CN104327138B - Preparation method of PSI-7977 intermediate compound - Google Patents
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- MNRRCDXNIXSJKL-IHWYPQMZSA-N CC(NC(/C=C\N)=O)=O Chemical compound CC(NC(/C=C\N)=O)=O MNRRCDXNIXSJKL-IHWYPQMZSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention belongs to the technical field of a medicine, and in particular relates to a preparation method for synthesizing a PSI-7977 intermediate compound. The method disclosed by the invention has the advantages of being simple to operate, mild in reaction condition, easy in post-treatment, short in reaction cycle, high in yield, and safe and controllable, and the prepared intermediate compound I has the advantages of high optical purity and stable nature; and the preparation method is more suitable for industrial scaled production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to one kind is used to synthesize anti-hepatitis C medicine rope fluorine cloth Wei (PSI-
7977) preparation method of midbody compound.
Background technology
Hepatitis C viruss (HCV) infection is a serious worldwide health problem.Estimate according to current World Health Organization (WHO)
Meter, it is chronic infection that the whole world there are about 1.7 hundred million people (accounting for the 3% of population in the world), and develops into liver cirrhosis or hepatocyte
The danger of cancer.Hepatitis C viruss were found in May, 2011, global neither one is for hepatitis C from research worker in 1989
Medicine, clinically can only with broad-spectrum antiviral effect alpha-interferon and ribavirin therapy hepatitis C.Though
So the drug combination of alpha-interferon and ribavirin has certain curative effect to treating hepatitis C, has saved many hepatitis C virus
The life of malicious patient, but the lasting antiviral response ratio of patient has much room for improvement, it is impossible to meet clinical needs.
In May, 2011, FDA (Food and Drug Adminstration) (FDA) successively have approved for La Puwei (Telaprevir) and ripple
Puri Wei (Boceprevir) is used as the medicine for treating hepatitis c, lasting antiviral response of both medicines patient
Ratio brings up to 60%～70% from the 40%～50% of alpha-interferon/ribavirin, but still can not cure hepatitis C.
Rope fluorine cloth Wei (also known as PSI-7977, English name Sofosbuvir), chemical name：(2S,3R)-3-[(4R)-2,
2- dimethyl-[1,3]-dioxolanyl -4] -2,3- dihydroxy -2 Methylpropionic acid ethyl ester, Shi Ji Leadd B.V is for the third type liver
A kind of uracil nucleotides of scorching virus exploitation are successfully listed in December, 2013 like thing AG14361 in the U.S.,
The treatment of the chronic destructive infection being mainly used in caused by hepatitis C virus.The medicine replicates necessary a kind of by blocking virus
Albumen with excellent anti-HCV activity, without the need for the auxiliary treatment of interferon, and can completely cure hepatitis C playing a role,
Practical benefits are brought for patient.
(2'R) the fluoro- 2'- MUs glycosides of -2'- deoxidations -2'- is the key intermediate for preparing rope fluorine cloth Wei (PSI-7977),
With the chemical constitution shown in Formulas I.
At present the preparation method of the intermediate of document report mainly has following several：Document (Nucleosides,
Nucleotides and Nucleic Acids, 2011, vol.30, #11, p.886-896) report as shown in Scheme 1
(2'R) preparation method of the fluoro- 2'- MUs glycosides of -2'- deoxidations -2'-, the route has good stereo selectivity, but reacts
Route length, yield are low, and operating process is loaded down with trivial details, be not suitable for commercial production.
At present application it is wider for route 2 (WO2006/031725, WO2008/045419 and J.Med.Chem.2010,
53,7202-7218), the route is relatively short, but response time length, reaction temperature height, condition are more harsh, and process is loaded down with trivial details, no
Beneficial to large-scale production.
The content of the invention
In view of the foregoing defects the prior art has, the present invention provides a kind of safely controllable, easily operated, product yield
It is high, purity is good, reaction condition is gentle, the fluoro- 2'- MUs glycosides of (2'R) -2'- deoxidation -2'- of suitable scale industrial production
Preparation method, the fluoro- 2'- MUs glycosides of gained (2'R) -2'- deoxidation -2'- has higher optical purity.
