CN112300081A - Intermediate of oxadegril and preparation method and application thereof - Google Patents
Intermediate of oxadegril and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
The invention provides a preparation method of a novel important intermediate compound 1 of oxa-rogue, and also provides two novel intermediate compounds 5 and 6. The new intermediate compound 5 is used to reduce the five-step synthesis in the prior art into three steps, thereby greatly improving the yield, having low reaction energy consumption, less three wastes and short preparation period, and being easy for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of intermediates of novel oral GnRH antagonist oxadegril and a synthesis method thereof.
Background
Endometriosis (EMs) refers to a common gynecological disease in women with intimal cells planted in abnormal locations. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the ovary and the pelvic cavity through the oviduct, the endometrial cells can enter the ovary, the pelvic cavity and the adjacent area of the uterus to grow ectopically through the oviduct. EMs are common clinical benign diseases of women in the childbearing age, the incidence rate of the diseases reaches 10.0%, and the diseases are in a remarkable rising trend, are mainly characterized by dysmenorrhea, pelvic pain and infertility, and seriously affect the reproductive health and the life quality of the women.
On 23/7/2018, the important product of erbavil, elagolix (loragol), was approved by the U.S. food and drug administration, which would be useful in treating pain due to EMs and became the first new oral drug for over 10 years for this indication, with a projected sale of $ 12.1 billion in 2022.
The chemical name of the oxa-rogle is as follows: 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] butanoic acid. WO2005007165A reports a synthesis method of oxa-rogue, in the route, 2-fluoro-6-trifluoromethyl benzonitrile is taken as a starting material, the starting material is subjected to borane reduction, condensation with urea, cyclization with diethylenone and other steps in sequence to obtain an intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4(1H,3H) -diketone, the intermediate is subjected to bromination, amine alkylation and other steps to obtain a key intermediate compound 1, the key intermediate compound and 2-fluoro-3-methoxyphenylboronic acid are subjected to Suzuki coupling reaction, finally, Boc protecting groups are removed, and the key intermediate compound and 4-bromo-n-butyric acid are subjected to condensation and hydrolysis reaction to obtain the oxa-rogue, and the synthesis route is shown as follows.
The synthetic route has the disadvantages of overlong steps, more complicated process, lower total yield, expensive starting materials, high risk of liquid bromine amplification production and high equipment requirement.
In the new synthesis method of the oxa-rogue, disclosed in the U.S. Pat. No. 4, 8765948B, o-fluoro anisole is used as a raw material, condensation with diethyl oxalate, reduction with sodium borohydride, bromination with lithium bromide, and condensation with acetonitrile under the action of zinc powder are sequentially carried out to obtain an enamine intermediate, then the amino group is protected by phenyl chloroformate and undergoes cyclization reaction with (R) -tert-butyl (2-amino-1-phenylethyl) amino carbonate under the action of alkali to obtain a mother ring molecule, then the mother ring molecule and the benzyl bromide intermediate undergo an N-alkylation reaction to obtain an oxa-rogue key intermediate, and the oxa-rogue is obtained after deprotection, condensation, hydrolysis and other steps.
Although the starting materials are simple and easy to obtain in the synthetic route, the reaction steps are long, a large amount of debrominated products are generated in the condensation process of bromide intermediates and acetonitrile, the yield is greatly reduced, and the large-scale production is severely limited.
Therefore, a method for synthesizing the loragoid, which has the advantages of improving the yield, reducing the cost and being suitable for industrial production, is still needed.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a novel method for preparing the loragolide in an industrial production mode.
Based on the new intermediate compound, the invention also provides a new intermediate compound for preparing the oxadegril and a preparation method of the new intermediate compound. Meanwhile, a novel preparation method of the existing key intermediate compound 1 is provided.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
novel compound 5 of the formula
Novel compound 6 of the formula
The preparation method of the new compound 5 is that a compound 3 with the following formula is condensed with R-alpha- (Boc-amino) phenethylamine to obtain an intermediate compound 4, and then the intermediate compound is cyclized to obtain:
said R1Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like; preferably C1-C6 alkyl, more preferably ethyl or methyl;
x is selected from R2O、R3O and imidazolyl and the like; r2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like, preferably aryl, more preferably phenyl; r3Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, etc., preferably C1-C6 alkyl, more preferably ethyl or methyl.
