CN111333544B - Intermediate for synthesizing nilapanib and preparation method thereof - Google Patents
Intermediate for synthesizing nilapanib and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- SZTZMTODFHPUHI-SNVBAGLBSA-N (3s)-3-(4-bromophenyl)piperidine Chemical compound C1=CC(Br)=CC=C1[C@H]1CNCCC1 SZTZMTODFHPUHI-SNVBAGLBSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 239000003446 ligand Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 239000012442 inert solvent Substances 0.000 claims description 17
- 150000001879 copper Chemical class 0.000 claims description 15
- 239000007800 oxidant agent Substances 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000007333 cyanation reaction Methods 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical group [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 8
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical group C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- BTEJSUVVNDDTPL-UHFFFAOYSA-N n-fluoro-n-phenylbenzenesulfonamide Chemical group C=1C=CC=CC=1S(=O)(=O)N(F)C1=CC=CC=C1 BTEJSUVVNDDTPL-UHFFFAOYSA-N 0.000 claims description 2
- 238000010626 work up procedure Methods 0.000 claims description 2
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 229910000510 noble metal Inorganic materials 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RSBSWYBZVIWBOP-VXKWHMMOSA-N (4S)-4-benzyl-2-[1-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]cyclopentyl]-4,5-dihydro-1,3-oxazole Chemical compound C([C@@H](N=1)CC=2C=CC=CC=2)OC=1C1(C=2OC[C@H](CC=3C=CC=CC=3)N=2)CCCC1 RSBSWYBZVIWBOP-VXKWHMMOSA-N 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012661 PARP inhibitor Substances 0.000 description 3
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- -1 i.e. Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960000572 olaparib Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- SZTZMTODFHPUHI-UHFFFAOYSA-N 3-(4-bromophenyl)piperidine Chemical class C1=CC(Br)=CC=C1C1CNCCC1 SZTZMTODFHPUHI-UHFFFAOYSA-N 0.000 description 1
- COUOFYDJUDASPJ-SNVBAGLBSA-N 4-[(3s)-piperidin-3-yl]aniline Chemical compound C1=CC(N)=CC=C1[C@H]1CNCCC1 COUOFYDJUDASPJ-SNVBAGLBSA-N 0.000 description 1
- 108091007743 BRCA1/2 Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101150101566 Parp gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XZIAFENWXIQIKR-UHFFFAOYSA-N ethyl 4-bromobenzoate Chemical compound CCOC(=O)C1=CC=C(Br)C=C1 XZIAFENWXIQIKR-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940100352 lynparza Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950011068 niraparib Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to an intermediate for synthesizing nilapanib and a preparation method thereof. In particular, the invention discloses intermediate compounds I; the compound can be used for preparing a key intermediate (S) -3- (4-bromophenyl) -piperidine for preparing the nilapanib; the invention also discloses a preparation method of the compound and a preparation method of (S) -3- (4-bromophenyl) -piperidine. The preparation method does not relate to noble metal catalytic reduction or coupling reaction, does not relate to enantiomer separation operation, and has the advantages of low equipment requirement, low three wastes, short steps, low cost, simple operation and high industrial feasibility.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an intermediate for synthesizing nilapanib and a preparation method thereof; more particularly relates to an intermediate for synthesizing (S) -3- (4-bromophenyl) -piperidine and a preparation method thereof.
Background
Nilaparib (Niraparib, 2- [4- ((3S) -3-piperidyl) phenyl ] -2H-indazole-7-formamide) belongs to a PARP inhibitor, is a targeted drug for a PARP gene, is mainly used for patients with BRCA1/2 gene mutation, has a definite target and accords with accurate medical treatment of cancer, and has the pre-submission indications of ovarian cancer and breast cancer related to BRCA gene mutation, and can be a second PARP inhibitor on sale, and the PARP inhibitor Olaparib (Olaparib, also called Lynparza) has been marketed in the last year by Astrakang, and the marketing peak value is expected to reach more than 20 billion dollars per year because the effect is remarkably approved to be used for the ovarian cancer with BRCA mutation.
