CN105566422B - The preparation method of Suo Feibuwei intermediate or derivatives thereof - Google Patents
The preparation method of Suo Feibuwei intermediate or derivatives thereof Download PDFInfo
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- CN105566422B CN105566422B CN201511017496.4A CN201511017496A CN105566422B CN 105566422 B CN105566422 B CN 105566422B CN 201511017496 A CN201511017496 A CN 201511017496A CN 105566422 B CN105566422 B CN 105566422B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a kind of preparation method of Suo Feibuwei intermediate or derivatives thereof, formula 3 and 6 compound of formula react 1 compound of the formula of being prepared with base catalyst DBU or DMAP at 20~70 DEG C.Operation of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention provides the new preparation methods of a kind of Suo Feibuwei intermediate and its derivative (1 compound of formula), belong to
In field of medicine and chemical technology.
Background technique
Suo Feibuwei (and being translated into rope fluorine cloth Wei, English name Sofosbuvir, trade name Sovaldi) is that lucky Leadd B.V opens
Hair is ratified in 6 Nikkei U.S. Food and Drug Administration (FDA) December in 2013 in beauty in the new drug for the treatment of chronic hepatitis C
State's listing, the approval of 16 Nikkei Europe drug administration (EMEA) January in 2014 are listed in EU countries.Also not in Discussion on Chinese Listed.
The drug is the first drug that certain type hepatitis can be safely and effectively treated without joint interferon.Clinical test
It confirms to be directed to 1 and 4 type hepatitis, the overall continued viral response rate of the medication combined Peg-IFN alpha-2b and Ribavirin
(SVR) it is up to 90%；For 2 type hepatitis, the SVR of the medication combined Ribavirin is 89%-95%；For 3 type hepatitis, the medicine
The SVR that Internet of Things close Ribavirin is 61%-63%.It is noted that the clinical test of Suo Feibuwei further comprises some third
Liver merges the patient of cirrhosis, and curative effect is also more significant, thus for the research of the medicine also increasingly by numerous concerns.
Patent WO2008/45419 discloses a kind of synthetic method of Suo Feibuwei intermediate, wherein relates to described
The preparation method of 1 compound of formula, key step are as follows:
The technique is respectively synthesized 4 compound of formula 5 and formula using formula 2 and 3 compound of formula as raw material, further in anhydrous tetrachloro
Change and is condensed to yield 1 compound of formula under tin effect, which uses tin tetrachloride this substance, and not only price is more expensive, but also
The stanniferous waste water generated is very difficult, and environmental protection pressure is big, and the product impurity that the technique obtains is more, and easy purification, does not lead
Cause 1 compound cost of target product formula very high, cost pressure is huge.
Summary of the invention
The purpose of the present invention is being directed to the deficiency of prior art, we have invented a kind of formula 1 by a large amount of experiment effort
The new preparation method of compound, the method is easy to operate, is suitble to industrialized production.
The purpose of the present invention can be achieved by the following measures:
The preparation method of a kind of Suo Feibuwei intermediate and its derivative, formula 3 and 6 compound of formula and base catalyst DBU or
DMAP reacts at 20~70 DEG C is prepared 1 compound of formula,
Wherein, R1、R2For the benzoyl group for replacing or not replacing.
In above-mentioned each compound, R1、R2The benzoyl group that can replace for groups such as the alkyl of C1~4, halogen, nitros,
It may be the benzoyl group of unsubstituted, preferably benzoyl group.
Formula 3 and 6 compound of formula it is anti-employed in base catalyst be DBU or DMAP, wherein DBU (1,8- diazabicylo
11 carbon -7- alkene) structure beThe structure of DMAP (4-dimethylaminopyridine) isBase catalyst
Dosage be 6 compound quality of formula 5~25%, preferably 10~20%.
Formula 3 and the solvent of 6 compound of formula reaction are selected from ethyl acetate, acetonitrile, THF, toluene, dimethylbenzene or methyl tertbutyl
Ether, preferably toluene, dimethylbenzene or ethyl acetate.
In the present invention, temperature condition appropriate can also promote reaction quick progress, suitable reaction temperature be 40~
70℃。
In the present invention, formula 3 and 6 compound of formula feed intake according to a certain percentage, in general formula 3 and formula 6 compound
Molar ratio can be 1:0.1~10.0, and optimum ratio is 1:0.5~3.0.
