CN100334101C - Method for synthesizing 2',3'-dideoxy cytidine - Google Patents
Method for synthesizing 2',3'-dideoxy cytidine Download PDFInfo
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- CN100334101C CN100334101C CNB200410015900XA CN200410015900A CN100334101C CN 100334101 C CN100334101 C CN 100334101C CN B200410015900X A CNB200410015900X A CN B200410015900XA CN 200410015900 A CN200410015900 A CN 200410015900A CN 100334101 C CN100334101 C CN 100334101C
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- deoxyribose cytidine
- dideoxycytidine
- solvent
- alkali
- compound
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Abstract
The present invention relates to a synthetic method of 2', 3'-dideoxy cytidine (I), which comprises the steps as follows: adopting 2'-dexoy cytidine hydrochloride as initial raw material; treating the 2'-dexoy cytidine hydrochloride with the reactions, such as desalination, selective amino and hydroxyl protection, selective deoxydation and deprotection, catalytic hydrogenation and deprotection, etc. to prepare the designed product. Compared with the existing synthetic methods, the method has the advantages of few steps, high yield and high purity of the prepared product.
Description
Technical field
The present invention relates to the synthetic method of deoxynucleoside class medicine, be specifically related to the synthetic method of 2 ', 3 '-dideoxycytidine.
Background technology
2 ', 3 '-dideoxycytidine (2 ', 3 '-dideoxycytidine) (I) has another name called ddc, Zalcitabine, and zalcitabine, trade(brand)name: Hivid, its structure is as follows:
This compound is HIV (human immunodeficiency virus) (HIV) reverse transcriptase inhibitors, and it can be phosphorylated to activated triphosphoric acid metabolite and suppress HIV virus in cell.Clinical indication is acquired immune deficiency syndrome (AIDS) and AIDS related complex, also can be used for treating the simple property of I type blister disease keratitis.This medicine was developed by Roche Holding Ag, in listing in 1992.
At present the synthetic method of disclosed 2 ', 3 '-dideoxycytidine is raw material usually with the cytosine(Cyt), through the protection of silicon etherificate, makes cytidine with the condensation of tetrem acyl ribose, separates tens steps reaction such as deprotection again through halo and selective protection, hydro-reduction, ammonia and makes product.Reactions steps is a lot, is difficult for carrying out suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is the synthetic method of existing 2 ', 3 '-dideoxycytidine is improved, and provides a kind of method easy, yield, the novel preparation method that purity is high.
The present invention begins with the raw material 2 '-Deoxyribose cytidine that is easy to get, and obtains highly purified 2 ', 3 '-dideoxycytidine with the 7 steps reaction of simple operations comparatively.
Disclosed by the invention 2 '; it is starting raw material that the synthetic method of 3 '-dideoxycytidine adopts 2 '-Deoxyribose cytidine hydrochloride; make formula I compound through reactions such as desalting treatment, selectivity amino and hydroxyl protection, selectivity deoxidation deprotection, catalytic hydrogenation deprotections, its synthetic route is as follows:
Wherein, R
1Expression C
1-10Fatty acyl group is as ethanoyl, positive propionyl, different propionyl, positive butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, positive caproyl etc.; Or aroyl, as benzoyl, to methyl benzoyl, p-nitrophenyl formyl radical, to anisoyl etc.
R
2Expression C
1-10Fatty acyl group is as ethanoyl, positive propionyl, different propionyl, positive butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, positive caproyl etc.; Or aroyl, as benzoyl, to methyl benzoyl, p-nitrophenyl formyl radical, to anisoyl etc.
R
3The expression alkyl sulphonyl is as methylsulfonyl, ethylsulfonyl, trifyl etc.; Or aryl sulfonyl, as benzenesulfonyl, p-toluenesulfonyl, 2,4,6-Three methyl Benzene alkylsulfonyl, to the anisole alkylsulfonyl, p-nitrophenyl alkylsulfonyl, to chlorobenzene alkylsulfonyl etc.
The preparation method of formula I compound of the present invention may further comprise the steps:
1) freeization of 2 '-Deoxyribose cytidine hydrochloride
2 '-Deoxyribose cytidine hydrochloride (1) is suspended in the appropriate amount of organic in this step reaction, makes 2 '-Deoxyribose cytidine free with alkali, collects the colourless crystallization solid, and drying gets 2 '-Deoxyribose cytidine (2).
Wherein organic solvent is selected from the alkyl alcohol of C1-C6 such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc.; Or halogenated hydrocarbon is as methylene dichloride, chloroform, ethylene dichloride, chlorobenzene, tetracol phenixin etc.; Or ester compound such as ethyl acetate, butylacetate, isopropyl acetate etc.; Or ethers such as ether, isopropyl ether, uncle's butyl ether, ethylene glycol monomethyl ether, ethylene glycol ethyl ether etc.
Alkali can be mineral alkali or organic amine, and mineral alkali comprises sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, and organic bases comprises pyridine, hexahydropyridine, dimethylamine agueous solution, diethylamine, triethylamine etc.
2) protection of amido in 2 '-Deoxyribose cytidine
Get 2 '-Deoxyribose cytidine (2) and in polar solvent, use acyl group protecting group (R
1Protecting group) reagent reacts the back concentrating under reduced pressure with it except that desolvating, and it is an amount of to add diethyl ether, and suction strainer is collected white crystals, and drying gets N-R
1-2 '-Deoxyribose cytidine (3).
Wherein said polar solvent is that organic solvent comprises pyridine, DMSO, DMF, N,N-dimethylacetamide, tetrahydrofuran (THF), acetonitrile, dimethyl formamide, ethyl acetate, methylene dichloride or chloroform etc.
R
1Protecting group reagent is selected from R as defined above
1The corresponding acylating agent of group comprises Acetyl Chloride 98Min., acetyl bromide, diacetyl oxide, Benzoyl chloride, benzoyl oxide etc., wherein preferred Benzoyl chloride.
3) 5 ' hydroxyl in the selective protection glycosyl
N-R
1-2 '-Deoxyribose cytidine (3) adds acyl group protecting group (R in the presence of organic solvent and acid binding agent
2Protecting group) reagent react obtains N-R
1-5 '-R
2-2 '-Deoxyribose cytidine (3 ').
Wherein acyl group protecting group reagent is selected from R as defined above
2The corresponding acylating agent of group comprises Acetyl Chloride 98Min., trimethyl-acetyl chloride, Benzoyl chloride etc., the preferred bigger pivaloyl acylating agent of steric hindrance.
Reaction solvent is selected general organic solvent for use, as methylene dichloride, chloroform, ethyl acetate, toluene, pyridine, and N,N-DIMETHYLACETAMIDE, dimethyl formamide etc., wherein preferred methylene dichloride pyridine.
Acid binding agent is selected from general mineral alkali and organic bases, mineral alkali such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc., organic bases such as pyridine, hexahydropyridine, dimethylamine agueous solution, diethylamine, triethylamine etc.
4) 3 ' of glycosyl hydroxyl is converted into and is easy to slough group
N-R
1-5 '-R
2-2 '-Deoxyribose cytidine (3 ') adds sulfonyl agent and obtains N-R in organic solvent
1-5 '-R
2-3 '-R
3-2 '-Deoxyribose cytidine (4).
Described sulfonyl agent is selected from R as defined above
3The corresponding sulphonyl agent of sulfonyl group comprises methylsulfonyl, p-toluenesulfonyl; trifyl, 2,4; 6-Three methyl Benzene alkylsulfonyl, to the anisole alkylsulfonyl, p-nitrophenyl alkylsulfonyl, to corresponding sulphonyl agent such as chlorobenzene alkylsulfonyl, wherein preferred methylsulfonyl chloride or sulphonic acid anhydride.Described organic solvent defines same step 3).
Usually this step react can with above-mentioned steps 3) in same reactor, carry out simultaneously.
5) 3 ', 5 ' deacylated tRNA radical reaction
N-R
1-5 '-R
2-3 '-R
3-2 '-Deoxyribose cytidine (4) adds alkali in reaction solvent, the alkylsulfonyl and the 5 ' acyl group that remove 3 ' generate N-R
1-2 ', 3 '-dehydrogenation-2 ', 3 '-dideoxycytidine (5).
Reaction solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, DMF, DMSO etc.; Alkali is selected from sodium methylate, sodium ethylate, dimethylamine agueous solution, diethylamine, triethylamine, pyridine etc.The reaction back can get product after neutralizing with acid.In this step reaction, owing to adopt alkali to remove, 5 ' acyl group protecting group that goes up on the hydroxyl of glycosyl also is hydrolyzed simultaneously.
