CN117683052A - Preparation method of KRAS G12D inhibitor MRTX1133 - Google Patents
Preparation method of KRAS G12D inhibitor MRTX1133 Download PDFInfo
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Abstract
本发明属药物化学合成技术领域，具体为一种KRASG12D抑制剂MRTX1133的制备方法。本发明合成方法反应步骤为：由原料7‑氯‑8‑氟‑2‑(甲硫基)吡啶并[4,3‑D]嘧啶‑4‑醇经卤化、取代、氧化、suzuki偶联反应得到关键中间体5，再与((2R，7aS)‑2‑氟四氢‑1H‑吡咯嗪‑7a(5H)‑基)甲醇(11)反应得到化合物6，最后脱氨基保护基、甲氧基甲醚保护基和三丁基硅烷得到目标化合物MRTX1133(8)。 The invention belongs to the technical field of pharmaceutical chemical synthesis, and is specifically a preparation method of KRASG12D inhibitor MRTX1133. The reaction steps of the synthesis method of the present invention are: starting from the raw material 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-D]pyrimidine-4-ol through halogenation, substitution, oxidation and suzuki coupling reaction Key intermediate 5 is obtained, and then reacted with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (11) to obtain compound 6, and finally deamination protecting group, methoxy Methyl ether protecting group and tributylsilane were used to obtain the target compound MRTX1133(8).
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry synthesis, and relates to a novel preparation method of a KRAS G12D inhibitor MRTX 1133.
Background
Although immune checkpoint inhibitors have progressed in many solid tumors, the effects of immune checkpoint inhibitors on pancreatic cancer are not apparent, and clinical trials to date have failed to find patient benefit. This is mainly the case with pancreatic cancer, which has a unique tumor microenvironment that inhibits the immune system and also lacks tumor infiltrating effector T cells. Another reason is that 90% of pancreatic cancers are KRAS gene mutations, most of which are G12D sites (40% by weight), which results in the current targeting AMG510 of KRAS genes not having significant effects for decades, mutant KRAS has been considered an attractive drug target for the treatment of a variety of cancers. KRASG12D is the most common KRAS mutation, however, the high affinity of KRAS for GDP/GTP and the lack of other distinct binding pockets greatly reduces the potency of KRAS. Also unlike KRASG12C, KRASG12D lacks active residues (enabling covalent modification of the protein) near the switch II binding pocket. Thus, new approaches are needed to develop selective inhibitors with high affinity, pharmaceutically effective potency.
The KRAS G12D inhibitor MRTX1133, although successful in animal models, eventually the tumor grows longer. However, combining the targeting agent of KRAS gene G12D with an immune checkpoint inhibitor, such treatment may achieve durable tumor elimination. And the survival result of preclinical model animals can be remarkably improved, so that the preclinical model animals start a primary clinical test. The specific mechanism of MRTX1133 is by activating the Fas pathway required for cancer cell death, which leads to an increase in the number of immune T cells in the tumor and a decrease in the number of bone marrow cells. Can improve microenvironment required by immunotherapy. Researchers are gradually exploring the best combination therapies and the most appropriate drug doses with good success by combining various immune checkpoint inhibitors with MRTX 1133.
