CN116332919A - ALK inhibitor compound and preparation method of intermediate thereof - Google Patents
ALK inhibitor compound and preparation method of intermediate thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 131
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 title abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000005859 coupling reaction Methods 0.000 claims abstract description 24
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000002829 reductive effect Effects 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 229910052751 metal Inorganic materials 0.000 claims abstract description 13
- 239000002184 metal Substances 0.000 claims abstract description 13
- 150000007524 organic acids Chemical class 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000006268 reductive amination reaction Methods 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 238000006722 reduction reaction Methods 0.000 claims description 21
- 239000003638 chemical reducing agent Substances 0.000 claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- 238000010511 deprotection reaction Methods 0.000 claims description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 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 group 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 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 239000003849 aromatic solvent Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 6
- -1 sodium triacetoxyborohydride Chemical group 0.000 claims description 6
- 150000003462 sulfoxides Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical group CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 2
- 150000001340 alkali metals Chemical class 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 150000008282 halocarbons Chemical group 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 8
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 8
- 230000001476 alcoholic effect Effects 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an ALK inhibitor compound and an intermediate thereof. Specifically, the invention discloses a preparation method of a compound A9, which comprises the following reaction steps: (1) In a solvent, in the presence of a metal catalyst and alkali, carrying out a coupling reaction on a compound A2 or salt thereof and a compound B3 or salt thereof to obtain a compound A4; (2) And (3) in a solvent, carrying out a coupling reaction on the compound A4 and the compound A8 in the presence of an organic acid to obtain a compound A9. The preparation method has the advantages of proper reaction steps, simple and convenient operation, cheap and easily obtained reaction raw materials, environmental friendliness, simple and convenient post-treatment, low safety risk, production period, reduced production cost and the like.
Description
Technical Field
The invention relates to a preparation method of ALK inhibitor compound and intermediate thereof.
Background
Anaplastic Lymphoma Kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in the development of hematopoietic and non-hematopoietic tumors. Aberrant expression of full-length ALK receptor proteins in renuroblastomas and glioblastomas has been reported; and ALK fusion proteins appear in anaplastic large cell lymphomas. Research on ALK fusion proteins also opens up new treatment possibilities for ALK positive malignancy patients. Small molecule ALK inhibitors have therapeutic potential for treating diseases and conditions in which ALK plays a role, including cancer.
The prior art discloses a preparation method of a compound A9 serving as an ALK inhibitor, and the preparation route is as follows:
the production cycle of the route is longer, the palladium catalyst is more in material consumption, the production cost is higher, and the synthetic route is complex.
Disclosure of Invention
The invention aims to solve the technical problems that the existing ALK inhibitor preparation method has longer production period, higher production cost and complex synthetic route, and provides the ALK inhibitor compound and the preparation method of the intermediate thereof.
The invention provides a preparation method of a compound A9, which comprises the following reaction steps: (1) In a solvent, in the presence of a metal catalyst and alkali, carrying out a coupling reaction on a compound A2 or salt thereof and a compound B3 or salt thereof to obtain a compound A4;
(2) In a solvent, carrying out coupling reaction on a compound A4 and a compound A8 in the presence of organic acid to obtain a compound A9;
X 1 OTf, cl, br or I;
X 2 and X 3 Each independently is H or C 1-6 An alkyl group; alternatively, X 2 And X 3 Connection formation-C (CH) 3 ) 2 -C(CH 3 ) 2 -。
In some embodiments, X 1 Is OTf, cl or I; cl is preferred.
In some embodiments, X 2 And X 3 Each independently is H or C 1-6 An alkyl group.
In some embodiments, in step (1), the solvent is one or more of an alcohol solvent, an ether solvent, an aromatic solvent, a nitrile solvent, a sulfoxide solvent, an amide solvent, and water, for example, a combination of an alcohol solvent and water, a combination of an ether solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent, or an amide solvent.
In some embodiments, in step (1), the alcoholic solvent is isopropanol.
In some embodiments, in step (1), the ether-based solvent is dioxane and/or methyl ether.
In some embodiments, in step (1), the aromatic solvent is toluene.
In some embodiments, in step (1), the nitrile solvent is acetonitrile.
In some embodiments, in step (1), the sulfoxide solvent is dimethyl sulfoxide.
In some embodiments, in step (1), the amide-based solvent is N, N-dimethylformamide.
In some embodiments, in step (1), when the solvent is a combination of an alcoholic solvent and water, the volume ratio of the alcoholic solvent to the water is (4-20): 1, such as 4.5:1, 19.9:1, or 10.0:1.
In some embodiments, in step (1), the salt of compound A2 is the hydrochloride salt form of compound A2.
In some embodiments, in step (1), when the salt of compound A2 is the hydrochloride salt form of compound A2, the molar ratio of compound A2 to hydrochloric acid is 1:1.
In some embodiments, in step (1), the salt of compound B3 is the hydrochloride salt form of compound B3.
In some embodiments, in step (1), when the salt of compound B3 is in the hydrochloride form of compound B3, the molar ratio of compound B3 to hydrochloric acid is 1:1.
In some embodiments, in step (1), the metal catalyst is a palladium catalystFor example Pd (PPh) 3 ) 2 Cl 2 、Pd(dppf) 2 Cl 2 、Pd(OAc) 2 And Pd (PPh) 3 ) 4 Preferably Pd (PPh) 3 ) 4 And/or Pd (OAc) 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably Pd (PPh) 3 ) 4 。
In some embodiments, in step (1), the base is an alkali metal carbonate and/or an alkali metal phosphate, such as potassium carbonate and/or potassium phosphate; potassium carbonate is preferred.
In some embodiments, in step (1), the molar ratio of compound B3 to compound A2 is (1-1.1) to 1, such as 1.1: 1,1.05:1 or 1.0:1.
In some embodiments, in step (1), the molar ratio of the metal catalyst to the compound A2 is (0.01-0.02) to 1, e.g., 0.01:1 or 0.02:1.
In some embodiments, in step (1), the molar ratio of the base to the compound A2 is (3.0-5.0) to 1, e.g., 3.0: 1,4.0:1 or 5.0:1.
In some embodiments, in step (1), when the solvent is a combination of an alcoholic solvent and water, the molar ratio of water to the compound A2 is (9-24) to 1, such as 9:1 or 9.5:1.
In some embodiments, in step (1), the reaction temperature of the coupling reaction is 80 to 120 ℃, preferably 80 to 85 ℃.
In some embodiments, in step (1), the coupling reaction is performed under an inert gas blanket, such as nitrogen blanket.
In some embodiments, in step (1), the coupling reaction further comprises the following post-treatment steps: concentration (e.g., spin-drying), extraction (e.g., using ethyl acetate and 10% sodium carbonate solution), filtration, removal of metal catalyst (e.g., using N-acetyl-L-cysteine), concentration of filtrate (e.g., concentration under reduced pressure), washing (e.g., washing with 10% sodium carbonate solution), drying (e.g., drying with anhydrous magnesium sulfate), and recrystallization (e.g., recrystallization with N-heptane).
In some embodiments, in step (2), the solvent is an alcoholic solvent, such as isopropanol.
In some embodiments, in step (2), the organic acid is p-toluenesulfonic acid, e.g., p-toluenesulfonic acid monohydrate.
In some embodiments, in step (2), the molar ratio of said compound A8 to said compound A4 is (1-1.5) to 1, e.g. 1.05:1.
In some embodiments, in step (2), the molar ratio of the organic acid to the compound A4 is (1-1.5) to 1, e.g., 1.2:1.
In some embodiments, in step (2), the mass to volume ratio of the compound A4 to the solvent is 1g to (6-15) ml, e.g., 1g to 8ml.
In some embodiments, in step (2), the temperature of the coupling reaction is 70-90 ℃, preferably 77-83 ℃.
In some embodiments, in step (2), the coupling reaction is performed under an inert gas blanket, such as nitrogen blanket.
In some embodiments, in step (2), the coupling reaction further comprises the following post-treatment steps: crystallization (e.g., crystallization using ethyl acetate), filtration, washing (e.g., washing with 10% sodium carbonate solution after dissolution with methylene chloride), extraction (e.g., extraction of the aqueous phase with methylene chloride), concentration under reduced pressure, crystallization (e.g., crystallization using acetonitrile), and drying.
In some embodiments, the method of preparing compound A9 further comprises the steps of: in a solvent, under the action of a reducing agent, carrying out a reduction reaction on the compound A1 to obtain a compound A2 or a salt thereof;
In some embodiments, X 1 Is OTf, cl or I; cl is preferred.
In some embodiments, the reduction reaction is performed using an alcohol solvent and water.
In some embodiments, the alcoholic solvent is methanol in the reduction reaction.
In some embodiments, the volume ratio of the alcoholic solvent to the water in the reduction reaction is (5-20) to 1, e.g., 5:1.
In some embodiments, the salt of compound A2 is the hydrochloride salt form of compound A2.
In some embodiments, when the salt of compound A2 is the hydrochloride salt form of compound A2, the molar ratio of compound A2 to hydrochloric acid is 1:1.
