CN111574523A - Method for preparing 1' -substituted carbon nucleoside analogue intermediate - Google Patents

Method for preparing 1' -substituted carbon nucleoside analogue intermediate Download PDF

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CN111574523A
CN111574523A CN202010527928.0A CN202010527928A CN111574523A CN 111574523 A CN111574523 A CN 111574523A CN 202010527928 A CN202010527928 A CN 202010527928A CN 111574523 A CN111574523 A CN 111574523A
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nucleoside analogue
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臧青民
陈荣
章烨雯
吕其壮
曾国芳
梁薇
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Yulin Normal University
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Abstract

The invention discloses a method for preparing a 1' -substituted carbon nucleoside analogue intermediate, belonging to the field of organic synthesis. The invention uses pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine to react with substituent butyrolactone under the protection of chlorosilane and in an alkaline environment to obtain a 1' -substituted carbon nucleoside analogue intermediate. The invention adopts a one-step method to directly synthesize the riboside compound of the base pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine, the route has less steps, simple operation and low cost, and simultaneously, the use of halogen-containing reagents is reduced. The invention effectively shortens the reaction steps and simultaneously reduces the environmental impact caused by the use of halogen in the prior art. Meanwhile, the synthesis method of the 1' -substituted nucleoside analogue has wide substrate applicability and is beneficial to the industrial production of various non-natural nucleoside compounds.

Description

Method for preparing 1' -substituted carbon nucleoside analogue intermediate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for preparing a 1' -substituted carbon nucleoside analogue intermediate.
Background
The riboside compound of base pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine has wide biological activity and has proved to have inhibitory effect on Ebola virus, respiratory syncytial virus, Hendra virus, coronavirus and other viruses. The nucleoside compound has a structure similar to that of natural nucleoside, cannot be recognized by virus, can inhibit the activity of virus DNA polymerase and reverse transcriptase and can compete with nucleotide to be incorporated into a virus DNA chain, thereby stopping or inhibiting the elongation and synthesis of the virus DNA chain, and inhibiting the replication of the virus to play an antiviral role. The Reidcevir is one of the riboside compounds of a plurality of pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine, and is a broad-spectrum antiviral compound. In 5 months of 2020, Reidesvir (Remdesivir) is approved by special approval routes in the United states and Japan as a therapeutic agent for the infection with the New coronavirus (SARS-CoV-2). Besides the inhibition effect on viruses, the riboside compound of the base pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine also has stronger treatment effect on diseases such as cancers and the like.
Currently, there are two main methods for the synthesis of riboside of the base pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine:
the first method is described in patent CN 102596979A: the 7-bromopyrrolo [1, 2-f ] [1, 2, 4] triazine-4 amine is adopted as a raw material to react with 2, 3, 4, 5-substituted butyrolactone, as shown in figure 1.
The second method, for example, CN105899216A, uses 7-iodopyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine as raw material to react with butyrolactone as substituent at 2, 3, 4, 5-position, as shown in FIG. 2.
Although both methods successfully prepare 1' -substituted carbon nucleoside analogues, the base adopted is 7-halogenated pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine, and the raw material is prepared from pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine through bromination and iodination, so that the steps are long, the required reagents are more, and a large amount of byproducts are generated in the halogenation process, thereby increasing the cost.
Disclosure of Invention
The present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a method for preparing an intermediate of a 1' -substituted carba-nucleoside analogue.
In order to realize the purpose of the invention, the method is realized by the following technical scheme:
a method for preparing a 1 '-substituted carbon nucleoside analogue intermediate, wherein pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine reacts with substituent butyrolactone in an alkaline environment under the protection of chlorosilane to obtain the 1' -substituted carbon nucleoside analogue intermediate;
the pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine has the structure:
Figure BDA0002534235900000021
the general formula of the substituent butyrolactone is as follows:
Figure BDA0002534235900000022
in the above structure, R1, R2, R3, R4, R5 and R6 each independently represent hydrogen, alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryloxy, halogen, alkenyl, alkynyl, substituted aryl, derivatives thereof and no group.
