WO2016177300A1 - (2'r)-2'-脱氧-2'-卤代-2'-甲基脲苷衍生物、其制备方法和用途 - Google Patents
(2'r)-2'-脱氧-2'-卤代-2'-甲基脲苷衍生物、其制备方法和用途 Download PDFInfo
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- GZQHZKXOXINHKU-UIYXHNAFSA-N CC(C)OC([C@@H](C)N[P@](OC[C@H](C[C@@H]1C)O[C@H]1N(C=CC(N1)=O)C1=O)(Oc1ccccc1)=O)=O Chemical compound CC(C)OC([C@@H](C)N[P@](OC[C@H](C[C@@H]1C)O[C@H]1N(C=CC(N1)=O)C1=O)(Oc1ccccc1)=O)=O GZQHZKXOXINHKU-UIYXHNAFSA-N 0.000 description 1
- OUDQYAYIRAUNLO-PDKZGUECSA-N C[C@@]1([C@H](N(C=CC(N2)=O)C2=O)O[C@H](COC(c2ccccc2)=O)[C@H]1OC(c1ccccc1)=O)F Chemical compound C[C@@]1([C@H](N(C=CC(N2)=O)C2=O)O[C@H](COC(c2ccccc2)=O)[C@H]1OC(c1ccccc1)=O)F OUDQYAYIRAUNLO-PDKZGUECSA-N 0.000 description 1
- VPUABZKPNKRERR-MMDZXOIJSA-N C[C@@]1([C@H](N(C=CC(N2)=O)C2=O)O[C@H](COC(c2ccccc2)=O)[C@H]1OC(c1ccccc1)=O)[ClH]#C Chemical compound C[C@@]1([C@H](N(C=CC(N2)=O)C2=O)O[C@H](COC(c2ccccc2)=O)[C@H]1OC(c1ccccc1)=O)[ClH]#C VPUABZKPNKRERR-MMDZXOIJSA-N 0.000 description 1
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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
Definitions
- the present invention relates to the field of medicinal chemistry, and more particularly to a compound of formula I, a process for the preparation thereof, and an intermediate for the preparation of a medicament for the treatment of a viral infection.
- a compound of formula I a process for the preparation thereof, and an intermediate for the preparation of a medicament for the treatment of a viral infection.
- Sofosbuvir (SFBV) was developed by Pharmasset and continued to be developed by Gilead Science. The published clinical phase III study showed that combination therapy with sofosbuvir (formerly known as GS-7977) + immunopotentiator Ribavirin was used to treat previously failed type 2 or type 3 hepatitis C. The patients were treated for 12 weeks and 16 weeks with satisfactory results. If sofbuvir is approved as a hepatitis C treatment, sofosbuvir will become an important component of the first all-oral combination therapy for hepatitis C treatment, with the advantages of high cure rate and low recurrence rate. . Soofibide is a prodrug that is metabolized in vivo to 2'-deoxy-2'-fluoro-2'-methyluridine-5'-monophosphate.
- sofosbuvir The synthesis of sofosbuvir is currently reported as follows:
- the present inventors have devised the synthesis of a compound represented by the following formula I, which can be used for the treatment of viral infectious diseases, and can be subjected to catalytic hydrogenation or hydrolysis under appropriate conditions. Fulbuvir and its analogues.
- a further object of the invention is to provide a process for the preparation of a compound of formula I.
- a further aspect of the invention aims to provide an intermediate for the preparation of a compound of formula I.
- a further aspect of the invention aims to provide the use of a compound of formula I for the manufacture of a medicament for the treatment of viral infectious diseases.
- It is an object of yet another aspect of the present invention to provide a pharmaceutical composition comprising a compound of formula I.
- a further aspect of the invention aims to provide the use of the compounds of the formula I in the preparation of the compounds of the formula VI.
- Another object of the invention is to provide a process for the preparation of a compound of formula VI using a compound of formula I.
- the present invention provides a compound represented by the following formula I or a salt thereof:
- R 1 is a C 1 -C 10 linear or branched alkyl group, a C 6 -C 12 aryl substituted C 1 -C 10 straight or branched alkyl group, a C 1 -C 10 straight or branched alkoxy group a carbonyl-substituted C 1 -C 10 linear or branched alkyl group, a C 6 -C 12 aryl group or a C 1 -C 10 linear or branched alkylcarbonyl group; preferably, R 1 is C 1 -C 5 Linear or branched alkyl, C 6 -C 12 aryl substituted C 1 -C 5 straight or branched alkyl, C 1 -C 5 straight or branched alkoxycarbonyl substituted C 1 -C 5 linear or branched alkyl, C 6 -C 12 aryl or C 1 -C 5 straight or branched alkylcarbonyl; more preferably, R 1 is benzyl, isopropoxy
- R 2 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted C 1 -C 10 straight or branched alkyl group, preferably, R 2 is substituted or unsubstituted as phenyl or substituted or An unsubstituted C 1 -C 5 straight or branched alkyl group; wherein the substituent is a hydroxyl group, a halogen, a nitrile group, a hydroxy-substituted C 1 -C 10 linear or branched alkylcarbonyloxy group or a hydroxyl group Substituted C 1 -C 10 linear or branched alkylcarbonylindenyl; preferably, the substituent is a hydroxy-substituted C 1 -C 5 straight or branched alkylcarbonyloxy group or a hydroxy substituted C 1 - a C 5 linear or branched alkylcarbonyl fluoreny
- R 2 is phenyl or
- R 3 is hydrogen, hydroxy, halogen, nitrile or C 1 -C 10 straight or branched alkyl; preferably, R 3 is hydrogen, hydroxy, fluoro, chloro, bromo, nitrile or C 1 -C 5 straight a chain or branched alkyl group; more preferably, R 3 is a hydroxyl group, a fluorine, a chlorine, a bromine or a nitrile group;
- A is a carbonyl group, a methylene group or a CHR 4 group .
