CN117964617A - Preparation method of GLP-1 receptor agonist Orforglipron - Google Patents
Preparation method of GLP-1 receptor agonist Orforglipron Download PDFInfo
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- CN117964617A CN117964617A CN202311862364.6A CN202311862364A CN117964617A CN 117964617 A CN117964617 A CN 117964617A CN 202311862364 A CN202311862364 A CN 202311862364A CN 117964617 A CN117964617 A CN 117964617A
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- fluoro
- acid
- orforglipron
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- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 title claims abstract description 15
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- FLQXKZFIZKTQJY-UHFFFAOYSA-N (4-fluoro-3,5-dimethylphenyl)hydrazine Chemical compound Cc1cc(NN)cc(C)c1F FLQXKZFIZKTQJY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- -1 1- (4-fluoro-1-methyl-1H-indazol-5-yl) -3- (2- (4-fluoro-3, 5-dimethylphenyl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-3-yl) -1, 3-dihydro-2H-imidazol-2-one hydrochloride Chemical compound 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
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- FCLRDVPREJSWBM-UHFFFAOYSA-N 2-isocyanato-1,1-dimethoxyethane Chemical compound COC(OC)CN=C=O FCLRDVPREJSWBM-UHFFFAOYSA-N 0.000 claims description 5
- VWANSYGDVGYGTG-RGDDPNHNSA-N 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid Chemical compound CC1(OCC[C@@H](C1)C=1C=C2C=C(N(C2=CC=1)[C@@]1([C@H](C1)C)C1=NOC(N1)=O)C(=O)O)C VWANSYGDVGYGTG-RGDDPNHNSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
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- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 9
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 8
- 238000000034 method Methods 0.000 claims 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 6
- 238000000746 purification Methods 0.000 claims 5
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 4
- 238000010009 beating Methods 0.000 claims 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
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- 229910052763 palladium Inorganic materials 0.000 claims 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 2
- 230000035484 reaction time Effects 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
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- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 4
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a GLP-1 receptor agonist Orforglipron (LY 3502970). The synthetic method comprises the following reaction steps: the dihydropyridines (1) containing different protecting groups and (4-fluoro-3, 5-dimethylphenyl) hydrazine (8) are cyclized to obtain a key intermediate (2), the key intermediate is subjected to addition, ring closure, buchwald coupling, deamination of the protecting groups and salification to obtain a compound (6), and finally the compound (6) is reacted with a compound (11) to obtain a target compound Orforglipron (LY 3502970)
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry synthesis, and relates to a novel preparation method of GLP-1 receptor agonist Orforglipron +.
Background
Glucagon-like peptide-1 (GLP-1) is a peptide hormone; when we begin to rise in blood glucose levels after eating, GLP-1 stimulates the body to produce insulin and reduces glucagon secretion to help control the body's blood glucose levels, which is critical for the treatment and management of diabetes. In addition, the hormone can inhibit gastric acid secretion, slow down gastrointestinal peristalsis, increase satiety and reduce appetite, thereby achieving the purpose of losing weight. In order to allow GLP-1 to exert therapeutic effects clinically, researchers have used active molecules that interact with the GLP-1 receptor to mimic the effects of GLP-1 (i.e., GLP-1 receptor agonists, GLP-1 RA) in vivo, with these molecules having longer half-lives, more stable chemical structures, and higher patentability. Currently, the application and potential value of GLP-1RA in fields other than diabetes have become research hotspots, and the most interesting application is weight reduction. GLP-1RA mimics the action of GLP-1 and can help obese patients lose weight. The first successfully marketed GLP-1 receptor agonist was exantide of Aspirin, which was approved by the United states FDA in 2005 for the treatment of type 2 diabetes. In view of the advantages and good safety of the medicaments in the aspect of reducing weight, the research and development investment on GLP-1 receptor agonists is increased, and more GLP-1 receptor agonists are developed.
