CN117800984A - Chiral resolution method for preparing Ulotaront and enantiomer thereof - Google Patents
Chiral resolution method for preparing Ulotaront and enantiomer thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 20
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 title claims abstract description 18
- 229940125119 ulotaront Drugs 0.000 title claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 51
- -1 (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine Chemical compound 0.000 claims abstract description 49
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 94
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 229940125782 compound 2 Drugs 0.000 claims description 27
- 229940126214 compound 3 Drugs 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 12
- 229940011051 isopropyl acetate Drugs 0.000 claims description 12
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VEYRLVWKCAOBSU-VIFPVBQESA-N (7S)-N,N-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-7-amine Chemical compound CN(C)[C@@H]1C2=C(CCO1)C=CS2 VEYRLVWKCAOBSU-VIFPVBQESA-N 0.000 claims description 9
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 229960001270 d- tartaric acid Drugs 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000007670 refining Methods 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CJABKOZRICGGNO-FVGYRXGTSA-N (7S)-N,N-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-7-amine hydrochloride Chemical compound CN(C)[C@@H]1C2=C(CCO1)C=CS2.Cl CJABKOZRICGGNO-FVGYRXGTSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HUMIEJNVCICTPJ-UHFFFAOYSA-N 2,2-dimethoxy-n-methylethanamine Chemical compound CNCC(OC)OC HUMIEJNVCICTPJ-UHFFFAOYSA-N 0.000 description 2
- YYPNNBPPDFTQFX-UHFFFAOYSA-N 2-thiophen-3-ylethanol Chemical compound OCCC=1C=CSC=1 YYPNNBPPDFTQFX-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 2
- 229940116298 l- malic acid Drugs 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000011829 Trace amine associated receptor Human genes 0.000 description 1
- 108050002178 Trace amine associated receptor Proteins 0.000 description 1
- 102000004406 Trace amine-associated receptor 1 Human genes 0.000 description 1
- 108090000946 Trace amine-associated receptor 1 Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000003438 effect on compound Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
Abstract
The invention discloses a chiral resolution method for preparing Ulotaront and enantiomer thereof, which relates to the technical field of chemical medicaments, and comprises the following specific process steps: dissolving (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine in a solvent, adding L-tartaric acid to form salt, filtering to obtain a crude product, adding the solvent, heating, refluxing and dissolving, crystallizing at room temperature, and filtering to obtain (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate, and dissociating alkali to form hydrochloride to obtain Ulotaront. The resolution yield of the method is 34.2%, the resolution yield of Ulotaront is improved, the operation is easier, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a chiral resolution method for preparing Ulotaront and enantiomer thereof.
Background
Ulotaront, chemical name (S) - (5, 7-dihydro-4H-thieno [2,3-c ]]Pyran-7-yl) -N-methyl-methylamine hydrochloride, a dual agonist developed by Sunovion Pharmaceuticals Inc., is predominantly produced by the trace amine associated receptor 1 (TAAR 1) and 5-hydroxytryptamine type 1A (5-HT 1A ) The receptor acts. Ulotaront is in the clinical research stage of various mental diseases such as schizophrenia and generalized anxiety disorder. Unlike atypical anti-schizophrenia drugs currently in clinical use, ulotarnit is not as active as dopamine 2 (D 2 )、5-HT 2A Receptor binding, thus does not lead to D 2 Related extrapyramidal reactions and endocrine-related side effects.
The prior invention patent (WO 2019/161236A 1) discloses a method that: the thiophene-3-ethanol (SM 1) and the methylaminoacetaldehyde dimethyl acetal (SM 2) are subjected to cyclization reaction under the condition of trifluoromethanesulfonic acid (TfOH) to obtain (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methylmethylamine trifluoromethanesulfonate, the (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methylmethylamine (R) -mandelate is obtained through free (R) -mandelic acid resolution and acetone refining, and then Ulotaront (compound 1) is obtained through free and hydrochloride forming, and the total yield is: 14%, resolution yield: 26.5%. In the original grinding process, crystallization is difficult during resolution of (R) -mandelic acid, and resolution efficiency is low, so that a process route which is easy to operate and has higher resolution efficiency is necessary to be developed, and the chiral resolution method for preparing Ulotaront and enantiomer thereof is provided.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a chiral resolution method for preparing Ulotaront and enantiomer thereof so as to solve the problems of the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions: a chiral resolution process for preparing ulotarnit and its enantiomers, comprising the steps of:
step one: in a solvent, compound 2: salifying (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine with L-tartaric acid to obtain a crude product of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate;
step two: heating, refluxing and stirring crude products of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate in a solvent until the system is clear, preserving heat and stirring, cooling to room temperature to separate out solid, filtering and washing to obtain a compound 3;
step three: the compound 3 is free under alkaline condition, and (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base is obtained by solvent extraction;
step four: (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base in a solvent HCl was added to form Compound 1: ulotaront.
