CN109810064B - Method for synthesizing Elagolix intermediate polysubstituted pyrimidine derivative by two-step method - Google Patents
Method for synthesizing Elagolix intermediate polysubstituted pyrimidine derivative by two-step method Download PDFInfo
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Abstract
The invention discloses a method for synthesizing an Elagolix intermediate polysubstituted pyrimidine derivative by a two-step method, which comprises the following steps: (1) reacting (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as a formula II inReacting with nitrite and water under an acidic condition to obtain (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V;
(2) carrying out N-alkylation reaction on 2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V and 6-methyl uracil shown as a formula VI to obtain a polysubstituted pyrimidine derivative shown as a formula I;
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medical intermediates, and particularly relates to a method for synthesizing an Elagolix intermediate polysubstituted pyrimidine derivative by a two-step method.
Background
Endometriosis (hereinafter referred to as endometriosis) is an estrogen-dependent chronic disease, often causing dysmenorrhea and pelvic pain. Elagolix is a non-peptide oral gonadotropin releasing hormone (GnRH) antagonist that produces partial or near complete estrogen inhibition in previous studies.
Elagolix requires the use of polysubstituted pyrimidine derivatives as shown in formula I:
according to the description of the U.S. patent WO2009062087, the polysubstituted pyrimidine derivative can be synthesized by the following route:
however, the highly toxic diketene is used in the route, the diketene has strong stimulation effect on tissue mucosa, the diketene has lacrimation, and patients with severe toxicity can cause emphysema, pulmonary edema and even pulmonary hemorrhage to die. Animal MLC: 1.0-1.5 mg/L cat, 2.5mg/L rabbit and 3.0mg/L rat. The maximum allowable concentration in air is 0.5-1.0 mg/m3。
Disclosure of Invention
The technical problem to be solved by the invention is as follows: conventional routes for the synthesis of polysubstituted pyrimidine derivatives as shown in formula I are somewhat hazardous.
The invention adopts the following technical scheme to solve the technical problems:
a two-step method for synthesizing an Elagolix intermediate polysubstituted pyrimidine derivative comprises the following steps:
(1) reacting (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as a formula II with nitrite and water under an acidic condition to obtain (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V;
(2) carrying out N-alkylation reaction on 2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V and 6-methyl uracil shown as a formula VI to obtain a polysubstituted pyrimidine derivative shown as a formula I;
preferably, the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method is specifically operated in the step (1) as follows: dissolving (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as a formula II in a solvent in a reactor, adjusting the pH of the mixture to be acidic, adding sodium nitrite into the mixture, and then carrying out reaction; after the reaction is finished, concentrating the reaction mixture to be dry, washing, drying and purifying the concentrate to obtain the (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown in the formula V.
Preferably, in the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by a two-step method, the specific operation of the step (2) is as follows: dissolving (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V in an organic solvent in a reactor, sequentially adding triphenylphosphine and an activating agent into the organic solvent, and then reacting; after the reaction is finished, washing, drying and purifying the reaction mixture to obtain the polysubstituted pyrimidine derivative shown as the formula I.
Preferably, in the method for synthesizing the Elagolix intermediate multi-substituted pyrimidine derivative by the two-step method, the organic solvent in the step (2) is selected from any one of THF, 1, 4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, DMF, DMAc, 1, 2-dichloroethane and dichloromethane; and/or
The activating agent in the step (2) is DIAD or DEAD.
Preferably, in the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step process, the washing operation in the step (2) is as follows: washing a reaction solution by adopting a mixed solution of ethyl acetate and a hydrochloric acid aqueous solution, and separating an organic phase; the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order.
Preferably, in the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step process, the solvent in the step (1) is an organic solvent, or the volume ratio of the organic solvent to water is (2-5): 1 mixing the obtained mixed solvent.
Preferably, the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method is characterized in that the organic solvent is any one of 1, 4-dioxane, THF, DMF, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, methanol and ethanol.
Preferably, in the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method, the pH value of the mixture is adjusted by using hydrochloric acid aqueous solution in the step (1), and the pH value is 1-6; and/or
In the step (1), a mixed solution consisting of dichloromethane and saturated aqueous solution of sodium bicarbonate is used as a detergent to wash the concentrate, and an organic phase is separated.
Preferably, according to the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method, every 1.0g of (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as the formula II in 1.0equiv is reacted with 1.0-3.0equiv nitrite; and/or
The reaction process of the step (1) is to heat the system to reflux for 1-6h, or to heat the system to 60-150 ℃ for 3-5 h.
Preferably, according to the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method, every 1.0g of the Elagolix intermediate polysubstituted pyrimidine derivative is reacted with 1.0equiv. 2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V and 0.9-2.4equiv. 6-methyl uracil shown as a formula VI, the using amount of the activating agent is 1.0-2.5equiv., and the equivalent ratio of triphenylphosphine to the activating agent is 1: 1; and/or
The process of the N-alkylation reaction is as follows: stirring and reacting for 2-8h at normal temperature; or reacting for 3-5h under the ice bath condition; or heating the system to reflux for 2-5 h.
The invention has the following beneficial effects:
the technical scheme of the invention adopts commercial chemical raw materials as starting materials, designs a synthetic route, and can obtain a target product only by two-step reaction; the raw materials used in the synthetic route are safe, reliable and nontoxic, and the safety of the production process is ensured.
Detailed Description
In order to facilitate the understanding of the technical solutions of the present invention for those skilled in the art, the technical solutions of the present invention will now be further described with reference to specific embodiments.
The chemical reagents used in the examples of the present invention are all commercially available chemicals.
The embodiment of the invention synthesizes the polysubstituted pyrimidine derivative shown as the formula I through the following route:
the following examples are given to illustrate the preparation of the desired product.
Example 1
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in formula II in a mixture of 10mL of 1,4 dioxane and 2mL of water in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 3, then adding 1.5equiv sodium nitrite, heating the system to reflux, and reacting for 3 hours; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.69equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 69%. Detecting by using a high resolution mass spectrum (ESI +), wherein the detection value is 195.0439; c8H7F4O+The calculated high resolution mass spectrum of 195.0428 was compared to confirm the structure of the product.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol, formula V, 1.2equiv. 6-methyluracil of formula VI dissolved in 10mL THF, at room temperature to add 1.5equiv. three phenyl phosphine, 1.5equiv. DIAD, then at room temperature reaction for 5 h; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying, the solvent is dried in a spinning mode, finally column chromatography is carried out, the 0.89equiv. polysubstituted pyrimidine derivative shown as the formula I is obtained, and the yield is 89%. Detecting by adopting a high-resolution mass spectrum (ESI +), wherein the detection value is 303.0758; m + H+Calculated high resolution mass spectrum of 303.0751, the alignment confirmed the structure of the product.
Example 2
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as formula II in 10mL of a mixture of 1, 4-glycol dimethyl ether and 2mL of water in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 1, then adding 1.5equiv sodium nitrite, heating the system to reflux, and reacting for 3 h; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.59equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 59%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 195.0429.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V, 0.9equiv 6-methyluracil as shown in formula VI are dissolved in 15mL of 2-methyltetrahydrofuran, and 1.5equiv triphenylphosphine and 1.5equiv DIAD are added in sequence at room temperature, and then the mixture is reacted for 5 hours at room temperature; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying, the solvent is dried in a spinning mode, finally, column chromatography is carried out to obtain 0.75equiv. polysubstituted pyrimidine derivative shown as the formula I, and the yield is 75%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 303.0753.
Example 3
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in formula II in a mixture of 15mL THF and 7.5mL water in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 6, then adding 1.5equiv sodium nitrite, heating the system to reflux, and reacting for 1 h; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.10equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 10%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 195.0435.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V and 2.4equiv 6-methyl uracil as shown in formula VI are dissolved in 12mL of ethylene glycol dimethyl ether, 2.5equiv triphenylphosphine and 2.5equiv DEAD are sequentially added at room temperature, and then the mixture is reacted for 8 hours at room temperature; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying, the solvent is dried in a spinning mode, finally column chromatography is carried out, the 0.89equiv. polysubstituted pyrimidine derivative shown as the formula I is obtained, and the yield is 89%. Detection was performed by high resolution mass spectrometry (ESI +) and the detection value was 303.0762.
Example 4
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in formula II in 15mL1, 4-dioxane in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 3, then adding 3.0equiv sodium nitrite, heating the system to reflux, and reacting for 6 h; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.70equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 70%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 195.0434.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthesis route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V and 1.2equiv 6-methyluracil as shown in formula VI are dissolved in 15mL of methyl tert-butyl ether, and 1.0equiv triphenylphosphine and 1.0equiv DIAD are added in sequence at room temperature, and then the mixture is reacted for 5 hours under ice bath conditions; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying, the solvent is dried in a spinning mode, finally, column chromatography is carried out, and 0.62equiv. polysubstituted pyrimidine derivative shown as formula I is obtained, and the yield is 62%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 303.0757.
Example 5
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in formula II in a mixture of 15mL of 2-methyltetrahydrofuran and 3mL of water in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 3, then adding 1.5equiv sodium nitrite, heating the system to 60 ℃ and reacting for 3 h; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.52equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 52%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 195.0435.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthesis route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V and 1.2equiv 6-methyl uracil as shown in formula VI are dissolved in 13mL DMF, 1.5equiv triphenylphosphine and 1.5equiv DIAD are added in sequence at room temperature, and the system is heated to reflux reaction for 5 h; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin-drying the solvent, and finally column chromatography is carried out to obtain the 0.43equiv. polysubstituted pyrimidine derivative shown as the formula I, wherein the yield is 43%. Detection was performed by high resolution mass spectrometry (ESI +) and the detection value was 303.0753.
Example 6
(1) Preparation of (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V
The synthetic route is as follows:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in formula II in 15mL of methanol in a reactor, adding a hydrochloric acid aqueous solution, adjusting the pH of the mixture to 3, then adding 1.5equiv sodium nitrite, sealing the system and heating to 150 ℃, and reacting for 3 h; after the reaction is finished, concentrating the reaction mixture to be dry, washing the concentrate by using a mixture of dichloromethane and saturated sodium bicarbonate water solution as a detergent, separating an organic phase, drying by using sodium sulfate, spin-drying, and finally performing column chromatography to obtain 0.50equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V, wherein the yield is 50%. Detection was performed by high resolution mass spectrometry (ESI +) and found 195.0432.
(2) Preparation of polysubstituted pyrimidine derivatives as shown in formula I
The synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methanol as shown in formula V, 1.2equiv 6-methyluracil as shown in formula VI are dissolved in 12mL of 1, 2-dichloroethane, and 1.5equiv triphenylphosphine and 1.5equiv DIAD are added in sequence at room temperature, followed by reaction at room temperature for 2 h; after the reaction is finished, the mixture of ethyl acetate and 1N hydrochloric acid aqueous solution is used as a detergent to wash the reaction mixed solution, an organic phase is separated, then a saturated sodium bicarbonate aqueous solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying, the solvent is dried in a spinning mode, finally, column chromatography is carried out to obtain 0.35equiv. polysubstituted pyrimidine derivative shown as formula I, and the yield is 35%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 303.0755.
Technical solution of the present invention, the present invention is described above by way of example with reference to the specific embodiments, and it is obvious that the specific implementation of the present invention is not limited by the above-described manner, and it is within the scope of the present invention to employ various insubstantial modifications of the method concept and technical solution of the present invention, or to directly apply the concept and technical solution of the present invention to other occasions without modification.
Claims (10)
1. A two-step method for synthesizing an Elagolix intermediate polysubstituted pyrimidine derivative is characterized by comprising the following steps:
(1) reacting (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as a formula II with nitrite and water under an acidic condition to obtain (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V;
(2) carrying out N-alkylation reaction on 2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V and 6-methyl uracil shown as a formula VI to obtain a polysubstituted pyrimidine derivative shown as a formula I;
2. the method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in the two-step way according to claim 1, wherein the specific operation of step (1) is as follows: dissolving (2-fluoro-6- (trifluoromethyl) phenyl) methylamine shown as a formula II in a solvent in a reactor, adjusting the pH of the mixture to be acidic, adding sodium nitrite into the mixture, and then reacting; after the reaction is finished, concentrating the reaction mixture to be dry, washing, drying and purifying the concentrate to obtain the (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown in the formula V.
3. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in the two-step way according to claim 1, wherein the specific operation of step (2) is as follows: dissolving (2-fluoro-6- (trifluoromethyl) phenyl) methanol shown as a formula V in an organic solvent in a reactor, sequentially adding triphenylphosphine and an activating agent into the organic solvent, and then reacting; after the reaction is finished, washing, drying and purifying the reaction mixture to obtain the polysubstituted pyrimidine derivative shown as the formula I.
4. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative by the two-step method according to claim 3, wherein the organic solvent in step (2) is selected from any one of THF, 1, 4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, DMF, DMAc, 1, 2-dichloroethane, and dichloromethane; and/or
The activating agent in the step (2) is DIAD or DEAD.
5. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in a two-step way according to claim 3, wherein the washing operation in step (2) is: washing a reaction solution by adopting a mixed solution of ethyl acetate and a hydrochloric acid aqueous solution, and separating an organic phase; the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order.
6. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in the two-step method according to claim 2, wherein the solvent in step (1) is an organic solvent, or the volume ratio of the organic solvent to water is (2-5): 1 mixing the obtained mixed solvent.
7. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in two steps according to claim 6, wherein the organic solvent is selected from any one of 1, 4-dioxane, THF, DMF, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, methanol and ethanol.
8. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in the two-step way according to claim 2, wherein the pH value of the mixture in step (1) is adjusted by hydrochloric acid aqueous solution, and the pH value is 1-6; and/or
In the step (1), a mixed solution consisting of dichloromethane and saturated aqueous solution of sodium bicarbonate is used as a detergent to wash the concentrate, and an organic phase is separated.
9. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative according to the claim 2, wherein every 1.0g, 1.0equiv. (2-fluoro-6- (trifluoromethyl) phenyl) methylamine as shown in the formula II is reacted with 1.0-3.0equiv nitrite; and/or
The reaction process of the step (1) is to heat the system to reflux for 1-6h, or to heat the system to 60-150 ℃ for 3-5 h.
10. The method for synthesizing the Elagolix intermediate polysubstituted pyrimidine derivative in the two-step manner according to claim 3, wherein every 1.0g of the Elagolix intermediate polysubstituted pyrimidine derivative is reacted with 1.0equiv. 2-fluoro-6- (trifluoromethyl) phenyl) methanol represented by formula V and 0.9-2.4equiv. 6-methyl uracil represented by formula VI, the amount of the activator is 1.0-2.5equiv., and the equivalent ratio of triphenylphosphine to the activator is 1: 1; and/or
The process of the N-alkylation reaction is as follows: stirring and reacting for 2-8h at normal temperature; or reacting for 3-5h under the ice bath condition; or heating the system to reflux for 2-5 h.
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| CN108586359A (en) * | 2018-06-26 | 2018-09-28 | 杭州科巢生物科技有限公司 | A kind of synthetic method for disliking La Geli |
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| CN108586359A (en) * | 2018-06-26 | 2018-09-28 | 杭州科巢生物科技有限公司 | A kind of synthetic method for disliking La Geli |
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