CN109956906B - Preparation method of key intermediate of oxalagogri - Google Patents
Preparation method of key intermediate of oxalagogri Download PDFInfo
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Abstract
The invention relates to the field of pharmacy, in particular to a preparation method of an Oxagolide key intermediate, which takes Boc-D-phenylglycinol which is simple and easy to obtain as a starting raw material and comprises six steps of reactions of amination, amidation, arylation coupling, cyclization, benzylamine substitution and deprotection.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a preparation method of a key intermediate of diragolide.
Background
Orilissa, an oral formulation, was developed by AbbVie together with Neurocine Biosciences Inc (NBIX), and its pharmaceutically active ingredient is elagolix, a non-peptide gonadotropin-releasing hormone GnRH receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in pituitary gland. Elagolix can cause luteinizing hormone and follicle stimulating hormone to show dose-dependent inhibition after being administered, finally, the level of the ovarian hormones estradiol and progesterone in blood circulation is reduced, and dysmenorrheal or non-menstrual period pelvic pain of patients with endometriosis is reduced.
In patent WO2009062087, 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] urea is used as an initial raw material and cyclized with acetoacetic acid tert-butyl ester to obtain a uracil intermediate, the uracil intermediate is subjected to iodination, Suzuki coupling and aminoalkylation reactions to obtain an intermediate protected by a Boc group, and finally acidolysis deprotection is performed to obtain a key intermediate of Oxagolide. As shown in the following synthetic route, the synthetic route uses noble metal for coupling reaction, has low yield and high cost, and is not suitable for industrial production.
In patent US7056927B2, 2-fluoro-6- (trifluoromethyl) benzonitrile is used as a starting material, and is subjected to borane tetrahydrofuran reduction, then reacts with urea to obtain 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] urea, then undergoes cyclization with diketene to obtain a uracil intermediate, then undergoes bromination with bromine, then undergoes Mitsunobu reaction and Suzuki coupling reaction, and finally undergoes acidolysis deprotection to obtain an oxalagril intermediate. As shown in the following synthetic route, the route uses substances with high toxicity, such as bromine, 1, 4-dioxane and the like, and the reaction conditions are harsh, so that the method is not suitable for industrial large-scale production.
In conclusion, a brand new process synthetic route is developed, for example, the production cost can be greatly reduced by searching for simple and easily-obtained starting materials, avoiding the use of noble metal catalysts, reducing reaction steps and the like, so that the synthesis of the key intermediate of the oxalagogrel is in line with industrial large-scale production.
Disclosure of Invention
The invention aims to provide a preparation method of a key intermediate of oxa-gol, which takes simple and easily obtained Boc-D-phenylglycinol as a starting material, has mild reaction conditions and simple post-treatment, avoids using a noble metal catalyst, greatly reduces the process synthesis cost, has high purity and yield of the obtained intermediate, and is very suitable for large-scale production in a workshop.
The invention provides a preparation method of an oxa-gol key intermediate, which adopts the following technical scheme and comprises the following steps:
(1) carrying out amination reaction on Boc-D-phenylglycinol and hydrazine hydrate to obtain a compound II;
(2) carrying out amidation reaction on the compound II and a chloroformate compound to obtain a compound IV;
wherein R is1Represents alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl or cyclopropyl;
(3) performing arylation coupling reaction on the compound V and a compound VI to obtain a compound VII;
wherein, X represents halogen chlorine, bromine and iodine; r2Represents alkyl including but not limited to methyl, ethyl, n-propyl, allyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or benzyl;
(4) carrying out cyclization reaction on the compound IV and the compound VII to obtain a compound VIII;
(5) carrying out substitution reaction on the compound VIII and 2-fluoro-6-trifluoromethylbenzylamine to obtain a compound IX;
(6) and carrying out deprotection reaction on the compound IX under an acidic condition to obtain a compound X.
