CN115651022A - Synthetic method of high-purity Reidesvir intermediate - Google Patents
Synthetic method of high-purity Reidesvir intermediate Download PDFInfo
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- CN115651022A CN115651022A CN202211326346.1A CN202211326346A CN115651022A CN 115651022 A CN115651022 A CN 115651022A CN 202211326346 A CN202211326346 A CN 202211326346A CN 115651022 A CN115651022 A CN 115651022A
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Abstract
The invention discloses a synthetic method of a high-purity Reidesvir intermediate, which comprises the following steps: s1, adding a compound B or hydrochloride thereof into a first reaction solvent, and cooling to-30 to-60 ℃; adding the compound A under stirring, and slowly dripping alkali or a solution thereof; stirring and reacting for 3-5 h at-5 ℃ after the dropwise adding is finished; adding compound C, adding alkali or its solution; continuously stirring for complete reaction; carrying out post-treatment and purification to obtain a compound D; s2: adding the compound D and the compound E into a second reaction solvent, adding alkali and Lewis acid, and reacting for 3-12 hours at the temperature of 20-30 ℃; and performing post-treatment and purification to obtain a Reidcciclovir intermediate F. The invention synthesizes the compound D by a one-pot method and then reacts with the compound E to prepare the Reidesciclovir intermediate, and has less synthesis steps and high yield. The compound C is used as a raw material, and the compound C is cheap and easily available in raw materials and high in safety.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of a high-purity Reidcvir intermediate.
Background
Reinecke is a ribonucleoside analogue produced by Gilead Biotech, USA, mainly interfering with the transcription process of viral RNA, and has broad-spectrum antiviral activity
Route 1: the route reported in WO2016069826 by the original Productwork Gilidde: (3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol is used as a starting material, and the Rudexilvir is obtained by oxidation, addition, substitution, resolution, debenzylation, protection, substitution and final resolution. The route has poor selectivity, and is not suitable for industrial production because the purification is carried out by a chiral column.
Route 2: nature 2016 (Warren T K, jordan R, lo M K, et al, therapeutic efficacy of the small polypeptide GS-5734 by new edition Ebola virus in rhesus monkey ys. J. Nature 2016,531 (7594): 381-385), reports a second generation synthesis which can be scaled up to hectograph. The yield of the reaction is 40%, 85%, 86%, 90%, 70% and 69% respectively in 6 steps. The route is optimized for route 1, during the cyano substitution step, the isomer ratio of the obtained product is 95% by adding trifluoromethanesulfonic acid, the ratio of the desired beta-anomer is greatly increased by trifluoromethanesulfonic acid, and the chiral purity can be further increased by subsequent recrystallization.
Wherein, a nitro substituent is introduced in the route 2 as a reactant, and the reactant needs p-nitrophenol as a raw material; p-nitrophenol is an explosive compound, is difficult to obtain, and requires careful experimental operation.
Disclosure of Invention
1. The technical problem to be solved is as follows:
aiming at the technical problems, the invention provides a synthetic method of a high-purity Reidesvir intermediate.
2. The technical scheme is as follows:
a synthetic method of a high-purity Reidcvir intermediate comprises the following reaction route:
the method comprises the following steps:
s1, adding a compound B or hydrochloride thereof into a first reaction solvent, and cooling to-30 to-60 ℃; adding the compound A under stirring, and slowly dripping alkali or a solution thereof; stirring and reacting for 3-5 h at-5 ℃ after the dropwise adding is finished; adding compound C, adding alkali or its solution; continuously stirring to react completely; carrying out post-treatment and purification to obtain a compound D;
s2: adding the compound D and the compound E into a second reaction solvent, adding alkali and Lewis acid, and reacting for 3-12 hours at the temperature of 20-30 ℃; and performing post-treatment and purification to obtain a Reidcciclovir intermediate F.
Further, the molar ratio of the compound A, the compound B and the compound C is 1-1.1: 1.
further, the molar ratio of the compound B to the first added alkali in the step S1 is 1; the molar ratio of the compound C to the second added alkali is 1.1-3.
Further, the bases added twice in the step S1 are the same and include triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate or sodium carbonate. Preferred are triethylamine and N, N-diisopropylethylamine.
Further, the first reaction solvent of step S1 includes dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.
Further, the post-treatment purification of step S1 comprises: washing with distilled water; drying the organic phase, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound D.
Further, the molar ratio of the compound D to the compound E in the step S2 is 1.05 to 1.1.
Further, the base of step S2 includes N, N-diisopropylethylamine, triethylamine, pyridine, and 2, 6-lutidine.
Further, the molar ratio of the compound E and the base in the step S2 is 1.2 to 3.
Further, the lewis acid of step S2 is one of zinc chloride, zinc bromide, zinc iodide, magnesium bromide, tin chloride, and copper chloride.
Further, the post-treatment purification of step S2 comprises washing the organic phase with distilled water; and drying the organic phase, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the Reidesciclovir intermediate F.
3. Has the advantages that:
(1) The invention synthesizes the compound D by a one-pot method and then reacts with the compound E to prepare the Reidesciclovir intermediate, and has less synthesis steps and high yield.
(2) The compound C is used as a raw material, and the compound C is cheap and easily available and has high safety.
Detailed Description
The present invention will be described in detail below.
A synthetic method of a high-purity Reidcvir intermediate comprises the following reaction route:
the method comprises the following steps:
s1, adding a compound B or hydrochloride thereof into a first reaction solvent, and cooling to-30 to-60 ℃; adding the compound A under stirring, and slowly dripping alkali or a solution thereof; stirring and reacting for 3-5 h at-5 ℃ after the dropwise adding is finished; adding compound C, adding alkali or its solution; continuously stirring to react completely; carrying out post-treatment and purification to obtain a compound D;
s2: adding the compound D and the compound E into a second reaction solvent, adding alkali and Lewis acid, and reacting for 3-12 hours at the temperature of 20-30 ℃; and performing post-treatment and purification to obtain a Rudeciclovir intermediate F.
The molar ratio of the compound A to the compound B to the compound C is 1-1.1: 1.
the molar ratio of the compound B to the first added alkali in the step S1 is 1; the molar ratio of the compound C to the second added alkali is 1.1-3.
The alkali added in the step S1 is the same, and comprises triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate or sodium carbonate. Preferred are triethylamine and N, N-diisopropylethylamine.
The first reaction solvent of step S1 includes dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.
The post-treatment purification of the step S1 comprises the following steps: washing with distilled water; drying the organic phase, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound D.
The molar ratio of the compound D to the compound E in the step S2 is 1.05-1.1.
The base of step S2 includes N, N-diisopropylethylamine, triethylamine, pyridine, and 2, 6-lutidine.
The molar ratio of the compound E and the base in the step S2 is 1.2-3.
The Lewis acid of the step S2 is one of zinc chloride, zinc bromide, zinc iodide, magnesium bromide, tin chloride and copper chloride.
The post-treatment purification of the step S2 comprises adding distilled water to wash the organic phase; drying the organic phase, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the intermediate F of the Reidesvir.
The specific embodiment is as follows:
example 1
S1, the hydrochloride of the compound B (10g, 47.7mmol) was added to methylene chloride (100 ml), and cooled to-40 ℃; compound A (20.1g, 95.3mmol) was added with stirring, and triethylamine (12g, 118.6mmol) was slowly added dropwise; stirring and reacting for 4 hours at the temperature of 0 ℃ in an ice water bath after the dropwise adding is finished; then adding a compound C (7.8g, 47.8mmol), adding triethylamine (6g, 59.3mmol), and continuously stirring for reaction for 3h; adding distilled water (50 ml) for washing; the organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give compound D (1lg, 33.7mmol) in 70.7% yield (calculated as compound B) and 99.5% purity.
S2: compound D (10g, 21.1mmol) and compound E (5.8g, 19.9mmol) were added to tetrahydrofuran (30 ml), and triethylamine (3.0g, 29.9mmol) and zinc bromide (6.2g, 27.5mmol) were added and reacted at ordinary temperature for 5 hours; adding distilled water to wash the organic phase; the organic phase is dried, decompressed, concentrated and purified by column chromatography to obtain the Rudexilvir intermediate F (9.4g, 15.6 mmol), the yield is 78.3% (calculated by the compound E) and the purity is 99.7%.
Example 2
S1, hydrochloride of Compound B (10g, 47.7mmol) was added to tetrahydrofuran (100 ml), and cooled to-40 ℃; compound A (20.1g, 95.3mmol) was added with stirring, and N, N-diisopropylethylamine (15g, 116mmol) was slowly added dropwise; stirring and reacting for 4 hours at the temperature of 0 ℃ in an ice water bath after the dropwise adding is finished; then adding a compound C (7.8g, 47.8mmol), supplementing N, N-diisopropylethylamine (7.5g, 58mmol), and continuously stirring for reaction for 3h; washing with distilled water (50 ml); the organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to give compound D (14.5g, 30.6 mmol) in a yield of 64.1% (based on compound B) and a purity of 99.4%.
S2: compound D (10g, 21.1mmol) and compound E (5.8g, 19.9mmol) were added to tetrahydrofuran (30 ml), and N, N-diisopropylethylamine (4g, 31.0mmol) and magnesium bromide (5g, 27.1mmol) were added and reacted at ordinary temperature for 6 hours; adding distilled water to wash the organic phase; the organic phase is dried, decompressed, concentrated and purified by column chromatography to obtain the ridciclovir intermediate F (9.0 g,14.9 mmol), the yield is 75.0 percent (calculated by the compound E) and the purity is 99.6 percent.
Example 3
S1 Compound B hydrochloride (10g, 47.7mmol) was added to methylene chloride (100 ml) and cooled to-40 ℃; compound A (20.1g, 95.3mmol) was added with stirring, and N, N-diisopropylethylamine (15g, 116mmol) was slowly added dropwise; stirring and reacting for 3 hours at the temperature of 0 ℃ in an ice water bath after the dropwise adding is finished; then adding a compound C (7.8g, 47.8mmol), supplementing N, N-diisopropylethylamine (7.5g, 58mmol), and continuously stirring for reaction for 3h; adding distilled water (50 ml) for washing; the organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to give compound D (15.5g, 32.7 mmol) in 68.5% yield (calculated as compound B) and 99.6% purity.
S2: compound D (10g, 21.1mmol) and compound E (5.8g, 19.9mmol) were added to methylene chloride (30 ml), and N, N-diisopropylethylamine (4g, 31.0mmol) and zinc chloride (3.7g, 27.1mmol) were added and reacted at ordinary temperature for 6 hours; adding distilled water to wash the organic phase; the organic phase is dried, concentrated under reduced pressure and purified by column chromatography to obtain the ridciclovir intermediate F (9.6g, 15.9mmol), the yield is 80% (calculated by the compound E) and the purity is 99.7%.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (9)
1. A synthetic method of a high-purity Reidcvir intermediate is characterized in that the reaction route of the synthetic method is as follows:
the method comprises the following steps:
s1, adding a compound B or hydrochloride thereof into a first reaction solvent, and cooling to-30 to-60 ℃; adding the compound A under stirring, and slowly dripping alkali or a solution thereof; stirring and reacting for 3-5 h at-5 ℃ after the dropwise adding is finished; adding compound C, adding alkali or its solution; continuously stirring for complete reaction; after-treatment and purification, a compound D is obtained;
s2: adding the compound D and the compound E into a second reaction solvent, adding alkali and Lewis acid, and reacting for 3-12 hours at the temperature of 20-30 ℃; and performing post-treatment and purification to obtain a Reidcciclovir intermediate F.
2. The method for synthesizing the high-purity Reidesciclovir intermediate according to claim 1, wherein the molar ratio of the compound A, the compound B and the compound C is 1-1.1: 1.
3. the method for synthesizing a high-purity Reidesciclovir intermediate according to claim 2, wherein the molar ratio of the compound B and the first added base in the step S1 is 1; the molar ratio of the compound C to the second added alkali is 1.1-3.
4. The method for synthesizing a high-purity reidexilvir intermediate as claimed in claim 3, wherein the base added twice in step S1 is the same, and comprises triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate or sodium carbonate.
5. The method for synthesizing a high-purity ridciclovir intermediate according to claim 4, wherein the first reaction solvent of step S1 comprises dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran and toluene.
6. The method for synthesizing a high-purity Reidesciclovir intermediate according to claim 5, wherein the molar ratio of compound D to compound E in step S2 is 1.05-1.1.
7. The method for synthesizing a high-purity ridciclovir intermediate according to claim 6, wherein the base in step S2 comprises N, N-diisopropylethylamine, triethylamine, pyridine and 2, 6-lutidine.
8. The method for synthesizing a high-purity ridciclovir intermediate according to claim 7, wherein the molar ratio of compound E to base in step S2 is 1.2-3.
9. The method for synthesizing a high-purity ridciclovir intermediate according to claim 1, wherein the lewis acid of step S2 is one of zinc chloride, zinc bromide, zinc iodide, magnesium bromide, tin chloride and copper chloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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