In some embodiments, the mass to volume ratio of the compound A1 to the alcoholic solvent in the reduction reaction is 1g to (3-15) ml, for example 1g to 5ml.
In some embodiments, the reducing agent is SnCl in the reduction reaction 2 ·2H 2 O and HCl.
In some embodiments, the temperature of the reduction reaction is 45-55 ℃, e.g., 50 ℃.
In some embodiments, the molar ratio of the reducing agent to the compound A1 in the reduction reaction is (3-10) to 1, e.g., 4:1. When the reducing agent is SnCl 2 ·2H 2 O and HCl, the reducing agent is used in the molar ratio of the reducing agent to the compound A1 as SnCl 2 ·2H 2 O meter.
In some embodiments, the reduction reaction further comprises the following post-treatment steps: after addition of water, concentration (for example, after addition of water, concentration under reduced pressure), extraction (for example, extraction with methyl tert-butyl ether), washing (for example, washing with saturated brine), concentration, filtration and drying.
In some embodiments, when the hydrochloride salt form of compound A2 is obtained, the post-treatment step further comprises adding an acid (e.g., adding a 4M ethyl hydrogen chloride acetate solution).
In some embodiments, the method of preparing compound A9 further comprises the steps of: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound B2 or salt thereof, tetrahydropyranone and acetic acid to obtain a compound B3 or salt thereof;
in some embodiments, X 2 And X 3 Each independently is H or C 1-6 An alkyl group.
In some embodiments, the solvent in the reductive amination reaction is a haloalkane solvent, such as dichloromethane.
In some embodiments, the salt of compound B2 is the hydrochloride salt form of compound B2.
In some embodiments, when the salt of compound B2 is the hydrochloride salt form of compound B2, the molar ratio of compound B2 to hydrochloric acid is 1:1.
In some embodiments, the salt of compound B3 is the hydrochloride salt form of compound B3.
In some embodiments, when the salt of compound B3 is the hydrochloride salt form of compound B3, the molar ratio of compound B3 to hydrochloric acid is 1:1.
In some embodiments, the reductive amination reaction wherein the reducing agent is sodium triacetoxyborohydride.
In some embodiments, the molar ratio of the tetrahydropyranone to the compound B2 in the reductive amination reaction is (2-5) to 1, for example 3:1.
In some embodiments, the molar ratio of acetic acid to compound B2 in the reductive amination reaction is (0.5-2) to 1, for example 0.85:1.
In some embodiments, the molar ratio of the reducing agent to the compound B2 in the reductive amination reaction is (2-5) to 1, e.g., 3:1.
In some embodiments, the mass to volume ratio of the compound B2 to the solvent in the reductive amination reaction is 1g to (5-20) ml, such as 1g to 10ml.
In some embodiments, the reductive amination reaction may also include the use of an organic acid, such as acetic acid.
In some embodiments, the reductive amination reaction further comprises the following post-treatment steps: extraction (e.g., with methylene chloride and 15% sodium carbonate solution), filtration (e.g., with celite), drying (e.g., with anhydrous magnesium sulfate), concentration (e.g., concentration under reduced pressure), and washing (e.g., washing with n-heptane).
In some embodiments, the temperature of the reductive amination reaction is room temperature.
In some embodiments, the method of preparing compound A9 further comprises the steps of: in a solvent, under an acidic condition, carrying out deprotection reaction on the compound B1 to obtain a compound B2 or a salt thereof;
X 4 is an amino protecting group; x is X 2 And X 3 Is defined as in any one of the present inventions.
In some embodiments, the amino protecting group is a group conventionally used in the art to protect an amino group, such as-Boc.
In some embodiments, X 2 And X 3 Each independently is H or C 1-6 An alkyl group.
In some embodiments, the deprotection reaction, the solvent is an ester solvent, such as ethyl acetate.
In some embodiments, the salt of compound B2 is the hydrochloride salt form of compound B2.
In some embodiments, when the salt of compound B2 is the hydrochloride salt form of compound B2, the molar ratio of compound B2 to hydrochloric acid is 1:1.
In some embodiments, in the deprotection reaction, the acid in the acidic condition is hydrogen chloride. The hydrogen chloride may be added in the form of an ethyl acetate solution of hydrogen chloride. The concentration of the ethyl acetate solution of hydrogen chloride may be 4M.
In some embodiments, the deprotection reaction comprises a mass to volume ratio of the compound B1 to the solvent of 1g to (3-20) ml, e.g., 1g to 4.8ml.
In some embodiments, the molar ratio of the acid to the compound B1 in the deprotection reaction is (3-10) to 1, e.g., 6:1.
