CN106188193A - (2`R)-2`-deoxidation-2`-halo-2`-MU glycoside derivates, Preparation Method And The Use - Google Patents
(2`R)-2`-deoxidation-2`-halo-2`-MU glycoside derivates, Preparation Method And The Use Download PDFInfo
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- CN106188193A CN106188193A CN201510229252.6A CN201510229252A CN106188193A CN 106188193 A CN106188193 A CN 106188193A CN 201510229252 A CN201510229252 A CN 201510229252A CN 106188193 A CN106188193 A CN 106188193A
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- 0 C[C@]1(*)[C@](N(CCC(*)N2*)C2=O)O[C@](CO)[C@]1O Chemical compound C[C@]1(*)[C@](N(CCC(*)N2*)C2=O)O[C@](CO)[C@]1O 0.000 description 1
Classifications
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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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
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Abstract
The invention discloses compound of formula I and preparation method thereof and intermediate;Compound of formula I is for preparing the purposes for the treatment of virus infection medicine;Compound of formula I purposes in preparing rope fluorine cloth Wei and the like and use the method that compound of formula I prepares rope fluorine cloth Wei and the like.Claimed method is by designing new reaction scheme, it is to avoid the side reaction using tert-butyl group magnesium chloride to cause in phosphorus acylation reaction, decreases the impurity of generation, reduces the difficulty of follow-up purification procedures.And tests prove that, claimed method, reaction condition is gentle, it is easy to operate, and yield is high, and the product quality obtained is stable, and purity is high, can carry out commercial scale and amplify production.
Description
Technical field
The present invention relates to medicinal chemistry art, more specifically, relate to compound of formula I and preparation method thereof and intermediate, described
Compound of formula I purposes in preparation treatment virus infection medicine, described compound of formula I is preparing rope fluorine cloth Wei and class thereof
Like the purposes in thing and use the method that described compound of formula I prepares rope fluorine cloth Wei and the like.
Background technology
Rope fluorine cloth Wei (Sofosbuvir, SFBV) is developed by Pharmasset company, by Gilead Science company's continuation later stage
Exploitation.The clinic three phase result of study announced shows, uses rope fluorine cloth Wei (the most entitled GS-7977)+immunostimulant
The combination treatment of ribavirin (Ribavirin) carries out 12 weeks by a definite date to 2 types or the 3 type hepatitis C patients of Endodontic failure before
With the treatment of 16 weeks, therapeutic outcome was satisfactory.If rope fluorine cloth Wei is granted as Remedies for hepatitis C thing, then rope fluorine cloth Wei
The important component part in the first full oral combination therapy scheme of hepatitis C treatment will be become, there is cure rate high, multiple simultaneously
The advantage that the rate of sending out is low.Rope fluorine cloth Wei is a kind of prodrug, is metabolised to 2 '-deoxidation-2 in vivo '-fluoro-2 '-methyluridine-5 '-monophosphate
Ester.
The synthetic method of report rope fluorine cloth Wei is as follows at present:
At document (Journal of Organic Chemistry, 76 (20), 8311-8319;2011), in, it is former with formula III compound
Material carries out phosphorus acylation reaction and obtains rope fluorine cloth Wei, but the phosphorus acylation reaction in this method needs with tert-butyl group magnesium chloride as alkali,
Tert-butyl group magnesium chloride can react with the hydrogen in uracil base atom N, consumes monovalent tert-butyl group magnesium chloride, and meeting
Cause side reaction, generate impurity, bring difficulty to purification below.
Summary of the invention
For above-mentioned technical problem, the present inventor designs the compound synthesized shown in below general formula I, described compound of Formula I
May be used for treating disease of viral infection, it is possible to carry out catalytic hydrogenation under suitable condition or hydrolysis obtains rope fluorine cloth
Wei and the like.
Therefore, the purpose of one aspect of the present invention is to provide the compound or its salt shown in formula I.
The purpose of another aspect of the invention is to provide the preparation method of compound of Formula I.
The purpose of another aspect of the invention is to provide for the intermediate preparing compound of Formula I.
The purpose of another aspect of the present invention is the use providing compound of Formula I for preparing treatment disease of viral infection medicine
On the way.
The purpose of another aspect of the present invention is to provide a kind of pharmaceutical composition, and it comprises compound of Formula I.
The purpose of another aspect of the present invention is the purposes providing described compound of Formula I in preparation Formula IV compound.
The purpose of another aspect of the present invention is to provide a kind of method using compound of Formula I to prepare Formula IV compound.
In order to realize foregoing invention purpose, the present invention adopts the following technical scheme that:
The present invention provides the compound or its salt shown in below formula I:
Wherein, in formula above I, each substituent group is defined as follows:
R1For C1-C10Straight or branched alkyl, C6-C12The substituted C of aryl1-C10Straight or branched alkyl, C1-C10Straight chain or
The substituted C of branched alkoxycarbonyl1-C10Straight or branched alkyl, C6-C12Aryl or C1-C10Straight or branched alkyl-carbonyl;
Preferably, R1For C1-C5Straight or branched alkyl, C6-C12The substituted C of aryl1-C5Straight or branched alkyl, C1-C5Straight chain
Or the substituted C of branched alkoxycarbonyl1-C5Straight or branched alkyl, C6-C12Aryl or C1-C5Straight or branched alkyl-carbonyl;
It is highly preferred that R1For benzyl, the substituted methyl of isopropoxy carbonyl.
R2For substituted or unsubstituted C6-C12Aryl or substituted or unsubstituted C1-C10Straight or branched alkyl, it is preferable that R2
For replacing or unsubstituted for phenyl or substituted or unsubstituted C1-C5Straight or branched alkyl;Wherein, described substituent group be hydroxyl,
The substituted C of halogen, itrile group, hydroxyl1-C10Straight or branched alkyl-carbonyl epoxide or the substituted C of hydroxyl1-C10Straight or branched alkane
Base carbonyl sulfydryl;Preferably, described substituent group is the substituted C of hydroxyl1-C5Straight or branched alkyl-carbonyl epoxide or hydroxyl replace
C1-C5Straight or branched alkyl-carbonyl sulfydryl;
It is highly preferred that R2For phenyl or
R3For hydrogen, hydroxyl, halogen, itrile group or C1-C10Straight or branched alkyl;Preferably, R3For hydrogen, hydroxyl, fluorine, chlorine,
Bromine, itrile group or C1-C5Straight or branched alkyl;It is highly preferred that R3For hydroxyl, fluorine, chlorine, bromine or itrile group;
Represent singly-bound or double bond;WhenDuring for singly-bound, R6For-A-R5、-A-O-R5;R7For oxo group
(=O);WhenDuring for double bond, R6Do not exist, R7For-O-A-O-R5、-O-A-R5;
A is carbonyl, methylene or CHR4,
Wherein,
R4For C1-C10Straight or branched alkyl, C1-C10Straight or branched alkoxyl;Preferably, C1-C5Straight or branched alkyl,
C1-C5Straight or branched alkoxyl;It is highly preferred that R4For methyl;
R5For H, C1-C10Straight or branched alkyl, benzyl, C1-C10Straight or branched alkyl-carbonyl, C1-C10Straight or branched
Alkyl amino-carbonyl, C3-C8Cycloalkyl amino carbonyl, C1-C10Straight or branched alkoxy carbonyl, C3-C8Cyclo alkoxy carbonyl,
C6-C12Aryloxycarbonyl;Preferably, R5For H, C1-C8Straight or branched alkyl, benzyl, C1-C5Straight or branched alkyl
Carbonyl, C1-C5Straight or branched alkyl amino-carbonyl, C3-C8Cycloalkyl amino carbonyl, C1-C5Straight or branched alkoxy carbonyl,
C3-C8Cyclo alkoxy carbonyl, C6-C12Aryloxycarbonyl;It is highly preferred that R5For methyl, the tert-butyl group, n-pentyl, benzyl, second
Acyl group, ethoxy carbonyl, cyclohexyl oxygen carbonyl.