As a preferable technical scheme of the invention, the solvent in the first step is selected from one or more than two solvents selected from toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-25% by mass relative to compound 2: 1.
as a preferred embodiment of the present invention, the equivalent amount of L-tartaric acid used in the first step to compound 2 is selected from 0.2 to 0.5.
As a preferable technical scheme of the invention, the solvent in the second step is selected from one or more than two solvents selected from toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the volume ratio of the solvent to the crude product of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate is 5-40:1.
as a preferable technical scheme of the invention, the alkali in the alkaline condition in the third step is any one or combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and cesium carbonate.
As a preferred technical scheme of the invention, the alkali dissociation in the step three is carried out as follows: after the compound 3 and water are stirred uniformly, adding an alkali solution, regulating the pH value to be 13, adding a solvent for extraction, stirring until the solid is completely dissolved, separating a liquid, adding an organic phase into saturated saline water for washing, concentrating and drying the organic phase under reduced pressure to obtain (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base.
As a preferred embodiment of the present invention, the solvent in step three and step four is selected from: toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol and dichloromethane; the solvent volume used was 5-25:1 by mass relative to compound 3.
A chiral resolution process for preparing a ulotarnit enantiomer comprising the steps of:
s1: in a solvent, compound 2: salifying (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine with D-tartaric acid to obtain a crude product of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate;
s2: heating, refluxing and stirring the crude product of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate in a solvent until the system is clear, preserving heat and stirring, cooling to room temperature to separate out solid, and performing suction filtration and washing to obtain a compound 3';
s3: the compound 3' is free under alkaline condition, and (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base is obtained by solvent extraction;
the method comprises the following steps: after the compound 3' and water are stirred uniformly, adding an alkali solution, adjusting the pH value to 13, adding a solvent for extraction, stirring until the solid is completely dissolved, and separating the liquid; washing the organic phase with saturated saline, concentrating the organic phase under reduced pressure, and drying to obtain (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base;
s4: (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base in a solvent HCl is added to generate a compound 1': (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride.
As a preferable technical scheme of the invention, the solvent in the S1 is selected from one or more than two solvents selected from toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-25% by mass relative to compound 2': 1, a step of; the equivalent amount of D-tartaric acid used with compound 2' is selected from 0.2-0.5;
the solvent in the S2 is selected from one or more than two of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-40% by mass relative to the 3' crude compound: 1.
as a preferable technical scheme of the invention, the alkali in the alkaline condition in S3 is any one or combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and cesium carbonate;
the solvents described in S3 and S4 are both selected from: toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol and dichloromethane; the solvent volume used was 5-25:1 by mass relative to compound 3'.
The beneficial effects of the invention are as follows: the resolution yield of the method is 34.2%, the resolution yield of the Ulotaront is improved, the operation is easier, the method is applicable to industrial production, and the defects of complicated operation and lower resolution yield of the existing Ulotaront chiral resolution method are overcome.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride according to the invention.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride according to the invention.
FIG. 3 shows the formula of the present invention, 1 is the formula of compound 1, 2 is the formula of compound 2,3 is the formula of compound 3, 4 is the formula of compound 4, 1 'is the formula of compound 1', and 3 'is the formula of compound 3'.
Detailed Description
The preferred embodiments of the present invention will be described in detail below with reference to the attached drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making clear and defining the scope of the present invention.
The invention relates to the addition, content and concentration of various substances, wherein the percentages refer to the mass percentages unless otherwise specified.
In the examples of the present invention, if no specific explanation is given for the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).
Reagent: the organic solvents and the like used in the embodiment of the invention are all analytical grade and are directly used. Reagents were purchased from national pharmaceutical groups chemical reagents, inc.
Polarimeter model: rudolphAutopol V PlusAutoFill;
nuclear magnetic resonance instrument model: bruker avance HD 500MHz;
mass spectrometer model: agilent 6540Q-TOF.
HPLC detection conditions for Ulotaront: CHIRALPAKAD-H (4.6 mm. Times.250 mm,5 μm); mobile phase: n-hexane: ethanol: diethylamine = 97.9:2:0.1, detection wavelength 234nm; the flow rate is 1ml/min; column temperature is 30 ℃; the sample injection amount was 20. Mu.L.
Example 1
Preparation of (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine (compound 2);
125.0g (0.975 mol,1 eq) SM1 (thiophene-3-ethanol), 110.3g (0.926 mol,0.95 eq) SM2 (methylamino acetaldehyde dimethyl acetal) and 1000mL dioxane are added into a reaction bottle, stirred and cooled in an ice water bath, 219.6g (1.463 mol,1.5 eq) of trifluoromethanesulfonic acid is added dropwise, the temperature T is controlled to be less than or equal to 25 ℃, and after the dropwise addition, the reaction is transferred to a constant temperature oil bath pot to be heated to 80 ℃ for 2 hours.
Post-treatment: transferring the reaction solution to a single-port bottle, removing dioxane by rotary evaporation, adding 500mL of water and 250mL of dichloromethane into the residue, regulating the pH of the system to 13 by using 30% sodium hydroxide, extracting and layering, extracting the aqueous layer with 250mL of dichloromethane for 2 times, washing the combined organic layer with 250mL of saturated saline, drying by using anhydrous sodium sulfate, filtering, transferring the filtrate into the reaction bottle, regulating the pH to 2 by using 4M ethyl acetate hydrochloride solution at the temperature T less than or equal to 25 ℃, and separating out a large amount of light yellow solid.
Filtration and washing of the filter cake with dichloromethane, drying with air at 55℃for 5H gives 140.5g of (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride (compound 4) in a yield of 65.6%.
140.0g of Compound 4, 280mL of water and 250mL of methylene chloride were added to a reaction flask and stirred to dissolve, the pH of the system was adjusted to 13 with 30% sodium hydroxide, the layers were separated by extraction, the aqueous layer was extracted 2 more times with 250mL of methylene chloride, the combined organic layers were washed with 250mL of saturated brine, dried over anhydrous sodium sulfate for 0.5h, suction filtered, and the filtrate was concentrated to give 111.2g of Compound 2 as a brown oil in 95.2% yield.
Example 2
Selecting a chiral resolving agent;
in order to obtain a resolving agent with better adaptability and higher resolving efficiency, a common resolving agent is selected to resolve the compound 2.
(S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine R-mandelate salt preparation;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of acetonitrile are added to a reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 0.831g (5.46 mmol,1 eq) R-mandelic acid in 5mL acetonitrile was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by acetonitrile to obtain an off-white solid (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine R-mandelate with the value of 0.63g, e.e: 59.8%.
(S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-malate preparation;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of acetonitrile are added to a reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 0.366g (2.73 mmol,0.5 eq) L-malic acid in 5mL acetonitrile was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by acetonitrile to obtain an off-white solid (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-malate with the value of 0.73g, e.e: 49.8%.
(S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-lactate preparation;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of acetonitrile are added to a reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 0.492g (5.46 mmol,1 eq) L-lactic acid in 5mL acetonitrile was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by acetonitrile to obtain an off-white solid (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-lactate with the value of 0.78g, e.e: 50.1%.
Crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of ethanol are added to the reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 0.409g (2.73 mmol,0.5 eq) L-tartaric acid in 5mL ethanol was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the heat for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by ethanol to obtain 1.07g of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate serving as an off-white solid, and obtaining the yield: 76%, e.e. value: 62.5%.
(S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-camphorsulfonate preparation;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of acetonitrile are added to a reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 1.268g (5.46 mmol,1 eq) L-camphorsulfonic acid in 5mL acetonitrile was added dropwise, the temperature was controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by acetonitrile to obtain an off-white solid (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-camphorsulfonate with the value of 0.92g, e.e: 50.8%.
(S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-camphoric acid salt preparation;
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of acetonitrile are added to a reaction flask and stirred well, and the temperature is raised to 50 ℃. A solution of 0.547g (2.73 mmol,0.5 eq) L-camphoric acid in 5mL acetonitrile was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by acetonitrile to obtain an off-white solid (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-camphoric acid salt with the value of 0.63g, e.e: 50.3%.
Table 1: resolution of Compound 2 by different resolving Agents
From Table 1, it can be seen that L-malic acid, L-lactic acid, L-camphorsulfonic acid had little resolving effect on Compound 2; the resolution of compound 2 by L-tartaric acid is better than R-mandelic acid.
Example 3
Investigation of the use equivalent of the chiral resolving agent L-tartaric acid;
crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate (crude compound 3);
1.00g (5.46 mmol,1 eq) of Compound 2, 5mL of ethanol are added to the reaction flask and stirred well, and the temperature is raised to 50 ℃. 0.2-0.5eq of L-tartaric acid dissolved in 5mL of ethanol is added dropwise, and the temperature is controlled at 50-60 ℃. After the dripping is finished, preserving the heat for 1h, slowly cooling to room temperature for crystallization for 1h, filtering, and leaching a filter cake by using ethanol to obtain a crude product of the off-white solid compound 3.
Table 2: resolution of Compound 2 by different equivalents of L-tartaric acid
From Table 2, it can be seen that the e.e. values after resolution of 0.25 and 0.35 equivalent L-tartaric acid are similar, but the yield of 0.3 equivalent is higher, preferably 0.3 equivalent.
Example 4
Selecting a refining solvent;
refining crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate;
1.00g of crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate is added into a solvent, heated, refluxed and dissolved, slowly cooled to room temperature for crystallization, and filtered, and the filter cake is leached by the solvent, thus obtaining (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate (compound 3).
Table 3: refining crude compound 3 by different solvents
From Table 3, it can be seen that the respective solvent purifications have equivalent e.e. values, and that ethanol purifications are the highest in yield, and ethanol purifications are preferred.
Example 5
The use amount of the solvent is selected;
refining crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate;
1.00g of crude (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate is added into ethanol, heated, refluxed and dissolved, slowly cooled to room temperature for crystallization, filtered, and the filter cake is leached by ethanol, thus obtaining (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate (compound 3).
Table 4: refining crude product of compound 3 by different absolute ethyl alcohol amounts
From Table 3, it can be seen that the e.e. values of 25 and 30-fold ethanol purification are equivalent, but the yield is higher when 25-fold ethanol purification is used, and 25-fold ethanol purification is preferable.
Example 6
Preparation of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride (ulotarnit);
38.5g of compound 3 is added into 80mL of water and 80mL of dichloromethane, the pH is regulated to 13 by 30% sodium hydroxide, the layers are extracted and separated, the aqueous layer is extracted for 2 times by 80mL of dichloromethane, the organic layers are combined, dried and evaporated to dryness, 192.5mL of ethyl acetate is added into the oily substance, dry hydrochloric acid gas is introduced under stirring, the pH is regulated to 2, the precipitated solid is filtered and dried to obtain 27.0g of Ulotaront, the yield is 90%, the resolution yield is 34.2%, and the e.e value is 99.90%.
Nuclear magnetic data: as shown in fig. 1: 1 h NMR (500 mhz, dmso) δ9.28 (br, 2H), 7.49 (d, j=4.9 hz, 1H), 6.94 (d, j=5.0 hz, 1H), 5.23 (d, j=8.7 hz, 1H), 4.13 (dt, j=11.4, 4.7hz, 1H), 3.76 (ddd, j=11.6, 8.5,4.4hz, 1H), 3.31 (dd, j=13.0, 2.7hz, 1H), 3.17 (dd, j=13.0, 10.1hz, 1H), 2.81-2.60 (m, 2H), 2.58 (s, 3H). As shown in fig. 2: 13 CNMR(126MHz,DMSO-d 6 )δ135.19,131.72,127.96,124.96,70.67,62.94,52.56,33.27,26.02.(c 0.50,MeOH)，(+)-HR-ESI-MS[M+H] + m/z184.0787。
example 7
(R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine hydrochloride;
5.00g (27.3 mmol,1 eq) of Compound 2, 25mL of ethanol are added to the reaction flask and stirred well and warmed to 50deg.C. A solution of 1.23g (7.3 mmol,0.3 eq) of D-tartaric acid in 25mL of ethanol was added dropwise, the temperature being controlled at 50-60 ℃. After the dripping is finished, preserving the temperature for 1H, slowly cooling to room temperature for crystallization for 1H, filtering, eluting a filter cake by ethanol to obtain 3.8g of white solid (R) - (5, 7-dihydro-4H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate crude product, and obtaining the yield: 54%, e.e. value: 84.1%.
3.8g of crude (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate and 76mL of ethanol are added into a reaction bottle, stirred and heated until the mixture is dissolved in reflux. Slowly cooling to 20-25 ℃ for crystallization for 1H, filtering, eluting a filter cake with ethanol to obtain an off-white solid (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate, drying the off-white solid to weight of 1.7g, and refining the off-white solid to obtain the refined yield: 45%, e.e. value: 99.0%.
1.7g of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methylmethylamine D-tartrate was added to 4mL of water and 8mL of methylene chloride, pH was adjusted to 13 with 30% sodium hydroxide, the layers were separated by extraction, the aqueous layer was extracted 2 times with 8mL of methylene chloride, the combined organic layers were dried and evaporated to dryness to give an oil, which was added to 8.5mL of ethyl acetate with stirring, the dried hydrochloric acid gas was introduced to adjust pH to 2, and the precipitated solid was filtered and dried to give 1.2g of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methylmethylamine hydrochloride in a yield of 90% and an e.e value of 99.90%.