The alkali comprises inorganic alkali such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like, and organic alkali such as triethylamine, N-diisopropylethylamine, pyridine, DBU and the like, preferably inorganic alkali, and more preferably potassium carbonate.
The reaction solvent is selected from toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, etc., and preferably N, N-dimethylformamide.
The cyclization reaction of the compound 4 to the compound 5 may be carried out at room temperature or under heating, preferably at 20 to 150 ℃, and more preferably at 60 to 100 ℃.
Compound 4 is obtained from condensation reaction, then compound 5 is obtained from cyclization reaction, the product 4 does not need to be separated in the middle, and the compound 5 can be obtained by one-pot method by directly heating up for cyclization reaction.
In a preferred embodiment, the compound 3 is obtained by condensation reaction of crotonate 2 and phenyl chloroformate:
R1selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like; preferably C1-C6 alkyl, more preferably ethyl or methyl;
x is selected from R2O、R3O and imidazolyl, R2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like, preferably aryl, more preferably phenyl; r3Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, etc., preferably C1-C6 alkyl, more preferably ethyl or methyl.
The above condensation reaction for preparing the compound 3, wherein the condensing agent comprises a chloro (bromo) formate
Dialkyl carbonatesEsters
N, N' -carbonyldiimidazole, etc., R2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like, preferably aryl, more preferably phenyl; r3Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, etc., preferably C1-C6 alkyl, more preferably ethyl or methyl.
In the condensation reaction for preparing the compound 3, the base includes inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like, and organic bases such as triethylamine, N-diisopropylethylamine, pyridine, DBU and the like, preferably inorganic bases, and more preferably potassium carbonate.
In the condensation reaction for preparing the compound 3, when water is generated in the reaction process, a drying agent is required to be added, and the drying agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, calcium oxide, a 4A molecular sieve and the like, and is preferably a 4A molecular sieve.
The condensation reaction for preparing the compound 3 is carried out in a solvent selected from toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone and the like, and preferably toluene.
The condensation reaction of the prepared compound 3 is carried out at the reaction temperature of 20-150 ℃, preferably 60-90 ℃.
The compound 6 is obtained by condensing the compound 5 and 2-fluoro-6-trifluoromethyl benzyl bromide under the action of alkali:
in the condensation reaction for preparing the compound 6, the base includes inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and the like, and organic bases such as triethylamine, N-diisopropylethylamine, pyridine, DBU, and the like, preferably inorganic bases, and more preferably sodium carbonate. The reaction solvent is selected from toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, etc., and preferably N, N-dimethylformamide. The reaction temperature is selected from room temperature to 150 ℃, and preferably 60 to 100 ℃. The condensation reaction needs to be added with a drying agent, and the drying agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, calcium oxide, a 4A molecular sieve and the like, and is preferably the 4A molecular sieve.
Halogenating the compound 6 with N-halogenated succinimide under the catalysis of a catalyst to obtain a compound 1(or7, 8):
the above compound 6 is catalyzed by inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as acetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably organic acids, more preferably p-toluenesulfonic acid. The reaction solvent is selected from dichloromethane, trichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1, 4-dioxane, toluene, etc., preferably dichloromethane. The reaction temperature is selected from-50 to 50 ℃, and preferably from-10 to 10 ℃.
The invention has the beneficial effects that:
1. the preparation of the compound 1 is reduced from five steps of the original patent to three steps, so that the yield is greatly improved, the reaction energy consumption is low, the 'three wastes' are less, the preparation period is short, and the industrial amplification production is easier.
2. 3-aminocrotonic acid ester which is cheap and easy to obtain can be further selected as a raw material, so that the cost of the raw material is greatly reduced, and reagents or intermediates used in each step can be purchased commercially.