Further, the compound shown in formula I preferably has a structure shown in below formula I-A or I-B:
In formula I-A and I-B, R1、R2And R3Definition identical with the definition in formula above I, R6For-A-R5、
-A-O-R5;R7For-O-A-O-R5Or-O-A-R5。
Most preferably, the compound of Formula I of the present invention is selected from:
Present invention also offers the preparation method of compound of Formula I, comprise the steps:
(1) compound III and hydrocarbylating agent obtain compound II through hydrocarbyl reaction;
(2) compound II and phosphorus esterification reagent obtain compound of Formula I through phosphorus acylation reaction;
Shown in the following reaction equation of course of reaction:
Wherein, R1、R2、R3、R6、R7WithDefinition identical with the definition in aforementioned formula I.
In described hydrocarbyl reaction, compound III can be with corresponding hydrocarbylating agentIn the presence of a base,
Carry out in a suitable solvent.Described alkali can be selected from organic base or inorganic base, more preferably selected from sodium bicarbonate, bicarbonate
One or more in potassium, sodium carbonate, potassium carbonate, triethylamine, DMAP.Described solvent can be selected from N, N-
Dimethylformamide (DMF), DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, two
One or more in oxygen six ring, pyridine;
Wherein, at described hydrocarbylating agentIn, B is methylene or CHR4, R4And R5Definition and aforementioned formula
Definition in I is identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group;
Compound III is 1:1~10 with the molar ratio of hydrocarbylating agent, preferably 1:1~3.
In described phosphorus acylation reaction, compound II with corresponding phosphorus esterification reagent in the presence of a base, is carried out in a suitable solvent.
Described alkali can be organic base or inorganic base, be preferably selected from tert-butyl group magnesium chloride, isopropylmagnesium chloride, phenyl-magnesium-chloride, three
One in ethamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride or
Multiple.Described solvent is selected from toluene, benzene, acetone, methyl tertiary butyl ether(MTBE), diisopropyl ether, oxolane (THF), dioxy six
One in ring, acetonitrile, dichloromethane, dichloroethanes, ethyl acetate, N,N-dimethylformamide, N-Methyl pyrrolidone
Or it is multiple.
Described phosphorus esterification reagent can be that phosphorus esterification reagent as known in the art is not particularly limited, such as
(S)-2-[(S)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (R)-2-[(S)-(fluoro-benzene of 2,3,4,5,6-five
Epoxide)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (S)-2-[(R)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphinylidyne amido] propanoic acid
Isopropyl ester, (R)-2-[(R)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (S)-2-[(S)-(4-nitro-
Phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (R)-2-[(S)-(4-nitro-phenoxy)-phenoxy group-phosphinylidyne amido] propanoic acid isopropyl
Ester, (S)-2-[(R)-(4-nitro-phenoxy)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (R)-2-[(R)-(4-nitro-phenoxy)-benzene
Epoxide-phosphinylidyne amido] isopropyl propionate, (S)-2-((chlorine (phenoxy group) phosphinylidyne amido) isopropyl propionate, (R)-2-((chlorine (phenoxy group) phosphinylidyne
Amido) isopropyl propionate, O-2-(3-hydroxyl-2,2-Dimethylpropanoyl sulfydryl)-O-(the fluoro-phenoxy group of 2,3,4,5,6-five)-N-benzyl phosphinylidyne
Amine;Compound II is 1:1~10 with the molar ratio of phosphorus esterification reagent, preferably 1:1~3.
Described step (1) and (2) can be carried out respectively, it is also possible to be carried out continuously, i.e. after step (1) completes without isolation
Directly carry out step (2).
Present invention also offers the preparation method of a kind of Compounds of formula II, comprise the steps:
(1) compound V and hydrocarbylating agent obtain compound through acylation reaction through hydrocarbyl reaction or with acylating reagent
IV;
(2) compound IV obtains Compounds of formula II through deprotection reaction;
Shown in the following reaction equation of course of reaction:
Wherein, R3、R6、R7WithDefinition identical with the definition in compound of Formula I;
In described hydrocarbyl reaction, compound V can be with corresponding hydrocarbylating agentIn the presence of a base,
Carry out in a suitable solvent.Described alkali can be organic base or inorganic base, be preferably selected from sodium bicarbonate, potassium bicarbonate,
One or more in sodium carbonate, potassium carbonate, triethylamine, DMAP.Described solvent can be selected from N, N-bis-
Methylformamide (DMF), DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxy
One or more in six rings, pyridine;
Wherein, at described hydrocarbylating agentIn, B is methylene or CHR4, R4And R5Definition and aforementioned formula
Definition in I is identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group;
Compound V is 1:1~10 with the molar ratio of hydrocarbylating agent, preferably 1:1~3.
In described acylation reaction, compound V can be with corresponding acylating reagentIn the presence of a base, closing
Suitable solvent is carried out.Described alkali can be organic base or inorganic base, is preferably selected from sodium bicarbonate, potassium bicarbonate, carbonic acid
One or more in sodium, potassium carbonate, triethylamine, DMAP.Described solvent can be selected from N, N-dimethyl
Methanamide (DMF), DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane,
One or more in pyridine;
Wherein, at described acylating reagentIn, M is carbonyl, R5Definition and aforementioned formula I in definition
Identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group;
Compound V is 1:1~10 with the molar ratio of acylating reagent, preferably 1:1~3.
In described deprotection reaction, compound IV reacts the most in a suitable solvent with alcohol, ammonia or amine and obtains
Product.Described alcohol be selected from methanol, ethanol, isopropanol one or more, described amine be selected from methylamine, ethamine, dimethylamine,
One or more of diethylamine, described alkali can be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine,
One or more in N-methylmorpholine, potassium carbonate, Feldalat NM, potassium tert-butoxide, described solvent be selected from toluene, benzene, acetone,
Methyl tertiary butyl ether(MTBE), diisopropyl ether, oxolane (THF), dioxane, acetonitrile, dichloromethane, dichloroethanes, acetic acid second
One or more in ester, N,N-dimethylformamide, N-Methyl pyrrolidone, methanol, ethanol, isopropanol, water.
Described step (1) and (2) can be carried out respectively, it is also possible to be carried out continuously, i.e. after step (1) completes without isolation
Directly carry out step (2).
The present invention also provides for the compound or its salt shown in below formula II:
Wherein, R3、R6、R7WithDefinition identical with the definition in formula I.
