IT201800007398A1 - PROCESS FOR THE SYNTHESIS OF DIMESILATED NETARSUDIL - Google Patents
PROCESS FOR THE SYNTHESIS OF DIMESILATED NETARSUDIL Download PDFInfo
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- IT201800007398A1 IT201800007398A1 IT102018000007398A IT201800007398A IT201800007398A1 IT 201800007398 A1 IT201800007398 A1 IT 201800007398A1 IT 102018000007398 A IT102018000007398 A IT 102018000007398A IT 201800007398 A IT201800007398 A IT 201800007398A IT 201800007398 A1 IT201800007398 A1 IT 201800007398A1
- Authority
- IT
- Italy
- Prior art keywords
- methyl
- phenyl
- oxy
- tetrahydro
- propanoate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 22
- OURRXQUGYQRVML-AREMUKBSSA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-AREMUKBSSA-N 0.000 title claims description 13
- 229950009210 netarsudil Drugs 0.000 title claims description 13
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- -1 (methylsulfonyl) oxy Chemical group 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 26
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 8
- DKLHRWHPVVDOCW-UHFFFAOYSA-N tert-butyl n-[2-[4-(hydroxymethyl)phenyl]-3-(isoquinolin-6-ylamino)-3-oxopropyl]carbamate Chemical compound C=1C=C2C=NC=CC2=CC=1NC(=O)C(CNC(=O)OC(C)(C)C)C1=CC=C(CO)C=C1 DKLHRWHPVVDOCW-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- BKYWPNROPGQIFZ-UHFFFAOYSA-N 2,4-dimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C)=C1 BKYWPNROPGQIFZ-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 5
- SGFXAHNZJCLVFE-GDLZYMKVSA-N [4-[(2s)-1-(isoquinolin-6-ylamino)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CNC(=O)OC(C)(C)C)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 SGFXAHNZJCLVFE-GDLZYMKVSA-N 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- NGFCTYXFMDWFRQ-UHFFFAOYSA-N isoquinolin-6-amine Chemical compound C1=NC=CC2=CC(N)=CC=C21 NGFCTYXFMDWFRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- LLDQUDYCTIKKFV-UHFFFAOYSA-N methyl 2-[4-(hydroxymethyl)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(CO)C=C1 LLDQUDYCTIKKFV-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- SGFXAHNZJCLVFE-UHFFFAOYSA-N [4-[1-(isoquinolin-6-ylamino)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C(C(CNC(=O)OC(C)(C)C)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 SGFXAHNZJCLVFE-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- DEGPIRUPAKWDBU-UHFFFAOYSA-N isoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)NC(=O)C2=C1 DEGPIRUPAKWDBU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000001143 conditioned effect Effects 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 238000010626 work up procedure Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- QQDRLKRHJOAQDC-FBHGDYMESA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 QQDRLKRHJOAQDC-FBHGDYMESA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 210000003128 head Anatomy 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- ZADSZNPGFHTHPB-UHFFFAOYSA-N benzyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=CC=C1 ZADSZNPGFHTHPB-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000007040 multi-step synthesis reaction Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FWZBPBKAANKOJQ-UHFFFAOYSA-N 2-[4-(hydroxymethyl)phenyl]acetic acid Chemical compound OCC1=CC=C(CC(O)=O)C=C1 FWZBPBKAANKOJQ-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PROCESSO PER LA SINTESI DI NETARSUDIL DIMESILATO” "PROCESS FOR THE SYNTHESIS OF DIMESILATED NETARSUDIL"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione ha per oggetto un processo per la preparazione di Netarsudil e del suo sale dimesilato. L’invenzione riguarda inoltre nuovi intermedi utili per la preparazione di Netarsudil. The present invention relates to a process for the preparation of Netarsudil and its dimesylated salt. The invention also concerns new intermediates useful for the preparation of Netarsudil.
SFONDO DELL’INVENZIONE BACKGROUND OF THE INVENTION
Netarsudil, conosciuto anche con l’acronimo AR-13324, è un farmaco recentemente approvato in USA e in sperimentazione clinica in altri paesi per il trattamento del glaucoma ad angolo aperto e dell’ipertensione oculare. Netarsudil, also known by the acronym AR-13324, is a drug recently approved in the US and in clinical trials in other countries for the treatment of open-angle glaucoma and ocular hypertension.
Netarsudil è un inibitore della rho-chinasi, in grado di ridurre la pressione intraoculare aumentando il deflusso dell'umore acqueo attraverso la via del trabecolato. Netarsudil is a rho-kinase inhibitor, capable of reducing intraocular pressure by increasing the outflow of aqueous humor through the trabecular pathway.
Il Netarsudil dimesilato ha la seguente formula (I): Netarsudil dimesylate has the following formula (I):
Attualmente la letteratura relativa al Netarsudil è piuttosto limitata; il principio attivo viene ottenuto attraverso sintesi piuttosto lunghe che talvolta prevedono step critici a basse temperature. Currently the literature relating to Netarsudil is rather limited; the active principle is obtained through rather long syntheses which sometimes involve critical steps at low temperatures.
US 8394826 descrive la preparazione di Netarsudil dimesilato attraverso una sintesi multistep (Schema 1) passando attraverso reazioni di protezione e deprotezione che prevedono l’impiego di gruppi protettivi alquanto costosi così come i reattivi necessari per la loro rimozione. Inoltre l’approccio sintetico descritto in US 8394826 prevede l’impiego di bassissime temperature per l’inserimento del centro stereogenico chirale. US 8394826 describes the preparation of Netarsudil dimesylate through a multistep synthesis (Scheme 1) by passing through protection and deprotection reactions which involve the use of rather expensive protective groups as well as the reagents necessary for their removal. Furthermore, the synthetic approach described in US 8394826 provides for the use of very low temperatures for the insertion of the chiral stereogenic center.
Schema 1 Scheme 1
US 9643927 riporta un processo enantioselettivo di ottenimento di Netarsudil dimesilato (Schema 2) e dei suoi intermedi; il principio attivo viene sintetizzato attraverso diversi passaggi, alcuni dei quali consistono in protezioni e deprotezioni delle funzioni sensibili della molecola al fine di costruirne l’intero scheletro. Pur essendo molto più efficiente rispetto al processo descritto in US 8394826, anche in questo caso l’inserimento del centro stereogenico avviene attraverso una reazione a bassissima temperatura, -78°C, non facilmente riproducibile a livello industriale. Inoltre, la ripartizione non ottimale delle materie prime più dispendiose, due delle quali sono US 9643927 reports an enantioselective process for obtaining Netarsudil dimesilate (Scheme 2) and its intermediates; the active ingredient is synthesized through several steps, some of which consist of protections and deprotections of the sensitive functions of the molecule in order to build the entire skeleton. Although it is much more efficient than the process described in US 8394826, also in this case the insertion of the stereogenic center takes place through a reaction at a very low temperature, -78 ° C, not easily reproducible at an industrial level. Furthermore, the sub-optimal distribution of the most expensive raw materials, two of which are
utilizzate fin dai primi passaggi sintetici, rende questo processo poco efficiente dal punto di vista economico. used since the first synthetic steps, makes this process inefficient from an economic point of view.
Similmente il brevetto CN107434780 descrive una sintesi multistep enantioselettiva del Netarsudil che prevede l’impiego di ligandi chirali, come già anticipato in US 9643927 per l’introduzione del centro stereogenico chirale. Analogamente, l’inserimento di suddetto centro stereogenico chirale avviene a temperature critiche, -78°C, difficilmente gestibili su ampia scala. Similarly, patent CN107434780 describes an enantioselective multistep synthesis of Netarsudil which involves the use of chiral ligands, as already anticipated in US 9643927 for the introduction of the chiral stereogenic center. Similarly, the insertion of the aforementioned chiral stereogenic center occurs at critical temperatures, -78 ° C, which are difficult to manage on a large scale.
Schema 2 Scheme 2
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
L’invenzione riguarda un procedimento per la sintesi di Netarsudil dimesilato (I) a partire dall’estere metilico dell’acido 2-(4-(idrossimetil)fenil)acetico 1 (Schema 3). The invention relates to a process for the synthesis of Netarsudil dimesylate (I) starting from the methyl ester of 2- (4- (hydroxymethyl) phenyl) acetic acid 1 (Scheme 3).
Schema 3 Scheme 3
Il processo dell’invenzione comprende: The process of the invention includes:
a) Reazione di metil 2-(4-(idrossimetil)fenil)acetato 1 con 3,4-diidro-2H-pirano in presenza di acidi a dare metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)acetato 2; a) Reaction of methyl 2- (4- (hydroxymethyl) phenyl) acetate 1 with 3,4-dihydro-2H-pyrane in the presence of acids to give methyl 2- (4 - (((tetrahydro-2H-pyran-2- II) oxy) methyl) -phenyl) acetate 2;
b) Reazione di metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)acetato 2 con formaldeide in un solvente dipolare aprotico in presenza di carbonati o bicarbonati alcalini a dare metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3; b) Reaction of methyl 2- (4 - (((tetrahydro-2H-piran-2-y) oxy) methyl) -phenyl) acetate 2 with formaldehyde in an aprotic dipolar solvent in the presence of alkaline carbonates or bicarbonates to give methyl 3 -hydroxy-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) propanoate 3;
c) Reazione di metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3 con cloruro di mesile in un solvente dipolare aprotico in presenza di basi a dare metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)propanoato 4; c) Reaction of methyl 3-hydroxy-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 3 with mesyl chloride in an aprotic dipolar solvent in the presence of bases to give methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) -phenyl) propanoate 4;
d) Reazione di metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 4 con potassio o sodio ftalimmide in un solvente dipolare aprotico a dare metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)-metil)fenil)propanoato 5; d) Reaction of methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 4 with potassium or sodium phthalimide in an aprotic dipolar solvent to give methyl 3- (1,3-dioxoisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) -methyl) phenyl) propanoate 5;
e) Reazione di metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 5 con idrazina in solvente alcolico a dare metil 3-ammino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 6; e) Reaction of methyl 3- (1,3-dioxioisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-pyran-2-y) oxy) methyl) phenyl) propanoate 5 with hydrazine in alcoholic solvent to give methyl 3-amino-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) propanoate 6;
f) Reazione di metil 3-ammino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)propanoato 6 con di di-tert-butil dicarbonato in un solvente dipolare aprotico in presenza di una base a dare metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7; f) Reaction of methyl 3-amino-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -phenyl) propanoate 6 with di-tert-butyl dicarbonate in an aprotic dipolar solvent in presence of a base to give methyl 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 7;
g) Idrolisi di metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7 in presenza di un idrossido alcalino in una soluzione acquosa o in una miscela di acqua e solvente organico a dare, dopo acidificazione, l’acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propanoico 8; g) Hydrolysis of methyl 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 7 in the presence of an alkaline hydroxide in a aqueous solution or in a mixture of water and organic solvent to give, after acidification, the acid 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy ) methyl) phenyl) -propanoic 8;
h) Reazione dell’acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoico 8 con 6-amino-isochinolina in un solvente dipolare aprotico in presenza di un agente condensante e di una base a dare tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propil)carbammato 9; h) Reaction of 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoic acid 8 with 6-amino-isoquinoline in an aprotic dipolar solvent in the presence of a condensing agent and a base to give tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - (((tetrahydro-2H-piran-2- i) oxy) methyl) phenyl) propyl) carbamate 9;
i) Trattamento di una soluzione di tert-butil (3-(isochinolin-6-il-ammino)-3osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propil)carbammato 9 in un solvente dipolare aprotico con una soluzione di un acido in un alcol a dare tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)-carbammato 10; j) Reazione di tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)carbammato 10 con acido 2,4-dimetilbenzoico in un solvente dipolare aprotico in presenza di un agente condensante e di una base a dare 4-(3-((tert-butossicarbonil)-ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 11; i) Treatment of a solution of tert-butyl (3- (isoquinolin-6-yl-amino) -3oxo-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propyl ) carbamate 9 in an aprotic dipolar solvent with a solution of an acid in an alcohol to give tert-butyl (2- (4- (hydroxymethyl) phenyl) -3- (isoquinolin-6-ylamino) -3-oxopropyl) -carbamate 10; j) Reaction of tert-butyl (2- (4- (hydroxymethyl) phenyl) -3- (isoquinolin-6-ylamino) -3-oxopropyl) carbamate 10 with 2,4-dimethylbenzoic acid in an aprotic dipolar solvent in the presence of a condensing agent and a base to give 4- (3 - ((tert-butoxycarbonyl) -amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 11;
k) Risoluzione della miscela racemica di 11 a dare (S)-4-(3-((tertbutossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 12; k) Resolution of the racemic mixture of 11 to give (S) -4- (3 - ((tertbutoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 12;
l) Rimozione del gruppo protettivo tert-butossicarbonile di 12 e salificazione con acido metansolfonico a dare Netarsudil dimesilato (I). l) Removal of the tert-butoxycarbonyl protective group of 12 and salification with methanesulfonic acid to give Netarsudil dimesilate (I).
Preferibilmente la base è una base organica scelta tra piridina, 4-dimetilamminopiridina, trietilammina, e diisopropiletilammina, più preferibilmente la base è 4-dimetilamminopiridina. Preferably the base is an organic base selected from pyridine, 4-dimethylaminopyridine, triethylamine, and diisopropylethylamine, more preferably the base is 4-dimethylaminopyridine.
Preferibilmente l’agente condensante è scelto tra N,N'-dicicloesil carbodiimmide, N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato, N-[(dimetilammino)-1H-1,2,3-triazolo-[4,5-b]piridin-1-ilmetilene]-N-metilmetanamminio esafluorofosfato N-ossido, 1,1'-carbonildiimidazolo e N,N′-disuccinimmidil carbonato, più preferibilmente l’agente condensante è N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato. Preferably the condensing agent is selected from N, N'-dicyclohexyl carbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, N - [(dimethylamino) -1H-1,2,3-triazole- [4, 5-b] pyridine-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide, 1,1'-carbonyldiimidazole and N, N′-disuccinimidyl carbonate, more preferably the condensing agent is N- (3-dimethylaminopropyl) -N ′ -Ethylcarbodiimide hydrochloride.
Il processo dell’invenzione è caratterizzato da un nuovo approccio sintetico per l’introduzione del centro stereogenico a livello dell’intermedio 3 (Schema 3), in contrasto con le metodologie esistenti in letteratura, poiché permette di generare tale centro stereogenico senza necessità di operare a basse temperature (ad es.: -78°C), contribuendo di conseguenza a migliorare sensibilmente la scalabilità industriale del processo. The process of the invention is characterized by a new synthetic approach for the introduction of the stereogenic center at the level of the intermediate 3 (Scheme 3), in contrast to the existing methodologies in the literature, since it allows to generate such a stereogenic center without the need to operate at low temperatures (e.g. -78 ° C), thus contributing to significantly improve the industrial scalability of the process.
Il processo dell’invenzione, a differenza di quelli noti, presenta diversi vantaggi. Innanzitutto non prevede l’utilizzo di gruppi protettivi contenenti silicio (ad es.: triisopropilsilil etere, TIPS) o di esteri (ad es.: legame estereo con acido 2,4-dimetilbenzoico) per la protezione del gruppo funzionale alcolico presente a livello dell’intermedio 1. E’ risaputo infatti che i gruppi protettivi contenenti silicio, oltre ad essere molto costosi, necessitano di sali ammonici quaternari per la loro rimozione, compromettendo così l’economia atomica del processo; inoltre, la diretta introduzione nelle fasi iniziali del processo di un legame estereo tra il gruppo alcolico presente nell’intermedio 1 e l’acido 2,4-dimetilbenzoico risulta essere svantaggiosa dal punto di vista della efficienza economica del processo stesso. Tale acido infatti è presente tal quale nella struttura di Netarsudil dimesilato ed è caratterizzato da un costo piuttosto rilevante; di conseguenza il suo utilizzo nelle fasi preliminari del processo risulta essere controproducente. The process of the invention, unlike the known ones, has several advantages. First of all, it does not provide for the use of protective groups containing silicon (eg: triisopropylsilyl ether, TIPS) or esters (eg: ester bond with 2,4-dimethylbenzoic acid) for the protection of the alcoholic functional group present at the level of the intermediate 1. It is well known that silicon-containing protective groups, in addition to being very expensive, require quaternary ammonium salts for their removal, thus compromising the atomic economy of the process; moreover, the direct introduction in the initial stages of the process of an ester bond between the alcoholic group present in intermediate 1 and 2,4-dimethylbenzoic acid turns out to be disadvantageous from the point of view of the economic efficiency of the process itself. In fact, this acid is present as it is in the structure of Netarsudil dimesilate and is characterized by a rather significant cost; consequently its use in the preliminary stages of the process is counterproductive.
L’introduzione di un gruppo protettivo di natura eterea (tetraidropirano, THP) per la protezione del gruppo funzionale alcolico presente a livello dell’intermedio 1 si è rivelata di sorprendente utilità. The introduction of an ethereal protective group (tetrahydropyran, THP) for the protection of the alcoholic functional group present at the level of intermediate 1 has proved surprisingly useful.
In primo luogo, il reattivo necessario per ottenere questo tipo di legame etereo (diidropirano) è economico e largamente reperibile. Inoltre, è stato scoperto che il trattamento dell’intermedio 9 con un acido inorganico (ad es.: una soluzione alcolica di acido cloridrico) consente di rimuovere il gruppo protettivo tetraidropiranile senza danneggiare il gruppo protettivo carbammico, anch’esso suscettibile di idrolisi acida. Probabilmente, a livello dell’intermedio 9, la presenza di un legame idrogeno intramolecolare tra il gruppo carbammico ed il gruppo ammidico previene l’idrolisi acida della funzione carbammica stessa. L’insieme di questi aspetti contribuisce ad aumentare sensibilmente sia l’efficienza economica sia l’economia atomica della presente invenzione. First, the reagent needed to obtain this type of ether bond (dihydropyran) is cheap and widely available. In addition, it was found that the treatment of intermediate 9 with an inorganic acid (eg: an alcoholic solution of hydrochloric acid) allows the removal of the tetrahydropyranyl protective group without damaging the carbamic protective group, which is also susceptible to acid hydrolysis. Probably, at the level of intermediate 9, the presence of an intramolecular hydrogen bond between the carbamate group and the amide group prevents the acid hydrolysis of the carbamate function itself. All of these aspects contribute to significantly increase both the economic efficiency and the atomic economy of the present invention.
Gli intermedi 2-9 sono nuovi e pertanto rappresentano un ulteriore oggetto dell’invenzione. The intermediates 2-9 are new and therefore represent a further object of the invention.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
L’ordine di aggiunta di solventi, materie prime, acidi o basi può differire da quello riportato di seguito. The order of adding solvents, raw materials, acids or bases may differ from that shown below.
In una realizzazione dell’invenzione il processo è condotto come segue: In an embodiment of the invention, the process is conducted as follows:
Passaggio a): 1 mole di metil 2-(4-(idrossimetil)fenil)acetato 1 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano. Alla soluzione così ottenuta, si aggiungono 3,4-diidro-2H-pirano 0.8-3 moli, preferibilmente 1-1.8 moli, e acido p-toluensolfonico monoidrato 0.005-0.08 moli, preferibilmente 0.008-0.04 moli ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 20 e 40°C e successivamente, la miscela così ottenuta è condizionata fino a completezza. In seguito a work-up acquoso alcalino si ottiene il metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)acetato 2. Step a): 1 mole of methyl 2- (4- (hydroxymethyl) phenyl) acetate 1 is dissolved in 2-50 volumes, preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dichloromethane. To the solution thus obtained, 3,4-dihydro-2H-pyran 0.8-3 moles, preferably 1-1.8 moles, and p-toluenesulfonic acid monohydrate 0.005-0.08 moles, preferably 0.008-0.04 moles are added at a temperature between 5 and 60 ° C, preferably between 20 and 40 ° C and subsequently, the mixture thus obtained is conditioned until completeness. Following an aqueous alkaline work-up, methyl 2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) acetate 2 is obtained.
Passaggio b): 1 mole di metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)acetato 2 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente dimetilsolfossido (DMSO). Alla soluzione così ottenuta, si aggiungono paraformaldeide 0.8-3 moli, preferibilmente 1-1.8 moli, e sodio bicarbonato 0.005-0.08 moli, preferibilmente 0.008-0.05 moli ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 30°C e successivamente, la miscela così ottenuta è scaldata ad una temperatura compresa tra 40 e 100°C, preferibilmente tra 45 e 85°C. In seguito a work-up acquoso si ottiene il metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3. Step b): 1 mole of methyl 2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -phenyl) acetate 2 is dissolved in 2-50 volumes, preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dimethyl sulfoxide (DMSO). To the solution thus obtained, paraformaldehyde 0.8-3 moles, preferably 1-1.8 moles, and sodium bicarbonate 0.005-0.08 moles, preferably 0.008-0.05 moles, at a temperature between 5 and 60 ° C, preferably between 15 and 30 ° C are added. and subsequently, the mixture thus obtained is heated to a temperature comprised between 40 and 100 ° C, preferably between 45 and 85 ° C. Following an aqueous work-up, methyl 3-hydroxy-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 3 is obtained.
Passaggio c): 1 mole di metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano . Alla soluzione così ottenuta, si aggiungono trietilammina 0.8-3 moli, preferibilmente 1-1.8 moli, e mesil cloruro 0.8-3 moli, preferibilmente 1-1.8 moli ad una temperatura compresa tra -10 e 30°C, preferibilmente tra -5 e 10°C e successivamente, la miscela così ottenuta è condizionata fino a completezza. In seguito a work-up acquoso acido si ottiene il metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 4. Step c): 1 mole of methyl 3-hydroxy-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 3 is dissolved in 2-50 volumes, preferably 5-20 volumes of a suitable aprotic dipolar solvent, preferably dichloromethane. To the solution thus obtained, 0.8-3 moles triethylamine, preferably 1-1.8 moles, and 0.8-3 moles mesyl chloride, preferably 1-1.8 moles at a temperature between -10 and 30 ° C, preferably between -5 and 10. ° C and subsequently, the mixture thus obtained is conditioned until completeness. Following an acid aqueous work-up, methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate is obtained 4.
Passaggio d): 1 mole di metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 4 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente dimetilformammide (DMF). Step d): 1 mole of methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 4 is dissolved in 2-50 volumes , preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dimethylformamide (DMF).
Alla soluzione così ottenuta, si aggiunge potassio ftalimmide 0.7-3 moli, preferibilmente 0.8-1.8 moli, e la miscela così ottenuta è condizionata fino a completezza. In seguito a work-up acquoso si ottiene il metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 5. To the solution thus obtained, potassium phthalimide 0.7-3 moles, preferably 0.8-1.8 moles, is added and the mixture thus obtained is conditioned until completeness. Following an aqueous work-up, methyl 3- (1,3-dioxoisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate is obtained 5.
Passaggio e): 1 mole di metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 5 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente alcolico, preferibilmente etanolo. Step e): 1 mole of methyl 3- (1,3-dioxoisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 5 is dissolved in 2-50 volumes, preferably 5-20 volumes, of a suitable alcoholic solvent, preferably ethanol.
Alla soluzione così ottenuta, si aggiunge idrazina monoidrata (65%) 0.9-3 moli, preferibilmente 1.2-2.0 moli e la miscela così ottenuta è scaldata ad una temperatura compresa tra 40 e 100°C, preferibilmente tra 45 e 85°C. Si ottiene per precipitazione il metil 3-amino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propanoato 6. To the solution thus obtained, 0.9-3 moles hydrazine monohydrate (65%), preferably 1.2-2.0 moles, is added and the mixture thus obtained is heated to a temperature of between 40 and 100 ° C, preferably between 45 and 85 ° C. Methyl 3-amino-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -propanoate 6 is obtained by precipitation.
Passaggio f): 1 mole di metil 3-amino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 6 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano, ad una temperatura compresa tra -10 e 30°C, preferibilmente tra -5 e 15°C. Step f): 1 mole of methyl 3-amino-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 6 is dissolved in 2-50 volumes, preferably 5-20 volumes of a suitable aprotic dipolar solvent, preferably dichloromethane, at a temperature between -10 and 30 ° C, preferably between -5 and 15 ° C.
Alla soluzione così ottenuta, si aggiungono di-tert-butil dicarbonato 0.8-3 moli, preferibilmente 1.0-2.0 moli e 4-dimetilamminopiridina 0.005-0.1 moli, preferibilmente 0.008-0.08 moli. La miscela così ottenuta è condizionata ad una temperatura compresa tra -10 e 30°C, preferibilmente tra -5 e 15°C, fino a completezza. In seguito a work-up acquoso alcalino si ottiene il metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7. To the solution thus obtained, 0.8-3 mol di-tert-butyl dicarbonate, preferably 1.0-2.0 mol and 4-dimethylaminopyridine 0.005-0.1 mol, preferably 0.008-0.08 mol. The mixture thus obtained is conditioned at a temperature comprised between -10 and 30 ° C, preferably between -5 and 15 ° C, until completeness. Following an aqueous alkaline work-up, methyl 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate is obtained 7.
Passaggio g): 1 mole di metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di una miscela di tetraidrofurano (THF) : acqua compresa tra 0.3 : 1 e 3 : 1, preferibilmente tra 0.7 : 1 e 1.7 : 1, ad una temperatura compresa tra -10 e 30°C, preferibilmente tra -5 e 15°C. Step g): 1 mole of methyl 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 7 is dissolved in 2- 50 volumes, preferably 5-20 volumes, of a mixture of tetrahydrofuran (THF): water between 0.3: 1 and 3: 1, preferably between 0.7: 1 and 1.7: 1, at a temperature between -10 and 30 ° C , preferably between -5 and 15 ° C.
Alla soluzione così ottenuta, si aggiunge litio idrossido 0.8-4 moli, preferibilmente 1.0-2.8 moli e si condiziona ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 35°C fino a completezza. In seguito a work-up acquoso acido si ottiene l’acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)propanoico 8. To the solution thus obtained, 0.8-4 moles lithium hydroxide is added, preferably 1.0-2.8 moles, and it is conditioned at a temperature comprised between 5 and 60 ° C, preferably between 15 and 35 ° C until completeness. Following an aqueous acid work-up, 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) -phenyl) propanoic acid is obtained 8.
Passaggio h): 1 mole di acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoico 8 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. Step h): 1 mole of 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoic acid 8 is dissolved in 2- 50 volumes, preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dichloromethane, at a temperature between 5 and 60 ° C, preferably between 15 and 45 ° C.
Alla soluzione così ottenuta, si aggiungono N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato (EDC HCl) 0.8-4 moli, preferibilmente 1.0-2.8 moli e 4-dimetilamminopiridina 0.005-0.1 moli, preferibilmente 0.008-0.08 moli, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. To the solution thus obtained, 0.8-4 moles, preferably 1.0-2.8 moles and 4-dimethylaminopyridine 0.005-0.1 moles, preferably 0.008-0.08 moles, are added to the solution thus obtained. a temperature comprised between 5 and 60 ° C, preferably between 15 and 45 ° C.
Infine si aggiunge 6-amino-isochinolina 0.5-2 moli, preferibilmente 0.6-1.2 moli e si condiziona ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 35°C fino a completezza. In seguito a work-up acquoso alcalino si ottiene il tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propil)carbammato 9. Finally, 0.5-2 moles, preferably 0.6-1.2 moles, 6-amino-isoquinoline are added and it is conditioned at a temperature between 5 and 60 ° C, preferably between 15 and 35 ° C until complete. Following an aqueous alkaline work-up tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - ((((tetrahydro-2H-pyran-2-yl) oxy) methyl is obtained ) phenyl) -propyl) carbamate 9.
Passaggio i): 1 mole di tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propil)carbammato 9 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano, ad una temperatura compresa tra -10 e 40°C, preferibilmente tra -5 e 15°C. Step i): 1 mole of tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propyl ) carbamate 9 is dissolved in 2-50 volumes, preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dichloromethane, at a temperature between -10 and 40 ° C, preferably between -5 and 15 ° C.
Alla soluzione così ottenuta, si aggiunge una quantità compresa tra 0.1 e 5 mL, preferibilmente tra 0.5 e 1.5 mL di una soluzione compresa tra 1 e 20%, preferibilmente tra 5 e 15% di acido cloridrico nell’opportuno solvente alcolico, preferibilmente etanolo. La miscela di reazione è condizionata ad una temperatura compresa tra -10 e 40°C, preferibilmente tra -5 e 15°C, fino a completezza. To the solution thus obtained, an amount between 0.1 and 5 mL, preferably between 0.5 and 1.5 mL of a solution between 1 and 20%, preferably between 5 and 15% of hydrochloric acid is added in the appropriate alcoholic solvent, preferably ethanol. The reaction mixture is conditioned at a temperature comprised between -10 and 40 ° C, preferably between -5 and 15 ° C, until completeness.
In seguito a work-up acquoso si ottiene il tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)carbammato 10. Following an aqueous work-up, tert-butyl (2- (4- (hydroxymethyl) phenyl) -3- (isoquinolin-6-ylamino) -3-oxopropyl) carbamate 10 is obtained.
Passaggio j): 1 mole di tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)carbammato 10 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. Step j): 1 mole of tert-butyl (2- (4- (hydroxymethyl) phenyl) -3- (isoquinolin-6-ylamino) -3-oxopropyl) carbamate 10 is dissolved in 2-50 volumes, preferably 5-20 volumes of a suitable aprotic dipolar solvent, preferably dichloromethane, at a temperature between 5 and 60 ° C, preferably between 15 and 45 ° C.
Alla soluzione così ottenuta, si aggiungono N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato 0.8-4 moli, preferibilmente 1.0-2.8 moli e 4-dimetilamminopiridina 0.005-0.1 moli, preferibilmente 0.008-0.08 moli, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. To the solution thus obtained, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride 0.8-4 moles, preferably 1.0-2.8 moles, and 4-dimethylaminopyridine 0.005-0.1 moles, preferably 0.008-0.08 moles, at a temperature ranging from 5 and 60 ° C, preferably between 15 and 45 ° C.
Infine si aggiunge acido 2,4-dimetilbenzoico 0.8-3 moli, preferibilmente 0.9-1.4 moli e si condiziona ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 35°C fino a completezza. In seguito a work-up acquoso si ottiene il (R,S)-4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 11. Finally, 2,4-dimethylbenzoic acid 0.8-3 moles, preferably 0.9-1.4 moles is added and it is conditioned at a temperature between 5 and 60 ° C, preferably between 15 and 35 ° C until completeness. Following an aqueous work-up, (R, S) -4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2 is obtained , 4-dimethylbenzoate 11.
Passaggio k) la risoluzione della miscela racemica del prodotto (R,S)-4-(3-((tertbutossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 11 è stata effettuata in accordo con le procedure di letteratura (US8394826), per dare (S)-4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 12. Step k) the resolution of the racemic mixture of the product (R, S) -4- (3 - ((tertbutoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4 -dimethylbenzoate 11 was carried out in accordance with the literature procedures (US8394826), to give (S) -4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan -2-yl) benzyl 2,4-dimethylbenzoate 12.
Passaggio l): 1 mole di (S)-4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 12 è sciolta in 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente dipolare aprotico, preferibilmente diclorometano, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. Step l): 1 mole of (S) -4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 12 it is dissolved in 2-50 volumes, preferably 5-20 volumes, of a suitable aprotic dipolar solvent, preferably dichloromethane, at a temperature comprised between 5 and 60 ° C, preferably between 15 and 45 ° C.
Alla soluzione così ottenuta, si aggiunge acido metansolfonico 2.0-4.0 moli, preferibilmente 2.1-3.0 moli, e si condiziona ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C, fino a completezza. To the solution thus obtained, 2.0-4.0 moles methanesulfonic acid is added, preferably 2.1-3.0 moles, and it is conditioned at a temperature between 5 and 60 ° C, preferably between 15 and 45 ° C, until completeness.
Infine si aggiungono 2-50 volumi, preferibilmente 5-20 volumi, di un opportuno solvente alcolico, preferibilmente isopropanolo, ad una temperatura compresa tra 5 e 60°C, preferibilmente tra 15 e 45°C. In seguito a filtrazione si ottiene il (S)-4-(3-ammino-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato dimetansolfonato (I). Finally, 2-50 volumes, preferably 5-20 volumes, of a suitable alcoholic solvent, preferably isopropanol, are added at a temperature between 5 and 60 ° C, preferably between 15 and 45 ° C. Following filtration, (S) -4- (3-amino-1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate dimethanesulfonate (I) is obtained.
L’invenzione è illustrata in dettaglio nei seguenti esempi. The invention is illustrated in detail in the following examples.
Esempio 1 - passaggio a) Example 1 - step a)
41.25 g di metil 2-(4-(idrossimetil)fenil)acetato 1 (0.229 moli) sono sciolti in diclorometano (440 mL). In seguito si aggiungono 22.2 g di 3,4-diidro-2H-pirano (0.264 moli) e 1 g di acido p-toluensolfonico monoidrato (0.005 moli). La miscela così ottenuta è agitata a temperatura ambiente fino a completezza (1 ora). 41.25 g of methyl 2- (4- (hydroxymethyl) phenyl) acetate 1 (0.229 mol) are dissolved in dichloromethane (440 mL). Then 22.2 g of 3,4-dihydro-2H-pyran (0.264 moles) and 1 g of p-toluenesulfonic acid monohydrate (0.005 moles) are added. The mixture thus obtained is stirred at room temperature until completeness (1 hour).
La miscela è lavata con bicarbonato acquoso al 5% (400 mL) e successivamente è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 54.5 g di metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)acetato 2 (olio giallo; resa 90%). The mixture is washed with 5% aqueous bicarbonate (400 mL) and subsequently concentrated under reduced pressure (T <30 ° C) to obtain 54.5 g of methyl 2- (4 - (((tetrahydro-2H-pyran- 2-y) oxy) methyl) phenyl) acetate 2 (yellow oil; yield 90%).
<1>H NMR (400 MHz, Cloroformio-d) δ 7.35 (d, J = 8.0 Hz, 2H), 7.33 – 7.22 (m, 2H), 4.79 (d, J = 12.0 Hz, 1H), 4.73 (t, J = 3.6 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 3.94 (ddd, J = 11.5, 8.3, 3.1 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H), 3.57 (ddd, J = 10.7, 6.0, 4.2 Hz, 1H), 1.97 – 1.47 (m, 6H). <1> H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 8.0 Hz, 2H), 7.33 - 7.22 (m, 2H), 4.79 (d, J = 12.0 Hz, 1H), 4.73 (t , J = 3.6 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 3.94 (ddd, J = 11.5, 8.3, 3.1 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H) , 3.57 (ddd, J = 10.7, 6.0, 4.2 Hz, 1H), 1.97 - 1.47 (m, 6H).
<13>C NMR (101 MHz, Cloroformio-d) δ 172.1, 137.3, 133.3, 129.4, 128.2, 97.8, 68.6, 62.2, 52.1, 41.0, 30.7, 25.6, 19.5. <13> C NMR (101 MHz, Chloroform-d) δ 172.1, 137.3, 133.3, 129.4, 128.2, 97.8, 68.6, 62.2, 52.1, 41.0, 30.7, 25.6, 19.5.
Esempio 2 - passaggio b) Example 2 - step b)
0.6 g di sodio bicarbonato (0.007 moli), 7.2 g di paraformaldeide (0.24 moli) e dimetilsolfossido (480 mL) sono caricati in un reattore sotto battente di azoto a temperatura ambiente. In seguito, si aggiungono 54.5 g di metil 2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)acetato 2 (0.208 moli) precedentemente sciolto in 120 mL di dimetilsolfossido. Successivamente, la miscela così ottenuta è scaldata a 60°C fino a completezza (3 ore). 0.6 g of sodium bicarbonate (0.007 moles), 7.2 g of paraformaldehyde (0.24 moles) and dimethyl sulfoxide (480 mL) are loaded into a reactor under nitrogen head at room temperature. Then, 54.5 g of methyl 2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) acetate 2 (0.208 moles) previously dissolved in 120 mL of dimethyl sulfoxide are added. Subsequently, the mixture thus obtained is heated to 60 ° C until complete (3 hours).
La miscela di reazione è lavata con eptano (480 mL); in seguito si aggiunge acqua (650 mL) e si estrae il prodotto con etere isopropilico (450 mL). La fase organica è lavata una volta con salamoia (300 mL) ed è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 54 g di metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3 (olio giallo; resa 88.16%). The reaction mixture is washed with heptane (480 mL); then water (650 mL) is added and the product is extracted with isopropyl ether (450 mL). The organic phase is washed once with brine (300 mL) and concentrated under reduced pressure (T <30 ° C) to obtain 54 g of methyl 3-hydroxy-2- (4 - (((tetrahydro-2H- piran-2-yl) oxy) methyl) phenyl) propanoate 3 (yellow oil; yield 88.16%).
<1>H NMR (400 MHz, Cloroformio-d) δ 7.39 – 7.33 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.78 (d, J = 12.0 Hz, 1H), 4.72 (t, J = 3.6 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.13 (dd, J = 10.6, 8.4 Hz, 1H), 3.92 (ddd, J = 11.3, 8.2, 3.0 Hz, 1H), 3.89 – 3.77 (m, 2H), 3.71 (s, 3H), 3.61 – 3.50 (m, 1H), 2.52 (s, 1H), 1.93 – 1.48 (m, 6H). <1> H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.33 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.78 (d, J = 12.0 Hz, 1H), 4.72 (t , J = 3.6 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.13 (dd, J = 10.6, 8.4 Hz, 1H), 3.92 (ddd, J = 11.3, 8.2, 3.0 Hz, 1H) , 3.89 - 3.77 (m, 2H), 3.71 (s, 3H), 3.61 - 3.50 (m, 1H), 2.52 (s, 1H), 1.93 - 1.48 (m, 6H).
<13>C NMR (101 MHz, Cloroformio-d) δ 173.6, 137.9, 134.8, 128.3, 128.2, 97.8, 68.4, 62.1, 53.7, 52.2, 30.5, 25.4, 22.8, 19.3. <13> C NMR (101 MHz, Chloroform-d) δ 173.6, 137.9, 134.8, 128.3, 128.2, 97.8, 68.4, 62.1, 53.7, 52.2, 30.5, 25.4, 22.8, 19.3.
Esempio 3 - passaggio c) Example 3 - step c)
20 g di metil 3-idrossi-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 3 (0.068 moli) sono sciolti in diclorometano (200 mL) in un reattore sotto battente di azoto a temperatura ambiente. 20 g of methyl 3-hydroxy-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) propanoate 3 (0.068 mol) are dissolved in dichloromethane (200 mL) in a reactor under nitrogen head at room temperature.
La miscela di reazione è raffreddata a 0°C ed in seguito di aggiungono 8.3 g di trietilammina (0.082 moli). Infine si aggiungono 8.6 g di mesil cloruro (0.075 moli) e la miscela così ottenuta è condizionata a 0°C fino a completezza (1 ora). The reaction mixture is cooled to 0 ° C and then 8.3 g of triethylamine (0.082 moles) are added. Finally, 8.6 g of mesyl chloride (0.075 moles) are added and the mixture thus obtained is conditioned at 0 ° C until complete (1 hour).
La miscela di reazione è diluita con diclorometano (200 mL) e lavata con ammonio cloruro acquoso 2 M (400 mL). The reaction mixture is diluted with dichloromethane (200 mL) and washed with 2 M aqueous ammonium chloride (400 mL).
La fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 22.79 g di metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propanoato 4, che è immediatamente utilizzato tal quale nello step sintetico successivo (olio giallo; resa 90%). The organic phase is concentrated at reduced pressure (T <30 ° C) so as to obtain 22.79 g of methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) -propanoate 4, which is immediately used as it is in the next synthetic step (yellow oil; yield 90%).
Esempio 4 - passaggio d) Example 4 - step d)
22.79 g di metil 3-((metilsolfonil)ossi)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)-fenil)-propanoato 4 (0.061 moli) sono sciolti in dimetilformammide (180 mL) a temperatura ambiente. In seguito si aggiungono 13.2 g di potassio ftalimmide (0.071 moli) e la miscela così ottenuta è condizionata a temperatura ambiente fino a completezza (2 ore). 22.79 g of methyl 3 - ((methylsulfonyl) oxy) -2- (4 - (((tetrahydro-2H-piran-2-y) oxy) methyl) -phenyl) -propanoate 4 (0.061 mol) are dissolved in dimethylformamide ( 180 mL) at room temperature. Then 13.2 g of potassium phthalimide (0.071 moles) are added and the mixture thus obtained is conditioned at room temperature until completeness (2 hours).
