CN110615818B - Synthesis method of fludarabine and nelarabine - Google Patents
Synthesis method of fludarabine and nelarabine Download PDFInfo
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Abstract
A method for synthesizing fludarabine and nelarabine is characterized in that ribofuranose derivatives are used as raw materials, ortho-alkynyl benzoate is introduced on 2-position hydroxyl to obtain a key glycosyl donor, the key glycosyl donor and purine bases are coupled by a Vorburggen glycosylation reaction, a beta-nucleoside bond can be efficiently constructed, 2 '-position ester groups are selectively removed under the catalysis of a gold catalyst to obtain important ribofuranoside, and the exposed 2' -hydroxyl is subjected to two-step reactions of hydroxyl overturning and deprotection to respectively obtain fludarabine and nelarabine. The synthesis strategy of the invention has the characteristics of simple and convenient operation, simple and easily obtained raw materials, easily separated products, high reaction yield and the like, and has better popularization and application prospects.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a novel synthesis method of fludarabine and nelarabine nucleoside medicaments.
Background
Nucleoside drugs are widely applied to the treatment of various viral diseases and tumors in clinic, especially play an irreplaceable role in the drugs for treating viral diseases such as AIDS, hepatitis, herpes and the like, and are always the first choice drugs for treatment. The dosage of nucleoside drugs in the aspect of antitumor is also increased year by year, and in 2011 of 500 best-sold antitumor drugs in the world, antimetabolites occupy 11.45% of market share, while most of the drugs are nucleosides.
Fludarabine (Fludarabine) is used for treating Chronic Lymphocytic Leukemia (CLL), the effective rate is over 80 percent, the Fludarabine also has good curative effect on the Fishcin lymphoma, and the combined moderate-dose cytarabine can effectively prolong the life cycle of a patient and reduce the recurrence rate in the treatment of acute myeloid leukemia. Chemoimmunotherapy (CIT) using fludarabine, cyclophosphamide and rituximab (FCR) is currently the standard care regimen for patients with chronic lymphocytic leukemia. The medicine is developed by German Xianling (Schering) company, is firstly marketed in the United states in 1991, and 6 domestic enterprises have produced the product, wherein the German Xianling (Nanjing) medicine industry finite company accounts for more than 50% of the national market share.
Nelarabine (Nelarabine) is used to treat T-cell acute lymphocytic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that have failed at least two treatment regimens or have relapsed after treatment. The medicine is developed by Kulansu (GSK) in UK, and is approved by FDA in US for marketing in 10 months of 2005, and is prepared into USP5424295 (1995), USP5747472 (1998).
Fludarabine and nelarabine both belong to arabinofuranosylpurine nucleosides, and the current synthetic preparation of the arabinosyl nucleosides mainly has three routes, wherein the most extensive 2,3, 5-tri-O-benzyl-1-chloro-D-arabinofuranose is adopted to carry out coupling reaction with corresponding nucleoside base, and the synthetic preparation method can generate alpha and beta isomers and has high separation difficulty. The raw material 2,3, 5-tri-O-benzyl-1-chloro-D-arabinofuranose has higher price, and is prepared by four-step reaction of arabinose, wherein the methylated arabinofuranose inevitably generates arabinose by-products in one step. In addition, when benzyl is used as a protecting group, dehalogenation can occur when noble metal palladium is used for removing the protecting group, and a mixture of fludarabine and defluorinated fludarabine (Ara-A) is obtained, which is tedious and tedious to separate, and has the following formula:
the second method is an enzyme catalysis method, for example, under the catalysis of the biological enzymes purine nucleoside phosphorylase and nyoximidine nucleoside phosphorylase, the nelarabine is obtained by base transfer reaction by taking 6-methoxy-2-aminopurine and uridine as raw materials, and the total yield is 15%. The invertase of the method is expensive, the strain is difficult to obtain, the condition is strictly controlled, and the industrialization is difficult.
The third method uses guanosine or 6-chloroguanosine as a starting material, for example, guanosine is used as the starting material, and the fludarabine is obtained by 9 steps of reactions such as acylation, fluorination, selective 2' -deacetylation, hydroxyl inversion, protecting group removal and the like with the total yield of 8 percent. The bottleneck of the scheme is the selective deacetylation of the 2' position of the ribofuranose, and the transesterification phenomenon is easy to occur by selectively removing the acetyl under the alkaline condition. Although the raw materials are cheap, the method has multiple steps and low yield, particularly, the step of selectively removing the glycosyl 2-acetyl is easy to generate isomers, so that the amplification of the process is limited, and the method has no practical application value, and has the following formula:
in summary, the three methods for synthesizing arabinopurine nucleosides reported at present have obvious disadvantages, so that it is important to develop a new general and simple method for synthesizing arabinopurine nucleosides.