Disclosure of Invention
In view of the above, the preparation of the KRAS G12D inhibitor MRTX1133 is very important. The inventor solves the technical problem of the compound through experimental study, and the reaction route is as follows:
the invention comprises the following steps:
(a) From starting 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidin-4-ol (1), the hydroxy group was substituted with halogen or trifluoromethanesulfonic acid ester group to give 4-halo-7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidine or 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidin-4-yl trifluoromethanesulfonic acid ester (2)
Wherein R is 1 ＝OTf、Cl、Br、I
(b) The compound (2) and 3, 8-diazabicyclo [3.2.1] octane compound (9) containing different protecting groups are subjected to substitution reaction under alkaline conditions to obtain a compound (3)
Wherein R is 2 ＝Cbz、Boc、Fmoc、Bn
(c) Oxidizing the compound (3) to obtain the methylsulfinyl pyrido [4,3-D ] pyrimidine compound (4)
(d) The compound (4) and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-1-yl) ethynyl) triisopropylsilane (10) are subjected to suzuki coupling reaction to obtain a compound (5)
(e) The compound (5) is reacted with ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (11) to give the compound (6)
(f) Deamination of compound (6) under acidic conditions gives compound (7)
(g) Finally, the demethoxymethyl ether protecting group and tributylsilane are hydrolyzed to obtain the target compound MRTX1133 (8)
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
Step A
The compound 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-d]Pyrimidine-4-ol (840 mg,3.42 mmol) was dissolved in phosphorus oxychloride (8 mL) and DIEA (884 mg,6.84 mmol) was added and reacted for 3 hours at 90 ℃. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and excess phosphorus oxychloride was removed. Then, it was dissolved in ethyl acetate, washed with saturated brine and water in this order, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was used directly in the next step (900 mg, yield 100%). LC-MS (ESI): m/z=264.1 [ m+h ]] + 。
Step B
4, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4,3-D]Pyrimidine (0.73 g,2.75 mmol), (1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester (0.55 g,2.6 mmol) and K 2 CO 3 (0.76 g,5.5 mmol) was dissolved in NMP (5 mL) and stirred at 80℃for 1 hour, then 12.5. 12.5mLH was added 2 O. The solid was collected by filtration to give the compound (1R, 5S) -3- (7-chloro-8-fluoro-2- (methylthio) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1.01 g, 89% yield), LC-MS (ESI): m/z=439.9 [ m+h ]] + 。
Step C
The compound (1R, 5S) -3- (7-chloro-8-fluoro-2- (methylthio) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (0.95 g,2.1 mmol), (S) - (-) -1,1' -bi-2-naphthol (0.062 g,0.21 mmol), dichloromethane (608 mL), ti (OiPr) 4 (6.54 mL,0.11 mmol) and water (7.72 mL) were added to the multi-necked flask and stirred at 20℃under nitrogen for 1h. T-butyl peroxide (70% aqueous solution, 2.36 mmol) was added in one portion at 21 ℃; after the temperature had risen to about 40 ℃, the mixture became completely homogeneous. The mixture was allowed to reach normal room temperature, stirred for 1.5h and filtered. Washing the filter cake with isopropyl acetate twice (3 mL each time), and air-drying the filter cake in a filter for more than 6h to obtainCompound (1R, 5S) -3- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester-methane (0.89 g, 88% yield). LC-MS (ESI): m/z=472 [ m+h ]] + 。
Step D
(1R, 5S) -3- (7-chloro-8-fluoro-2- (methylsulfinyl) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester-methane (0.85 mg, 1.810mol) and CS 2 CO 3 (1.77 g,5.440 mol) in dioxane (75 mL) and H 2 The mixture in O (25 mL) was degassed. Pd (dppf) Cl was then added 2 (133 mg,0.18 mol) and tributyl ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (1.31 g,2.36 mol) and are described in N 2 Stirring is carried out at 100℃for 2.5 hours. After the reaction was completed, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with saturated brine (50 ml×2), dried over NaiSCri, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (720 mg, yield 47%). LC-MS (ESI): m/z=848.1 [ m+h ]] + 。
Step E