La miscela di reazione è diluita con acetato di etile (250 mL) e lavata una volta con acqua (400 mL) ed una volta con salamoia (250 mL). La fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 23.25 g di metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 5 (solido giallo; resa 90%). The reaction mixture is diluted with ethyl acetate (250 mL) and washed once with water (400 mL) and once with brine (250 mL). The organic phase is concentrated at reduced pressure (T <30 ° C) so as to obtain 23.25 g of methyl 3- (1,3-dioxoisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-piran -2-yl) oxy) methyl) phenyl) propanoate 5 (yellow solid; yield 90%).
<1>H NMR (400 MHz, Cloroformio-d) δ 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.1 Hz, 2H), 7.37 – 7.26 (m, 4H), 4.75 (dd, J = 12.2, 2.2 Hz, 1H), 4.68 (t, J = 3.6 Hz, 1H), 4.46 (dd, J = 12.2, 2.0 Hz, 1H), 4.38 – 4.14 (m, 3H), 3.89 (s, 1H), 3.68 (s, 3H), 3.55 (s, 1H), 1.94 – 1.50 (m, 6H). <1> H NMR (400 MHz, Chloroform-d) δ 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.1 Hz, 2H), 7.37 - 7.26 (m, 4H) , 4.75 (dd, J = 12.2, 2.2 Hz, 1H), 4.68 (t, J = 3.6 Hz, 1H), 4.46 (dd, J = 12.2, 2.0 Hz, 1H), 4.38 - 4.14 (m, 3H), 3.89 (s, 1H), 3.68 (s, 3H), 3.55 (s, 1H), 1.94 - 1.50 (m, 6H).
<13>C NMR (101 MHz, Cloroformio-d) δ 172.1, 167.9, 138.1, 138.1, 134.6, 133.9, 131.8, 128.3, 128.1, 123.3, 97.8, 68.4, 62.1, 52.3, 48.9, 40.3, 30.5, 25.4, 19.3. <13> C NMR (101 MHz, Chloroform-d) δ 172.1, 167.9, 138.1, 138.1, 134.6, 133.9, 131.8, 128.3, 128.1, 123.3, 97.8, 68.4, 62.1, 52.3, 48.9, 40.3, 30.5, 25.4, 19.3.
Esempio 5 - passaggio e) Example 5 - step e)
23.25 g di metil 3-(1,3-diossoisoindolin-2-il)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 5 (0.055 moli) sono sciolti in etanolo (400 mL) a temperatura ambiente. In seguito si aggiungono 7.26 g di idrazina monoidrata (65%) (0.0943 moli) e si agita a temperatura ambiente (1 ora). Successivamente la miscela di reazione è scaldata a 65°C fino a completezza (3.5 ore). 23.25 g of methyl 3- (1,3-dioxoisoindolin-2-yl) -2- (4 - (((tetrahydro-2H-piran-2-y) oxy) methyl) phenyl) propanoate 5 (0.055 mol) are dissolved in ethanol (400 mL) at room temperature. Then 7.26 g of hydrazine monohydrate (65%) (0.0943 moles) are added and the mixture is stirred at room temperature (1 hour). Subsequently the reaction mixture is heated to 65 ° C until completeness (3.5 hours).
La miscela di reazione è diluita con etanolo (300 mL) e raffreddata a temperatura ambiente. Si forma un precipitato che è rimosso per filtrazione. La fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere un residuo oleoso che è immediatamente sciolto in diclorometano (400 mL). Il precipitato che si forma viene eliminato per filtrazione e la fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 14.84 g di metil 3-amino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 6 (olio giallo; resa 92%) The reaction mixture is diluted with ethanol (300 mL) and cooled to room temperature. A precipitate is formed which is removed by filtration. The organic phase is concentrated at reduced pressure (T <30 ° C) in order to obtain an oily residue which is immediately dissolved in dichloromethane (400 mL). The precipitate that forms is removed by filtration and the organic phase is concentrated at reduced pressure (T <30 ° C) so as to obtain 14.84 g of methyl 3-amino-2- (4 - (((tetrahydro-2H-piran -2-yl) oxy) methyl) phenyl) propanoate 6 (yellow oil; yield 92%)
<1>H NMR (400 MHz, Cloroformio-d) δ 7.39 – 7.23 (m, 4H), 4.77 (d, J = 12.1 Hz, 1H), 4.71 (q, J = 3.4, 3.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.91 (ddt, J = 14.7, 9.5, 4.6 Hz, 1H), 3.68 (d, J = 2.6 Hz, 1H), 3.67 (s, 3H), 3.55 (qd, J = 7.4, 6.5, 2.5 Hz, 1H), 3.34 (br s, 2H), 3.28 (dd, J = 13.0, 8.2 Hz, 1H), 3.08 – 2.95 (m, 1H), 2.03 – 1.43 (m, 6H). <1> H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.23 (m, 4H), 4.77 (d, J = 12.1 Hz, 1H), 4.71 (q, J = 3.4, 3.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.91 (ddt, J = 14.7, 9.5, 4.6 Hz, 1H), 3.68 (d, J = 2.6 Hz, 1H), 3.67 (s, 3H), 3.55 (qd, J = 7.4, 6.5, 2.5 Hz, 1H), 3.34 (br s, 2H), 3.28 (dd, J = 13.0, 8.2 Hz, 1H), 3.08 - 2.95 (m, 1H), 2.03 - 1.43 (m, 6H ).
Esempio 6 - passaggio f) Example 6 - step f)
14.8 g di metil 3-amino-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 6 (0.05 moli) sono sciolti in diclorometano (200 mL) e la miscela è raffreddata a 0°C. 14.8 g of methyl 3-amino-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 6 (0.05 mol) are dissolved in dichloromethane (200 mL) and the mixture is cooled to 0 ° C.
Alla soluzione così ottenuta, si aggiungono 16.2 g di di-tert-butil dicarbonato (0.074 moli) e 0.38 g di 4-dimetilamminopiridina (0.0031 moli). Si agita a 0°C fino a completezza (2 ore). To the solution thus obtained, 16.2 g of di-tert-butyl dicarbonate (0.074 moles) and 0.38 g of 4-dimethylaminopyridine (0.0031 moles) are added. It is stirred at 0 ° C until completeness (2 hours).
La miscela di reazione è lavata con una soluzione di bicarbonato in acqua al 2% (200 mL) e successivamente la fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 17.3 g di metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7 (olio giallo; resa 88%) The reaction mixture is washed with a solution of bicarbonate in water at 2% (200 mL) and subsequently the organic phase is concentrated under reduced pressure (T <30 ° C) in order to obtain 17.3 g of methyl 3 - ((tert -butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) propanoate 7 (yellow oil; yield 88%)
<1>H NMR (400 MHz, Cloroformio-d) δ 7.41 – 7.18 (m, 4H), 5.03 – 4.90 (m, 1H), 4.76 (dd, J = 12.1, 4.8 Hz, 1H), 4.69 (ddt, J = 9.7, 7.0, 3.9 Hz, 1H), 4.54 – 4.40 (m, 1H), 3.90 (dtd, J = 11.1, 7.4, 3.2 Hz, 2H), 3.67 (d, J = 2.6 Hz, 3H), 3.64 – 3.45 (m, 3H), 1.99 – 1.32 (m, 15H). <1> H NMR (400 MHz, Chloroform-d) δ 7.41 - 7.18 (m, 4H), 5.03 - 4.90 (m, 1H), 4.76 (dd, J = 12.1, 4.8 Hz, 1H), 4.69 (ddt, J = 9.7, 7.0, 3.9 Hz, 1H), 4.54 - 4.40 (m, 1H), 3.90 (dtd, J = 11.1, 7.4, 3.2 Hz, 2H), 3.67 (d, J = 2.6 Hz, 3H), 3.64 - 3.45 (m, 3H), 1.99 - 1.32 (m, 15H).
Esempio 7 - passaggio g) Example 7 - step g)
17.3 g di metil 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoato 7 (0.044 moli) sono sciolti in una miscela 1 : 1 di tetraidrofurano: acqua (300 mL) e la miscela è raffreddata a 0°C. 17.3 g of methyl 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoate 7 (0.044 mol) are dissolved in a mixture 1: 1 of tetrahydrofuran: water (300 mL) and the mixture is cooled to 0 ° C.
Alla soluzione così ottenuta, si aggiungono 4.69 g di litio idrossido (0.112 moli) e si agita a temperatura ambiente fino a completezza (5 ore). To the solution thus obtained, 4.69 g of lithium hydroxide (0.112 moles) are added and it is stirred at room temperature until completeness (5 hours).
