CN108373491A - A kind of preparation method of nelarabine - Google Patents
A kind of preparation method of nelarabine Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of nelarabine; using Ancitabine and 2 amino, 6 chloropurine as raw material; after Ancitabine hydrolysis amino and hydroxyl are protected with acetyl group; form four acetyl cytarabines; base transition occurs under the effect of lewis acid Trimethylsilyl trifluoromethanesulfonate with 2 amino, 6 methoxypurine of silanization again to react, obtains target product nelarabine.The relatively cheap easily buying of the cost of material that the present invention uses, reaction route is shorter, and mild condition, equipment requirement is low, and production cost is low, and reaction safety is easily controllable, and the manufacturing cost to reduce nelarabine provides possibility.
Description
(1) technical field
The present invention relates to the chemical preparation process of nelarabine, belong to field of medicine and chemical technology.
(2) background technology
Nelarabine is the precursor medicine of guanosine analogue 9- β-D-arabinose furanose guanine (Ara-G).Chemistry is entitled：
9- β-D- arabinofuranose -6- methoxyl group -9H- purine -2- amine.It is white as treatment hematological system tumor and T lymphatics
The medicine of blood disease has significant curative effect.Its structural formula is as follows：
Report that the synthetic route of nelarabine mainly has before the present invention makes, on document：
1, catalyzed by biological enzyme
European patent EP 0294114；Tetrahedron Letters, 2005,46,2961-2964 report with 2- ammonia
The Arabinoside of base -6- methoxypurines and uracil is raw material, in purine nucleoside phosphorylase and uridine phosphorylase
Under effect, nelarabine is obtained by fermenting for a long time.Invertase used in this method is not easy to be made, expensive, reaction
Time is long, purification difficult, and production capacity is difficult to amplify.
2, ribofuranose configuration transformation approach
Chinese patent CN101092441A is disclosed using 6- chlorine guanosine as raw material, by six step chemical syntheses by ribofuranose
It is converted into arabinose, to which nelarabine be made.The method synthetic route is longer, and total recovery is relatively low, is needed in reaction process chosen
Property protection, the very difficult operation such as configuration conversion, product chemistry purity and optical purity are difficult to control.
3, arabinosy ladenosine method
Chinese patent CN104892709 discloses one kind using arabinosy ladenosine as raw material, through acetylation, methoxylation, nitro
The method that the four-step reactions such as change and reduction prepare nelarabine.The great advantage raw material of this method is arabinose beta comfiguration, without conversion.
4, chemical coupling synthetic method
J.Heterocyclic Chem.1988,25,1899-1903 report using D-arabinose as raw material, through excessive
The reaction prepare compound of protecting group sets up glycosidic bond in step, obtains nelarabine.This method is mainly characterized by synthetic route
Longer, severe reaction conditions, yield is relatively low, cumbersome.
Chinese patent CN101469012A is the improved method based on former approach.The method step is compared with former approach
Shortened, but it is still more, and total recovery is still relatively low.
The problem of prior art is primarily present be：Route is long, and cost of material is high, and total recovery is low.
(3) invention content
Process route provided by the invention and previously reported route are different.With Ancitabine and 6 chlorine guanines
For raw material, amino and hydroxyl are protected with acetyl group after ancitabine hydrolysis, forms four acetyl cytarabines, then fast with the bird of silanization
Base transition reaction occurs under lewis acid Trimethylsilyl trifluoromethanesulfonate (TMSOTf) effect for purine, to obtain naira
Shore.
