CN109810065B - Synthesis method of oxaagolide - Google Patents
Synthesis method of oxaagolide Download PDFInfo
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- CN109810065B CN109810065B CN201910121555.4A CN201910121555A CN109810065B CN 109810065 B CN109810065 B CN 109810065B CN 201910121555 A CN201910121555 A CN 201910121555A CN 109810065 B CN109810065 B CN 109810065B
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Abstract
The invention discloses a synthesis method of oxaagolide, which comprises the following steps: (1) (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-Carrying out N-alkylation on 3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenethyl) tert-butyl carbamate and ethyl 4-bromobutyrate shown in a formula IV to obtain an intermediate shown in a formula VI;
(2) removing N-BOC and O-Et from the intermediate shown in the formula VI to obtain Elagolix shown in the formula (I);
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medical intermediates, and particularly relates to a synthesis method of oxaagolide.
Background
Under normal conditions, the endometrium covers the uterine cavity surface, and if certain factors cause the endometrium to grow on other parts of the body, the endometriosis can be formed. This ectopic intima is histologically surrounded by not only the intimal glands, but also the intimal interstitium; functionally, the estrogen level varies significantly, i.e., with the menstrual cycle, but is only partially affected by progestogen, producing a small "menses" which causes a variety of clinical manifestations.
In patients with pregnancy, the ectopic intima may have decidua-like changes. This ectopic intima grows in other tissues or organs, but is distinguished from the invasion of malignant tumors. The peak of the disease is 30-40 years old. The actual incidence of endometriosis is far greater than that seen clinically. For example, when the abdominal cavity examination is performed during other gynecological diseases and the excised adnexa specimen is carefully examined pathologically, about 20-25% of patients can be found to have ectopic endometrium.
The oral GnRH antagonist, known by the english name Elagolix, is approved by the U.S. food and drug administration for the treatment of pain due to endometriosis. The structure of Elagolix is shown in formula I:
according to the description of us patent WO2009062087, Elagolix can be synthesized by the following route:
however, this synthetic route is not only low in yield, but also the second reaction step thereof is liable to cause a side reaction of N-polyalkylation, thereby introducing impurities which are difficult to remove, resulting in insufficient purity of the objective product.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the existing synthesis method of the oxaagolide has low yield, introduces impurities and reduces the purity of a target product.
The invention solves the technical problems by adopting the following technical scheme:
a synthesis method of the loragolide comprises the following steps:
(1) n-alkylating (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamic acid tert-butyl ester shown in a formula II and 4-bromobutyric acid ethyl ester shown in a formula IV to obtain (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2 shown in a formula VI, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butanoic acid ethyl ester;
(2) removing N-BOC and O-Et from ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown as a formula VI to obtain Elagolix shown as a formula (I);
preferably, the synthesis method of the loragolide provided by the present invention comprises the following specific steps of (1): using tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown in a formula II as an organic solvent, adding ethyl 4-bromobutyrate shown in a formula IV, a base and a catalyst into the organic solvent, and then carrying out N-alkylation reaction; after the reaction is finished, concentrating the reaction mixture to be dry, washing, drying and purifying the concentrate to obtain the ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI.
Preferably, in the synthesis method of the loragolide, the step (2) is specifically performed as follows: dissolving ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI in a solvent, adding a base thereto, and then reacting; after the reaction is finished, washing, drying and purifying the mixture to obtain the Elagolix shown in the formula I.
Preferably, in the synthesis method of the loragolide, the organic solvent used in the step (1) is any one selected from DMF, DMAc, THF, methyl tert-butyl ether, ethylene glycol dimethyl ether and 1, 2-dichloroethane; and/or
The alkali in the step (1) is any one of DIPEA, triethylamine, pyridine, DBU, potassium carbonate and DMAP; and/or
The catalyst in the step (1) is TBAB, TBAOTf or TBAI.
Preferably, according to the synthesis method of the loragolide, the washing step of the concentrate in the step (1) is as follows: the concentrate was washed with a mixture of dichloromethane and ice-cold aqueous saline solution, and the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution and saturated brine in this order.
Preferably, in the synthesis method of the loragolide, the solvent in the step (2) is a mixture of an organic solvent and water.
Preferably, according to the synthesis method of the loragolide, the organic solvent is selected from THF, DMF, DMAc, 2-methyltetrahydrofuran, diethylene glycol dimethyl ether, methanol or ethanol; and/or
The alkali in the step (2) is any one selected from potassium carbonate, sodium carbonate, cesium carbonate, dipotassium hydrogen phosphate, potassium hydrogen carbonate, ammonia, potassium hydroxide and calcium hydroxide.
Preferably, the synthesis method of the diragolide, the washing method in the step (2) is as follows: the reaction mixture was washed with a mixture of ethyl acetate and aqueous brine, the organic phase was separated, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order.
Preferably, in the synthesis method of the loragolide, in the step (1), every 1.0g, 1.0equiv of the tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) - λ 2-carbamate shown in the formula II corresponds to 1.0-2.2equiv of ethyl 4-bromobutyrate shown in the formula IV, 1.0-4.0equiv of a base and 0.1-0.2equiv of a catalyst; and/or
The N-alkylation reaction in the step (1) is carried out by heating to 90 ℃ and reacting for 6-32 h; or heating to reflux for 18 h.
Preferably, the synthesis method of the oxagorside provided by the invention comprises the step of reacting ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown as a formula VI with 2.0-10.0equiv. of base per 1.0g and 1.0 equiv; and/or
The reaction process of the step (2) is to heat to 25-50 ℃ for 2-24h or heat to reflux for 6 h.
The invention has the technical beneficial effects that:
according to the method, the Elagolix is synthesized from commercial raw materials through two-step reaction, the synthetic route of the Elagolix is greatly simplified, when the target product is synthesized through the route, the yield of each step of reaction is high, unnecessary side reactions are effectively reduced, the product is easy to purify, and the purity of the target compound is improved.
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 route for synthesizing Elagolix in the examples of the present invention is as follows:
. The preparation process is illustrated in detail below by means of specific examples.
Example 1
(1) Preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butanoate, represented by formula VI, the synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. of tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate, shown in formula II, was dissolved in 10mL of 1, 2-dichloroethaneAdding 1.5equiv. ethyl 4-bromobutyrate shown in formula IV, 2.0equiv. pyridine and 0.1equiv. TBAI, heating the system to 90 ℃, and reacting for 18h under stirring; after the reaction is finished, concentrating the mixture to be dry; the concentrate is washed by using a mixture of dichloromethane and ice-cold 1N aqueous hydrochloric acid solution as a washing agent, the organic phase is separated, then the organic phase is washed by saturated aqueous sodium bicarbonate solution and saturated saline solution in turn, then the organic phase is dried by sodium sulfate and spin-dried, and finally the ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI is obtained by column chromatography with the yield of 74 percent. Detecting by using a high resolution mass spectrum (ESI +), wherein the detection value is 760.3022; m + H+Calculated high resolution mass spectrum of 760.3016; the structure of the product can be confirmed by comparison.
(2) The preparation of Elagolix shown in formula I has the following synthetic route:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in formula VI in a mixed solvent of 10mL of THF and 2mL of water in a reactor, adding 5equiv. potassium carbonate, heating the system to 50 ℃, and reacting for 6H under stirring; after the reaction is finished, a mixture of ethyl acetate and 1N saline water solution is used as a detergent to wash the reaction mixture, an organic phase is separated, then a saturated sodium bicarbonate water solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin drying, finally, column chromatography is carried out to obtain 0.82equiv. Elagolix shown in formula I, and the yield is 82%. Detecting with high resolution mass spectrometry (ESI-), with the measured value of 630.2041, M-H-Calculated high resolution mass spectrum of 630.2033; the structure of the product can be confirmed by comparison.
Example 2
(1) Preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate, shown in formula VI, by the following synthetic route:
the operation steps are as follows: dissolving 1.0g, 1.0equiv. (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamic acid tert-butyl ester shown in formula II in 15ml DMAc in a reactor, adding 1.0equiv 4-bromobutyric acid ethyl ester shown in formula IV, 2.0equiv DIPEA and 0.2equiv TBAI, heating the system to 90 ℃, and reacting for 6H under stirring; after the reaction is finished, concentrating the mixture to be dry; the concentrate is washed by using a mixture of dichloromethane and ice-cold 1N aqueous hydrochloric acid solution as a washing agent, the organic phase is separated, then the organic phase is washed by saturated aqueous sodium bicarbonate solution and saturated saline solution in turn, then the organic phase is dried by sodium sulfate and spin-dried, and finally the ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI is obtained by column chromatography with the yield of 59 percent. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 760.3021.
