CN117209537A - Rayleigh Lu Geli intermediate impurity, rayleigh Lu Geli impurity and preparation method thereof - Google Patents
Rayleigh Lu Geli intermediate impurity, rayleigh Lu Geli impurity and preparation method thereof Download PDFInfo
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- CN117209537A CN117209537A CN202210617828.6A CN202210617828A CN117209537A CN 117209537 A CN117209537 A CN 117209537A CN 202210617828 A CN202210617828 A CN 202210617828A CN 117209537 A CN117209537 A CN 117209537A
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- 239000012535 impurity Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title abstract description 21
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006366 phosphorylation reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010046798 Uterine leiomyoma Diseases 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229950004238 relugolix Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The application discloses a Rayleigh Lu Geli intermediate impurity II and a Rayleigh Lu Geli impurity I and a preparation method thereof. The impurity I is prepared by taking a compound III as a starting material, carrying out phosphorylation reaction to obtain an intermediate impurity II, and carrying out cyclization reaction on the intermediate impurity II. The impurity purity and yield obtained by the preparation method are high, and the impurity purity and yield can be used as a reference substance for detecting related substances of the Rui Lu Geli and intermediates, and used for controlling the purity of the Rui Lu Geli bulk drug.
Description
Technical Field
The application belongs to the field of medicine synthesis, and particularly relates to a Rayleigh Lu Geli intermediate impurity, a Rayleigh Lu Geli impurity and a preparation method thereof.
Background
Rayleigh Lu Geli (Relugolix) is a gonadotrophin (GnRH) receptor antagonist developed by the Japanese Wuta-tsu corporation, marketed in Japan in 2018 for use in bleeding and pain caused by uterine fibroids. In addition to being used for treating uterine fibroids, the drug is being developed in various countries for pain caused by endometriosis, prostate cancer, and the like. The molecular structure of Relugolix is as follows:
at present, there are reports on the synthesis method of the Rayleigh Lu Geli, wherein the most common synthesis route is shown as follows (reference CN113444105A, CN 111333633A):
in the raw material medicine of the Rui Lu Geli prepared by the method, a plurality of unknown impurities generated by the preparation process often exist, so that the quality control difficulty of the raw material medicine of the Rui Lu Geli and intermediates is improved.
Disclosure of Invention
The application aims to: the application aims to provide a Rayleigh Lu Geli intermediate impurity and a Rayleigh Lu Geli impurity, and a preparation method of the impurity and the intermediate impurity.
The technical scheme is as follows: the intermediate impurity of the application, namely the Rayleigh Lu Geli, has the following structure:
the impurity of the application, namely the Rui Lu Geli, has the following structure:
in the conventional preparation method of the Rui Lu Geli, the inventor finds that under the preparation process condition of the compound VII, the generated compound VII reacts with the condensing agent 1-propylphosphoric anhydride to obtain an impurity intermediate II (shown in the attached figure 1), and the impurity intermediate II continuously participates in the next reaction to finally obtain the impurity compound I (shown in the attached figure 2). Impurity compounds I and II are difficult to remove under the process conditions, so that the purity of the crude drug substance Rayleigh Lu Geli is influenced, and the impurity intermediate II and the impurity compound I are required to be detected and controlled in the synthesis process of the Rayleigh Lu Geli and the intermediate, so that the quality of the crude drug substance Rayleigh Lu Geli is controlled. Impurity compounds I and II are used as one of main impurities generated in the synthesis process of the Rayleigh Lu Geli, the impurity compounds I and II have low content in the synthesis process of the Rayleigh Lu Geli and are difficult to separate, the synthesis report of the impurity compound I, II is not available in the prior art, a large amount of high-purity compound I, II is difficult to obtain by people, corresponding reference substances are absent, and qualitative and quantitative detection of the impurity is difficult to carry out in the synthesis process of the Rayleigh Lu Geli.
The preparation method of the impurities of the Rayleigh Lu Geli comprises the following steps:
firstly, adding the compound III into a reaction solvent, adding an acid binding agent in a nitrogen atmosphere, adding 1-propyl phosphoric anhydride at 20-30 ℃, and carrying out heat preservation reaction to obtain the compound II.
And secondly, sequentially adding the compound III, alkali and a phase transfer catalyst into a reaction solvent, heating to 45-55 ℃, and carrying out heat preservation reaction to obtain the compound I.