The present invention provides a kind of method for preparing midbody compound shown in Formulas I, and the method is by compound IV and chemical combination
Thing III reacts under stannic chloride catalysis and obtains midbody compound II, and then compound II deprotections base R obtains Formulas I institute
The midbody compound for showing.Specifically, the method is comprised the following steps：
(1) in the presence of butter of tin, compound III and compound IV reacts, and obtains compound II；
(2) compound II deprotections base R obtains the midbody compound shown in Formulas I；
Wherein, R is hydroxy-protective group, independently selected from acetyl group (Ac), benzyl (Bn), benzoyl (Bz), preferably
Benzoyl (Bz), acetyl group (Ac), more preferably benzoyl (Bz)；
L is leaving group, selected from acetoxyl group (AcO), benzoyloxy (BzO), mesyloxy (MsO), toluene sulphur
Acyloxy (OTs), bromine (Br), chlorine (Cl), preferred chlorine.
The molar ratio of compound III and compound IV is 1 in step (1)：0.8～1.5, preferably 1：1～1.5, more
It is preferred that 1：1～1.2；Compound III is 1 with the mass volume ratio (g/ml) of butter of tin：0.5～0.8, preferably 1：0.6；Reaction
Temperature is 40～80 DEG C, preferably 50～70 DEG C, more preferably 60～65 DEG C；Response time is 5～25h, preferably 10～20h.
Blocking group R is removed in following dicyandiamide solution in step (2)：The alcoholic solution of sodium alkoxide, the alcoholic solution of alkylamine, nothing
The aqueous solution of machine alkali, the sodium alkoxide is selected from Feldalat NM, Sodium ethylate, sodium tert-butoxide；The alcoholic solution is molten selected from methanol solution, ethanol
Liquid；The inorganic base is selected from NaOH, KOH, Na2CO3、K2CO3；Reaction temperature is -5～10 DEG C, preferred -5～5 DEG C, more preferably 0
～5 DEG C.
The step of one embodiment of the invention in (1), first compound III is dissolved in into reaction dissolvent I, adds four chlorinations
Stannum, adds compound IV；One kind in acetonitrile, 1,2- dichloroethanes, dichloromethane, the chlorobenzene of the reaction dissolvent I or
It is various, preferred chlorobenzene.
The step of a preferred embodiment of the present invention in (1), first compound III is dissolved in chlorobenzene, be as cold as to 0～
5 DEG C, butter of tin is added, then the chlorobenzene solution of Deca compound IV, after completion of dropping, reacting by heating, TLC shows compound
III reactions are complete, are cooled to room temperature, add dchloromethane reactant liquor, and sodium bicarbonate and diatom are added in the solution
The dichloromethane suspension of soil.Water is slowly added to so that reaction is quenched, is filtered after being stirred at room temperature, compound is obtained after filtration cakes torrefaction
II。
The step of one embodiment of the invention in (2), blocking group R is removed in following dicyandiamide solution：Feldalat NM
Methanol solution, the ethanol solution of Sodium ethylate, the methanol solution of the methyl amine of methanol, the ethanol solution of butylamine, the methanol of ammonia
The methanol solution of solution, ammonia, protection group R group is in following solvent body in another preferred embodiment of the present invention step (2)
Remove in system：Mass fraction is the methanol solution of 25% ammonia (or ammonia).
In a preferred embodiment of the present invention step (2), compound II is dissolved in into the methanol solution (quality point of ammonia
Number for 15～40%), and maintain 0～5 DEG C to stir 2 hours, then heat to be stirred at room temperature 24 hours, filter, filtrate decompression is dense
Contracting, is beaten with ethyl acetate, obtains midbody compound I.
Alternatively, the preparation method of above-mentioned midbody compound I also includes to (3) the step of prepare compound IV, should
Step with uracil (SM1) as initial reactant, with hmds (HMDS) reactionization under the catalysis of ammonium sulfate
Compound IV, specifically：
(3) in the presence of ammonium sulfate, uracil (SM1) obtains compound IV with hmds (HMDS) reaction；
Wherein, ammonium sulfate is catalytic amount, preferably the 0.1～5% of uracil quality or 0.2～3%, more preferably
0.3～0.6%；
Uracil in step (3) is 1 with the mass volume ratio (g/ml) of HMDS：5～15, preferably 1：8～12, more preferably
1：10；Reaction temperature is 50～150 DEG C, preferably 60～130 DEG C, more preferably 80～120 DEG C.