(2) The preparation of Elagolix shown in formula I has the following synthetic route:
the operation steps are as follows: dissolving 1.0g, 1.0equiv. (R) -4- ((tert-butoxycarbonyl) (ethyl 2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in formula VI in a mixed solvent consisting of 10mL of DMF and 5mL of water in a reactor, adding 2.0equiv cesium carbonate, heating the system to 50 ℃, and reacting for 6H under stirring; after the reaction is finished, a mixture of ethyl acetate and 1N saline water solution is used as a detergent to wash the reaction mixture, an organic phase is separated, then a saturated sodium bicarbonate water solution and a saturated saline solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin drying, finally, column chromatography is carried out to obtain 0.80equiv of Elagolix shown in formula I, and the yield is 80%. Detection was performed by high resolution mass spectrometry (ESI-) with an observed value of 630.2039.
Example 3
(1) Preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate, shown in formula VI, by the following synthetic route:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown as formula II in 12ml DMF in a reactor, adding 2.2equiv. ethyl 4-bromobutyrate shown as formula IV, 2.0equiv. triethylamine and 0.1equiv. TBAB, heating the system to 90 ℃, and reacting for 18H under stirring; after the reaction is finished, concentrating the mixture to be dry; the concentrate was washed with a mixture of dichloromethane and ice-cold aqueous 1N hydrochloric acid as a detergent, the organic phase was separated, washed with saturated aqueous sodium bicarbonate and saturated brine in this order, dried over sodium sulfate and spin-dried, and finally subjected to column chromatography to give 0.76equinv, a preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate represented by formula VI, with a yield of 76%. Detection was performed by high resolution mass spectrometry (ESI +) and found 760.3023.
(2) The preparation of Elagolix shown in formula I has the following synthetic route:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in formula VI in a mixed solvent consisting of 15mL of DMF and 1mL of water in a reactor, adding 5.0equiv. of dipotassium hydrogen phosphate into the mixed solvent, heating the system to reflux, and reacting for 6 hours under stirring; after the reaction is finished, a mixture of ethyl acetate and 1N saline water solution is used as a detergent to wash the reaction mixture, an organic phase is separated, then a saturated sodium bicarbonate water solution and a saturated saline water solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin drying, finally, column chromatography is carried out to obtain 0.75equiv. Elagolix shown in formula I, and the yield is 75%. Detection was performed by high resolution mass spectrometry (ESI-) with an observed value of 630.2042.
Example 4
(1) Preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butanoate, represented by formula VI, the synthetic route is as follows:
the method comprises the following operation steps: in a reactor, 1.0g, 1.0equiv. tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown in formula II is dissolved in 12mL of methyl tert-butyl ether, 1.5equiv. ethyl 4-bromobutyrate shown in formula IV, 4.0equiv. potassium carbonate and 0.2equiv. TBAI are added thereto, the system is heated to 90 ℃ and reacted for 32H under stirring; after the reaction is finished, concentrating the mixture to be dry; the concentrate is washed by using a mixture of dichloromethane and ice-cold 1N aqueous hydrochloric acid solution as a washing agent, the organic phase is separated, then the organic phase is washed by saturated aqueous sodium bicarbonate solution and saturated saline solution in turn, then the organic phase is dried by sodium sulfate and spin-dried, and finally the ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI is prepared by column chromatography with the yield of 78%. Detection was performed by high resolution mass spectrometry (ESI +) and found 760.3022.
(2) The preparation of Elagolix shown in formula I has the following synthetic route:
the operation steps are as follows: dissolving 1.0g, 1.0equiv. of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in formula VI in a mixed solvent of 10mL of diethylene glycol dimethyl ether and 2mL of water in a reactor, adding 5.0equiv. of potassium hydroxide, heating the system to 50 ℃, and reacting for 24 hours under stirring; after the reaction is finished, a mixture of ethyl acetate and 1N saline water solution is used as a detergent to wash the reaction mixture, an organic phase is separated, then a saturated sodium bicarbonate water solution and a saturated saline water solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin drying, finally, column chromatography is carried out to obtain 0.71equiv. Elagolix shown in formula I, and the yield is 71%. Detection was performed by high resolution mass spectrometry (ESI-) with an observed value of 630.2037.
Example 5
(1) Preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butanoate, represented by formula VI, the synthetic route is as follows:
the operation steps are as follows: dissolving 1.0g, 1.0equiv tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown in formula II in 10mL ethylene glycol dimethyl ether in a reactor, adding 2.0equiv ethyl 4-bromobutyrate shown in formula IV, 1.0equiv DIPEA and 0.1equiv TBAI, heating the system to reflux, and reacting for 18H under stirring; after the reaction is finished, concentrating the mixture to be dry; the concentrate was washed with a mixture of dichloromethane and ice-cold aqueous 1N hydrochloric acid as a detergent, the organic phase was separated, washed with saturated aqueous sodium bicarbonate and saturated brine in this order, dried over sodium sulfate and spin-dried, and finally subjected to column chromatography to give 0.61equiv. preparation of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate represented by formula VI in 61% yield. Detection was performed by high resolution mass spectrometry (ESI +) and found 760.3021.