- R 4 is a C 1 -C 10 linear or branched alkyl group, a C 1 -C 10 linear or branched alkoxy group; preferably, a C 1 -C 5 straight or branched alkyl group, C 1 -C 5 straight or branched alkoxy; more preferably, R 4 is methyl;
- R 5 is H, C 1 -C 10 linear or branched alkyl, benzyl, C 1 -C 10 straight or branched alkylcarbonyl, C 1 -C 10 straight or branched alkylaminocarbonyl, C 3 -C 8 cycloalkylaminocarbonyl, C 1 -C 10 linear or branched alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 6 -C 12 aryloxycarbonyl; preferably, R 5 is H, C 1 -C 8 straight or branched alkyl, benzyl, C 1 -C 5 straight or branched alkylcarbonyl, C 1 -C 5 straight or branched alkylaminocarbonyl, C 3 -C 8 cycloalkylaminocarbonyl, C 1 -C 5 straight or branched alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 6 -C 12
- the compound of the formula I preferably has the structure represented by the following formula I-A or I-B:
- R 1 , R 2 and R 3 are the same as defined in the above compound of the formula I, R 6 is -AR 5 , -AOR 5 ; R 7 is -OAOR 5 or -OAR 5 .
- the compound of formula I of the invention is selected from the group consisting of:
- the invention also provides a preparation method of the compound of formula I, comprising the following steps:
- R 1 , R 2 , R 3 , R 6 , R 7 and The definition is the same as defined in the aforementioned compound of the general formula I.
- compound III can be reacted with the corresponding hydrocarbylating agent It is carried out in the presence of a base in a suitable solvent.
- the base may be selected from an organic base or an inorganic base, and more preferably one or more selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, and 4-dimethylaminopyridine.
- the solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane One or more of pyridine;
- hydrocarbylating agent Wherein B is methylene or CHR 4 , and R 4 and R 5 are as defined in the above formula I, and R 8 is a leaving group, preferably a halogen atom, a mesylate group, p-toluene Sulfonate group;
- the molar ratio of the compound III to the hydrocarbylating agent is from 1:1 to 10, preferably from 1:1 to 3.
- the base may be an organic base or an inorganic base, preferably selected from the group consisting of t-butyl magnesium chloride, isopropyl magnesium chloride, phenyl magnesium chloride, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, One or more of N-methylmorpholine, potassium carbonate, and sodium hydride.
- the solvent is selected from the group consisting of toluene, benzene, acetone, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N, One or more of N-dimethylformamide and N-methylpyrrolidone.
- the phosphorylating agent may be a phosphorylating agent known in the art without particular limitation, for example, (S)-2-[(S)-(2,3,4,5,6-pentafluoro-benzene Oxy)-phenoxy-phosphoramido]isopropyl isopropylate, (R)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy Isopropylphosphonyl]isopropyl isopropylate, (S)-2-[(R)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphoramido] Isopropyl propionate, (R)-2-[(R)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphoramido]propionic acid isopropyl ester, (S)-2-[(S)-(4-Nitro-phenoxy)-phenoxy-phosphoramid
- the steps (1) and (2) may be carried out separately or continuously, that is, after the completion of the step (1), the step (2) is directly carried out without separation.
- the invention also provides a preparation method of the compound of the general formula II, comprising the following steps:
- compound V can be reacted with the corresponding hydrocarbylating agent It is carried out in the presence of a base in a suitable solvent.
- the base may be an organic base or an inorganic base, and is preferably one or more selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, and 4-dimethylaminopyridine.
- the solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane One or more of pyridine;
- hydrocarbylating agent Wherein B is methylene or CHR 4 , and R 4 and R 5 are as defined in the above formula I, and R 8 is a leaving group, preferably a halogen atom, a mesylate group, p-toluene Sulfonate group;
- the molar ratio of the compound V to the hydrocarbylating agent is from 1:1 to 10, preferably from 1:1 to 3.
- compound V can be combined with the corresponding acylating reagent It is carried out in the presence of a base in a suitable solvent.
- the base may be an organic base or an inorganic base, and is preferably one or more selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, and 4-dimethylaminopyridine.
- the solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, dioxane One or more of pyridine;
- acylating reagent Wherein M is a carbonyl group, and R 5 has the same meaning as defined in the above compound of the formula I, and R 8 is a leaving group, preferably a halogen atom, a mesylate group or a p-toluenesulfonate group;
- the molar ratio of the compound V to the acylating agent is from 1:1 to 10, preferably from 1:1 to 3.
- compound IV is reacted with an alcohol, ammonia or an amine under basic conditions in a suitable solvent to give the product.
- the alcohol is one or more selected from the group consisting of methanol, ethanol, and isopropanol
- the amine is one or more selected from the group consisting of methylamine, ethylamine, dimethylamine, and diethylamine.
- the solvent is selected from the group consisting of toluene, benzene, acetone, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N, N - one or more of dimethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, water.
- THF tetrahydrofuran
- the steps (1) and (2) may be carried out separately or continuously, that is, after the completion of the step (1), the step (2) is directly carried out without separation.
- the present invention also provides a compound of the following formula II or a salt thereof:
- the compound represented by the formula II preferably has a structure represented by the following formula II-A or II-B:
- R 3 , R 6 and R 7 are the same as defined in the formulae IA and IB.
- the above compound of formula II is selected from the group consisting of:
- the invention also provides the use of a compound of formula I or a salt thereof for the manufacture of a medicament for the treatment of a viral infectious disease.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I or a salt thereof.
- the compound of formula I or a salt thereof may be present in the pharmaceutical composition in a therapeutically effective amount.
- the pharmaceutical composition also optionally comprises conventional pharmaceutical excipients such as excipients, lubricants, coatings, sweeteners, flavors, binders, fillers, diluents, release agents, dispersants, coloring Agents, etc.