Wherein the organic solvent in the first step is one or more of ethyl acetate, tetrahydrofuran and acetonitrile; the acid binding agent is N, N-diisopropylethylamine, triethylamine or DMAP.
The reaction solvent in the second step is one or more of tetrahydrofuran, ethyl acetate and benzonitrile; the alkali is one or more of triethylamine, pyridine, potassium carbonate and sodium carbonate; the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide.
The beneficial effects are that: compared with the prior art, the application has the following remarkable advantages:
(1) Through structural confirmation of unknown impurities generated in the preparation process of the Rui Lu Geli and the intermediates, and the preparation of impurities with high purity (HPLC purity is more than or equal to 95%) and the quantity meeting detection requirements, the corresponding impurities in the Rui Lu Geli bulk drug can be accurately qualitative and quantitative, and the product quality is improved;
(2) The impurity preparation method is simple and convenient, and the purity and the yield of the obtained impurity are high.
Drawings
FIG. 1: obtaining a liquid phase spectrogram of a Rayleigh Lu Geli intermediate compound VII through a conventional process;
fig. 2: obtaining a liquid phase spectrogram of the Rayleigh Lu Geli by a conventional process;
fig. 3: impurity II 1 HNMR spectrogram;
fig. 4: impurity I 1 HNMR spectra.
Detailed description of the preferred embodiments
The application will be further illustrated with reference to specific examples, but the scope of the application is not limited by the examples.
Example 1
(1) Preparation of Compound II: 3.0g of compound III and 15mL of ethyl acetate are added into a 25mL four-necked flask, stirring is started, nitrogen replacement is performed, 0.9g of N, N-diisopropylethylamine is added, the reaction temperature is controlled to be 20-25 ℃, 2.7g of ethyl acetate solution of 50% 1-propylphosphoric anhydride is added dropwise, and the reaction is performed under heat preservation until the raw materials disappear. The reaction was quenched with water, the pH of the system was adjusted to alkaline with 0.3g of potassium carbonate, 25mL of dichloromethane was added for extraction, the organic phase was concentrated, and the mixture was separated and purified by column chromatography to give Compound II in 85% yield and 95.6% purity (HPLC). MS: [ M+1 ]] + ＝776.24。 1 HNMR (DMSO-D6, 400 MHz) data are shown in FIG. 3.
(2) Preparation of Compound I: to a 25mL reaction flask, 1.1g of Compound II,10mL of tetrahydrofuran and 0.45g of tetrabutylammonium bromide were added, followed by stirring, 0.59g of potassium carbonate was added, and after the addition, the temperature was raised to 45-50℃and the temperature was maintained until the material disappeared. Cooling to room temperature, adding water and dichloromethane, spin drying the organic phase, separating and purifying by column chromatography to obtain compound I with yield of 80% and purity (HPLC) of 96.3%. MS: [ M+1 ]] + ＝730.0。 1 HNMR (DMSO-D6, 400 MHz) data are shown in FIG. 4.
Example 2
(1) Preparation of Compound II: 3.0g of compound III and 20mL of tetrahydrofuran are added into a 25mL four-necked flask, stirring is started, nitrogen is replaced, 0.7g of triethylamine is added, the reaction temperature is controlled to be 25-30 ℃, 2.8g of 50% ethyl acetate solution of 1-propylphosphoric anhydride is added dropwise, and the temperature is kept until the raw materials disappear. The reaction was quenched with water, the pH of the system was adjusted to be basic with 0.3g of potassium carbonate, and 25mL of methylene chloride was added for extraction, followed by column chromatography for separation and purification to give compound II in 82% yield and 95.8% purity (HPLC).
(2) Preparation of Compound I: to a 25mL reaction flask, 1.1g of Compound II,10mL of ethyl acetate, 0.5g of tetrabutylammonium iodide, and 0.45g of sodium carbonate were added, followed by stirring, heating to 45-50℃and stirring at a constant temperature until the material disappeared. Cooling to room temperature, adding water and dichloromethane, spin drying the organic phase, separating and purifying by column chromatography to obtain compound I with yield of 85% and purity (HPLC) of 96.8%.
