CN115181047B - Preparation method of chiral 3- (dimethylamino) pyrrolidine - Google Patents
Preparation method of chiral 3- (dimethylamino) pyrrolidine Download PDFInfo
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- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 21
- 229940126214 compound 3 Drugs 0.000 claims description 21
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- 238000003760 magnetic stirring Methods 0.000 claims description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 3
- 230000036632 reaction speed Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention provides a synthesis method of chiral 3- (dimethylamino) pyrrolidine, which uses a compound which is easy to obtain and low in price as a starting material, and prepares the chiral 3- (dimethylamino) pyrrolidine through four steps of reactions, the reaction process does not need chiral resolution, and the whole route has novel design, strong practicability, high yield, high reaction speed and few byproducts, thereby being very suitable for industrial application.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to chiral 3- (dimethylamino) pyrrolidine, in particular to a preparation method for chiral synthesis of chiral 3- (dimethylamino) pyrrolidine.
Background
Chiral 3- (dimethylamino) pyrrolidine is a very important fine chemical and intermediate, and can be used for synthesizing specific dual AbL-Lyn inhibitor antitumor drug barfitinib. However, chiral 3- (dimethylamino) pyrrolidines of the prior art generally require chiral resolution, which greatly increases the cost of the process.
Therefore, there is a need to develop a low cost synthesis method of chiral 3- (dimethylamino) pyrrolidine.
Disclosure of Invention
In order to solve the problems in the prior art, according to a first aspect of the present invention, the present invention aims to provide a compound 3, wherein the compound 3 is used as a raw material or an intermediate for synthesizing chiral 3- (dimethylamino) pyrrolidine, the chiral resolution is not required in the reaction process, the practicability is high, the yield is high, the reaction speed is high, and the byproducts are few, so that the method is very suitable for industrial application.
The parts are parts by weight, except for specific descriptions, and the percentages are mass percentages.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
compound 3, having the structural formula:
compound 3 of the present invention is converted from compound 2, wherein compound 2 has the structural formula:
the compound 2 is converted from a compound 1, wherein the compound 1 has the structural formula:
in a second aspect, the present invention provides a process for the preparation of chiral 3- (dimethylamino) pyrrolidine.
A preparation method of chiral 3- (dimethylamino) pyrrolidine comprises the steps of taking a compound 1 as a raw material, reacting with formaldehyde to obtain a compound 2, then cyclizing to obtain a compound 3, reducing to obtain a compound 4, and removing benzyl to obtain chiral 3- (dimethylamino) pyrrolidine (compound 5).
The synthetic route is as follows:
in the process of preparing the compound 2 by reacting the compound 1 with formaldehyde under the action of Pd/C, in order to reduce the generation of imine, obtain more satisfactory yield, accelerate the reaction process, and react for 5-7h at 40-60 ℃ in hydrogen atmosphere by adopting water as a solvent.
In the process of preparing the compound 3 by reacting the compound 2 with the benzylamine, once the control is not good, the dimethylamino group at the 3-position of the pyrrolidine can have configuration inversion, so that the content of chiral impurities is increased, and the product yield is reduced. After a plurality of experiments, it is found that Nb is adopted 2 O 5 As the catalyst, n-hexane is used as a solvent, and the reaction condition of 7-9 hours of reflux under the protection of nitrogen can greatly reduce the production of chiral impurities and improve the yield of the compound 3. Further, compound 2, benzenemethylamine, nb 2 O 5 And adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8 hours under the protection of nitrogen, cooling the reaction liquid to room temperature, adding ethyl acetate, filtering by diatomite, washing filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution respectively, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound 3.
In the preparation of compound 4 by reduction of compound 3 in the presence of LAH, to obtain a satisfactory yield, compound 3 and anhydrous THF were added to a dry reaction flask with magnetic stirring, followed by LAH and reflux under nitrogen for 8-12h.
In the process of preparing the compound 5 by Pd/C reduction of the compound 4, in order to accelerate the reaction process and obtain more satisfactory yield, the compound 4, pd/C, hydrochloric acid and solvent methanol are firstly added into a reaction bottle, then the reaction is carried out for 8-12 hours under the hydrogen atmosphere at 30-50 ℃, then the reaction liquid is cooled to room temperature, naOH is added, the filtration is carried out, the solid is washed by methanol, the filtrate is concentrated under reduced pressure, the remainder is washed by ethyl acetate, the organic layer is respectively washed by saturated sodium bicarbonate and saturated saline solution, and then the compound 5 is obtained by drying, filtration and concentration through anhydrous sodium sulfate.