- the invention also provides the use of a compound of formula I or a salt thereof for the preparation of a compound of formula VI,
- R 1 , R 2 and R 3 have the same meanings as defined in the compound of formula I in claim 1; preferably, R 1 is an isopropoxycarbonyl substituted methyl group, R 2 is a phenyl group, R 3 It is fluorine.
- the invention also provides a process for the preparation of a compound of formula VI using a compound of formula I, as shown in the following scheme:
- the method includes:
- R 1 , R 2 , R 3 , R 6 , R 7 and The definition is the same as defined in the above compound of the formula I; preferably, R 1 is an isopropoxycarbonyl substituted methyl group, R 2 is a phenyl group, and R 3 is a fluorine;
- the catalytic hydrogenolysis reaction can be carried out in the presence of a catalytic hydrogenation catalyst in a suitable solvent.
- the catalytic hydrogenation catalyst may be a catalytic hydrogenation catalyst known in the art without particular limitation, and is preferably one or more selected from the group consisting of palladium carbon, activated nickel, platinum carbon, platinum hydroxide, platinum oxide, and palladium hydroxide.
- the solvent is not particularly limited as long as it can dissolve the compound, and preferably may be selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and dimethyl sulfoxide.
- the hydrolysis reaction can be carried out in the presence of an acidic catalyst in a suitable solvent.
- the acidic catalyst may be an acidic catalyst known in the art without particular limitation, and is preferably one or more selected from the group consisting of formic acid, acetic acid, hydrogen chloride, sulfuric acid, trifluoromethanesulfonic acid, and trifluoroacetic acid.
- the solvent is not particularly limited as long as it can dissolve the compound, and may preferably be selected from the group consisting of methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran.
- dioxane acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N,N-dimethylformamide and N-methylpyrrolidone.
- the method claimed in the present invention avoids the side reaction caused by the use of t-butyl magnesium chloride in the phosphorylation reaction by designing a new reaction route, reduces the generated impurities, and reduces the difficulty of the subsequent purification process. Moreover, it has been proved by experiments that the method claimed in the invention has mild reaction conditions, easy operation, high yield, stable product quality, high purity, and can be scaled up on an industrial scale.
- Soofibide (0.53 g, 1 mmol) was dissolved in DMF (2 ml), potassium carbonate (0.14 ml, 1 mmol) was added, and the mixture was stirred on ice for about 15 minutes, then chloromethyl acetate (108 mg, 1 mmol) was added and stirred. After 12 hours, 20 ml of ethyl acetate and 20 ml of water were added, and the mixture was stirred and evaporated.
- Soofibide (0.53 g, 1 mmol) was dissolved in DMF (2 ml), potassium carbonate (0.14 ml, 1 mmol) was added, and the mixture was stirred on ice for about 15 minutes, then chloromethyl pivalate (150 mg, 1 mmol) was added. After stirring for 12 hours, 20 ml of ethyl acetate and 20 ml of water were added, and the mixture was stirred and evaporated.
- Soofibide (0.53 g, 1 mmol) was dissolved in DMF (2 mL), EtOAc (EtOAc (EtOAc) After stirring for 12 hours, 20 ml of ethyl acetate and 20 ml of water were added, and the mixture was stirred, and the organic layer was dried over anhydrous sodium sulfate.
- Soofibide (0.53 g, 1 mmol) was dissolved in DMF (2 ml), triethylamine (0.15 g, 1 mmol) was added, and the mixture was stirred on ice for about 15 minutes, then n-pentyl chloroformate (0.15 g, 1 mmol) After stirring for 12 hours, 20 ml of ethyl acetate and 20 ml of water were added, and the mixture was stirred, and the organic layer was dried over anhydrous sodium sulfate.
- Compound IV-4 (3.4 g) was added to a mixture of 20 ml of methanol and 2 ml of triethylamine and heated to reflux for 6 hours. The solvent was removed under reduced pressure, and then 10 ml of petroleum ether and 10 ml of ethyl acetate were added, and the mixture was stirred for 0.5 hr.
- sofosbuvir was weighed and dissolved in 95% PEG 400, 5% Tween 80, and the concentration was 10 mg/mL, which was a colorless clear solution (pH ⁇ 7) for oral administration.
- ICR mice weight 18.0-19.8 g
- the oral group was fasted for 10-14 hours before administration.
- time points 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h.
- blood was collected by cardiac puncture and about 0.5 mL of blood was collected, and heparin sodium was anticoagulated.
- Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 4 ° C). The collected plasma was stored at -80 °C prior to analysis.
- the pharmacokinetic parameters of III-2 were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2, respectively, as shown in the following table.
- mice with a single oral dose of sofosbuvir, I-18, and I-19 mice with a single oral dose of sofosbuvir, I-18, and I-19
Abstract
本发明公开了式I化合物及其制备方法和中间体;式I化合物用于制备治疗病毒感染疾病药物的用途;式I化合物在制备索氟布韦及其类似物中的用途以及使用式I化合物制备索氟布韦及其类似物的方法。本发明要求保护的方法通过设计新的反应路线,避免了磷酰化反应中使用叔丁基氯化镁引起的副反应,减少了生成的杂质,降低了后续的纯化工序的难度。而且经试验证明,本发明要求保护的方法,反应条件温和,易于操作,收率高,得到的产物质量稳定,纯度高,可以进行工业规模放大生产。
Description
本发明涉及药物化学领域,更具体而言,涉及式I化合物及其制备方法和中间体,所述式I化合物在制备治疗病毒感染疾病药物中的用途,所述式I化合物在制备索氟布韦及其类似物中的用途以及使用所述式I化合物制备索氟布韦及其类似物的方法。
索氟布韦(Sofosbuvir,SFBV)由Pharmasset公司开发,由Gilead Science公司继续后期开发。已经公布的临床三期研究结果表明,使用索氟布韦(之前名为GS-7977)+免疫增强剂利巴韦林(Ribavirin)的组合疗法对之前治疗失败的2型或3型C型肝炎患者进行为期12周和16周的治疗,治疗结果令人满意。索氟布韦作为丙型肝炎治疗药物若获批,那么索氟布韦将成为用于丙肝治疗的首个全口服组合治疗方案中的重要组成部分,同时具有治愈率高、复发率低的优势。索氟布韦是一种前药,在体内被代谢为2’-脱氧-2’-氟-2’-甲基尿苷-5’-单磷酸酯。
目前报道索氟布韦的合成方法如下:
在文献(Journal of Organic Chemistry,76(20),8311-8319;2011)中,以式III化合物为原料进行磷酰化反应得到索氟布韦,但是这种方法中的磷酰化反应需要用叔丁基氯化镁作为碱,叔丁基氯化镁可以与尿嘧啶碱基N原子上的氢发生反应,消耗一当量叔丁基氯化镁,并且会引起副反应,生成杂质,给后面的纯化带来困难。
发明内容
针对上述技术问题,本发明人设计合成了以下通式I所示的化合物,所述通式I化合物可以用于治疗病毒感染性疾病,并可以在适当的条件下进行催化氢化或水解反应得到索氟布韦及其类似物。
因此,本发明一方面的目的在于提供通式I所示的化合物或其盐。
本发明的再一方面的目的在于提供通式I化合物的制备方法。
本发明的再一方面的目的在于提供用于制备通式I化合物的中间体。
本发明的又一方面的目的在于提供通式I化合物用于制备治疗病毒感染性疾病药物的用途。
本发明的又一方面的目的在于提供一种药物组合物,其包含通式I化合物。
本发明的又一方面的目的在于提供所述通式I化合物在制备式VI化合物中的用途。
本发明的另一方面的目的在于提供一种使用通式I化合物制备式VI化合物的方法。
为了实现上述发明目的,本发明采用如下的技术方案:
本发明提供如下通式I所示的化合物或其盐:
其中,在以上通式I中,各取代基的定义如下:
R1为C1-C10直链或支链烷基、C6-C12芳基取代的C1-C10直链或支链烷基、C1-C10直链或支链烷氧基羰基取代的C1-C10直链或支链烷基、C6-C12芳基或C1-C10直链或支链烷基羰基;优选地,R1为C1-C5直链或支链烷基、C6-C12芳基取代的C1-C5直链或支链烷基、C1-C5直链或支链烷氧基羰基取代的C1-C5直链或支链烷基、C6-C12芳基或C1-C5直链或支链烷基羰基;更优选地,R1为苯甲基、异丙氧基羰基取代的甲基。
R2为取代或未取代的C6-C12芳基或取代或未取代的C1-C10直链或支链烷基,优选地,R2为取代或未取代为苯基或取代或未取代的C1-C5直链或支链烷基;其中,所述取代基为羟基、卤素、腈基、羟基取代的C1-C10直链或支链烷基羰基氧基或羟基取代的C1-C10直链或支链烷基羰基巯基;优选地,所述取代基为羟基取代的C1-C5直链或支链烷基羰基氧基或羟基取代的C1-C5直链或支链烷基羰基巯基;
R3为氢、羟基、卤素、腈基或C1-C10直链或支链烷基;优选地,R3为氢、羟基、氟、氯、溴、腈基或C1-C5直链或支链烷基;更优选地,R3为羟基、氟、氯、溴或腈基;
A为羰基、亚甲基或CHR4,
其中,
R4为C1-C10直链或支链烷基、C1-C10直链或支链烷氧基;优选地,C1-C5直链或支链烷基、C1-C5直链或支链烷氧基;更优选地,R4为甲基;
R5为H、C1-C10直链或支链烷基、苄基、C1-C10直链或支链烷基羰基、C1-C10直链或支链烷基氨基羰基、C3-C8环烷基氨基羰基、C1-C10直链或支链烷氧基羰基、C3-C8环烷氧基羰基、C6-C12芳氧基羰基;优选地,R5为H、C1-C8直链或支链烷基、苄基、C1-C5直链或支链烷基羰基、C1-C5直链或支链烷基氨基羰基、C3-C8环烷基氨基羰基、C1-C5直链或支链烷氧基羰基、C3-C8环烷氧基羰基、C6-C12芳氧基羰基;更优选地,R5为甲基、叔丁基、正戊基、苄基、乙酰基、乙氧基羰基、环己基氧羰基。
进一步地,通式I所示的化合物优选具有如下通式I-A或I-B所示的结构:
在通式I-A和I-B中,R1、R2和R3的定义与以上通式I化合物中的定义相同,R6为-A-R5、-A-O-R5;R7为-O-A-O-R5或-O-A-R5。
最优选地,本发明的通式I化合物选自:
本发明还提供了通式I化合物的制备方法,包括如下步骤:
(1)化合物III与烃基化试剂经过烃基化反应得到化合物II;
(2)化合物II与磷酰化试剂经磷酰化反应得到通式I化合物;
反应过程如下反应式所示:
在所述烃基化反应中,化合物III可以与相应的烃基化试剂在碱存在的条件下,在合适的溶剂中进行。所述的碱可以选自有机碱或无机碱,更优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种。所述的溶剂可以为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、甲苯、二
氧六环、吡啶中的一种或多种;
化合物III与烃基化试剂的摩尔比例为1:1~10,优选为1:1~3。
在所述磷酰化反应中,化合物II与相应的磷酰化试剂在碱存在下,在合适的溶剂中进行。所述碱可以为有机碱或无机碱,优选为选自叔丁基氯化镁、异丙基氯化镁、苯基氯化镁、三乙胺、吡啶、4-二甲基氨基吡啶、二异丙基乙胺、N-甲基吗啉、碳酸钾、氢化钠中的一种或多种。所述溶剂为选自甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃(THF)、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮中的一种或多种。
所述磷酰化试剂可以为本领域中已知的磷酰化试剂而没有特殊限制,例如(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(R)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(R)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(S)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(S)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(R)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(R)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-((氯(苯氧基)磷酰胺基)丙酸异丙酯、(R)-2-((氯(苯氧基)磷酰胺基)丙酸异丙酯、O-2-(3-羟基-2,2-二甲基丙酰基巯基)-O-(2,3,4,5,6-五氟-苯氧基)-N-苄基磷酰胺;化合物II与磷酰化试剂的摩尔比例为1:1~10,优选为1:1~3。
所述步骤(1)和(2)可以分别进行,也可以连续进行,即在步骤(1)完成后不经分离直接进行步骤(2)。
本发明还提供了一种通式II化合物的制备方法,包括如下步骤:
(1)化合物V与烃基化试剂经过烃基化反应或者与酰化试剂经过酰化反应得到化合物IV;
(2)化合物IV经过脱保护反应得到通式II化合物;
反应过程如下反应式所示:
在所述烃基化反应中,化合物V可以与相应的烃基化试剂在碱存在的条件下,在合适的溶剂中进行。所述的碱可以为有机碱或无机碱,优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种。所述的溶剂可以为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、甲苯、二氧六环、吡啶中的一种或多种;
化合物V与烃基化试剂的摩尔比例为1:1~10,优选为1:1~3。
在所述酰化反应中,化合物V可以与相应的酰化试剂在碱存在的条件下,在合适的溶剂中进行。所述的碱可以为有机碱或无机碱,优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种。所述的溶剂可以为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、甲苯、二氧六环、吡啶中的一种或多种;
化合物V与酰化试剂的摩尔比例为1:1~10,优选为1:1~3。
在所述脱保护反应中,化合物IV与醇、氨气或胺在碱性条件下在合适的溶剂中反应得到产物。所述醇为选自甲醇、乙醇、异丙醇的一种或多种,所述胺为选自甲胺、乙胺、二甲胺、二乙胺的一种或多种,所述碱可以为选自三乙胺、吡啶、4-二甲基氨基吡啶、二异丙基乙胺、N-甲基吗啉、碳酸钾、甲醇钠、叔丁醇钾中的一种或多种,所述溶剂为选自甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃(THF)、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、异丙醇、水中的一种或多种。
所述步骤(1)和(2)可以分别进行,也可以连续进行,即在步骤(1)完成后不经分离直接进行步骤(2)。
本发明还提供如下通式II所示的化合物或其盐:
进一步地,通式II所示的化合物优选具有如下通式II-A或II-B所示的结构:
在通式II-A和II-B中,R3、R6和R7的定义与通式I-A和I-B中的定义相同。
更优选地,上述通式II化合物选自:
本发明还提供通式I化合物或其盐在制备治疗病毒感染性疾病药物中的用途。
本发明还提供一种药物组合物,其包含通式I化合物或其盐。所述通式I化合物或其盐可以以治疗有效量存在于药物组合物中。所述药物组合物还任选包含常规的药物辅料,例如赋形剂、润滑剂、包衣剂、甜味剂、风味剂、粘合剂、填料、稀释剂、防粘剂、分散剂、着色剂等。
本发明还提供所述通式I化合物或其盐在制备式VI化合物中的用途,
其中,R1、R2和R3的定义与权利要求1中通式I化合物中的定义相同;优选地,R1为异丙氧基羰基取代的甲基,R2为苯基,R3为氟。
本发明还提供一种使用通式I化合物制备式VI化合物的方法,如下反应式所示:
所述方法包括:
式I化合物经C-N催化氢解反应得到式VI化合物;或者
式I化合物经水解反应得到式VI化合物;
优选地,
所述催化氢解反应可以在催化氢化催化剂存在下,在合适的溶剂中进行。所述催化氢化催化剂可以为本领域中已知的催化氢化催化剂而没有特殊限制,优选为选自钯碳、活性镍、铂碳、氢氧化铂、氧化铂和氢氧化钯中的一种或多种。所述溶剂没有特殊限制,只要其可以溶解所述化合物即可,优选可以为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、乙酸乙酯、四氢呋喃、甲醇、乙醇、异丙醇、甲苯、二氧六环和吡啶中的一种或多种;
所述的水解反应可以在酸性催化剂存在下,在合适的溶剂中进行。所述的酸性催化剂可以为本领域中已知的酸性催化剂而没有特殊限制,优选为选自甲酸、乙酸、氯化氢、硫酸、三氟甲磺酸和三氟醋酸中的一种或多种。所述溶剂没有特殊限制,只要其可以溶解所述化合物即可,优选可以为选自甲醇、乙醇、异丙醇、水、甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺和N-甲基吡咯烷酮中的一种或多种。
本发明要求保护的方法通过设计新的反应路线,避免了磷酰化反应中使用叔丁基氯化镁引起的副反应,减少了生成的杂质,降低了后续的纯化工序的难度。而且经试验证明,本发明要求保护的方法,反应条件温和,易于操作,收率高,得到的产物质量稳定,纯度高,可以进行工业规模放大生产。
实施例1:
将化合物III-2(0.260g,1mmol)溶于DMF(2ml)中,加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)(0.30ml,2mmol),冰浴,搅拌约15分钟后,加入氯甲基甲醚(76μl,1mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物II-1(200mg)。
1HNMR(300MHz,DMSO):8.05(d,J=8.23Hz,1H),6.01(d,J=18.28Hz,1H),5.80(d,J=8.21Hz,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).
实施例2:
将化合物II-1(0.76g,2mmol)溶于THF(10mL)中,冷却至-5℃,加入叔丁基氯化镁(2.4mL,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得917mg化合物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).
