CN111808016A - Preparation method of nilapanib intermediate (S) -3- (4-bromophenyl) piperidine - Google Patents
Preparation method of nilapanib intermediate (S) -3- (4-bromophenyl) piperidine Download PDFInfo
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- bromophenyl
- piperidine
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- SZTZMTODFHPUHI-SNVBAGLBSA-N (3s)-3-(4-bromophenyl)piperidine Chemical compound C1=CC(Br)=CC=C1[C@H]1CNCCC1 SZTZMTODFHPUHI-SNVBAGLBSA-N 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 239000002994 raw material Substances 0.000 claims abstract description 25
- 125000006239 protecting group Chemical group 0.000 claims abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 15
- 230000009467 reduction Effects 0.000 claims abstract description 11
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 9
- 230000029936 alkylation Effects 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 5
- 230000005494 condensation Effects 0.000 claims abstract description 5
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 94
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000003960 organic solvent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000012074 organic phase 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
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical group ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- -1 HBTU Substances 0.000 claims description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000007821 HATU Substances 0.000 claims description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 239000002085 irritant Substances 0.000 abstract description 2
- 231100000021 irritant Toxicity 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 231100001261 hazardous Toxicity 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 23
- 238000005457 optimization Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 238000009776 industrial production Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 102000003929 Transaminases Human genes 0.000 description 4
- 108090000340 Transaminases Proteins 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 3
- 229950011068 niraparib Drugs 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OEDBSOLEAXINLT-UHFFFAOYSA-N C(C)(=O)OCC.BrC1=CC=CC=C1 Chemical compound C(C)(=O)OCC.BrC1=CC=CC=C1 OEDBSOLEAXINLT-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 239000012661 PARP inhibitor Substances 0.000 description 2
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
Abstract
The invention discloses a preparation method of a nilapanib intermediate (S) -3- (4-bromophenyl) piperidine, which comprises the steps of taking chiral 1-phenylethylamine as a raw material, carrying out alkylation, condensation, ring closing and reduction, and finally removing an amino protecting group to prepare the (S) -3- (4-bromophenyl) piperidine. The preparation method of (S) -3- (4-bromophenyl) piperidine has the advantages of short route, fewer steps, simple and convenient process operation, avoidance of use of hazardous reagents, highly toxic reagents and irritant odor reagents, reduction of potential safety hazards to operators, reduction of the operation safety level of production, greenness, environmental protection and contribution to realization of industrialization.
Description
Technical Field
The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of a nilapanib intermediate (S) -3- (4-bromophenyl) piperidine.
Background
The novel anticancer drug Nilaparib (Niraparib) is a PARP inhibitor, has a trade name of Zejula jele, is approved by the American FDA to be on the market in 3 months of 2017, and is used for the maintenance treatment of female patients with recurrent epithelial ovarian cancer, namely fallopian tube cancer or primary peritoneal cancer. Nilapanib (Niraparib) is the first FDA-approved PARP inhibitor to be used in therapy without detection of BRCA mutations or other biomarkers, and blocks enzymes involved in the repair of damaged DNA by which DNA within cancer cells is not repaired, resulting in cell death and possibly slowing or stopping tumor growth.
