CN115181047A - Preparation method of chiral 3- (dimethylamino) pyrrolidine - Google Patents
Preparation method of chiral 3- (dimethylamino) pyrrolidine Download PDFInfo
- Publication number
- CN115181047A CN115181047A CN202210918513.5A CN202210918513A CN115181047A CN 115181047 A CN115181047 A CN 115181047A CN 202210918513 A CN202210918513 A CN 202210918513A CN 115181047 A CN115181047 A CN 115181047A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- washing
- under
- concentrating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 229940126214 compound 3 Drugs 0.000 claims description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 21
- 229940125782 compound 2 Drugs 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 239000000243 solution Substances 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
- 239000000706 filtrate Substances 0.000 claims description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- 229940125904 compound 1 Drugs 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000003760 magnetic stirring 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000003756 stirring Methods 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
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012266 salt solution 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
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 150000003839 salts Chemical class 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 2
- 239000007858 starting material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 3
- 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
- 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
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 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
- 239000003208 petroleum Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of chiral 3- (dimethylamino) pyrrolidine, which uses an easily-obtained and cheap compound as a starting material to prepare the chiral 3- (dimethylamino) pyrrolidine through four-step reaction, does not need chiral resolution in the reaction process, and has novel whole route design, stronger 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, relates to chiral 3- (dimethylamino) pyrrolidine, and particularly relates 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 a specific double AbL-Lyn inhibitor antitumor drug baflutinib. However, chiral 3- (dimethylamino) pyrrolidine in the prior art typically requires chiral resolution, which greatly increases the cost of the process.
Therefore, there is a need to develop a low-cost method for synthesizing 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, and the reaction process does not require chiral resolution, has strong practicability, high yield, high reaction speed and few byproducts, and is very suitable for industrial application.
Except for special description, the parts are parts by weight, and the percentage is mass percent.
In order to realize the purpose, the technical scheme of the invention is as follows:
compound 3, having the following structural formula:
the compound 3 of the invention is converted from a compound 2, and the structural formula of the compound 2 is as follows:
the compound 2 of the invention is converted from a compound 1, wherein the structural formula of the compound 1 is as follows:
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 uses a compound 1 as a raw material to react with formaldehyde to prepare a compound 2, then cyclizes to obtain a compound 3, reduces to obtain a compound 4, and removes benzyl to obtain the 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 a satisfactory yield and accelerate the reaction process, water is used as a solvent, and the reaction is carried out for 5-7h at 40-60 ℃ under hydrogen atmosphere.
In the process of preparing the compound 3 by reacting the compound 2 with the benzylamine, once the control is poor, the dimethylamino group at the 3-position of the pyrrolidineConfiguration inversion can occur, the content of chiral impurities is increased, and the yield of the product is reduced. After a large number of experiments, the Nb is adopted 2 O 5 The catalyst is normal hexane which is used as a solvent, and the production of chiral impurities can be greatly reduced under the reaction condition of refluxing for 7-9 hours under the protection of nitrogen, so that the yield of the compound 3 is improved. Further, compound 2, benzylamine, 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 using kieselguhr, washing the filtrate by using NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated salt solution respectively, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound 3.
In the process of preparing the compound 4 by reducing the compound 3 in the presence of LAH, in order to obtain a satisfactory yield, the compound 3 and anhydrous THF are added into a dry reaction bottle with magnetic stirring, then LAH is added, and the mixture is refluxed for 8-12h under the protection of nitrogen.
In the process of preparing the compound 5 by reducing the compound 4 by Pd/C, in order to accelerate the reaction process and obtain a satisfactory yield, the compound 4, pd/C, hydrochloric acid and a solvent methanol are added into a reaction flask, then the reaction is carried out for 8-12h at 30-50 ℃ under hydrogen atmosphere, then the reaction solution is cooled to room temperature, naOH is added, filtration is carried out, the solid is washed by methanol, the filtrate is decompressed and concentrated, the remainder is washed by ethyl acetate, an organic layer is respectively washed by saturated sodium bicarbonate and saturated sodium chloride, and then the drying, filtration and concentration are carried out by anhydrous sodium sulfate to obtain the compound 5.
Specifically, the preparation method of chiral 3- (dimethylamino) pyrrolidine comprises the following steps:
(1) Adding the compound 1, pd/C, water and formaldehyde into a reaction flask with magnetic stirring, stirring for 6h at 50 ℃ under hydrogen atmosphere, cooling the reaction solution 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, phenylmethylamine, nb 2 O 5 Adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8h under the protection of nitrogen, cooling the reaction solution to room temperature, adding acetic acidFiltering with ethyl ester and diatomite, washing the filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated salt water respectively, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain solid compound 3;
(3) Adding the compound 3 and anhydrous THF into a dry reaction bottle with magnetic stirring, then adding LAH, refluxing for 10h 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 for dilution, then stirring for 5h at room temperature, adding anhydrous sodium sulfate into the reaction liquid for drying, concentrating and purifying to obtain a compound 4;
(4) Adding the compound 4, pd/C, hydrochloric acid and methanol into a reaction flask with magnetic force, stirring overnight at 40 ℃ under hydrogen atmosphere, cooling the reaction solution 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 sodium chloride respectively, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound 5.
