CN113135934A - Intermediate compound for preparing Ruugeli, preparation method of intermediate compound and preparation method of Ruugeli - Google Patents
Intermediate compound for preparing Ruugeli, preparation method of intermediate compound and preparation method of Ruugeli Download PDFInfo
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Abstract
The invention relates to the technical field of drug synthesis, in particular to an intermediate compound for preparing Ruugeli, a preparation method thereof and a preparation method of Ruugeli. The intermediate compound for preparing Ruogeli is any one of the compounds shown in the following structural formula:
and
wherein R is a leaving group. The embodiment of the invention provides a novel intermediate for preparing Ruugeli and a novel method for synthesizing Ruugeli, which can improve the yield and reduce the impurity content.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to an intermediate compound for preparing Ruugeli, a preparation method thereof and a preparation method of Ruugeli.
Background
Rilogelix (Relugolix) is a non-peptide gonadotropin releasing hormone (GnRH) antagonist that blocks the effects of GnRH by potent and selective antagonism of GnRH receptors in the anterior pituitary of humans. The application of Ruogeli can inhibit secretion of pituitary gland neutral gland stimulating hormone (luteinizing hormone LH and follicle stimulating hormone FSH), thereby inhibiting secretion of sex hormone such as E2 (estradiol) and progestogen in ovary, and can be used for treating prostate cancer and hysteromyoma related symptoms. In the prior art, the process of synthesizing the Ruugeli has various problems, such as complex operation, more impurities, low yield and the like.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide an intermediate compound for preparing Ruugeli, a preparation method thereof and a preparation method of Ruugeli. The embodiment of the invention provides a novel intermediate for preparing Ruugeli and a novel method for synthesizing Ruugeli, which can improve the yield and reduce the impurity content.
The invention is realized by the following steps:
in a first aspect, the present invention provides an intermediate compound for preparing Ruugeli, which is any one of the compounds represented by the following structural formula:
In a second aspect, the present invention provides a method for preparing an intermediate compound for preparing relugori according to the previous embodiment, comprising: carrying out a series of chemical reactions on compound raw materials to synthesize the intermediate compound, wherein the compound raw materials are as follows:
in an alternative embodiment, the method comprises the following steps: the intermediate compound is synthesized with reference to any one of the following synthetic routes:
and
in an alternative embodiment, the operation of step 1 comprises: mixing the compound raw material with a catalyst, acid and reducing gas to react;
preferably, the mass of the catalyst is 0.5 to 1% of the mass of the compound raw material, the mass of the acid is 10 to 50% of the mass of the compound raw material, and the molar amount of the reducing gas is larger than the molar amount of the compound raw material;
preferably, the catalyst is selected from any one of palladium carbon, iron powder and zinc powder; the acid is selected from any one of hydrochloric acid, acetic acid, formic acid and carbonic acid; the reducing gas is hydrogen;
preferably, the operation of step 1 comprises: mixing palladium carbon, a solvent and the compound raw material, uniformly stirring with acid, sealing, vacuumizing, replacing hydrogen, maintaining 1-20 atmospheric pressures, reacting at 10-30 ℃, and monitoring the reaction by adopting LC-MS in the reaction process until the reaction is finished;
preferably, the operation of step 1 comprises: after the reaction, post-treating the reaction system;
preferably, the post-processing comprises: mixing a reaction system with a nitrile solvent and an alkaline substance to ensure that the pH of the reaction system is 7-8, then heating and refluxing, filtering to remove solid impurities, and then cooling, filtering and drying;
preferably, the nitrile solvent is acetonitrile, and the basic substance includes any one of an amine substance, a hydroxide, and a carbonate.