At present, 4- (3S) -3-piperidyl-aniline is used as a raw material in the method mainly used for synthesizing the nilapanib, but the method cannot avoid the use of sodium azide which is a high-risk reagent, and a safe and green synthesis means becomes the mainstream under the increasingly severe safety situation.
In 2014, a major improvement was proposed in the synthesis route in org.process res.dev.2014,18,215-227, as follows:
the intermediate (S) -3- (4-bromophenyl) -piperidine is used for synthesis of nilapanib for the first time, sodium azide is avoided, and meanwhile, the (S) -3- (4-bromophenyl) -piperidine intermediate is synthesized creatively by using enzyme catalysis, so that the ee value is high. However, the synthesis steps of the route are long, the required enzyme needs to be cultured specially, and the industrialization difficulty is high.
Although the method for obtaining the optically pure product by resolving the 3- (4-bromophenyl) -piperidine racemate is reported, the qualified optically pure product can be obtained by three times of recrystallization, and the total cost is high, so that the intermediate is not always an industrial raw material for producing the nilapanib.
Disclosure of Invention
The invention aims to provide a simpler preparation method of (S) -3- (4-bromophenyl) -piperidine.
The invention also aims to provide a novel intermediate for synthesizing (S) -3- (4-bromophenyl) -piperidine and a stereoselective preparation method thereof.
In a first aspect, the present invention provides a process for the preparation of (S) -3- (4-bromophenyl) -piperidine, said process comprising the steps of:
(1) In an inert solvent, under the catalytic action of a copper salt and a chiral bisoxazoline ligand and in the presence of an oxidant, carrying out a cyanation reaction on a compound II and a cyanation reagent to obtain a compound I: wherein R is 1 Is C1-5 alkyl;
(2) Subjecting compound I to a reductive ring closure reaction in an inert solvent in the presence of hydrogen and a catalyst to give compound III: wherein R is 1 Is C1-5 alkyl;
(3) In an inert solvent, carrying out reduction reaction on the compound III in the presence of sodium borohydride and Lewis acid to obtain (S) -3- (4-bromophenyl) -piperidine;
in another preferred example, the copper salt may be cuprous acetate.
In another preferred embodiment, the equivalent amount of the copper salt is 1 to 20% equivalent.
In another preferred embodiment, the oxidizing agent is N-fluoro-bis-benzenesulfonamide.
In another preferred embodiment, the number of equivalents of the oxidizing agent is 1 to 4 equivalents.
In another preferred embodiment, the cyaniding reagent is trimethylsilylcyanide.
In another preferred embodiment, the number of equivalents of the cyanating agent is 1-4 equivalents.
In another preferred embodiment, the chiral bisoxazoline ligand is a ligand a or a ligand b:
in another preferred embodiment, the equivalent of the chiral bisoxazoline ligand is 1 to 20% equivalent.
In another preferred embodiment, the catalyst is raney nickel or palladium on carbon.
In another preferred embodiment, the lewis acid is boron trifluoride tetrahydrofuran.
In another preferred embodiment, the equivalent of sodium borohydride is 1-3 equivalents.
In another preferred embodiment, the Lewis acid has an equivalent weight of 1 to 4 equivalents.
In another preferred embodiment, after the cyanation reaction in step (1) is completed, the compound I obtained by the following work-up can be used directly in the next step: after the reaction solution is filtered, the solvent is removed from the obtained filtrate, the obtained residue is dissolved in an organic solvent (e.g., dichloromethane) and washed with water, and then the organic solvent layer is concentrated to dryness, thereby obtaining compound I.
In another preferred example, after the reduction and ring closure reaction in step (2) is finished, the compound III obtained by the following post-treatment can be directly used in the next step: after the reaction solution was filtered, the filtrate was concentrated to dryness to obtain compound III.