6) amino deprotection
Get N-R
1-2 ', 3 '-dehydrogenation-2 ', 3 '-dideoxycytidine (5) is suspended in an amount of polar solvent, gets 2 ', 3 '-dehydrogenation, 2 ', 3 '-dideoxycytidine (6) after reacting with base catalysis.
Wherein solvent is selected from methyl alcohol, ethanol, DMSO, DMF, N,N-dimethylacetamide etc., and alkali is selected from sodium methylate, sodium ethylate, triethylamine, hexahydropyridine, pyridine or OH type anionite-exchange resin.
7) catalytic hydrogenation
2 ', 3 '-dehydrogenation, 2 ', 3 '-dideoxycytidine (6) adopts normal pressure or pressure hydration, gets 2 ', 3 '-dideoxycytidine (I) behind the recrystallization purifying.
Be reflected in the common solvent as carrying out in water, methyl alcohol, the ethanol etc., comparatively fast carry out, generally should adopt pressure hydration for reacting.Wherein said catalyzer can be Pd-C, Raney Ni or PtO
2Hydrogen source is best with hydrogen.
Below by embodiment the present invention is further described.
Embodiment
Embodiment 12 '-preparation of Deoxyribose cytidine (2)
During 2 '-oxygen cytidine hydrochloride (4.22 moles) (1kg) is suspended in 10 liters of methylene dichloride, add 590 milliliters of (4.22 moles) diethylamine, suspension is high degree of agitation three hours at room temperature, collect the colourless crystallization solid, wash with methylene dichloride, dry air obtains 880 grams, 2 '-Deoxyribose cytidine, yield 100%, fusing point 185-195 ℃.
The preparation method of embodiment 2 N-benzoyl-2 '-Deoxyribose cytidines (3)
2 '-Deoxyribose cytidine (2) (3300 grams, 14.52 mole) and Benzoyl chloride (15 moles), the mixture of N,N-DIMETHYLACETAMIDE (33 liters) at room temperature stirs and spends the night, and concentrating under reduced pressure removes and desolvates gained residue re-crystallizing in ethyl acetate, suction filtration, wash with ethyl acetate, drying gets white solid (3990 gram), yield 83%, fusing point 223-225 ℃ (dec.).
The preparation method of embodiment 3 N-benzoyl-2 '-Deoxyribose cytidines (3)
With 2 '-Deoxyribose cytidine (2) (600 grams, 2.64 benzoyl oxide (590 grams mole),, 2.64 mole) and the solution of dehydrated alcohol (10 liters) backflow two hours, solution decompression is concentrated into small volume, dilutes with ethyl acetate, filter, wash with ethyl acetate and sherwood oil successively, drying gets product 743 grams, productive rate 85%, 230 ℃ of fusing points (dec.).
The preparation of embodiment 4 N-benzoyl-3 '-methylsulfonyl-5 '-pivaloyl-2 '-Deoxyribose cytidines (4)
With trimethyl-acetyl chloride (955 gram) slowly be added drop-wise to N-benzoyl-2 '-pyridine (40 liters) solution of Deoxyribose cytidine (3) (2 kilograms, 6.04 moles) in, add the back and stir and spend the night.Then, under the ice bath cooling, in reaction solution, slowly drip methylsulfonyl chloride (1.4 kilograms), continued stirring reaction 6 hours.Mixture is under agitation poured in 100 premium on currency, got gluey white precipitate, filter, use 95% ethyl alcohol recrystallization, drying gets 2.1 kilograms of products, yield 71%, fusing point 144-146 ℃ (dec.).Analytically pure sample is by 95% ethanol recrystallization once more, fusing point 149-150 ℃ (dec.).UVλ
max(MeOH)258nm，300nm；
1H?NMRδ
H(DMSO-d
6)：9.0((1H，br?S，NH)，8.01(1H，d，J＝7.5Hz，6-H)，7.80(2H，m，Ar)，7.56(3H，m，Ar)，7.52(1H，d，J＝7.5Hz，5-H)，6.22(1H，m，1′-H)，5.27(1H，m，3′-H)，4.61(1H，m，4′-H)，4.37(2H，d，J＝4.5Hz，5′-H)，3.12(3H，s，MeS0
2-)，2.24(2H，m，2′-H)，1.23(9H，s，(CH
3)
3CCO)；E.A.C，53.54，H，5.51，N，8.51，S，6.49％.