Further, the compound shown in formula II preferably has a structure shown in below formula II-A or II-B:
In formula II-A and II-B, R3、R6And R7Definition identical with the definition in formula I-A and I-B.
It is highly preferred that above-mentioned Compounds of formula II is selected from:
The present invention also provides for compound of Formula I or its salt purposes in preparation treatment disease of viral infection medicine.
The present invention also provides for a kind of pharmaceutical composition, and it comprises compound of Formula I or its salt.Described compound of Formula I or its salt
Can be present in pharmaceutical composition with therapeutically effective amount.Described pharmaceutical composition the most optionally comprises the excipient substance of routine, such as
Excipient, lubricant, coating materials, sweeting agent, flavoring agent, binding agent, filler, diluent, antitack agent, dispersant,
Toner etc..
The present invention also provides for described compound of Formula I or its salt purposes in preparation Formula IV compound,
Wherein, R1、R2And R3Definition identical with the definition in claim 1 formula of I;Preferably, R1For different
The substituted methyl of propoxycarbonyl, R2For phenyl, R3For fluorine.
The present invention also provides for a kind of method using compound of Formula I to prepare Formula IV compound, shown in following reaction equation:
Described method includes:
Compound of formula I obtains Formula IV compound through C-N catalytic hydrogenolytic cleavage;Or
Compound of formula I obtains Formula IV compound through hydrolysis;
Wherein, R1、R2、R3、R6、R7WithDefinition identical with the definition in aforementioned formula I;Preferably
Ground, R1For the substituted methyl of isopropoxy carbonyl, R2For phenyl, R3For fluorine;
Preferably,
Described catalytic hydrogenolytic cleavage can be carried out in the presence of catalytic hydrogenation catalyst in a suitable solvent.Described catalytic hydrogenation
Catalyst can be that catalytic hydrogenation catalyst as known in the art is not particularly limited, be preferably selected from palladium carbon, active nickel,
One or more in platinum carbon, platinic hydroxide, platinum oxide and palladium dydroxide.Described solvent is not particularly limited, as long as it is permissible
Dissolve described compound, can be preferably selected from DMF (DMF), N,N-dimethylacetamide, two
Methyl sulfoxide (DMSO), acetonitrile, acetone, ethyl acetate, oxolane, methanol, ethanol, isopropanol, toluene, dioxy
One or more in six rings and pyridine;
Described hydrolysis can be carried out in the presence of acidic in a suitable solvent.Described acidic catalyst can
Think that acidic catalyst as known in the art is not particularly limited, be preferably selected from formic acid, acetic acid, hydrogen chloride, sulphuric acid,
One or more in trifluoromethanesulfonic acid and trifluoracetic acid.Described solvent is not particularly limited, as long as it can dissolve described chemical combination
Thing, can be preferably selected from methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tertiary butyl ether(MTBE), isopropyl
Ether, oxolane, dioxane, acetonitrile, dichloromethane, dichloroethanes, ethyl acetate, N,N-dimethylformamide and N-
One or more in methyl pyrrolidone.
Claimed method is by designing new reaction scheme, it is to avoid use tert-butyl group magnesium chloride in phosphorus acylation reaction
The side reaction caused, decreases the impurity of generation, reduces the difficulty of follow-up purification procedures.And tests prove that, this
Bright claimed method, reaction condition is gentle, it is easy to operation, and yield is high, and the product quality obtained is stable, and purity is high, can
To carry out commercial scale amplification production.
Detailed description of the invention
Embodiment 1:
Compound III-2 (0.260g, 1mmol) is dissolved in DMF (2ml), adds 1,8-diazabicylo [5.4.0] 11 carbon
-7-alkene (DBU) (0.30ml, 2mmol), ice bath, stir about, after 15 minutes, adds chloromethyl methyl ether (76 μ l, 1mmol),
After about 1 hour, TLC display raw material fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound
II-1(200mg)。
1HNMR (300MHz, DMSO): 8.05 (d, J=8.23Hz, 1H), 6.01 (d, J=18.28Hz, 1H), 5.80 (d, J=8.21
Hz, 1H), 5.67 (d, J=6.27Hz, 1H), 5.31 (t, J=5.72Hz, 1H), 5.17 (s, 2H), 3.82 (dt, J=6.32,13.43Hz,
3H), 3.63 (d, J=10.81Hz, 1H), 3.25 (s, 3H), 1.25 (d, J=22.45Hz, 3H);ESI(M+Cl:339).
Embodiment 2:
Compound II-1 (0.76g, 2mmol) is dissolved in THF (10mL), is cooled to-5 DEG C, add tert-butyl group magnesium chloride
(2.4mL, 2.4mmol), stirs 30 minutes, is warmed to room temperature stirring 30 minutes, is cooled to 5 DEG C, adds (S)-2-[(S)-(2,3,4,5,6-
Five fluoro-phenoxy groups)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows base
This reaction is complete, and column chromatography obtains 917mg compound I-1.
1HNMR (400M, DMSO): 7.64 (d, J=8.19Hz, 1H), 7.38 (t, J=7.89Hz, 2H), 7.21 (m, 3H), 6.06 (dd,
J=9.93,12.96Hz, 2H), 5.88 (d, J=7.03Hz, 1H), 5.70 (d, J=8.15Hz, 1H), 5.18 (s, 2H), 4.85 (p,
J=6.27Hz, 1H), 4.38 (m, 1H), 4.25 (dt, J=5.67,12.02Hz, 1H), 4.03 (dd, J=4.73,10.05Hz, 1H),
3.81 (m, 2H), 3.27 (s, 3H), 1.24 (m, 6H), 1.15 (d, J=6.26Hz, 6H);ESI (M-1:572).
Embodiment 3:
Being dissolved in oxolane (4ml) by compound I-1 (100mg, 0.17mmol), add the hydrochloric acid of 1ml 10%, heating is anti-
Should, after about 4 hours, completely, column chromatography obtains rope fluorine cloth Wei (10mg) in reaction.
1HNMR (400M, DMSO): 11.52 (s, 1H), 7.57 (d, J=8.17Hz, 1H), 7.37 (m, 2H), 7.22 (m, 3H),
6.04 (m, 2H), 5.86 (d, J=7.08Hz, 1H), 5.54 (d, J=8.06Hz, 1H), 4.86 (p, J=6.25Hz, 1H), 4.38 (dd,
J=5.82,11.71Hz), 4.24 (dt, J=5.77,11.74Hz, 1H), 4.01 (m, 1H), 3.81 (m, 2H), 1.25 (m, 6H), 1.15 (d,
J=6.29Hz, 6H).
Embodiment 4:
Being dissolved in oxolane (4ml) by compound I-5 (100mg, 0.17mmol), add the hydrochloric acid of 1ml 10%, heating is anti-
Should, after about 4 hours, completely, column chromatography obtains VI-1 (60mg) in reaction.
1HNMR (300M, DMSO): 11.53 (s, 1H), 7.58 (d, J=8.17Hz, 1H), 7.37 (m, 2H), 7.22 (m, 3H),
(6.26 s, 1H), 6.17 (m, 2H), 5.86 (d, J=7.08Hz, 1H), 5.57 (d, J=8.06Hz, 1H), 4.85 (p, J=6.25Hz, 1H),
4.29-4.38 (m, 2H), 4.06 (m, 1H), 3.81 (m, 2H), 1.39 (s, 3H), 1.22 (d, J=7.2Hz, 3H), 1.13 (m, 6H).