In some embodiments, the deprotection reaction is performed at room temperature.
In some embodiments, the deprotection reaction further comprises the following post-treatment steps: concentrating under reduced pressure, pulping (e.g., pulping with methyl tert-butyl ether), filtering, and drying.
The invention also provides a preparation method of the compound A4, which comprises the following reaction steps: in a solvent, in the presence of a metal catalyst and alkali, carrying out a coupling reaction on an A2 compound or salt thereof and a B3 compound or salt thereof to obtain a compound A4;
X 1 OTf, cl, br or I;
X 2 and X 3 Each independently is H or C 1-6 An alkyl group; alternatively, X 2 And X 3 Connection formation-C (CH) 3 ) 2 -C(CH 3 ) 2 -。
In some embodiments, X 1 Is OTf, cl or I; cl is preferred.
In some embodiments, X 2 And X 3 Each independently is H or C 1-6 An alkyl group.
In some embodiments, each step and reaction conditions in the process for the preparation of compound A4 are as described in any one of the preceding claims.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method has the advantages of proper reaction steps, simple and convenient operation, cheap and easily obtained reaction raw materials, environmental friendliness, simple and convenient post-treatment, low safety risk, production period, reduced production cost and the like.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
Stannous chloride dihydrate (65.86 g), methanol (100 ml), water (20 ml), concentrated hydrochloric acid (12 ml) and compound Al' (20.0 g) were sequentially added to a 1L reaction flask, heated to an internal temperature of 50℃and stirred for 4 hours, and the reaction was completed. The reaction system was cooled to room temperature, water (100 ml) was added, after concentrating under reduced pressure until the remaining about 100g, methyl tertiary ether (200 ml) was added and stirred, 20% sodium hydroxide solution was added dropwise to the aqueous phase ph=11 to 12, and the organic phase was collected as a liquid. The aqueous phase was back-extracted once with methyl tertiary ether (100 ml). The organic phases were combined and washed once with 15% sodium chloride solution (100 ml). The organic phase was concentrated to replace the solvent with ethyl acetate (100 ml x 2) to a residual of about 50g, 4M ethyl hydrogen chloride solution (70 ml) was added dropwise, stirred at room temperature for 1 hour, concentrated to replace with ethyl acetate (100 ml x 2) to a residual of about 100g, suction filtered and dried to give the A2' compound (18.05 g), purity 99.51%, yield 87%.
MS:[M+H]+=244.0
1 H NMR(400MHz,DMSO-d6)δ7.37(s,1H),7.28(s,1H),4.78-4.67(m,1H),2.26(d,J=1.28Hz,3H),1.29(dd,J=6.04,1.31Hz,6H).
Example 2
To a 2L reaction flask, a compound of formula B1' (61.9 g) and ethyl acetate (300 ml) were successively added, and after the mixture was dissolved by stirring, a 4M ethyl acetate solution (300 ml) of hydrogen chloride was added dropwise at room temperature, followed by stirring for 2 hours, whereby the reaction was completed. The reaction mixture was concentrated to dryness under reduced pressure, methyl t-butyl ether (200 ml) was added thereto, and the mixture was slurried at room temperature for 2 hours, suction filtration and drying to give the compound of formula B2' (48.81 g), purity 97.9%, yield 99%.
1 H NMR(400MHz,DMSO-d6)δ9.29(s,2H),6.36(td,J=3.10,1.53Hz,1H),3.58(dp,J=5.08,2.47Hz,2H),3.13-3.03(m,2H),2.28(tq,J=4.66,2.15Hz,2H),1.22(s,12H).
Example 3
To a 2L reaction flask were successively added a compound of formula B2' (36.13 g), methylene chloride (360 ml), tetrahydropyranone (51.58 g) and acetic acid (8.84 g), and after stirring and purging, sodium triacetoxyborohydride (109.17 g) was added in portions, and the mixture was stirred at room temperature for 2.5 hours, whereby the reaction was completed. Dichloromethane (360 ml) was added to the system, 15% sodium carbonate solution (900 ml) was slowly added, 20% sodium hydroxide solution (150 ml) was added, the pH was adjusted to about 10 to 11, the mixture was filtered through celite, and the organic phase was collected. The aqueous phase was back extracted three times with dichloromethane (360 ml x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, suction filtered, spin dried, ethyl acetate was added, concentrated under reduced pressure to constant weight, n-heptane (90 g) was added dropwise at room temperature, cooled to 0-5 ℃, stirred for 2 hours, suction filtered, dried compound of formula B3' (32.52 g), purity 99.68%, yield 75%.
1 H NMR(400MHz,Chloroform-d)δ6.53(tt,J=3.52,1.87Hz,1H),4.11-3.97(m,2H),3.40(td,J=11.88,1.99Hz,2H),3.20(q,J=3.03Hz,2H),2.64(t,J=5.62Hz,2H),2.53(tt,J=11.57,3.89Hz,1H),2.34-2.25(m,2H),1.81(ddd,J=12.50,4.19,2.09Hz,2H),1.64(qd,J=12.18,4.51Hz,2H),1.26(s,12H).
Example 4
To the reaction flask, compound A2 '(20.0 g), compound B3' (20.09 g), isopropyl alcohol (230 ml), water (11.55 g) and potassium carbonate (39.41 g) were sequentially added, stirring was started, nitrogen was replaced three times, tetrakis triphenylphosphine palladium (0.8237 g) was added, nitrogen was replaced three times, and the temperature was raised to 80 to 85 ℃ under nitrogen protection, stirring was performed for 24 hours, and the reaction was completed. The reaction system was cooled to 50-55℃and N-acetyl-L-cysteine (1.16 g) was added thereto, followed by stirring for 1 hour and cooling to room temperature. The system was concentrated to about 130g remaining, displaced twice with ethyl acetate (100 ml x 2) to about 130g remaining, ethyl acetate (200 ml) was added, washed once with 10% sodium carbonate solution (200 ml), suction filtered and the filtrate was collected. The filtrate was separated, N-acetyl-L-cysteine (1.16 g) was added to the organic phase, the temperature was raised to 50 to 55℃and stirred for 1 hour, cooled to room temperature, and washed once with 10% sodium carbonate solution (150 ml). N-acetyl-L-cysteine (1.16 g) was added to the organic phase, warmed to 50-55℃and stirred for 1 hour, cooled to room temperature and washed once with 10% sodium carbonate solution (150 ml). The organic phase is concentrated under reduced pressure until about 60g remains, methyl tertiary butyl ether (40 g) is added dropwise, n-heptane (100 g) is added dropwise at 20-25 ℃, after stirring for 30 minutes, the mixture is concentrated under reduced pressure until about 100g remains, n-heptane (100 g) is continuously added, the mixture is concentrated under reduced pressure until about 100g remains, the temperature is reduced to 0-5 ℃, stirring is carried out for 4 hours, suction filtration is carried out, and compound A4 (20.22 g) is obtained after drying, the purity is 97.6%, and the yield is 86%.
MS:[M+H]+=331.20
1 H NMR(400MHz,DMSO-d6)δ6.49(s,1H),6.44(s,1H),5.42(dq,J=3.54,1.65Hz,1H),4.47(s,2H),4.38(h,J=6.05Hz,1H),3.95-3.86(m,2H),3.13(q,J=2.95Hz,2H),2.66(t,J=5.51Hz,2H),2.46(dt,J=11.17,3.71Hz,1H),2.23(dq,J=6.10,3.43,2.92Hz,2H),2.07(s,3H),1.75(ddd,J=12.26,4.11,1.98Hz,2H),1.46(qd,J=12.16,4.44Hz,2H),1.23(d,J=6.01Hz,6H).
Example 5
With reference to the synthetic method of the compound of example 4, the reaction parameters were optimized and adjusted to obtain the following results.
Example 6
To the reaction flask was successively added isopropanol (120 ml), A4 (15.0 g), A8 (16.5 g), p-toluenesulfonic acid monohydrate (10.36 g), stirred, and replaced with nitrogen three times. Heating to 80+/-3 ℃ under the protection of nitrogen, stirring and reacting for 24 hours, and finishing the reaction. Cooling to 60-65 ℃, dropwise adding ethyl acetate (120 ml), slowly cooling to 15+/-5 ℃, stirring for 2 hours, and carrying out suction filtration. The filter cake was dissolved in dichloromethane (90 m 1) with stirring, washed twice with 10% aqueous sodium carbonate (75 ml x 2). The aqueous phases were combined and extracted once with dichloromethane (45 ml). The organic phases were combined, concentrated under reduced pressure to a residual weight of about 37.5g, acetonitrile (75 ml) was added dropwise, concentrated under reduced pressure to a residual weight of about 67.5g, acetonitrile (75 ml) was added dropwise at a controlled temperature of 30.+ -. 10 ℃, cooled to 20.+ -. 5 ℃, stirred for 6 hours, and suction filtered. Oven-dried to give compound A9 (23.0 g), purity 99.74%, yield 79%.