In a second aspect, the invention provides an intermediate compound I, wherein R is 1 Is C1-5 alkyl;
in a third aspect, the present invention provides a process for the preparation of compound I, said process comprising the steps of: in an inert solvent, under the catalytic action of a copper salt and a chiral bisoxazoline ligand and in the presence of an oxidant, carrying out a cyanation reaction on a compound II and a cyanation reagent to obtain a compound I: wherein R is 1 Is C1-5 alkyl;
in another preferred embodiment, the copper salt may be cuprous acetate.
In another preferred embodiment, the equivalent amount of the copper salt is 1 to 20% equivalent.
In another preferred embodiment, the oxidizing agent is N-fluoro-bis-benzenesulfonamide.
In another preferred embodiment, the number of equivalents of the oxidizing agent is 1 to 4 equivalents.
In another preferred embodiment, the cyaniding reagent is trimethylsilylcyanide.
In another preferred embodiment, the number of equivalents of the cyanating agent is 1 to 4 equivalents.
In another preferred embodiment, the chiral bisoxazoline ligand is ligand a or ligand b:
in another preferred example, the equivalent of the chiral bisoxazoline ligand is 1 to 20 percent equivalent.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.
Detailed Description
The present inventors have conducted intensive studies to find a novel bromo fragment of nilapanib, of which the structure has never been reported, namely an intermediate compound I useful for preparing (S) -3- (4-bromophenyl) -piperidine, a key intermediate for preparing nilapanib.
Meanwhile, the invention also develops a method for preparing the novel bromine fragment of the nilapanib. The method avoids the problems of expensive raw materials, harsh reaction conditions, chiral resolution and the like in the existing (S) -3- (4-bromophenyl) -piperidine preparation process, and utilizes metal asymmetric catalysis to directly construct a chiral center at a benzyl position, so that the overall route for subsequently preparing the (S) -3- (4-bromophenyl) -piperidine is greatly shortened, and the cost is greatly reduced.
In the process for preparing (S) -3- (4-bromophenyl) -piperidine, the intermediate compound I can be used for obtaining the high-optical-purity key intermediate (S) -3- (4-bromophenyl) -piperidine for preparing the nilapanib through two simple steps of reduction ring closing and reduction, and complex operation steps such as chiral resolution or enzyme catalysis and the like are not required in the whole route.
Specifically, the present invention provides a process for the preparation of compound I, said process comprising the steps of: in an inert solvent, under the catalytic action of a copper salt and a chiral bisoxazoline ligand and in the presence of an oxidant, carrying out a cyanation reaction on a compound II and a cyanation reagent to obtain a compound I:
wherein R is 1 Is C1-5 alkyl.
In the present invention, R is 1 Is C1-5 alkyl, i.e., alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.
In the preparation method of the compound I, the inert solvent can be a solvent which is conventional in the reaction in the field, so long as the reaction is not affected. Benzene, chlorobenzene, trifluoromethylbenzene and acetonitrile are preferred. The amount of the inert solvent to be used is not particularly limited as long as the reaction is not affected.
In the present invention, the number of equivalents of compound II is 1 equivalent.
In the preparation method of the compound I, the copper salt can be cuprous acetate. The equivalent number of the copper salt is 1-20 percent equivalent; preferably 1% to 10% equivalent or 5% to 10% equivalent.
In the preparation method of the compound I, the oxidant is N-fluoro-diphenyl sulfonamide. The equivalent number of the oxidant is 1-4 equivalents.
In the preparation method of the compound I, the cyaniding reagent is trimethylsilylcyanide. The number of equivalents of the cyanating reagent is 1-4 equivalents.
In the preparation method of the compound I, the chiral bisoxazoline ligand is a ligand a or a ligand b:
(4S,4 'S) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-benzyl-4,5-dihydrooxazole);
(3AS,3 ' AS,8AR,8' AR) -2,2' -cyclopentylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole.
The equivalent of the chiral bisoxazoline ligand is 1 to 20 percent equivalent; preferably 1% to 10% equivalent or 5% to 10% equivalent.
In the preparation method of the compound I, after the cyanidation reaction is finished, the compound I obtained by the following post-treatment can be directly used in the next step: the reaction solution is filtered, the solvent is removed from the resulting filtrate, the resulting residue is dissolved in an organic solvent (e.g., dichloromethane) and washed with water, and then the organic solvent layer is concentrated to dryness, thereby obtaining compound I.
The invention also provides a preparation method of (S) -3- (4-bromophenyl) -piperidine, which comprises the following steps:
(1) Compound I was prepared using the above method;
(2) Subjecting compound I to a reductive ring closure reaction in an inert solvent in the presence of hydrogen and a catalyst to give compound III: wherein the catalyst is Raney nickel or palladium carbon; r 1 Is C1-5 alkyl;
(3) In an inert solvent, carrying out reduction reaction on the compound III in the presence of sodium borohydride and Lewis acid to obtain (S) -3- (4-bromophenyl) -piperidine; wherein the Lewis acid is boron trifluoride tetrahydrofuran;
in step (2), the inert solvent may be a solvent conventional in the art for such a reaction, as long as the reaction is not affected. Methanol, ethanol, and the like are preferred. The amount of the inert solvent to be used is not particularly limited as long as the reaction is not affected.
In the step (2), the temperature of the reduction ring-closing reaction can be 60-70 ℃.
In the step (2), after the reduction and ring closure reaction is finished, the compound III obtained by the following post-treatment can be directly used in the next step: the reaction solution was filtered and the filtrate was concentrated to dryness to obtain compound III.
In step (3), the inert solvent may be a solvent conventional in the art for such a reaction, as long as the reaction is not affected. Tetrahydrofuran and the like are preferred. The amount of the inert solvent to be used is not particularly limited as long as the reaction proceeds.
In the step (3), the equivalent number of the sodium borohydride is 1-3 equivalents.
In the step (3), the equivalent number of the Lewis acid is 1-4 equivalents.
In the step (3), the temperature of the reduction reaction is room temperature.
In the step (3), after the reduction reaction is finished, (S) -3- (4-bromophenyl) -piperidine can be obtained by the following post-treatment: dropwise adding water and hydrochloric acid (e.g. 6N hydrochloric acid) to the reaction solution at an internal temperature of 15-30 deg.C; then heating to 40-60 ℃ and stirring (for example, stirring for 1-6 hours or 2-4 hours); removing the solvent (such as tetrahydrofuran) from the mixture, and adjusting pH to 12-14; followed by extraction with an organic solvent (e.g., dichloromethane); concentrating the extract to dryness, and dissolving in ethanol; under the reflux condition, dropwise adding the ethanol solution obtained in the previous step into the ethanol solution of L-tartaric acid; cooling to room temperature and stirring (e.g., stirring for 8-12 hours); then filtering and collecting tartrate solids; the tartrate salt was then liberated to give (S) -3- (4-bromophenyl) -piperidine. Wherein the equivalent amount of the L-tartaric acid is 0.1-0.5 equivalent.
The (S) -3- (4-bromophenyl) -piperidine prepared by the method can obtain a product with high optical purity, and the optical purity of the product can reach 99%. And the reaction conditions in the steps are simple, and the post-treatment steps are simple and convenient.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. The reagents and starting materials used in the present invention are commercially available.
In the present invention, the room temperature is generally 10 to 30 ℃.
The CAS number of (4 S,4 'S) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-benzyl-4, 5-dihydrooxazole) was 1003886-05-2.
(3AS,3 ' AS,8AR,8' AR) -2,2' -cyclopentylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole has a CAS number of 182122-12-9.
Ligands a and b of the invention can also be found in Organic and Biomolecular Chemistry; vol.5; nb.24; (2007); p.3932-3937.
