CN117945983A - Intermediate for preparing CDK4/6 active compound and preparation method thereof - Google Patents
Intermediate for preparing CDK4/6 active compound and preparation method thereof Download PDFInfo
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- CN117945983A CN117945983A CN202211276731.XA CN202211276731A CN117945983A CN 117945983 A CN117945983 A CN 117945983A CN 202211276731 A CN202211276731 A CN 202211276731A CN 117945983 A CN117945983 A CN 117945983A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 159
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 title abstract description 4
- 239000012442 inert solvent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- -1 t-butyloxycarbonyl Chemical group 0.000 claims description 11
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AGMZSYQMSHMXLT-SCSAIBSYSA-N (3r)-3-aminobutan-1-ol Chemical compound C[C@@H](N)CCO AGMZSYQMSHMXLT-SCSAIBSYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- AAUSLOKBERXEER-UHFFFAOYSA-N 2,3,4,5,6-pentachlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl AAUSLOKBERXEER-UHFFFAOYSA-N 0.000 description 1
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- GTLWADFFABIGAE-SSDOTTSWSA-N [(1r)-1-chloroethyl]benzene Chemical compound C[C@@H](Cl)C1=CC=CC=C1 GTLWADFFABIGAE-SSDOTTSWSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- MYHOHFDYWMPGJY-UHFFFAOYSA-N pentafluorobenzoyl chloride Chemical compound FC1=C(F)C(F)=C(C(Cl)=O)C(F)=C1F MYHOHFDYWMPGJY-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses intermediates for preparing CDK4/6 active compounds and a preparation method thereof, in particular, the invention discloses intermediates such as a compound of a formula (I), a compound of a formula (I-4), a compound of a formula (I-5) and the like, and a preparation method for preparing the intermediate compounds.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an intermediate for preparing (R) -6-fluoro-1-substituted-8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 4-tetrahydrobenzo [4,5] imidazo [1,2-a ] pyridine and a preparation method thereof.
Background
The intermediate compound of formula (II), for example when R b is methyl, is a key pharmaceutical intermediate compound for the preparation of CDK4/6 active compounds, and the current beda patent application WO2019242719 discloses a process for the preparation of the relevant intermediate compound 1-01 starting from (R) -3-aminobutanol, which is carried out in 9 steps to obtain intermediate compound 1-01. The method has the advantages of more synthetic steps, low total yield, expensive reagents, difficult purification and inapplicability to industrial production.
Therefore, it is important to find a method for preparing an intermediate compound shown in the formula (II) which is more suitable for industrial production.
Disclosure of Invention
The invention aims to provide a brand-new preparation method of an intermediate compound shown in a formula (II) suitable for industrial application, and an intermediate compound with a novel structure for preparing the compound.
Specifically, in one aspect, the invention provides a method for preparing a compound of formula (I) or a salt thereof, comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
(3) Reacting a compound of formula (I-4) with a reducing agent in an inert solvent to form a compound of formula (I-5);
(4) Subjecting a compound of formula (I-5) to a cyclization reaction in an inert solvent, thereby forming a compound of formula (I);
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
In another aspect, the present invention provides a compound represented by formula (X), formula (X-4) or formula (X-5), or a salt thereof:
In the formulae, R a' is hydrogen or R a; wherein R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
In another aspect, the present invention provides a compound of formula (I), formula (I-4) or formula (I-5), or a salt thereof:
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
In another aspect, the present invention provides a process for the preparation of a compound of formula (I-4), comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
In another aspect, the present invention provides a process for the preparation of a compound of formula (I-5), comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
(3) Reacting a compound of formula (I-4) with a reducing agent in an inert solvent to form a compound of formula (I-5);
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
In some embodiments, in step (1), the amino protecting agent is selected from the group consisting of: benzyloxycarbonyl chloride (CbzCl), di-tert-butyl dicarbonate (Boc 2 O), benzyl chloride (BnCl), benzyl bromide (BnBr), pentafluorobenzoyl chloride, pentachlorobenzoyl chloride, allyl chloride, R- (1-chloroethyl) benzene, L- (1-chloroethyl) benzene, benzoyl chloride (Bz-Cl) or allyl chloroformate (Alloc-Cl).
In some embodiments, in step (2), the condensing agent is selected from the group consisting of: EDCI, DCC, CDI, BOP-Cl, HATU, HBTU, or a combination thereof. Preferably, the condensing agent is EDCI.
In some embodiments, in step (3), the reducing agent is selected from the group consisting of: sodium borohydride, sodium hydrogen, red aluminum, lithium aluminum hydride, and combinations thereof. Preferably, the reducing agent is sodium borohydride.
In some embodiments, the inert solvent is selected from the group consisting of: dioxane, water, dichloromethane, tetrahydrofuran, toluene, xylene, NMP, DMF, and combinations thereof.
In some embodiments, in step (1), the inert solvent is a combination of dioxane and water.
In some embodiments, in step (2), the inert solvent is dichloromethane or tetrahydrofuran.
In some embodiments, in step (3), the inert solvent is dichloromethane or tetrahydrofuran.
In some embodiments, in step (4), the inert solvent is toluene or xylene.
In some embodiments, in step (1), the reaction is performed in the presence of a base. Preferably, the base is selected from the group consisting of: triethylamine, diethylamine, dimethylaminopyridine and combinations thereof.
In some embodiments, in step (2), the reaction is performed in the presence of a base. Preferably, the base is selected from the group consisting of: triethylamine, diethylamine, dimethylaminopyridine (DMAP), DIPEA, pyridine, and combinations thereof. Preferably, the base is DMAP.
In some embodiments, in step (2), the compound of formula (I-2) and the compound of formula (I-3) are used in a 1:1 ratio.
In some embodiments, in step (2), the ratio of the amount of compound of formula (I-2) to condensing agent is 1 (1-2). Preferably 1:1.2.
In some embodiments, in step (2), the ratio of the amount of compound of formula (I-2) to the amount of base used is 1 (1-2). Preferably 1 (1.5-2).
In some embodiments, the step (2) is: reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, washing the obtained reaction solution with saturated brine after the reaction is finished, drying, filtering, and collecting filtrate to obtain a liquid containing the compound of formula (I-4); and
The step (3) is as follows: reacting the liquid containing the compound of formula (I-4) obtained in step (2) with a reducing agent in an inert solvent, thereby forming the compound of formula (I-5).
In some embodiments, in step (3), the reduction reaction is performed in the presence of an acid. Preferably, the acid is selected from the group consisting of: acetic acid, magnesium chloride, aluminum trichloride, and combinations thereof. Preferably the acid is acetic acid.
In some embodiments, in step (3), the ratio of the amount of compound of formula (I-4) to the amount of reducing agent used is 1 (1-3). Preferably 1:2.
In some embodiments, in step (4), the ratio of the amount of compound of formula (I-4) to the amount of acid used is 1 (1-10). Preferably 1 (2-5).
In some embodiments, in step (1), step (2), step (3), the temperature of the reaction is between 0-35 ℃. For example between 0 and 10℃or between 0 and 15℃or between 10 and 20℃or between 10 and 15 ℃.
In some embodiments, in step (4), the temperature of the reaction is between 80-140 ℃. For example, between 90-120℃or between 90-100 ℃.
In some embodiments, the step (4) is: and (3) in an inert solvent, carrying out a cyclization reaction on the compound shown in the formula (I-5), and cooling the reaction mixture after the cyclization reaction is finished to obtain a liquid containing the compound shown in the formula (I). The liquid containing the compound of formula (I) can be used directly for synthesizing the compound of formula (II-2) without isolation and purification.
In some embodiments, in each step, the reaction is carried out for 1 to 24 hours. For example 1-2 hours or 1-16 hours, etc.
In some embodiments, the compound of formula (I-3) is a compound selected from the group consisting of:
In some embodiments, R a is benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), benzyl (Bn), a-phenethyl (racemate or D/L configuration), pentafluorobenzoyl, pentachlorobenzoyl, allyl, benzoyl (Bz), or allyloxycarbonyl (Alloc).
In some embodiments, R b is cyclopentyl, cyclohexyl, methyl, ethyl, isopropyl, phenyl, or benzyl.
In some embodiments, each R 1、R2 is independently-O-methyl, -O-ethyl, or-O-n-propyl; or R 1 is connected with R 2 to form the following structure:
in some embodiments, the compound of formula (I) is
In some embodiments, the compound of formula (I-4) is
In some embodiments, the compound of formula (I-5) is
In another aspect, the present invention provides a compound of formula (II-2), a compound of formula (II-3) or a process for the preparation of a compound of formula (II),
The preparation method of the compound of the formula (II-2) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
the preparation method of the compound of the formula (II-3) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
The preparation method of the compound of the formula (II) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
(c) Reacting a compound of formula (II-3) with a compound of formula (II-4) in an inert solvent to form a compound of formula (II);
In the formula, X is a leaving group (for example, a leaving group such as halogen, carboxyl, -O-Tf, -O-ms, -O-Ts, etc.); r a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl.
In some embodiments, R a is benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), benzyl (Bn), a-phenethyl (racemate or D/L configuration), benzoyl (Bz), pentafluorobenzoyl, pentachlorobenzoyl, allyl or allyloxycarbonyl (Alloc).
In some embodiments, R b is cyclopentyl, cyclohexyl, methyl, ethyl, isopropyl, phenyl, or benzyl.
The prior art has the following defects: the whole route is obtained by reducing natural amino acid, and the 1-01 intermediate is obtained through 9 steps of reactions. The oxidizing conditions in the second step are highly polluting and dangerous. The reagent in the third step is relatively expensive, the reaction yield is low, and the impurities are more, so that column chromatography purification is needed. The fourth, fifth step is a conversion step of the ester protecting group, which is not helpful for the overall advancement of the compound and can be considered as an ineffective step. In general, the route has high raw material cost, longer steps, low atom utilization rate, environmental friendliness, difficult intermediate purification and difficult industrial scale-up.
The application adopts natural amino acid which is cheap and easy to obtain, no step which is ineffective in structure promotion is arranged in the route, and the reaction liquid can be used for continuously feeding in the middle between the step (2) and the step (3) (particularly for example between the embodiment 2 and the embodiment 3) and between the step (4) and the step (a) (particularly for example between the embodiment 4 and the embodiment 5), so that the post-treatment operation between the steps is simplified. The finishing and lifting route is very common reaction, the operation is simple, the purification is easy, the average yield of each reaction is more than 85%, and the cost is about one eighth of the original route. Therefore, the method has the advantages and effects of low cost, environmental friendliness, easy purification, low risk, high atom utilization rate, no need of special equipment, short production period, convenient operation, factory amplification and the like.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
As used herein, the mixing of two materials may be by adding (including dropping) one material to the other, or by adding in reverse order or simultaneously, unless otherwise indicated. The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, the starting materials are commercially available. Room temperature means a temperature between 5-30 c (preferably 20-25 c).
Example 1: preparation of Compound B2
Compound B1 (200 g,1940 mmol) was added to dioxane (1L) and water (1L), and triethylamine (254 g,1.5 eq) was added. Boc 2 O (508 g,1.2 eq) was added dropwise, the reaction was allowed to proceed at room temperature for 16h, TLC (acetic acid/n-butanol/water=4/4/1) was monitored, ninhydrin developed, and the reaction was completed. Dioxa-hexacyclic ring was removed by concentration, water 1L was added, pH 3-4 was adjusted with acetic acid, water (600 mL) was added, extracted with ethyl acetate (1 L.times.2), after TLC showed no product in aqueous phase, ethyl acetate phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to give compound B2 as a colorless oil 394g (purity >99%, yield=100%).
Example 2: preparation of Compound B4
Compound B2 (386 g,246mmol,1.0 eq) and compound B3 (250 g,246mmol,1.0 eq) were added to dichloromethane (2L) and dissolved completely, cooled to 0-10℃and dimethylaminopyridine DMAP (318 g,1.5 eq) was added, the temperature was controlled below 10℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI (400 g,1.2 eq) was added and the mixture was naturally heated to 10-20℃to react for 16h. TLC (dichloromethane/methanol=20/1) monitored the reaction and ninhydrin developed. The organic phase was washed with saturated brine (1L). Dried over anhydrous sodium sulfate, filtered, and the filtrate was directly used for the next reaction. Taking a small amount of filtrate, spin-drying to obtain yellowish oily substance, solidifying to obtain yellowish solid, and delivering to nuclear magnetism ,1H-NMR(400MHz,CDCl3)δ1.24-1.25(d,3H),1.4(s,9H),1.59(s,6H),2.7(m,2H),4.02(m,1H),4.55(s-1H),6.04(s,1H)
The example 2 was repeated and the following experiments were performed with reference to the following table:
The result shows that: DMAP is used as a base, so that the conversion rate is highest. DCC was used as a condensing agent, and its by-products were difficult to remove, resulting in a yield of more than 100%.
Example 3: preparation of Compound B5
NaBH 4 (132 g,2.0 eq) was added to 0-5℃methylene chloride (300 mL) under nitrogen. The filtrate obtained in example 2 was added dropwise, and the mixture was stored at an internal temperature of 10℃or below. Acetic acid (521 g,5.0 eq) was slowly added dropwise, the internal temperature being controlled at 10-15 ℃. After the addition, the reaction was monitored by TLC (dichloromethane/methanol=20/1) and ninhydrin developed. And (5) finishing the reaction. The reaction mixture was cooled to 0-10℃and quenched by slow dropwise addition of water (1.5L). The pH was adjusted to about 7 with saturated sodium carbonate, the layers were separated, and washed with saturated brine (500 mL). Dried over anhydrous sodium sulfate and concentrated to dryness to give 523.0g of a pale yellow solid product B5. Adding 1L of n-heptane, pulping for 1h at room temperature, filtering, washing the solid with a small amount of n-heptane, and oven drying to obtain 490g of compound B5 as pale yellow solid with two-step yield of 82%, purity of 97%, and ee% unchanged .1H-NMR(400MHz,CDCl3)δ1.13-1.14(d,3H),1.41(s,9H),1.74(s,6H),1.81(s,2H),2.11-2.14(m,2H),3.68(m,1H),3.82(s,1H),4.39-4.41(d,1H).
The following experiment was performed by repeating example 3 with reference to the following table:
| Sequence number | Reducing agent (eq) | Lewis acid (eq) | Solvent(s) | Conversion rate | Yield is good |
| 1 | NaBH4(2eq) | Aluminum trichloride (2 eq) | THF | 100％ | 45％ |
| 2 | Red aluminium (4 eq) | - | THF | 100％ | 75％ |
| 3 | NaBH4(2eq) | Magnesium chloride (2 eq) | THF | 83％ | 80％ |
| 4 | NaBH4(2eq) | Acetic acid (5 eq) | THF | 100％ | 85％ |
| 5 | NaBH4(2eq) | Acetic acid (5 eq) | DCM | 100％ | 85％ |
EXAMPLE 3-1 deprotection of Compound B5
1 G of compound B5 was added to 5mL of 6N dioxane hydrochloride solution, stirred for half an hour, the reaction was complete by HPLC, the solvent was spin-dried, and 10mL of methyl tert-butyl ether was added, followed by rapid stirring for 5 minutes, filtration, washing of the filter cake with 2mL of methyl tert-butyl ether, and drying of the filter cake under reduced pressure to give 0.77g of an off-white solid, which was the hydrochloride salt of compound B5-1. Yield is good 96％.1H-NMR(400MHz,DMSO)δ1.17-1.19(d,3H),1.45-1.51(m,1H),1.64(s,3H),1.66-1.78(m,1H),1.80(s,3H),1.89-1.93(m,2H),3.12-3.16(m,1H),4.58-4.61(m,1H),8.09-8.12(d,2H).
Example 4: preparation of Compound B7
200G of compound B5 was dissolved in 1L of toluene, and the mixture was reacted at an internal temperature of 90℃to 100℃for 13 hours. LCMS monitored reaction, reaction was complete and the reaction solution was cooled and used directly in the next reaction. Taking part of the reaction solution, spin-drying the solvent to obtain a pure product B7 with the purity of 98.9 percent and yellow oily matter .1H-NMR(400MHz,CDCl3)δ1.25-1.27(d,3H),1.52(s,9H),1.65-1.69(m,2H),1.90-1.93(m,2H),2.44-2.49(m,2H),4.27-4.28(m,1H).
The following experiment was performed by repeating example 4 with reference to the following table:
| Sequence number | Solvent(s) | Reaction temperature | Conversion rate | Yield is good | Reaction time |
| 1 | Toluene (toluene) | 95-100℃ | 100％ | 100％ | 18 Hours |
| 2 | Xylene (P) | 115-120℃ | 100％ | 100％ | 8 Hours |
| 3 | NMP | 125-130℃ | 100％ | 98％ | 5 Hours |
| 4 | DMF | 115-120℃ | 100％ | 95％ | 5 Hours |
Example 5: preparation of Compound B9
The reaction solution obtained in example 4 was cooled to 0-10℃in an ice-water bath, and Compound B8 (119 g,0.9 eq) was added. The internal temperature is controlled below 5 ℃, phosphorus oxychloride (136 g,1.4 eq) is added dropwise, the ice water bath is removed after the dropwise addition, the reaction is continued after natural heating, and the reaction is continued for 3 hours after heating to 90-100 ℃. The reaction was monitored by HPLC. After the reaction, cooling to 5-15 ℃, adding 50% potassium carbonate aqueous solution to quench the reaction, and adjusting the pH to 8-9. The layers were separated and the aqueous phase was extracted once with methyl tert-butyl ether (1L). The methyl tert-butyl ether phase and toluene phase were combined, 2M hydrochloric acid (1L) was added and stirred for 20 minutes, and the layers were separated. Methyl tert-butyl ether (2L) was added to the aqueous phase and the pH was adjusted to 8-9 with saturated aqueous potassium carbonate, the layers were separated, and the aqueous phase was extracted with toluene (500 mL). The organic phases were combined, washed with saturated brine (400 mL), dried and concentrated to give 130g of a pale yellow solid product B9 in 67.6% two-step yield (97% purity) with unchanged ee% .1H-NMR(400MHz,d-DMSO)δ1.06-1.07(d,3H),1.21-1.25(m,2H),1.50-1.52(m,2H),1.66-1.81(m,3H),3.41-3.42(d,1H),7.25-7.27(m-2H).
Example 6
Compound B9 (130 kg,1 eq) was dissolved in DMF (10L), cesium carbonate (208 kg,1.5 eq) was added, heated in an oil bath at 110 ℃ and the reaction was complete for 20 hours, the system was diluted with 1.5L ethyl acetate, filtered, washed with saturated brine (250 ml x 5), the organic phase dried over anhydrous sodium sulfate, concentrated and slurried 2 times with 150ml methyl tert-butyl ether, respectively, to give compound B10 (105 g, pure) as a earthy yellow solid. Yield is good 86.5％.1H-NMR(400MHz,CDCl3)δ1.49-1.50(d,3H),1.95-2.18(m,4H),2.91-3.00(m,1H),3.10-3.17(m,1H),4.51-4.55(m,1H),7.06-7.09(d,1H),7.26-7.27(s,1H).
Example 7
Compound B10 (70 g,1 eq), bis (pinacolato) diboron (74.8 g,1.3 eq), potassium acetate (72.2 g,3 eq), palladium acetate (1.1 g,0.02 eq), tricyclohexylphosphorus (1.4 g,0.02 eq) were added to 1, 4-dioxane (0.5L), nitrogen protected, oil bath at 90 ℃ for 1.5h. After the reaction, the mixture was filtered, concentrated to remove most of the dioxane, the system was extracted with 0.3L of water, ethyl acetate (0.5 l×2), the organic phase was washed with saturated brine solution (0.5 l×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting solid was slurried with n-heptane and ethyl acetate (2/1,1L) to give compound B12, 60.5g of a yellow solid. Yield is good 74％.1H-NMR(400MHz,CDCl3)δ1.36(s,12H),1.53-1.54(d,3H),1.95-2.19(m,4H),3.00-3.04(m,1H),3.15-3.22(m,1H),4.60-4.67(m,1H),7.34-7.37(d,1H),7.58(s,1H).