MS:[M+H] + =640.10
1 H NMR(400MHz,Chloroform-d)δ9.51(s,1H),8.59(dd,J=8.41,1.08Hz,1H),8.18(s,1H),8.05(s,1H),7.95(dd,J=8.00,1.63Hz,1H),7.65(ddd,J=8.60,7.38,1.67Hz,1H),7.60(s,1H),6.72(s,1H),5.59(dt,J=3.64,1.96Hz,1H),4.55(hept,J=6.17Hz,1H),4.09(dd,J=11.28,4.24Hz,2H),3.45(td,J=11.88,1.93Hz,2H),3.36-3.21(m,3H),2.80(t,J=5.56Hz,2H),2.43(s,2H),2.14(s,3H),1.88(d,J=12.42Hz,2H),1.78-1.69(m,2H),1.36(dd,J=17.08,6.47Hz,13H)。
Claims (17)
1. A process for the preparation of compound A9 comprising the following reaction steps:
(1) In a solvent, in the presence of a metal catalyst and alkali, carrying out a coupling reaction on a compound A2 or salt thereof and a compound B3 or salt thereof to obtain a compound A4;
(2) In a solvent, carrying out coupling reaction on a compound A4 and a compound A8 in the presence of organic acid to obtain a compound A9;
X 1 OTf, cl, br or I;
X 2 and X 3 Each independently is H or C 1-6 An alkyl group; alternatively, X 2 And X 3 Connection formation-C (CH) 3 ) 2 -C(CH 3 ) 2 -。
3. The process for the preparation of compound A9 according to claim 1, wherein said process satisfies one or more of the following conditions:
(1)X 1 is OTf, cl or I; preferably Cl;
(2)X 2 and X 3 Each independently is H or C 1-6 An alkyl group.
4. A process for the preparation of compound A9 according to any one of claims 1 to 3, wherein the process meets one or more of the following conditions:
(1) In the step (1), the solvent is one or more of alcohol solvents, ether solvents, aromatic solvents, nitrile solvents, sulfoxide solvents, amide solvents and water;
(2) In step (1), the salt of compound A2 is the hydrochloride salt form of compound A2;
(3) In step (1), the salt of compound B3 is the hydrochloride salt form of compound B3;
(4) In the step (1), the metal catalyst is a palladium catalyst;
(5) In the step (1), the alkali is carbonate of alkali metal and/or phosphate of alkali metal;
(6) In the step (1), the molar ratio of the compound B3 to the compound A2 is (1-1.1) to 1;
(7) In the step (1), the molar ratio of the metal catalyst to the compound A2 is (0.01-0.02) to 1;
(8) In the step (1), the molar ratio of the alkali to the compound A2 is (3.0-5.0) to 1;
(9) In the step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of the water to the compound A2 is (9-24) to 1;
(10) In the step (1), the reaction temperature of the coupling reaction is 80-120 ℃;
(11) In the step (1), the coupling reaction is carried out under the protection of inert gas;
(12) In step (1), the coupling reaction further comprises the following post-treatment steps: concentrating, extracting, filtering, removing metal catalyst, concentrating filtrate, washing, drying and recrystallizing;
(13) In the step (2), the solvent is an alcohol solvent;
(14) In the step (2), the organic acid is p-toluenesulfonic acid;
(15) In the step (2), the molar ratio of the compound A8 to the compound A4 is (1-1.5) to 1;
(16) In the step (2), the molar ratio of the organic acid to the compound A4 is (1-1.5) to 1;
(17) In the step (2), the mass volume ratio of the compound A4 to the solvent is 1g to (6-15) ml;
(18) In the step (2), the temperature of the coupling reaction is 70-90 ℃;
(19) In the step (2), the coupling reaction is carried out under the protection of inert gas;
(20) In step (2), the coupling reaction further comprises the following post-treatment steps: crystallization, filtration, washing, extraction, reduced pressure concentration, crystallization and drying.