In order to achieve the above objectives, the present invention adopts the following technical scheme that：
A kind of preparation method of nelarabine, the method are prepared in accordance with the following steps：
(1) by 2- amido-6-chloropurines shown in formula 1, the reaction was complete in methyl alcohol with sodium methoxide, and gained reaction solution A is after
Processing obtains 2- amino -6- methoxypurines shown in formula 2；
(2) 2- amino -6- methoxypurines shown in formula 2 are dissolved in organic solvent A, in trim,ethylchlorosilane and tie up acid
Under the effect of agent triethylamine, 2- amino -6- methoxypurines shown in the gained post-treated obtained formulas 3 of reaction solution B after the reaction was complete
Hydrosilylation product；
(3) by Ancitabine shown in formula 4, the reaction was complete in the aqueous solution of alkaline matter, and gained reaction liquid C is after
Cytarabine shown in formula 5 is made in processing；
(4) by cytarabine shown in formula 5, the reaction was complete in aceticanhydride, and gained reaction solution D is post-treated to be obtained shown in formula 6
Acetylation cytarabine；
(5) hydrosilylation product of 2- amino -6- methoxypurines shown in formula 3 is dissolved in organic solvent B and is mixed
Liquid A, acetylation cytarabine shown in formula 6, which is dissolved in organic solvent C, obtains mixed liquid B, then by the mixed liquor A and mixed
It closes liquid B and is mixed and added into catalyst TMSOTf, reacted at 60~84 DEG C, after the reaction was complete, the post-treated systems of gained reaction solution E
Obtain 7 compound represented 7 of formula；In same reaction, the organic solvent B is consistent with the organic solvent C；The formula
The hydrosilylation product of 2- amino -6- methoxypurines shown in 3 and acetylation cytarabine, TMSOTf shown in the formula 6
The ratio between amount of substance is 1:1~1.2：0.05~0.2；
(6) by 7 compound represented 7 of formula in methanolic ammonia solution or methanol solution of sodium methylate, after the reaction was complete, gained is anti-
Answer liquid F is post-treated to obtain nelarabine shown in formula 8；
Further, in step (1), the method is：By 2- amido-6-chloropurines shown in formula 1 and sodium methoxide in first
In alcohol, the reaction was complete at a reflux temperature, and solvent is evaporated off in gained reaction solution A, and obtained a large amount of white solids are soluble in water, so
PH value is adjusted to 7.5 with dilute hydrochloric acid solution afterwards, and white solid is precipitated, is filtered after standing, gained filter cake is 2- ammonia shown in formula 2
Base -6- methoxypurines；The ratio between amount of substance of 2- amino 6-chloropurine and sodium methoxide shown in the formula 1 is 1:1.2, institute
The addition for the methanol stated is calculated as 5~15mL/g with the sodium methoxide mass ratio.
Further, preferred reaction time 10h, reaction temperature are 67 DEG C.
Further, in step (2), the method is：2- amino -6- methoxypurines shown in formula 2 are added organic
In solvent A, under trim,ethylchlorosilane and the effect of acid binding agent triethylamine, 6~20h is reacted at 38~60 DEG C, after the reaction was complete,
Gained reaction solution B filters out insoluble matter, and gained filtrate is spin-dried for that the silane of 2- amino -6- methoxypurines shown in formula 3 is made
Change product；The ratio between the 6- methoxyl groups guanine and the amount of substance of trim,ethylchlorosilane, triethylamine are 1:1.5~5:1.2
~5 (preferably 1：2：3).
Further, the organic solvent A is one kind in dichloromethane, chloroform, 1,2- dichloroethanes；It is described
The addition of organic solvent A 10~15mL/g is calculated as with the quality of the 2- amino -6- methoxypurines.
Further, in step (3), Ancitabine shown in formula 4 is soluble in water, the Ancitabine and water
Mass ratio is：1:2~5, the aqueous solution of alkaline matter is then added, adjusts pH value to 12.0~14.0, (preferably at 20~60 DEG C
Be 25~40 DEG C) under 4~10h of reaction (preferably 6~7h), after the reaction was complete, moisture is evaporated off in gained reaction liquid C, is obtained white
Solid, again with methanol dissolve whiteness, filtering, and filtrate is evaporated, and obtains solid cytarabine shown in formula 5；The basic species
Matter is potassium hydroxide or sodium hydroxide.