In an alternative embodiment, the operation of step 2 comprises: mixing N, N' -carbonyl diimidazole, a basic substance, methoxylamine hydrochloride and a compound shown in a formula (1) for reaction;
preferably, the operation of step 2 comprises: stirring and clarifying the N, N' -carbonyldiimidazole, the solvent and the alkaline substance at the temperature of 10-20 ℃, then stirring and clarifying the mixture with the methoxyamine hydrochloride, mixing the mixture with the compound shown in the formula (1), heating and refluxing, and monitoring the reaction by adopting TLC in the refluxing process until the reaction is finished;
preferably, the compound of formula (1), the N, N "-carbonyldiimidazole and the methoxyamine hydrochloride: the molar ratio of the alkaline substances is as follows: 1:1-3:1-3: 2-8.
In an alternative embodiment, the operation of step 3 comprises: mixing a compound shown in a formula (2) and a raw material containing a leaving group for reaction;
preferably, the reaction conditions are: the reaction temperature is 0-10 ℃, and the molar ratio of the compound shown in the formula (2) to the raw material containing the leaving group is 1: 1-5.
In a third aspect, the present invention provides a method for preparing relogeli, comprising: the relugogie is formed by performing a synthesis reaction using the intermediate compound for the preparation of relugogie described in the previous embodiment.
In an alternative embodiment, the method comprises the following steps: the Ruugeli was synthesized with reference to the following synthetic pathway:
in an alternative embodiment, the method comprises the following steps: the operation of step 4 comprises: mixing dimethylamine and a compound shown in a formula (3) for reaction;
preferably, the operation of the step 4 comprises mixing the tetrahydrofuran solution of dimethylamine with a reaction system at 0-10 ℃ to react at 0-10 ℃, wherein the reaction system is a system after the reaction of the compound shown in the formula (2) to form the compound shown in the formula (3).
In an alternative embodiment, the method comprises the following steps: and the operation of the step 4 comprises post-treatment of the reaction solution after the reaction is finished.
The invention has the following beneficial effects: the embodiment of the invention provides a novel intermediate compound for preparing Ruugeli, Ruugeli can be efficiently prepared by using the intermediate compound, impurity content is reduced, and meanwhile, a novel method for synthesizing Ruugeli is provided.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a nuclear magnetic hydrogen spectrum of an intermediate compound provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of an intermediate compound provided in example 1 of the present invention;
FIG. 3 is a graph of the dot cake results during the preparation of intermediate compounds provided in example 2 of the present invention;
FIG. 4 is a liquid mass spectrum of an intermediate compound provided in example 2 of the present invention;
FIG. 5 is a nuclear magnetic hydrogen spectrum of an intermediate compound provided in example 2 of the present invention;
FIG. 6 is a nuclear magnetic carbon spectrum of an intermediate compound provided in example 2 of the present invention;
fig. 7 is a nuclear magnetic hydrogen spectrum of relugeli provided in example 3 of the present invention;
fig. 8 is a nuclear magnetic carbon spectrum of relugeli provided in example 3 of the present invention;
fig. 9 is a mass spectrum of relugeli provided in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides an intermediate compound for preparing Ruogeli, which is any one of compounds shown in the following structural formula:
The embodiment of the invention also provides a preparation method of the intermediate compound for preparing Ruugeli, which comprises the following steps of carrying out a series of chemical reactions on compound raw materials to synthesize the intermediate compound, wherein the compound raw materials are as follows:
the method specifically comprises the following steps:
the intermediate compound is synthesized with reference to any one of the following synthetic routes:
and
it should be noted that the above synthetic routes are only examples of the present invention, and it is also within the scope of the present invention if any compound represented by formula (1) to formula (3) can be obtained from the compound raw material by other synthetic methods.
Specifically, the specific operations of step 1 in the synthesis path include: the compound raw material is mixed with a catalyst, an acid and a reducing gas to react. The catalyst catalyzes a compound raw material to carry out hydrogenation reaction with reducing gas, and then a compound shown in a formula (1) is formed. The solubility of the compound raw material is poor, and the addition of acid can promote the solubility of the compound raw material, so that the reaction is accelerated.