Embodiment 5 N-benzoyls-2 ', 3 '-dehydrogenation-2 ', 3 '-preparation of dideoxycytidine (5)
Mix down in the ice bath cooling; with be suspended in no water sodium hydroxide among 4 liters of DMF (450 gram) slowly add the N-benzoyl-3 that is dissolved in 4 liters of DMF '-methylsulfonyl 5 '-ethanoyl 2 '-(1.096 kilograms of Deoxyribose cytidines; 2.22 mole) in the solution, add the back and continue to stir one hour.Add no water sodium hydroxide 20 grams again, restir one hour.To pH7, behind the pressure reducing and steaming solvent, add entry (5 liters) to residue with Glacial acetic acid neutralization reaction liquid, in 5 ℃ of placements 16 hours, the filtering separation crystallization was washed with frozen water, and drying obtains 652 gram (5) crude products, (productive rate 92%).Analytic sample is with ethyl alcohol recrystallization, and fusing point is greater than 265 ℃.UVλ
max(MeOH)257nm，301nm；
1H?NMRδ
H(DMSO-d
6)：11.37((1H，br?S，NH)，8.38(1H，d，J＝7.5Hz，6-H，8.12(2H，m，Ar)，7.53-7.80(3H，m，Ar)，7.37(1H，d，J＝7.5Hz，5-H)，7.00(1H，m，1′-H)，6.50(1H，brd，J＝6Hz?3′-H)，6.10(1H，br，d，J＝6Hz，2′-H)，5.13(1H，t，J＝5.4Hz，OH)，4.95(1H，m，4′-H)，3.70(2H，m，5′-H)；E.A.C，61.33，H，4.82，N，13.41％。
Embodiment 62 ', 3 '-preparation of dideoxycytidine (I)
N-benzoyl-2 ', 3 '-dehydrogenation-2 ', 3 '-dideoxycytidine (5) (650 gram, 2.07 moles) is suspended in 12 liters of methyl alcohol, adds sodium methylate (250 gram), stirs 15 hours under the room temperature, removes by filter insolubles, wash with 11 liters of methyl alcohol and 8 premium on currency respectively.Merging filtrate also is concentrated into about 15 liters, adds 5%Pd-C catalyzer (150 gram), and hydrogenation under 10 pounds hydrogen pressure per square inch after about 2 hours, stops hydrogenation.Filter, filtrate is evaporated to dried, gets white crystals 334 grams, productive rate 76%, 215 ℃ of fusing points.Crude product gets 272 gram analytically pure crystallizations (I), fusing point 216-218 ℃ from 95% ethanol (3.5 liters) recrystallization.UVλ
max(0.1NHC1)280nm；
1H?NMRδ
H(DMSO-d
6)：7.91(1H，d，J＝7.5Hz，6-H)，7.13(2H，S，NH
2)，5.98(1H，m，1′-H)，5.76(1H，d，J＝7.5Hz，5-H)，4.98(1H，m，OH)，4.07(1H，m，4′-H)，3.63(2H，m，5′-H)，1.56-2.56(4H，m，2′-and3′-H)；E.A.C，51.18，H，6.20，N，19.89％。
Claims (9)
1,2 ', the synthetic method of 3 '-dideoxycytidine I, it is characterized in that, it is starting raw material that this method adopts 2-Deoxyribose cytidine hydrochloride 1, gets compound 2, selectivity amido protecting through desalting treatment and gets compound 3, selectivity hydroxyl protection and get compound 4, selectivity deoxidation deprotection and get compound 5, deaminizating and protect to such an extent that obtain Compound I after compound 6, the catalytic hydrogenation;
Wherein, R
1Be C
1-10Fatty acyl group or aroyl;
R
2Be C
1-10Fatty acyl group or aroyl;
R
3Be alkyl sulphonyl or aryl sulfonyl.
2, method according to claim 1, it is characterized in that wherein said desalting treatment method is that 2 '-Deoxyribose cytidine hydrochloride 1 is suspended in the appropriate amount of organic, make 2 '-Deoxyribose cytidine free, collect the colourless crystallization solid with alkali, drying gets 2 '-Deoxyribose cytidine 2.
3, method according to claim 2 is characterized in that wherein said organic solvent is selected from the alkyl alcohol of C1-C6, halohydrocarbon, ester compound or ethers; Described alkali is selected from mineral alkali or organic amine.
4, method according to claim 1; it is characterized in that wherein said selectivity amido protecting method comprises that getting 2 '-Deoxyribose cytidine 2 reacts the back concentrating under reduced pressure with it except that desolvating with acyl group protecting group reagent in polar solvent, it is an amount of to add diethyl ether, and suction strainer is collected white crystals; drying gets N-R
1-2 '-Deoxyribose cytidine 3.
5, method according to claim 4 is characterized in that wherein said polar solvent is selected from pyridine, DMSO, DMF, N,N-dimethylacetamide, tetrahydrofuran (THF), acetonitrile, dimethyl formamide, ethyl acetate, methylene dichloride or chloroform; Described acyl group protecting group reagent is as the defined R of claim 1
1The corresponding acylating agent of group.
6, method according to claim 1 is characterized in that wherein said selectivity hydroxyl protection method comprises to get N-R
1-2 '-Deoxyribose cytidine 3 in organic solvent at the same time or separately with as the defined R of claim 1
2, R
3The corresponding sulfonyl agent reaction of protecting group obtains N-R
1-5 '-R
2-3 '-R
3-2 '-Deoxyribose cytidine 4.
7, method according to claim 1 is characterized in that wherein said selectivity deoxidation deprotection method comprises N-R
1-5 '-R
2-3 '-R
3-2 '-Deoxyribose cytidine 4 adds alkali in reaction solvent, the alkylsulfonyl and the 5 ' acyl group that remove 3 ' generate N-R
1-2 ', 3 '-dehydrogenation-2 ', 3 '-dideoxycytidine 5;
Wherein said reaction solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, DMF or DMSO; Alkali is selected from sodium methylate, sodium ethylate, dimethylamine agueous solution, diethylamine, triethylamine or pyridine.
8, method according to claim 1 is characterized in that wherein said deaminizating guard method comprises, gets N-R
1-2 ', 3 '-dehydrogenation-2 ', 3 '-dideoxycytidine 5 are suspended in an amount of polar solvent, get 2 ', 3 '-dehydrogenation, 2 ', 3 '-dideoxycytidine 6 after reacting with base catalysis;
Wherein said solvent is selected from methyl alcohol, ethanol, DMSO, DMF or N,N-dimethylacetamide; Alkali is selected from sodium methylate, sodium ethylate, triethylamine, hexahydropyridine, pyridine or OH type anionite-exchange resin.
9, method according to claim 1 is characterized in that wherein said catalytic hydrogenation is that 2 ', 3 '-dehydrogenation, 2 ', 3 '-dideoxycytidine 6 adopts normal pressure or pressure hydration, gets 2 ', 3 '-dideoxycytidine I behind the recrystallization purifying; Wherein the solvent of hydrogenation adopts water, methyl alcohol or ethanol, and the catalyzer of pressure hydration adopts Pd-C, Raney Ni or PtO
2
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999029702A2 (en) * | 1997-12-10 | 1999-06-17 | The Government Of The United States Of America Reppresented By The Secretary, Department Of Health And Human Services | METHOD FOR SYNTHESIZING 9-(2,3-DIDEOXY-2-FLUORO-β-D-THREO-PENTOFURANOSYL)ADENINE (β-FddA) |
| WO2001030791A2 (en) * | 1999-10-25 | 2001-05-03 | Samchully Pharm. Co., Ltd. | Method for the preparation of 2',3'-didehydro-2',3'-dideoxycytidine derivatives |
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2004
- 2004-01-17 CN CNB200410015900XA patent/CN100334101C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999029702A2 (en) * | 1997-12-10 | 1999-06-17 | The Government Of The United States Of America Reppresented By The Secretary, Department Of Health And Human Services | METHOD FOR SYNTHESIZING 9-(2,3-DIDEOXY-2-FLUORO-β-D-THREO-PENTOFURANOSYL)ADENINE (β-FddA) |
| WO2001030791A2 (en) * | 1999-10-25 | 2001-05-03 | Samchully Pharm. Co., Ltd. | Method for the preparation of 2',3'-didehydro-2',3'-dideoxycytidine derivatives |
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