In particular to a preparation method of chiral 3- (dimethylamino) pyrrolidine, which comprises the following steps:
(1) Adding the compound 1, pd/C, water and formaldehyde into a reaction bottle with magnetic stirring, stirring for 6 hours at 50 ℃ under hydrogen atmosphere, cooling the reaction liquid to room temperature, filtering, concentrating the filtrate under reduced pressure, washing the crude product with acetone, and drying to obtain a solid compound 2;
(2) Compound 2, benzyl amine and Nb 2 O 5 And n-hexaneAdding the mixture into a reaction bottle with magnetic stirring, refluxing for 8 hours under the protection of nitrogen, cooling the reaction liquid to room temperature, adding ethyl acetate and diatomite for filtering, respectively washing filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a solid compound 3;
(3) Adding the compound 3 and anhydrous THF into a dry reaction bottle with magnetic stirring, then adding LAH, refluxing for 10 hours under the protection of nitrogen, cooling the reaction liquid to-20 ℃, dropwise adding water to terminate the reaction, adding NaOH aqueous solution and diethyl ether to dilute, then stirring at room temperature for 5 hours, adding anhydrous sodium sulfate into the reaction liquid to dry, concentrating and purifying to obtain a compound 4;
(4) The compound 4, pd/C, hydrochloric acid and methanol are added into a reaction bottle with magnetic force, the mixture is stirred overnight under the hydrogen atmosphere at 40 ℃, the reaction solution is cooled to room temperature, naOH is added, the solid is filtered, the methanol is used for washing, the filtrate is concentrated under reduced pressure, the remainder is washed with ethyl acetate, the organic layer is respectively washed with saturated sodium bicarbonate and saturated saline solution, and then the compound 5 is obtained by drying, filtering and concentrating anhydrous sodium sulfate.
Advantageous effects
The invention provides a synthesis method of chiral 3- (dimethylamino) pyrrolidine, which uses a compound 1 which is easy to obtain and low in price as a starting material, and prepares the chiral 3- (dimethylamino) pyrrolidine through four steps of reactions, the reaction process does not need chiral resolution, and the whole route has novel design, strong practicability, high yield, high reaction speed and few byproducts, thereby being very suitable for industrial application.
Detailed Description
The present invention is described in detail below by way of specific examples, which are given herein for the purpose of further illustration only and are not to be construed as limiting the scope of the present invention, as many insubstantial modifications and variations of the present invention will become apparent to those skilled in the art in light of the foregoing disclosure. The raw materials and the reagents used in the invention are all commercial products.
Example 1
Synthesis of Compound 2:
the synthetic route is as follows:
the operation steps are as follows: compound 1 (50 mmol,6.7 g), 2.5g Pd/C (10%, w/w), 25mL water and formaldehyde (37%) and 70mL water were added to a reaction flask with magnetic stirring, then stirred under a hydrogen atmosphere at 50℃for 6h, and TLC showed completion of the reaction. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was washed with acetone (25 ml x 3) and dried to give solid compound 2 (7.3 g, 91%). Ms [ M+H] + :162.1。
Example 2
Synthesis of Compound 3:
the synthetic route is as follows:
the operation steps are as follows: compound 2 (10 mmol,1.61 g), benzyl amine (10 mmol,1.07 g), nb 2 O 5 (5 mmol,1.33 g) and 50mL of n-hexane were added to a reaction flask with magnetic stirring and refluxed under nitrogen for 8h, and TLC showed completion of the reaction. The reaction mixture was cooled to room temperature, 50mL of ethyl acetate was added, and then the mixture was filtered through celite, and the filtrate was washed with aqueous NaOH (1 m,20ml×2), aqueous saturated sodium bicarbonate (25 ml×3) and saturated brine (25 ml×2), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give solid compound 3 (2.18 g, 94%). 1 H NMR(400MHz，CDCl3)δ7.40-7.32(m，2H)，7.32-7.26(m，3H)，4.68(d，J＝13.1Hz,2H)，3.77(m，1H)，2.79(m，1H)，2.60(m，1H)，2.32(s，6H)； 13 C NMR(101MHz，CDCl3)δ176.5，175.1，135.9，128.7，128.9，128.2，62.8，42.2，41.6，31.2；Ms[M+H] + :233.1。
Example 3
Synthesis of Compound 4:
the synthetic route is as follows:
the operation steps are as follows: compound 3 (5 mmol,1.16 g) and 20mL dry THF were added to a dry reaction flask with magnetic stirring, then LAH (20 mmol,0.76 g) was added in portions followed by reflux under nitrogen for 10h and TLC showed completion of the reaction. The reaction mixture was cooled to-20℃and 1mL of water was slowly added dropwise to terminate the reaction. 1mL of aqueous LNaOH (15%) and 30mL of diethyl ether were added and diluted, followed by stirring at room temperature for a further 5h. The reaction solution was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (ethyl acetate/petroleum ether=1:10) to give compound 4 (0.91 g, 89%). 1 H NMR(400MHz，CDCl3)δ1.62-1.74(m，H)，1.88-2.06(m，2H)，2.20(s,6H)，2.28(m，1H)，2.49(m，1H)，2.68-2.89(m，2H)，3.52(d，J＝12.7Hz，1H)，3.64(d，J＝12.7Hz，1H)，7.22-7.33(m，5H)； 13 C NMR(101MHz，CDCl3)δ29.1,43.6,53.3,58.5,60.2,65.1,126.6,128.0,128.4,138.8.HMs[M+H] + :205.1。
Example 4
Synthesis of Compound 5:
