CN115521238A - Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine - Google Patents
Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine Download PDFInfo
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- CN115521238A CN115521238A CN202210776154.4A CN202210776154A CN115521238A CN 115521238 A CN115521238 A CN 115521238A CN 202210776154 A CN202210776154 A CN 202210776154A CN 115521238 A CN115521238 A CN 115521238A
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- pyrrolidine
- chloroethyl
- methyl
- hydroxyethyl
- boc
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- CLVNTYZKUHNUEF-UHFFFAOYSA-N 2-(2-chloroethyl)-1-methylpyrrolidine Chemical compound CN1CCCC1CCCl CLVNTYZKUHNUEF-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 16
- MXPOLUPSEVGAAS-UHFFFAOYSA-N tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1CCO MXPOLUPSEVGAAS-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 1-Boc-2- (2-hydroxyethyl) pyrrole Chemical compound 0.000 claims abstract description 11
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 10
- RGUJKYQDJZCYJB-UHFFFAOYSA-N 2-(2-chloroethyl)pyrrolidin-1-ium;chloride Chemical compound Cl.ClCCC1CCCN1 RGUJKYQDJZCYJB-UHFFFAOYSA-N 0.000 claims abstract description 9
- LUVQSCCABURXJL-UHFFFAOYSA-N 1-tert-butylpyrrolidin-2-one Chemical compound CC(C)(C)N1CCCC1=O LUVQSCCABURXJL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 6
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical group CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229940071139 pyrrolidone carboxylate Drugs 0.000 claims description 3
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- BNXZHVUCNYMNOS-UHFFFAOYSA-N 1-butylpyrrolidin-2-one Chemical compound CCCCN1CCCC1=O BNXZHVUCNYMNOS-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 229910000085 borane Inorganic materials 0.000 abstract description 2
- 230000022244 formylation Effects 0.000 abstract description 2
- 238000006170 formylation reaction Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYVMBPXFPFAECB-UHFFFAOYSA-N 2-(1-methylpyrrolidin-2-yl)ethanol Chemical compound CN1CCCC1CCO FYVMBPXFPFAECB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- FSNGFFWICFYWQC-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine;hydron;chloride Chemical compound Cl.ClCCN1CCCC1 FSNGFFWICFYWQC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- YVDYKCMRDRWDJT-UHFFFAOYSA-N 2,2-dimethyl-5-(1-methylpyrrolidin-2-ylidene)-1,3-dioxane-4,6-dione Chemical compound CN1CCCC1=C1C(=O)OC(C)(C)OC1=O YVDYKCMRDRWDJT-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D207/04—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
- C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention specifically discloses a preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine, belonging to the technical field of medical intermediates. Taking N-t-butyl pyrrolidone as a raw material, lithiating to remove protons, reacting with ethylene oxide to obtain 1-Boc-2- (2-hydroxyethyl) pyrrole, carrying out catalytic hydrogenation under the action of a catalyst to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine, reacting with thionyl chloride to obtain 2- (2-chloroethyl) pyrrolidine hydrochloride, and carrying out borane reduction after formylation to obtain N-methyl-2- (2-chloroethyl) pyrrolidine. The invention has the advantages of high single-step yield, easy separation of impurities and low cost, wherein the total yield is up to 65 percent, the purity is more than 99.5 percent, and the invention is more suitable for industrialization.
Description
Technical Field
The invention relates to a preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine, belonging to the technical field of medical intermediates.
Background
N-methyl-2- (2-chloroethyl) pyrrolidine, CAS:54777-54-7, english name: 2- (2-Chloroethyl) -1-methyl-pyrolidine, which is an important intermediate of clonidine/clemastin, is also used for synthesizing an ARC-111 lactam analogue with strong topoisomerase I targeting activity and cytotoxicity.
KR2016/141950,2016, A reports the synthesis of N-methyl-2- (2-hydroxyethyl) pyrrolidine, which uses N-methylpyrrolidone as a starting material, and reacts with triphosgene for nucleophilic reaction, then Meldrum's acid and triethylamine are added to react at room temperature to generate 2,2-dimethyl-5- (1-methylpyrrolidine-2-ylidene) -1, 3-dioxane-4, 6-dione, alkali hydrolysis is carried out to obtain 2- (1-methyl-2-pyrrolidinylidene) methyl acetate, then Pd/C double bond reduction is carried out, and finally sodium borohydride is reduced to obtain N-methyl-2- (2-hydroxyethyl) pyrrolidine. Although the raw materials are relatively cheap, the hazardous chemical triphosgene is used; the chemical equation is as follows:
patent CN107011228,2017, A reports that N-methyl-2- (2-chloroethyl) pyrrolidine and thionyl chloride are chlorinated to obtain N-methyl-2- (2-chloroethyl) pyrrolidine. However, the N-methyl-2- (2-hydroxyethyl) pyrrolidine is expensive in raw material and the preparation steps are long directly according to the scheme; the reaction equation is as follows:
aiming at the defects of the method, the invention adopts the preparation method which has simple and convenient flow, few reaction steps and high total yield, is suitable for large-scale synthesis and meets the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine. Taking N-t-butyl pyrrolidone as a raw material, lithiating to remove protons, reacting with ethylene oxide to obtain 1-Boc-2- (2-hydroxyethyl) pyrrole, then carrying out catalytic hydrogenation under the action of a catalyst to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine, reacting with thionyl chloride to obtain 2- (2-chloroethyl) pyrrolidine hydrochloride, and reducing borane after formylation to obtain N-methyl-2- (2-chloroethyl) pyrrolidine. The invention has the advantages of high single-step yield, easy separation of impurities and low cost, wherein the total yield is up to 65 percent, the purity is more than 99.5 percent, and the invention is more suitable for industrialization.
The invention relates to a preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine, which comprises the following steps:
the first step is as follows: mixing N-t-butyl pyrrolidone carboxylate, an activating agent and tetrahydrofuran, reacting with a lithium reagent to remove protons, and then reacting with ethylene oxide to obtain 1-Boc-2- (2-hydroxyethyl) pyrrole;
the second step: mixing 1-Boc-2- (2-hydroxyethyl) pyrrole, a metal catalyst and methanol, and carrying out catalytic hydrogenation reaction to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine;
the third step: reacting 1-Boc-2- (2-hydroxyethyl) pyrrolidine with thionyl chloride, and then adding alcohol for continuous reaction to obtain 2- (2-chloroethyl) pyrrolidine hydrochloride;
the fourth step: adding alkali to the 2- (2-chloroethyl) pyrrolidine hydrochloride for dissociating, heating and carrying out reflux reaction on the hydrochloride and formate, then reacting with a borane-tetrahydrofuran solution to obtain a crude product of the N-methyl-2- (2-chloroethyl) pyrrolidine, and recrystallizing with N-heptane to obtain a pure product.
Further, in the above technical solution, in the first step, the activating agent is selected from tetramethylethylenediamine or 2, 6-tetramethylpiperidine.
Further, in the above technical solution, in the first step, the lithium reagent is selected from n-butyllithium, and the concentration is 2.5M or 1.6M.
Further, in the above technical solution, in the first step, the molar ratio of N-t-butyl pyrrolidone, ethylene oxide, an activating agent and a lithium reagent is 1:1-1.05:1-1.2:1.1-1.5. The reaction obtains a single substituted product by strictly controlling the equivalent weight of the ethylene oxide, and the excessive amount of the lithium reagent has no obvious influence.
Further, in the above technical means, in the second step, the metal catalyst is selected from 5% Ru/C or 10% Pd/C.
Further, in the technical scheme, in the third step, the molar ratio of the 1-Boc-2- (2-hydroxyethyl) pyrrolidine to thionyl chloride is 1:1-2.
Further, in the above technical solution, in the fourth step, the formate is selected from methyl formate or ethyl formate. After raw materials are dissociated, the raw materials are directly subjected to reflux reaction in a methyl formate or ethyl formate solvent, and after the reaction is finished, the solvent is evaporated to dryness and directly subjected to the next step.
Further, in the above technical solution, in the fourth step, the molar ratio of the 2- (2-chloroethyl) pyrrolidine hydrochloride, the base and the borane-tetrahydrofuran is 1:1.0-1.5:1.5-3.0.
Advantageous effects of the invention
1. The invention provides a new synthetic route, has less overall reaction steps, is easy to separate impurities, is a raw material with low price and easy obtainment in the market, and has low comprehensive cost and total yield up to 65 percent.
2. In the first step, the reaction achieves the aim of single substitution by controlling the equivalent weight of ethylene oxide, and in the fourth step, ethyl formate is directly formylated and then reduced, so that the transition methylation on N is avoided.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
83.6g (0.5 mol,1.0 eq) of N-t-butyl pyrrolidone carboxylate, 58.0g (0.50 mol) of TMEDA and 450mL of tetrahydrofuran are mixed under the protection of nitrogen, the temperature is reduced to-65 to-70 ℃, 288mL of 2.0M N-butyl lithium solution is added dropwise, the reaction is carried out for 2 hours under the condition of heat preservation and stirring after the dropwise addition is finished, and then 22.9g (0.52 mol) of ethylene oxide/60 mL of tetrahydrofuran solution is added dropwise. Maintaining the temperature for continuous reaction for 2 hours, naturally heating to 0 ℃, stirring overnight, quenching by ammonium chloride aqueous solution, extracting by ethyl acetate, concentrating the organic phase under reduced pressure, adding n-heptane for pulping, and filtering to obtain 78.8g of 1-Boc-2- (2-hydroxyethyl) pyrrole; yield 74.6%, HPLC 98.2%. 1 HNMR(400MHz,CDCl3):δ7.05-7.00(m,1H),6.12-5.89(m,2H),4.58(s,1H),3.63-3.60(m,2H),2.81-2.78(m,2H),1.56(s,9H).
Example 2
Under the protection of nitrogen, 83.6g (0.5 mol, 1.0eq) of N-t-butyl pyrrolidone, 77.7g (0.55mol, 1.1eq) of TEMP and 450mL of tetrahydrofuran are mixed, the temperature is reduced to-65 to-70 ℃, 288mL of 2.0M N-butyl lithium N-hexane solution is added dropwise, the reaction is kept at the temperature for 2 hours under stirring after the dropwise addition is finished, and then 22.1g (0.50 mol) of ethylene oxide/60 mL of tetrahydrofuran solution is added dropwise. Maintaining the temperature for continuous reaction for 2 hours, naturally heating to 0 ℃, stirring overnight, quenching by ammonium chloride aqueous solution, extracting by ethyl acetate, concentrating the organic phase under reduced pressure, adding n-heptane for pulping, and filtering to obtain 84.6g of 1-Boc-2- (2-hydroxyethyl) pyrrole; yield 80.1%, HPLC 94.4%.
Example 3
The Boc-2- (2-hydroxyethyl) pyrrole (73.9 g, 0.35 mol), ru 5/C7.4 g and methanol (500 mL) were mixed in an autoclave, and after replacement with nitrogen and hydrogen, respectively, hydrogen was introduced and the temperature was raised to 80 ℃ while maintaining the pressure at 2.0MPa, the reaction was carried out for 16 hours, filtration was carried out while lowering the temperature, and the filtrate was concentrated under reduced pressure until no flow occurred to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine (75.4 g) in a yield of 100%. 1 HNMR(400MHz,DMSO-d 6 ):δ4.37(s,1H),3.73-3.71(m,1H),3.42-3.37(m,2H),3.22-3.19(m,2H),1.81-1.68(m,5H),1.43-1.41(m,1H),1.39(s,9H).
Example 4
Mixing Boc-2- (2-hydroxyethyl) pyrrolidine 73.9g (0.35 mol), 10% Pd/C15.0 g and methanol 500mL in an autoclave, replacing with nitrogen and hydrogen respectively, introducing hydrogen and heating to 90 deg.C, maintaining the pressure at 2.2MPa for reaction overnight, cooling, filtering, and concentrating the filtrate under reduced pressure until no liquid flows to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine 75.4g with a yield of 100%.
Example 5
75.4g (0.35mol, 1eq) of N-Boc-2- (2-hydroxyethyl) pyrrolidine was mixed with dichloromethane, and 67g (0.56 mol) of thionyl chloride was slowly added dropwise at room temperature, followed by slowly raising the temperature to reflux for 3 hours. Then, the temperature is reduced to 30-35 ℃, 100mL of methanol solution is added dropwise, and the reflux reaction is continuously maintained for 1 hour. Cooling to 0 ℃, decompressing and concentrating the reaction liquid, pulping the methyl tert-butyl ether, and filtering to obtain 54.5g of 2- (2-chloroethyl) pyrrolidine hydrochloride with the yield of 91.5%.