Example 1
Cuprous acetate (278mg, 0.05eq), (4s, 4's) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-benzyl-4, 5-dihydrooxazole) (755mg, 0.05eq), and 100mL of benzene were added to a reaction flask and stirred under nitrogen for 1 hour. N-fluorobisbenzenesulfonamide (49.1g, 4eq) and methyl 4-bromobenzoate (10g, 1eq) were then added. Further addition of trimethylsilylcyanide (11.6g, 3eq) was added and stirring was continued until the reaction was no longer inverted. After insoluble matter was removed by filtration, the filtrate was concentrated to dryness. The residue was dissolved in dichloromethane (50 mL) and washed 2 times with water (50 mL). The organic phase was concentrated to dryness to give crude 4- (4-bromophenyl) -4-cyano-butyric acid methyl ester, which was directly subjected to the next step.
A part of the crude product is separated by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-10) to obtain a pure product for characterizing the structure. ee =87%; 1 H NMR(CDCl 3 ,400MHz):δ＝7.52(d,J＝8.8Hz,2H),7.22(d,J＝8.4Hz,2H),3.96(t,J＝7.6Hz,1H),3.68(s,3H),2.49(m,2H),2.19ppm(dt,J＝7.6,6.8Hz,2H).
example 2
The crude 4- (4-bromophenyl) -4-cyano-butyric acid methyl ester obtained by the reaction in example 1, raney nickel (1g, 10% wt), methanol (100 mL) were charged into a hydrogenation reaction flask, and stirred at 60 to 70 degrees under a hydrogen pressure of 5 to 10Kg until the reaction was complete. After the reaction was completed, the insoluble matter was removed by filtration through celite, the filtrate was concentrated to dryness, and the resulting crude product was directly subjected to the next step.
Example 3
Tetrahydrofuran (50 mL) and the crude product obtained in example 2 were added to a reaction flask, and after cooling to 0-5 ℃, sodium borohydride (4.0g, 3eq) and boron trifluoride tetrahydrofuran (19.7g, 4eq) were added dropwise to the reaction flask. After the dripping is finished, stirring is carried out at room temperature until the reaction is complete. While maintaining the internal temperature at 20 ℃ or lower, water (25 mL) and 6N hydrochloric acid (25 mL) were added dropwise in this order. After the dripping is finished, the temperature is raised to 50 ℃, and the stirring is continued for 3 hours. After tetrahydrofuran is removed by vacuum concentration, the pH value is adjusted to 12-14 by liquid alkali. The mixture was extracted twice with dichloromethane (50 mL), the organic phases were combined and washed with water, and after concentration to dryness, the crude product was dissolved in 25mL of ethanol.
Another reaction flask was charged with L-tartaric acid (2.66g, 0.5 eq) and ethanol (20 mL). After heating to reflux, the crude ethanol solution is added dropwise. After dropping, the temperature is slowly reduced to room temperature and stirred for 12 hours. Filtering, and drying the filter cake to obtain the tartrate of the product. The target product (S) -3- (4-bromophenyl) -piperidine 4.2g can be obtained after dissociation. The total yield of the three steps is 49 percent. ee =99%. 1 H NMR(CDCl 3 ,400MHz):δ＝7.40(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H),3.20-3.04(m,2H),2.70-2.50(m,3H),2.05-1.90(m,1H),1.90-1.70(m,2H),1.65-1.50ppm(m,2H).
Example 4
To a reaction flask were added cuprous acetate (120mg, 0.05eq), (3AS, 3' AS,8AR,8' AR) -2,2' -cyclopentylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole (374mg, 0.05eq) and 50mL chlorobenzene, and the mixture was stirred under nitrogen for 1 hour. N-fluorobisbenzenesulfonamide (12.3g, 2eq) and methyl 4-bromobenzoate (5g, 1eq) were then added. Further adding trimethylsilylcyanide (5.8g, 3eq), and continuing stirring until the reaction is not converted any more. After insoluble matter was removed by filtration, the filtrate was concentrated to dryness. The residue was dissolved in dichloromethane (50 mL) and washed 2 times with water (50 mL). After the organic phase was concentrated to dryness, the cyanated product was isolated by silica gel column chromatography in 71% yield with ee =86%.