(2) The preparation of Elagolix shown in formula I has the following synthetic route:
the method comprises the following operation steps: dissolving 1.0g, 1.0equiv. ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in formula VI in 15mL of methanol in a reactor, adding 10.0equiv. calcium hydroxide thereto, heating the system to 50 ℃, and reacting for 2H with stirring; after the reaction is finished, a mixture of ethyl acetate and 1N saline water solution is used as a detergent to wash the reaction mixture, an organic phase is separated, then a saturated sodium bicarbonate water solution and a saturated saline water solution are sequentially used to wash the organic phase, then sodium sulfate is used for drying and spin drying, finally, column chromatography is carried out to obtain 0.59equiv. Elagolix shown in formula I, and the yield is 59%. Detection was performed by high resolution mass spectrometry (ESI-) with an observed value of 630.2040.
The various reaction starting materials and reagents used in the above examples are commercially available products. Of course, in the course of the actual production, the relevant organic compounds can also be obtained by corresponding synthetic methods.
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 (1)
1. A synthesis method of loragolide is characterized by comprising the following steps:
(1) n-alkylating (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamic acid tert-butyl ester shown in a formula II and 4-bromobutyric acid ethyl ester shown in a formula IV to obtain (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2 shown in a formula VI, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) -amino) butanoic acid ethyl ester;
(2) removing N-BOC and O-Et from ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown as a formula VI to obtain Elagolix shown as a formula I;
the specific operation of the step (1) is as follows: dissolving tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown in a formula II in an organic solvent, adding ethyl 4-bromobutyrate shown in a formula IV, a base and a catalyst into the organic solvent, and then carrying out N-alkylation reaction; after the reaction is finished, concentrating the reaction mixture to be dry, washing, drying and purifying the concentrate to obtain ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI;
the specific operation of the step (2) is as follows: dissolving ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI in a solvent, adding a base thereto, and then reacting; after the reaction is finished, washing, drying and purifying the mixture to obtain Elagolix shown in the formula I;
the organic solvent used in the step (1) is any one selected from DMF, DMAc, THF, methyl tert-butyl ether, ethylene glycol dimethyl ether and 1, 2-dichloroethane; and/or the base in the step (1) is any one of DIPEA, triethylamine, pyridine, DBU, potassium carbonate and DMAP; and/or the catalyst in step (1) is TBAB, TBAOTf or TBAI;
the washing step of the concentrate in the step (1) is as follows: the concentrate is firstly placed in a mixture of dichloromethane and ice-cold saline water solution for washing, and after an organic phase is separated, the organic phase is washed by saturated sodium bicarbonate water solution and saturated saline water in turn;
the solvent in the step (2) is THF, methanol or a mixture of an organic solvent and water;
the organic solvent is selected from THF, DMF, DMAc, 2-methyltetrahydrofuran, diethylene glycol dimethyl ether, methanol or ethanol; and/or the base in the step (2) is selected from any one of potassium carbonate, cesium carbonate, dipotassium hydrogen phosphate, potassium hydroxide and calcium hydroxide;
the washing method in the step (2) is as follows: firstly, placing a reaction mixture into a mixture of ethyl acetate and a saline water solution for washing, separating an organic phase, and then washing the organic phase by adopting saturated sodium bicarbonate and saturated saline water in sequence;
in the step (1), every 1.0equiv of tert-butyl (R) - (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -1-phenylethyl) carbamate shown as the formula II corresponds to 1.0-2.2equiv of ethyl 4-bromobutyrate shown as the formula IV, 1.0-4.0equiv of base and 0.1-0.2equiv of catalyst; and/or the N-alkylation reaction in the step (1) is carried out by heating to 90 ℃ for 6-32 h; or heating to reflux for 18 h;
in the step (2), every 1.0equiv. of ethyl (R) -4- ((tert-butoxycarbonyl) (2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1- (2H) -yl) -1-phenylethyl) amino) butyrate shown in the formula VI is reacted with 2.0-10.0equiv. of a base; and/or the reaction process of the step (2) is heating to 25-50 ℃ for reaction for 2-24h, or heating to reflux for reaction for 6 h.
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