Wherein the mass of the catalyst is 0.5 to 1% of the mass of the compound raw material, and is, for example, any value between 0.5% and 1%, such as 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1%; the mass of the acid is 10 to 50% of the mass of the compound raw material, and is, for example, any value between 10 to 50%, such as 10%, 15%, 20%, 30%, 37%, 40%, 45%, and 50%; the molar amount of the reducing gas is larger than the molar amount of the compound raw material; i.e. an excess of reducing gas. The use of the above range can facilitate the reaction and the formation of the compound represented by the formula (1).
Further, the catalyst is selected from any one of palladium carbon, iron powder and zinc powder; the acid is selected from any one of hydrochloric acid, acetic acid, formic acid and carbonic acid; the reducing gas is hydrogen. The catalyst, acid and reducing gas are only examples of the embodiment of the present invention, and other catalysts, acids and reducing gases capable of forming the compound represented by formula (1) from the compound raw material are also within the scope of the embodiment of the present invention.
Specifically, the operation of step 1 in the synthesis path includes: mixing palladium carbon, a solvent and the compound raw material, uniformly stirring with acid, sealing and vacuumizing, then replacing hydrogen, maintaining 1-20 atmospheric pressures, reacting at 10-30 ℃, monitoring the reaction by adopting LC-MS in the reaction process until the reaction is finished, and carrying out post-treatment after the reaction is finished.
The post-processing operations include: mixing the reaction system with a nitrile solvent and a basic substance so that the pH of the reaction system is 7-8, for example, any value between 7 and 8 such as 7, 7.2, 7.5, 7.7 and 8; then heating and refluxing, filtering to remove solid impurities, and then cooling, filtering and drying; the compound shown in the formula (1) formed in the step 1 has poor solubility in a reaction system, and then a product and a catalyst and the like in the final reaction system are difficult to separate, so that in the embodiment of the invention, an alkaline substance is added into the reaction system, the pH of the reaction system is adjusted, a mixed system added with a nitrile solvent is heated, and then the product, namely the compound shown in the formula (1), is dissolved, and palladium carbon and other impurities are insoluble, and then the mixture is filtered to remove the impurities. And cooling to separate out a product, and filtering and drying to obtain the compound shown in the formula (1).
Wherein, the nitrile solvent is acetonitrile, and the alkaline substance comprises any one of amine substance, hydroxide and carbonate. The selection of the solvent and the basic substance is merely an example, and other nitrile solvents and basic substances which can be post-treated are also within the scope of the embodiments of the present invention.
The operation of step 2 in the synthesis path includes: mixing N, N' -carbonyl diimidazole, a basic substance, methoxylamine hydrochloride and a compound shown in a formula (1) for reaction. Specifically, the N, N' -carbonyldiimidazole, the solvent and the alkaline substance are stirred and clarified at 10-20 ℃, for example, at any value between 10-20 ℃ such as 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃ and 20 ℃; and then stirring the mixture and the methoxyamine hydrochloride for clarification, mixing the mixture with the compound shown in the formula (1), heating and refluxing the mixture, and monitoring the reaction by adopting TLC in the refluxing process until the reaction is finished.
Wherein the compound represented by the formula (1), the N, N' -carbonyldiimidazole and the methoxyamine hydrochloride: the molar ratio of the alkaline substances is as follows: 1:1-3:1-3: 2-8, for example: 1:1:1:2, 1:1.5:2:8, 1:3:1.5:5, 1:3: 8. 1:1: 8, 1: 2: 2.5:6 and 1:2.5:3:4, etc. 1:1-3: any number between 2 and 8. The basic substance may be an amine substance (e.g., ammonia, triethylamine, methylamine, etc.), a carbonate (e.g., potassium carbonate, sodium carbonate, etc.), a bicarbonate (e.g., potassium bicarbonate, sodium bicarbonate, etc.), a hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.). The above synthesis steps and conditions are adopted to facilitate the reaction of the compound represented by the formula (1) and then facilitate the formation of the compound represented by the formula (2).