Advantageous effects
The invention provides a synthesis method of chiral 3- (dimethylamino) pyrrolidine, which is characterized in that a compound 1 which is easy to obtain and low in price is used as an initial raw material, the chiral 3- (dimethylamino) pyrrolidine is prepared through four-step reaction, chiral resolution is not needed in the reaction process, the whole route is novel in design, strong in practicability, high in yield, high in reaction speed and few in byproducts, and the method is very suitable for industrial application.
Detailed Description
The present invention is described in detail in the following examples, which are given for the purpose of illustration only and are not to be construed as limiting the scope of the invention, which is defined in the claims. The raw materials and 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 (50mmol, 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, followed by stirring at 50 ℃ for 6h under hydrogen atmosphere and TLC to show completion of the reaction. Cooling the reaction solution to room temperature, filtering, and concentrating the filtrate under reduced pressure. The crude product was washed with acetone (25ml x 3) and dried to give compound 2 as a solid (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 (10mmol, 1.61g), benzylamine (10mmol, 1.07g) and Nb 2 O 5 (5mmol, 1.33g) and 50mL of n-hexane were added to a magnetically stirred reaction flask, refluxed for 8h under nitrogen, and TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature, 50mL of ethyl acetate was added thereto, the mixture was filtered through celite, and the filtrate was washed with an aqueous NaOH solution (1m, 20ml × 2), a saturated aqueous sodium bicarbonate solution (25ml × 3), and a saturated brine (25ml × 2), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain solid compound 3 (2.18g, 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 (5mmol, 1.16g) and 20mL of anhydrous THF were added to a dry reaction flask with magnetic stirring, then LAH (20mmol, 0.76g) was added in portions, and after refluxing for 10h under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was cooled to-20 ℃ and 1mL of water was slowly added dropwise to terminate the reaction. 1mL of aqueous NaOH (15%) and 30mL of diethyl ether were added to dilute the solution, followed by stirring at room temperature for 5h. The reaction solution was directly added with anhydrous sodium sulfate, dried, concentrated and purified by a silica gel column (ethyl acetate/petroleum ether = 1). 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 (5mmol, 1g), pd/C (10%, 260 mg), 5mL hydrochloric acid (2.5M), and 20mL methanol were added to a magnetic reaction flask, stirred overnight at 40 ℃ under a hydrogen atmosphere, and TLC indicated completion of the reaction. The reaction mixture was cooled to room temperature, 5mL of an aqueous solution of naoh (2.5M) was slowly dropped, filtered, the solid was washed with 50mL of methanol, the filtrate was concentrated under reduced pressure, the residue was washed with ethyl acetate (25ml x 4), and the organic layer was washed with saturated sodium bicarbonate (25ml x 2) and saturated brine (25ml x 2), respectively, and then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (520mg, 92%) as a pale yellow liquid. Ms [ M + H] + :115.1。
Claims (10)
1. Compound 3, having the following structural formula:
2. a compound according to claim 1, wherein: the compound 3 is converted from a compound 2, and the structural formula of the compound 2 is as follows:
3. compound 3 according to claim 1, wherein: the compound 2 is converted from a compound 1, and the structural formula of the compound 1 is as follows:
4. a preparation method of chiral 3- (dimethylamino) pyrrolidine uses a compound 1 as a raw material, reacts with formaldehyde to prepare a compound 2, then cyclizes to obtain a compound 3, then reduces to obtain a compound 4, and removes benzyl to obtain chiral 3- (dimethylamino) pyrrolidine (a compound 5); the synthetic route is as follows:
5. the method of claim 4, 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 ℃ under hydrogen atmosphere.
6. The method of claim 4, wherein: in the process of preparing a compound 3 by reacting a compound 2 with benzylamine, nb is adopted 2 O 5 As catalyst, n-hexane as solventAnd refluxing for 7-9h under the protection of nitrogen.
7. The method of claim 4, wherein: compound 2, phenylmethylamine, nb 2 O 5 And adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8h under the protection of nitrogen, cooling the reaction liquid to room temperature, adding ethyl acetate, filtering by using kieselguhr, washing the filtrate by using NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated salt solution respectively, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound 3.
8. The method of claim 4, wherein: in the process of preparing the compound 4 by reducing the compound 3 in the presence of LAH, the compound 3 and anhydrous THF are added into a dry reaction bottle with magnetic stirring, then the LAH is added, and the mixture is refluxed for 8-12h under the protection of nitrogen.
9. The method of claim 4, wherein: in the process of preparing a compound 5 by Pd/C reduction of a compound 4, adding the compound 4, pd/C, hydrochloric acid and a solvent methanol into a reaction flask, reacting for 8-12h at 30-50 ℃ under hydrogen atmosphere, cooling the reaction solution to room temperature, adding NaOH, filtering, washing a solid with methanol, decompressing and concentrating the filtrate, washing the residue with ethyl acetate, washing an organic layer with saturated sodium bicarbonate and saturated salt water respectively, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the compound 5.