Preferably, when the compound II is synthesized by amination, the molar ratio of the compound I, the phthalimide, the triphenylphosphine and the diethyl azodicarboxylate is 1: 1-1.2: 1-1.5, and more preferably 1:1.05:1.1: 1.2;
preferably, when compound ii is synthesized by the amination, the solvent used is DMF, DMAC or THF, more preferably THF;
preferably, when the compound II is synthesized by the amination reaction, the amination reagent used is hydrazine hydrate or ammonia water, and hydrazine hydrate is more preferred;
preferably, when the compound iv is synthesized by amidation, the chloroformate compound used is methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, tert-butyl chloroformate, benzyl chloroformate or cyclopropyl chloroformate, more preferably n-propyl chloroformate;
preferably, when the compound IV is synthesized by amidation, the organic base used is piperidine, pyridine, triethylamine, diethylamine, 4-methylmorpholine or 4-dimethylaminopyridine, and more preferably triethylamine;
preferably, when the compound IV is synthesized by amidation, the molar ratio of the compound II to the compound III to the base is 1:1 to 5, and more preferably 1:4: 4.
Preferably, when the compound VII is synthesized by arylation coupling reaction, the compound VI is methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, allyl acetoacetate, isopropyl acetoacetate, isobutyl acetoacetate, sec-butyl acetoacetate, tert-butyl acetoacetate, n-pentyl acetoacetate, n-hexyl acetoacetate, more preferably ethyl acetoacetate;
preferably, when the compound VII is synthesized by arylation coupling reaction, the coupling catalyst used is CuI, CuCl or CuI2CuO or Cu (OAc)2Further, Cu (OAc)2；
The coupling catalyst can influence the reaction rate when the compound VII is synthesized by the arylation coupling reaction, but the yield of the compound VII is greatly improved by selecting a plurality of coupling catalysts in the scheme, particularly selecting Cu (OAc)2The effect is more obvious.
Preferably, when compound vii is synthesized by arylation coupling reaction, DMF, DMAC, or DMSO is used as a reaction solvent, and DMF is more preferred;
preferably, when the compound VII is synthesized by arylation coupling reaction, the molar ratio of the compound V, the compound VI and the catalyst is 1: 1-2: 0.05-0.2, and more preferably 1:1.2: 0.1.
Preferably, when the compound VIII is synthesized by a cyclization reaction, benzene, toluene or xylene is used as a reaction solvent, and toluene is more preferred;
preferably, when the compound VIII is synthesized by cyclization, the catalyst used is p-toluenesulfonic acid or benzenesulfonic acid, and more preferably p-toluenesulfonic acid;
preferably, when the compound VIII is synthesized by a cyclization reaction, the molar ratio of the compound IV, the compound VII and p-toluenesulfonic acid is 1:1: 1-1.5, and more preferably 1:1: 1.2.
Preferably, when the compound IX is synthesized by benzylamine substitution reaction, the organic base used is triethylamine, diethylamine, diisopropylethylamine or diazabicyclo, and more preferably triethylamine;
preferably, when the compound IX is synthesized by the benzylamine substitution reaction, benzene, toluene, methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran is used as a reaction solvent, and ethanol is more preferred;
preferably, when the compound IX is synthesized by benzylamine substitution reaction, the molar ratio of the compound VIII to the 2-fluoro-6-trifluoromethylbenzylamine to the organic base is 1:1 to 1.5:1 to 2, preferably 1:1.1: 1.2.
Preferably, when compound X is synthesized by deprotection reaction, the acid used is methanesulfonic acid or hydrochloric acid, and more preferably methanesulfonic acid;
preferably, when compound X is synthesized by deprotection reaction, ethyl acetate, isopropyl acetate or butyl acetate is used as a reaction solvent, and isopropyl acetate is more preferred;
preferably, when compound X is synthesized by deprotection reaction, the molar ratio of compound IX to methanesulfonic acid is 1:1 to 5, and more preferably 1: 3.
By implementing the technical scheme, the method takes the simple and easily obtained Boc-D-phenylglycinol as the initial raw material, has mild reaction conditions and simple post-treatment, avoids using a noble metal catalyst, greatly reduces the process synthesis cost, has high purity and yield of the obtained intermediate, and is very suitable for large-scale production in a workshop.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept and the scope of the appended claims is intended to be protected by the following claims. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited.
Example 1:
amination: under ice bath, 23.7g of Boc-D-phenylglycinol, 15.5g of phthalimide, 28.8g of triphenylphosphine, 20.9g of diethyl azodicarboxylate and 500mL of tetrahydrofuran are added into a reaction bottle, stirred for 15min, heated to room temperature for reaction for 6h, concentrated to remove tetrahydrofuran, added with 50mL of ethanol and 250mL of hydrazine hydrate for continuous reflux reaction for 2h, added with dichloromethane for extraction after the reaction is finished, concentrated to remove an organic layer, and 23.5g of intermediate II with the purity of 98.5% and the weight yield of 99% is obtained.