5. The process for producing compound A9 according to claim 4, wherein one or more of the following conditions are satisfied:
(1) In the step (1), the solvent is a combination of an alcohol solvent and water, a combination of an ether solvent and water, an aromatic solvent, a nitrile solvent, a sulfoxide solvent or an amide solvent;
(2) In the step (1), when the solvent is a combination of an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (4-20) to 1;
(3) In the step (1), the alcohol solvent is isopropanol;
(4) In the step (1), the ether solvent is dioxane and/or methyl ether;
(5) In the step (1), the aromatic solvent is toluene;
(6) In the step (1), the nitrile solvent is acetonitrile;
(7) In the step (1), the sulfoxide solvent is dimethyl sulfoxide;
(8) In the step (1), the amide solvent is N, N-dimethylformamide;
(9) In the step (1), when the solvent is a combination of an alcohol solvent and water, the volume ratio of the alcohol solvent to the water is 4.5:1, 19.9:1 or 10.0:1;
(10) In the step (1), when the salt of the compound A2 is in the hydrochloride form of the compound A2, the molar ratio of the compound A2 to the hydrochloric acid is 1:1;
(11) In the step (1), when the salt of the compound B3 is in the hydrochloride form of the compound B3, the molar ratio of the compound B3 to the hydrochloric acid is 1:1;
(12) In the step (1), the metal catalyst is Pd (PPh) 3 ) 2 Cl 2 、Pd(dppf) 2 Cl 2 、Pd(OAc) 2 And Pd (PPh) 3 ) 4 Preferably Pd (PPh) 3 ) 4 And/or Pd (OAc) 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably Pd (PPh) 3 ) 4 ;
(13) In the step (1), the alkali is potassium carbonate and/or potassium phosphate; preferably potassium carbonate;
(14) In step (1), the molar ratio of the compound B3 to the compound A2 is 1.1: 1,1.05:1 or 1.0:1;
(15) In step (1), the molar ratio of the metal catalyst to the compound A2 is 0.01:1 or 0.02:1;
(16) In step (1), the molar ratio of the base to the compound A2 is 3.0: 1,4.0:1 or 5.0:1;
(17) In the step (1), when the solvent is a combination of an alcohol solvent and water, the molar ratio of the water to the compound A2 is 9:1 or 9.5:1;
(18) In the step (1), the reaction temperature of the coupling reaction is 80-85 ℃;
(19) In the step (1), the coupling reaction is carried out under the protection of nitrogen;
(20) In the step (2), the solvent is isopropanol;
(21) In step (2), the organic acid is p-toluenesulfonic acid monohydrate;
(22) In the step (2), the molar ratio of the compound A8 to the compound A4 is 1.05:1;
(23) In step (2), the molar ratio of the organic acid to the compound A4 is 1.2:1;
(24) In the step (2), the mass-volume ratio of the compound A4 to the solvent is 1g to 8ml;
(25) In the step (2), the temperature of the coupling reaction is 77-83 ℃;
(26) In the step (2), the coupling reaction is carried out under the protection of nitrogen.
6. A process for the preparation of compound A9 according to any one of claims 1 to 3, characterized in that in step (1) it further comprises the steps of: in a solvent, under the action of a reducing agent, carrying out a reduction reaction on the compound A1 to obtain a compound A2 or a salt thereof;
X 1 is defined as in any one of claims 1 to 3.
7. The method of preparing compound A9 according to claim 6, wherein the method of preparing satisfies one or more of the following conditions:
(1) In the reduction reaction, the solvent is an alcohol solvent and water;
(2) The salt of the compound A2 is in the hydrochloride form of the compound A2;
(3) In the reduction reaction, the mass volume ratio of the compound A1 to the alcohol solvent is 1g to (3-15) ml;
(4) In the reduction reaction, the reducing agent is SnCl 2 ·2H 2 O and HCl;
(5) The temperature of the reduction reaction is 45-55 ℃;
(6) In the reduction reaction, the mol ratio of the reducing agent to the compound A1 is (3-10) to 1; when the reducing agent is SnCl 2 ·2H 2 O and HCl, the reducing agent is used in the molar ratio of the reducing agent to the compound A1 as SnCl 2 ·2H 2 An O meter;
(7) The reduction reaction further comprises the following post-treatment steps: adding water, concentrating, extracting, washing, concentrating, filtering, and drying.
8. The process for producing compound A9 according to claim 7, wherein one or more of the following conditions are satisfied
(1) In the reduction reaction, the alcohol solvent is methanol;
(2) In the reduction reaction, the volume ratio of the alcohol solvent to the water is (5-20) to 1; for example 5:1;
(3) When the salt of the compound A2 is in the hydrochloride form of the compound A2, the molar ratio of the compound A2 to the hydrochloric acid is 1:1;
(4) In the reduction reaction, the mass volume ratio of the compound A1 to the alcohol solvent is 1g to 5ml;
(5) The temperature of the reduction reaction is 50 ℃;
(6) In the reduction reaction, the molar ratio of the reducing agent to the compound A1 is 4:1;
(7) When the hydrochloride form of compound A2 is obtained, the post-treatment step further comprises the addition of an acid.
9. A process for the preparation of compound A9 according to any one of claims 1 to 3, characterized in that in step (1) it further comprises the steps of: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound B2 or salt thereof, tetrahydropyranone and acetic acid to obtain a compound B3 or salt thereof;
X 2 and X 3 Is defined as in any one of claims 1 to 3.