Embodiment 5:
Being dissolved in methanol (4ml) by compound I-5 (100mg, 0.17mmol), add the palladium carbon (10mg) of 10%, room temperature is stirred
Mixing reaction, after about 48 hours, completely, column chromatography obtains VI-1 (60mg) in reaction.
1HNMR (300M, DMSO): 11.53 (s, 1H), 7.58 (d, J=8.17Hz, 1H), 7.37 (m, 2H), 7.22 (m, 3H),
6.26 (s, 1H), 6.17 (m, 2H), 5.86 (d, J=7.08Hz, 1H), 5.57 (d, J=8.06Hz, 1H), 4.85 (p, J=6.25Hz, 1H),
4.29-4.38 (m, 2H), 4.06 (m, 1H), 3.81 (m, 2H), 1.39 (s, 3H), 1.22 (d, J=7.2Hz, 3H), 1.13 (m, 6H).
Embodiment 6:
Compound III-2 (0.26g, 1mmol) is dissolved in DMF (2ml), adds DBU (0.30mL, 2mmol),
Ice bath, stir about, after 15 minutes, adds BnOCH2Cl (0.26ml, 1.8mmol), after about 1 hour, TLC shows raw material
Fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound II-2 (300mg).
II-2:1HNMR (300MHz, DMSO): 8.06 (d, J=8.20Hz, 1H), 7.31 (m, 5H), 6.03 (d, J=18.43Hz,
1H), 5.82 (d, J=8.16Hz, 1H), 5.69 (d ,=6.43,1H), 5.33 (s, 3H), 4.59 (s, 2H), 3.83 (dt, J=5.67,15.84Hz,
3H), 3.64 (dd, J=4.58,11.08Hz, 1H), 1.25 (d, J=22.50Hz, 3H);ESI(M+Na:403)
Embodiment 7:
Compound V-2 (6.7g, 14.3mmol) is dissolved in 20ml DMF, be sequentially added into sodium iodide (0.43g,
2.86mmol), DIPEA (4g, 28.6mmol), Benzyl chloromethyl ether (2.68g, 17.2mmol), 25 degree
Stir 24 hours, add 40ml ethyl acetate, 40ml water, stirring, stand separatory, organic layer 20ml saturated aqueous common salt
Washing, anhydrous sodium sulfate is dried, and filters, and concentrates, and gained grease is crude product IV-2, is directly used in next step reaction.
Compound IV-2 (3.4g) adds to the mixture of 20ml methanol and 2ml triethylamine, is heated to reflux 6 hours.Decompression
Remove solvent, be sequentially added into 10ml petroleum ether and 10ml ethyl acetate, stir 0.5 hour, be filtrated to get 2.06g white solid
Product II-2, yield 94%.
Compound II-2 (0.76g, 2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, add tert-butyl group chlorination
Magnesium (2.4ml, 2.4mmol), stirs 30 minutes, is warmed to room temperature stirring 30 minutes, is cooled to 5 DEG C, adds (S)-2-[(S)-(2,3,4,5,6-
Five fluoro-phenoxy groups)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows base
This reaction is complete, and column chromatography obtains compound I-2 (1.065g).
I-2:1HNMR (400M, DMSO): 7.62 (d, J=8.14Hz, 1H), 7.27 (m, 10H), 6.05 (dd, J=9.85,12.89Hz,
2H), 5.86 (d, J=6.95Hz, 1H), 5.68 (d, J=8.16Hz, 1H), 5.32 (s, 2H), 4.84 (d, J=6.31Hz, 1H), 4.57 (s,
2H), 4.37 (dd, J=6.00,11.35Hz, 1H), 4.24 (dt, J=5.90,11.81Hz, 1H), 4.02 (dd, J=4.69,9.72Hz,
1H), 3.80 (ddt, J=7.09,10.17,17.23Hz, 2H), 1.23 (m, 6H), 1.14 (d, J=6.23Hz, 6H);ESI(M+H:650).
Embodiment 8:
I-2 → rope fluorine cloth Wei
I-2 (100mg, 0.15mmol) is dissolved in methanol (4ml), addition palladium carbon (10mg), logical hydrogen, about 4 hours
Rear TLC display raw material has reacted complete, filters, concentrates, and column chromatography obtains rope fluorine cloth Wei (50mg);
1HNMR (400M, DMSO): 11.52 (s, 1H), 7.57 (d, J=8.17Hz, 1H), 7.37 (m, 2H), 7.22 (m, 3H),
6.04 (m, 2H), 5.86 (d, J=7.08Hz, 1H), 5.54 (d, J=8.06Hz, 1H), 4.86 (p, J=6.25Hz, 1H), 4.38 (dd,
J=5.82,11.71Hz, 1H), 4.24 (dt, J=5.77,11.74Hz, 1H), 4.01 (m, 1H), 3.81 (m, 2H), 1.25 (m, 6H),
1.15 (d, J=6.29Hz, 6H).
Embodiment 9:
Compound III-2 (0.26g, 1mmol) is dissolved in DMF (2ml), adds potassium carbonate (0.3g, 2mmol),
Ice bath, stir about, after 15 minutes, adds BnOCH2Cl (0.26ml, 1.8mmol), after about 1 hour, TLC shows raw material
Fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound II-3 (290mg).
Embodiment 10:
Compound III-3 (0.276g, 1mmol) is dissolved in DMF (2ml), adds DBU (0.30mL, 2mmol),
Ice bath, stir about, after 15 minutes, adds chloromethyl methyl ether (0.16g, 2mmol), and after about 1 hour, TLC display raw material is
Fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound II-4 (260mg).
1HNMR (300MHz, DMSO): 8.07 (d, J=8.23Hz, 1H), 6.07 (d, J=18.28Hz, 1H), 5.78 (d, J=8.21
Hz, 1H), 5.60 (d, J=6.27Hz, 1H), 5.33 (t, J=5.72Hz, 1H), 5.15 (s, 2H), 3.80 (dt, J=6.32,13.43Hz,
3H), 3.53 (d, J=10.81Hz, 1H), 3.25 (s, 3H), 1.19 (s, 3H).
Embodiment 11:
By in compound III-3 (0.276g, 1mmol) molten DMF (2ml), add DBU (0.30mL, 2mmol),
Ice bath, stir about, after 15 minutes, adds BnOCH2Cl (0.26ml, 1.8mmol), after about 1 hour, TLC shows raw material
Fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound II-5 (310mg).
II-2:1HNMR (300MHz, DMSO): 8.05 (d, J=8.20Hz, 1H), 7.35 (m, 5H), 6.01 (d, J=18.43Hz,
1H), 5.83 (d, J=8.16Hz, 1H), 5.65 (d ,=6.43,1H), 5.31 (s, 3H), 4.54 (s, 2H), 3.84 (m, 3H), 3.64 (m, 1H),
1.21(s,3H).
Embodiment 12:
II-5→I-5
Compound II-5 (0.76g, 2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, add tert-butyl group chlorination
Magnesium (2.4ml, 2.4mmol), stirs 30 minutes, is warmed to room temperature stirring 30 minutes, is cooled to 5 DEG C, adds (R)-2-[(S)-(2,3,4,5,6-
Five fluoro-phenoxy groups)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows base
This reaction is complete, and column chromatography obtains compound I-5 (1.065g).
Embodiment 13:
Compound III-3 (0.26g, 1mmol) is dissolved in DMF (2ml), adds potassium carbonate (0.3g, 2mmol),
Ice bath, stir about, after 15 minutes, adds BnOCH2Cl (0.26ml, 1.8mmol), after about 1 hour, TLC shows raw material
Fundamental reaction is complete, adds about 1ml methanol cancellation reaction, and evaporating column chromatographs to obtain compound II-6 (200mg).
Embodiment 14:
II-6→I-6
Compound II-6 (2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, addition tert-butyl group magnesium chloride (2.4ml,
2.4mmol), stir 30 minutes, be warmed to room temperature stirring 30 minutes, be cooled to 5 DEG C, add (R)-2-[(S)-(2,3,4,5,6-five fluorine
-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows the most anti-
Should be complete, column chromatography obtains compound I-6 (0.8g).
Embodiment 15:
Compound III-2 (1mmol) is dissolved in DMF (2ml), addition DBU (0.30mL, 2mmol), ice bath,
After stir about 15 minutes, adding 1-chloroethyl cyclohexyl carbonic ester (1.8mmol), after about 1 hour, TLC display raw material is
Fundamental reaction is complete, and evaporating column chromatographs to obtain compound II-8 (210mg).
Embodiment 16:
II-8→I-8
Compound II-8 (2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, addition tert-butyl group magnesium chloride (2.4ml,
2.4mmol), stir 30 minutes, be warmed to room temperature stirring 30 minutes, be cooled to 5 DEG C, add (S)-2-[(S)-(2,3,4,5,6-five fluorine
-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows the most anti-
Should be complete, column chromatography obtains compound I-8 (0.6g).
Embodiment 17:
Compound III-3 (1mmol) is dissolved in DMF (2ml), addition DBU (0.30mL, 2mmol), ice bath,
After stir about 15 minutes, adding 1-chloroethyl acetas (1.8mmol), after about 1 hour, TLC display raw material is the most anti-
Should be complete, evaporating column chromatographs to obtain compound II-10 (250mg).
Embodiment 18:
II-10→I-10
Compound II-10 (2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, addition tert-butyl group magnesium chloride (2.4ml,
2.4mmol), stir 30 minutes, be warmed to room temperature stirring 30 minutes, be cooled to 5 DEG C, add (R)-2-[(S)-(2,3,4,5,6-five fluorine
-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), after reacting about 4 hours, TLC shows the most anti-
Should be complete, column chromatography obtains compound I-10 (0.9g).
Embodiment 19:
II-7→I-14
Compound II-7 (2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, addition tert-butyl group magnesium chloride (2.4ml,
2.4mmol), stir 30 minutes, be warmed to room temperature stirring 30 minutes, be cooled to 5 DEG C, add phenoxy-phenoxy S-(2-(((benzyl
Base amido) chloro phosphoryl) epoxide) ethyl)-3-hydroxyl-2,2-dimethyl thio propionic ester (2.4mmol), after reacting about 4 hours
TLC display fundamental reaction is complete, and column chromatography obtains compound I-14 (0.2g).
Embodiment 20:
Rope fluorine cloth Wei (0.53g, 1mmol) is dissolved in DMF (2ml), adds potassium carbonate (0.14ml, 1mmol), ice
Bath, stir about after 15 minutes, adds chloromethyl acetate (108mg, 1mmol), stirs 12 hours, adds 20ml acetic acid
Ethyl ester, 20ml water, stirring, separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-22 (510mg).
1HNMR(400M,CDCl3): 8.43 (s, 1H), 7.52 (d, J=8.1Hz, 1H), 7.34 (m, 2H), 7.18-7.26 (m, 5H),
6.18 (d, J=18.6Hz, 1H), 5.51 (d, J=8.1Hz, 1H), 5.19 (dd, J=20.7,9.0Hz, 1H), 5.00 (m, 1H), 4.54 (m,
1H),4.23-4.33(m,2H),3.83-3.99(m,2H),2.18(s,3H),1.38(m,6H),1.23(m,6H).ESI(M-1:600.5)
Embodiment 21:
Rope fluorine cloth Wei (0.53g, 1mmol) is dissolved in DMF (2ml), adds potassium carbonate (0.14ml, 1mmol), ice
Bath, stir about after 15 minutes, adds chloromethyl pivalate (150mg, 1mmol), stirs 12 hours, adds 20ml second
Acetoacetic ester, 20ml water, stirring, separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-23 (520mg).
1HNMR(400M,CDCl3): 7.48 (d, J=8.1Hz, 1H), 7.34 (m, 2H), 7.18-7.26 (m, 3H), 6.21 (d, J=18.6
Hz, 1H), 5.94 (s, 2H), 5.75 (d, J=8.1Hz, 1H), 5.19 (dd, J=20.7,9.0Hz, 1H), 5.00 (m, 1H), 4.52 (m,
1H),4.11-4.33(m,2H),3.86-3.97(m,2H),2.18(s,3H),1.23-1.35(m,18H).ESI(M-1:642)
Embodiment 22:
Rope fluorine cloth Wei (0.53g, 1mmol) is dissolved in DMF (2ml), adds potassium carbonate (0.14ml, 1mmol), ice
Bath, stir about after 15 minutes, adds 1-chloroethyl ethyl carbonate (152mg, 1mmol), stirs 12 hours, adds 20ml
Ethyl acetate, 20ml water, stirring, separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-18 (430mg).
1HNMR(400M,CDCl3): 9.10 (s, 1H), 7.48 (d, J=8.1Hz, 1H), 7.32 (m, 2H), 7.14-7.23 (m, 3H),
6.17 (d, J=18.6Hz, 1H), 5.53 (d, J=8.1Hz, 1H), 4.97-5.10 (m, 2H), 4.56 (dd, J=11,5.4Hz, 1H),
4.23-4.35 (m, 4H), 3.97 (m, 2H), 2.18 (s, 3H), 1.31-1.43 (m, 9H), 1.23 (d, J=6.3Hz, 6H) .ESI (M+1:
646)
Embodiment 23:
Rope fluorine cloth Wei (0.53g, 1mmol) is dissolved in DMF (2ml), addition triethylamine (0.15g, 1mmol), ice bath,
After stir about 15 minutes, add n-amyl chlorocarbonate (0.15g, 1mmol), stir 12 hours, add 20ml ethyl acetate,
20ml water, stirring, separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-19 (450mg).
1HNMR(400M,CDCl3): 8.96 (s, 1H), 7.49 (d, J=8.1Hz, 1H), 7.32 (m, 2H), 7.17-7.23 (m, 3H),
6.17 (d, J=18.6Hz, 1H), 5.51 (d, J=8.1Hz, 1H), 4.97-5.10 (m, 2H), 4.56 (m, 1H), 4.16-4.35 (m, 4H),
3.97 (m, 2H), 2.18 (s, 3H), 1.71 (m, 4H), 1.33-1.41 (m, 8H), 1.23 (d, J=6.3Hz, 6H), 0.92 (t, 3H) .ESI
(M-1:642)
Embodiment 24:
By N-[[P (S), 2 ' R]-2 '-deoxygenate-2 '-fluoro-2 '-methyl-P-phenyl-5 '-uridnine base]-D-alanine 1-Methylethyl ester (0.53g,
1mmol) being dissolved in DMF (2ml), add potassium carbonate (0.14ml, 1mmol), ice bath, stir about, after 15 minutes, adds
Enter 1-chloroethyl ethyl carbonate (152mg, 1mmol), stir 12 hours, add 20ml ethyl acetate, 20ml water, stir,
Separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-25 (410mg).