Disclosure of Invention
The invention aims to provide a synthesis method for preparing the arabinopurine nucleosides fludarabine and nelarabine from ribofuranose, which has the advantages of high reaction yield, simple and convenient operation, easily obtained raw materials and easily separated products.
The synthetic method of fludarabine and nelarabine adopts a ribofuranose derivative as a raw material, preferably 1,3, 5-tri-O-benzoyl-alpha-D-ribofuranose, introduces O-alkynyl benzoate at a glycosyl 2 position to obtain a key glycosyl donor I, uses Vorbruggen glycosylation reaction to obtain beta type ribonucleoside with high selectivity, and then carries out gold catalysis (monovalent gold catalyst, preferably currently prepared triphenylphosphine gold trifluoroacetate Ph) 3 PAuOTFA) to selectively remove the o-alkynyl benzoate group at the 2 'position to obtain ribofuranoside II, then carrying out sulfonylation reaction at the 2' position of ribofuranoside II, carrying out hydroxyl turnover by using nitrite ions as a nucleophilic reagent to obtain arabinofuranoside III, and finally removing the protecting group to prepare fludarabine and nelarabine.
The structural formula of the key glycosyl donor I is as follows:
the structural formula of the ribofuranoside II is as follows:
the structure formula of the furan arabinose nucleoside III is as follows:
wherein R is one substituent of benzoyl, acetyl and benzyl, preferably benzoyl; r 1 Is one substituent of n-butyl, cyclopropyl, phenyl and isopropyl, and preferably hexynyl or cyclopropaneynyl; r 2 Is one of amino, chloro, methoxy and carbonyl; r 3 Is one of fluoro, amino, pivaloyl amido, acetamido, benzoylamino and tert-butoxy amido.
The synthesis method of fludarabine and nelarabine has the following reaction formula:
the synthesis steps are as follows:
1) Coupling 2-hydroxyl exposed ribofuranose derivative with O-alkynyl benzoate to synthesize key glycosyl donor I, preferably 1,3, 5-tri-O-benzoyl-alpha-D-ribofuranose with low cost and easy availability as raw material;
2) Coupling purine bases with (I) by using a Vorbruggen glycosylation reaction, specifically obtaining beta-type ribonucleosides due to the participation of ortho-alkynyl benzoate ortho-groups, wherein the temperature control in the reaction is important, the reaction temperature is preferably 75-80 ℃, and the reaction solvent is preferably ultra-dry acetonitrile;
3) The beta-type ribonucleoside is selectively deprived of 2' -position ortho-alkynyl benzoate group in the presence of gold catalyst to obtain ribofuranoside (II), wherein the catalyst is monovalent gold catalyst, preferably the currently prepared triphenylphosphine trifluoroacetic acid gold Ph 3 POTFA (with triphenylphosphine gold chloride (Ph) 3 PAuCl) and silver trifluoroacetate (AgOTFA) are prepared in a dichloromethane solvent, a supernatant solution is taken, and the reaction conditions are that the optimal catalyst amount is (0.05 eq-0.1 eq), the optimal ethanol amount is (4 eq-8 eq), and H is 2 The O amount is (0 eq-2 eq), and the reaction solvent is preferably dichloromethane;
4) Converting ribofuranosyl nucleoside (II) into arabinofuranosyl nucleoside III by two steps of reaction, firstly sulfonylating hydroxyl at 2' position, preferably trifluoromethanesulfonyl with smaller steric hindrance, and in the step of hydroxyl inversion, preferably using nitrite ion as nucleophilic reagent, preferably using potassium nitrite;
5) And (3) deprotection reaction, wherein the deprotection of fludarabine is preferably carried out in methanol solution saturated by ammonia gas, and the deprotection of nelarabine is preferably carried out in methanol solution of sodium hydroxide.
Compared with the prior art, the synthetic method of fludarabine and nelarabine has the advantages that: (1) Provides a new synthetic strategy to construct arabinopurine nucleosides; (2) The invention realizes the preparation and synthesis of fludarabine and nelarabine by taking the ribofuranose derivative as the raw material for the first time; (3) The method has the advantages that the selective removal of ester groups is realized for the first time under the neutral condition of the gold catalyst, and the ester transfer phenomenon of other ester groups on glycosyl is avoided; (4) The invention has the advantages of simple and easily obtained raw materials and wide reaction application range.