Amidation reaction: under ice bath, 21.2g of the compound II, 36.4g of triethylamine and 200mL of acetonitrile are added into a reaction bottle, 44.1g of n-propyl chloroformate is slowly dripped, after dripping is finished, the reaction is finished after the heat preservation reaction is carried out for 3.5h, the reaction solution is flushed into 2L of ice water for solid precipitation, suction filtration and drying are carried out, and 28.6g of the intermediate IV is obtained, wherein the purity is 99.1 percent, and the weight yield is 135 percent.
Arylation coupling reaction: under the protection of nitrogen in a reaction bottle, 32.2g of 3-chloro-2-fluoroanisole, 31.2g of ethyl acetoacetate and 160mL of DMF are added at room temperature, stirred to be dissolved clearly, 4g of copper acetate is added, and the temperature is raised to 50 ℃ for reaction for 8 hours. After the reaction is finished, 300mL of saturated ammonium chloride aqueous solution is added to quench the reaction, 200mL of ethyl acetate is added for extraction for three times, organic layers are combined, and after being dried by anhydrous sodium sulfate, the mixture is concentrated to be dry, so that 25.8g of the intermediate VII with the purity of 99.3% and the weight yield of 80.2% is obtained.
And (3) cyclization reaction: at room temperature, adding 25.8g of compound IV, 20.3g of compound VII, 22.8g of p-toluenesulfonic acid and 250mL of toluene into a reaction bottle, building a water diversion device, starting reflux reaction for 7h, adding triethylamine to adjust the pH value to be alkalescent after the reaction is finished, cooling to room temperature, concentrating to be dry, adding 250mL of water for pulping, filtering, and drying to obtain 36.8g of intermediate VIII, wherein the purity is 98.6%, and the weight yield is 142.6%.
Benzylamine substitution reaction: 37.6g of the compound VIII, 17.0g of 2-fluoro-6-trifluoromethylbenzylamine, 9.7g of triethylamine and 150mL of ethanol are added into a reaction bottle, the mixture is heated to reflux, after 8 hours of reaction, 100mL of ethyl acetate is added for extraction for three times, organic layers are combined, and after drying by anhydrous sodium sulfate, the mixture is concentrated to dryness to obtain 45.5g of an intermediate IX, the purity is 98.7%, and the weight yield is 121%.
Deprotection reaction: adding 32.3g of the intermediate IX, 14.4g of methanesulfonic acid and 150mL of isopropyl acetate into a reaction bottle, raising the temperature to 60 ℃ for reaction overnight, adding a potassium carbonate aqueous solution to regulate the pH value to be approximately 8, stirring and layering, adding a phosphoric acid aqueous solution into an organic layer, layering, slowly adding a potassium carbonate aqueous solution into an aqueous layer to regulate the pH value to be approximately 7-8, adding isopropyl acetate for extraction, stirring and layering, washing the organic layer with water and saturated saline solution once respectively, finally drying with anhydrous sodium sulfate, filtering, concentrating and drying filtrate to obtain 25.2g of the intermediate X, wherein the purity is 99.4%, and the weight yield is 78%.
Example 2:
amination: following the procedure of example 1, the addition of 500mL of tetrahydrofuran was changed to 250mL of DMF, and the addition of 250mL of hydrazine hydrate was changed to 400mL of aqueous ammonia, to give 22.5g of intermediate II, 97.5% purity, and 95% weight yield.
Amidation reaction: in the same manner as in example 1, 44.1g of ethyl chloroformate was changed from 44.1g of n-propyl chloroformate dropwise thereto to obtain 25g of intermediate IV having a purity of 98.6% and a weight yield of 106.1%.
Arylation coupling reaction: following the procedure of example 1, the addition of 4g of cupric acetate was changed to 2g of cuprous chloride, yielding 24.2g of intermediate VII, 97.2% pure, 75% weight yield.
And (3) cyclization reaction: following the same procedure as in example 1, 28.5g of p-toluenesulfonic acid was substituted by 22.8g of p-toluenesulfonic acid, yielding 35.2g of intermediate VIII with a purity of 98.1% and a weight yield of 136.4%.