Examples 6 and 7 can also be carried out with reference to the process in WO 2019242719.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A process for the preparation of a compound of formula (I) or a salt thereof, comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
(3) Reacting a compound of formula (I-4) with a reducing agent in an inert solvent to form a compound of formula (I-5);
(4) Subjecting a compound of formula (I-5) to a cyclization reaction in an inert solvent, thereby forming a compound of formula (I);
in the various types of the compositions,
R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl;
R 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
2. A compound represented by the formula (X), the formula (X-4) or the formula (X-5):
in the various types of the compositions,
R a' is hydrogen or R a; wherein R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
3. A compound represented by the formula (I), the formula (I-4) or the formula (I-5):
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
4. A process for the preparation of a compound of formula (I-4) or a salt thereof comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
5. A process for the preparation of a compound of formula (I-5) or a salt thereof comprising the steps of:
(1) Reacting a compound of formula (I-1) with an amino protecting reagent in an inert solvent to form a compound of formula (I-2);
(2) Reacting a compound of formula (I-2) with a compound of formula (I-3) in an inert solvent in the presence of a condensing agent, thereby forming a compound of formula (I-4);
(3) Reacting a compound of formula (I-4) with a reducing agent in an inert solvent to form a compound of formula (I-5);
In the formula, R a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl; r 1、R2 is each independently-O-C1-4 alkyl; or R 1 is connected with R 2 to form the following structure: wherein R, R' are each independently C1-4 alkyl.
6. The production method according to any one of claims 1,4 and 5, or the compound according to claim 2 or 3, or a salt thereof, wherein R a is benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), benzyl (Bn), α -phenylethyl (racemate or D/L configuration), pentafluorobenzoyl, pentachlorobenzoyl, allyl, benzoyl (Bz) or allyloxycarbonyl (Alloc).
7. The method of any one of claims 1, 4 and 5 or the compound of claim 2 or 3 or a salt thereof, wherein R b is cyclopentyl, cyclohexyl, methyl, ethyl, isopropyl, phenyl, or benzyl.
8. The method of any one of claims 1, 4 and 5 or the compound of claim 2 or 3 or a salt thereof, wherein each R 1、R2 is independently-O-methyl, -O-ethyl or-O-n-propyl; or R 1 is connected with R 2 to form the following structure:
9. the method according to any one of claim 1, 4 and 5,
In step (2), the reaction is carried out in the presence of a base; preferably, the base is selected from the group consisting of: triethylamine, diethylamine, dimethylaminopyridine (DMAP), DIPEA, pyridine, and combinations thereof; preferably, the base is DMAP; and/or
In step (3), the reduction reaction is performed in the presence of an acid; preferably, the acid is selected from the group consisting of: acetic acid, magnesium chloride, aluminum trichloride, and combinations thereof; preferably the acid is acetic acid.
10. A process for the preparation of a compound of formula (II-2), a compound of formula (II-3) or a compound of formula (II), characterized in that,
The preparation method of the compound of the formula (II-2) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
the preparation method of the compound of the formula (II-3) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
The preparation method of the compound of the formula (II) comprises the following steps:
(a) Reacting a compound of formula (I) with a compound of formula (II-1) in an inert solvent to form a compound of formula (II-2);
(b) Subjecting a compound of formula (II-2) to a ring-forming reaction in an inert solvent, thereby forming a compound of formula (II-3);
(c) Reacting a compound of formula (II-3) with a compound of formula (II-4) in an inert solvent to form a compound of formula (II);
In the formula, X is a leaving group; r a is an amino protecting group; r b is C3-6 cycloalkyl, C1-4 alkyl, phenyl or benzyl.
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