The operation of step 3 in the synthesis path includes: mixing the compound shown in the formula (2) and a raw material containing a leaving group (for example, when the leaving group is chlorine, the raw material containing the leaving group is N-chlorosuccinimide) for reaction; wherein the reaction conditions are as follows: the reaction temperature is 0-10 deg.C, such as 0 deg.C, 1 deg.C, 2 deg.C, 3 deg.C, 4 deg.C, 5 deg.C, 6 deg.C, 7 deg.C, 8 deg.C, 9 deg.C and 10 deg.C, and any value or range value between 0-10 deg.C. The molar ratio of the compound represented by formula (2) to the leaving group-containing starting material is 1:1 to 5, and is any value or range of values between 1:1 and 5, such as 1:1, 1:2, 1:2.5, 1:3, 1:4, 1:4.5, and 1: 5. The above conditions are employed to facilitate the formation of the compound of formula (3).
The embodiment of the invention also provides a preparation method of Ruugeli, which is synthesized by referring to the following synthetic route:
the operations of step 1, step 2 and step 3 in this synthesis route are the same as those of step 1, step 2 and step 3 described above. And the operation of step 4 includes: mixing dimethylamine and a compound shown in a formula (3) for reaction; specifically, the reaction is carried out at 0 to 10 ℃ by mixing a tetrahydrofuran solution of dimethylamine with a reaction system after the reaction of the compound represented by the formula (2) to form the compound represented by the formula (3), that is, after the step 3, and reacting at 0 to 10 ℃. And reacting the tetrahydrofuran solution of dimethylamine with the reaction system, and then carrying out post-treatment on the reaction solution to obtain the Ruogeli.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The invention provides an intermediate compound for preparing Ruogeli, which has a structural formula as follows:
This example provides a process for the preparation of the intermediate compound comprising:
synthesis was performed with reference to the following synthesis route:
adding 7.2g Pd/C into a three-neck flask, mixing in 100ml purified water, adding 3000ml methanol and S23-LX 3-6120 g, stirring, suspending the solid in a solvent, adding 22g concentrated hydrochloric acid, stirring uniformly, sealing, vacuumizing, performing hydrogen replacement for 2 times, keeping the hydrogen pressure at 4 atm, and reacting at 25 ℃.
Reaction monitoring: LC-MS monitors until the reaction is complete.
And (3) post-treatment: adding 500ml of purified water into a reaction system, stirring for 10 minutes, adding 3500ml of acetonitrile, adjusting pH to 8 by using 150ml of triethylamine, heating until the mixture is completely dissolved by refluxing, filtering by using kieselguhr, concentrating the filtrate until solid is separated out, stopping concentration, cooling to 15 ℃, stirring to separate out the solid, filtering the solid, drying in a vacuum drying oven (vacuum degree of-0.01 Mpa) at 50 ℃ to constant weight to obtain light yellow solid, namely S23-LX3-7, 98.2g, and obtaining the yield: 86.67 percent.
The compound was characterized, and the results are shown in fig. 1 and fig. 2, and the detection data are as follows:1H-NMR (DMSO,400MHz):2.373(s, 3H); 4.102(s, 3H); 5.149-5.190(m, 1H); 5.363(m, 1H); 5.363-5.442(s, 2H); 6.649-6.671(d, 2H); 7.090-7.153(m, 4H); 7.412-7.493(d, 2H); 7.743-7.766(d,1H), as can be seen from FIGS. 1 and 2, S23-LX3-7 was successfully prepared by this method, and its structure was correct.
Example 2
The invention provides an intermediate compound for preparing Ruogeli, which has a structural formula as follows:
This example provides a process for the preparation of the intermediate compound comprising:
synthesis was performed with reference to the following synthesis route:
feeding and reacting: into a three-necked flask, 5.14g of CDI5, 160ml of acetonitrile and 8.0g of TEA were added, and the mixture was dissolved and clarified at 10 to 20 ℃ with stirring, 2.8g of methoxylamine hydrochloride was added, and S23-LX-7 (8.0 g) obtained in example 1 was added, and the mixture was stirred and clarified to react at 80 ℃ for 3.5 hours while warming.