6 compound of formula in the present invention can be esterified by 2 compound of formula with mesyl chloride under alkaline condition to be prepared；
Wherein, R1、R2It is as defined above.
The reaction dissolvent of 6 compound of preparation formula is methylene chloride, ethyl acetate or toluene, and used alkali is selected from three second
Amine, N- methyl piperidine, pyridine, potassium carbonate, sodium carbonate, saleratus or sodium bicarbonate, preferably triethylamine, potassium carbonate or carbonic acid
Sodium.Can specifically prepare by the following method: it (can be methylene chloride, ethyl acetate, first that 2 compound of formula, which is dissolved in solvent,
The Conventional solvents such as benzene) in, a certain amount of inorganic or organic base is added as acid binding agent, controls certain temperature, is slowly added to
Mesyl chloride.It is layered after water stirring is added after reaction, organic layer is concentrated to dryness to obtain 6 compound of formula.
Beneficial effects of the present invention: it in the present invention, is first reacted with mesyl chloride using 2 compound of formula and activity is prepared
6 compound of ester formula further reacts to obtain 1 compound of formula with 3 compound of formula, and mild condition, operation is simple, step letter
Short, with short production cycle, conversion rate of products is high, is suitable for mass production.
Specific embodiment
The present invention will be described in detail referring to following non-limiting examples, this is not necessarily to be construed as the range of limitation invention
Embodiment 1:((2R, 3R, 4R) the fluoro- 5- mesyloxy -4- methyltetrahydrofuran-of -3- (benzoyloxy) -4-
2- yl) methyl benzoate preparation
(the fluoro- 5- hydroxy-4-methyl tetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyloxy) -4-) methyl benzoate
37.2g and 300ml methylene chloride is put into bottle, and triethylamine 15g is added, and mesyl chloride 13g is slowly added dropwise, and drop, which finishes, is stirred at room temperature 4-
5 hours, stop reaction, is layered after the stirring of 100ml water is added, organic layer is concentrated to dryness after being washed with saturated brine and is produced
6 compound 42.5g, HPLC purity 96% of product formula.
Embodiment 2:(2'R) fluoro- 2'- methylcytidine 3', 5'- the dibenzoate system of-N- benzoyl -2'- deoxidation -2'-
It is standby
By in the product being prepared in 40g embodiment 1 and 500ml ethyl acetate investment bottle, benzoyl cytosine is added
(3 compound of formula) 22g and 8gDBU is heated to 65 DEG C and stirs 3 hours, stop reaction, water 150ml is added, uses ethyl acetate
100ml*2 is extracted twice, and merges organic layer, saturated salt solution 100ml washing, after the drying of 10g anhydrous sodium sulfate is added in organic layer
It filters, filtrate decompression is concentrated to dryness, and residue is added first alcohol crystallization and obtains product (2'R)-N- benzoyl -2'- deoxidation -
Fluoro- 2'- methylcytidine 3', 5'- dibenzoate 32.9g, the HPLC purity 97% of 2'-.
Embodiment 3:(2'R) fluoro- 2'- methylcytidine 3', 5'- the dibenzoate system of-N- benzoyl -2'- deoxidation -2'-
It is standby
By in the product being prepared in 40g embodiment 1 and 600ml ethyl acetate investment bottle, benzoyl cytosine is added
(3 compound of formula) 25g and 9gDBU is heated to 64 DEG C and stirs 3 hours, stop reaction, water 150ml is added, uses ethyl acetate
100ml*2 is extracted twice, and merges organic layer, saturated salt solution 100ml washing, after the drying of 10g anhydrous sodium sulfate is added in organic layer
It filters, filtrate decompression is concentrated to dryness, and residue is added first alcohol crystallization and obtains product (2'R)-N- benzoyl -2'- deoxidation -
Fluoro- 2'- methylcytidine 3', 5'- dibenzoate 33.2g, the HPLC purity 97% of 2'-.