Preferably, the method comprises the following steps:
(1) adding pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine and chlorosilane into a container, and adjusting the environment to be alkaline;
(2) adding an alkyl derivative of lithium;
(3) adding substituent butyrolactone for reaction;
(4) the reaction was quenched.
Further preferably, the step (2) requires adjusting the internal temperature of the reactants to-20 ℃ or lower.
Further preferably, the step (3) requires adjusting the internal temperature of the reactants to-60 ℃ or lower.
Further preferably, the quenching reaction of step (4) specifically comprises the following steps: raising the temperature to be more than or equal to 0 ℃, adding an acidic substance to quench the reaction, then extracting, drying, decompressing, separating, removing the solvent and purifying.
Still more preferably, the acidic substance is ammonium chloride or acetic acid; the extraction is carried out by using ethyl acetate; drying the organic layer using anhydrous sodium sulfate; the purification was performed using column chromatography.
Preferably, the chlorosilane comprises at least one of 1, 2-bis (chlorodimethylsilyl) ethane, trimethylchlorosilane or tert-butyldiphenylchlorosilane.
Preferably, the reactants are dissolved in an organic solvent during the preparation process.
Further preferably, the solvent is tetrahydrofuran or hexane.
Preferably, in step (2), the alkyl derivative of lithium comprises n-butyllithium or lithium diisopropylamide.
The invention adopts a one-step method to directly synthesize the riboside compound of the base pyrrolo [1, 2-f ] [1, 2, 4] triazine-4-amine, the route has less steps, simple operation and low cost, and simultaneously, the use of halogen-containing reagents is reduced. The invention effectively shortens the reaction steps and simultaneously reduces the environmental impact caused by the use of halogen in the prior art. Meanwhile, the synthesis method of the 1' -substituted nucleoside analogue has wide substrate applicability and is beneficial to the industrial production of various non-natural nucleoside compounds.
Drawings
FIG. 1 is a synthetic route of 1' -substituted carbon nucleoside analogue intermediate in patent CN 102596979A;
FIG. 2 is a synthetic route of 1' -substituted carbon nucleoside analogue intermediate in patent CN 105899216A;
FIG. 3 is a synthetic route of a 1' -substituted carbocyclic nucleoside analogue intermediate of the present invention;
FIG. 4 shows the structural formula of pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine.
In FIGS. 1 to 3, R1、R2、R3、R4、R5And R6Each independently represents hydrogen, alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryloxy, halogen, alkenyl, alkynyl, substituted aryl, derivatives thereof, and the like.
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. The drawings are only for purposes of illustration and are not intended to be limiting, and are merely schematic and non-limiting. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
The stirring in the following examples may use equipment-assisted stirring or manual stirring, and the stirring speed is limited so that no liquid splash occurs in the reaction system, resulting in additional phase unconfinement in the reaction system. Unless otherwise specified, the temperature refers to the internal temperature.
Example one
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (4.23g, 31.9mmol, 1.1equiv.) and anhydrous THF (80mL) were added to a round bottom flask under nitrogen blanket, NaH (2.55g, 63.8mmol, 60% content, 2.2equiv.) was added at 0 deg.C, and stirred for 0.5 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (7.40g, 33.4mmol, 1.2equiv.) was added and stirred for 1 h.
(3) After the reaction mixture was cooled to an internal temperature of-78 ℃, a hexane solution of n-butyllithium (59.2mL, 1.6mol/L, 3.3equiv.) was slowly added thereto and stirred at-78 ℃ for 1.5 hours.
(4) Then a solution of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (12.0g, 28.7mmol, 1.0equiv.) in THF (tetrahydrofuran) (250mL) was added slowly and stirred at-78 deg.C for 1 h.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenching with Cl aqueous solution, extracting with ethyl acetate, drying organic layer with anhydrous sodium sulfate, removing solvent under reduced pressure, and purifying by column chromatography to obtain (3R, 4R, 5R) -2 (4-aminopyrrole [2, 1-f ]][1,2,4]Triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -tetrahydrofuran-2-ol (11.3g, yield: 71%).
1HNMR (nuclear magnetic resonance hydrogen spectrum) (400MHz, DMSO-d6):8.07(br s, 2H), 7.99(s, 1H), 7.36-7.23(m, 11H), 7.18-7.10(m, 3H), 7.02-6.98(m, 2H), 6.95(d, J ═ 4.8Hz, 1H), 5.39(d, J ═ 5.8Hz, 1H), 5.05(d, J ═ 5.2Hz, 1H), 4.61-4.55(m, 2H), 4.52-4.42(m, 4H), 4.04-3.98(m, ddh), 3.93 (J ═ 5.9, 4.4Hz, 1H), 3.69(dd, J ═ 10.1, 3.4Hz, 1H), 3.48(dd, 10.1, 3.48, J ═ 10.6, 1H).
LC/MS (liquid chromatography-Mass Spectrometry) (M/z: 553.2[ M + H ]). LC/MS (M/z: 553.4[ M + H ]).
Example two
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (6.34g, 47.3mmol, 1.1equiv) and anhydrous THF (120mL) were added to a round bottom flask under nitrogen blanket, NaH (7.57g, 189.2mmol, 60% content, 4.4equiv.) was added at-10 ℃ and stirred for 1 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (11.1g, 51.6mmol, 1.2equiv.) was added and stirred for 1 h.
(3) After the reaction mixture was cooled to an internal temperature of-60 ℃, a hexane solution of n-butyllithium (177.4mL, 1.6mol/L, 6.6equiv.) was slowly added thereto, and the mixture was stirred at-60 ℃ for 1 hour.
(4) The temperature was reduced to-78 ℃ and a THF solution (360mL) of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (18.0g, 43.0mmol, 1.0equiv.) was added slowly and stirred at-78 ℃ for 1 h.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenching with aqueous Cl solution, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, removing the solvent under reduced pressure, and purifying by column chromatography to obtain (3R, -4R, -5R) -2 (4-aminopyrrole[2,1-f][1,2,4]Triazin-7-yl) -3, 4-bis (phenoxy) -5- ((phenoxy) methyl) -tetrahydrofuran-2-ol (19.5g, yield: 82%).
EXAMPLE III
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (3.8g, 28.4mmol, 1.1equiv) and anhydrous THF (80mL) were added to a round bottom flask under nitrogen blanket, NaH (2.5g, 62.5mmol, 60% content, 2.2equiv.) was added at-10 ℃ and stirred for 1 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (7.33g, 34.1mmol, 1.2equiv.) was added and stirred for 1 h.
(3) The reaction mixture was cooled to an internal temperature of-40 ℃ and a hexane solution of n-butyllithium (161.3mL, 1.6mol/L, 10.0equiv) was slowly added thereto, followed by stirring at-60 ℃ for 0.5 h.
(4) A THF solution (200mL) of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (10.8g, 25.8mmol, 1.0equiv.) was added slowly and stirred at-60 ℃ for 1 h.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenching with Cl aqueous solution, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, removing the solvent under reduced pressure, and purifying by column chromatography to obtain (3R, -4R, -5R) -2 (4-aminopyrrole [2, 1-f ]][1,2,4]Triazin-7-yl) -3, 4-bis (phenoxy) -5- ((phenoxy) methyl) -tetrahydrofuran-2-ol (10.8g, yield: 76%).
Example four
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (1.90g, 14.2mmol, 1.1equiv) and anhydrous THF (40mL) were added to a round bottom flask under nitrogen blanket, NaH (1.14g, 28.4mmol, 60% content, 2.2equiv.) was added at 0 deg.C, and stirred for 1 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (4.16g, 19.4mmol, 1.5euqiv.) was added and stirred for 1 h.
(3) After the reaction mixture was cooled to an internal temperature of-20 ℃, a THF solution of lithium diisopropylamide (21.3mL, 2mol/L, 3equiv.) was slowly added and stirred at-20 ℃ for 0.5 h.