Alla miscela di reazione si aggiungono una soluzione acquosa satura di ammonio cloruro (500 mL) e acetato di etile (600 mL). Si aggiunge acido cloridrico 3 N (180 mL) e si separano le fasi. La fase organica è lavata una volta con salamoia (300 mL) e successivamente è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 17 g di acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propanoico 8 (olio giallo; resa tal quale > 85%). A saturated aqueous solution of ammonium chloride (500 mL) and ethyl acetate (600 mL) are added to the reaction mixture. 3 N hydrochloric acid (180 mL) is added and the phases separated. The organic phase is washed once with brine (300 mL) and subsequently concentrated under reduced pressure (T <30 ° C) to obtain 17 g of 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -propanoic 8 (yellow oil; yield as is> 85%).
1H NMR (400 MHz, Cloroformio-d) δ 7.38 – 7.27 (m, 4H), 4.78 (d, J = 12.0 Hz, 1H), 4.73 (q, J = 3.2 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 3.94 (ddt, J = 11.5, 8.6, 4.0 Hz, 2H), 3.70 – 3.45 (m, 3H), 1.94 – 1.53 (m, 6H), 1.50 – 1.44 (m, 9H). 1H NMR (400 MHz, Chloroform-d) δ 7.38 - 7.27 (m, 4H), 4.78 (d, J = 12.0 Hz, 1H), 4.73 (q, J = 3.2 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 3.94 (ddt, J = 11.5, 8.6, 4.0 Hz, 2H), 3.70 - 3.45 (m, 3H), 1.94 - 1.53 (m, 6H), 1.50 - 1.44 (m, 9H).
Esempio 8 - passaggio h) Example 8 - step h)
3.5 g di acido 3-((tert-butossicarbonil)ammino)-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propanoico 8 (9.22 mmoli) sono sciolti in diclorometano (35 mL) a temperatura ambiente sotto battente di azoto. Alla soluzione così ottenuta, si aggiungono 2.12 g di N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato (11.06 mmoli) e 0.056 g di 4-dimetilamminopiridina (0.46 mmoli) e si lascia in agitazione per 10 minuti. Successivamente, si aggiungono 0.93 g di 6-ammino-isochinolina (6.45 mmoli) e si agita fino a completezza (16 h). 3.5 g of 3 - ((tert-butoxycarbonyl) amino) -2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propanoic acid 8 (9.22 mmol) are dissolved in dichloromethane ( 35 mL) at room temperature under nitrogen head. To the solution thus obtained, 2.12 g of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (11.06 mmoles) and 0.056 g of 4-dimethylaminopyridine (0.46 mmoles) are added and the mixture is left under stirring for 10 minutes. Subsequently, 0.93 g of 6-amino-isoquinoline (6.45 mmoles) are added and stirred until complete (16 h).
Alla miscela di reazione si aggiunge una soluzione acquosa satura di sodio bicarbonato (30 mL) e si agita 10 minuti a temperatura ambiente. La fase organica è lavata una volta con acqua (30 mL) e una volta con salamoia (30 mL) ed in seguito è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 3 g di tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)-propil)carbammato grezzo (olio rosso; resa tal quale 64%). Il composto grezzo è purificato mediante cromatografia flash (SiO2) con un gradiente di metanolo in diclorometano da 0 a 10%. Si ottengono 0.9 g di tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propil)carbammato 9 (solido giallo). A saturated aqueous solution of sodium bicarbonate (30 mL) is added to the reaction mixture and stirred for 10 minutes at room temperature. The organic phase is washed once with water (30 mL) and once with brine (30 mL) and then concentrated under reduced pressure (T <30 ° C) to obtain 3 g of tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -propyl) crude carbamate (red oil; yield as it is 64% ). The crude compound is purified by flash chromatography (SiO2) with a 0 to 10% methanol to dichloromethane gradient. 0.9 g of tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propyl) carbamate are obtained 9 (yellow solid).
<1>H NMR (400 MHz, Cloroformio-d) δ 9.26 – 9.09 (m, 1H), 8.46 (d, J = 5.8 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.45 – 7.34 (m, 4H), 4.81 (dd, J = 12.1, 1.1 Hz, 1H), 4.73 (t, J = 3.6 Hz, 1H), 4.50 (dd, J = 12.2, 1.3 Hz, 1H), 4.05 (q, J = 7.1, 6.0 Hz, 1H), 3.94 (d, J = 1.6 Hz, 1H), 3.76 (dt, J = 14.5, 7.3 Hz, 1H), 3.68 – 3.51 (m, 2H), 2.08 (s, 1H), 1.97 – 1.52 (m, 6H), 1.45 (s, 9H). <1> H NMR (400 MHz, Chloroform-d) δ 9.26 - 9.09 (m, 1H), 8.46 (d, J = 5.8 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.45 - 7.34 (m, 4H), 4.81 (dd, J = 12.1, 1.1 Hz, 1H), 4.73 (t, J = 3.6 Hz, 1H), 4.50 (dd, J = 12.2, 1.3 Hz, 1H), 4.05 (q, J = 7.1, 6.0 Hz, 1H), 3.94 (d, J = 1.6 Hz, 1H), 3.76 (dt, J = 14.5, 7.3 Hz, 1H), 3.68 - 3.51 (m, 2H), 2.08 (s, 1H), 1.97 - 1.52 (m, 6H) , 1.45 (s, 9H).
Esempio 9 - passaggio i) Example 9 - step i)
0.24 g di tert-butil (3-(isochinolin-6-ilammino)-3-osso-2-(4-(((tetraidro-2H-piran-2-il)ossi)metil)fenil)propil)carbammato 9 (0.475 mmoli) sono sciolti in diclorometano (10 mL) e la soluzione è raffreddata a 0°C. Si aggiunge goccia a goccia una soluzione di acido cloridrico in etanolo al 10% (1 mL) e si condiziona fino a completezza (1.5 ore). 0.24 g of tert-butyl (3- (isoquinolin-6-ylamino) -3-oxo-2- (4 - (((tetrahydro-2H-piran-2-yl) oxy) methyl) phenyl) propyl) carbamate 9 ( 0.475 mmol) are dissolved in dichloromethane (10 mL) and the solution is cooled to 0 ° C. A solution of hydrochloric acid in 10% ethanol (1 mL) is added drop by drop and conditioned until complete (1.5 hours).
La miscela di reazione è diluita con diclorometano (40 mL) ed è lavata con una soluzione acquosa satura di sodio bicarbonato (50 mL). La fase organica è lavata una volta con salamoia (50 mL) ed in seguito è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 0.18 g di tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)carbammato 10 (solido giallo; resa 90%). The reaction mixture is diluted with dichloromethane (40 mL) and washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The organic phase is washed once with brine (50 mL) and then concentrated under reduced pressure (T <30 ° C) in order to obtain 0.18 g of tert-butyl (2- (4- (hydroxymethyl) phenyl) - 3- (isoquinolin-6-ylamino) -3-oxopropyl) carbamate 10 (yellow solid; yield 90%).
<1>H NMR (400 MHz, Metanolo-d4) δ 9.32 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 6.1 Hz, 1H), 8.27 – 8.18 (m, 1H), 8.01 (d, J = 6.3 Hz, 1H), 7.91 – 7.81 (m, 1H), 7.51 – 7.42 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 4.61 (s, 2H), 4.11 (t, J = 7.4 Hz, 1H), 3.83 – 3.66 (m, 1H), 3.55 – 3.42 (m, 1H), 1.42 (s, 9H). <1> H NMR (400 MHz, Methanol-d4) δ 9.32 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 6.1 Hz, 1H), 8.27 - 8.18 (m , 1H), 8.01 (d, J = 6.3 Hz, 1H), 7.91 - 7.81 (m, 1H), 7.51 - 7.42 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 4.61 (s, 2H), 4.11 (t, J = 7.4 Hz, 1H), 3.83 - 3.66 (m, 1H), 3.55 - 3.42 (m, 1H), 1.42 (s, 9H).