3. The use of high-level, strong-stimulation and explosive reagents such as borane tetrahydrofuran, butyl lithium, diketene and the like is avoided, a large amount of strong-corrosivity reagents such as concentrated hydrochloric acid, bromine and the like are avoided, and the requirement on amplification production equipment is greatly reduced.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adaptations of the present invention based on the above-described disclosure.
The synthesis route of the synthesis method of the key intermediate (compound 1) of oxalagrange provided by the invention is shown as follows:
example 1:
ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry toluene (100mL), anhydrous potassium carbonate (16.05g, 116.14mmol), 4A molecular sieve (325 mesh, 10g) and phenyl chloroformate (11.64mL, 92.91mmol) were added at room temperature, the suspension was raised to 75 deg.C, the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and after 4h the conversion of the starting material was complete. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness to give 19.35g of a yellow-brown oil, 90% purity, 100% yield, ms (esi): [ M + H ]]+250, directly put into the next step without purification.
Example 2:
methyl 3-aminocrotonate (10g, 86.96mmol) was dissolved in dry toluene (100mL), triethylamine (18.16mL, 130.29mmol) and phenyl chloroformate (16.32g, 104.23mmol) were added at room temperature, the suspension was raised to 70 deg.C and the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and after 6h the conversion of the starting material was complete. The reaction mixture was filtered through celite and the filtrate evaporated to dryness to give a yellow-brown oil 18.88g, purity89%, yield 92.40%, ms (esi): [ M + H ]]+＝236。
Example 3:
ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry toluene (100mL), anhydrous potassium carbonate (16.05g, 116.14mmol), 4A molecular sieve (325 mesh, 10g) and ethyl chloroformate (10.08g, 92.91mmol) were added at room temperature, the suspension was raised to 75 deg.C, the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and the conversion of the starting material was complete after 4.5 h. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness to give 15.60g of a yellow-brown oil, 95% purity, 100% yield, ms (esi): [ M + H ]]+＝202。
Example 4:
ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry toluene (100mL), N' -carbonyldiimidazole (15.07g, 92.91mmol) was added at room temperature, the mixture was warmed to 85 ℃ and stirred rapidly, LC-MS monitored the progress of the reaction, and after 3h the conversion of the starting material was complete. Cooling to room temperature, adding 0.1mol/L hydrochloric acid into the reaction mixture, stirring, separating liquid, washing an organic phase with water, and evaporating to dryness to obtain 15.56g of yellow-brown oily matter with the purity of 92% and the yield of 90%, and MS (ESI): [ M + H ]]+＝224。
Example 5:
dissolving the compound 3-1 (crude product, 19.3g, 77.43mmol) in anhydrous DMF (100mL), adding R-alpha- (Boc-amino) phenethylamine (25.33g, 85.17mmol) and anhydrous potassium carbonate (16.05g, 116.14mmol), stirring at room temperature for reaction, monitoring the reaction progress by LC-MS, completely converting the raw material after 3h, and directly heating the product without separation for the second-stage reaction.
And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate compound 4-1 into the compound 5 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give an off-white powder (17.6 g), purity of LC-MS (LC-MS) 99.78%, yield 58.07% (based on Compound 2-1), MS (ESI): [ M + H ]]+＝346。1HNMR:δ1.25-1.30(9H，s)，2.18(3H，s)，4.02-4.15(1H，d)，4.25-4.33(1H，d)，5.69-5.72(1H，m)，5.86(1H，s)，7.10-7.45(5H，m)，7.56-7.57(1H，d)。
Example 6:
compound 5(5g, 14.48mmol) was dissolved in anhydrous DMF (50 mL); anhydrous sodium carbonate (5.22g, 49.22mmol) and 4A molecular sieve (5g) were added, 2-fluoro-6-trifluoromethylbromobenzyl (5.58g, 21.71mmol) was added, the reaction was stirred at 80 ℃ and the progress of the reaction was monitored by LC-MS, and after 15h the starting material was completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.3g of a yellow oil, 98.13% purity by LC-MS, 96.7% yield, MS (esi): [ M + H ]]+＝522。1HNMR:δ1.23-1.28(9H，s)，2.46(3H，s)，4.10-4.13(1H，d)，4.39-4.44(1H，d)，4.56(2H，s),5.67-5.71(1H，m)，5.75(1H,s),7.25-7.48(8H，m)，7.58-7.59(1H，d)。
Example 7:
compound 5(5g, 14.48mmol) was dissolved in anhydrous DMF (50 mL); anhydrous sodium carbonate (5.22g, 49.22mmol), 4A molecular sieve (5g) were added, 2-fluoro-6-trifluoromethylbromobenzyl (5.58g, 21.71mmol) was added, the reaction was stirred at 50 ℃ and the progress of the reaction was monitored by LC-MS, and after 48h the starting material was essentially converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 5.6g of a yellow oil, 95.23% purity by LC-MS, 74.2% yield.
