CN103483409A

CN103483409A - Synthetic method for preparing nelarabine

Info

Publication number: CN103483409A
Application number: CN201310460155.9A
Authority: CN
Inventors: 翟永利; 汪娟
Original assignee: BEIJING MANGE PHARMACEUTICAL SCIENCE AND TECHNOLOGY Co Ltd
Current assignee: BEIJING MANGE PHARMACEUTICAL SCIENCE AND TECHNOLOGY Co Ltd
Priority date: 2013-09-24
Filing date: 2013-09-24
Publication date: 2014-01-01

Abstract

The invention relates to a synthetic method for preparing nelarabine, and the method comprises the following steps: using 2-amino-6-methoxypurine as the raw material and under the catalysis of ammonium sulfate, carrying out silylation protection on 2-amino-6-methoxypurine by hexamethyl disilazane; then performing the room temperature reaction on the obtained product and 2,3,5-tri-O-benzyl-1-chlorine-arabinose for 10 to 24 hours in a dichloromethane solvent by using trimethylsilyl fluorosulfonate as a catalyst so as to obtain a key intermediate, i.e. 2-amino-6-methoxy-9-beta-D-(2',3',5'-tri-O-benzyl-arabinosyl) purine; carrying out deprotection on the key intermediate in dichloromethane solution by boron trichloride to obtain a nelarabine crude product; and carrying out column chromatography isolation and recrystallization to obtain the nelarabine finished product.

Description

A kind of synthetic method for preparing Nelzarabine

Invention field

The invention belongs to the medicine preparing technical field, particularly relate to a kind of preparation method of Nelzarabine.

Technical background

The trade(brand)name of Nelzarabine (Nelarabine) is Arranon, chemistry 2-amino by name-9-β-D-R furyl glycosyl-6-methoxyl group-9H-purine, and molecular formula is C ₁₁h ₁₅n ₅o ₅.It is the water-soluble prodrug of cytotoxin pancreatic desoxyribonuclease ara-G, be used for the treatment of at least two kinds of chemotherapy regimens reactionless, or the treatment after again the recurrence acute T cell lymphoblastic leukemia (T-ALL) and T-cell LBL (T-LBL).Its enter after blood can be under the effect of adenosine deaminase demethylation rapidly, change into the triphosphate of ara-G9-β-D-R furanose guanine, by suppressing the synthetic of DNA, induce de-the biting of permissive cell and work.In recent years, suffer from the acute lymphoblastic leukemia children and grownup's curative ratio has had raising, children approach 80% but grownup's curative ratio less than 40%, far below children, therefore find safer and more effective methods for the treatment of and medicine extremely urgent, nucleoside analog has proved the cell toxicity medicament of the treatment hematological system tumor of successful.Nelzarabine is researched and developed by Ge Lansu (GlaxoSmithKline) company, obtain the approval of U.S. FDA in October, 2005,2006 at first at U.S.'s official listing, in November, 2007, in Britain, go on the market subsequently, go on the market in December, 2007 in Japan, is used for the treatment of acute T cell lymphoblastic leukemia (T-ALL) and T-cell LBL (T-LBL).

The synthetic method of Nelzarabine has following several method:

Method 1, Chen Lei etc. were " Chinese pharmacists " 2010, in " improvement in synthesis of Nelzarabine "-Wen of the 13rd the 4th phase of volume, the amino 6-chloropurine and 2,3 of the 2-of take, 5-tri--oxygen-benzyl-1-oxygen-p-nitrophenyl formyl-D-arbinofuranose are the synthetic Nelzarabine of raw material.The amino 6-chloropurine of 2-first generates 2-amino-6-methoxyl group purine (III) through the methyl alcohol nucleophilic substitution; then with 2,3,5-tri--oxygen-benzyl-1-oxygen-p-nitrophenyl formyl-D-arbinofuranose obtains Nelzarabine key intermediate II through the product (IV) of chlorination under the tin tetrachloride effect; II uses the boron trichloride deprotection in dichloromethane solution subsequently, makes Nelzarabine I.This method technique is simple, but because 2-amino-6-methoxyl group purine solubleness in all kinds of SOLVENTS is all less, in this reaction, tin tetrachloride is not only made solvent but also make catalyzer, consumption is very large, causes the Nelzarabine production cost higher, the aftertreatment difficulty, be not suitable for and suitability for industrialized production, its synthetic reaction equation is as follows:

Method 2, European patent EP 0294114, take 2-amino-6-methoxyl group purine and uracil arabinoside is raw material, use biochemical process to obtain target product, specific as follows: that the amino 6-methoxyl group of 2-purine is dissolved in potassium phosphate salt and propanol solution together with uracil arabinoside, regulating pH value is 6.7, then purine nucleoside phosphorylase and uridine Starch phosphorylase are joined in above-mentioned system, constant temperature water bath is at 37 ℃, react after 26 days, product is filtered, after filtrate is adjusted to 10.5 with ammoniacal liquor by pH value, through formate column ion exchange resin, separate, then with 7% propyl alcohol washing, portion of product is together with solvent like this, washing is except after desolventizing in a vacuum, residue extracts with deionized water, the upper strata material just obtains Nelzarabine after drying in a vacuum.The difficult point of this method is that bacterial classification is more difficult to get, and the reaction times is oversize, strict to equipment requirements, and cost is also thereupon high.

Method 3 Chinese patent CN101092441A, the 6-chlorine guanosine of take is raw material, and the 6-chlorine guanosine of take is raw material, through six step chemosynthesis, by the ribofuranose configuration conversion, is pectinose, makes Nelzarabine, and its composition principle is as follows:

This route has the advantage that raw material is easy to get, but, because reaction scheme is long, total recovery is lower, and production cost is still higher.

Method 4, have bibliographical information, and intermediate III and intermediate compound IV, in anhydrous acetonitrile, are the synthetic key intermediate II of catalyzer with sodium hydrogen.

Because intermediate III solubleness in acetonitrile is less, belong to solid-liquid reaction, speed of response is very slow, and intermediate compound IV is unstable under alkaline condition, so yield is lower, and aftertreatment is more difficult, is difficult to suitability for industrialized production.

The present invention; the various synthetic report of comprehensive Nelzarabine; in conjunction with its structure and raw material condition, we have carried out the silylation protection to intermediate III, are prepared into compound V; owing to having introduced the silylation group; improve the solvability of compound V, can react in solution with intermediate compound IV, accelerated speed of response; improved yield, obvious industrial advantages has been arranged.Route is as follows:

Embodiment

The present invention is further illustrated to enumerate the following examples.Should correct understanding: these embodiment only provide for the present invention is described, rather than limitation of the present invention, so, on the basis of these embodiment, to simple modifications of the present invention, all belong to the scope of protection of present invention.

Embodiment 1:

Synthesizing of 2-(TMS)-amino-6-methoxyl group-9-(TMS)-purine (V)

Add 16.5g (0.1mol) 2-amino-6-methoxyl group-purine in three mouthfuls of reaction flasks of drying, add 100ml hexamethyldisilane amine (HMDS), add 0.2g ammonium sulfate, back flow reaction 6 hours, until solid is entirely molten, clarification, steam excessive HDMS, obtaining residue 32g, is compound V.

Embodiment 2:

Synthesizing of 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-tri--O-benzyl-arbinofuranose base) purine (II)

The product that example 1 is made, be dissolved in the 300ml methylene dichloride, stirring at room 10 minutes, add 43.89g (0.1mol) 2 ', 3 ', the chloro-arbinofuranose of 5 '-tri--O-benzyl-1-(IV), be stirred to dissolve fully, drip 23.4g (0.105mol) trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf) under room temperature, approximately within 30 minutes, add, after adding, stirred overnight at room temperature (being no less than 12 hours).