Reaction monitoring: TLC monitoring (developing agent: ethyl acetate: n-hexane: 1, color development: UV 254nm), cooling in water bath after reaction. See fig. 3.
And (3) post-treatment: and (2) at the temperature of 18 ℃, adding the reaction system into 480ml of purified water, stirring to separate out a solid, sticking the solid to the wall, pouring out the liquid, adding 200ml of water into the solid with the wall, stirring for 1 hour, filtering to obtain the solid, leaching 50ml of purified water of the solid once to obtain a light yellow solid, namely S23-LX3-8, 9g and obtaining the yield of 98.36%.
The compound was characterized, and the results are shown in fig. 4-6, with the following assay data:1H-NMR (DMSO,400MHz):2.410(s, 3H); 3.648(s, 3H); 4.097(s, 3H); 5.201-5.373(br, 2H); 7.119-7.160(m, 2H); 7.349-7.370(d, 2H); 7.451-7.474(d, 2H); 7.722-7.766(m, 3H); 9.093(s, 1H); 9.623(s,1H), M +1: 581; as can be seen from FIGS. 4-6, S23-LX3-8 was successfully prepared by this method, and its structure was correct.
Example 3
This example provides an intermediate compound for the preparation of rilogeli, having the following structural formula:
the embodiment provides a preparation method of Ruogeli, which comprises the following steps:
synthesis was performed with reference to the following synthesis route:
in the case of a liquid crystal display device, in particular,
10g of S23-LX3-8 prepared in example 2 and acetonitrile are added into a three-neck flask, stirred and cooled to 4 ℃, and 3.44g of NCS is added at one time under the protection of nitrogen and protected from light. The temperature was controlled at 4 ℃ and the mixture was stirred for 3 hours.
Reaction monitoring: TLC monitoring (developing agent: ethyl acetate: n-hexane: 2:1, color development: UV 254nm, 1 reaction solution, 2, cross-over, 3 starting materials), reaction was complete.
The reaction solution was poured into 28g of dimethylamine tetrahydrofuran solution (2M) with stirring at a temperature of 4 ℃ and then stirred for 2 hours.
And (3) post-treatment: controlling the temperature to be 25 ℃, concentrating under reduced pressure, and performing 100-200-mesh silica gel column chromatography on the obtained product, wherein the eluent is methanol: dichloromethane ═ 2:1 (volume ratio) to give a white to off-white product, about 7.3 g. The yield thereof was found to be 68%.
The characterization results of this compound are shown in fig. 7-9, and the characterization data are as follows:1H-NMR (CDCl3,400MHz) 2.123(s, 6H); 3.519(m, 1H); 3.775(m, 4H); 4.175(s, 3H); 5.266-5.353(br, 2H); 6.877-6.938(m, 2H); 7.124-7.146(d, 1H); 7.269-7.286(m, 1H); 7.302-7.340(m, 2H); 7.403-7.470(m, 1H); 7.534-7.554(d, 2H); 7.847(s, 1H); 7.951(s,1H), M +1: 624; as can be seen from fig. 7-9, in this example, relugeli was successfully prepared.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An intermediate compound for preparing Ruogeli, which is any one of the compounds represented by the following structural formula:
2. An intermediate compound for the preparation of relogelide according to claim 1, wherein R is selected from any one of halogen, OTs, OMs, and OTf;
preferably, the halogen is selected from any one of chlorine, bromine and iodine.