The compound (S) -3- (4-bromophenyl) piperidine is a key intermediate for synthesizing the nilapanibThe molecular formula is: c11H14BrN, english name: (S) -3- (4-bromophenyl) piperidine, the structural formula is shown as the following formula:
a method for preparing (S) -3- (4-bromophenyl) piperidine is disclosed, wherein bromobenzene is used as a starting material, sodium bisulfite addition product of aldehyde is obtained through acylation, esterification, epoxidation, rearrangement and addition, chiral amide is obtained through transaminase catalysis in a key step, and finally intermediate (S) -3- (4-bromophenyl) piperidine is obtained through reduction, and a preparation method route is shown as a scheme A;
route a:
the preparation method of the route A has long reaction steps, a chiral compound is obtained by catalyzing with specific transaminase, and the transaminase is high in price, large in dosage and high in overall cost and is not beneficial to industrial production of products;
in the document CN108409638, 4-bromobenzene ethyl acetate is used as a starting material, and the product (S) -3- (4-bromophenyl) piperidine is obtained by alkylation, Boc protection removal, ring closure, carbonyl reduction, and tartaric acid resolution, and the preparation method route is shown in the following scheme B;
route B:
in the preparation method of the route B, dangerous reagents of sodium hydride and borane tetrahydrofuran are used, so that the danger is high, and the risk in the aspect of industrial production safety is high; the alkylation step in the first step is easy to generate polyalkylation byproducts, and the polyalkylation byproducts have similar polarity with a target product, are difficult to separate and purify and are not beneficial to industrial production;
in the document CN107663190, 4-bromobenzene ethyl acetate and EVENS prosthetic group are used as starting materials, and are subjected to condensation and conjugate addition with acrylate, and then reduction, hydroxyl sulfonylation, aniline or hydroxylamine ring closure and nitrogen upper protecting group removal are carried out to obtain a product (S) -3- (4-bromophenyl) piperidine, wherein the preparation method route is shown as the following route C;
route C:
the reagent acrylate and methanesulfonyl chloride used in the preparation method of route C have high toxicity; the acrylate odor is bad, the pivaloyl chloride has large pungent odor, high corrosivity and large environmental protection pressure; the EVENS prosthetic group has high price and high cost, and is not beneficial to industrial production.
Although researchers have proposed various synthetic methods based on different raw materials and synthetic routes for (S) -3- (4-bromophenyl) piperidine intermediate compounds so far, the preparation method of (S) -3- (4-bromophenyl) piperidine intermediate compounds has not been satisfactory in terms of improvement of results in terms of cost, environmental protection, safety, and complicated steps. In the prior disclosed preparation method of (S) -3- (4-bromophenyl) piperidine, the preparation and purification steps are multiple, the process is complicated, and the yield is low; expensive raw materials and reagents and high preparation cost; dangerous chemicals and pungent smell chemicals are used, so that the preparation danger is increased, and the industrial production, popularization and application are not facilitated.
Therefore, there is a need for developing and optimizing a preparation method of (S) -3- (4-bromophenyl) piperidine, improving the defects of the existing preparation method, and particularly developing a preparation method which can be used for workshop amplification and meets the requirements of environmental protection.
Disclosure of Invention
In view of the above defects in the prior art, the technical problems to be solved by the present invention are that the existing preparation method of (S) -3- (4-bromophenyl) piperidine has many steps, is complicated, has expensive raw materials and reagents and high preparation cost, uses dangerous chemicals such as sodium hydride, borane and the like, uses hypertoxic drugs such as acrylate, methanesulfonyl chloride and the like, uses reagents with foul odor and pungent air temperature, has high danger coefficient and poor operation safety, and is not beneficial to industrialization.
In order to realize the aim, the invention provides a preparation method of a nilapanib intermediate (S) -3- (4-bromophenyl) piperidine, which comprises the steps of taking chiral 1-phenylethylamine as a raw material, carrying out alkylation, condensation, ring closure and reduction, and finally removing an amino protecting group to prepare the (S) -3- (4-bromophenyl) piperidine;
wherein the structure of the nilapanib intermediate (S) -3- (4-bromophenyl) piperidine is shown as the following formula A,
the preparation method of the nilapanib intermediate (S) -3- (4-bromophenyl) piperidine has the following route I:
route I:
the operation steps are as follows:
step 1, carrying out alkylation reaction on raw material compounds SMA and SMB at room temperature in the presence of an aprotic organic solvent, and carrying out aftertreatment to obtain a compound A-1;
step 2, carrying out condensation reaction on the compound A-1 and a raw material compound SMC in the presence of alkali and a condensing agent, and carrying out post-treatment to obtain a compound A-2;
step 3, performing ring closure reaction on the compound A-2 in alkali and an organic solvent at room temperature, and performing post-treatment to obtain a compound A-3;
step 4, dissolving the compound A-3 in an aprotic organic solvent, adding a reducing agent, carrying out low-temperature reduction reaction, and carrying out post-treatment to obtain a compound A-4;
step 5, adding a chlorine-containing organic solvent and an amino protecting group removing agent into the compound A-4, heating to react and remove the amino protecting group, and carrying out post-treatment to obtain a target compound (S) -3- (4-bromophenyl) piperidine (formula A);
further, in the step 1, the aprotic organic solvent is one or more of acetonitrile, DMF, DMA, DMSO, THF, dioxane, toluene, DCM; preferably acetonitrile;
further, in the step 1, the molar ratio of the SMA to the SMB is 1: 1-5: 1; preferably 1.5: 1-3: 1; most preferably 2.2: 1;
further, in the step 1, the room temperature is 20-30 ℃;
further, in the step 1, the weight volume ratio (g: ml) of the raw material compound SMA to the aprotic organic solvent is 1: 1-1: 20; preferably 1:2 to 1: 5;
further, in the step 2, the base is triethylamine, DIPEA, NaHCO3、KHCO3、Na2CO3、K2CO3One or more of (a); preferably triethylamine;
further, in the step 2, the condensing agent is one or more of HATU, HBTU, CDI, HOBT and EDC; preferably CDI;
further, in the step 2, the molar ratio of the compound A-1 to the raw material compound SMC is 1: 1-5: 1; preferably 1: 1-1.5: 1;
further, in the step 2, the molar ratio of the compound A-1 to the condensing agent is 1: 1-1: 1.5; preferably 1:1.5
Further, in the step 2, the molar ratio of the compound A-1 to the base is 1: 1-1: 1.5, preferably 1: 1.1;
further, in the step 3, the alkali is one or more of t-BuOK, t-BuONa, NaH, MeONa and EtONa; preferably t-BuOK;
further, in the step 3, the organic solvent is one or more of DMF, DMA, DMSO, THF, dioxane and toluene; preferably DMF;
further, in the step 3, the room temperature is 20-30 ℃;
further, in the step 3, the molar ratio of the compound A-2 to the base is 1: 1-2: 1; preferably 1.5: 1-2: 1;
further, in the step 3, the weight-to-volume ratio (g: ml) of the compound A-2 to the organic solvent is 1: 1-1: 20; preferably 1:3 to 1: 5;
further, in the step 4, the aprotic organic solvent is one or more of THF and 2-methyltetrahydrofuran; preferably THF;
further, in the step 4, the reducing agent is a mixed reducing agent of sodium borohydride and boron trifluoride;
further, the molar ratio of the reducing agent to the compound A-3 is 2.5: 1-4: 1; preferably 3: 1;
further, in the step 4, the weight-to-volume ratio (g: ml) of the compound A-3 to the aprotic organic solvent is 1:3 to 1: 20; preferably 1:8 to 1: 12;
further, in the step 5, the chlorine-containing organic solvent is one or more of chlorobenzene, dichloromethane and 1, 2-dichloroethane; preferably chlorobenzene;
further, in the step 5, the amino protecting group removing agent is chloro ethyl chloroformate;
further, in the step 5, the temperature rise temperature is 90-110 ℃;
further, in the step 5, the weight-to-volume ratio (g: ml) of the compound A-4 to the chlorine-containing organic solvent is 1: 1-1: 20; preferably 1:1 to 1: 5;
further, in the step 5, the molar ratio of the compound A-4 to the amino protecting group removing agent is 1: 1-1: 2;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the molar ratio of the SMA to the SMB is 1.6: 1;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the molar ratio of the SMA to the SMB is 1.9: 1;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the molar ratio of the SMA to the SMB is 2.2: 1;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the weight-to-volume ratio (g: ml) of the starting compound SMA to the aprotic organic solvent is 1: 2;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the weight-to-volume ratio (g: ml) of the starting compound SMA to the aprotic organic solvent is 1: 3;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 1, the weight-to-volume ratio (g: ml) of the starting compound SMA to the aprotic organic solvent is 1: 