Reaction solution is dropped in sodium carbonate/bicarbonate solution, adjust PH 7～8, during dropping, temperature remains on 0～10 ℃, layering, water layer 100ml dichloromethane extraction, merge organic layer, 100ml for organic layer * 3 water washings are to neutrality, anhydrous sodium sulfate drying, be evaporated to dry, obtain faint yellow product (II), heavily about 52.3g, yield 92.3% (in compound IV).

Example 3:

The synthetic of 2-amino-6-methoxyl group-9-β-D-arbinofuranose base-purine (I) is dissolved in 42.2g (74mmol) II in the 600ml methylene dichloride, and the nitrogen replacement protection, be cooled to-70 ℃, starts to drip BCl ₃the about 450ml of DCM solution (1M) (450mmol), control temperature during dropping not higher than-60 ℃, in about 30min, drip off, be incubated-60 ℃～-70 ℃ and reacts 2h, during reaction solution become gradually muddy; Then be warming up to gradually-20 ℃, insulation reaction 2 hours.

Be cooled to-70 ℃, slowly drip 200mL anhydrous methanol and 450ml triethylamine, drip Bi Ziran and be warming up to 20 ℃～30 ℃.Vacuum is steamed except desolventizing, uses water dissolution, uses saturated Na ₂cO ₃solution is regulated PH to 8.5～9, and with methylene dichloride 250ml * 3, extraction, water layer adds 20～30 ℃ of decolourings of 7.5g gac 30 minutes, filter, filtrate decompression is spin-dried for, and adds anhydrous methanol to stir temperature rising reflux 2h, filtered while hot, filtrate, be spin-dried for to obtain about 25g brown solid.Cross silicagel column, use recrystallizing methanol twice, obtain Nelzarabine finished product 11.2g, yield 51.8%.

¹h-NMR (300MHz, DMSO-D ₆) δ: 7.91 (s, H, purine skeletons), 6.40 (s, 2H, purine skeleton amino), 6.12～5.48 (b, H, the furanose ring), 5.03 (t, H, furanose rings), 4.03～4.09 (m, 2H, furanose rings), 3.97 (s, 3H, furanose ring methoxyl group), 3.73～3.76 (m, H, the furanose ring), 3.60～3.65 (m, 2H, methylene radical).

Claims

1. a synthetic method for preparing Nelzarabine, is characterized in that with 2-amino-6-methoxyl group purine be raw material, take ammonium sulfate as catalyzer, with silylation reagent back flow reaction 6 hours, generates silylation protection product.

2. silylation product and 1-halo-2,3,5-tri--O-benzyl-pectinose is under lewis acid catalyst catalysis, room temperature reaction 10 hours, make key intermediate 2-amino-6-methoxyl group-9-β-D-(2 ' with the alkali aqueous solution hydrolysis, 3 ', 5 '-tri--O-benzyl-aralino) purine.

3.2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-tri--O-benzyl-aralino) purine, in the boron trichloride dichloromethane solution, the low temperature deprotection, be prepared into Nelzarabine.

4. require 1 described preparation method according to patent, silylation reagent comprises hexamethyldisilane amine (HMDS), trimethylchlorosilane (TMSCl), chlorotriethyl silane (TESCl), dimethyl tertiary butyl chloride silane (TBDMSCl) etc.

5. require 1 described preparation method according to patent, temperature of reaction in room temperature between the alkylating reagent boiling point.

6. require 1 described preparation method according to patent, the reaction times is between 1 hour to 24 hours.

7. require 2 described preparation methods according to patent, the Louis acid catalyst comprises titanium tetrachloride, tin tetrachloride, fluosulfonic acid TMS triflate (TMSOTf), TMSOSO2C4F9 etc.

8. require 2 described preparation methods according to patent, its alkali aqueous solution is the aqueous solution that sodium carbonate, sodium bicarbonate, volatile salt, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide or its mixture etc. form.

9. require 2 described preparation methods according to patent, its temperature of reaction is-10 ℃～110 ℃, and optimum condition is-5 ℃～40 ℃.