Further, described to react cytarabine shown in formula 5 in aceticanhydride in step (4), react 8 at 128 DEG C
~12h (preferably 10h) filters gained reaction solution D, and gained filtrate obtains brownish black syrupy shape substance after being spin-dried for, and then uses acetic acid
Ethyl ester recrystallizes, and heating makes it dissolve, and white solid matter is precipitated after cooling up to acetylation cytarabine shown in formula 6；Institute
The addition for the aceticanhydride stated is calculated as 3~8mL/g with the quality of cytarabine shown in the formula 5.
Further, in step (5), the organic solvent B or organic solvent C are ethyl acetate, acetonitrile or 1,2- dichloros
Ethane.
Further, in step (5), the addition of the organic solvent B is with the 2- amino -6- methoxypurines
The quality of hydrosilylation product be calculated as 2.5~10.0mL/g, the addition of the organic solvent C is with the acetylation arabinose
The mass ratio of cytidine is 2.5~10.0mL/g.
Further, in step (5), the post-processing approach of gained reaction solution E is：After the reaction was complete, reaction solution E is poured into
In ice water, then with saturated sodium bicarbonate solution adjust pH value to 7 or so, filtering, 3 extractions of ethyl acetate point of gained filtrate,
Merge organic phase, product passes through column chromatography after concentration, with volume ratio for 2:1 ethyl acetate and the mixed solvent of petroleum ether are to wash
De- agent, isolates and purifies to obtain 7 compound represented acetylation nelarabine 7 of formula.
Further, in step (6), the method is：By 7 compound represented 7 of formula be added saturation methanolic ammonia solution or
In the methanol solution of 0.5M sodium methoxides, 2h is reacted at 65~70 DEG C, after the reaction was complete, by the water of gained reaction solution F acetic acid
Solution adjusts pH value to 7.0 or so, is purified through column chromatography after concentration, with volume ratio for 10:The mixing of 1 ethyl acetate and methanol
Solvent is solvent, isolates and purifies to obtain nelarabine shown in formula 8；The ammonia solution of the methanol or the methanol solution of sodium methoxide
Addition 2.5~10.0mL/g is calculated as with the quality of 7 compound represented of formula.
Compared with prior art, beneficial effects of the present invention are embodied in：
Build to obtain cytarabine with Ancitabine cheap and easy to get, then with 2- amino -6- methoxyl groups guanine into
Row base transition avoids the process route of the expensive metabolizing enzymes being difficult to obtain, provides a kind of change that nelarabine is new
Learn synthetic method.The relatively cheap easily buying of the raw materials used price of the reaction, reaction route is shorter, and mild condition, equipment requirement is low, raw
Produce it is at low cost, reaction safety it is easily controllable, for reduce nelarabine manufacturing cost provide possibility.
(4) specific implementation mode
The specific technical solution of the present invention is illustrated with specific embodiment below, but protection scope of the present invention is not limited to
This.
Embodiment one
The preparation of 2- amino -6- methoxypurines (2)
51.0g 2- amino 6-chloropurines (1) and 34.0g sodium methoxides are added in 500ml methanol, stirring and dissolving is placed in 67
It is heated in DEG C oil bath, back flow reaction 10h, TLC monitor reaction process.Reaction terminates, and solvent is evaporated off, and generates a large amount of white solids,
500ml water dissolutions are added, then adjusts pH value to 7.5 with dilute hydrochloric acid solution, a large amount of white solids is precipitated, stand mistake after 30min
Filter, obtains filter cake 44.4g, yield 98.0%.
Embodiment two
The preparation of 2- amino 6- methoxypurines hydrosilylation products (3)
500ml 1 is added in 2 amino -6- methoxypurines (2) of 45.3g, in 2- dichloroethanes, stirs 10min, it is insoluble.
Then 66.0g trim,ethylchlorosilanes and 61.0g triethylamines is added, 6~7h, TLC monitoring reactions are stirred to react at a temperature of 60 DEG C
Process.After reaction, insoluble matter is filtered out, filtrate is spin-dried for obtaining bis- (front three of rufous oily mater 6- methoxyl groups-N, 9-
Base silicon substrate) -9H- purine -2- amine 72.4g, yield 78.0%.
By 6- methoxyl groups guanine (2)：Trim,ethylchlorosilane：The amount rate of charge of the substance of triethylamine is changed to 1:5:5, other
Condition is the same as embodiment two.Obtain bis- (trimethyl silicon substrate) -9H- purine -2- amine of rufous syrup substance 6- methoxyl groups-N, 9-
69.5g, yield 71.1%.
Organic solvent is changed to dichloromethane, reaction temperature is changed to 38 DEG C, and the reaction time is changed to 20h, and other conditions are the same as real
Apply example two.Obtain rufous oily mater 70.6g, yield 76.2%.
Embodiment three
The preparation of cytarabine (4)
52.9g Ancitabines are added in 500ml water, are stirred to dissolve, are then adjusted with sodium hydroxide solution molten
Liquid pH value is stirred to react 10h to 12.0-14.0 at 25 DEG C, and TLC monitors reaction process.After reaction, moisture content is evaporated off, obtains
A large amount of white solids, then whiteness, filtering are dissolved with 500ml methanol, filtrate is evaporated, and obtains white powdery solids cytarabine
43.8g m.p.：212-214℃.Yield 90.1%.
Reaction temperature is changed to 60 DEG C, the reaction time is changed to 4h.Other conditions are the same as embodiment three.Obtain white powdery solids
Cytarabine 44.8g, m.p.：213-214℃.Yield 92.2%.
Example IV
The preparation of four acetyl cytarabines (6)
48.6g cytarabines are added in 250ml aceticanhydrides, heating makes it dissolve, and is placed at 128 DEG C and reacts 8h, TLC monitorings
Reaction process.After reaction, it filters, filtrate obtains brownish black syrupy shape substance after being spin-dried for, and is then tied again with 200ml ethyl acetate
Crystalline substance, heating make it dissolve, and white solid matter 73.3g, m.p. is precipitated after cooling：165-167℃.Yield 89.2%.
Embodiment five
The preparation of acetylation nelarabine (7)
By 3.09g compounds (3) 30ml 1, the dissolving of 2- dichloroethanes, 9.04g compounds (6) 30ml acetonitriles dissolve,
Then be added in reactor simultaneously, be eventually adding 0.22g TMSOTf, be stirred to react 16h at 80 DEG C, TLC monitorings react into
Journey.After the reaction was complete, reaction solution is poured into 30ml ice water, then pH value is adjusted to 7 or so with saturated sodium bicarbonate solution, mistake
Filter, filtrate 3 extractions of 30ml ethyl acetate point, merges organic phase, product passes through column chromatography (solvent after concentration：Acetic acid second
Ester：Petroleum ether V/V=2:1) after isolating and purifying, white powder solid 5.25g, m.p. are obtained：181-183 DEG C, yield 53.2%.
The quality of catalyst TMSOTf is changed to 0.88g, other conditions are the same as embodiment five.Obtain white powder solid
6.53g, yield 66.0%.
Embodiment six
The preparation of nelarabine (8)
4.95g compounds (7) and 0.54g sodium methoxides are added in 50ml methanol, 2h, TLC monitorings are reacted at 67 DEG C
Reaction process.After the reaction was complete, pH value is adjusted to 7.0 or so with the aqueous solution of acetic acid.Concentrate rear pillar chromatographic purifying (solvent：
Ethyl acetate：Methanol V/V=10:1) 2.88g white foam solids, m.p., are obtained：208-210℃.Yield is 97.0%.
[α]25 D=+55.56 (c=0.27, DMF)；1H NMR(500MHz,d6-DMSO)δ:7.92(s,1H),6.44(d,2H),6.11-
6.12(d,1H),5.62-5.63(s,1H),5.51-5.52(d,1H),5.07-5.09(t,1H),4.05-4.08(q,2H),
3.96(s,3H),3.75-3.76(d,1H),3.60-3.64(m,2H)；MS(ESI):m/z:298(M+H).
