CN113512031B - Preparation method of LSD1enzyme inhibitor TAK-418 intermediate compound - Google Patents
Preparation method of LSD1enzyme inhibitor TAK-418 intermediate compound Download PDFInfo
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- CN113512031B CN113512031B CN202110740966.9A CN202110740966A CN113512031B CN 113512031 B CN113512031 B CN 113512031B CN 202110740966 A CN202110740966 A CN 202110740966A CN 113512031 B CN113512031 B CN 113512031B
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- LEEWMGOHGNRDKC-CTHHTMFSSA-N Cl.C1(CC1)CN[C@H]1[C@@H](C1)C1=CC(=CS1)C(=O)NC1CCOCC1 Chemical compound Cl.C1(CC1)CN[C@H]1[C@@H](C1)C1=CC(=CS1)C(=O)NC1CCOCC1 LEEWMGOHGNRDKC-CTHHTMFSSA-N 0.000 title claims abstract description 32
- 229940126183 TAK-418 Drugs 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 239000003112 inhibitor Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- YCNXGPMGMAKDPM-UHFFFAOYSA-N 5-bromothiophene-3-carboxylic acid Chemical compound OC(=O)C1=CSC(Br)=C1 YCNXGPMGMAKDPM-UHFFFAOYSA-N 0.000 claims abstract description 7
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 229940125904 compound 1 Drugs 0.000 claims description 13
- 229940125782 compound 2 Drugs 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- -1 (1R, 2R) -2- (methoxycarbonyl) cyclopropylboric acid Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- KWCHQJSISLQWHH-UHFFFAOYSA-N phosphoric acid;trihydrate Chemical compound O.O.O.OP(O)(O)=O KWCHQJSISLQWHH-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 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 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000003828 vacuum filtration Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 230000001594 aberrant effect Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 206010003805 Autism Diseases 0.000 description 2
- 208000020706 Autistic disease Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 230000007608 epigenetic mechanism Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 5-bromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CS1 ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 description 1
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000004049 epigenetic modification Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a preparation method of an LSD1enzyme inhibitor TAK-418 intermediate compound, which takes 5-bromothiophene-3-carboxylic acid and 4-aminotetrahydropyran as raw materials, and obtains the target TAK-418 intermediate compound through condensation reaction, coupling reaction, hydrolysis reaction and Ke Disi rearrangement reaction. The synthetic method has the advantages of simple reaction route operation, no need of constructing chiral three-membered rings, avoiding the chiral resolution step of conventional synthesis, higher atomic utilization rate of the synthetic route and great economic value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an LSD1enzyme inhibitor TAK-418 intermediate compound.
Background
The results of the research paper "LSD1enzyme inhibitor TAK-418unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models" on Science Advances "show that: LSD1enzyme inhibitor TAK-418 may relieve aberrant epigenetic mechanisms and improve autism symptoms. The research team of this paper also found that inhibition of LSD1enzyme activity by TAK-418 almost normalized gene expression levels in the brain and reduced ASD-like abnormal behavior in various rodents with pre-developmental disorders. TAK-418 may also normalize aberrant epigenetic modifications such as DNA methylation. The results of the study show that early environmental insults may lead to sustained epigenetic dysregulation and abnormal gene expression, while inhibition of LSD1 by TAK-418 may unlock the epigenetic mechanism that stabilizes abnormal gene expression. In summary, TAK-418, a specific inhibitor of the LSD1enzyme, may benefit from a patient with a neurological disorder, and the study of the preparation of this compound is of great importance.
The document WO2015156417A1 reports the synthesis of such compounds:
the synthesis route takes 5-bromothiophene-3-formaldehyde as a raw material, and obtains the TAK-418 intermediate compound through 7-step linear reactions such as a Hoener-Eymond reaction, a three-membered ring cyclization reaction, a hydrolysis reaction, a carbonyl inserting reaction, a condensation reaction and the like, and has long synthesis period and low total yield.
The invention provides a simple and rapid preparation method of an LSD1enzyme inhibitor TAK-418 intermediate compound in order to overcome the defects in the prior art. The method is mainly realized by the following technical scheme: the invention discloses a preparation method of an LSD1enzyme inhibitor TAK-418 intermediate compound, which takes 5-bromothiophene-3-carboxylic acid and 4-aminotetrahydropyran as raw materials, the compound 1 is obtained through condensation reaction, the compound 1 and (1R, 2R) -2- (methoxycarbonyl) cyclopropyl boride are subjected to coupling reaction to obtain a compound 2, and the compound 2 is subjected to hydrolysis reaction and Ke Disi rearrangement reaction to obtain the target TAK-418 intermediate compound. The synthetic reaction route is as follows:
the preparation method of the LSD1enzyme inhibitor TAK-418 intermediate compound specifically comprises the following steps:
step 1: condensation reaction
10.0g of 5-bromothiophene-3-carboxylic acid was added to a 250mL round bottom flask under nitrogen protection, 80mL of N, N-dimethylformamide was poured in and dissolved into a clear solution, then 5.13g of 4-aminotetrahydropyran, 27.6g of 1.5 equivalent of benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (HBTu) and 12.46g of 2.0 equivalent of N, N-diisopropylethylamine were added to the flask, and after the reaction was completed, 80mL of water was added to quench the reaction system, extraction was performed 3 times with 100mL ethyl acetate, the organic phase was combined, washed with an aqueous solution of sodium hydrogencarbonate, concentrated and dried to obtain 12.8g of white solid compound 1 in 91.3% yield.
Step 2: coupling reaction:
into a 250mL round bottom flask under nitrogen was charged 12.8g of 1.0 equivalent of Compound 1, 35.2g of 3.0 equivalent of phosphoric acid trihydrate, poured 100mL of 1,4-dioxane (1, 4-dioxane) and 10.0mL of water to dissolve, followed by a further addition of 12.6g of 1.1 equivalent(1R, 2R) -2- (methoxycarbonyl) cyclopropylboronic acid and 0.1 eq [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl) 2 (dppf)) was stirred at 80℃for 12 hours, after the completion of the reaction, the solid was removed by suction filtration under reduced pressure, 100mL of water was added to the remaining reaction solution, the layers were separated, and the organic phase was concentrated and then subjected to column chromatography (petroleum ether/ethyl acetate=4/1), followed by concentration to give 9.3g of pale yellow solid compound 2 in a yield of 68.5%.
Step 3: hydrolysis reaction
9.3g of Compound 2 and 1.80g of lithium hydroxide, 2.5 equivalents of lithium hydroxide, 100mL of methanol and 20mL of water are added into a 250mL round-bottomed flask, the mixture is stirred at room temperature (25 ℃) for 4 hours, after the reaction is completed, most of methanol is distilled off under reduced pressure, 2mol/L of diluted hydrochloric acid is added to adjust the pH to about 6.0, 8.5g of white solid compound 3 is obtained after suction filtration and drying, and the yield is 96.3%. Step 4: ke Disi rearrangement reaction
To a 100mL round bottom flask under nitrogen protection, 8.5g of compound 3 was added, 40mL of t-butanol and triethylamine were poured in, and the mixture was stirred and dissolved at room temperature to give a clear solution, then 14.3g of diphenyl azide phosphate was slowly added dropwise under ice bath, 1.8 equivalents of diphenyl azide phosphate was added dropwise, and after the dropwise addition was completed, the reaction system was heated to 65℃and stirring was continued for 16 hours. The reaction was stopped, cooled to room temperature, quenched with 40mL of water, extracted 3 times with 80mL of ethyl acetate, the organic phases combined, washed with saturated brine, and the dried oil was concentrated to give 8.2g of a white solid (TAK-418 intermediate compound) in 78.1% yield.
The beneficial effects of the invention are as follows: the invention takes 5-bromothiophene-3-carboxylic acid and 4-aminotetrahydropyran as raw materials, a compound 1 is obtained through condensation reaction, the compound 1 and (1R, 2R) -2- (methoxycarbonyl) cyclopropyl boride are subjected to coupling reaction to obtain a compound 2, and the compound 2 is subjected to hydrolysis reaction and Ke Disi rearrangement reaction to obtain the target TAK-418 intermediate compound. The synthetic method has the advantages of simple reaction route operation, no need of constructing chiral three-membered rings, avoiding the chiral resolution step of conventional synthesis, higher atomic utilization rate of the synthetic route and great economic value.
Drawings
FIG. 1 is a flow chart of a process for preparing a TAK-418 intermediate compound provided by the present invention;
FIG. 2 is a flow chart of a process for preparing TAK-418 intermediate compounds reported in document WO2015156417A 1.
Detailed Description
The present invention will be described in detail with reference to the following specific embodiments.
Example 1:
step 1: condensation reaction
10.0g of 5-bromothiophene-3-carboxylic acid was added to a 250mL round bottom flask under nitrogen protection, 80mL of N, N-dimethylformamide was poured in and dissolved into a clear solution, then 5.13g of 4-aminotetrahydropyran, 27.6g of 1.5 equivalent of benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (HBTu) and 12.46g of 2.0 equivalent of N, N-diisopropylethylamine were added to the flask, and after the reaction was completed, 80mL of water was added to quench the reaction system, extraction was performed 3 times with 100mL ethyl acetate, the organic phase was combined, washed with an aqueous solution of sodium hydrogencarbonate, concentrated and dried to obtain 12.8g of white solid compound 1 in 91.3% yield. LC-MS (es+) m/z=290.1&292.1[M+H] + 。
Step 2: coupling reaction:
into a 250mL round bottom flask under nitrogen is added 12.8g, 1.0 equivalent of Compound 1, 35.2g, 3.0 equivalent of phosphoric acid trihydrate to 100mL of 1,4-dioxane (1, 4-dioxane) and 10.0mL of water to dissolve, followed by 12.6g, 1.1 equivalent of (1R, 2R) -2- (methoxycarbonyl) cyclopropylboronic acid and 0.1 equivalent of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl) 2 (dppf)) was stirred at 80℃for 12 hours, after the completion of the reaction, the solid was removed by suction filtration under reduced pressure, 100mL of water was added to the remaining reaction solution, the layers were separated, and the organic phase was concentrated and then subjected to column chromatography (petroleum ether/ethyl acetate=4/1), followed by concentration to give 9.3g of pale yellow solid compound 2 in a yield of 68.5%. LC-MS (es+) m/z=310.1 [ m+h ]] + 。
Step 3: hydrolysis reaction
Into a 250mL round bottom flask was charged 9.3g of Compound 2 and 1.80g, 2.5 equivalents of lithium hydroxide, 100mL of methylAlcohol and 20mL of water are stirred for 4 hours at room temperature (25 ℃), after the reaction is finished, the reaction system is distilled off most of methanol under reduced pressure, 2mol/L of dilute hydrochloric acid is added to adjust the pH to about 6.0, 8.5g of white solid compound 3 is obtained after suction filtration and drying, and the yield is 96.3%. LC-MS (es+) m/z=296.1 [ m+h ]] + 。
Step 4: ke Disi rearrangement reaction
To a 100mL round bottom flask under nitrogen protection, 8.5g of compound 3 was added, 40mL of t-butanol and triethylamine were poured in, and the mixture was stirred and dissolved at room temperature to give a clear solution, then 14.3g of diphenyl azide phosphate was slowly added dropwise under ice bath, 1.8 equivalents of diphenyl azide phosphate was added dropwise, and after the dropwise addition was completed, the reaction system was heated to 65℃and stirring was continued for 16 hours. The reaction was stopped, cooled to room temperature, quenched with 40mL of water, extracted 3 times with 80mL of ethyl acetate, the organic phases combined, washed with saturated brine, and the dried oil was concentrated to continue column chromatography (petroleum ether/ethyl acetate=2/1) to give 8.2g of a white solid (TAK-418 intermediate compound) in 78.1% yield. LC-MS (es+) m/z=267.1 [ m-99] + 。
Example 2:
in the coupling reaction of step 2, (1 r,2 r) -2- (methoxycarbonyl) cyclopropylboronic acid was exchanged for an equivalent number of potassium (1 r,2 r) -2- (methoxycarbonyl) cyclopropylfluoroborate and the palladium catalyst was exchanged for an equivalent number of tetraphenylpalladium to give compound 2 (9.8 g, yield 72.2%) as a pale yellow solid.
Example 3:
in the hydrolysis reaction of step 3, the equivalent number of lithium hydroxide was changed to 3.0, and 8.1g of white solid compound 3 was obtained in a yield of 91.8%.
Example 4:
in the rearrangement reaction of step 4 Ke Disi, the eluent system of column chromatography was changed to petroleum ether/ethyl acetate=1/1, to obtain 7.9g of a TAK-418 intermediate compound in a yield of 75.2%.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (9)
1. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound, comprising the steps of: taking 5-bromothiophene-3-carboxylic acid and 4-aminotetrahydropyran as raw materials, performing condensation reaction to obtain a compound 1, and performing coupling reaction on the compound 1 and (1R, 2R) -2- (methoxycarbonyl) cyclopropyl boride to obtain a compound 2, wherein the (1R, 2R) -2- (methoxycarbonyl) cyclopropyl boride is (1R, 2R) -2- (methoxycarbonyl) cyclopropylboric acid or (1R, 2R) -2- (methoxycarbonyl) cyclopropylfluoroboric acid potassium, and the catalyst used in the coupling reaction is [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl) 2 (dppf)) or tetrakis (triphenylphosphine) palladium, the compound 3 is obtained after the hydrolysis reaction of the compound 2, and the compound 3 is subjected to Ke Disi rearrangement reaction to obtain the target TAK-418 intermediate compound, wherein the synthetic route is as follows:
2. a process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the synthesis method specifically comprises the following steps:
step 1: condensation reaction
10.0g of 5-bromothiophene-3-carboxylic acid is added into a 250mL round bottom flask under the protection of nitrogen, 80mL of N, N-dimethylformamide is poured into the flask, the mixture is dissolved into clear solution, then 5.13g of 4-aminotetrahydropyran, 27.6g of 1.5 equivalent of benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (HBTu) and 12.46g of 2.0 equivalent of N, N-diisopropylethylamine are added into the clear solution, the mixture is stirred for 16 hours at the temperature of 25 ℃, after the reaction is completed, 80mL of water is added into the reaction system to quench the mixture, the mixture is extracted for 3 times by 100mL of ethyl acetate, the organic phase is combined, the organic phase is washed by using aqueous solution of sodium bicarbonate, and then the mixture is concentrated and dried to obtain 12.8g of white solid compound 1, and the yield is 91.3%;
step 2: coupling reaction:
under the protection of nitrogen, adding 12.8g, 1.0 equivalent of compound 1, 35.2g and 3.0 equivalent of phosphoric acid trihydrate into a 250mL round bottom flask, pouring 100mL of 1,4-dioxane (1, 4-dioxane) and 10.0mL of water for dissolution, then adding 12.6g, 1.1 equivalent of (1R, 2R) -2- (methoxycarbonyl) cyclopropylboronic acid and 0.1 equivalent of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, stirring at 80 ℃ for 12 hours, removing a solid part by vacuum filtration after the reaction is finished, adding 100mL of water into the rest reaction solution, layering, concentrating an organic phase, and carrying out column chromatography, wherein the eluent system and the ratio are petroleum ether, namely ethyl acetate=4:1, and 9.3g of pale yellow solid compound 2 is obtained after concentration, and the yield is 68.5%;
step 3: hydrolysis reaction
9.3g of compound 2, 1.80g of lithium hydroxide, 2.5 equivalent of lithium hydroxide, 100mL of methanol and 20mL of water are added into a 250mL round bottom flask, the mixture is stirred for 4 hours at 25 ℃, after the reaction is finished, the reaction system is distilled off most of the methanol under reduced pressure, 2mol/L of dilute hydrochloric acid is added to adjust the pH to about 6.0, 8.5g of white solid compound 3 is obtained after suction filtration and drying, and the yield is 96.3%;
step 4: ke Disi rearrangement reaction
Adding 8.5g of compound 3 into a 100mL round bottom flask under the protection of nitrogen, pouring 40mL of tertiary butanol and triethylamine, stirring at room temperature to dissolve to obtain a clear solution, slowly dropwise adding 14.3g of diphenyl azide phosphate with the equivalent weight of 1.8 in an ice bath, and heating the reaction system to 65 ℃ after the dropwise addition is finished, and continuously stirring for 16 hours; stopping the reaction, cooling the reaction to room temperature, adding 40mL of water to quench the reaction system, extracting 3 times with 80mL of ethyl acetate, combining the organic phases, washing with saturated saline, concentrating the dried oily substance, continuing column chromatography, and obtaining 8.2g of white solid which is TAK-418 intermediate compound with the yield of 78.1 percent, wherein the eluent system is petroleum ether and ethyl acetate.
3. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the reaction temperature in the condensation reaction in the step 1 is 15-35 ℃.
4. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 3, characterized in that: the reaction temperature in the condensation reaction in the step 1 is 20-25 ℃.
5. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the molar feed ratio of the catalyst to the compound 1 is 0.01-0.2:1.
6. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the equivalent number of lithium hydroxide in the hydrolysis reaction in the step 3 is 1.0-3.0.
7. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the equivalent number of lithium hydroxide in the hydrolysis reaction in the step 3 is 1.5-2.5.
8. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the eluent of column chromatography in the rearrangement reaction of the step 4 Ke Disi is petroleum ether, wherein the ethyl acetate=0.5-3:1.
9. A process for the preparation of an LSD1enzyme inhibitor TAK-418 intermediate compound according to claim 1, characterized in that: the eluent of column chromatography in the rearrangement reaction of the step 4 Ke Disi is petroleum ether, namely ethyl acetate=1-2:1.
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| WO2012013727A1 (en) * | 2010-07-29 | 2012-02-02 | Oryzon Genomics S.A. | Cyclopropylamine derivatives useful as lsd1 inhibitors |
| CN103857393A (en) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权（第2号）有限公司 | Cyclopropylamines as LSD1 inhibitors |
| CN106459024A (en) * | 2014-04-11 | 2017-02-22 | 武田药品工业株式会社 | Cyclopropanamine compound and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012013727A1 (en) * | 2010-07-29 | 2012-02-02 | Oryzon Genomics S.A. | Cyclopropylamine derivatives useful as lsd1 inhibitors |
| CN103857393A (en) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权（第2号）有限公司 | Cyclopropylamines as LSD1 inhibitors |
| CN106459024A (en) * | 2014-04-11 | 2017-02-22 | 武田药品工业株式会社 | Cyclopropanamine compound and use thereof |
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