Esempio 10 - passaggio j) Example 10 - step j)
0.18 g di tert-butil (2-(4-(idrossimetil)fenil)-3-(isochinolin-6-ilammino)-3-ossopropil)carbammato 10 (0.427 mmoli) sono sciolti in diclorometano (5 mL) a temperatura ambiente sotto battente di azoto. Alla soluzione così ottenuta, si aggiungono 0.123 g di N-(3-dimetilamminopropil)-N′-etilcarbodiimmide cloridrato (0.642 mmoli) e 0.0026 g di 4-dimetilamminopiridina (0.0213 mmoli) e si lascia in agitazione per 10 minuti. Successivamente, si aggiungono 0.071 g di acido 2,4-dimetilbenzoico (0.473 mmoli) e si agita fino a completezza (16 h). 0.18 g of tert-butyl (2- (4- (hydroxymethyl) phenyl) -3- (isoquinolin-6-ylamino) -3-oxopropyl) carbamate 10 (0.427 mmol) are dissolved in dichloromethane (5 mL) at room temperature below nitrogen head. To the solution thus obtained, 0.123 g of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.642 mmoles) and 0.0026 g of 4-dimethylaminopyridine (0.0213 mmoles) are added and the mixture is left under stirring for 10 minutes. Subsequently, 0.071 g of 2,4-dimethylbenzoic acid (0.473 mmoles) are added and the mixture is stirred until complete (16 h).
La miscela di reazione è diluita con diclorometano (20 mL) e lavata con una soluzione acquosa satura di sodio bicarbonato (20 mL). La fase organica è lavata una volta con una soluzione acquosa di acido citrico al 5% (20 mL) ed una volta con salamoia (20 mL). In seguito, la fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere 0.2 g di 4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-oxopropan-2-il)benzil 2,4-dimetilbenzoato grezzo (olio giallo; resa tal quale 84%). Il composto grezzo è purificato mediante cromatografia flash (SiO2) con un gradiente di MeOH in diclorometano da 0 a 20%. Si ottengono 0.07 g di 4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 11 (olio giallo). The reaction mixture is diluted with dichloromethane (20 mL) and washed with a saturated aqueous solution of sodium bicarbonate (20 mL). The organic phase is washed once with a 5% aqueous solution of citric acid (20 mL) and once with brine (20 mL). Subsequently, the organic phase is concentrated at reduced pressure (T <30 ° C) so as to obtain 0.2 g of 4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1 crude -oxopropan-2-yl) benzyl 2,4-dimethylbenzoate (yellow oil; yield 84%). The crude compound is purified by flash chromatography (SiO2) with a gradient of MeOH in dichloromethane from 0 to 20%. 0.07 g of 4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 11 (yellow oil) are obtained.
<1>H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.16 (s, 1H), 8.41 (d, J = 5.7 Hz, 2H), 8.04 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.74 – 7.65 (m, 2H), 7.44 (s, 4H), 7.15 – 7.06 (m, 2H), 7.03 (s, 1H), 5.27 (s, 2H), 4.13 (s, 1H), 3.63 – 3.51 (m, 1H), 3.32 (d, J = 6.4 Hz, 1H), 2.49 (s, 3H), 2.30 (s, 3H), 1.35 (s, 9H). <1> H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.16 (s, 1H), 8.41 (d, J = 5.7 Hz, 2H), 8.04 (d, J = 9.0 Hz, 1H ), 7.76 (d, J = 7.9 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.44 (s, 4H), 7.15 - 7.06 (m, 2H), 7.03 (s, 1H), 5.27 (s, 2H), 4.13 (s, 1H), 3.63 - 3.51 (m, 1H), 3.32 (d, J = 6.4 Hz, 1H), 2.49 (s, 3H), 2.30 (s, 3H), 1.35 (s, 9H ).
Esempio 11 - passaggio k) Example 11 - step k)
La risoluzione della miscela racemica del prodotto (R,S)-4-(3-((tertbutossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 11 è stata effettuata in accordo con le procedure di letteratura (US8394826B2), per dare (S)-4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato 12. The resolution of the racemic mixture of the product (R, S) -4- (3 - ((tertbutoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 11 was carried out in accordance with the literature procedures (US8394826B2), to give (S) -4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ilamino) -1-oxopropan-2- II) benzyl 2,4-dimethylbenzoate 12.
Esempio 12 - passaggio l) Example 12 - step l)
70 mg di (S)-4-(3-((tert-butossicarbonil)ammino)-1-(isochinolin-6-ilammino)-1ossopropan-2-il)benzil 2,4-dimetilbenzoato 12 (0.12 mmoli) sono sciolti in diclorometano (2 mL) a temperatura ambiente sotto battente di azoto. Alla soluzione così ottenuta, si aggiungono 28.8 mg di acido metansolfonico (0.3 mmoli) e si agita a temperatura ambiente fino a completezza (25 ore). 70 mg of (S) -4- (3 - ((tert-butoxycarbonyl) amino) -1- (isoquinolin-6-ylamino) -1oxopropan-2-yl) benzyl 2,4-dimethylbenzoate 12 (0.12 mmol) are dissolved in dichloromethane (2 mL) at room temperature under nitrogen head. To the solution thus obtained, 28.8 mg of methanesulfonic acid (0.3 mmoles) are added and the mixture is stirred at room temperature until complete (25 hours).
In seguito, la fase organica è concentrata a pressione ridotta (T < 30°C) in modo da ottenere un residuo oleoso, al quale è aggiunto isopropanolo (2 mL). Il solvente è nuovamente eliminato a pressione ridotta (T < 30°C) ed è effettuata una seconda aggiunta di isopropanolo (2 mL). La miscela è condizionata a temperatura ambiente per 3 ore; in seguito si isolano per filtrazione 57.15 mg di (S)-4-(3-ammino-1-(isochinolin-6-ilammino)-1-ossopropan-2-il)benzil 2,4-dimetilbenzoato dimetansolfonato (I) (solido giallino; resa 70%) Subsequently, the organic phase is concentrated at reduced pressure (T <30 ° C) in order to obtain an oily residue, to which isopropanol (2 mL) is added. The solvent is again removed under reduced pressure (T <30 ° C) and a second addition of isopropanol (2 mL) is made. The mixture is conditioned at room temperature for 3 hours; then 57.15 mg of (S) -4- (3-amino-1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate dimethanesulfonate (I) (solid yellowish; yield 70%)
<1>H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.69 (s, 1H), 8.69 (s, 1H), 8.56 (d, J = 6.6 Hz, 1H), 8.45 (d, J = 9.0 Hz, 1H), 8.35 (m, 1H), 7.95 (m, 4H), 7.78 (d, J = 7.9 Hz, 1H), 7.52 – 7.46 (m, 4H), 7.15 – 7.05 (m, 2H), 5.29 (s, 2H), 4.21 (dd, J = 8.9, 5.4 Hz, 1H), 3.61 (m, 1H), 3.14 (m, 1H), 2.49 (s, 3H), 2.40 (s, 6H), 2.31 (s, 3H). <1> H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.69 (s, 1H), 8.69 (s, 1H), 8.56 (d, J = 6.6 Hz, 1H), 8.45 (d , J = 9.0 Hz, 1H), 8.35 (m, 1H), 7.95 (m, 4H), 7.78 (d, J = 7.9 Hz, 1H), 7.52 - 7.46 (m, 4H), 7.15 - 7.05 (m, 2H), 5.29 (s, 2H), 4.21 (dd, J = 8.9, 5.4 Hz, 1H), 3.61 (m, 1H), 3.14 (m, 1H), 2.49 (s, 3H), 2.40 (s, 6H ), 2.31 (s, 3H).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8394826B2 (en) * | 2009-05-01 | 2013-03-12 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
| US9643927B1 (en) * | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| WO2017086941A1 (en) * | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| CN107434780A (en) * | 2016-05-26 | 2017-12-05 | 上海韬勤生物医药科技有限公司 | A kind of AR-13324 preparation method |
-
2018
- 2018-07-20 IT IT102018000007398A patent/IT201800007398A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8394826B2 (en) * | 2009-05-01 | 2013-03-12 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
| US9643927B1 (en) * | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| WO2017086941A1 (en) * | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| CN107434780A (en) * | 2016-05-26 | 2017-12-05 | 上海韬勤生物医药科技有限公司 | A kind of AR-13324 preparation method |
Non-Patent Citations (1)
| Title |
|---|
| JILL M. STURDIVANT ET AL: "Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, no. 10, 1 May 2016 (2016-05-01), AMSTERDAM, NL, pages 2475 - 2480, XP055536666, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.03.104 * |
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