Claims (2)
1. a kind of preparation method of Suo Feibuwei intermediate, it is characterised in that include the following steps:
(1), (the fluoro- 5- mesyloxy -4- methyltetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzene first
Sour methyl esters preparation: (the fluoro- 5- hydroxy-4-methyl tetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzoic acid
Methyl esters 37.2g and 300ml methylene chloride is put into bottle, and triethylamine 15g is added, and mesyl chloride 13g is slowly added dropwise, and is dripped complete room temperature and is stirred
It mixes 4-5 hours, stops reaction, be layered after the stirring of 100ml water is added, organic layer is concentrated to dryness after being washed with saturated brine
To 6 compound 42.5g, HPLC purity 96% of product type；
Wherein, R1And R2For benzoyl group；
(2), fluoro- 2'- methylcytidine 3', the 5'- dibenzoate preparation of (2'R)-N- benzoyl -2'- deoxidation -2'-: by 40g
In 6 compound of formula and 500ml ethyl acetate the investment bottle that step (1) is prepared, 3 compound benzoyl cytosine of formula is added
22g and 8gDBU is heated to 65 DEG C and stirs 3 hours, stop reaction, water 150ml is added, with ethyl acetate 100ml*2 extraction two
It is secondary, merge organic layer, saturated salt solution 100ml washing, organic layer filters after the drying of 10g anhydrous sodium sulfate is added, filtrate decompression
It is concentrated to dryness, residue is added first alcohol crystallization and obtains the fluoro- 2'- methyl born of the same parents of product (2'R)-N- benzoyl -2'- deoxidation -2'-
Glycosides 3', 5'- dibenzoate 32.9g, HPLC purity 97%.
2. a kind of preparation method of Suo Feibuwei intermediate, it is characterised in that include the following steps:
(1), (the fluoro- 5- mesyloxy -4- methyltetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzene first
Sour methyl esters preparation: (the fluoro- 5- hydroxy-4-methyl tetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzoic acid
Methyl esters 37.2g and 300ml methylene chloride is put into bottle, and triethylamine 15g is added, and mesyl chloride 13g is slowly added dropwise, and is dripped complete room temperature and is stirred
It mixes 4-5 hours, stops reaction, be layered after the stirring of 100ml water is added, organic layer is concentrated to dryness after being washed with saturated brine
To 6 compound 42.5g, HPLC purity 96% of product type；
Wherein, R1And R2For benzoyl group；
(2), fluoro- 2'- methylcytidine 3', the 5'- dibenzoate preparation of (2'R)-N- benzoyl -2'- deoxidation -2'-: by 40g
In 6 compound of formula and 600ml ethyl acetate the investment bottle that step (1) is prepared, 3 compound benzoyl cytosine of formula is added
25g and 9gDBU is heated to 64 DEG C and stirs 3 hours, stop reaction, water 150ml is added, with ethyl acetate 100ml*2 extraction two
It is secondary, merge organic layer, saturated salt solution 100ml washing, organic layer filters after the drying of 10g anhydrous sodium sulfate is added, filtrate decompression
It is concentrated to dryness, residue is added first alcohol crystallization and obtains the fluoro- 2'- methyl born of the same parents of product (2'R)-N- benzoyl -2'- deoxidation -2'-
Glycosides 3', 5'- dibenzoate 33.2g, HPLC purity 97%.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | The preparation nucleosides ribofuranosyl pyrimidines |
| WO2014124430A1 (en) * | 2013-02-11 | 2014-08-14 | Emory University | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
| CN104327137A (en) * | 2014-11-07 | 2015-02-04 | 王彩琴 | Deuterated Sofosbuvir and application thereof |
| CN104610404A (en) * | 2015-01-16 | 2015-05-13 | 南通常佑药业科技有限公司 | Preparation method of ribofuranose phosphate derivative |
| CN104829672A (en) * | 2015-05-19 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method of drug intermediate |
| CN105153256A (en) * | 2014-06-12 | 2015-12-16 | 上海创诺医药集团有限公司 | Preparation method for uracil fluoride nucleoside analogue |
-
2015
- 2015-12-29 CN CN201511017496.4A patent/CN105566422B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | The preparation nucleosides ribofuranosyl pyrimidines |
| WO2014124430A1 (en) * | 2013-02-11 | 2014-08-14 | Emory University | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
| CN105153256A (en) * | 2014-06-12 | 2015-12-16 | 上海创诺医药集团有限公司 | Preparation method for uracil fluoride nucleoside analogue |
| CN104327137A (en) * | 2014-11-07 | 2015-02-04 | 王彩琴 | Deuterated Sofosbuvir and application thereof |
| CN104610404A (en) * | 2015-01-16 | 2015-05-13 | 南通常佑药业科技有限公司 | Preparation method of ribofuranose phosphate derivative |
| CN104829672A (en) * | 2015-05-19 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method of drug intermediate |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.9 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |