CN111333544A - Intermediate for synthesizing nilapanib and preparation method thereof - Google Patents

Intermediate for synthesizing nilapanib and preparation method thereof Download PDF

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CN111333544A
CN111333544A CN202010231736.5A CN202010231736A CN111333544A CN 111333544 A CN111333544 A CN 111333544A CN 202010231736 A CN202010231736 A CN 202010231736A CN 111333544 A CN111333544 A CN 111333544A
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CN111333544B (en
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郭朋
朱文峰
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Shanghai Vastpro Technology Development Co ltd
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    • 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

Intermediate for synthesizing nilapanib and preparation method thereof
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 (Nilaparib, 2- [4- ((3S) -3-piperidyl) phenyl ] -2H-indazole-7-carboxamide), 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 clear target point, accords with accurate medical treatment of cancer, and has the advantages that the pre-submission indication of the Nilaparib is ovarian cancer and breast cancer related to BRCA gene mutation, the Nilaparib should be a second PARP inhibitor to be marketed, and the last year Aslican has marketed the PARP inhibitor Olaparib (also called Lylaparib) because the effect is remarkably approved to be used for the ovarian cancer with BRCA mutation, and the sale peak value is expected to reach more than 20 billion dollars per year.
Figure BDA0002429487490000011
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 great improvement was proposed in the synthesis route in org. process res.dev.2014,18, 215-:
Figure BDA0002429487490000021
the intermediate (S) -3- (4-bromophenyl) -piperidine is used for synthesis of the nilapanib for the first time, sodium azide is avoided, and meanwhile, the (S) -3- (4-bromophenyl) -piperidine intermediate is synthesized through enzymatic catalysis in an invasive manner, 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 purpose of the present invention is to provide a simpler method for producing (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 is1Is C1-5 alkyl;
Figure BDA0002429487490000031
(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 is1Is C1-5 alkyl;
Figure BDA0002429487490000032
(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;
Figure BDA0002429487490000033
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 1-4 equivalents.
In another preferred embodiment, the chiral bisoxazoline ligand is ligand a or ligand b:
Figure BDA0002429487490000034
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 is1Is C1-5 alkyl;
Figure BDA0002429487490000041
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 is1Is C1-5 alkyl;
Figure BDA0002429487490000042
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 1-4 equivalents.
In another preferred embodiment, the chiral bisoxazoline ligand is ligand a or ligand b:
Figure BDA0002429487490000043
in another preferred embodiment, the equivalent of the chiral bisoxazoline ligand is 1 to 20% 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 reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has found a structure has never been reported to novel bromine fragment of nilapanib, namely, intermediate compound I used for preparing key intermediate (S) -3- (4-bromophenyl) -piperidine for preparing nilapanib.
Figure BDA0002429487490000051
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:
Figure BDA0002429487490000052
wherein R is1Is a C1-5 alkyl group.
In the present invention, R is1C1-5 alkyl, i.e., alkyl having 1-5 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:
Figure BDA0002429487490000061
(4S,4'S) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-benzyl-4, 5-dihydrooxazole);
Figure BDA0002429487490000062
(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; r1Is C1-5 alkyl;
Figure BDA0002429487490000063
(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;
Figure BDA0002429487490000071
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 is not affected.
In the step (3), the equivalent number of the sodium borohydride is 1-3 equivalents.
In the step (3), the number of equivalents of the Lewis acid is 1 to 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 to 30 ℃; then heating to 40-60 ℃ and stirring (for example, stirring for 1-6 hours or 2-4 hours); removing 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 (4S,4'S) -2,2' - (cyclopentane-1, 1-diyl) -bis (4-benzyl-4, 5-dihydrooxazole) is 1003886-05-2.
The CAS number for (3AS,3' AS,8AR,8' AR) -2,2' -cyclopentylidenebis [3A, 8A-dihydro-8H-indeno [1,2-D ] oxazole is 182122-12-9.
Ligands a and b of the invention can also be referred to in Organic and biomolecular chemistry; vol.5; nb.24; (2007) (ii) a 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. Trimethylsilanitrile (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 (50mL) 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.
And (3) separating a part of crude products by silica gel column chromatography (petroleum ether: ethyl acetate: 20: 1-10: 1) to obtain pure products for characterizing the structure. ee-87%;1H NMR(CDCl3,400MHz):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 product of 4- (4-bromophenyl) -4-cyano-methyl butyrate obtained in example 1, raney nickel (1g, 10% wt) and methanol (100mL) are added into a hydrogenation reaction flask, and stirred at 60-70 ℃ under the pressure of 5-10 Kg hydrogen until the reaction is completed. After the reaction was completed, the insoluble matter was removed by filtration through celite, the filtrate was concentrated to dryness, and the obtained crude product was directly subjected to the next step.
Example 3
Tetrahydrofuran (50mL) and the crude product obtained in the reaction in example 2 are added into a reaction bottle, after the temperature is reduced to 0-5 ℃, sodium borohydride (4.0g, 3eq) and boron trifluoride tetrahydrofuran (19.7g, 4eq) are added dropwise into the reaction bottle. After dropping, the mixture is stirred at room temperature until the reaction is completed. While maintaining the internal temperature at 20 ℃ or lower, water (25mL) and 6N hydrochloric acid (25mL) were added dropwise in this order. After dropping, the temperature is raised to 50 ℃, and stirring is continued for 3 hours. Concentrating under reduced pressure to remove tetrahydrofuran, and adjusting the pH value to 12-14 by using liquid alkali. The mixture was extracted twice with dichloromethane (50mL), 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, 0.5eq) 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 is 99%.1H NMR(CDCl3,400MHz):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 stirred under nitrogen for 1 hour. N-fluorobisbenzenesulfonamide (12.3g, 2eq) and methyl 4-bromobenzoate (5g, 1eq) were then added. Trimethylsilanitrile (5.8g, 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 (50mL) and washed 2 times with water (50 mL). After the organic phase was concentrated to dryness, the product was isolated by silica gel column chromatography to give 3.9g of the cyanide in 71% yield and ee 86%.
Example 5
To a reaction flask, 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 were added, and stirred under nitrogen for 1 hour. N-fluorobisbenzenesulfonamide (1.16g, 1eq) and ethyl 4-bromobenzoate (1g, 1eq) were then added. Trimethylsilanitrile (1.1g, 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 subjected to 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 (10)

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 is1Is C1-5 alkyl;
Figure FDA0002429487480000011
(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 is1Is C1-5 alkyl;
Figure FDA0002429487480000012
(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;
Figure FDA0002429487480000013
2. the method of claim 1, wherein the copper salt is cuprous acetate.
3. The method of claim 1, wherein the oxidizing agent is N-fluorobisbenzenesulfonamide.
4. The method of claim 1, wherein the cyanating reagent is trimethylsilylcyanide.
5. The process according to claim 1, wherein the chiral bisoxazoline ligand is a ligand a or a ligand b:
Figure FDA0002429487480000021
6. the method of claim 1, wherein the catalyst is raney nickel or palladium on carbon.
7. The method according to claim 1, wherein the Lewis acid is boron trifluoride tetrahydrofuran.
8. An intermediate compound I, wherein R1Is C1-5 alkyl;
Figure FDA0002429487480000022
9. 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 is1Is C1-5 alkyl;
Figure FDA0002429487480000023
10. the process according to claim 9, wherein the chiral bisoxazoline ligand is a ligand a or a ligand b:
Figure FDA0002429487480000024
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