实施例3:
将化合物I-1(100mg,0.17mmol)溶于四氢呋喃(4ml)中,加入1ml 10%的盐酸,加热反应,约4小时后反应完全,柱层析得索氟布韦(10mg)。
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).
实施例4:
将化合物I-5(100mg,0.17mmol)溶于四氢呋喃(4ml)中,加入1ml 10%的盐酸,加热反应,约4小时后反应完全,柱层析得VI-1(60mg)。
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).
实施例5:
将化合物I-5(100mg,0.17mmol)溶于甲醇(4ml)中,加入10%的钯碳(10mg),室温搅拌反应,约48小时后反应完全,柱层析得VI-1(60mg)。
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).
实施例6:
将化合物III-2(0.26g,1mmol)溶于DMF(2ml)中,加入DBU(0.30mL,2mmol),冰浴,搅拌约15分钟后,加入BnOCH2Cl(0.26ml,1.8mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物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)
实施例7:
将化合物V-2(6.7g,14.3mmol)溶于20ml N,N-二甲基甲酰胺中,依次加入碘化钠(0.43g,2.86mmol),N,N-二异丙基乙胺(4g,28.6mmol),苄基氯甲基醚(2.68g,17.2mmol),25度搅拌24小时,加入40ml乙酸乙酯,40ml水,搅拌,静置分液,有机层用20ml饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,所得油状物为粗品IV-2,直接用于下一步反应。
化合物IV-2(3.4g)加入至20ml甲醇与2ml三乙胺的混合物中,加热回流6小时。减压除去溶剂,依次加入10ml石油醚和10ml乙酸乙酯,搅拌0.5小时,过滤得到2.06g白色固体产物II-2,收率94%。
将化合物II-2(0.76g,2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物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).
实施例8:
I-2→索氟布韦
将I-2(100mg,0.15mmol)溶于甲醇(4ml)中,加入钯碳(10mg),通氢气,约4小时后TLC显示原料已反应完全,过滤,浓缩,柱层析得索氟布韦(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).
实施例9:
将化合物III-2(0.26g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.3g,2mmol),冰浴,搅拌约15分钟后,加入BnOCH2Cl(0.26ml,1.8mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物II-3(290mg)。
实施例10:
将化合物III-3(0.276g,1mmol)溶于DMF(2ml)中,加入DBU(0.30mL,2mmol),冰浴,搅拌约15分钟后,加入氯甲基甲醚(0.16g,2mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物II-4(260mg)。
1HNMR(300MHz,DMSO):8.07(d,J=8.23Hz,1H),6.07(d,J=18.28Hz,1H),5.78(d,J=8.21Hz,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).
实施例11:
将化合物III-3(0.276g,1mmol)溶于DMF(2ml)中,加入DBU(0.30mL,2mmol),冰浴,搅拌约15分钟后,加入BnOCH2Cl(0.26ml,1.8mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物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).
实施例12:
II-5→I-5
将化合物II-5(0.76g,2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物I-5(1.065g)。
实施例13:
将化合物III-3(0.26g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.3g,2mmol),冰浴,搅拌约15分钟后,加入BnOCH2Cl(0.26ml,1.8mmol),约1小时后TLC显示原料已基本反应完全,加入约1ml甲醇淬灭反应,浓缩柱层析得化合物II-6(200mg)。
实施例14:
II-6→I-6
将化合物II-6(2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物I-6(0.8g)。
实施例15:
将化合物III-2(1mmol)溶于DMF(2ml)中,加入DBU(0.30mL,2mmol),冰浴,搅拌约15分钟后,加入1-氯乙基环己基碳酸酯(1.8mmol),约1小时后TLC显示原料已基本反应完全,浓缩柱层析得化合物II-8(210mg)。
实施例16:
II-8→I-8
将化合物II-8(2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物I-8(0.6g)。
实施例17:
将化合物III-3(1mmol)溶于DMF(2ml)中,加入DBU(0.30mL,2mmol),冰浴,搅拌约15分钟后,加入1-氯乙基乙酸酯(1.8mmol),约1小时后TLC显示原料已基本反应完全,浓缩柱层析得化合物II-10(250mg)。
实施例18:
II-10→I-10
将化合物II-10(2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物I-10(0.9g)。
实施例19:
II-7→I-14
将化合物II-7(2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入苯氧基苯氧基S-(2-(((苄基胺基)氯代磷酰基)氧基)乙基)-3-羟基-2,2-二甲基硫代丙酸酯(2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物I-14(0.2g)。
实施例20:
将索氟布韦(0.53g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.14ml,1mmol),冰浴,搅拌约15分钟后,加入醋酸氯甲酯(108mg,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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)
实施例21:
将索氟布韦(0.53g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.14ml,1mmol),冰浴,搅拌约15分钟后,加入特戊酸氯甲酯(150mg,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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=18.6Hz,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)
实施例22:
将索氟布韦(0.53g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.14ml,1mmol),冰浴,搅拌约15分钟后,加入1-氯乙基碳酸乙酯(152mg,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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)
实施例23:
将索氟布韦(0.53g,1mmol)溶于DMF(2ml)中,加入三乙胺(0.15g,1mmol),冰浴,搅拌约15分钟后,加入氯甲酸正戊酯(0.15g,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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)
实施例24:
将N-[[P(S),2'R]-2'-去氧-2'-氟-2'-甲基-P-苯基-5'-尿苷基]-D-丙氨酸1-甲基乙基酯(0.53g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.14ml,1mmol),冰浴,搅拌约15分钟后,加入1-氯乙基碳酸乙酯(152mg,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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)
实施例25:
将N-[[P(S),2'R]-2'-去氧-2'-氯-2'-甲基-P-苯基-5'-尿苷基]-D-丙氨酸1-甲基乙基酯(0.545g,1mmol)溶于DMF(2ml)中,加入碳酸钾(0.14ml,1mmol),冰浴,搅拌约15分钟后,加入1-氯乙基碳酸乙酯(152mg,1mmol),搅拌12小时,加入20ml乙酸乙酯,20ml水,搅拌,分液,有机层用无水硫酸钠干燥,浓缩柱层析得化合物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)
实施例26:
将化合物V-2(6.7g,14.3mmol)溶于20mlN,N-二甲基甲酰胺中,依次加入N,N-二异丙基乙胺(4g,28.6mmol)和氯甲酸正戊酯(17.2mmol),25度搅拌24小时,加入40ml乙酸乙酯,40ml水,搅拌,静置分液,有机层用20ml饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,所得油状物为粗品IV-3,直接用于下一步反应。
化合物IV-3(3.4g)加入至20ml甲醇与2ml三乙胺的混合物中,加热回流6小时。减压除去溶剂,依次加入10ml石油醚和10ml乙酸乙酯,搅拌0.5小时,过滤得到1g白色固体产物II-17。
将化合物II-17(0.76g,2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物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)
实施例27:
将化合物V-3(14.3mmol)溶于20ml N,N-二甲基甲酰胺中,依次加入N,N-二异丙基乙胺(4g,28.6mmol)和氯甲酸正戊酯(17.2mmol),25度搅拌24小时,加入40ml乙酸乙酯,40ml水,搅拌,静置分液,有机层用20ml饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,所得油状物直接用于下一步反应。
化合物IV-4(3.4g)加入至20ml甲醇与2ml三乙胺的混合物中,加热回流6小时。减压除去溶剂,依次加入10ml石油醚和10ml乙酸乙酯,搅拌0.5小时,过滤得到1.2g白色固体产物II-20。
将化合物II-20(0.76g,2mmol)溶于四氢呋喃(10ml)中,冷却至-5℃,加入叔丁基氯化镁(2.4ml,2.4mmol),搅拌30分钟,升至室温搅拌30分钟,冷却至5℃,加入(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯(1.09g,2.4mmol),反应约4小时后TLC显示基本反应完全,柱层析得化合物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)
实施例28
28.1受试物配制
称取适量索氟布韦,溶于95%PEG 400,5%Tween 80中,配制浓度为10mg/mL,为无色澄清溶液(pH~7),用于口服给药。
称取适量I-18,溶于95%PEG 400,5%Tween 80中,配制浓度为12.2mg/mL,为淡黄色澄清溶液(pH~7),用于口服给药。
称取适量I-19,溶于95%PEG 400,5%Tween 80中,配制浓度为12.2mg/mL,为淡黄色澄清溶液(pH~7),用于口服给药。
28.2给药剂量与给药方式
雄性ICR小鼠72只(体重18.0-19.8g),购于上海西普尔-必凯实验动物有限公司。按下表给药。口服组给药前禁食10-14小时。剂量:索氟布韦(100mg/Kg),I-18(122mg/Kg),I-19(122mg/Kg)给药后4小时后恢复饲料。
28.3样本采集及处理
每个时间点三个动物用于采血,时间点为:15min,30min,1h,2h,4h,6h,8h和24h。每只动物安乐死后经心脏穿刺采血采约0.5mL血液,肝素钠抗凝。血液样本采集后置于冰上,离心分离血浆(离心条件:8000转/分钟,6分钟,4℃)。收集的血浆分析前存放于-80℃。
28.4仪器设备
Waters UPLC色谱仪(岛津)。质谱仪(API4000,美国应用生物系统公司),电喷雾离子源(ESI),串联四极杆质量分析器。数据处理系统为Analyst软件(美国应用生物系统公司,软件版本号1.5.1)。
28.5药代动力学结果
根据药物的血药浓度数据,使用药代动力学计算软件WinNonlin5.2非房室模型分别计算III-2的药代动力学参数,见下表。
小鼠单次口服给予索氟布韦,I-18,I-19后III-2主要药动学参数
实验结果表明:化合物I-18和I-19具有与索氟布韦相似的药代动力学性质,化合物I-19的代谢时间较索氟布韦慢。
Claims (10)
- 如下通式I所示的化合物或其盐:其中,R1为C1-C10直链或支链烷基、C6-C12芳基取代的C1-C10直链或支链烷基、C1-C10直链或支链烷氧基羰基取代的C1-C10直链或支链烷基、C6-C12芳基或C1-C10直链或支链烷基羰基;优选地,R1为C1-C5直链或支链烷基、C6-C12芳基取代的C1-C5直链或支链烷基、C1-C5直链或支链烷氧基羰基取代的C1-C5直链或支链烷基、C6-C12芳基或C1-C5直链或支链烷基羰基;更优选地,R1为苯甲基、异丙氧基羰基取代的甲基;R2为取代或未取代的C6-C12芳基或取代或未取代的C1-C10直链或支链烷基,优选地,R2为取代或未取代为苯基或取代或未取代的C1-C5直链或支链烷基;其中,所述取代基为羟基、卤素、腈基、羟基取代的C1-C10直链或支链烷基羰基氧基或羟基取代的C1-C10直链或支链烷基羰基巯基;优选地,所述取代基为羟基取代的C1-C5直链或支链烷基羰基氧基或羟基取代的C1-C5直链或支链烷基羰基巯基;R3为氢、羟基、卤素、腈基或C1-C10直链或支链烷基;优选地,R3为氢、羟基、氟、氯、溴、腈基或C1-C5直链或支链烷基;更优选地,R3为羟基、氟、氯、溴或腈基;A为羰基、亚甲基或CHR4,其中,R4为C1-C10直链或支链烷基、C1-C10直链或支链烷氧基;优选地,C1-C5直链或支链烷基、C1-C5直链或支链烷氧基;更优选地,R4为甲基;R5为H、C1-C10直链或支链烷基、苄基、C1-C10直链或支链烷基羰基、C1-C10直链或支链烷基氨基羰基、C3-C8环烷基氨基羰基、C1-C10直链或支链烷氧基羰基、C3-C8环烷氧基羰基、 C6-C12芳氧基羰基;优选地,R5为H、C1-C8直链或支链烷基、苄基、C1-C5直链或支链烷基羰基、C1-C5直链或支链烷基氨基羰基、C3-C8环烷基氨基羰基、C1-C5直链或支链烷氧基羰基、C3-C8环烷氧基羰基、C6-C12芳氧基羰基;更优选地,R5为甲基、叔丁基、正戊基、苄基、乙酰基、乙氧基羰基、环己基氧羰基。
- 权利要求1或2所述的通式I化合物的制备方法,包括如下步骤:(1)化合物III与烃基化试剂经过烃基化反应得到化合物II;(2)化合物II与磷酰化试剂经磷酰化反应得到通式I化合物;反应过程如下反应式所示:优选地,在所述烃基化反应中,化合物III与相应的烃基化试剂在碱存在的条件下在溶剂中进行;所述的碱选自有机碱或无机碱,更优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种;所述的溶剂为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、甲苯、二氧六环、吡啶中的一种或多种;化合物III与烃基化试剂的摩尔比例为1:1~10,优选为1:1~3;在所述磷酰化反应中,化合物II与相应的磷酰化试剂在碱存在下在溶剂中进行;所述碱选自有机碱或无机碱,更优选为选自叔丁基氯化镁、异丙基氯化镁、苯基氯化镁、三乙胺、 吡啶、4-二甲基氨基吡啶、二异丙基乙胺、N-甲基吗啉、碳酸钾、氢化钠中的一种或多种;所述溶剂优选为选自甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃(THF)、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮中的一种或多种;所述磷酰化试剂优选为选自(S)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(S)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(R)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(R)-(2,3,4,5,6-五氟-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(S)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(S)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-[(R)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(R)-2-[(R)-(4-硝基-苯氧基)-苯氧基-磷酰胺基]丙酸异丙酯、(S)-2-((氯(苯氧基)磷酰胺基)丙酸异丙酯、(R)-2-((氯(苯氧基)磷酰胺基)丙酸异丙酯和O-2-(3-羟基-2,2-二甲基丙酰基巯基)-O-(2,3,4,5,6-五氟-苯氧基)-N-苄基磷酰胺中的一种或多种;化合物II与磷酰化试剂的摩尔比例为1:1~10,优选为1:1~3;所述步骤(1)和(2)分别进行或连续进行。
- 权利要求4或5所述的通式II化合物的制备方法,包括如下步骤:(1)化合物V与烃基化试剂经过烃基化反应或者与酰化试剂经过酰化反应得到化合物IV;(2)化合物IV经过脱保护反应得到通式II化合物;反应过程如下反应式所示:优选地,在所述烃基化反应中,化合物V与相应的烃基化试剂在碱存在的条件下在溶剂中进行;所述的碱选自有机碱或无机碱,优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种;所述的溶剂为选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲基亚砜(DMSO)、乙腈、丙酮、甲苯、二氧六环、吡啶中的一种或多种;其中,在所述烃基化试剂中,B为亚甲基或CHR4,R4和R5的定义与权利要求1中通式I化合物中的定义相同,R8为离去基团,优选为卤素原子、甲磺酸酯基、对甲苯磺酸酯基;化合物V与烃基化试剂的摩尔比例为1:1~10,优选为1:1~3;在所述酰化反应中,化合物V与相应的酰化试剂在碱存在的条件下在溶剂中进行;所述的碱选自有机碱或无机碱,优选为选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、4-二甲氨基吡啶中的一种或多种;所述的溶剂为选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、丙酮、甲苯、二氧六环、吡啶中的一种或多种;化合物V与酰化试剂的摩尔比例为1:1~10,优选为1:1~3;在所述脱保护反应中,化合物IV与醇、氨气或胺在碱性条件下在溶剂中反应;所述醇为选自甲醇、乙醇、异丙醇的一种或多种,所述胺为选自甲胺、乙胺、二甲胺、二乙胺的一种或多种,所述碱为选自三乙胺、吡啶、4-二甲基氨基吡啶、二异丙基乙胺、N-甲基吗啉、碳酸钾、甲醇钠、叔丁醇钾中的一种或多种,所述溶剂为选自甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、异丙醇、水中的一种或多种;所述步骤(1)和(2)分别或连续进行。
- 权利要求1或2所述的通式I化合物或其盐在制备治疗病毒感染性疾病的药物中的用途。
- 一种药物组合物,其包含权利要求1或2所述的通式I化合物或其盐。
- 一种使用权利要求1或2所述的通式I化合物或其盐制备式VI化合物的方法,如下反应式所示:所述方法包括:式I化合物经C-N催化氢解反应得到式VI化合物;或者式I化合物经水解反应得到式VI化合物;优选地,所述催化氢解反应在催化氢化催化剂存在下在溶剂中进行;所述催化氢化催化剂优选为选自钯碳、活性镍、铂碳、氢氧化铂、氧化铂和氢氧化钯中的一种或多种;所述溶剂优选为选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、丙酮、乙酸乙酯、四氢呋喃、甲醇、乙醇、异丙醇、甲苯、二氧六环和吡啶中的一种或多种;所述的水解反应在酸性催化剂存在下在溶剂中进行;所述的酸性催化剂优选为选自甲酸、乙酸、氯化氢、硫酸、三氟甲磺酸和三氟醋酸中的一种或多种;所述溶剂优选为选自甲醇、乙醇、异丙醇、水、甲苯、苯、丙酮、甲基叔丁基醚、异丙醚、四氢呋喃、二氧六环、乙腈、二氯甲烷、二氯乙烷、乙酸乙酯、N,N-二甲基甲酰胺和N-甲基吡咯烷酮中的一种或多种。
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