Benzylamine substitution reaction: following the same procedure as in example 1, 8.2g of diisopropylethylamine was substituted for 9.7g of triethylamine to obtain 41.8g of intermediate IX, purity 97.2%, weight yield 111.2%.
Deprotection reaction: following the same procedure as in example 1, the addition of 14.4g of methanesulfonic acid was changed to 23.9g of methanesulfonic acid, yielding 24.2g of intermediate X with a purity of 98.8% and a weight yield of 75%.
Example 3:
amination: the procedure of example 1 was repeated, except that 20.9g of diethyl azodicarboxylate was changed to 19.5g of diethyl azodicarboxylate, the reaction time was prolonged to 7 hours, and the reflux reaction was continued for 4 hours to obtain 21.8g of intermediate II, purity of 97.9%, and weight yield of 92%.
Amidation reaction: in the same manner as in example 1, 44.1g of methyl chloroformate was used instead of 44.1g of n-propyl chloroformate, and the reaction was carried out for 3 hours while maintaining the temperature, whereby 24.5g of intermediate IV having a purity of 98.5% and a weight yield of 115.6% was obtained.
Arylation coupling reaction: in the same manner as in example 1, 3g of copper oxide was replaced by 4g of copper acetate, and the mixture was heated to 55 ℃ to react for 9 hours, whereby 25.1g of intermediate VII was obtained with a purity of 98.2% and a weight yield of 78%.
And (3) cyclization reaction: the procedure of example 1 was repeated except that 22.8g of p-toluenesulfonic acid was changed to 21.2g of p-toluenesulfonic acid, and the reaction was refluxed for 8 hours to obtain 34.5g of intermediate VIII with a purity of 97.2% and a weight yield of 133.7%.
Benzylamine substitution reaction: in the same manner as in example 1, 10.5g of diethylamine was substituted by 9.7g of triethylamine, and the reaction was carried out for 10 hours to obtain 41.5g of intermediate IX with a purity of 98.1 and a weight yield of 110.5%.
Deprotection reaction: the procedure of example 1 was followed, except that the temperature was raised to 55 ℃ for overnight reaction, and 14.4g of methanesulfonic acid was added instead of 20.7 hydrochloric acid, to obtain 23.3g of intermediate X with a purity of 98.4% and a weight yield of 72%.
Example 4:
amination: following the same procedure as in example 1, the reaction was carried out at room temperature for 8 hours by changing the amount of triphenylphosphine added to 28.8g to 32.9g, and the reaction was refluxed for 3 hours to obtain 23.4g of intermediate II, which had a purity of 97.9% and a weight yield of 98.7%.
Amidation reaction: following the same procedure as in example 1, 32.5g of 4-dimethylaminopyridine was substituted for 36.4g of triethylamine and the reaction was carried out for 4 hours while maintaining the temperature, whereby 27.8g of intermediate IV was obtained, the purity was 97.9% and the weight yield was 131.2%.
Arylation coupling reaction: following the procedure of example 1, the addition of 4g of cupric acetate was changed to 2g of cupric acetate, yielding 24.7g of intermediate VII having a purity of 98.5% and a weight yield of 76.7%.
And (3) cyclization reaction: following the procedure of example 1, 250mL of xylene was substituted by 250mL of toluene to give 35.8g of intermediate VIII, 98.1% pure, and 138.8% weight yield.
Benzylamine substitution reaction: following the procedure of example 1, 150mL of acetonitrile was substituted with 150mL of ethanol to give 33.9g of intermediate IX, 97.3% purity, and 90.2% weight yield.
Deprotection reaction: following the same procedure as in example 1, 14.4g of hydrochloric acid was substituted for 14.4g of methanesulfonic acid to give 23.1g of intermediate X with a purity of 99.0% and a weight yield of 71.7%.
Example 5:
amination: following the same procedure as in example 1, 14.8g of phthalimide was substituted for 15.5g of phthalimide to provide 22.1g of intermediate II, 98.0% purity, and 93.2% weight yield.
Amidation reaction: following the same procedure as in example 1, 32.5g of piperidine was substituted for 36.4g of triethylamine to afford 26.8g of intermediate IV having a purity of 98.7% and a weight yield of 126.4%.