the synthetic route is as follows:
the operation steps are as follows: compound 4 (5 mmol,1 g), pd/C (10%, 260 mg), 5mL hydrochloric acid (2.5M) and 20mL methanol were added to a reaction flask with magnetic force and stirred overnight at 40℃under a hydrogen atmosphere, TLC indicating completion of the reaction. The reaction was cooled to room temperature, 5mL of aqueous lnaoh (2.5M) was slowly added dropwise, the solid was washed with 50mL of methanol, the filtrate was concentrated under reduced pressure, the residue was washed with ethyl acetate (25 mL x 4), the organic layer was washed with saturated sodium bicarbonate (25 mL x 2) and saturated brine (25 mL x 2), and then dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5 (520 mg, 92%) as a pale yellow liquid. Ms [ M+H] + :115.1。
Claims (7)
1. The preparation method of chiral 3- (dimethylamino) pyrrolidine comprises the steps of taking a compound 1 as a raw material, reacting with formaldehyde to prepare a compound 2, then cyclizing to obtain a compound 3, reducing to obtain a compound 4, and removing benzyl to obtain chiral 3- (dimethylamino) pyrrolidine; the synthetic route is as follows:
2. the method of claim 1, wherein: in the process of preparing the compound 2 by reacting the compound 1 with formaldehyde under the action of Pd/C, water is adopted as a solvent, and the reaction is carried out for 5-7h at 40-60 ℃ in hydrogen atmosphere.
3. The method of claim 1, wherein: in the preparation of compound 3 by reacting compound 2 with benzylamine, nb is used 2 O 5 N-hexane is used as a catalyst, and reflux is performed for 7-9h under the protection of nitrogen.
4. The method of claim 1, wherein: compound 2, benzyl amine and Nb 2 O 5 And adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8 hours under the protection of nitrogen, cooling the reaction liquid to room temperature, adding ethyl acetate, filtering by diatomite, washing filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution respectively, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound 3.
5. The method of claim 1, wherein: in the preparation of compound 4 by reduction of compound 3 in the presence of LAH, compound 3 and anhydrous THF were added to a dry reaction flask with magnetic stirring, followed by LAH and reflux under nitrogen for 8-12h.
6. The method of claim 1, wherein: in the process of preparing the compound 5 by Pd/C reduction of the compound 4, adding the compound 4, pd/C, hydrochloric acid and solvent methanol into a reaction bottle, reacting for 8-12 hours at 30-50 ℃ under hydrogen atmosphere, cooling the reaction liquid to room temperature, adding NaOH, filtering, washing the solid with methanol, concentrating the filtrate under reduced pressure, washing the residue with ethyl acetate, washing the organic layer with saturated sodium bicarbonate and saturated saline respectively, and drying, filtering and concentrating the mixture with anhydrous sodium sulfate to obtain the compound 5.
7. The method of claim 1, comprising the steps of:
(1) Adding the compound 1, pd/C, water and formaldehyde into a reaction bottle with magnetic stirring, stirring for 6 hours at 50 ℃ under hydrogen atmosphere, cooling the reaction liquid to room temperature, filtering, concentrating the filtrate under reduced pressure, washing the crude product with acetone, and drying to obtain a solid compound 2;
(2) Compound 2, benzyl amine and Nb 2 O 5 Adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8 hours under the protection of nitrogen, cooling the reaction liquid to room temperature, adding ethyl acetate, filtering by diatomite, washing filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution respectively, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a solid compound 3;
(3) Adding the compound 3 and anhydrous THF into a dry reaction bottle with magnetic stirring, then adding LAH, refluxing for 10 hours under the protection of nitrogen, cooling the reaction liquid to-20 ℃, dropwise adding water to terminate the reaction, adding NaOH aqueous solution and diethyl ether to dilute, then stirring at room temperature for 5 hours, adding anhydrous sodium sulfate into the reaction liquid to dry, concentrating and purifying to obtain a compound 4;
(4) The compound 4, pd/C, hydrochloric acid and methanol are added into a reaction bottle with magnetic force, the mixture is stirred overnight under the hydrogen atmosphere at 40 ℃, the reaction solution is cooled to room temperature, naOH is added, the solid is filtered, the methanol is used for washing, the filtrate is concentrated under reduced pressure, the remainder is washed with ethyl acetate, the organic layer is respectively washed with saturated sodium bicarbonate and saturated saline solution, and then the compound 5 is obtained by drying, filtering and concentrating anhydrous sodium sulfate.
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| TW201010968A (en) * | 2008-09-11 | 2010-03-16 | China Petrochemical Dev Corp | Method for preparing amide |
| WO2014140310A1 (en) * | 2013-03-15 | 2014-09-18 | AbbVie Deutschland GmbH & Co. KG | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| CN104592163A (en) * | 2015-01-08 | 2015-05-06 | 爱斯特（成都）生物制药有限公司 | Synthetic method of chiral 2-phenylpyrrolidine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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