5/22/2021 CN102127136 Method for preparing important intermediate of cytidine and analogues thereof

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1. CN102127136-METHOD FOR PREPARING

IMPORTANT INTERMEDIATE OF CYTIDINE AND
ANALOGUES THEREOF
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[ZH]

A method for preparing important intermediates of

cytidine and its analogues

Technical field
The invention relates to a method for producing important intermediates of cytidine and its analogs by
chemical synthesis.
Background technique
Cytosine and its analogues are mainly used to produce intermediates of anti-tumor and antiviral drugs,
and are used to produce cytarabine (Ara-CR), cyclocytidine (Cyclo C), cytidine triphosphate (CTP), The main
raw material of drugs such as CDP-Choline. The development of cytidine products can provide sufficient raw
materials for a series of cytidine drugs and biochemical reagents, and play a certain role in promoting the
development of genetic engineering and the pharmaceutical industry.
In the chemical synthesis of cytosine nucleosides and their analogs, glycosylation is a key step in the
synthesis process.
European patent EP 0136693 reports the use of Lewis acid as a catalyst to prepare cytidine and its
derivatives. Its characteristic is that SnCl 4 , TMSOTf is a catalyst to catalyze the condensation of amino
hydrogen protected cytosine and glycosyl to obtain cytosine nucleosides. However, this method has a low
yield and cannot be industrialized.
Vorbruggen H et al. prepared cytidine by condensation of fully silylated cytosine and 1-2,3,5-
tribenzoylribose under the action of Lewis acid and deprotection.
The above two methods of preparing cytosine use Lewis acid as catalyst, generally SnCl 4 Or TMSOTf,
but these two catalysts are expensive and the production cost is higher.
Summary of the invention
The purpose of the present invention is to provide a method for synthesizing important intermediates
(compound I) of cytidine and its analogs with mild reaction conditions and low cost. It includes the following
steps: the compound of formula II and the compound of formula III are reacted in an organic solvent,
catalyzed by alkali metal halide, at a certain temperature to obtain the compound of formula I.

Among them, compound II is a carbohydrate derivative, and the P can be H or OR 1 , R 1 It is a hydroxyl

protecting group. When P is H, compound II is a deoxyribose derivative, when P is OR 1 When, compound II
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5/22/2021 CN102127136 Method for preparing important intermediate of cytidine and analogues thereof

is a ribose derivative. Compound III is a protected cytosine base.

The R 1 , R 2 , R 3 It is independently selected from C1-C4 alkane acyl or substituted aryl formyl,
preferably, acetyl benzoyl, p-toluoyl, p-nitro benzoyl, bibenzoyl or phenyl with halogen ( (Fluorine, chlorine,
bromine, iodine) substituted benzoyl.
In the present invention, L is a leaving group, selected from halogen, C1-C4 alkane acyl group, C1-C4
alkane sulfonyloxy group, arylsulfonyloxy group, substituted alkylsulfonyloxy group or substituted aryl group
Sulfonyloxy, preferably, chlorine, bromine, iodine, acetyl, methanesulfonyloxy, ethanesulfonyloxy,
toluenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy base.
In the present invention, R 4 It is a silicon protecting group, selected from C1-C7 trialkylsilyl groups, and
the C1-C7 trialkylsilyl groups can be trimethylsilyl, isopropyldimethylsilyl, methyldiisopropyl Silyl group,
triisopropylsilyl group, tert-butyldimethylsilyl group, etc.
The organic solvent in the present invention is selected from nitriles, halogenated hydrocarbons, aromatic
hydrocarbons, ethers and other inert solvents, preferably acetonitrile, 1,2-dichloromethane, toluene, xylene,
substituted benzene, anisole One or more of, diphenyl ether, or substituted diphenyl ether.
The alkali metal halide in the present invention is selected from potassium fluoride, sodium fluoride,
lithium chloride, lithium bromide, lithium iodide, potassium iodide, sodium iodide, sodium bromide,
potassium bromide, cesium chloride, cesium iodide, etc. .
The molar ratio of the compound of formula II to the compound of formula III in the present invention is
1:1 to 1:35, preferably 1:2 to 1:15.
Among them, the molar ratio of the alkali metal halide to the compound of formula II is 1:1 to 1:16,
preferably 1:1 to 1:8.
The reaction temperature is 50 to 200°C, preferably 70 to 100°C; the reaction time is 5 to 48 hours,
preferably 10 to 30 hours.
The method of the present invention abandons expensive catalysts and reduces costs; the reaction
conditions are mild and the post-treatment is simple; all mild reagents are used for easy recovery, the process
is environmentally friendly, and the operation is simple and suitable for industrial production.
Detailed ways
Example 1
Preparation of compound III
Under the protection of nitrogen, add 11g of cytosine to 65ml of hexamethyldisilazane, and add 0.01g of
ammonium sulfate, heat and reflux until the solution is clear, continue to keep the reaction for 4 hours, reduce
to room temperature, and concentrate under reduced pressure to remove the excess hexamethyldisilazane.
Methyl disilazane, white solid compound III is obtained.
Example 2
Preparation of Compound I
N 2 To protect, add 100ml of 1,2-dichloroethane to compound III to make it completely dissolved, add
1.28g of NaBr, and dropwise add 5.3g (0.0125mol) of 2-deoxy-D-ribosefuran-3,5-di- A 20 ml 1,2-
dichloroethane solution of O-benzoyl-methanesulfonate compound (Compound II) (α:β=2.4:1) was dripped
and heated and refluxed until the raw material disappeared. Cool to room temperature, add 100ml of ice water
dropwise, continue to stir for 30 minutes after the dropwise addition is complete, filter with suction, and wash
the filter cake twice with 1,2-dichloroethane. The organic phase was concentrated and dried to obtain the
target compound I4.9 g, with an HPLC purity of 96.5% (α:β=1:1.5).
Example 3
N 2 For protection, 100ml of xylene was added to the compound III obtained in Example 1 to make it
completely dissolved, 2.8g of KBr was added, and 4.86g of 2-deoxy-3,5-di-oxy-p-toluoyl-D-ribose was added
dropwise Furan-1-chloride (compound II) (α:β=1:1) in 20 ml of xylene solution was dripped and heated and
refluxed until the raw material disappeared. Cool to room temperature, add 65ml of ice water dropwise,
continue to stir for 30 minutes after the dropwise addition is complete, filter with suction, and wash the filter
cake twice with 1,2-dichloroethane. The organic phase was concentrated and dried to obtain 4.9 g of target
compound I with a purity of 96.6% by HPLC (α:β=1.4:1).
Example 4
N 2 To protect, add 80ml of acetonitrile to the compound III obtained in Example 1 to completely dissolve
it, add 3.8g of NaI, and dropwise add 4.0g of tetraacetyl ribose (compound II) (α:β=3:1) in 20ml of acetonitrile
The solution is heated and refluxed after dripping until the raw material disappears. Cool down to room
temperature, add 500 ml of ice water dropwise, continue to stir for 30 minutes after the dropwise addition is
completed, filter with suction, and rinse the filter cake twice with acetonitrile. The organic phase was
concentrated and dried to obtain 4.2 g of target compound I with an HPLC purity of 93.5% (α:β=1:2.0).
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5/22/2021 CN102127136 Method for preparing important intermediate of cytidine and analogues thereof

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