Example 3
(1) Preparation of Compound II: 3.0g of compound III and 15mL of acetonitrile are added into a 25mL four-necked flask, stirring is started, nitrogen is replaced, 0.9g of DMAP is added, the reaction temperature is controlled to be 25-30 ℃, 2.7g of ethyl acetate solution of 50% 1-propyl phosphoric anhydride is added dropwise, and the temperature is kept until the raw materials disappear. The reaction was quenched with water, the pH of the system was adjusted to alkaline with 0.3g of potassium carbonate, and 25mL of methylene chloride was added for extraction, followed by column chromatography for separation and purification to give Compound II in 75% yield and 96.1% purity (HPLC).
(2) Preparation of Compound I: to a 25mL reaction flask, 1.1g of Compound II,10mL of benzonitrile, 0.39g of tetrabutylammonium chloride and 0.43g of triethylamine were added, followed by stirring, heating to 50-55℃and stirring until the starting material disappeared. Cooling to room temperature, adding water and dichloromethane, spin drying the organic phase, separating and purifying by column chromatography to obtain compound I with yield of 84% and purity (HPLC) of 96.2%.
Example 4
(1) Preparation of Compound II: 3.0g of compound III and 20mL of ethyl acetate are added into a 25mL four-necked flask, stirring is started, nitrogen replacement is performed, 0.9g of N, N-diisopropylethylamine is added, the reaction temperature is controlled at 25-30 ℃, 2.7g of ethyl acetate solution of 50% 1-propylphosphoric anhydride is added dropwise, and the reaction is performed under heat preservation until the raw materials disappear. The reaction was quenched with water, the pH of the system was adjusted to alkaline with 0.3g of potassium carbonate, 25mL of dichloromethane was added for extraction, the organic phase was concentrated, and the mixture was separated and purified by column chromatography to give Compound II in 83% yield and 95.8% purity (HPLC).
(2) Preparation of Compound I: to a 25mL reaction flask, 1.1g of Compound II,15mL of tetrahydrofuran and 0.48g of tetrabutylammonium bromide were added, followed by stirring, 0.6g of potassium carbonate was added, and after the addition, the temperature was raised to 50-55℃and the temperature was maintained until the material disappeared. Cooling to room temperature, adding water and dichloromethane, spin-drying the organic phase, separating and purifying by column chromatography to obtain compound I with a yield of 82% and a purity (HPLC) of 96.6%.
Claims (8)
1. A rayleigh Lu Geli impurity intermediate, wherein said impurity intermediate has the structure:
2. a rayleigh Lu Geli impurity, said impurity having the structure:
3. a method of preparing the rayleigh Lu Geli impurity of claim 2, comprising:
firstly, adding a compound III into a reaction solvent, adding an acid binding agent in a nitrogen atmosphere, adding 1-propyl phosphoric anhydride at 20-30 ℃, and carrying out heat preservation reaction to obtain a compound II;
sequentially adding the compound III, alkali and a phase transfer catalyst into a reaction solvent, heating to 45-55 ℃, and carrying out heat preservation reaction to obtain a compound I; the reaction formula is as follows:
4. the process according to claim 3, wherein the reaction solvent in the first step is ethyl acetate, tetrahydrofuran or acetonitrile.
5. A process according to claim 3, wherein the acid-binding agent in the first step is N, N-diisopropylethylamine, triethylamine or DMAP.
6. The process according to claim 3, wherein the reaction solvent in the second step is tetrahydrofuran, ethyl acetate or benzonitrile.
7. The method according to claim 3, wherein the base in the second step is one or more of triethylamine, pyridine, potassium carbonate and sodium carbonate.
8. A process according to claim 3, wherein the phase transfer catalyst in the second step is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210617828.6A CN117209537A (en) | 2022-06-01 | 2022-06-01 | Rayleigh Lu Geli intermediate impurity, rayleigh Lu Geli impurity and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210617828.6A CN117209537A (en) | 2022-06-01 | 2022-06-01 | Rayleigh Lu Geli intermediate impurity, rayleigh Lu Geli impurity and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
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| CN117209537A true CN117209537A (en) | 2023-12-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210617828.6A Pending CN117209537A (en) | 2022-06-01 | 2022-06-01 | Rayleigh Lu Geli intermediate impurity, rayleigh Lu Geli impurity and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117209537A (en) |
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2022
- 2022-06-01 CN CN202210617828.6A patent/CN117209537A/en active Pending
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