The foregoing is merely the preferred embodiments of the present invention, are not intended to limit the invention, all the present invention's
Spirit and principle within, made by any modification, equivalent replacement, improve etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of preparation method of nelarabine, it is characterised in that：The method is prepared in accordance with the following steps：
(1) by 2- amido-6-chloropurines shown in formula 1, the reaction was complete in methyl alcohol with sodium methoxide, and gained reaction solution A is post-treated
Obtain 2- amino -6- methoxypurines shown in formula 2；
(2) 2- amino -6- methoxypurines shown in formula 2 are dissolved in organic solvent A, in trim,ethylchlorosilane and acid binding agent three
Under ethamine effect, the silicon of 2- amino -6- methoxypurines shown in the gained post-treated obtained formulas 3 of reaction solution B after the reaction was complete
Alkylated product；
(3) by Ancitabine shown in formula 4, the reaction was complete in the aqueous solution of alkaline matter, and gained reaction liquid C is post-treated
Cytarabine shown in formula 5 is made；
(4) by cytarabine shown in formula 5, the reaction was complete in aceticanhydride, and gained reaction solution D is post-treated to obtain acetyl shown in formula 6
Change cytarabine；
(5) hydrosilylation product of 2- amino -6- methoxypurines shown in formula 3 is dissolved in organic solvent B and obtains mixed liquor A,
Acetylation cytarabine shown in formula 6, which is dissolved in organic solvent C, obtains mixed liquid B, then by the mixed liquor A and mixed liquor
B is mixed and added into catalyst TMSOTf, is reacted at 60~84 DEG C, after the reaction was complete, the post-treated obtained formulas of gained reaction solution E
7 compounds represented 7；In same reaction, the organic solvent B is consistent with the organic solvent C；3 institute of the formula
The substance of the hydrosilylation product of the 2- amino -6- methoxypurines shown and acetylation cytarabine, TMSOTf shown in the formula 6
The ratio between amount be 1:1~1.2：0.05~0.2；
(6) by 7 compound represented 7 of formula in methanolic ammonia solution or methanol solution of sodium methylate, after the reaction was complete, gained reaction solution
F is post-treated to obtain nelarabine shown in formula 8；
2. the method as described in claim 1, it is characterised in that：In step (1), the method is：By 2- ammonia shown in formula 1
In methyl alcohol with sodium methoxide, the reaction was complete at a reflux temperature, and solvent is evaporated off in gained reaction solution A, by what is obtained for base -6-chloropurine
White solid is soluble in water, then adjusts pH value to 7.5 with dilute hydrochloric acid solution, white solid is precipitated, is filtered after standing, gained filter
Cake is 2- amino -6- methoxypurines shown in formula 2；The object of 2- amino 6-chloropurine and sodium methoxide shown in the formula 1
The ratio between amount of matter is 1:1.2, the addition of the methanol is calculated as 5~15mL/g with the sodium methoxide mass ratio.
3. the method as described in claim 1, it is characterised in that：In step (2), the method is：By 2- ammonia shown in formula 2
Base -6- methoxypurines are added in organic solvent A, under trim,ethylchlorosilane and the effect of acid binding agent triethylamine, at 38~60 DEG C
6~20h of lower reaction, after the reaction was complete, gained reaction solution B filters out insoluble matter, and gained filtrate is spin-dried for that 2- shown in formula 3 is made
The hydrosilylation product of amino -6- methoxypurines；The 6- methoxyl groups guanine and trim,ethylchlorosilane, the substance of triethylamine
The ratio between amount be 1:1.5~5:1.2~5.
4. method as claimed in claim 3, it is characterised in that：The organic solvent A be dichloromethane, chloroform, 1,
One kind in 2- dichloroethanes；The addition of the organic solvent A is in terms of the quality of the 2- amino -6- methoxypurines
For 10~15mL/g.