Detailed Description
Example 1
Synthesis of 2-O- (2-hexynylbenzoyl) -1,3, 5-tri-O-benzoyl-alpha-D-ribose (3) according to the reaction formula:
compound 2 (3.46g, 5.0 mmol), cuI (47.6 mg, 0.25mmol) and PdCl 2 (PPh 3 ) 2 (175.5mg, 0.25mmol) was dissolved in 40mL of a tetrahydrofuran/triethylamine mixed solvent (3. Under the protection of argon, 1-hexyne (493mg, 6.0 mmol) was slowly added dropwise. The reaction was warmed to 50 ℃ for 5 hours. The completion of the reaction of the starting materials was confirmed by thin layer monitoring on silica gel, the reaction solution was filtered through celite to remove solids, the filtrate was washed with dichloromethane, and the solvent was removed by concentrating the filtrate under reduced pressure to give a dark red residue. The crude extract was isolated and purified by flash column chromatography on silica gel using petroleum ether/ethyl acetate (10.
1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝7.4Hz,2H),8.08(t,J＝7.1Hz,4H),7.70(d,J＝7.8Hz,1H),7.62–7.52(m,3H),7.50–7.44(m,3H),7.42–7.31(m,5H),7.05(t,J＝7.6Hz,1H),6.97(d,J＝4.3Hz,1H),5.93(dd,J＝6.5,2.0Hz,1H),5.72–5.70(m,1H),4.91–4.90(m,1H),4.79(dd,J＝12.1,2.9Hz,1H),4.70(dd,J＝12.1,3.5Hz,1H),2.36(t,J＝7.0Hz,2H),1.60–1.48(m,2H),1.48–1.37(m,2H),0.89(t,J＝7.3Hz,3H)；
13 C NMR(101MHz,CDCl 3 )δ166.1,165.8,165.2,164.2,134.5,133.6,133.5,133.4,132.1,130.1,130.0,129.9,129.8,129.7,129.5,129.3,128.6,128.5,128.4,126.9,125.6,97.1,94.9,82.9,78.8,71.6,70.9,64.1,30.6,22.0,19.4,13.6；
HRMS(ESI + ):m/z calcd for:C 39 H 34 O 9 [M+Na] + :669.2101,found:669.2107。
Example 2
Synthesis of ribonucleoside (4) of the formula:
the base (1.2mmol, 1.2eq) was suspended in an ultra-dry acetonitrile solvent (15 mL). BSA (4.0mmol, 4eq) was added under the protection of argon, the reaction system was heated to 60 ℃ to react for 30 minutes, and the reaction solution became a clear solution. After cooling to room temperature, compound 3 (1.0 mmo1.0 eq) dissolved in acetonitrile (2 mL) solvent was injected into the reaction mixture. TMSOTf (4.0 mmol,4.0 eq) was slowly added dropwise to the above reaction system in ice bath, and after stirring was continued for 20 minutes, the temperature was raised to 80 ℃ and the reaction was continued for 4 hours. The completion of the reaction was monitored by thin layer spotting plates and the reaction solution was poured into saturated NaHCO 3 The solution (30 mL) was extracted with methylene chloride (2X 30 mL). The organic layer was then treated with saturated NaHCO 3 Saturated brine extraction 2 times, anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and spin-drying solvent to obtain crude extract. The crude extract was isolated and purified by flash column chromatography on silica gel with an elution phase of dichloromethane/methanol (100.
Example 3
Synthesis of ribonucleoside II, the reaction formula is:
compound 4 (1.0 mmol,1.0 eq) was weighed into a 25mL single-neck flask, and dissolved in 15.0mL of purified methylene chloride solvent. Deionized water (1.0 eq) and absolute ethanol (6.0 eq) were added at room temperature under argon for 20 minutes. During this period, triphenylphosphine gold trifluoroacetate (Ph) is prepared in situ 3 Paufa) catalyst (0.3ml, 0.05eq). Method for preparing triphenylphosphine gold trifluoroacetate: accurately weighing silver trifluoroacetate (0.5 eq) in a test tube, adding refined dichloromethane (3.0 mL) for dissolving, wrapping with tinfoil paper, stirring in a dark place, weighing triphenylphosphine gold chloride (0.5 eq) in the test tube, stirring at room temperature for 5 minutes for full reaction, standing for layering, taking 0.3mL of supernate, injecting into a reaction flask, continuing to react for about 5 hours, and monitoring by a silica gel thin layer to confirm that the reaction is complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by flash medium-pressure column chromatography using dichloromethane and methanol (50.