10. The method of claim 4, comprising the steps of:
(1) Adding the compound 1, pd/C, water and formaldehyde into a reaction flask with magnetic stirring, stirring for 6h at 50 ℃ under hydrogen atmosphere, cooling the reaction solution 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, phenylmethylamine, nb 2 O 5 Adding n-hexane into a reaction bottle with magnetic stirring, refluxing for 8h under the protection of nitrogen, cooling the reaction solution to room temperatureAdding ethyl acetate, filtering with diatomite, washing the filtrate with NaOH aqueous solution, saturated sodium bicarbonate aqueous solution and saturated salt solution respectively, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain solid compound 3;
(3) Adding the compound 3 and anhydrous THF into a dry reaction bottle with magnetic stirring, then adding LAH, refluxing for 10h 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 for dilution, then stirring for 5h at room temperature, adding anhydrous sodium sulfate into the reaction liquid for drying, concentrating and purifying to obtain a compound 4;
(4) Adding the compound 4, pd/C, hydrochloric acid and methanol into a reaction flask with magnetic force, stirring overnight at 40 ℃ under hydrogen atmosphere, cooling the reaction solution 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 sodium chloride respectively, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210918513.5A CN115181047B (en) | 2022-08-01 | 2022-08-01 | Preparation method of chiral 3- (dimethylamino) pyrrolidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210918513.5A CN115181047B (en) | 2022-08-01 | 2022-08-01 | Preparation method of chiral 3- (dimethylamino) pyrrolidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115181047A true CN115181047A (en) | 2022-10-14 |
| CN115181047B CN115181047B (en) | 2024-01-30 |
Family
ID=83520376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210918513.5A Active CN115181047B (en) | 2022-08-01 | 2022-08-01 | Preparation method of chiral 3- (dimethylamino) pyrrolidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115181047B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2022
- 2022-08-01 CN CN202210918513.5A patent/CN115181047B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105209457A (en) * | 2013-03-15 | 2015-12-30 | 艾伯维德国有限责任两合公司 | 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 |
Non-Patent Citations (6)
| Title |
|---|
| FREE DE SCHOUWER等: "Metal-catalyzed reductive deamination of glutamic acid to bio-based dimethyl glutarate and methylamines" * |
| RAMANA SREENIVASA RAO等: "γ-Al2O3/triflic acid as cooperative catalysts for the tandem Michael addition/carbocyclization: An easy access to 2-substituted pyrrolo[2,1-a]isoquinolines and 3-substituted pyrrolidine-2,5-diones" * |
| TOSHIHIDE WATANABE等: "ASYMMETRIC DIECKMANN CONDENSATION VIA MEMORY OF CHIRALITY: SYNTHESIS OF THE KEY INTERMEDIATE FOR AS-3201, AN ALDOSE REDUCTASE INHIBITOR" * |
| V. CECHINEL FILHO等: "Inhibition of Guinea-pig Ileum Contraction by Phyllanthimide Analogues: Structure-activity Relationships" * |
| 李顺来等: "巴氟替尼中间体( Ｒ) － 3-二甲氨基吡咯烷的合成" * |
| 袁勇等: "一种N-甲基氨基酸酯的合成方法" * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115181047B (en) | 2024-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107805205B (en) | Preparation method of (R) -3-aminobutanol | |
| CN114014787A (en) | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| CN107778141B (en) | Purification method of 1, 4-butanediol | |
| CN115181047B (en) | Preparation method of chiral 3- (dimethylamino) pyrrolidine | |
| CN111533745A (en) | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester | |
| CN109824516B (en) | Preparation method of trans-4-hydroxycyclohexanecarboxylic acid tert-butyl ester | |
| CN114835645A (en) | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine | |
| CN110092726B (en) | Synthesis method of Bictegravir intermediate | |
| CN113717132A (en) | Key intermediate of antiepileptic drug and preparation method thereof | |
| CN108147988B (en) | Preparation method of lactam compound with high chiral purity | |
| CN110452172B (en) | Synthesis method of benzocaprolactam | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| CN114853619B (en) | Preparation method of N-methyltyramine hydrochloride suitable for industrial production | |
| CN115322143B (en) | Preparation method of 4-tert-butyl piperidine formate hydrochloride | |
| CN111100062A (en) | Synthesis method of donepezil hydrochloride | |
| CN114853624B (en) | Preparation method of 4-amino-1-butanol and N-protected derivative thereof | |
| CN115181093B (en) | Preparation method of Sunvozertinib intermediate | |
| CN115819232B (en) | Synthesis method of cycloalkyl acrylate compound | |
| CN111471001B (en) | Preparation method of 4- [ (1R) -1-amino-2-hydroxyethyl ] -3-fluoro-benzonitrile | |
| CN111592451B (en) | Preparation method of 4- (4-phenylbutoxy) benzoic acid | |
| CN109265385A (en) | A kind of synthesis technology of chiral catalyst | |
| CN116199614B (en) | N-axis chiral indole-pyrrole compound and synthesis method thereof | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN117843510A (en) | Preparation method of aminomethylbenzoic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |