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CN113880883A - Preparation method of nucleoside phosphate prodrug - Google Patents

Preparation method of nucleoside phosphate prodrug Download PDF

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Publication number
CN113880883A
CN113880883A CN202111332813.7A CN202111332813A CN113880883A CN 113880883 A CN113880883 A CN 113880883A CN 202111332813 A CN202111332813 A CN 202111332813A CN 113880883 A CN113880883 A CN 113880883A
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Prior art keywords
ethyl acetate
mmol
phosphate ester
compound
nucleoside
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褚定军
倪峰
吴凡
张毅
谢晓强
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Aurisco Pharmaceutical Co ltd
Ningbo University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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  • Organic Chemistry (AREA)
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Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a nucleoside phosphate ester prodrug, wherein a diphenol phosphate intermediate A and an alcohol compound B are subjected to transesterification reaction to obtain the nucleoside phosphate ester prodrug.

Description

Nucleoside phosphate prodrug preparation method
Technical Field
The invention relates to a preparation method of a nucleoside phosphate ester prodrug, belonging to the field of pharmaceutical chemicals.
Background
Nucleoside antiviral drugs are drugs which are widely applied clinically and used for treating infection of Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Herpes virus (HSV) and the like. Representative drugs, tenofovir, adefovir, cidofovir and the like, have very good activity against DNA virus and retrovirus infection, but the polar phosphate group in the structure of the drugs causes the drugs to have low bioavailability and cell penetrability. On the basis of the structures, further research shows that phosphate groups are protected to prepare phosphate and phosphoramide prodrugs, so that the bioavailability can be greatly improved, and the toxic and side effects of the drugs can be greatly improved. Therefore, the prodrug research strategy is the main research direction of the drugs, and the feasibility of the research is proved by the successful marketing of the drug in the same weight as tenofovir disoproxil fumarate, tenofovir alafenamide, adefovir dipivoxil and the like.
The phosphate ester prodrug is synthesized by alkylating nucleoside analogues, strongly acidic deprotecting and alkylating. The prior production process has the defects of long steps, low yield, high cost, more three wastes and the like. Therefore, the method for synthesizing the nucleoside phosphate ester prodrug has important practical significance, is low in cost, simple to operate, less in three wastes and compatible with different types of nucleoside phosphate ester prodrugs.
Disclosure of Invention
The invention aims to provide a novel preparation method of a nucleoside phosphate ester prodrug, which is to develop an alcohol exchange condition of alcohol and active diphenyl ester, realize the synthesis of a target compound by one-step reaction, simultaneously avoid the use of strong acid and chlorinated substances with high toxicity, improve the safety of generation, reduce the cost, discharge of three wastes and the like.
The invention provides a preparation method of a nucleoside phosphate ester prodrug, which is characterized in that a diphenol phosphate ester intermediate A and an alcohol compound B are subjected to transesterification reaction to obtain the nucleoside phosphate ester prodrug, and the method comprises the following steps:
Figure DEST_PATH_IMAGE002
diphenolate compound A (1.0 equiv.) is dissolved in dry solvent followed by addition of alcohol compound B (2.0-4.0 equiv.) and base (2.0-5.0 equiv.). And after the reagent is added, stirring the mixture at normal temperature for overnight, and performing post-treatment and purification to obtain a corresponding product C.
Preferably, the above technical means is that R1Is selected from
Figure DEST_PATH_IMAGE004
；
R2Is selected from
Figure DEST_PATH_IMAGE006
。
In the above aspect, the base is preferably one or more selected from potassium carbonate, potassium tert-butoxide, triethylamine, pyridine, imidazole, 4-Dimethylaminopyridine (DMAP), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo non-5-ene (DBN), Tetramethylguanidine (TMG), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD).
Preferably, the solvent is selected from acetonitrile (CH)3CN), Dichloromethane (DCM), 1, 2-Dichloroethane (DCE), N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and Tetrahydrofuran (THF).
Through the implementation of the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the invention realizes the rapid synthesis of different nucleoside prodrugs by exchanging the nucleoside diphenyl phosphate intermediate with alcohol under the catalysis of alkali, realizes the synthesis of a target compound by one-step reaction, avoids the use of strong acid and chlorinated substances with high toxicity, can improve the safety of the generation, and reduces the cost and the discharge of three wastes.
Detailed Description
The implementation procedures and the resulting advantages described in detail below by specific examples are intended to help the reader to better understand the essence and features of the present invention, and are not intended to limit the implementable scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR was measured using a (Bruker ADVANCE III 500 MHz) nuclear magnetic spectrometer using deuterated chloroform (CDCl)3) Deuterated dimethyl sulfoxide (DMSO-d 6), internal standard Tetramethylsilane (TMS), 1H NMR information is tabulated in the following format: chemical shifts (multiplet (s, singlet: d, doublet: t, triplet: q, quartet; m, multiplet), number of protons).
For MS measurement, a silica gel plate for thin layer chromatography (Thermo Q active Plus) is selected from HSGF254 of Taiwan yellow sea or GF254 of Qingdao island, and a silica gel plate for Thin Layer Chromatography (TLC) is selected from 0.20mm-0.25 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by methods known in the art or purchased from Annaiji chemistry, Merlin chemistry, Bid medicine, pharmaceutical products of the national drug group, Inc., Bailingwei science and technology Co., Sigma-Aldrich, etc.
Example 1:
Figure DEST_PATH_IMAGE008
compound 1 (439 mg,1.0 mmol) was dissolved in 5mL of dry acetonitrile, followed by the addition of ethanol (175 uL,3.0 mmol) and DBU (0.45 mL, 3.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 2 as a pale yellow solid (0.196 g, 57% yield).
1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.97 (s, 1H), 5.80 (br.s, 2H), 4.36 (dd, J = 14.4 Hz and J = 7.7 Hz, 1 H,), 4.00-4.18 (m, 5H), 3.90-3.94 (m, 1H), 3.55-3.86 (m, 2H), 1.30 (t, J = 7.1Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H).
LC-MS m/z = 344.14 [M+1]
Example 2:
Figure DEST_PATH_IMAGE010
compound 1 (439 mg,1.0 mmol) was dissolved in 5mL of dry acetonitrile, followed by the addition of ethanol (175 uL,3.0 mmol) and TMG (0.461 g,4.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 2 as a pale yellow solid (0.110 g, 32% yield).
Example 3:
Figure DEST_PATH_IMAGE012
compound 1 (439 mg,1.0 mmol) was dissolved in 5mL of dry acetonitrile, followed by the addition of ethanol (175 uL,3.0 mmol) and imidazole (0.204 g,3.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 2 as a pale yellow solid (0.038 g, 11% yield).
Example 4:
Figure DEST_PATH_IMAGE014
compound 1 (439 mg,1.0 mmol) was dissolved in 5mL of dry tetrahydrofuran, followed by addition of benzyl alcohol (300 uL,3.0 mmol) and potassium tert-butoxide (336 mg,3.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 3 as a pale yellow oil, compound intermediate 3 was obtained as a colorless solid (0.214 g, yield 46%).
1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 8.03 (s, 1H), 7.37-7.26 (m, 10H), 5.6 (br.s, 2H), 5.00 (dt, J = 8.4, 0.9 Hz, 4H), 4.20-4.13 (m, 1H), 4.19-4.08 (m, 2H), 3.95-3.85 (m, 2H), 1.25 (d, J = 5.0 Hz, 3H).
LC-MS m/z = 467.18 [M+1]
Example 5:
Figure DEST_PATH_IMAGE016
compound 1 (439 mg,1.0 mmol) was dissolved in 5mL of dry 1, 2-dichloroethane, followed by the addition of hydroxymethyl isopropyl carbonate (537 mg,4.0 mmol) and TBD (0.556 g,4.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to obtain compound 4 as a pale yellow solid (0.192 g,37% yield).
1H NMR (CDCl3, 500 MHz) δ 8.38 (s, 1H), 7.94 (s, 1H), 5.54 (m, 4H), 4.91-4.86 (m, 2H), 4.35 (dd, J = 3.0,13.8 Hz,1H), 4.23 (dd, J = 7.1, 14.0 H, 1H), 3.90-3.86 (m, 2H), 3.79-3.76 (dd, J = 9.2, 13.2 Hz, 1H), 1.31 (d, J = 14.3Hz, 12H), 1.26 (d, J = 7. 1 Hz, 3H).
LC-MS m/z = 519.18 [M+1]
Example 6
Figure DEST_PATH_IMAGE018
Compound 5 (425 mg,1.0 mmol) was dissolved in 5mL dry acetonitrile followed by the addition of ethanol (175 uL,2.0 mmol) and DBN (0.31 g, 2.5 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 6 as a pale yellow solid (0.214 g, 65% yield).
1H NMR (CD3OD) δ 8.10 (s, 1H), 8.03 (s, 1H), 4.35 (t, J = 5.0 Hz, 2H), 3.93 (dq, J = 8.0 and J =7.0 Hz, 4H), 3.86 (t, J =5.0 Hz, 2H), 3.76 (d, J = 8.5 Hz, 2H), 1.11 (t, J =7.0, 6H).
LC-MS m/z = 329.13 [M+1]
Example 7:
Figure DEST_PATH_IMAGE020
compound 1 (425 mg,1.0 mmol) was dissolved in 5mL dry acetonitrile followed by the addition of the alcohol starting material (528 mg,4.0 mmol) and DBU (0.3 mL, 4.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent was ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 7 as a colorless solid (0.216 g,43% yield).
1H NMR (400MHz, CDCl3) δ 8.33 (s, 1H), 7.96 (s, 1H), 5.65 (dq, J = 11.2, 5.1 Hz, 4H), 4.39 (t,
J = 5.0 Hz, 2H), 3.94 (t, J = 4.9 Hz, 2H), 3.85 (d, J = 7.7 Hz, 2H), 1.20 (s, 18H).
LC-MS m/z = 501.20 [M+1]
Example 8
Figure DEST_PATH_IMAGE022
Compound 8 (451 mg,1.0 mmol) was dissolved in 5mL of dry dichloromethane, followed by the addition of ethanol (263 uL,3.0 mmol) and DBU (0.38 g, 2.5 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was diluted with 5mL of ethyl acetate, washed with 5mL of water, the aqueous phase was extracted with 5mL of ethyl acetate after separation of the organic phases, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 9 as a pale yellow solid (0.195 g, 55% yield).
1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.74 (s, 1H), 8.0 (br s, 2H), 4.33 (s, 2H), 3.95 (dq, J = 8.0 and J =7.0 Hz, 4H), 3.76 (d, J =12.0 Hz, 2H), 1.15 (t, J =7.0, 6H), 0.92 (br q, 4H).
LC-MS m/z = 356.14 [M+1]
Example 9:
Figure DEST_PATH_IMAGE024
compound 8 (451 mg,1.0 mmol) was dissolved in 5mL dry DMF followed by the addition of the alcohol starting material (396 mg,3.0 mmol) and TBD (0.418 g,3.0 mmol). The reaction is stirred for 16 hours at normal temperature, and then the phosphorus spectrum detection raw material disappears. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent was ethyl acetate/petroleum ether (v/v) =3/1 to pure ethyl acetate) to give compound 10 as a colorless solid (0.174 g,33% yield).
1H NMR (500 MHz, CDCl3): δ 8.68 (s, 1H), 8.01 (s, 1H), 5.62 (m, 2H), 5.0 (br s, 2H), 4.23 (s, 2H), 3.97 (d, J = 10.0 Hz, 2H), 1.21 (s, 18H), 1.06 (br t, 2H), 0.89 (br t, 2H).
LC-MS m/z = 528.22 [M+1]。

Claims (6)

1. A preparation method of nucleoside phosphate ester prodrug is characterized in that a diphenyl phosphate ester intermediate A and an alcohol compound B are subjected to transesterification reaction to obtain the nucleoside phosphate ester prodrug, and the reaction structural formula is as follows:
Figure DEST_PATH_IMAGE001
。
2. the method of claim 1, wherein R1 is selected from the group consisting of
Figure DEST_PATH_IMAGE003
One kind of (1).
3. The method of claim 1 or 2, wherein R2 is selected from the group consisting of
Figure DEST_PATH_IMAGE005
One kind of (1).
4. The method of claim 1, wherein the diphenol phosphate intermediate a, the alcohol compound B and the base are added in a ratio of 1: 2.0-4.0: 2.0 to 5.0.
5. The method of claim 1, wherein the base is one or more selected from the group consisting of potassium carbonate, potassium tert-butoxide, triethylamine, pyridine, imidazole, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo non-5-ene, tetramethylguanidine, and 1,5, 7-triazabicyclo [4.4.0] dec-5-ene.
6. The method of claim 1, wherein the solvent is one or more selected from the group consisting of acetonitrile, dichloromethane, 1, 2-dichloroethane, N, N-dimethylformamide, dimethylsulfoxide, and tetrahydrofuran.
CN202111332813.7A 2021-11-11 2021-11-11 Preparation method of nucleoside phosphate prodrug Pending CN113880883A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1301182A (en) * 1969-03-10 1972-12-29 Syntex Corp Improvements in or relating to nucleoside phosphonates, phosphonic acids and phosphonic acid salts
US5663159A (en) * 1990-09-14 1997-09-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
CN1487949A (en) * 2001-01-19 2004-04-07 ��ʽ����LG������ѧ New acyclic nucleoside phosphonate derivatives, their salts and their preparation methods
CN107021984A (en) * 2017-04-28 2017-08-08 福建广生堂药业股份有限公司 A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates
CN111018916A (en) * 2019-12-30 2020-04-17 天津天士力圣特制药有限公司 Synthesis method of tenofovir phenyl alkyl ester phosphonamide precursor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1301182A (en) * 1969-03-10 1972-12-29 Syntex Corp Improvements in or relating to nucleoside phosphonates, phosphonic acids and phosphonic acid salts
US5663159A (en) * 1990-09-14 1997-09-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
CN1487949A (en) * 2001-01-19 2004-04-07 ��ʽ����LG������ѧ New acyclic nucleoside phosphonate derivatives, their salts and their preparation methods
CN107021984A (en) * 2017-04-28 2017-08-08 福建广生堂药业股份有限公司 A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates
CN111018916A (en) * 2019-12-30 2020-04-17 天津天士力圣特制药有限公司 Synthesis method of tenofovir phenyl alkyl ester phosphonamide precursor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOHN E. STARRETT ET AL.: "Synthesis, Oral Bioavailability Determination, and in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA)", 《J. MED. CHEM.》, vol. 37, pages 1857 - 1864, XP002095314, DOI: 10.1021/jm00038a015 *

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