((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (1 g,6.28 mmol) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (0.5 g,12.5 mmol) was added at 0deg.C, after stirring for 10 min, (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (2.14 g,2.52 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purifying the crude product by silica gel column chromatography to obtain (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3)- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1.67 g, 70% yield). LC-MS (ESI): m/z=943.2 [ m+h ]] + 。
Step F
(1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (0.94 g,1 mmol) was dissolved in dichloromethane (1.5 ml) and then trifluoroacetic acid (0.12 g,1.1 mmol) was added to a three-necked flask, the resulting mixture was stirred at room temperature for 10 hours, after completion of the reaction, quenched with sodium hydrogencarbonate solution (1 ml), then extracted with dichloromethane (1.5 ml. Times.2), the resulting organic phase was washed with sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and concentrated to give 4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d]Pyrimidine (0.76 g, 90% yield). LC-MS (ESI): m/z=842.1 [ m+h] + 。
Step G
At N 2 Under the condition, 4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((tributylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d]Pyrimidine (222 mg,264 pmol) was dissolved in DMF (1 mL) and CsF (40.13 mg,264 pmol) was added. The mixture was stirred at 20℃for 1 hour. After completion, the mixture was purified by HPLC to give the title compound MRTX1133 (33 mg, 21% yield). LC-MS (ESI): m/z=600.6 [ m+h ]] + 。 1 HNMR(400MHz,MeOD)δ9.00,7.87-7.83(m,1H),7.35-7.29(m,2H),7.20(s,1H),5.37-5.23(d,1H),4.88-4.62(m,2H),4.59-4.56(m,2H),4.31-4.20(m,2H),3.73-3.65(m,4H),3.35-3.18(m,4H),3.02-2.98(m,1H),2.37-2.11(m,3H),2.01-1.77(m,7H)。
The examples are only for illustrating embodiments of the present invention, but the present invention is not limited to the above examples only. The invention is capable of numerous modifications and adaptations without departing from the spirit and scope of the invention as set forth in the claims and their equivalents.
Claims (9)
1. A preparation method of a KRAS G12D inhibitor MRTX1133 is characterized by comprising the following specific steps:
(1) From starting 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidin-4-ol, the hydroxy group is substituted with halogen or trifluoromethanesulfonic acid ester group to give 4-halo-7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidine or 7-chloro-8-fluoro-2- (methylthio) pyrido [4,3-D ] pyrimidin-4-yl trifluoromethanesulfonic acid ester;
(2) The compound 2 and 3, 8-diazabicyclo [3.2.1] octane compound 9 containing different protecting groups undergo substitution reaction under alkaline conditions to obtain a compound 3;
(3) Oxidizing the compound 3 to obtain a methylsulfinyl pyrido [4,3-D ] pyrimidine compound 4;
(4) The compound 4 and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-1-yl) ethynyl) triisopropylsilane undergo a suzuki coupling reaction to obtain a compound 5;
(5) Reacting the compound 5 with ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol to obtain a compound 6;
(6) Deamination of compound 6 under acidic conditions gives the compound 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester;
(7) Finally hydrolyzing the demethoxymethyl ether protecting group and tributylsilane to obtain a target compound MRTX1133 (8)
2. The method of claim 1 wherein step (1) comprises the step of reacting compound (2) R 1 One of = OTf, cl, br, I; in step (2), compound (9) R 2 One of = Cbz, boc, fmoc, bn.
3. The method for preparing the KRAS G12D inhibitor MRTX1133 as claimed in claim 1, wherein in the step (1), the reaction temperature is selected from 50-120 ℃, the time is selected from 0-10h, the solvent is selected from one or more of ethanol, acetone, methanol, dichloromethane, water, formonitrile, N-dimethylformamide, dimethyl sulfoxide and N, N-diisopropylethylamine, the halogenating agent is selected from one of halogen acid, phosphorus trihalide, phosphorus pentahalide and thionyl chloride, and the purification can be selected from filtration, filter cake washing, column passing, beating or recrystallization.