5;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 2, the molar ratio of the compound A-1 to the starting compound SMC is 1.1: 1;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 2, the molar ratio of the compound A-1 to the condensing agent is 1: 1.5;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in the step 2, the molar ratio of the compound A-1 to the base is 1: 1.1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in step 3, the molar ratio of the compound A-2 to the base is 1.75: 1;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, in the step 3, the weight-to-volume ratio (g: ml) of the compound A-2 to the organic solvent is 1: 4;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in step 4, the molar ratio of the reducing agent to compound A-3 is 3: 1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in the step 4, the molar ratio of the reducing agent to the compound A-3 is 2.5: 1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in step 4, the molar ratio of the reducing agent to compound A-3 is 4: 1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, in step 4, the weight to volume ratio (g: ml) of the compound A-3 to the aprotic organic solvent is 1: 11;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine, in the step 5, the weight-to-volume ratio (g: ml) of the compound A-4 to the chlorine-containing organic solvent is 1: 1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine, in the step 5, the molar ratio of the compound A-4 to the amino protecting group removing agent is 1: 1.1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine, the step 1 is specifically operated as follows: adding a raw material compound SMB and an aprotic organic solvent into a reaction container, cooling to 0-10 ℃, dropwise adding a raw material compound SMA, heating a reaction solution to 20-30 ℃ after the addition is finished, and stirring for reaction for 14-16 h; the post-treatment comprises adding ethyl acetate into the reaction liquid for extraction, washing an organic phase by 1M hydrochloric acid, adding concentrated hydrochloric acid, filtering, washing a solid, and drying to obtain a compound A-1;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the invention, the step 3 is specifically operated as follows: adding potassium tert-butoxide and an organic solvent DMF into a reaction vessel, cooling to 0-10 ℃, then adding a DMF solution of a compound A-2, heating the reaction solution to 20-30 ℃, stirring and reacting for 10-12h, and carrying out a ring closure reaction; the post-treatment comprises adding water and ethyl acetate for extraction, removing the solvent from the organic phase, adding petroleum ether into the residue, stirring, filtering, and drying the solid by air blast at 40-50 ℃ to obtain a compound A-3;
according to the preparation method of (S) -3- (4-bromophenyl) piperidine of the present invention, the step 5 is specifically operated as follows: adding the compound A-4, a chlorine-containing organic solvent and chloroethyl chloroformate into a reaction vessel, heating to 90-110 ℃, and stirring for reacting for 8-10 h; removing amino protecting group by reaction, and performing post-treatment including concentrating to remove solvent, adding ethyl acetate and 1M hydrochloric acid for extraction, adjusting pH of a water phase to 8-9, extracting with ethyl acetate, combining organic phases, concentrating under reduced pressure, adding petroleum ether into residues, stirring, performing suction filtration, and performing vacuum drying on solids to obtain a target compound (S) -3- (4-bromophenyl) piperidine (formula A);
in a preferred embodiment of the invention, the (S) -3- (4-bromophenyl) piperidine is prepared by a method comprising the following steps of extracting, adjusting pH value, washing, filtering, concentrating to remove a solvent, drying and the like;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solid and liquid in the reaction solution, including ordinary filtration, centrifugation, suction filtration; wherein, the common filtration separation includes but is not limited to the use of filter cloth, filter membrane, etc.;
the concentration refers to a process of removing a liquid solvent, and comprises reduced pressure concentration, normal pressure concentration and the like;
the extraction solvent used for extraction is ethyl acetate;
the washing includes but is not limited to water washing, 1M hydrochloric acid washing, organic solvent washing;
the drying is forced air drying, reduced pressure drying and vacuum drying;
the steps, solvents, reagents, filtration, concentration, washing, drying and the like in the preparation method of the (S) -3- (4-bromophenyl) piperidine can be combined or separated at will, and the purpose of the invention can be achieved.
