CN114380810A - Rugosril intermediate impurity and preparation method thereof - Google Patents
Rugosril intermediate impurity and preparation method thereof Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention discloses a Rugoly intermediate impurity and a preparation method thereof, wherein the Rugoly intermediate impurity has a structure shown in a formula VI, and is prepared by taking a compound I as an initial material through hydrolysis, condensation, reduction, cyclization and ring-opening reaction. The impurities prepared by the method have stable purity and yield, and can be used for quality control of Ruugeli intermediate substances, so that the quality of Ruugeli raw material medicines is improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a Ruogeli intermediate impurity and a preparation method thereof.
Background
Ruuggolix (Relugolix) is a gonadotropin (GnRH) antagonist, and reduces the release of GnRH (luteinizing hormone and follicle stimulating hormone) by combining and blocking GnRH receptors (GnRHR) in the anterior lobe of the pituitary, thereby reducing the secretion of estrogen and progesterone in female ovary and finally achieving the effect of effectively reducing hysteromyoma. In addition to being used for treating uterine fibroids, clinical phase III tests for indications such as pain due to endometriosis and prostate cancer are being conducted in many countries.
The structural formula of Ruogeli is as follows:
at present, there is little report on the impurities of Ruugeli and its intermediates in the published literature, and further there is no disclosure of the chemical names or structural formulae or preparation methods of these impurities.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a Ruugeli intermediate impurity, and aims to provide a preparation method of the Ruugeli intermediate impurity.
The technical scheme is as follows: the Ruogeli intermediate impurity disclosed by the invention has the following structural formula:
during the process of preparation of rilogelide, the applicant found that the rilogelide intermediate contains a certain amount of the above unknown impurities, which are difficult to remove and can participate in the subsequent reaction, affecting the purity of the final rilogelide product. Therefore, the unknown impurity needs to be monitored and detected in the synthesis process of the Ruugeli intermediate, so as to control the quality of the bulk drug Ruugeli. However, the content of the impurities in the Ruugeli synthesis process is low, the impurities are difficult to separate, and no synthesis report of the impurity compound exists in the prior art, so that people are difficult to obtain a large amount of the impurities with high purity, and the impurities lack corresponding reference substances, thereby bringing great difficulty to qualitative and quantitative analysis of the impurities.
The preparation method of the Ruogeli intermediate impurity comprises the following steps:
the Ruugeli intermediate impurity with the structure shown in the formula VI is prepared by hydrolyzing, condensing, reducing, cyclizing and ring-opening reaction of the compound I.
Dissolving a compound I in a solvent, adding alkali, heating to a certain temperature, and reacting to obtain a compound II;
secondly, adding the compound II into a solvent, adding an acid binding agent in a nitrogen atmosphere, heating to a certain temperature, adding a condensing agent, and carrying out heat preservation reaction to obtain a compound III;
thirdly, adding the compound III into a solvent, adding a catalyst and alkali, and reducing under certain hydrogen pressure to obtain a compound IV;
fourthly, dissolving the compound IV in a solvent, and adding alkali and a catalyst to carry out ring closing to prepare a compound V;
and step five, dissolving the compound V in a solvent, adding alkali, and carrying out ring opening to prepare a compound VI.
Wherein, the solvent in the first step is one or more of acetonitrile, water, methanol, ethanol or tetrahydrofuran; the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; the reaction temperature is 30-70 ℃.
Further preferably, the first-step reaction solvent is methanol or ethanol; the alkali is sodium hydroxide; the reaction temperature is 45-55 ℃.
The solvent in the second step is acetonitrile, toluene, dichloromethane, chloroform or ethyl acetate; the acid-binding agent is triethylamine, pyridine or N, N-diisopropylethylamine; the condensing agent is DIC, DCC, HOBT, HBTU, TBTU or 1-propyl phosphoric anhydride; the reaction temperature is 20-50 ℃.
Further preferably, the solvent in the second step is ethyl acetate; the acid-binding agent is N, N-diisopropylethylamine; the condensing agent is 1-propyl phosphoric anhydride; the temperature is 35-45 ℃.
The solvent in the third step is acetonitrile, toluene, dichloromethane, chloroform or ethyl acetate; the catalyst is palladium carbon, platinum carbon or Raney Ni; the alkali is pyridine, triethylamine or N, N-diisopropylethylamine; the reaction pressure is 1.5-2.0 MPa.