3. The process for the preparation of an intermediate compound for the preparation of relogelide according to claim 1, comprising: carrying out a series of chemical reactions on compound raw materials to synthesize the intermediate compound, wherein the compound raw materials are as follows:
4. the method of claim 3, comprising: the intermediate compound is synthesized with reference to any one of the following synthetic routes:
and
5. the method according to claim 4, wherein the operation of step 1 comprises: mixing the compound raw material with a catalyst, acid and reducing gas to react;
preferably, the mass of the catalyst is 0.5 to 1% of the mass of the compound raw material, the mass of the acid is 10 to 50% of the mass of the compound raw material, and the molar amount of the reducing gas is larger than the molar amount of the compound raw material;
preferably, the catalyst is selected from any one of palladium carbon, iron powder and zinc powder; the acid is selected from any one of hydrochloric acid, acetic acid, formic acid and carbonic acid; the reducing gas is hydrogen;
preferably, the operation of step 1 comprises: mixing palladium carbon, a solvent and the compound raw material, uniformly stirring with acid, sealing, vacuumizing, replacing hydrogen, maintaining 1-20 atmospheric pressures, reacting at 10-30 ℃, and monitoring the reaction by adopting LC-MS in the reaction process until the reaction is finished;
preferably, the operation of step 1 comprises: after the reaction, post-treating the reaction system;
preferably, the post-processing comprises: mixing a reaction system with a nitrile solvent and an alkaline substance to ensure that the pH of the reaction system is 7-8, then heating and refluxing, filtering to remove solid impurities, and then cooling, filtering and drying;
preferably, the nitrile solvent is acetonitrile, and the basic substance includes any one of an amine substance, a hydroxide, and a carbonate.
6. The method according to claim 4, wherein the operation of step 2 comprises: mixing N, N' -carbonyldiimidazole, a basic substance, methoxylamine hydrochloride and a compound shown in a formula (1) for reaction;
preferably, the operation of step 2 comprises: stirring the N, N' -carbonyldiimidazole, the solvent and the alkaline substance at the temperature of 10-20 ℃ for clarification, then stirring the mixture with the methoxyamine hydrochloride for clarification, mixing the mixture with the compound shown in the formula (1), heating and refluxing, and monitoring the reaction by adopting TLC in the refluxing process until the reaction is finished;
preferably, the compound represented by formula (1), the N, N' -carbonyldiimidazole and the methoxyamine hydrochloride: the molar ratio of the alkaline substances is as follows: 1:1-3:1-3: 2-8.
7. The method according to claim 4, wherein the operation of step 3 comprises: mixing a compound shown in a formula (2) and a raw material containing a leaving group for reaction;
preferably, the reaction conditions are: the reaction temperature is 0-10 ℃, and the molar ratio of the compound shown in the formula (2) to the raw material containing the leaving group is 1: 1-5.
8. A preparation method of Ruogeli is characterized by comprising the following steps: performing a synthetic reaction using the intermediate compound for the preparation of relugelide of claim 1 to form the relugelide.
9. The method of claim 8, comprising: the Ruugeli was synthesized with reference to the following synthetic pathway:
10. the method of claim 9, comprising: the operation of step 4 comprises: mixing dimethylamine and a compound shown in a formula (3) for reaction;
preferably, the operation of the step 4 comprises mixing the tetrahydrofuran solution of dimethylamine with a reaction system at 0-10 ℃ to react at 0-10 ℃, wherein the reaction system is a system after the reaction of the compound shown in the formula (2) to form the compound shown in the formula (3).
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| CN114409642A (en) * | 2021-12-27 | 2022-04-29 | 南京方生和医药科技有限公司 | Method for preparing Ruogeli intermediate impurity |
| CN114478503A (en) * | 2021-12-27 | 2022-05-13 | 南京方生和医药科技有限公司 | Ruogeli impurity and preparation method thereof |
| CN114805326A (en) * | 2022-06-06 | 2022-07-29 | 南京方生和医药科技有限公司 | Preparation process of Ruogeli impurity |
| WO2024126674A1 (en) | 2022-12-15 | 2024-06-20 | Medichem, S.A. | Process for the preparation of relugolix |
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