Compared with the prior art, the preparation method of (S) -3- (4-bromophenyl) piperidine adopts chiral 1-phenylethylamine as a raw material, and prepares the (S) -3- (4-bromophenyl) piperidine product through alkylation, condensation, ring closure and reduction and finally amino protecting group removal, so that the chiral target compound is directly obtained by avoiding using expensive transaminase catalysis, EVENS auxiliary group and the like for chiral conversion, the total reaction cost is greatly reduced, and the industrial production of the product is facilitated;
the preparation method of (S) -3- (4-bromophenyl) piperidine avoids using dangerous reagents of sodium hydride and borane tetrahydrofuran, reduces the danger of the method, and is beneficial to industrial production safety; the alkylation reaction conditions of the first step are optimized, extra alkali reagent is creatively not used, the feed ratio of the raw material compounds SMA and SMB is optimized, polyalkylation byproducts are effectively avoided, the post-treatment purification operation is simplified on the basis of saving cost, and the production of an industrial workshop is favorably amplified;
the preparation method of (S) -3- (4-bromophenyl) piperidine avoids using virulent reagent acrylate and methanesulfonyl chloride, avoids using pungent smell and corrosive compound acrylate and pivaloyl chloride, has mild reaction conditions, reduces the potential safety hazard to operators, reduces the operation safety level of production, is green and environment-friendly, effectively reduces the total cost, and is beneficial to realizing industrial amplification production;
according to the preparation method of the (S) -3- (4-bromophenyl) piperidine, the yield of each step of reaction is not lower than 70%, the yield is high, the production cost is favorably reduced, and the workshop enlarged production is favorably realized;
in conclusion, the preparation method of (S) -3- (4-bromophenyl) piperidine has the advantages of short route, fewer steps, simple and convenient process operation, avoidance of use of dangerous reagents, highly toxic reagents and irritant malodorous reagents, reduction of potential safety hazards to operators, reduction of the operation safety level of production, greenness, environmental protection, high yield and contribution to realization of industrial amplification production.
The conception, the specific technical solutions and the technical effects of the present invention will be further described with reference to the following embodiments, so as to fully understand the objects, the features and the effects of the present invention.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Example 1 preparation of Compound A-1
Adding 156g of raw material compound SMB and 780ml of acetonitrile into a reaction container, cooling to 0-10 ℃, dropwise adding 264g of raw material compound SMA, heating to 20-30 ℃ after the addition is finished, keeping the temperature, and stirring for reacting for 14-16 h; adding ethyl acetate into the reaction liquid for extraction, combining organic layers, adding 1M hydrochloric acid for washing, adding concentrated hydrochloric acid to separate out a solid, performing suction filtration, washing a filter cake with ethyl acetate, and performing forced air drying at 50-60 ℃ for 10-12h to obtain a compound A-1(163g, yield 70%);
example 1 on the basis of the above experiment, the optimization condition experiment further includes:
optimized parallel experiments with DMF and THF as solvents;
optimization parallel experiments at reaction temperatures of 40-50 ℃ and 0-10 ℃;
optimization parallel experiments with 1 equivalent of raw material compound SMB and 1.9 and 1.6 equivalents of raw material compound SMA.
Example 2 preparation of Compound A-2
Adding 160g of compound A-1, 1.6L of dichloromethane and 147g of raw material compound SMC into a reaction container, cooling the reaction liquid to 0-10 ℃, adding 69g of triethylamine, then adding 144g of condensing agent CDI in batches, heating the reaction liquid to 20-30 ℃, and stirring for reaction for 10-12 hours; adding water into the reaction solution for quenching, adding dilute hydrochloric acid to adjust the pH value to be 1-2, removing the water phase, and concentrating the organic phase under reduced pressure to remove a dichloromethane solvent to obtain a compound A-2(263g, yield 98%);
example 2 on the basis of the above experiment, the optimization condition experiment further includes:
the base is DIPEA and NaHCO3The optimization parallel experiment of (2);
optimization of organic solvent as THF parallels the experiments.
Example 3 preparation of Compound A-3
Adding 125g of potassium tert-butoxide and 450ml of DMF solvent into a reaction vessel, cooling the reaction solution to 0-10 ℃, adding 220g of compound A-2 (dissolved in 450ml of DMF), heating the reaction solution to 20-30 ℃, and stirring for reaction for 10-12 h; adding water and ethyl acetate into the post-treatment for extraction, combining organic layers, washing with water, concentrating under reduced pressure to remove ethyl acetate, adding petroleum ether into residues, stirring, filtering, and drying the solid by blowing at 40-50 ℃ to obtain a compound A-3(76g, the yield is 38%) (which is equivalent to 76% of the theoretical yield);
example 3 on the basis of the above experiment, the optimization condition experiment further includes:
optimized parallel experiments with THF as solvent;
optimized parallel experiments at reaction temperatures of 30-40 ℃ and 0-10 ℃;
the alkali is NaH and MeONa.
Example 4 preparation of Compound A-4
Adding 7.3g of sodium borohydride and 200ml of THF into a reaction vessel, cooling to 0-5 ℃, adding 26.9g of tetrahydrofuran solution of boron trifluoride, stirring for 1h at 0-5 ℃, adding 23g of compound A-3 (dissolved in 46ml of THF), heating the reaction solution to 20-30 ℃, and stirring for reaction for 10 h; after-treatment, water and ethyl acetate are added for extraction, organic layers are combined, washed by water, decompressed, concentrated and removed of ethyl acetate, and dried to obtain a compound A-4(19.5g, yield 88%);
example 4 on the basis of the above experiment, the optimization condition experiment further includes:
optimization parallel experiment with reaction temperature of 0-10 deg.c;
and (3) carrying out optimization parallel experiments with the compound A-3 as 1 equivalent and the sodium borohydride and boron trifluoride tetrahydrofuran as 2.5 and 4 equivalents.
Example 5 preparation of product Compound A
Adding 14g of compound A-4, 14ml of chlorobenzene and 8.7g of chloroethyl chloroformate into a reaction container, heating the reaction solution to 90-110 ℃, and stirring for reacting for 8-10 h; performing post-treatment, concentrating under reduced pressure, adding ethyl acetate, washing with 1M hydrochloric acid, adjusting the pH of an aqueous phase to 8-9 after washing, extracting with ethyl acetate, combining organic phases, concentrating under reduced pressure, adding petroleum ether into residues, stirring, performing suction filtration, and performing vacuum drying on solids to obtain a target compound, namely a compound A (6.8g, the yield is 70%);
example 5 on the basis of the above experiment, the optimization condition experiment further includes:
when the organic solvent is chlorobenzene, carrying out an optimized parallel experiment at the reaction temperature of 70-80 ℃;
and (3) carrying out optimized parallel experiments at the reaction temperature of 40-80 ℃ by using dichloromethane and 1, 2-dichloroethane as organic solvents.
In the preparation process route of the (S) -3- (4-bromophenyl) piperidine prepared in the embodiment 1-5, the yield of the 5-step reaction is not lower than 70%, and compared with the existing preparation method, the yield is improved, and the cost is reduced.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings, and that process parameters can be varied within reasonable limits. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (10)
1. A preparation method of a nilapanib intermediate (S) -3- (4-bromophenyl) piperidine is characterized in that chiral 1-phenylethylamine is used as a raw material, and the (S) -3- (4-bromophenyl) piperidine is prepared by alkylation, condensation, ring closure, reduction and final removal of an amino protecting group;
the structure of the nilapanib intermediate (S) -3- (4-bromophenyl) piperidine is shown as the following formula A,
2. the method of claim 1,
the preparation method of the nilapanib intermediate (S) -3- (4-bromophenyl) piperidine has the following route I,
route I:
the operation steps are as follows:
step 1, carrying out alkylation reaction on raw material compounds SMA and SMB at room temperature in the presence of an aprotic organic solvent, and carrying out aftertreatment to obtain a compound A-1;
step 2, carrying out condensation reaction on the compound A-1 and a raw material compound SMC in the presence of alkali and a condensing agent, and carrying out post-treatment to obtain a compound A-2;
step 3, performing ring closure reaction on the compound A-2 in alkali and an organic solvent at room temperature, and performing post-treatment to obtain a compound A-3;
step 4, dissolving the compound A-3 in an aprotic organic solvent, adding a reducing agent, carrying out low-temperature reduction reaction, and carrying out post-treatment to obtain a compound A-4;
and step 5, adding a chlorine-containing organic solvent and an amino protecting group removing agent into the compound A-4, heating to react and remove the amino protecting group, and carrying out aftertreatment to obtain the target compound (S) -3- (4-bromophenyl) piperidine.
3. The method according to claim 2, wherein, in step 1,
the aprotic organic solvent is one or more of acetonitrile, DMF, DMA, DMSO, THF, dioxane, toluene and DCM;
the molar ratio of the SMA to the SMB is 1: 1-5: 1;
the weight volume ratio of the raw material compound SMA to the aprotic organic solvent is 1: 1-1: 20.
4. The method according to claim 2, wherein, in the step 2,
the alkali is triethylamine, DIPEA and NaHCO3、KHCO3、Na2CO3、K2CO3One or more of (a);
the condensing agent is one or more of HATU, HBTU, CDI, HOBT and EDC;
the molar ratio of the compound A-1 to the raw material compound SMC is 1: 1-5: 1;
the molar ratio of the compound A-1 to the condensing agent is 1: 1-1: 1.5;
the molar ratio of the compound A-1 to the alkali is 1: 1-1: 1.5.
5. The method according to claim 2, wherein, in the step 3,
the alkali is one or more of t-BuOK, t-BuONa, NaH, MeONa and EtONa;
the organic solvent is one or more of DMF, DMA, DMSO, THF, dioxane and toluene;
the molar ratio of the compound A-2 to the alkali is 1: 1-2: 1;
the weight-volume ratio of the compound A-2 to the organic solvent is 1: 1-1: 20.
6. The method according to claim 2, wherein, in the step 4,
the aprotic organic solvent is one or more of THF and 2-methyltetrahydrofuran;
the reducing agent is a mixed reducing agent of sodium borohydride and boron trifluoride;
the molar ratio of the reducing agent to the compound A-3 is 2.5: 1-4: 1;
the weight-volume ratio of the compound A-3 to the aprotic organic solvent is 1: 3-1: 20.
7. The method according to claim 2, wherein, in the step 5,
the chlorine-containing organic solvent is one or more of chlorobenzene, dichloromethane and 1, 2-dichloroethane;
the amino protecting group remover is chloro ethyl chloroformate;
the weight volume ratio of the compound A-4 to the chlorine-containing organic solvent is 1: 1-1: 20;
the molar ratio of the compound A-4 to the amino protecting group removing agent is 1: 1-1: 2.
8. The method of claim 2, wherein step 1 is specifically operative to: adding a raw material compound SMB and an aprotic organic solvent into a reaction container, cooling to 0-10 ℃, dropwise adding a raw material compound SMA, heating a reaction solution to 20-30 ℃ after the addition is finished, and stirring for reaction for 14-16 h; the post-treatment comprises adding ethyl acetate into the reaction liquid for extraction, washing an organic phase by 1M hydrochloric acid, adding concentrated hydrochloric acid, filtering, washing a solid, and drying to obtain the compound A-1.
9. The method of claim 2, wherein step 3 is specifically operative to: adding potassium tert-butoxide and an organic solvent DMF into a reaction vessel, cooling to 0-10 ℃, then adding a DMF solution of a compound A-2, heating the reaction solution to 20-30 ℃, stirring and reacting for 10-12h, and carrying out a ring closure reaction; the post-treatment comprises adding water and ethyl acetate for extraction, removing the solvent from the organic phase, adding petroleum ether into the residue, stirring, filtering, and drying the solid by blowing at 40-50 ℃ to obtain the compound A-3.
10. The method of claim 2, wherein said step 5 is specifically operative to: adding the compound A-4, a chlorine-containing organic solvent and chloroethyl chloroformate into a reaction vessel, heating to 90-110 ℃, and stirring for reacting for 8-10 h; and (2) removing an amino protecting group through reaction, performing post-treatment including concentration to remove a solvent, adding ethyl acetate and 1M hydrochloric acid for extraction, adjusting the pH value of a water phase to be 8-9, then extracting with ethyl acetate, combining organic phases, performing reduced pressure concentration, adding petroleum ether into residues, performing suction filtration after stirring, and performing vacuum drying on solids to obtain the target compound (S) -3- (4-bromophenyl) piperidine formula A.
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Application publication date: 20201023 |