(4) A THF solution (100mL) of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (5.4g, 12.9mmol, 1.0equiv.) was slowly added at-78 deg.C and stirred at-78 deg.C for 1 h.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenching with Cl aqueous solution, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, removing the solvent under reduced pressure, and purifying by column chromatography to obtain (3R, -4R, -5R) -2 (4-aminopyrrole [2, 1-f ]][1,2,4]Triazin-7-yl) -3, 4-bis (phenoxy) -5- ((phenoxy) methyl) -tetrahydrofuran-2-ol (5.99g, yield: 84%).
EXAMPLE five
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (3.18g, 23.7mmol, 1.1equiv) and anhydrous THF (60mL) were added to a round bottom flask under nitrogen blanket, and TMSCl (trimethylchlorosilane, 5.15g, 47.4mmol, 2.2equiv.) was added at room temperature and stirred for 0.5 h.
(2) After the reaction mixture was cooled to an internal temperature of-78 ℃, n-butyllithium (44.8mL, 1.6mol/L, 3equiv.) was slowly added thereto, and the mixture was stirred at-78 ℃ for 2 hours.
(3) Then a solution of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (9.0g, 21.5mmol, 1.0equiv.) in THF (180mL) was added slowly and stirred at-78 deg.C for 1 h.
(4) The temperature was gradually raised to 0 ℃, acetic acid (10mL) was added to quench, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography to give (3R, -4R, -5R) -2 (4-aminopyrrole [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenoxy) -5- ((phenoxy) methyl) -tetrahydrofuran-2-ol (6.65g, yield: 56%).
EXAMPLE six
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (2.77g, 20.6mmol, 1.2equiv.) and anhydrous THF (60mL) were added to a round bottom flask under nitrogen protection, followed by tert-butyldiphenylchlorosilane (11.3g, 41.2mmol, 2.4equiv.) and stirred for 1 h.
(2) The reaction mixture was cooled to an internal temperature of-78 ℃ and a hexane solution of n-butyllithium (42.5mL, 1.6mol/L, 4.0equiv.) was added slowly and stirred at-78 ℃ for 1.5 h.
(3) A solution of 2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone (7.2g, 17.2mmol, 1.0equiv.) in THF (20mL) was added slowly and stirred at-78 deg.C for 1 h.
(4) Gradually heating to 0 ℃, and adding saturated NH4Quenching with aqueous Cl (40mL), extracting with ethyl acetate, drying the organic layer over anhydrous sodium sulfate, removing the solvent under reduced pressure, and purifying by column chromatography to give (3R, -4R, -5R) -2 (4-aminopyrrole [2, 1-f ]][1,2,4]Triazin-7-yl) -3, 4-bis (phenoxy) -5- ((phenoxy) methyl) -tetrahydrofuran-2-ol (6.37g, yield: 67%).
EXAMPLE seven
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (0.74g, 5.5mmol, 1.1equiv) and anhydrous THF (10mL) were added to a round bottom flask under nitrogen blanket, NaH (0.44g, 11.0mmol, 60% content, 2.2equiv.) was added at 0 deg.C, and stirred for 1 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (1.29g, 6.0mmol, 1.2equiv.) was added and stirred for 1 h.
(3) The reaction mixture was cooled to an internal temperature of-78 ℃ and a hexane solution of n-butyllithium (12.5. mu.L, 20mmol, 1.6M, 4.0equiv) was slowly added thereto, followed by stirring at-78 ℃ for 1 hour.
(4) A solution of 2, 3, 5-tribenzyloxy-2-methyl-D-ribono-1, 4-lactone (2.16g, 5mmol, 1.0equiv.) in THF (40mL) was added slowly and stirred at-78 deg.C for 1 h.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenched with aqueous Cl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography to obtain the product (2.46g, yield: 87%).
1HNMR(300MHz,CDCl3):7.85(m,1H),7.27(m,15H),7.01(m,1H),6.51(m,1H),4.66(m,8H),4.40(m,2H),3.79(m,3H),1.62(s,1.3H),1.18(s,1.7H)。
LC/MS(m/z:567.6[M+H])。
Example eight
(1) Pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine (1.47g, 11.0mmol, 1.1equiv) and anhydrous THF (30mL) were added to a round bottom flask under nitrogen blanket, NaH (0.88g, 22.0mmol, 60% content, 2.2equiv.) was added at 0 deg.C, and stirred for 1 h.