More specifically, in an optimal technical scheme of the present invention, the preparation method bag of compound shown in described Formulas I
Containing following steps：
(1) compound III is dissolved in chlorobenzene, is as cold as to 0～5 DEG C, add butter of tin, then Deca compound IV
Chlorobenzene solution, after completion of dropping, reacting by heating, TLC shows that compound III reactions are complete, is cooled to room temperature, adds dichloromethane
Dilute reaction solution, and sodium bicarbonate and diatomaceous dichloromethane suspension are added in the solution, it is slowly added to water to be quenched
Reaction, filters after being stirred at room temperature, and compound II is obtained after filtration cakes torrefaction；
(2) compound II is dissolved in the methanol solution (mass fraction is 15～40%) of ammonia, maintains 0～5 DEG C of stirring 2 little
When, then heat to be stirred at room temperature 24 hours, to filter, filtrate concentration is beaten with ethyl acetate, obtains midbody compound I；
Wherein, R is selected from benzoyl (Bz), acetyl group (Ac), and L is chlorine.
In the present invention, if no special instruction is made, the consumption and organic base of the reaction dissolvent, the consumption of inorganic base are
The conventional amount used of reaction, those skilled in the art can determine that according to prior art；Alternatively, in an optimal technical scheme
In, any of the above-described step reaction can be protected independently using nitrogen or argon.
The reagent that the present invention is used is conventional reagent, can be commercially available by market, initiation material used and reaction
Thing can be prepared by prior art or disclosed existing document, it is also possible to be commercially available by market, such as uracil
Can be commercially available from Shanghai Yuan Ju bio tech ltd, hmds (HMDS) can be polymerized to million industry from Guangzhou
Organosilicon materials company limited is commercially available, and compound IV can be by purchase or according to embodiments of the present invention 1-2 is prepared.
In the present invention, " compound I " has identical with " compound shown in Formulas I " or " midbody compound shown in Formulas I "
Implication；" compound II " has identical implication with " compound shown in Formula II " or " midbody compound shown in Formula II "；" chemical combination
Thing III " has identical implication with " compound shown in formula III " or " midbody compound shown in formula III "；" compound IV " with
" compound shown in formula IV " or " midbody compound shown in formula IV " has identical implication；- OTMS refers to trimethyl in formula IV
Siloxy.
The method of compound shown in the preparations Formulas I that the present invention is provided has simple to operate, reaction condition is gentle, be easy to after place
Reason, short reaction time, high income, safely controllable advantage, the compound I of gained has optical purity high, and stable in properties is excellent
Point, up to more than 87%, optical purity is more suitable for industrial-scale production to yield up to 99.7%.
Specific embodiment
Below by way of specific embodiment, the above of the present invention is described in further detail, but should not be by
This is interpreted as any restriction to subject matter of the present invention.All technical schemes realized based on the above of the present invention are belonged to
The scope of the present invention.The present invention to used in test to material and test method carry out generality and/or specifically retouch
State.It will be apparent to those skilled in the art that hereinafter, if not specified, the operation that the present invention is carried out is this area routine
Room temperature condition under carry out, the room temperature has art-recognized meanings well known in the art, generally refers to 20～35 DEG C, preferably 20～30
DEG C, more preferably 20～25 DEG C.
The preparation of embodiment 1,2,4- bis- (three silyloxies) pyrimidine
Under nitrogen protection, 3.0g uracil (SM1) is added into 30ml hmds (HMDS), be subsequently adding 70mg sulfur
Sour ammonium, is heated to reflux clear (about 1 hour) molten to solution, it is molten it is clear after insulation reaction 1 hour again, be then cooled to 70 DEG C, decompression
Unreacted hmds is evaporated off, title compound 6.7g is obtained, without the need for purification the next step is directly used in.
The preparation of embodiment 2,2,4- bis- (three silyloxies) pyrimidine
Under nitrogen protection, 30g uracil (SM1) is added into 250ml hmds (HMDS), be subsequently adding 0.9g sulfur
Sour ammonium, is heated to reflux clear (about 1 hour) molten to solution, it is molten it is clear after insulation reaction 1 hour again, be then cooled to 70 DEG C, decompression
Unreacted hmds is evaporated off, title compound 67.8g is obtained, without the need for purification the next step is directly used in.