1HNMR(300MHz,CDCl3): 8.88 (s, 1H), 7.47 (d, J=8.1Hz, 1H), 7.34 (m, 2H), 7.14-7.23 (m, 3H),
6.20 (d, J=18.6Hz, 1H), 5.66 (d, J=8.1Hz, 1H), 4.97-5.05 (m, 2H), 4.56 (m, 1H), 4.23-4.35 (m, 4H),
3.97(m,2H),1.33-1.43(m,9H),1.31-1.21(m,9H).ESI(M+1:646)
Embodiment 25:
By N-[[P (S), 2 ' R]-2 '-deoxygenate-2 '-chloro-2 '-methyl-P-phenyl-5 '-uridnine base]-D-alanine 1-Methylethyl ester (0.545g,
1mmol) being dissolved in DMF (2ml), add potassium carbonate (0.14ml, 1mmol), ice bath, stir about, after 15 minutes, adds
Enter 1-chloroethyl ethyl carbonate (152mg, 1mmol), stir 12 hours, add 20ml ethyl acetate, 20ml water, stir,
Separatory, organic layer anhydrous sodium sulfate is dried, and evaporating column chromatographs to obtain compound I-26 (430mg).
1HNMR(300MHz,CDCl3): 8.92 (s, 1H), 7.60 (d, J=8.1Hz, 1H), 7.34 (m, 2H), 7.14-7.23 (m, 3H),
6.44 (d, J=18.6Hz, 1H), 5.63 (d, J=8.1Hz, 1H), 4.99-5.08 (m, 2H), 4.56 (m, 1H), 4.21-4.40 (m, 4H),
3.92-4.04(m,2H),1.56(s,3H),1.20-1.38(m,15H).ESI(M+1:662)
Embodiment 26:
Compound V-2 (6.7g, 14.3mmol) is dissolved in 20mlN, in dinethylformamide, is sequentially added into N, N-diisopropyl
Base ethamine (4g, 28.6mmol) and n-amyl chlorocarbonate (17.2mmol), 25 degree are stirred 24 hours, add 40ml acetic acid
Ethyl ester, 40ml water, stirring, stand separatory, organic layer 20ml saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters,
Concentrating, gained grease is crude product IV-3, is directly used in next step reaction.
Compound IV-3 (3.4g) adds to the mixture of 20ml methanol and 2ml triethylamine, is heated to reflux 6 hours.Decompression
Remove solvent, be sequentially added into 10ml petroleum ether and 10ml ethyl acetate, stir 0.5 hour, be filtrated to get 1g white solid and produce
Thing II-17.
Compound II-17 (0.76g, 2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, add tertiary butyl chloride
Change magnesium (2.4ml, 2.4mmol), stir 30 minutes, be warmed to room temperature stirring 30 minutes, be cooled to 5 DEG C, add
(S)-2-[(S)-(2,3,4,5,6-five fluoro-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), reacts about 4
After hour, TLC display fundamental reaction is complete, and column chromatography obtains compound I-19 (1.065g).
1HNMR(400M,CDCl3): 8.96 (s, 1H), 7.49 (d, J=8.1Hz, 1H), 7.32 (m, 2H), 7.17-7.23 (m, 3H),
6.17 (d, J=18.6Hz, 1H), 5.51 (d, J=8.1Hz, 1H), 4.97-5.10 (m, 2H), 4.56 (m, 1H), 4.16-4.35 (m, 4H),
3.97 (m, 2H), 2.18 (s, 3H), 1.71 (m, 4H), 1.33-1.41 (m, 8H), 1.23 (d, J=6.3Hz, 6H), 0.92 (t, 3H) .ESI
(M-1:642)
Embodiment 27:
Compound V-3 (14.3mmol) is dissolved in 20ml DMF, is sequentially added into N, N-diisopropyl second
Amine (4g, 28.6mmol) and n-amyl chlorocarbonate (17.2mmol), 25 degree are stirred 24 hours, add 40ml ethyl acetate,
40ml water, stirring, stand separatory, organic layer 20ml saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and concentrates,
Gained grease is directly used in next step reaction.
Compound IV-4 (3.4g) adds to the mixture of 20ml methanol and 2ml triethylamine, is heated to reflux 6 hours.Decompression
Remove solvent, be sequentially added into 10ml petroleum ether and 10ml ethyl acetate, stir 0.5 hour, be filtrated to get 1.2g white solid
Product II-20.
Compound II-20 (0.76g, 2mmol) is dissolved in oxolane (10ml), is cooled to-5 DEG C, add tertiary fourth
Base magnesium chloride (2.4ml, 2.4mmol), stirs 30 minutes, is warmed to room temperature stirring 30 minutes, is cooled to 5 DEG C, adds
(R)-2-[(S)-(2,3,4,5,6-five fluoro-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate (1.09g, 2.4mmol), reacts about 4
After hour, TLC display fundamental reaction is complete, and column chromatography obtains compound I-27 (1.065g).
1HNMR(400M,CDCl3): 8.96 (s, 1H), 7.49 (d, J=8.1Hz, 1H), 7.32 (m, 2H), 7.17-7.23 (m, 3H),
6.17 (d, J=18.6Hz, 1H), 5.51 (d, J=8.1Hz, 1H), 4.97-5.10 (m, 2H), 4.56 (m, 1H), 4.16-4.35 (m, 4H),
3.97 (m, 2H), 2.08 (s, 3H), 1.65-1.78 (m, 4H), 1.25-1.41 (m, 8H), 1.22 (d, J=6.3Hz, 6H), 0.90 (t, 3H).
ESI(M-1:626)
Embodiment 28
28.1 tested material is prepared
Weighing appropriate rope fluorine cloth Wei, be dissolved in 95%PEG 400, in 5%Tween 80, compound concentration is 10mg/mL, for colourless
Settled solution (pH~7), for oral administration.
Weighing appropriate I-18, be dissolved in 95%PEG 400, in 5%Tween 80, compound concentration is 12.2mg/mL, for faint yellow
Settled solution (pH~7), for oral administration.
Weighing appropriate I-19, be dissolved in 95%PEG 400, in 5%Tween 80, compound concentration is 12.2mg/mL, for faint yellow
Settled solution (pH~7), for oral administration.
28.2 dosages and administering mode
Male ICR mouse 72 (body weight 18.0-19.8g), is purchased from Shanghai western pul-Bi Kai laboratory animal company limited.Press
Table is administered.Oral group is administered front fasting 10-14 hour.Dosage: rope fluorine cloth Wei (100mg/Kg), I-18 (122mg/Kg),
I-19 (122mg/Kg) recovers feedstuff after being administered latter 4 hours.