Example 6
Adding 51g (0.3 mol,1.0 eq) of (2-chloroethyl) pyrrolidine hydrochloride to 30% sodium hydroxide solution, adjusting the solution pH =11-12, and stirring for 10 minutes; ethyl formate was extracted twice (100ml × 2) and the organic layers were combined and warmed to reflux for 3 hours. After the TLC detection reaction is finished, the solvent is evaporated to dryness, 150mL of tetrahydrofuran is added, the mixture is dropwise added into 450mL of 1.0M borane-tetrahydrofuran solution at room temperature, the mixture is stirred for 30 minutes at room temperature, then reflux reaction is carried out for 3 hours, 10% hydrochloric acid is used for quenching the reaction solution, ethyl acetate is used for extracting impurities, then aqueous phase is added with 30% NaOH for adjusting the pH to be =11-12, dichloromethane is used for extraction, organic phase is subjected to pressure reduction concentration until liquid does not flow, reduced pressure distillation is carried out instead to obtain a crude product of N-methyl-2- (2-chloroethyl) pyrrolidine, N-heptane is added for recrystallization to obtain 36.6g of a pure product, the yield is 82.7%, and GC is 99.8%. 1 HNMR(400M Hz,CDCl3):δ3.83-3.74(m,2H),2.51-2.25(m,6H),1.98-1.67(m,6H).
Example 7
Adding 51g (0.3 mol,1.0 eq) of (2-chloroethyl) pyrrolidine hydrochloride to 30% sodium hydroxide solution, adjusting the solution pH =11-12, and stirring for 10 minutes; the methyl formate was extracted twice (100ml × 2) and the organic layers were combined and warmed to reflux for 3 hours. After the TLC detection reaction, the solvent is evaporated to dryness, tetrahydrofuran is added into 150mL, the mixture is added into 450mL of 1.0M borane-tetrahydrofuran solution at room temperature, the mixture is stirred for 30 minutes at room temperature, then the reflux reaction is carried out for 3 hours, 10% hydrochloric acid is used for quenching the reaction solution, ethyl acetate is used for extracting impurities, then 30% NaOH is added into a water phase for adjusting the pH to be =11-12, dichloromethane is used for extraction, the organic phase is subjected to pressure concentration until the solution does not flow, reduced pressure distillation is carried out instead to obtain a crude product of N-methyl-2- (2-chloroethyl) pyrrolidine, and N-heptane is added for recrystallization to obtain 35.6g of a pure product. The yield was 80.4%, GC99.6%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. A preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine is characterized by comprising the following steps:
the first step is as follows: mixing N-t-butyl pyrrolidone carboxylate, an activating agent and tetrahydrofuran, reacting with a lithium reagent to remove protons, and then reacting with ethylene oxide to obtain 1-Boc-2- (2-hydroxyethyl) pyrrole;
the second step: mixing 1-Boc-2- (2-hydroxyethyl) pyrrole, a metal catalyst and methanol, and carrying out catalytic hydrogenation reaction to obtain 1-Boc-2- (2-hydroxyethyl) pyrrolidine;
the third step: reacting 1-Boc-2- (2-hydroxyethyl) pyrrolidine with thionyl chloride, and then adding methanol for continuous reaction to obtain 2- (2-chloroethyl) pyrrolidine hydrochloride;
the fourth step: adding alkali into 2- (2-chloroethyl) pyrrolidine hydrochloride for dissociating, then heating and carrying out reflux reaction on the hydrochloride and formate, then reacting with borane-tetrahydrofuran solution to obtain a crude product of N-methyl-2- (2-chloroethyl) pyrrolidine, and recrystallizing with N-heptane to obtain a pure product.
2. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the first step, the activating agent is selected from tetramethylethylenediamine or 2, 6-tetramethylpiperidine.
3. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the first step, the lithium reagent is selected from n-butyllithium at a concentration of 2.5M or 1.6M.
4. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the first step, the molar ratio of the N-butyl pyrrolidone, ethylene oxide, the activating agent and the lithium reagent is 1:1.1-1.2:1-1.2:1.1-1.2.
5. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the second step, the metal catalyst is selected from 5% Ru/C or 10% Pd/C.
6. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the third step, the mol ratio of the 1-Boc-2- (2-hydroxyethyl) pyrrolidine to thionyl chloride is 1:1-2.
7. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the fourth step, the formate is selected from methyl formate or ethyl formate.
8. The process for producing N-methyl-2- (2-chloroethyl) pyrrolidine according to claim 1, wherein: in the fourth step, the molar ratio of the 2- (2-chloroethyl) pyrrolidine hydrochloride, the base and the borane-tetrahydrofuran is 1:1.0-1.5:1.5-3.0.
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