichloro with the copper nitrate of same molar
Changing palladium, obtain decitabine 10.8g, yield is 47.4%, purity 98.05%.
Comparative example 2
Such as the preparation method of the decitabine of embodiment 1, except that, substitute dichloro with the zinc nitrate of same molar
Changing palladium, obtain decitabine 10.8g, yield is 47.6%, purity 98.74%.
Comparative example 3
Such as the preparation method of the decitabine of embodiment 1, except that, it is added without palladium chloride, obtains decitabine 8g,
Yield is 35.2%, purity 98.85%.
Comparative example 4
Such as the preparation method of the decitabine of embodiment 1, except that, with (R) of same molar-(-)-1,1 '-
Dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine replacement (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyls)
Phosphine, obtains decitabine 9.3g, and yield is 40.8%, purity 98.39%.
Comparative example 5
Such as the preparation method of the decitabine of embodiment 1, except that, be added without (S)-(-)-1,1 '-dinaphthalene-2,
2 '-bis-two (3,5-xylyl) phosphines, obtain decitabine 6.5g, and yield is 28.5%, purity 98.67%.
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited in above-mentioned embodiment
Detail, in the technology concept of the present invention, technical scheme can be carried out multiple simple variant, this
A little simple variant belong to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, at not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to various can
The compound mode of energy illustrates the most separately.Additionally, any group can also be carried out between the various different embodiment of the present invention
Closing, as long as it is without prejudice to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (5)
1. the preparation method of a cancer therapy drug decitabine, it is characterised in that the method includes:
1) by chloro-for 1-2-deoxy-D-ribofuranose, palladium chloride, (S)-(-)-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-diformazans
Phenyl) phosphine joins in DMF, 45～60 DEG C of stirring mixing 1-2 hour, and it is then cooled to room temperature, filters, obtain containing 1-chloro-
The mixture M of 2-deoxy-D-ribofuranose coordination compound；
2) in the presence of triethylamine, by 2, the double trimethyl silica-based-S-triazine of 4-adds step 1) 30-40 in the mixture M that obtains
DEG C stirring reaction 6-8 hour, be poured in water, dichloromethane extract, dilute hydrochloric acid washing, saturated sodium bicarbonate washing, concentrate, ethanol
Recrystallization obtains decitabine.
Preparation method the most according to claim 1, it is characterised in that 1-chloro-2-deoxy-D-ribofuranose and dichloride
Palladium, (S)-(-) the consumption mol ratio of-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine be 1:0.3～0.6:0.5～
1。
Preparation method the most according to claim 2, it is characterised in that 1-chloro-2-deoxy-D-ribofuranose and dichloride
Palladium, (S)-(-) the consumption mol ratio of-1,1 '-dinaphthalene-2,2 '-bis-two (3,5-xylyl) phosphine be 1:0.3～0.4:0.6～
0.8。
Preparation method the most according to claim 3, it is characterised in that 2,4-double trimethyl silica-based-S-triazines and the chloro-2-of 1-
Deoxy-D-ribofuranose, the amount ratio of triethylamine are 1:1.05～1.2:1.5～2.
5. according to the preparation method described in claim 1-4, it is characterised in that step 1) reaction in the presence of protective gas
Carrying out, described protective gas is nitrogen, helium or argon.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101712708A (en) * | 2008-10-07 | 2010-05-26 | 上海秀新臣邦医药科技有限公司 | Method for preparing decitabine |
| WO2010129211A2 (en) * | 2009-04-27 | 2010-11-11 | Dr. Reddy's Laboratories Ltd. | Preparation of decitabine |
| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
-
2016
- 2016-06-27 CN CN201610479449.XA patent/CN106117290A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
| CN101712708A (en) * | 2008-10-07 | 2010-05-26 | 上海秀新臣邦医药科技有限公司 | Method for preparing decitabine |
| WO2010129211A2 (en) * | 2009-04-27 | 2010-11-11 | Dr. Reddy's Laboratories Ltd. | Preparation of decitabine |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 李立冬 等: "C-N偶联反应制备芳胺研究进展", 《化学研究与应用》 * |
| 靳玄烨 等: "钯催化合成嘧啶核苷衍生物的研究进展", 《有机化学》 * |
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