28.3 sample collections and process
Three animals of each time point are used for taking a blood sample, and time point is: 15min, 30min, 1h, 2h, 4h, 6h, 8h
And 24h.About 0.5mL blood, heparin sodium anticoagulant is adopted through cardiac puncture after every animal euthanasia.After Blood specimen collection
It is placed on ice, centrifugal separation plasma (centrifugal condition: 8000 revs/min, 6 minutes, 4 DEG C).Deposit in before the plasma analysis collected
-80℃。
28.4 instrument and equipments
Waters UPLC chromatograph (Shimadzu).Mass spectrograph (API4000, Applied biosystems), electric spray ion source
(ESI), series connection quadrupole rod mass analyzer.Data handling system is Analyst software (Applied biosystems, software
Version number 1.5.1).
28.5 pharmacokinetic results
According to the plasma drug concentration data of medicine, the pharmacokinetics non-compartment model of software for calculation WinNonlin5.2 is used to calculate respectively
The pharmacokinetic parameter of III-2, see table.
Mice single oral gives rope fluorine cloth Wei, III-2 main pharmacokinetic parameters after I-18, I-19
Test result indicate that: compound I-18 and I-19 have with rope fluorine cloth Wei mutually as pharmacokinetic property, compound I-19
The metabolism time slow compared with rope fluorine cloth Wei.
Claims (10)
1. the compound or its salt shown in below formula I:
Wherein, R1For C1-C10Straight or branched alkyl, C6-C12The substituted C of aryl1-C10Straight or branched alkyl, C1-C10
The substituted C of straight or branched alkoxy carbonyl1-C10Straight or branched alkyl, C6-C12Aryl or C1-C10Straight or branched alkyl
Carbonyl;Preferably, R1For C1-C5Straight or branched alkyl, C6-C12The substituted C of aryl1-C5Straight or branched alkyl, C1-C5
The substituted C of straight or branched alkoxy carbonyl1-C5Straight or branched alkyl, C6-C12Aryl or C1-C5Straight or branched alkyl oxycarbonyl
Base;It is highly preferred that R1For benzyl, the substituted methyl of isopropoxy carbonyl;
R2For substituted or unsubstituted C6-C12Aryl or substituted or unsubstituted C1-C10Straight or branched alkyl, it is preferable that R2
For replacing or unsubstituted for phenyl or substituted or unsubstituted C1-C5Straight or branched alkyl;Wherein, described substituent group be hydroxyl,
The substituted C of halogen, itrile group, hydroxyl1-C10Straight or branched alkyl-carbonyl epoxide or the substituted C of hydroxyl1-C10Straight or branched alkane
Base carbonyl sulfydryl;Preferably, described substituent group is the substituted C of hydroxyl1-C5Straight or branched alkyl-carbonyl epoxide or hydroxyl replace
C1-C5Straight or branched alkyl-carbonyl sulfydryl;
It is highly preferred that R2For phenyl or
R3For hydrogen, hydroxyl, halogen, itrile group or C1-C10Straight or branched alkyl;Preferably, R3For hydrogen, hydroxyl, fluorine, chlorine,
Bromine, itrile group or C1-C5Straight or branched alkyl;It is highly preferred that R3For hydroxyl, fluorine, chlorine, bromine or itrile group;
Represent singly-bound or double bond;WhenDuring for singly-bound, R6For-A-R5、-A-O-R5;R7For=O;When
During for double bond, R6Do not exist, R7For-O-A-O-R5、-O-A-R5;
A is carbonyl, methylene or CHR4,
Wherein,
R4For C1-C10Straight or branched alkyl, C1-C10Straight or branched alkoxyl;Preferably, C1-C5Straight or branched alkyl,
C1-C5Straight or branched alkoxyl;It is highly preferred that R4For methyl;
R5For H, C1-C10Straight or branched alkyl, benzyl, C1-C10Straight or branched alkyl-carbonyl, C1-C10Straight or branched
Alkyl amino-carbonyl, C3-C8Cycloalkyl amino carbonyl, C1-C10Straight or branched alkoxy carbonyl, C3-C8Cyclo alkoxy carbonyl,
C6-C12Aryloxycarbonyl;Preferably, R5For H, C1-C8Straight or branched alkyl, benzyl, C1-C5Straight or branched alkyl
Carbonyl, C1-C5Straight or branched alkyl amino-carbonyl, C3-C8Cycloalkyl amino carbonyl, C1-C5Straight or branched alkoxy carbonyl,
C3-C8Cyclo alkoxy carbonyl, C6-C12Aryloxycarbonyl;It is highly preferred that R5For methyl, the tert-butyl group, n-pentyl, benzyl, second
Acyl group, ethoxy carbonyl, cyclohexyl oxygen carbonyl.
Compound or its salt the most according to claim 1, wherein, compound of Formula I is selected from:
3. the preparation method of the compound of Formula I described in claim 1 or 2, comprises the steps:
(1) compound III and hydrocarbylating agent obtain compound II through hydrocarbyl reaction;
(2) compound II and phosphorus esterification reagent obtain compound of Formula I through phosphorus acylation reaction;
Shown in the following reaction equation of course of reaction:
Wherein, R1、R2、R3、R6、R7WithDefinition and the definition phase in claim 1 formula of I
With;
Preferably,
In described hydrocarbyl reaction, compound III and corresponding hydrocarbylating agentIn the presence of a base at solvent
In carry out;Described alkali is selected from organic base or inorganic base, more preferably selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, carbonic acid
One or more in potassium, triethylamine, DMAP;Described solvent be selected from N,N-dimethylformamide (DMF),
One in DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane, pyridine or
Multiple;
Wherein, at described hydrocarbylating agentIn, B is methylene or CHR4, R4And R5Definition and aforementioned formula
Definition in I is identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group;
Compound III is 1:1~10 with the molar ratio of hydrocarbylating agent, preferably 1:1~3;
In described phosphorus acylation reaction, compound II is carried out the most in a solvent with corresponding phosphorus esterification reagent;Described alkali
Selected from organic base or inorganic base, more preferably selected from tert-butyl group magnesium chloride, isopropylmagnesium chloride, phenyl-magnesium-chloride, triethylamine,
One or more in pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride;
Described solvent be preferably selected from toluene, benzene, acetone, methyl tertiary butyl ether(MTBE), diisopropyl ether, oxolane (THF), dioxane,
One or many in acetonitrile, dichloromethane, dichloroethanes, ethyl acetate, N,N-dimethylformamide, N-Methyl pyrrolidone
Kind;
Described phosphorus esterification reagent is preferably selected from (S)-2-[(S)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphinylidyne amido] propanoic acid isopropyl
Ester, (R)-2-[(S)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (S)-2-[(R)-(2,3,4,5,6-five
Fluoro-phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (R)-2-[(R)-(the fluoro-phenoxy group of 2,3,4,5,6-five)-phenoxy group-phosphamide
Base] isopropyl propionate, (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (R)-2-[(S)-(4-nitro-
Phenoxy group)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (S)-2-[(R)-(4-nitro-phenoxy)-phenoxy group-phosphinylidyne amido] propanoic acid isopropyl
Ester, (R)-2-[(R)-(4-nitro-phenoxy)-phenoxy group-phosphinylidyne amido] isopropyl propionate, (S)-2-((chlorine (phenoxy group) phosphinylidyne amido)
Isopropyl propionate, (R)-2-((chlorine (phenoxy group) phosphinylidyne amido) isopropyl propionate and O-2-(3-hydroxyl-2,2-Dimethylpropanoyl sulfydryl)
One or more in-O-(the fluoro-phenoxy group of 2,3,4,5,6-five)-N-benzyl phosphamide;
Compound II is 1:1~10 with the molar ratio of phosphorus esterification reagent, preferably 1:1~3;
Described step (1) and (2) carry out respectively or are carried out continuously.
4. the compound or its salt shown in below formula II:
Wherein,
R3、R6、R7WithDefinition identical with the definition in claim 1 formula I.
Compound or its salt the most according to claim 4, described Compounds of formula II is selected from:
6. the preparation method of the Compounds of formula II described in claim 4 or 5, comprises the steps:
(1) compound V and hydrocarbylating agent obtain compound through acylation reaction through hydrocarbyl reaction or with acylating reagent
IV;
(2) compound IV obtains Compounds of formula II through deprotection reaction;
Shown in the following reaction equation of course of reaction:
Wherein, R3、R6、R7WithDefinition identical with the definition in claim 1 formula of I;
Preferably,
In described hydrocarbyl reaction, compound V and corresponding hydrocarbylating agentIn the presence of a base at solvent
In carry out;Described alkali be selected from organic base or inorganic base, be preferably selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate,
One or more in triethylamine, DMAP;Described solvent be selected from N,N-dimethylformamide (DMF),
One in DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane, pyridine or
Multiple;Wherein, at described hydrocarbylating agentIn, B is methylene or CHR4, R4And R5Definition and right want
Ask the definition in 1 formula of I identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, to toluene
Sulfonate group;
Compound V is 1:1~10 with the molar ratio of hydrocarbylating agent, preferably 1:1~3;
In described acylation reaction, compound V and corresponding acylating reagentEnter the most in a solvent
OK;Described alkali be selected from organic base or inorganic base, be preferably selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, three
One or more in ethamine, DMAP;Described solvent is selected from N,N-dimethylformamide, N, N-dimethyl
One or more in acetamide, dimethyl sulfoxide, acetonitrile, acetone, toluene, dioxane, pyridine;
Wherein, at described acylating reagentIn, M is carbonyl, R5Definition and claim 1 formula of I
In definition identical, R8For leaving group, preferably halogen atom, methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group;
Compound V is 1:1~10 with the molar ratio of acylating reagent, preferably 1:1~3;
In described deprotection reaction, compound IV reacts the most in a solvent with alcohol, ammonia or amine;Described alcohol is
Selected from methanol, ethanol, isopropanol one or more, described amine is selected from methylamine, ethamine, dimethylamine, the one of diethylamine
Or multiple, described alkali is selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, carbon
Acid potassium, Feldalat NM, potassium tert-butoxide in one or more, described solvent be selected from toluene, benzene, acetone, methyl tertiary butyl ether(MTBE),
Diisopropyl ether, oxolane, dioxane, acetonitrile, dichloromethane, dichloroethanes, ethyl acetate, N,N-dimethylformamide,
One or more in N-Methyl pyrrolidone, methanol, ethanol, isopropanol, water;
Described step (1) and (2) respectively or are carried out continuously.
7. the compound of Formula I described in claim 1 or 2 or its salt use in the medicine of preparation treatment disease of viral infection
On the way.
8. the compound of Formula I described in claim 1 or 2 or its salt purposes in preparation Formula IV compound,
Wherein, R1、R2And R3Definition identical with the definition in claim 1 formula of I;Preferably, R1For different
The substituted methyl of propoxycarbonyl, R2For phenyl, R3For fluorine.
9. a pharmaceutical composition, it comprises the compound of Formula I described in claim 1 or 2 or its salt.
10. use the method that Formula IV compound prepared by the compound of Formula I described in claim 1 or 2 or its salt, as follows
Shown in reaction equation:
Described method includes:
Compound of formula I obtains Formula IV compound through C-N catalytic hydrogenolytic cleavage;Or
Compound of formula I obtains Formula IV compound through hydrolysis;
Wherein, R1、R2、R3、R6、R7WithDefinition and the definition phase in claim 1 formula of I
With;Preferably, R1For the substituted methyl of isopropoxy carbonyl, R2For phenyl, R3For fluorine;
Preferably,
Described catalytic hydrogenolytic cleavage is carried out in the presence of catalytic hydrogenation catalyst in a solvent;Described catalytic hydrogenation catalyst is preferably
One or more in palladium carbon, active nickel, platinum carbon, platinic hydroxide, platinum oxide and palladium dydroxide;Described solvent is preferably
Selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, tetrahydrochysene furan
Mutter, one or more in methanol, ethanol, isopropanol, toluene, dioxane and pyridine;
Described hydrolysis is carried out the most in a solvent;Described acidic catalyst be preferably selected from formic acid,
One or more in acetic acid, hydrogen chloride, sulphuric acid, trifluoromethanesulfonic acid and trifluoracetic acid;Described solvent be preferably selected from methanol,
Ethanol, isopropanol, water, toluene, benzene, acetone, methyl tertiary butyl ether(MTBE), diisopropyl ether, oxolane, dioxane, acetonitrile,
One or more in dichloromethane, dichloroethanes, ethyl acetate, N,N-dimethylformamide and N-Methyl pyrrolidone.
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WO2018121678A1 (en) * | 2016-12-29 | 2018-07-05 | 广东东阳光药业有限公司 | Prodrug of antiviral nucleoside analogues, and composition and use thereof |
CN111004300A (en) * | 2019-12-25 | 2020-04-14 | 江苏永安制药有限公司 | Method for preparing Sofosbuvir |
CN113354699A (en) * | 2020-03-04 | 2021-09-07 | 中国科学院上海药物研究所 | Intermediate of Reidesciclovir and preparation method thereof |
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US7964580B2 (en) * | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US20120070411A1 (en) * | 2010-09-22 | 2012-03-22 | Alios Biopharma, Inc. | Substituted nucleotide analogs |
WO2015017713A1 (en) * | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018121678A1 (en) * | 2016-12-29 | 2018-07-05 | 广东东阳光药业有限公司 | Prodrug of antiviral nucleoside analogues, and composition and use thereof |
CN108299532A (en) * | 2016-12-29 | 2018-07-20 | 广东东阳光药业有限公司 | A kind of antiviral nucleoside analogue prodrug and combinations thereof, purposes |
CN108299532B (en) * | 2016-12-29 | 2020-12-22 | 广东东阳光药业有限公司 | Antiviral nucleoside analogue prodrug and composition and application thereof |
CN111004300A (en) * | 2019-12-25 | 2020-04-14 | 江苏永安制药有限公司 | Method for preparing Sofosbuvir |
CN113354699A (en) * | 2020-03-04 | 2021-09-07 | 中国科学院上海药物研究所 | Intermediate of Reidesciclovir and preparation method thereof |
CN113354699B (en) * | 2020-03-04 | 2023-07-18 | 中国科学院上海药物研究所 | Intermediate of Ruidexivir and preparation method thereof |
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