10. The method of preparing compound A9 of claim 9, wherein the method of preparing satisfies one or more of the following conditions:
(1) In the reductive amination reaction, the solvent is halogenated hydrocarbon solvent;
(2) The salt of the compound B2 is in the hydrochloride form of the compound B2;
(3) The salt of the compound B3 is in the hydrochloride form of the compound B3;
(4) In the reductive amination reaction, the reducing agent is sodium triacetoxyborohydride;
(5) In the reductive amination reaction, the molar ratio of the tetrahydropyranone to the compound B2 is (2-5) to 1;
(6) In the reductive amination reaction, the molar ratio of the acetic acid to the compound B2 is (0.5-2) to 1;
(7) In the reductive amination reaction, the mol ratio of the reducing agent to the compound B2 is (2-5) to 1;
(8) In the reductive amination reaction, the mass volume ratio of the compound B2 to the solvent is 1g to (5-20) ml;
(9) The reductive amination reaction may also include the use of organic acids;
(10) The reductive amination reaction further comprises the following post-treatment steps: extracting, filtering, drying, concentrating and washing;
(11) The temperature of the reductive amination reaction is room temperature.
11. The method of preparing compound A9 of claim 10, wherein the method of preparing satisfies one or more of the following conditions:
(1) In the reductive amination reaction, the solvent is dichloromethane;
(2) When the salt of the compound B2 is in the hydrochloride form of the compound B2, the molar ratio of the compound B2 to the hydrochloric acid is 1:1;
(3) When the salt of the compound B3 is in the hydrochloride form of the compound B3, the molar ratio of the compound B3 to the hydrochloric acid is 1:1;
(4) In the reductive amination reaction, the molar ratio of the tetrahydropyranone to the compound B2 is 3:1;
(5) In the reductive amination reaction, the molar ratio of the acetic acid to the compound B2 is 0.85:1;
(6) In the reductive amination reaction, the mol ratio of the reducing agent to the compound B2 is 3:1;
(7) In the reductive amination reaction, the mass volume ratio of the compound B2 to the solvent is 1g to 10ml;
(8) The organic acid is acetic acid.
12. The method for producing compound A9 according to claim 9, wherein in step (1), further comprising the steps of: in a solvent, under an acidic condition, carrying out deprotection reaction on the compound B1 to obtain a compound B2 or a salt thereof;
X 4 is an amino protecting group; x is X 2 And X 3 Is defined as set forth in claim 9.
14. The process for preparing compound A9 according to claim 12, wherein the process satisfies the following conditions:
X 2 and X 3 Each independently is H or C 1-6 An alkyl group.
15. The process for the preparation of compound A9 according to any one of claims 12 to 14, wherein said process satisfies one or more of the following conditions:
(1) In the deprotection reaction, the solvent is an ester solvent;
(2) The salt of the compound B2 is in the hydrochloride form of the compound B2;
(3) In the deprotection reaction, the acid in the acidic condition is hydrogen chloride;
(4) In the deprotection reaction, the mass volume ratio of the compound B1 to the solvent is 1g to (3-20) ml;
(5) In the deprotection reaction, the molar ratio of the acid to the compound B1 is (3-10) to 1;
(6) The deprotection reaction is carried out at room temperature;
(7) The deprotection reaction further comprises the following post-treatment steps: concentrating under reduced pressure, pulping, filtering, and drying.
16. The method of preparing compound A9 of claim 15, wherein the method of preparing satisfies one or more of the following conditions:
(1) In the deprotection reaction, the solvent is ethyl acetate;
(2) When the salt of the compound B2 is in the hydrochloride form of the compound B2, the molar ratio of the compound B2 to the hydrochloric acid is 1:1;
(3) The hydrogen chloride is added in the form of ethyl acetate solution of hydrogen chloride;
(4) When the hydrogen chloride is added in the form of an ethyl acetate solution of hydrogen chloride, the concentration of the ethyl acetate solution of hydrogen chloride is 4M;
(5) In the deprotection reaction, the mass volume ratio of the compound B1 to the solvent is 1g to 4.8ml;
(6) In the deprotection reaction, the molar ratio of the acid to the compound B1 is 6:1.
17. A process for the preparation of compound A4 comprising the following reaction steps: in a solvent, in the presence of a metal catalyst and alkali, carrying out a coupling reaction on an A2 compound or salt thereof and a B3 compound or salt thereof to obtain a compound A4;
wherein X is 1 、X 2 And X 3 And the steps and reaction conditions are as described in step (1) of any one of claims 1 to 16.
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