Further preferably, the solvent in the third step is dichloromethane; the catalyst is palladium carbon; the alkali is triethylamine.
The solvent in the fourth step is tetrahydrofuran, acetonitrile or ethanol; the alkali is potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; the catalyst is quaternary ammonium salt; the reaction temperature is 55-65 ℃.
Further preferably, the solvent in the fourth step is tetrahydrofuran; the alkali is potassium carbonate; the catalyst is tetrabutylammonium bromide.
Fifthly, the solvent is methanol or ethanol; the alkali is sodium methoxide or sodium ethoxide; the reaction temperature is 55-70 ℃.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:
(1) the intermediate impurities generated in the Ruogeli preparation process are subjected to structure confirmation, the impurities with the purity (more than or equal to 98%) and the quantity (the batch yield of the impurities reaches gram level) meeting the detection requirements are prepared, the Ruogeli intermediate and the corresponding impurities in the bulk drugs can be accurately analyzed, and the product quality is favorably improved.
(2) The impurity preparation method provided by the invention is simple and convenient, and the purity and yield of the obtained impurity are stable.
Detailed description of the invention
The present invention is further illustrated by the following specific examples.
Example 1
(1) Process for the preparation of compounds II
Adding 70.0g of compound I and 250g of ethanol into a 1L four-mouth bottle, stirring, heating to 55 ℃, beginning to dropwise add 210mL of 5% sodium hydroxide aqueous solution for 30min, and preserving the temperature at 50-55 ℃ until the reaction is completed. Adjusting the pH value to acidity with acetic acid, extracting an organic phase with dichloromethane, and concentrating to obtain a light yellow solid.
(2) Process for the preparation of compound III
58.0g of Compound II, 15.37g of 3-amino-6-methoxypyridazine and 220g of ethyl acetate were placed in a 1L four-necked flask, stirred while purging with nitrogen, and 36g N, N-diisopropyl ester was addedAnd (3) heating the reaction temperature of the ethylamine to 40-45 ℃, adding 71g of 1-propyl phosphoric anhydride, and carrying out heat preservation reaction until the raw materials disappear. Adding water to quench the reaction, adjusting the pH of the system to be alkaline by potassium carbonate, precipitating a large amount of solid, and performing suction filtration to obtain a compound III, wherein the yield is 90%, and the purity (HPLC): 98.65 percent.1HNMR（DMSO-D6，400MHz）：δppm13.83 (s, 1H)，8.37-8.31(q, 3H)，7.64-7.62 (m, 2H)，7.31-7.28 (m, 2H)，7.00-6.96(m, 2H)，4.91（s, 2H），3.99（s, 2H），3.57（s, 3H），3.48（s, 2H），2.08（s, 6H），1.07（s, 3H）。m/z[M +H]+：627.72，m/z[M -H]- ：625.37。
(3) Process for the preparation of compound IV
Adding 59.0g of compound III, 200mL of dichloromethane, 5.9g of 10% palladium carbon and 4.62g of triethylamine into a 1L autoclave, stirring, pressurizing to 1.5-2.0 MPa with hydrogen, reacting completely for about 3h, performing suction filtration, and concentrating the filtrate to obtain compound IV with the yield of 95% and the purity (HPLC): 96.75 percent.1HNMR（DMSO-D6，400MHz）：δppm14.02 (s, 1H)，8.39 (s, 1H)，8.36-7.25(m, 2H)，6.99-6.92 (m, 4H)，6.91-6.59(d, 2H)，5.42（s, 2H），4.87-4.80（s, 2H），4.09（s, 2H），4.06-4.00（q, 3H），3.51-3.48（d, 2H），2.51-2.49（m, 6H），1.07（s, 3H）。m/z[M +H]+：597.62。
(4) Process for the preparation of compound V
To a reaction flask were added 10.0g of Compound IV, 45mL of tetrahydrofuran, 4.63g of potassium carbonate and 0.27g of tetrabutylammonium bromide. Stirring, heating to 55-60 ℃, and reacting under heat preservation until the raw materials disappear. The reaction was extracted with ethyl acetate, water, the product dissolved in the organic phase and concentrated to give the compound of formula V as a white solid in 90% yield and purity (HPLC): 98.74 percent.1HNMR（DMSO-D6，400MHz）：δppm7.75-7.73 (d, 1H)，7.50-7.43(m, 2H)，7.27-7.25(d, 2H)，7.16-7.11 (m, 2H)，6.63-6.61(t, 2H)，5.44-5.37（m, 2H），5.20-5.16（d, 2H），4.09（s, 3H），3.60-3.47（d, 2H），2.03（s, 6H）。
(5) Process for the preparation of compound VI
To a reaction flask were added 50.0g of Compound V, 2.9g of sodium methoxide, and 100mL of methanol. Starting stirring, heating to 70 ℃, and carrying out reflux reaction. TLC monitored the reaction complete, extracted with ethyl acetate and the organic phase concentrated to give compound VI as a yellow solid in 90% yield, purity (HPLC): 99.78 percent.1HNMR（DMSO-D6，400MHz）：δppm14.25 (s,1H)，8.93 (s,1H)，8.33-8.31 (d,1H)，7.44(s,1H)，7.19-7.12 (m,3H)，6.98-6.95(d,2H)，6.60-6.58（t,2H），5.32（s,2H），4.51-4.49（d,2H），3.96（s,3H），3.41-3.32（d,2H）,2.49-2.20（d,6H）。m/z[M +H]+：525.62。
Example 2
(1) Process for the preparation of compounds II
Adding 70.0g of compound I and 250g of methanol into a 1L four-mouth bottle, starting stirring, heating to 45 ℃, beginning to dropwise add 210mL of 5% sodium hydroxide aqueous solution for 30min, and preserving the temperature at 45-50 ℃ until the reaction is completed. Adjusting the pH value to acidity with acetic acid, extracting an organic phase with dichloromethane, and concentrating to obtain a light yellow solid.
(2) Process for the preparation of compound III
Adding 58.0g of compound II, 15.4g of 3-amino-6-methoxypyridazine and 220g of ethyl acetate into a 1L four-neck bottle, starting stirring, replacing with nitrogen, adding 36.5g N, N-diisopropylethylamine, heating the reaction temperature to 35-40 ℃, adding 72g of 1-propylphosphoric anhydride, and keeping the temperature for reaction until the raw materials disappear. Adding water to quench the reaction, adjusting the pH of the system to be alkaline by potassium carbonate, precipitating a large amount of solid, and performing suction filtration to obtain a compound III, wherein the yield is 85%, and the purity (HPLC): 98 percent.
(3) Process for the preparation of compound IV
A1L autoclave was charged with 59.0g of Compound III, 150mL of dichloromethane, 5.5g of 10% palladium on carbon and 4.6g of triethylamine. Starting stirring, pressurizing hydrogen to 1.5-2.0 MPa, completely reacting for about 3 hours, performing suction filtration, and concentrating the filtrate to obtain a compound IV with the yield of 93% and the purity (HPLC): 96.2 percent.
(4) Process for the preparation of compound V
To a reaction flask were added 10.0g of Compound IV, 50mL of tetrahydrofuran, 4.63g of potassium carbonate, 0.27g of tetrabutylammonium bromide. Stirring, heating to 60-65 ℃, and reacting while keeping the temperature until the raw materials disappear. The reaction solution was extracted with ethyl acetate and water, the product was dissolved in the organic phase and concentrated to give a white solid compound in 92% yield and purity (HPLC): 98.5 percent.
(5) Process for the preparation of compound VI
To the reaction flask was added 50.0g of compound formula V, 3.8g of sodium ethoxide, 100mL of ethanol. Starting stirring, heating to 55 ℃, and carrying out reflux reaction. TLC monitored the reaction complete, extracted with ethyl acetate and the organic phase concentrated to give compound V as a yellow solid in 85% yield, purity (HPLC): 99.02 percent.
Claims (10)
1. A Ruugeli intermediate impurity, wherein the impurity has the structure of formula VI:
2. a method for preparing the Ruugeli intermediate impurity of claim 1, wherein the method comprises the steps of:
dissolving a compound I in a solvent, adding alkali, heating to a certain temperature, and reacting to obtain a compound II;
secondly, adding the compound II into a solvent, adding an acid binding agent in a nitrogen atmosphere, heating to a certain temperature, adding a condensing agent, and carrying out heat preservation reaction to obtain a compound III;
thirdly, adding the compound III into a solvent, adding a catalyst and alkali, and reducing under certain hydrogen pressure to obtain a compound IV;
fourthly, dissolving the compound IV in a solvent, and adding alkali and a catalyst to carry out ring closing to prepare a compound V;
and step five, dissolving the compound V in a solvent, adding alkali, and carrying out ring opening to prepare a compound VI.
3. The preparation method according to claim 2, wherein the solvent in the first step is one or more of acetonitrile, water, methanol, ethanol or tetrahydrofuran; the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; the reaction temperature is 30-70 ℃.
4. The process according to claim 3, wherein the first-step reaction solvent is methanol or ethanol; the alkali is sodium hydroxide; the reaction temperature is 45-55 ℃.
5. The method according to claim 2, wherein the solvent in the second step is acetonitrile, toluene, dichloromethane, chloroform or ethyl acetate; the acid-binding agent is triethylamine, pyridine or N, N-diisopropylethylamine; the condensing agent is DIC, DCC, HOBT, HBTU, TBTU or 1-propyl phosphoric anhydride; the reaction temperature is 20-50 ℃.
6. The method according to claim 5, wherein the solvent in the second step is ethyl acetate; the acid-binding agent is N, N-diisopropylethylamine; the condensing agent is 1-propyl phosphoric anhydride; the temperature is 35-45 ℃.
7. The method according to claim 2, wherein the solvent in the third step is acetonitrile, toluene, dichloromethane, chloroform or ethyl acetate; the catalyst is palladium carbon, platinum carbon or Raney Ni; the alkali is pyridine, triethylamine or N, N-diisopropylethylamine; the reaction pressure is 1.5-2.0 MPa.
8. The method according to claim 7, wherein the solvent in the third step is dichloromethane; the catalyst is palladium carbon; the alkali is triethylamine.
9. The process according to claim 2, wherein the solvent in the fourth step is tetrahydrofuran; the alkali is potassium carbonate; the catalyst is tetrabutylammonium bromide.
10. The method according to claim 2, wherein the solvent in the fifth step is methanol or ethanol; the alkali is sodium methoxide or sodium ethoxide; the reaction temperature is 55-70 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232078A (en) * | 2022-07-08 | 2022-10-25 | 金陵药业股份有限公司 | Oxagolide sodium impurity and preparation method thereof |
| CN115650950A (en) * | 2022-11-03 | 2023-01-31 | 江西同和药业股份有限公司 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
| CN115650965A (en) * | 2022-12-26 | 2023-01-31 | 南京威凯尔生物医药科技有限公司 | Preparation method of Rui Lu Geli key intermediate |
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| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN113444105A (en) * | 2020-03-27 | 2021-09-28 | 南京海润医药有限公司 | Preparation method of Relugolix |
| CN113563304A (en) * | 2020-12-30 | 2021-10-29 | 上海博志研新药物技术有限公司 | Rugoside intermediate and preparation method thereof |
| CN113717149A (en) * | 2021-09-29 | 2021-11-30 | 成都伊诺达博医药科技有限公司 | Ruogeli key intermediate and preparation method thereof |
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2021
- 2021-12-27 CN CN202111609004.6A patent/CN114380810A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113444105A (en) * | 2020-03-27 | 2021-09-28 | 南京海润医药有限公司 | Preparation method of Relugolix |
| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN113563304A (en) * | 2020-12-30 | 2021-10-29 | 上海博志研新药物技术有限公司 | Rugoside intermediate and preparation method thereof |
| CN113563303A (en) * | 2020-12-30 | 2021-10-29 | 上海博志研新药物技术有限公司 | Rugoside intermediate and preparation method thereof |
| CN113717149A (en) * | 2021-09-29 | 2021-11-30 | 成都伊诺达博医药科技有限公司 | Ruogeli key intermediate and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232078A (en) * | 2022-07-08 | 2022-10-25 | 金陵药业股份有限公司 | Oxagolide sodium impurity and preparation method thereof |
| CN115650950A (en) * | 2022-11-03 | 2023-01-31 | 江西同和药业股份有限公司 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
| CN115650965A (en) * | 2022-12-26 | 2023-01-31 | 南京威凯尔生物医药科技有限公司 | Preparation method of Rui Lu Geli key intermediate |
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