Embodiment 3, the fluoro- 2'- methyluridines -3' of (2'R) -2'- deoxidation -2'-, 5'- dibenzoates (compound II)
Prepare
Under nitrogen protection, 1g compound III-1 are dissolved in the chlorobenzene of 10ml, are as cold as to 0 DEG C, add 0.6ml butters of tin,
Then chlorobenzene (10ml) solution of Deca 1g compound IV, after completion of dropping, is heated to 70 DEG C and reacts 20 hours, TLC displayizations
Compound III-1 reactions are complete, are cooled to room temperature, add 50ml dichloromethane, and add in the solution sodium bicarbonate (10g) and
Dichloromethane (20ml) suspension of kieselguhr (5g).It is slowly added to 20ml water and 30min is stirred at room temperature so that reaction is quenched, then,
Filter, filter cake dichloromethane wash, obtain 0.77g pale solids, yield 87.7% after drying.
Embodiment 4, the fluoro- 2'- methyluridines -3' of (2'R) -2'- deoxidation -2'-, the preparation of 5'- diacetate esters
Under nitrogen protection, 10g compound III-2 are dissolved in the chlorobenzene of 100ml, are as cold as to 0 DEG C, add the chlorinations of 5ml tetra-
Stannum, then the chlorobenzene solution (100ml) of Deca 10g compound IV, after completion of dropping, is heated to 65 DEG C and reacts 20 hours, and TLC shows
Show that compound III-2 reactions are complete, be cooled to room temperature, add 300ml dichloromethane, and sodium bicarbonate is added in the solution
(100g) with dichloromethane (200ml) suspension of kieselguhr (50g).200ml water is slowly added to so that reaction is quenched, then room temperature
Stirring 30min, filters, and filter cake is washed with dichloromethane, and after being dried 11.2g pale solids, yield 87.5% are obtained.
The preparation of embodiment 5, the fluoro- 2'- methyluridines of (2'R) -2'- deoxidation -2'- (midbody compound I)
At 0 DEG C, the fluoro- 2'- methyluridines 3' of (2'R) -2'- deoxidation -2'- that embodiment 3 is prepared, 5'- hexichol
Formic acid esters 0.6g be dissolved in 25% ammonia methanol solution (10ml, mass fraction be 25%), and maintain 0 DEG C stir 3 hours, then
It is warming up to 15 DEG C to stir 24 hours, filters, filtrate reduced in volume, be beaten with ethyl acetate, obtains 0.31g white solids, yield
94%, optical purity 99.8%, MS (m/z)：[M+H]+261.1。
The preparation of embodiment 6, the fluoro- 2'- methyluridines of (2'R) -2'- deoxidation -2'- (midbody compound I)
At 5 DEG C, embodiment 4 is prepared into the fluoro- 2'- methyluridines 3' of (2'R) -2'- deoxidation -2'-, 5'- oxalic acid
Ester 3g be dissolved in ammonia methanol solution (20ml, mass fraction be 25%), and maintain 5 DEG C stir 2 hours, then heat to 25 DEG C
Stirring 24 hours, filters, filtrate reduced in volume, is beaten with ethyl acetate, obtains 2.1g white solids, yield 92.5%, optics
Purity 99.7%, MS (m/z)：[M+H]+261.1。
The stability test of embodiment 7, midbody compound I
Example 5, embodiment 6 prepare midbody compound I samples and are individually positioned under conditions of 35 DEG C, investigate
In the stability of 10d, 20d, 30d, the method for specific study on the stability is referred to second annex of Chinese Pharmacopoeia 2010 edition
The method of XIX C；Purity detecting HPLC methods, are referred to the method for second annex V D of Chinese Pharmacopoeia 2010 edition.As a result see
Table 1.
The stability test result of the midbody compound I of the present invention of table 1.
The midbody compound I for preparing of the invention can be seen that by above-mentioned experiment there is good chemical stability.
Claims (15)
1. the preparation method of one kind fluoro- 2'- MUs glycosides of (2'R) -2'- deoxidation -2'-, the method includes the steps of：By chemical combination
Thing III is dissolved in chlorobenzene, is cooled to 0～5 DEG C, adds butter of tin, then the chlorobenzene solution of Deca compound IV, completion of dropping
Afterwards, reacting by heating, TLC shows that compound III reactions are complete, is cooled to room temperature, adds dchloromethane reactant liquor, and to this
Sodium bicarbonate and diatomaceous dichloromethane suspension are added in solution, water is slowly added to so that reaction is quenched, mistake after being stirred at room temperature
Filter, obtains compound II after filtration cakes torrefaction；
Wherein, R is hydroxy-protective group, independently selected from acetyl group, benzyl, benzoyl；
L is leaving group, selected from acetoxyl group, benzoyloxy, mesyloxy, tosyloxy, bromine, chlorine.