5. the method as described in claim 1, it is characterised in that：In step (3), Ancitabine shown in formula 4 is dissolved in water
In, the aqueous solution of alkaline matter is then added, adjusts pH value to 12.0~14.0,4~10h, reaction are reacted at 20~60 DEG C
After completely, moisture is evaporated off in gained reaction liquid C, obtains white solid, again with methanol dissolves whiteness, filtering, and filtrate is evaporated, obtains
Solid cytarabine shown in formula 5；The alkaline matter is potassium hydroxide or sodium hydroxide.
6. the method as described in claim 1, it is characterised in that：It is described that cytarabine shown in formula 5 exists in step (4)
It is reacted in aceticanhydride, 8~12h is reacted at 128 DEG C, gained reaction solution D is filtered, gained filtrate obtains brownish black syrupy shape after being spin-dried for
Then substance uses re-crystallizing in ethyl acetate, heating to make it dissolve, white solid matter is precipitated after cooling up to second shown in formula 6
Acylated cytarabine；The addition of the aceticanhydride is calculated as 3~8mL/g with the quality of cytarabine shown in the formula 5.
7. the method as described in claim 1, it is characterised in that：In step (5), in step (5), the organic solvent B or
Organic solvent C is ethyl acetate, acetonitrile or 1,2- dichloroethanes.
8. method as claimed in claim 1 or 7, it is characterised in that：In step (5), the addition of the organic solvent B with
The quality of the hydrosilylation product of the 2- amino -6- methoxypurines is calculated as 2.5~10.0mL/g, the organic solvent C
Addition with the mass ratio of the acetylation cytarabine be 2.5~10.0mL/g.
9. the method as described in claim 1, it is characterised in that：In step (5), the post-processing approach of gained reaction solution E is：Instead
After answering completely, reaction solution E is poured into ice water, then pH value is adjusted to 7 or so with saturated sodium bicarbonate solution, filtering, gained is filtered
Liquid 3 extractions of ethyl acetate point, merge organic phase, product passes through column chromatography after concentration, with volume ratio for 2:1 ethyl acetate
Mixed solvent with petroleum ether is eluant, eluent, isolates and purifies to obtain 7 compound represented 7 of formula.
10. the method as described in claim 1, it is characterised in that：In step (6), the method is：It will change shown in formula 7
It closes object 7 to be added in the methanol solution of saturation methanolic ammonia solution or 0.5M sodium methoxides, reacts 2h at 65~70 DEG C, the reaction was complete
Afterwards, the aqueous solution of gained reaction solution F acetic acid is adjusted into pH value to 7.0 or so, is purified through column chromatography after concentration, is with volume ratio
10:1 ethyl acetate and the mixed solvent of methanol are solvent, isolate and purify to obtain nelarabine shown in formula 8；The methanol
Ammonia solution or sodium methoxide methanol solution addition be calculated as 2.5 with the quality of 7 compound represented of formula~
10.0mL/g。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
| CN103483409A (en) * | 2013-09-24 | 2014-01-01 | 北京满格医药科技有限公司 | Synthetic method for preparing nelarabine |
-
2018
- 2018-04-18 CN CN201810349317.4A patent/CN108373491B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
| CN103483409A (en) * | 2013-09-24 | 2014-01-01 | 北京满格医药科技有限公司 | Synthetic method for preparing nelarabine |
Non-Patent Citations (3)
| Title |
|---|
| LEONID BEIGELMAN，等: "Improved Synthetic Approaches Toward 2’-O-Methyl-Adenosine", 《TETRAHEDRON》 * |
| 北京医学院药学系: "核酸的利用（一）半合成阿糖胞苷和阿糖胞苷-5’-磷酸", 《化学通报》 * |
| 陆鸿飞，等: "嘌呤2位卤素取代衍生物的合成", 《应用化学》 * |
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