Orforglipron is a once daily oral, non-peptide GLP-1 receptor small molecule agonist developed by gillyx. The results of phase 2 clinical trials showed that of the patients with overweight, obesity and at least one weight-related complication (not associated with diabetes) treated with different doses orforglipron, 46-75% of the patients lost at least 10% of their weight at week 36, whereas the proportion of lost corresponding weight was only 9% in the patients treated with placebo. Currently orforglipron is still tested in phase 3 clinical trials, with indications including obesity and diabetes.
Disclosure of Invention
In view of the above, the preparation of GLP-1 receptor agonist Orforglipron (LY 3502970) 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) The key intermediate (2) is obtained by the ring closure of dihydropyridines (1) containing different protecting groups and (4-fluoro-3, 5-dimethylphenyl) hydrazine (8)
Wherein r= Fmoc, cbz, bn, boc
(B) The compound (2) and 2-isocyanato-1, 1-dimethoxyethane (9) are subjected to addition reaction under alkaline condition to obtain 2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine compound (3)
(C) Compound (3) is cyclized under acidic conditions to give compound (4)
(D) Buchwald coupling reaction of Compound (4) with 5-halo-4-fluoro-1-methyl-1H-indazole (10) to give Compound (5)
Wherein x=br, I, OTf
(E) Hydrochloride and removing amino protecting group to obtain 1- (4-fluoro-1-methyl-1H-indazol-5-yl) -3- (2- (4-fluoro-3, 5-dimethylphenyl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-3-yl) -1, 3-dihydro-2H-imidazol-2-one hydrochloride (6)
(F) Finally, reaction with 5- ((S) -2, 2-dimethyltetrahydro-2H-pyran-4-yl) -1- ((1S, 2S) -2-methyl-1- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl) -1H-indole-2-carboxylic acid (11) gives the title compound Orforglipron (LY 3502970) (7)
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
Tert-butyl 5-cyano-4-hydroxy-3, 6-dihydropyridine-1 (2H) -carboxylate (0.93 g,4.14 mmol) and (4-fluoro-3, 5-dimethylphenyl) hydrazine (0.64 g,4.14 mmol) were dissolved in ethanol (8 ml) and 2N hydrochloric acid (3.3 ml,6.61 mmol) was added thereto and the mixture was stirred at 50℃for 1 hour. After cooling the reaction to 0deg.C, 5M aqueous sodium hydroxide (1.33 mL,6.61 mmol) and di-tert-butyl dicarbonate (0.95 g,4.34 mmol) were added and the mixture stirred at 0deg.C for 1h. Water was added, extraction was performed with ethyl acetate, and then the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl 3-amino-2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylate (1.04 g, yield 70%). LC-MS (ESI): m/z=360.4 [ m+h ] +.
Step B
To a solution of tert-butyl 3-amino-2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylate (0.89 g,2.46 mmol) in pyridine (246 mL) was added 2-isocyanato-1, 1-dimethoxyethane (0.65 g,4.93 mmol) and the mixture was stirred at room temperature for 3 hours 15 minutes, diethylamine (0.36 g,5 mmol) was added and stirred at room temperature for 5 minutes, then water (15 mL) was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture, which had become a suspension, was filtered, and the resulting solid was washed with water (5 mL) and then dried under reduced pressure to give tert-butyl 3- (3- (2, 2-dimethoxyethyl) ureido) -2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylate (1.02 g, yield 84%). LC-MS (ESI): m/z=491.6 [ m+h ] +.
Step C
To 3- (3- (2, 2-dimethoxyethyl) ureido) -2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylic acid tert-butyl ester (1.64 g,3.34 mmol) was added formic acid (38.4 mL,1 mol) and the mixture stirred at room temperature for 21 hours. The mixture was concentrated under reduced pressure, toluene was added, and the solvent was removed by evaporation under reduced pressure. Dichloromethane (10 mL) was added to dissolve the residue, followed by hydrogen chloride (4M dioxane solution, 8.35 mL) at room temperature. The reaction mixture was concentrated. Toluene was added and the solvent was evaporated under reduced pressure to give tert-butyl 2- (4-fluoro-3, 5-dimethylphenyl) -3- (2-oxo-2, 3-dihydro-1H-imidazol-1-yl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylate (1 g, 71% yield). LC-MS (ESI): m/z=427.5 [ m+h ] +.
Step D
2- (4-Fluoro-3, 5-dimethylphenyl) -3- (2-oxo-2, 3-dihydro-1H-imidazol-1-yl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylic acid tert-butyl ester (0.86 g,2 mmol) was dissolved in 5ml toluene, catalytic amounts Xphos and Pd 2(dba)3 were added, potassium carbonate 0.57g, 5-bromo-4-fluoro-1-methyl-1H-indazole (0.46 g,2 mmol) was added, stirring was carried out to 80℃under nitrogen protection, reflux was carried out for 12 hours, TLC was performed to detect the compound consumption, the filtrate was concentrated by celite filtration, and column chromatography was used to purify the compound 3- (3- (4-fluoro-1-methyl-1H-indazol-5-yl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) -2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-pyrazolo [4,3-c ] pyridine-carboxylic acid (97 g, yield). LC-MS (ESI): m/z=575.6 [ m+h ] +.
Step E
3- (3- (4-Fluoro-1-methyl-1H-indazol-5-yl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) -2- (4-fluoro-3, 5-dimethylphenyl) -2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine-5-carboxylic acid tert-butyl ester was dissolved in 5mL of dichloromethane and HCl-added dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated in vacuo to give 1- (4-fluoro-1-methyl-1H-indazol-5-yl) -3- (2- (4-fluoro-3, 5-dimethylphenyl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-3-yl) -1, 3-dihydro-2H-imidazol-2-one hydrochloride. LC-MS (ESI): m/z=512 [ m+h ] +.
Step F
To a solution of 1- (4-fluoro-1-methyl-1H-indazol-5-yl) -3- (2- (4-fluoro-3, 5-dimethylphenyl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-3-yl) -1, 3-dihydro-2H-imidazol-2-one hydrochloride (16.9 mg,0.033 mmol) and Dimethylformamide (DMF) (2 mL) of 5- ((S) -2, 2-dimethyltetrahydro-2H-pyran-4-yl) -1- ((1S, 2S) -2-methyl-1- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl) -1H-indole-2-carboxylic acid (15.6 mg,0.038 mmol) and 2- (7-azabenzotriazol) -tetramethylurea hexafluorophosphate (15.1 mg,3.98 mmol) was added diisopropylethylamine (0.018 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was purified by reverse phase column chromatography to give the objective compound Orforglipron (LY 3502970) (29 mg, yield 91％).LC-MS(ESI)：m/z＝882.97[M+H]+.1H NMR(400MHz,CDCl3)δppm1.06-1.20(m,2H),1.26-1.29(m,3H),1.32-1.35(m,3H),1.50-1.55(m,2H),1.57(d,3H),1.59-1.62(m,1H),1.63-1.69(m,2H),1.72-1.79(m,3H),1.86-1.98(m,1H),2.22-2.31(m,6H),2.96-3.20(m,3H),3.48-3.64(m,1H),3.78-3.92(m,2H),4.05-4.15(m,3H),4.40-4.51(m,1H),5.74-5.83(m,1H),6.31(d,1H),6.61(m,1H),7.05-7.16(m,2H),7.20-7.26(m,1H),7.27-7.30(m,1H),7.48(m,1H),7.51-7.53(m,1H),7.53-7.61(m,1H),8.08-8.15(m,1H).
Table one: buchwald coupling reaction of Compound (4) with 5-halo-4-fluoro-1-methyl-1H-indazole (10) to give Compound (5)
X＝Br,I,OTf
R＝Fmoc、Cbz、Bn、Boc
| Entry | Catalyst | Time(h) | Temp(℃) | Yield(％) |
| 1 | Pd2(dba)3 | 6 | 20 | 94.1 |
| 2 | Pd(OAc)2 | 8 | 120 | 84 |
| 3 | Pd2(dba)3 | 12 | 80 | 97 |
| 4 | PdCl2(dppf) | 24 | 110 | 76 |
| 5 | Pd(PPh3)4 | 20 | 100 | 90 |
| 6 | Pd(OAc)2 | 20 | 100 | 71 |
| 7 | CuI | 20 | 130 | 76 |
| 8 | CuI | 20 | 80 | 73 |
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 defined by the appended claims and their equivalents.
Claims (8)
1. A method for preparing a GLP-1 receptor agonist Orforglipron (LY 3502970), comprising the steps of:
(1) Dihydropyridines (1) containing different protecting groups are cyclized with (4-fluoro-3, 5-dimethylphenyl) hydrazine (8) to obtain a key intermediate (2)
(2) The compound (2) and 2-isocyanato-1, 1-dimethoxyethane (9) are subjected to addition reaction under alkaline conditions to obtain a compound (3)
(3) Compound (3) is cyclized under acidic conditions to give compound (4)
(4) Buchwald coupling reaction of Compound (4) with 5-halo-4-fluoro-1-methyl-1H-indazole (10) to give Compound (5)
(5) Hydrochloride and removing amino protecting group to obtain 1- (4-fluoro-1-methyl-1H-indazol-5-yl) -3- (2- (4-fluoro-3, 5-dimethylphenyl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-3-yl) -1, 3-dihydro-2H-imidazol-2-one hydrochloride (6)
(6) Finally, reaction with 5- ((S) -2, 2-dimethyltetrahydro-2H-pyran-4-yl) -1- ((1S, 2S) -2-methyl-1- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl) -1H-indole-2-carboxylic acid (11) gives the title compound Orforglipron (LY 3502970) (7)
2. The method of claim 1, wherein in step (1), R is selected from Fmoc, cbz, bn, boc, and in step (3), 5-halo-4-fluoro-1-methyl-1H-indazole, halogen substituents are selected from Br, I, and OTf.
3. The method of claim 1, wherein in step (1), the organic solvent is selected from one or more of methanol, ethanol, acetonitrile, acetic acid, n-butanol, acetone, and tetrahydrofuran; the reaction temperature is 0-120 ℃, the reaction time is 0-15h, and the purification can be performed by column, beating or recrystallization.
4. The method of claim 1, wherein in step (2), the temperature is selected from the group consisting of 20-150 ℃, and the solvent is selected from one or more of Dimethylformamide (DMF), N-methylpyrrolidone (NMP), and pyridine. The base is selected from sodium hydride, sodium hydroxide, potassium hydride, potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine or N, N-diisopropylethylamine, and the purification can be selected from filtering, washing filter cake, column passing, pulping or recrystallization.
5. The method of preparing a GLP-1 receptor agonist Orforglipron (LY 3502970) of claim 1, wherein in step (3), the temperature of the reaction is 10-140 ℃; the time is 3-24h, the acidic condition is one or more selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid and formic acid, and the solvent is one or more selected from toluene, methanol, ethanol and dioxane.
6. The method of claim 1, wherein in step (4), the reaction temperature is 90-120 ℃ for 2-10 hours; the alkali is metal-containing alkali, and is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium carbonate, potassium carbonate and cesium carbonate; one or more phosphine ligands are selected XanPhos, davePhos, johnPhos; the palladium catalyst is one or more of Pd (OAc) 2、Pd2(dba)3、Pd(PPh3)4; the solvent is selected from one or more of toluene, xylene, THF, DME, dioxane and DMF, NMP, DMSO; the molar ratio of halogenated aryl to amine, palladium catalyst, phosphine ligand and base is 1: (1.2-1.8): (0.05-0.08): (0.06-0.1): (1.5-2.5). Purification can be by column, beating or recrystallization.
7. The method for preparing GLP-1 receptor agonist Orforglipron (LY 3502970) according to claim 1, wherein in step (5), the reaction temperature is selected from 0-100deg.C, and the solvent is selected from one or more of diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H 2 O, NMP, DMA, DMSO, benzene, toluene, chlorobenzene, anisole, xylene, DCM, and 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.
8. The method of claim 1, wherein in step (6), the solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetonitrile, N-Dimethylformamide (DMF), and Dimethylformamide (DMA). The reaction temperature is-40-50 ℃, the catalyst is selected from N, N-Dimethylformamide (DMF), phosphoric acid and other activating agents, the reaction time is 0-24h, and the purification can be selected from column, beating or recrystallization.
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