Arylation coupling reaction: following the same procedure as in example 1, 3g of cuprous iodide was substituted with 4g of cupric acetate to obtain 24.2g of intermediate VII with a purity of 97.2% and a weight yield of 75.2%.
And (3) cyclization reaction: following the same procedure as in example 1, 22.8g of p-toluenesulfonic acid was replaced with 22.8g of benzenesulfonic acid to give 32.2g of intermediate VIII with a purity of 96.6% and a weight yield of 124.8%.
Benzylamine substitution reaction: following the procedure of example 1, 150mL of isopropanol was changed from 150mL of ethanol to 34.2g of intermediate IX, 97.1% purity, 132.6% weight yield.
Deprotection reaction: following the procedure of example 1, 150mL ethyl acetate was substituted for 150mL isopropyl acetate to provide 23.8g of intermediate X, 98.8% purity, 73.7% weight yield.
Comparative example 1:
the difference from example 5 is that:
amination: following the procedure of example 1, 500mL DMAC was substituted for 500mL tetrahydrofuran to give 21.4g intermediate II, 97.4% purity, 90.2% weight yield.
Comparative example 2:
the difference from example 5 is that:
amidation reaction: in the same manner as in example 1, 54.6g of triethylamine was substituted by 36.4g of triethylamine to obtain 24.5g of intermediate IV having a purity of 98.1% and a weight yield of 115.6%.
Comparative example 3:
the difference from example 5 is that:
arylation coupling reaction: following the same procedure as in example 1, 1.5g of copper powder was substituted by 4g of copper acetate to obtain 21.2g of intermediate VII with a purity of 95.2% and a weight yield of 65.8%.
Comparative example 4:
the difference from example 5 is that:
arylation coupling reaction: in the same manner as in example 1, 46.1g of benzyl acetoacetate instead of 31.2g of ethyl acetoacetate were charged to give 22.3g of intermediate VII with a purity of 94.4% and a weight yield of 69.2%.
Comparative example 5:
the difference from example 5 is that:
arylation coupling reaction: in the same manner as in example 1, 42.5g of ethyl acetoacetate was changed from the addition of 31.2g of ethyl acetoacetate to give 25.2g of intermediate VII with a purity of 98.8% and a weight yield of 78.3%.
Comparative example 6:
the difference from example 5 is that:
benzylamine substitution reaction: following the procedure of example 1, 150mL of acetone was substituted with 150mL of ethanol to give 42.1g of intermediate IX, 96.5% purity, 112% weight yield.
Claims (13)
1. The preparation method of the key intermediate of the oxagol is characterized in that Boc-D-phenylglycinol is used as a starting material, and comprises six reactions of amination, amidation, arylation coupling, cyclization, benzylamine substitution and deprotection:
(1) carrying out amination reaction on Boc-D-phenylglycinol and an amination reagent to obtain a compound II;
(2) carrying out amidation reaction on the compound II and a chlorinated reagent to obtain a compound IV;
wherein R1 represents an alkyl group;
(3) performing arylation coupling reaction on the compound V and a compound VI to obtain a compound VII;
wherein, X represents halogen; r2 represents alkyl, and the catalyst is p-toluenesulfonic acid or benzenesulfonic acid;
(4) carrying out cyclization reaction on the compound IV and the compound VII to obtain a compound VIII;
(5) carrying out substitution reaction on the compound VIII and 2-fluoro-6-trifluoromethylbenzylamine to obtain a compound IX;
(6) carrying out deprotection reaction on a compound IX under an acidic condition to obtain a compound X;
wherein, the used organic base is triethylamine, diethylamine, diisopropylethylamine or diazabicyclo, and the reaction solvent is benzene, toluene, methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran.
2. The preparation method according to claim 1, characterized by comprising the following specific steps:
(1) amination: adding Boc-D-phenylglycinol, phthalimide, triphenylphosphine, diethyl azodicarboxylate and a solvent into a reaction bottle in ice bath, stirring, heating to room temperature for reacting for 6-8 h, adding ethanol and an amination reagent, continuing reflux reaction for 2-4 h, extracting after the reaction is finished, and concentrating to remove an organic layer to obtain a compound II;
(2) amidation reaction: under ice bath, adding the compound II, organic base and acetonitrile into a reaction bottle, slowly dropwise adding a chlorinated reagent, after dropwise adding, keeping the temperature and reacting for 3-4 h, then finishing the reaction, separating out the solid, performing suction filtration, and drying to obtain a compound IV;
(3) arylation coupling reaction: under the protection of nitrogen in a reaction bottle, adding a compound V, a compound VI and a solvent at room temperature, stirring for dissolving, adding a coupling catalyst, heating to 50-60 ℃, reacting for 8-10 h, flushing saturated ammonium chloride aqueous solution after the reaction is finished, quenching the reaction, extracting, and concentrating an organic layer to be dry to obtain a compound VII;
(4) and (3) cyclization reaction: adding a compound IV, a compound VII, a catalyst and a solvent into a reaction bottle at room temperature, carrying out reflux reaction for 7-9 h, adding triethylamine to adjust the pH value to be alkalescent after the reaction is finished, cooling to room temperature, concentrating to be dry, adding water, pulping, filtering and drying to obtain a compound VIII;
(5) benzylamine substitution reaction: adding a compound VIII, 2-fluoro-6-trifluoromethylbenzylamine, an organic base and a reaction solvent into a reaction bottle, heating to reflux, reacting for 8-10 h, extracting, and concentrating an organic layer to be dry to obtain an intermediate IX; heating to reflux, reacting for 8-10 h, extracting, and concentrating an organic layer to be dry to obtain an intermediate IX;
(6) deprotection reaction: adding an intermediate IX, an acid and a solvent into a reaction bottle, raising the temperature to 50-60 ℃, reacting overnight, stirring and layering, adding a phosphoric acid aqueous solution into an organic layer, layering, adding isopropyl acetate into a water layer, extracting, stirring and layering, washing the organic layer with water and saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating and drying filtrate to obtain an intermediate X.
3. The preparation method according to claim 1 or 2, wherein the compound I, the phthalimide, the triphenylphosphine and the diethyl azodicarboxylate are used in a molar ratio of 1:1 to 1.2:1 to 1.5 in the synthesis of the compound II through the amination.
4. The method according to claim 1 or 2, wherein the chlorinating reagent used in the amidation reaction to synthesize the compound IV is methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, tert-butyl chloroformate, or cyclopropyl chloroformate.
5. The process according to claim 2, wherein the compound IV is synthesized by amidation using piperidine, pyridine, triethylamine, diethylamine, 4-methylmorpholine or 4-dimethylaminopyridine as the organic base.
6. The preparation method of claim 2, wherein the compound II, the compound III and the organic base are mixed in a molar ratio of 1:1 to 5 when the compound IV is synthesized by amidation.
7. The process according to claim 1 or 2, wherein compound VI is methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, isopropyl acetoacetate, isobutyl acetoacetate, sec-butyl acetoacetate, tert-butyl acetoacetate, n-pentyl acetoacetate or n-hexyl acetoacetate.
8. The process according to claim 1 or 2, wherein the compound VII is synthesized by arylation coupling using a coupling catalyst selected from the group consisting of CuI, CuCl, CuI2, CuO and Cu (OAc) 2; the molar ratio of the compound V to the compound VI to the catalyst is 1: 1-2: 0.05-0.2.
9. The process according to claim 2, wherein the compound VIII is synthesized by the cyclization reaction in a solvent selected from the group consisting of benzene, toluene and xylene.
10. The preparation method according to claim 9, wherein when the compound VIII is synthesized by a cyclization reaction, the molar ratio of the compound IV to the compound VII to p-toluenesulfonic acid is 1:1: 1-1.5.
11. The process according to claim 2, wherein when the compound IX is synthesized by the substitution reaction of benzylamine, the molar ratio of the compound VIII, 2-fluoro-6-trifluoromethylbenzylamine and the organic base is 1:1 to 1.5:1 to 2.
12. The process according to claim 1 or 2, wherein when compound X is synthesized by deprotection reaction, the acid used is methanesulfonic acid or hydrochloric acid; the reaction solvent used was ethyl acetate, isopropyl acetate or butyl acetate.
13. The method according to claim 1 or 2, wherein when the compound X is synthesized by deprotection, the molar ratio of the compound IX to methanesulfonic acid is 1:1 to 5.
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| 6-甲基-尿嘧啶及其N-取代衍生物合成;齐晓丽等;《西北大学学报(自然科学版)》;20090228;第39卷(第1期);63-66 * |
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