CN117865880A - Synthesis process of KX2-361-D4 benzenesulfonate - Google Patents
Synthesis process of KX2-361-D4 benzenesulfonate Download PDFInfo
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- CN117865880A CN117865880A CN202410284557.6A CN202410284557A CN117865880A CN 117865880 A CN117865880 A CN 117865880A CN 202410284557 A CN202410284557 A CN 202410284557A CN 117865880 A CN117865880 A CN 117865880A
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- benzenesulfonate
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- morpholine
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 title claims abstract description 33
- 229940077388 benzenesulfonate Drugs 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical class [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- SWJPEBQEEAHIGZ-RHQRLBAQSA-N 1,4-dibromo-2,3,5,6-tetradeuteriobenzene Chemical compound [2H]C1=C([2H])C(Br)=C([2H])C([2H])=C1Br SWJPEBQEEAHIGZ-RHQRLBAQSA-N 0.000 claims description 8
- -1 4-morpholinylphenyl-2, 3,5,6-d 4 Chemical class 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 abstract description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 7
- 239000012467 final product Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 102000001332 SRC Human genes 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 108010087686 src-Family Kinases Proteins 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 235000010703 Modiola caroliniana Nutrition 0.000 description 1
- 244000038561 Modiola caroliniana Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000029115 microtubule polymerization Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis process of KX2-361-D4 benzene sulfonate. The synthesis process of KX2-361-D4 benzenesulfonate takes a compound I1, 4-dibromobenzene-D4 as a raw material, and is coupled with morpholine in the presence of Pd2 (dba) 3, BINAP and sodium tert-butoxide to obtain a deuterated compound intermediate 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine; then sequentially pass through Suzuki coupling, S N Ar reaction, cyano hydrolysis reaction and amide condensation reaction, wherein KX2-361-D4 is prepared in five steps, and finally salt formation is carried out with benzenesulfonic acid to obtain four deuterium-marked KX2-361-D4 benzenesulfonate. The invention has the following technical effects: the KX2-361-D4 benzene sulfonate has simple and convenient synthesis method and easily obtained raw materialsThe steps are short and easy to operate.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis process of KX2-361-D4 benzene sulfonate.
Background
The medicine molecule KX2-361, also called KX02, is a novel oral small molecule medicine. It has dual action mechanism, is not only Src kinase activity inhibitor, but also can inhibit microtubule polymerization, so that it has potential anti-tumor activity. KX2-361 was able to bind and inhibit Src kinase activity upon oral administration. The drug shows activity against GL261 glioma in a mouse model and can provide long-term survival effect. KX2-361 is a member of a novel family of compounds having Src kinase and tubulin polymerization inhibiting activity. It shows good oral bioavailability in mice and can easily cross the blood brain barrier. This drug was originally developed by athex, inc. Worldwide, the highest state of development of KX2-361 reaches clinical stage 1. It is mainly used for treating tumor and nervous system diseases, and the current research indications include glioma, glioblastoma and solid tumor. In addition, there is a phase 1 clinical study directed to patients with advanced malignancy, mainly assessing safety, tolerability and pharmacokinetic properties of KX2-361, especially for those patients who do not respond to conventional therapies. (cf. U.S. Pat. No. 5,2007/0015752 A1, journal of Neuro-Oncology (2018) 140:519-527, CN 106902357A, WO2014036426 A1)
The structural formula of KX2-361-D4 benzene sulfonate is as follows:
KX2-361-D4 benzenesulfonate is a stable isotope deuterium-labeled compound of hydrogen, and the compound can be used for researching the toxicology and pharmacology of KX2-361, and no synthesis method of KX2-361-D4 benzenesulfonate is reported at present.
The KX2-361 conventional route is as follows: (J. Med. Chem. 2018, 61, 4704-4719; WO2014036426A 1)
If the isotopically labeled KX2-361-D4 is synthesized according to the method for synthesizing KX2-361 in the prior art, the following technical problems exist:
1) No 4- (4-bromophenyl-2, 3,5,6-d 4) morpholine is commercially available;
2) 4- (4-bromophenyl-2, 3,5,6-d 4) morpholine cannot be selectively deuterated by conventional transition metal-catalyzed hydrogen deuterium substitution methods.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a synthesis process of KX2-361-D4 benzene sulfonate.
The technical scheme for solving the technical problems is as follows:
a synthetic process of KX2-361-D4 benzene sulfonate comprises the following steps:
the method comprises the following steps:
1) Takes a compound 1, namely p-dibromobenzene D4 and morpholine as raw materials, and takes Pd as a raw material 2 (dba) 3 Toluene is used as a solvent in the presence of BINAP and sodium tert-butoxide, heating is carried out to reflux, and the reaction is carried out for 4 hours, thus obtaining deuterated compound intermediate, namely compound 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine;
2) Dissolving compound 3, namely 6-fluoropyridyl-3-boric acid and deuterated intermediate compound 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine prepared in step 1) in 1, 4-dioxane, and carrying out reflux reaction for four hours in the presence of tetraphenylphosphine palladium and potassium carbonate under the protection of nitrogen to prepare intermediate compound 4, namely 4- (4- (6-fluoropyridyl-3-) phenyl-2, 3,5, 6-D4) morpholine;
3) Dissolving a compound 4 and anhydrous acetonitrile in anhydrous tetrahydrofuran, cooling the system to-10 ℃ under the protection of nitrogen, adding KHMDS into an injection, and reacting for 30 minutes; naturally heating to room temperature, adding water to quench the reaction to obtain an intermediate compound 5, namely 2- (5- (4-morpholinylphenyl-2, 3,5,6-d 4) pyridyl-2-acetonitrile;
4) Compound 5 was added to 1N NaOH and heated to 90 ℃ for 16 hours; adjusting the pH of the solution to 1-2 with 1N HCl, and extracting with dichloromethane to obtain an intermediate compound 6, namely 2- (5- (4-morpholinylphenyl-2, 3,5,6-d 4) pyridyl-2-acetic acid;
5) Stirring compound 6 and compound 7 m-fluorobenzylamine at room temperature overnight in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and diisopropylethylamine by using absolute methanol as a solvent to prepare a compound 8, KX2-361-D4;
6) The compound 8, namely KX2-361-D4, is heated to 110 ℃ to dissolve with anisole, the compound 9 benzenesulfonic acid is dissolved with proper acetonitrile, and is added dropwise into the reaction liquid, and the KX2-361-D4 benzenesulfonate is prepared by slowly dropping methyl tertiary butyl ether through slowly decreasing oil bath temperature of about 30 ℃/h, cooling to room temperature.
Preferably, in the step 1), the compound 1 is prepared by adding commercially available deuterated benzene-D6 (99.5% D, wherein 99.5% D represents the specification of the commodity, and deuteration rate) and N-bromosuccinimide to N, N-dimethylformamide, adding trace amount of iodine for catalysis, and reacting at 50 ℃ overnight to obtain p-dibromobenzene D4; wherein the mole ratio of deuterated benzene-D6 to N-bromosuccinimide is 1:2.5; deuterated benzene-D6 and N, N-dimethylformamide in mass-volume ratio of 1g:10mL.
Preferably, in the step 1), the molar ratio of the compound 1 to the dibromobenzene D4 to the morpholine is: 1:1 to 1:1.1. more preferably, the molar ratio of compound 1 to dibromobenzene D4 and morpholine is: 1:1.06.
preferably, in the step 2), the molar ratio of the compound 2 to the compound 3 is: 1:1.
preferably, in the step 4), the mass-volume ratio of the compound 5 to the 1N sodium hydroxide aqueous solution is not less than 1g:50mL.
Preferably, in the step 5), the molar ratio of the compound 6, the compound 7 3-fluorobenzylamine, EDCI, HOBt and diisopropylethylamine is 1.05:1:1.7:1.6:3.2.
preferably, in the step 6), the mass-volume ratio of KX2-361-D4 to anisole is 1g:62mL.
The invention has the following technical effects:
1) The KX2-361-D4 benzenesulfonate synthesis method is simple and convenient, and the raw materials are easy to obtain, the steps are short and the operation is easy.
2) The invention innovatively establishes a synthetic method of 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, and successfully synthesizes the 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, wherein the deuteration rate is more than 98%.
3) The invention further synthesizes KX2-361-D4 benzene sulfonate by using 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, and the deuteration rate of the final product reaches more than 98 percent.
Drawings
FIG. 1 shows the nuclear magnetic resonance detection result of KX2-361-D4 benzenesulfonate as the final product in example 1.
FIG. 2 is a mass spectrum of the final product KX2-361-D4 benzenesulfonate in example 1.
FIG. 3 shows the results of chromatographic detection of the final product KX2-361-D4 benzenesulfonate in example 1.
Detailed Description
The present invention will be further described in detail below with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent, and it is apparent that the described examples are only some of the examples of the present invention, but not all of the examples.
As analyzed in the background of the present application, the prior art has the following technical problems: 1) No 4- (4-bromophenyl-2, 3,5,6-d 4) morpholine is commercially available; 2) 4- (4-bromophenyl-2, 3,5,6-d 4) morpholine cannot be selectively deuterated by conventional transition metal-catalyzed hydrogen deuterium substitution methods. In order to solve the problems, the inventor takes an autonomously synthesized compound 1, 4-dibromobenzene-D4 as a raw material, and couples the compound with morpholine in the presence of Pd2 (dba) 3, BINAP and sodium tert-butoxide to obtain a deuterated intermediate compound 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine; then sequentially carrying out suzuki coupling, SNAr reaction, cyano hydrolysis reaction and amide condensation reaction, five steps are carried out to prepare KX2-361-D4, and finally the KX2-361-D4 benzenesulfonate marked by four deuterium is obtained after salifying with benzenesulfonic acid. In the invention, the inventor innovatively establishes a synthetic method of 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, successfully synthesizes 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, further synthesizes KX2-361-D4 benzenesulfonate by using 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine, and the deuteration rate of a final product reaches more than 98 percent.
Wherein, the compound 1, 4-dibromobenzene-D4 is synthesized by the inventor autonomously, the preparation method of the compound 1 is as follows, commercial deuterated benzene-D6 (99.5 percent D, wherein 99.5 percent D represents the specification of commodity, deuteration rate) and N-bromosuccinimide are added into N, N-dimethylformamide, trace iodine is added for catalysis, and the reaction is carried out overnight at 50 ℃, thus obtaining the p-dibromobenzene D4; wherein the mole ratio of deuterated benzene-D6 to N-bromosuccinimide is 1:2.5; deuterated benzene-D6 and N, N-dimethylformamide in mass-volume ratio of 1g:10mL.
The other conventional raw materials are all commercially available.
The invention will be described in further detail below by means of detailed embodiments in conjunction with the accompanying drawings.
The specific preparation method of the compound 1 used in the examples in the invention is as follows: 8.4g of commercially available deuterated benzene D6 (99.5% D,0.1 mol) and 44.5g of N-bromosuccinimide (0.25 mol) were added together to 84mL of N, N-dimethylformamide, and 20mg of trace iodine was added for catalysis, and the mixture was reacted overnight at 50℃to obtain 20.8g of p-dibromobenzene D4 in 87% yield.
Example 1
The synthetic process of KX2-361-D4 benzenesulfonate in this example is as follows:
the method specifically comprises the following steps:
1. preparation of Compound 2
Sequentially adding in a 100mL three-port bottle:
compound 1 (1.00 g,4 mmol)
• Pd 2 (dba) 3 (26mg，0.028mmol)
• BINAP(53mg, 0.085mmol)
• t-BuONa(611mg, 6.36mmol)
Three substitutions were made by nitrogen. Morpholine (369 mg, 4.24 mmol) was dissolved in 20mL toluene and added to the reaction solution, followed by three more nitrogen substitutions. The system was heated to reflux to form a mauve solution and reacted for 4 hours. After removing the heat source and naturally cooling to room temperature, water (50 mL) was added, ethyl acetate (20 ml×3), saturated brine (50 mL) was rinsed, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA/pe=1/3) to give 720mg of compound 2 as a yellow solid in 73% yield.
2. Preparation of Compound 4
Sequentially adding in a 100mL single-port bottle:
compound 2 (1.22 g, 4.95 mmol)
Compound 3 (710 mg, 5 mmol)
Potassium carbonate (1.08 g, 7.82 mmol)
TetratriphenylPalladium phosphate (300 mg, 0.26 mmol)
Three substitutions were made by nitrogen. A1, 4-dioxane/water (25 mL/5 mL) mixture was added and the nitrogen substitution was performed three more times. The system was heated to reflux to form a yellow clear solution which was reacted for 4 hours. The reaction was monitored by TLC, the heat source was removed, and after cooling to room temperature, extraction was performed with ethyl acetate (50 mL. Times.3). The organic phases were combined, rinsed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA/pe=1/5) to give 1.14g of compound 4 as a white solid in 88% yield.
3. Preparation of Compound 5
Compound 4 (502 mg,1.9 mmol), anhydrous acetonitrile (315 mg, 7.68 mmol), anhydrous tetrahydrofuran (40 mL) were added to a three-necked flask and replaced three times with nitrogen. The system was cooled to-10℃and KHMDS (1M in THF) (10 mL) was added to the injection and reacted for 30 minutes. Naturally heating to room temperature, adding water (20 mL) to quench the reaction, and adjusting the pH to 1-2 by 1N HCl. Extraction was performed with ethyl acetate (30 mL. Times.3), pH was adjusted to 9-10 with 1N NaOH, and extraction was performed with ethyl acetate (50 mL. Times.3). The organic phases were combined, rinsed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (EA/pe=1/3 to EA/pe=1/1) to give 300mg of compound 5 as a yellow solid in 55.8% yield.
4. Preparation of Compound 6
Compound 5 (210 mg,0.74 mmol) was added to 1N NaOH (10 mL) and reacted at 90℃for 16 hours. And removing the heating source, and naturally cooling to room temperature. The pH of the solution was adjusted to 1-2 with 1N HCl and extracted with methylene chloride (20 mL. Times.5). Dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM/meoh=10:1, 1% acetic acid) to give 120mg of compound 6 as a white solid in 53.7% yield.
5. Preparation of Compound 8
Sequentially adding in a 50mL single-port bottle:
compound 6 (120 mg,0.39 mmol)
Compound 7 (46 mg,0.37 mmol)
• EDCI(120mg，0.628mml)
• HOBt（81mg，0.60mmol）
• DIEA(155mg，1.2mmol)
Anhydrous methanol (10 mL)
Stirring at room temperature to obtain yellow transparent solution. The reaction was monitored by LC-MS and after completion of the reaction column chromatography (EA/pe=1/1) gave 116mg of compound 8 in 72.7% yield.
6. Preparation of KX2-361-D4 benzenesulfonate
Compound 8 (81 mg) was dissolved with anisole (5 mL) and heated to 110deg.C to dissolve, affording a yellow clear solution. Compound 9 benzenesulfonic acid (38.6 mg) was dissolved in appropriate acetonitrile and added dropwise to the reaction solution to obtain a brick-red solution. The temperature was lowered to room temperature by slowly decreasing the oil bath temperature, about 30 c/h. Methyl tert-butyl ether (10 mL) was slowly added dropwise, and a large amount of brown solid precipitated. Methyl tert-butyl ether (15 mL) was added dropwise and suction filtered to give about 100mg of a brown solid. The mixture was rinsed with methyl tert-butyl ether (10 mL) and dried to give 97.5mg of solid KX2-361-D4 benzenesulfonate in 87% yield.
And performing nuclear magnetic resonance detection and chromatographic detection on the final product. 1 H-NMR(400MHz, DMSO-d6) δ 9.12 (s, 1H), 8.92 (d,J = 7.0Hz, 1H), 8.72 (d,J = 8.2Hz, 1H), 7.94 (d,J = 8.5Hz, 1H), 7.60 (d,J = 6.4Hz, 2H), 7.39 (d,J = 7.5Hz, 1H), 7.32 (d,J = 6.0Hz, 3H), 7.14 (d,J = 11.1Hz, 4H), 4.37 (s, 2H), 4.06 (s, 2H), 3.76 (d, j=6.1 Hz, 4H), 3.23 (d, j=5.7 Hz, 4H). MS (ESI) 408, 409, see fig. 1-3.
As can be seen from fig. 1 and 2: the product was KX2-361-D4 benzenesulfonate.
As can be seen from fig. 3: in the HPLC purity analysis, the ionization balance of the salt is that KX2-361-D4 benzene sulfonate is used for 3.972min and 6.694min, and the mass spectrum detector shows that the molecular weight including fragment peaks are identical, so that the actual purity of the product reaches 99.6%, and the requirement of the product serving as a standard substance for analysis and control is completely met.
The foregoing is merely exemplary embodiments of the present invention and are not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention or direct or indirect application in other related technical fields are included in the scope of the present invention.
Claims (7)
1. A synthesis process of KX2-361-D4 benzenesulfonate is characterized by comprising the following steps:
1) Takes a compound 1, namely p-dibromobenzene D4 and morpholine as raw materials, and takes Pd as a raw material 2 (dba) 3 Toluene is used as a solvent in the presence of BINAP and sodium tert-butoxide, heating is carried out to reflux, and the reaction is carried out for 4 hours, thus obtaining deuterated compound intermediate, namely compound 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine;
2) Dissolving compound 3, namely 6-fluoropyridyl-3-boric acid and deuterated intermediate compound 2, namely 4- (4-bromophenyl-2, 3,5, 6-D4) morpholine prepared in step 1) in 1, 4-dioxane, and carrying out reflux reaction for four hours in the presence of tetraphenylphosphine palladium and potassium carbonate under the protection of nitrogen to prepare intermediate compound 4, namely 4- (4- (6-fluoropyridyl-3-) phenyl-2, 3,5, 6-D4) morpholine;
3) Dissolving a compound 4 and anhydrous acetonitrile in anhydrous tetrahydrofuran, cooling the system to-10 ℃ under the protection of nitrogen, adding KHMDS into an injection, and reacting for 30 minutes; naturally heating to room temperature, adding water to quench the reaction to obtain an intermediate compound 5, namely 2- (5- (4-morpholinylphenyl-2, 3,5,6-d 4) pyridyl-2-acetonitrile;
4) Compound 5 was added to 1N NaOH and heated to 90 ℃ for 16 hours; adjusting the pH of the solution to 1-2 with 1N HCl, and extracting with dichloromethane to obtain an intermediate compound 6, namely 2- (5- (4-morpholinylphenyl-2, 3,5,6-d 4) pyridyl-2-acetic acid;
5) Stirring compound 6 and compound 7 m-fluorobenzylamine at room temperature overnight in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and diisopropylethylamine by using absolute methanol as a solvent to prepare a compound 8, KX2-361-D4;
6) Heating KX2-361-D4 as compound 8 to 110 ℃ with anisole to dissolve, dissolving 9-benzenesulfonic acid as compound with proper acetonitrile, dropwise adding into the reaction liquid, slowly dropwise adding methyl tertiary butyl ether through slowly decreasing oil bath temperature at 30 ℃/h to room temperature, and obtaining KX2-361-D4 benzenesulfonate.
2. The process for synthesizing KX2-361-D4 benzenesulfonate as claimed in claim 1, wherein in said step 1), the preparation method of compound 1 is as follows, deuterated benzene-D6 and N-bromosuccinimide are added into N, N-dimethylformamide, iodine is added for catalysis, and reaction is carried out at 50 ℃ overnight to obtain p-dibromobenzene D4; wherein the mole ratio of deuterated benzene-D6 to N-bromosuccinimide is 1:2.5; deuterated benzene-D6 and N, N-dimethylformamide in mass-volume ratio of 1g:10mL.
3. The process for synthesizing KX2-361-D4 benzenesulfonate as claimed in claim 1, wherein in said step 1), the molar ratio of the compound 1 to dibromobenzene D4 to morpholine is: 1:1 to 1:1.1.
4. the process for synthesizing KX2-361-D4 benzenesulfonate as claimed in claim 1, wherein in said step 2), the molar ratio of compound 2 to compound 3 is: 1:1.
5. the process for synthesizing KX2-361-D4 benzenesulfonate as claimed in claim 1, wherein in said step 4), the mass-to-volume ratio of the compound 5 to the 1N aqueous sodium hydroxide solution is not less than 1g:50mL.
6. The process for synthesizing KX2-361-D4 benzenesulfonate according to claim 1, wherein in said step 5), the molar ratio of compound 6, compound 7 3-fluorobenzylamine, EDCI, HOBt and diisopropylethylamine is 1.05:1:1.7:1.6:3.2.
7. the process for synthesizing KX2-361-D4 benzenesulfonate as claimed in claim 1, wherein in said step 6), the mass-to-volume ratio of KX2-361-D4 to anisole is 1g:62mL.
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