Example 8:
compound 5(5g, 14.48mmol) was dissolved in anhydrous DMF (50 mL); triethylamine (4.97g, 49.22mmol) and 4A molecular sieve (5g) were added, 2-fluoro-6-trifluoromethylbromobenzyl (5.58g, 21.71mmol) was added, the reaction was stirred at 80 ℃ and the progress of the reaction was monitored by LC-MS, and the starting material was substantially converted after 40 h. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 5.8g of a yellow oil, purity by LC-MS 93.16%, yield 76.9%.
Example 9:
compound 6(9g, 17.26mmol) was dissolved in dichloromethane (90mL) and the solution was stirred. P-toluenesulfonic acid (0.3g, 1.73mmol) was added and the temperature was reduced to 0 ℃. N-bromosuccinimide (3.07g, 17.26mmol) was added and the reaction was stirred at 0-5 ℃. TLC and LC-MS are used for monitoring the reaction progress,the conversion of the starting material was complete after 1 h. A saturated sodium bicarbonate solution (90mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 9.3g of a pale yellow foamy solid, purity of LC-MS 97.04%, yield 89.75%, MS (esi): [ M + H ]]+＝600。1HNMR:δ1.26-1.30(9H，s)，2.52(3H，s)，4.11-4.15(1H，d)，4.43-4.47(1H，d)，4.59(2H，s),5.65-5.74(1H，m),7.18-7.51(8H，m)，7.57-7.62(1H，d)。
Example 10:
compound 6(5g, 9.59mmol) was dissolved in ethyl acetate (90mL) and the solution was stirred. P-methanesulfonic acid (0.3g, 1.73mmol) was added and the temperature was reduced to 0 ℃. N-bromosuccinimide (1.71g, 9.59mmol) was added and the reaction was stirred at 0-5 ℃. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. A saturated sodium bicarbonate solution (90mL) was added thereto, and the mixture was stirred for 10min and then separated. Washing the organic phase with water, drying with anhydrous sodium sulfate, evaporating to dryness to obtain light yellow foamy solid 9.1g, LC-MS purity 95.88%, yield 87.84%
Example 11:
compound 6(5g, 9.59mmol) was dissolved in dichloromethane (50mL) and the solution was stirred. Methanesulfonic acid (92mg, 0.96mmol) was added and the temperature was reduced to 0 ℃. N-chlorosuccinimide (1.28g, 17.26mmol) was added, and the reaction was stirred gradually up to room temperature. TLC and LC-MS monitor the reaction progress, and after 3h the conversion of the raw material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow foamy solid (4.65 g), LC-MS purity 96.33%, yield 87.24%, MS (esi): [ M + H ]]+＝556。1HNMR:δ1.23-1.29(9H，s)，2.50(3H，s)，4.12-4.17(1H，d)，4.40-4.48(1H，d)，4.61(2H，s),5.60-5.71(1H，m),7.20-7.49(8H，m)，7.56-7.61(1H，d)。
Example 12:
compound 6(5g, 9.59mmol) was dissolved in dichloromethane (50mL) and the solution was stirred. P-toluenesulfonic acid (0.17g, 0.96mmol) was added and the temperature was reduced to 0 ℃. N-iodosuccinimide (2.16g, 9.59mmol) was added and the reaction was stirred at 0-5 ℃. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase is washed with water, dried by anhydrous sodium sulfate and evaporated to dryness to obtain 5.63g of a light yellow foamy solid, the purity of LC-MS is 96.87%, the yield is 90.7%, and MS (ESI): [ M + H ]]+＝648。1HNMR:δ1.25-1.33(9H，s)，2.57(3H，s)，4.14-4.19(1H，d)，4.42-4.50(1H，d)，4.62(2H，s),5.63-5.72H，m),7.22-7.56(8H，m)，7.59-7.68(1H，d)。
Claims (12)
1. Compound 5 of the formula
2. Compound 6 of the formula
3. The preparation method of the compound 5 is that a compound 3 with the following formula is condensed with R-alpha- (Boc-amino) phenethylamine to obtain an intermediate compound 4, and then cyclization is carried out to obtain the compound:
said R1Substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl selected from C1-C12;
x is selected from R2O、R3O and imidazolyl, R2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, R3Is selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl.