4. The method for preparing the KRAS G12D inhibitor MRTX1133 as claimed in claim 1, wherein in the step (2), the reaction temperature is selected from 10-200 ℃, the time is selected from 0-72h, and the solvent is selected from one or more of N, N-Dimethylformamide (DMF), dichloromethane and the like. The alkaline agent is one or more selected from sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydride, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
5. The method for preparing the KRAS G12D inhibitor MRTX1133 as claimed in claim 1, wherein in the step (3), the reaction temperature is selected from 25-70 ℃, the time is selected from 0-24h, and the solvent is selected from one or more of methanol, dichloromethane, ethanol, water, formonitrile, N-dimethylformamide, dimethyl sulfoxide and the like. The oxidant is selected from tert-butyl peroxide, hydrogen peroxide, oxygen and N 2 O 4 、NaIO 4 One or more of the following. The catalyst is selected from alumina, ti (OiPr) 4 One or more of selenic acid, selenium dioxide, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
6. The method of claim 1, wherein in step (4), the reaction temperature of the suzuki coupling reaction is 10-200deg.C, the reaction time is 0-72H, and the solvent is selected from diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, or H 2 O, NMP, DMA, DMSO, benzene, toluene, or one or more of them. The catalyst used in the reaction can be selected from bis (triphenylphosphine) -palladium dichloride, bis (triphenylphosphine) ferrocene palladium dichloride dichloromethane complex, pd 2 (dba) 3 、pd(dppe)Cl 2 Tetraphenylpalladium phosphate, bis (triphenyl)Phosphine) ferrocene nickel dichloride, 0.01% -20% (M/M mole ratio) of compound, wherein the alkali used in the reaction is selected from triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine and CsCO 3 、KOAc、NaOAc、K 2 CO 3 、Na 2 CO 3 、Li 2 CO 3 、tBuOK、tBuONa、K 3 PO 4 、NaOH、KOH、Ba(OH) 2 One of them. 1-10 times (M/M molar ratio) of the amount. Purification may be selected from column passing, beating or recrystallisation.
7. The method of claim 1, wherein in step (5), the reaction temperature is selected from the group consisting of 10-200deg.C, and the solvent is selected from the group consisting of acetonitrile, THF, 1, 4-dioxane, H 2 O, DMSO, DCM, 1, 2-dichloroethane. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
8. The process for preparing a KRAS G12D inhibitor MRTX1133 as claimed in claim 1, wherein in step (6), the reaction temperature is selected from the group consisting of 0-100 ℃, and the solvent is selected from the group consisting of diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H 2 O, NMP, DMA, DMSO, benzene, toluene, chlorobenzene, anisole, xylene, DCM, 1, 2-dichloroethane. The acid is one or more selected from trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
9. The method for preparing the KRAS G12D inhibitor MRTX1133 as claimed in claim 1, wherein in the step (7), the reaction temperature is selected from 20-30 ℃, and the solvent is selected from one or more of dichloromethane, boron trifluoride diethyl ether, tertiary butanol, isopropanol, methanol, tetrahydrofuran, ethanol and N, N-dimethylformamide.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114615981A (en) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | KRAS G12D inhibitors |
| WO2022262838A1 (en) * | 2021-06-18 | 2022-12-22 | Silexon Ai Technology Co., Ltd. | Deuterated compounds useful as kras g12d inhibitors |
| CN115968286A (en) * | 2020-08-26 | 2023-04-14 | 益方生物科技(上海)股份有限公司 | Heteroaryl compounds, their preparation and use |
| CN115974896A (en) * | 2021-10-15 | 2023-04-18 | 广东东阳光药业有限公司 | Novel pyrimidopyridine compounds, their pharmaceutical compositions and their uses |
| WO2023098425A1 (en) * | 2021-12-02 | 2023-06-08 | 上海和誉生物医药科技有限公司 | Kras inhibitors, preparation method therefor, and pharmaceutical use thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114615981A (en) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | KRAS G12D inhibitors |
| CN115968286A (en) * | 2020-08-26 | 2023-04-14 | 益方生物科技(上海)股份有限公司 | Heteroaryl compounds, their preparation and use |
| WO2022262838A1 (en) * | 2021-06-18 | 2022-12-22 | Silexon Ai Technology Co., Ltd. | Deuterated compounds useful as kras g12d inhibitors |
| CN115974896A (en) * | 2021-10-15 | 2023-04-18 | 广东东阳光药业有限公司 | Novel pyrimidopyridine compounds, their pharmaceutical compositions and their uses |
| WO2023098425A1 (en) * | 2021-12-02 | 2023-06-08 | 上海和誉生物医药科技有限公司 | Kras inhibitors, preparation method therefor, and pharmaceutical use thereof |
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