(2) 1, 2-bis (chlorodimethylsilyl) ethane (2.58g, 12.0mmol, 1.2equiv.) was added and stirred for 1 h.
(3) The reaction mixture was cooled to an internal temperature of-78 deg.C, n-butyllithium (25. mu.L, 40mmol, 1.6M, 4.0equiv.) was slowly added thereto, and the mixture was stirred at-78 deg.C for 2 hours.
(4) A solution of (3R, 5S) -3-benzyloxy-5-benzyloxymethyl dihydrofuran-2 (3H) -one (3.12g, 10mmol, 1.0equiv.) in THF (60mL) was added slowly and stirred at-78 deg.C for 2H.
(5) Gradually heating to 0 ℃, and adding saturated NH4Quenched with aqueous Cl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography to obtain the product (3.40g, yield: 76%).
LC/MS(m/z:447.3-[M+H])。

Claims (10)

1. A method for preparing a 1' -substituted carbon nucleoside analogue intermediate, comprising:
pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine reacts with substituent butyrolactone under the protection of chlorosilane and in an alkaline environment to obtain a 1' -substituted carbon nucleoside analogue intermediate;
the pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine has the structure:
Figure FDA0002534235890000011
the general formula of the substituent butyrolactone is as follows:
Figure FDA0002534235890000012
in the above structure, R1, R2, R3, R4, R5 and R6 each independently represent hydrogen, alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryloxy, halogen, alkenyl, alkynyl, substituted aryl, derivatives thereof and no group.
2. The method for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 1, comprising the steps of:
(1) adding pyrrolo [1, 2-f ] [1, 2, 4] triazin-4-amine and chlorosilane into a container, and adjusting the environment to be alkaline;
(2) adding an alkyl derivative of lithium;
(3) adding substituent butyrolactone for reaction;
(4) the reaction was quenched.
3. The method for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 2, wherein: the step (2) requires adjusting the internal temperature of the reactants to below-20 ℃.
4. The method for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 2, wherein: in the step (3), the internal temperature of the reactants needs to be adjusted to-60 ℃ or lower.
5. The method for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 2, wherein: the quenching reaction in the step (4) comprises the following specific steps: raising the temperature to be more than or equal to 0 ℃, adding an acidic substance to quench the reaction, then extracting, drying, decompressing, separating, removing the solvent and purifying.
6. The method for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 5, wherein: the acidic substance is ammonium chloride or acetic acid; the extraction is carried out by using ethyl acetate; drying the organic layer using anhydrous sodium sulfate; the purification was performed using column chromatography.
7. The process for preparing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claims 1 to 6, wherein: the chlorosilane includes at least one of 1, 2-bis (chlorodimethylsilyl) ethane, trimethylchlorosilane or tert-butyldiphenylchlorosilane.
8. The process for producing a 1' -substituted carbocyclic nucleoside analogue intermediate according to any of claims 1 to 6, wherein: the reactants are dissolved in an organic solvent during the preparation process.
9. The process for producing a 1' -substituted carbocyclic nucleoside analogue intermediate according to claim 8, wherein: the solvent is tetrahydrofuran or hexane.
10. The process for producing a 1' -substituted carbocyclic nucleoside analogue intermediate according to any of claims 2 to 6, wherein: in step (2), the alkyl derivative of lithium includes n-butyllithium or lithium diisopropylamide.
CN202010527928.0A 2020-06-11 2020-06-11 Method for preparing 1' -substituted carbon nucleoside analogue intermediate Withdrawn CN111574523A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112358513A (en) * 2020-12-02 2021-02-12 上海朴颐化学科技有限公司 Method for preparing Reidesciclovir intermediate by using continuous flow reactor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112358513A (en) * 2020-12-02 2021-02-12 上海朴颐化学科技有限公司 Method for preparing Reidesciclovir intermediate by using continuous flow reactor

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Application publication date: 20200825