Example 4
Synthesis of 2-fluoro-9- (3, 5-di-O-benzoyl-2-O-trifluoromethanesulfonyl- β -D-ribofuranose) adenosine (6) with the reaction formula:
compound II-1 (1.00g, 2.0mmol) was placed in a 50mL single-neck flask, and 20mL of methylene chloride and acid-binding agent pyridine (0.4mL, 5.0mmol) were added thereto. The reaction system is stirred for ten minutes at the temperature of minus 20 ℃, then trifluoromethanesulfonic anhydride is injected by an injector for 3 times, after the reaction system is continuously stirred for 5 hours, saturated NaHCO is added 3 The reaction was quenched with solution (30 mL). The reaction solution was extracted with dichloromethane (2X 20 mL). The organic layer was then treated with saturated NaHCO 3 The solution (20 mL. Times.2) and the saturated NaCl solution (20 mL. Times.2) were washed twice with anhydrous Na 2 SO 4 Drying and rotary evaporation under reduced pressure to remove the solvent gave 1.20g of residue in 95% yield.
1 H NMR(400MHz,CDCl 3 ):δ8.17–8.06(m,2H),8.05–7.96(m,2H),7.87(s,1H),7.64(t,J＝7.5Hz,1H),7.56(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),7.42(t,J＝7.7Hz,2H),6.32(brs,2H),6.29–6.25(m,2H),6.22-6.20(m,1H),4.85(dd,J＝12.4,3.1Hz,1H),4.78-4.75(m,1H),4.65(dd,J＝12.4,4.1Hz,1H)；
HRMS(ESI):m/z[M+H] + calcd for C 25 H 20 F 4 N 5 O 8 S:626.0969；found:626.0968。
Example 5
The synthesis of 2-fluoro-9- (3, 5-di-O-benzoyl-beta-D-arabinofuranosyl) adenosine (7) with the reaction formula:
compound 6 (500mg, 0.8mmol), potassium nitrite (340mg, 4.0mmol) and 18-crown-6 (21mg, 0.08mmol) were dissolved in 10mL of N, N-dimethylformamide solution. After the reaction system was stirred at room temperature for 24 hours, 30mL of methylene chloride was added. The reaction solution was washed twice with deionized water (20 mL. Times.2) and saturated NaCl solution (30 mL. Times.2), and dried over anhydrous Na 2 SO 4 Drying, and rotary evaporating under reduced pressure to remove solvent. The residue was separated by silica gel column chromatography eluting with methylene chloride/methanol (60.
1 H NMR(400MHz,DMSO-d 6 ):δ8.20(s,1H),8.08(d,J＝7.3Hz,2H),7.99(d,J＝7.3Hz,2H),7.72(t,J＝7.2Hz,1H),7.66(t,J＝7.2Hz,1H),7.58(t,J＝7.6Hz,2H),7.51(t,J＝7.7Hz,2H),6.34(d,J＝4.4Hz,1H),6.30(d,J＝4.6Hz,1H),5.64-5.62(m,1H),4.76(dd,J＝11.6,6.9Hz,1H),4.73–4.62(m,2H),4.54-4.50(m,1H).
13 C NMR(101MHz,DMSO-d 6 ):δ166.0,165.5,159.1(d, 1 J CF ＝202.3Hz),157.9,151.1(d, 3 J CF ＝19.9Hz),141.1,134.3,134.0,130.0(C×2),129.9,129.7(C×2),129.5,129.3(C×2),129.2(C×2),117.1(d, 4 J CF ＝4.0Hz),84.6,79.3,79.2,73.4,64.6.
HRMS(ESI):m/z[M+H] + calcd for C 24 H 20 FN 5 O 6 :494.1476；found:494.1478。
Example 6
The synthesis of fludarabine has the reaction formula:
compound 7 (300mg, 0.61mmol) was placed in a 25mL pressure tube, 10mL ammonia saturated methanol solution was quickly added, and the mouth of the tube was sealed. After the reaction mixture was reacted at 40 ℃ for 6 hours, the solvent was removed by rotary evaporation under reduced pressure. The concentrate was isolated and purified by flash column chromatography on silica gel eluting with methylene chloride/methanol (20. m.p. 260-262.