Nuclear magnetic data: 1 H NMR(500MHz,DMSO-d 6 )δ9.28(br,2H),9.04(s,1H),7.49(d,J＝5.0Hz,1H),6.94(d,J＝5.0Hz,1H),5.25(dd,J＝9.9,1.3Hz,1H),4.12(dt,J＝11.4,4.7Hz,1H),3.76(ddd,J＝11.6,8.4,4.4Hz,1H),3.31(dd,J＝13.0,2.5Hz,1H),3.18(dd,J＝12.9,10.2Hz,1H),2.80–2.62(m,2H),2.59(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ135.18,131.71,127.96,124.95,70.67,62.94,52.56,33.27,26.01.(c 0.50,MeOH)，(+)-HR-ESI-MS[M+H] + m/z 184.0791。
the foregoing examples merely illustrate embodiments of the invention and are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.
Claims (10)
1. A chiral resolution method for preparing Ulotaront is characterized in that: the method comprises the following steps:
step one: in a solvent, compound 2: salifying (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine with L-tartaric acid to obtain a crude product of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate;
step two: heating, refluxing and stirring crude products of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate in a solvent until the system is clear, preserving heat and stirring, cooling to room temperature to separate out solid, filtering and washing to obtain a compound 3;
step three: the compound 3 is free under alkaline condition, and (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base is obtained by solvent extraction;
step four: (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base in a solvent HCl was added to form Compound 1: ulotaront.
2. A chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the solvent in the first step is selected from one or more than two of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-25% by mass relative to compound 2: 1.
3. a chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the equivalent of L-tartaric acid used in the first step to compound 2 is selected from 0.2 to 0.5.
4. A chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the solvent in the second step is selected from one or more than two mixed solvents of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the volume ratio of the solvent to the crude product of (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine L-tartrate is 5-40:1.
5. a chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the alkali in the alkaline condition in the third step is any one or a combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and cesium carbonate.
6. A chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the base ionization in step three is performed as follows: after the compound 3 and water are stirred uniformly, adding an alkali solution, regulating the pH value to be 13, adding a solvent for extraction, stirring until the solid is completely dissolved, separating a liquid, adding an organic phase into saturated saline water for washing, concentrating and drying the organic phase under reduced pressure to obtain (S) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base.
7. A chiral resolution process for preparing ulotarnit according to claim 1, characterized in that: the solvent in the third step and the fourth step is selected from the following: toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol and dichloromethane; the solvent volume used was 5-25:1 by mass relative to compound 3.
8. A chiral resolution process for preparing a ulotarnit enantiomer, characterized in that: the method comprises the following steps:
s1: in a solvent, compound 2: salifying (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine with D-tartaric acid to obtain a crude product of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate;
s2: heating, refluxing and stirring the crude product of (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine D-tartrate in a solvent until the system is clear, preserving heat and stirring, cooling to room temperature to separate out solid, and performing suction filtration and washing to obtain a compound 3';
s3: the compound 3' is free under alkaline condition, and (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base is obtained by solvent extraction;
the method comprises the following steps: after the compound 3' and water are stirred uniformly, adding an alkali solution, adjusting the pH value to 13, adding a solvent for extraction, stirring until the solid is completely dissolved, and separating the liquid; washing the organic phase with saturated saline, concentrating the organic phase under reduced pressure, and drying to obtain (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base;
s4: (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl methylamine base in a solvent HCl is added to generate a compound 1': (R) - (5, 7-dihydro-4H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine hydrochloride.
9. A chiral resolution process for preparing ulotarnit enantiomers as defined in claim 8, characterized in that:
the solvent in the S1 is selected from one or more than two of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-25% by mass relative to compound 2': 1, a step of; the equivalent amount of D-tartaric acid used with compound 2' is selected from 0.2-0.5;
the solvent in the S2 is selected from one or more than two of toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol, isopropanol and dichloromethane; the solvent volume used was 5-40% by mass relative to the 3' crude compound: 1.
10. a chiral resolution process for preparing ulotarnit enantiomers as defined in claim 8, characterized in that: the alkali in the alkaline condition in the S3 is any one or combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and cesium carbonate;
the solvents described in S3 and S4 are both selected from: toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tertiary butyl ether, n-heptane, methanol, ethanol and dichloromethane; the solvent volume used was 5-25:1 by mass relative to compound 3'.
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