2. preparation method according to claim 1, R is selected from benzoyl, acetyl group, and L is chlorine.
3. preparation method according to claim 1, it is characterised in that the molar ratio of compound III and compound IV
For 1：0.8～1.5；Compound III is 1 with the mass volume ratio of butter of tin：0.5～0.8, unit：g/ml；Reaction temperature is
40～80 DEG C；Response time is 5～25h.
4. preparation method according to claim 1, it is characterised in that the molar ratio of compound III and compound IV
For 1：1～1.5.
5. preparation method according to claim 1, it is characterised in that the molar ratio of compound III and compound IV
For 1：1～1.2.
6. preparation method according to claim 1, it is characterised in that the mass volume ratio of compound III and butter of tin
For 1：0.6, unit：g/ml.
7. preparation method according to claim 1, it is characterised in that reaction temperature is 50～70 DEG C.
8. preparation method according to claim 1, it is characterised in that reaction temperature is 60～65 DEG C.
9. preparation method according to claim 1, it is characterised in that the response time is 10～20h.
10. preparation method according to claim 1, it is characterised in that the method also includes following step：Compound II takes off
The midbody compound shown in Formulas I is obtained except protection group R；
Wherein, R has claim 1 identical implication.
11. preparation methoies according to claim 10, it is characterised in that removed in following dicyandiamide solution：Sodium alkoxide
Alcoholic solution, the alcoholic solution of alkylamine, the aqueous solution of inorganic base；The sodium alkoxide is selected from Feldalat NM, Sodium ethylate, sodium tert-butoxide；Institute
Alcoholic solution is stated selected from methanol solution, ethanol solution；The inorganic base is selected from NaOH, KOH, Na2CO3、K2CO3。
12. preparation methoies according to claim 10, it is characterised in that reaction temperature is -5～10 DEG C.
13. preparation methoies according to claim 10, it is characterised in that reaction temperature is -5～5 DEG C.
14. preparation methoies according to claim 10, it is characterised in that reaction temperature is 0～5 DEG C.
The preparation method of the fluoro- 2'- MUs glycosides of (2'R) -2'- deoxidation -2'- shown in a kind of 15. Formulas I, the method is comprising following
Step：
(1) compound III is dissolved in chlorobenzene, is cooled to 0～5 DEG C, add butter of tin, then the chlorobenzene of Deca compound IV
Solution, after completion of dropping, reacting by heating, TLC shows that compound III reactions are complete, is cooled to room temperature, adds dchloromethane
Reactant liquor, and sodium bicarbonate and diatomaceous dichloromethane suspension are added in the solution, water is slowly added to so that reaction is quenched,
Filter after being stirred at room temperature, compound II is obtained after filtration cakes torrefaction；
(2) compound II is dissolved in the methanol solution of ammonia, maintains 0～5 DEG C to stir 2 hours, then heat to be stirred at room temperature 24
Hour, to filter, filtrate concentration is beaten with ethyl acetate, obtains midbody compound I；
Wherein, R is selected from benzoyl, acetyl group, and L is chlorine；
The mass fraction of ammonia is 15～40% in the methanol solution of ammonia.
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| CN104710491A (en) * | 2015-02-06 | 2015-06-17 | 宁波九胜创新医药科技有限公司 | Preparation method for (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine |
| CN106146586A (en) * | 2015-04-09 | 2016-11-23 | 厦门蔚扬药业有限公司 | The preparation method of (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine, 3 ', 5 '-dibenzoate |
| ITUB20161079A1 (en) | 2016-02-25 | 2017-08-25 | Hc Pharma Ag | PROCEDURE FOR THE PREPARATION OF SOFOSBUVIR |
| CN105859811A (en) * | 2016-05-05 | 2016-08-17 | 精华制药集团南通有限公司 | Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine |
| CN107200757B (en) * | 2017-06-29 | 2020-06-02 | 上海泓博智源医药股份有限公司 | Bridged fluorinated ester and preparation method and application thereof |
| CN111606961A (en) * | 2019-02-26 | 2020-09-01 | 顾世海 | Process production method of (2 'R) -2' -deoxy-2 '-fluoro-2' -methyluridine |
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