4. A process for the preparation of compound 5 according to claim 3, characterized in that: r1Alkyl selected from C1-C6; x is selected from R2O、R3O and imidazolyl, R2Is aryl, R3Selected from C1-C6 alkyl groups.
5. A process for the preparation of compound 5 according to claim 3, characterized in that: compound 4 is obtained from the condensation reaction, and then compound 5 is obtained from the cyclization reaction, and compound 5 is obtained by directly heating and carrying out the cyclization reaction by a one-pot method without separating product 4.
6. A process for the preparation of compound 5 according to claim 3, characterized in that: the compound 3 is obtained by condensation reaction of crotonate 2 and a condensing agent:
R1substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl selected from C1-C12;
x is selected from R2O、R3O and imidazolyl, R2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, R3Is selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl.
7. A process for the preparation of compound 5 according to claim 6, wherein: said R1Alkyl selected from C1-C6; x is selected from R2O、R3O and imidazolyl, R2Is aryl, R3Selected from C1-C6 alkyl groups.
8. A process for the preparation of compound 5 according to claim 6, wherein: the condensation reaction to prepare compound 3 employs a condensing agent comprising: chloro (bromo) formate
Dialkyl carbonate
N, N' carbonyldiimidazole, R2Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, R3Is selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl.
9. A process for the preparation of compound 5 according to claim 6, wherein: when water is generated in the condensation reaction process for preparing the compound 3, a drying agent is required to be added.
10. The compound 6 is prepared by condensing the compound 5 and 2-fluoro-6-trifluoromethyl benzyl bromide under the action of alkali:
11. a process for the preparation of compound 6 according to claim 10, characterized in that: and drying agent is added in the condensation reaction.
12. The preparation method of the compound 1(or7, 8) is that the compound 6 in claim 2 is halogenated by N-halogenated succinimide under the catalysis of a catalyst to obtain:
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826119A (en) * | 2003-07-07 | 2006-08-30 | 纽罗克里生物科学有限公司 | Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| WO2016169908A1 (en) * | 2015-04-21 | 2016-10-27 | Glaxosmithkline Intellectual Property Development Limited | Uracil derivatives for the treatment of malaria |
| WO2019115019A1 (en) * | 2017-12-11 | 2019-06-20 | Synthon B.V. | Process for preparing elagolix |
-
2019
- 2019-07-31 CN CN201910698843.6A patent/CN112300081A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826119A (en) * | 2003-07-07 | 2006-08-30 | 纽罗克里生物科学有限公司 | Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| WO2016169908A1 (en) * | 2015-04-21 | 2016-10-27 | Glaxosmithkline Intellectual Property Development Limited | Uracil derivatives for the treatment of malaria |
| WO2019115019A1 (en) * | 2017-12-11 | 2019-06-20 | Synthon B.V. | Process for preparing elagolix |
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