Example 5
To a reaction flask were added cuprous acetate (45mg, 0.1eq), (3AS, 3' AS,8AR,8' AR) -2,2' -cyclopentylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole (142mg, 0.1eq) and 20mL benzene, and the mixture was stirred under nitrogen for 1 hour. N-fluorobisbenzenesulfonamide (1.16g, 1eq) and ethyl 4-bromobenzoate (1g, 1eq) were then added. Further, trimethylsilylcyanide (1.1g, 3eq) was added and stirring was continued until the reaction was stopped. After insoluble matter was removed by filtration, the filtrate was concentrated to dryness. The residue was isolated by silica gel column chromatography to give 720mg of the cyanated product in 66% yield, ee =87%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (12)
1. A method for preparing (S) -3- (4-bromophenyl) -piperidine, comprising the steps of:
(1) In an inert solvent, under the catalytic action of a copper salt and a chiral bisoxazoline ligand and in the presence of an oxidant, carrying out a cyanation reaction on a compound II and a cyanation reagent to obtain a compound I: wherein R is 1 Is C1-5 alkyl;
the copper salt is cuprous acetate; the oxidant is N-fluoro-diphenyl sulfonamide; the cyaniding reagent is trimethylsilyl cyanide; the chiral bisoxazoline ligand is a ligand a or a ligand b:
(2) Reacting the compound in an inert solvent in the presence of hydrogen and a catalystI is subjected to a reductive ring closure reaction to give compound III: wherein R is 1 Is C1-5 alkyl; the catalyst is Raney nickel or palladium carbon;
(3) In an inert solvent, carrying out reduction reaction on the compound III in the presence of sodium borohydride and Lewis acid to obtain (S) -3- (4-bromophenyl) -piperidine; the Lewis acid is boron trifluoride tetrahydrofuran;
2. the method of claim 1, wherein the copper salt is present in an equivalent amount of 1 to 20% equivalents.
3. The method of claim 1, wherein the number of equivalents of the oxidizing agent is 1 to 4 equivalents.
4. The method of claim 1, wherein the number of equivalents of cyanating agent is 1 to 4 equivalents.
5. The method of claim 1, wherein the chiral bisoxazoline ligand has an equivalent weight of 1 to 20% equivalent weight.
6. The method of claim 1, wherein the equivalent weight of sodium borohydride is 1 to 3 equivalents.
7. The method of claim 1, wherein the lewis acid has an equivalent weight of 1 to 4 equivalents.
8. The process according to claim 1, wherein, in step (1), after the cyanation reaction is completed, compound I obtained by the following workup is used directly in the next step: after the reaction solution was filtered, the solvent was removed from the obtained filtrate, the obtained residue was dissolved in an organic solvent and washed with water, and then the organic solvent layer was concentrated to dryness, thereby obtaining compound I.
9. The process according to claim 1, wherein, after the completion of the reductive ring closure reaction in the step (2), the compound III obtained by the following post-treatment is directly used in the next step: after the reaction solution was filtered, the filtrate was concentrated to dryness to obtain compound III.
10. An intermediate compound I, wherein R 1 Is C1-5 alkyl;
11. a process for the preparation of compound I, characterized in that said process comprises the steps of: in an inert solvent, under the catalytic action of a copper salt and a chiral bisoxazoline ligand and in the presence of an oxidant, carrying out a cyanation reaction on a compound II and a cyanation reagent to obtain a compound I: wherein R is 1 Is C1-5 alkyl;
the copper salt is cuprous acetate; the oxidant is N-fluoro-bis-benzene sulfonamide; the cyaniding reagent is trimethylsilylcyanide; the chiral bisoxazoline ligand is a ligand a or a ligand b:
12. the method according to claim 11,
the equivalent number of the copper salt is 1-20 percent equivalent; the equivalent number of the oxidant is 1-4 equivalents; the number of equivalents of the cyanating reagent is 1-4 equivalents; the equivalent of the chiral bisoxazoline ligand is 1 to 20 percent.
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