1H NMR(400MHz,DMSO-d 6 ):δ8.17(s,1H),7.77(s,2H),6.10(d,J＝5.0Hz,1H),5.67(d,J＝5.4Hz,1H),5.57(d,J＝4.6Hz,1H),5.11(t,J＝5.4Hz,1H),4.17–4.09(m,2H),3.77–3.48(m,1H),3.69–3.59(m,2H)；
13C NMR(101MHz,DMSO-d 6 ):δ159.0(d,1J CF ＝203.7Hz),157.9(d, 3 J CF ＝21.4Hz),151.1(d, 3 J CF ＝20.4Hz),141.0,117.1(d, 4 J CF ＝3.5Hz),84.5,84.1,76.0,75.2,61.2；
HRMS(ESI):m/z[M+H]+calcd for C10H13FN5O4:286.0952；found:286.0952。
Claims (5)
1. A synthetic method of fludarabine and nelarabine is characterized by comprising the following steps: it comprises the following steps:
(1) Coupling the 2-hydroxyl exposed ribofuranose derivative with ortho-alkynyl benzoate to synthesize a key glycosyl donor I;
(2) Coupling purine bases with key glycosyl donors (I) by using a Vorbruggen glycosylation reaction to obtain beta-type ribonucleosides;
(3) Beta type ribonucleoside is selectively deprived of 2' position ortho alkynyl benzoate group in a gold catalyst to obtain ribofuranoside II, wherein the catalyst is triphenylphosphine gold trifluoroacetate;
(4) Sulfonylating the 2' -hydroxyl, wherein the sulfonating agent is trifluoromethanesulfonyl, and then obtaining the arabinofuranoside III through hydroxyl turnover reaction;
(5) Carrying out deprotection reaction on furanose nucleoside III in ammonia saturated methanol solution to obtain fludarabine; carrying out deprotection reaction on furan arabinoside III in a methanol solution of sodium hydroxide to obtain nelarabine;
the structural formula of the 2-position hydroxyl exposed ribofuranose derivative is as follows:
；
the beta-type ribonucleoside has the structural formula:
；
the structural formula of the key glycosyl donor I is as follows:
；
the structural formula of the ribofuranoside II is as follows:
；
the structure formula of the furan arabinose nucleoside III is as follows:
；
wherein R is one substituent group of benzoyl, acetyl and benzyl; r 1 Is one substituent of n-butyl, cyclopropyl, phenyl and isopropyl; r 2 Is one of amino, chloro, methoxy and carbonyl; r 3 Is one of fluoro, amino, pivaloyl amido, acetamido, benzoylamino and tert-butoxy amido.
2. The method for synthesizing fludarabine and nelarabine according to claim 1, which is characterized in that: in the step (1), the ribofuranose derivative with naked 2-hydroxy in position is 1,3, 5-tri-O-benzoyl-alpha-D-ribofuranose.
3. The method for synthesizing fludarabine and nelarabine according to claim 1, which is characterized in that: in the step (2), the reaction temperature is 75-80 ℃, and the reaction solvent is acetonitrile.
4. The method for synthesizing fludarabine and nelarabine according to claim 1, which is characterized in that: in the step (3), the reaction conditions are that the amount of the triphenylphosphine gold trifluoroacetate is 0.05eq to 0.1eq, the amount of the ethanol is 4eq to 8eq 2 The amount of O is 0eq-2eq and the reaction solvent is dichloromethane.
5. The method for synthesizing fludarabine and nelarabine according to claim 1, which is characterized in that: in the step (4), the hydroxyl group reversal reaction takes potassium nitrite as a nucleophilic reagent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102311472A (en) * | 2010-07-09 | 2012-01-11 | 神隆(昆山)生化科技有限公司 | Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine |
| US20150238640A1 (en) * | 2008-01-03 | 2015-08-27 | Commissariat A I'energie Atomique Et Aux Energies Alternatives | Method for preparing a marked purine derivative, said derivative and uses thereof |
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| US20150238640A1 (en) * | 2008-01-03 | 2015-08-27 | Commissariat A I'energie Atomique Et Aux Energies Alternatives | Method for preparing a marked purine derivative, said derivative and uses thereof |
| CN102311472A (en) * | 2010-07-09 | 2012-01-11 | 神隆(昆山)生化科技有限公司 | Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine |
Non-Patent Citations (1)
| Title |
|---|
| Stereoselective synthesis of 2"-modified nucleosides by using ortho-alkynyl benzoate as a gold(I)-catalyzed removable neighboring participation group;Haixin Ding等;《RSC Advances》;20170112;第7卷(第4期);全文 * |
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