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CN1051765C - Stereoselective synthesizing process for enantiomorph pure 3-amino-1,2-twice substituted pyrrolidine - Google Patents

Stereoselective synthesizing process for enantiomorph pure 3-amino-1,2-twice substituted pyrrolidine Download PDF

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CN1051765C
CN1051765C CN96108337A CN96108337A CN1051765C CN 1051765 C CN1051765 C CN 1051765C CN 96108337 A CN96108337 A CN 96108337A CN 96108337 A CN96108337 A CN 96108337A CN 1051765 C CN1051765 C CN 1051765C
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CN1143635A (en
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黄培强
王世立
郑洪�
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Xiamen University
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Abstract

The present invention relates to a heterocyclic compound with a nitrogen atom, which comprises a pentatomic ring and does not fuse with other rings. The nitrogen atom is used as a unique heterocyclic atom. (2R, 3R)-3-amino-1-1-phenyl-2-methyl pyrrolidine is a key intermediate body for synthesizing a novel antipsychotic drug of Yimobili. The heterocyclic compound uses (S)-malic acid as a raw material to start the high-stereoselectivity (larger than 95: 5) synthesis of trans-(4S, 5R)-1, 5-dialkyl-4-hydroxy-2-pyrrolidone so as to synthesize cis-(2R, 3R)-3-amino-1, 2-dibasic pyrrolidine with a pure enantiomer. The synthetic method provided by the present invention has the advantages of easy acquirement of raw materials, high yield of target products and low synthetic cost.

Description

A kind of stereoselectivity is synthesized enantiomer-pure 3-amino-1, the method for 2-disubstituted pyrrolidines
The present invention relates to a kind of heterogeneous ring compound, contain pentatomic ring, do not condense with other ring, with a nitrogen-atoms as unique ring hetero atom.
Emonapride (Emonapride) is the little antipsychotics of developing recently of a kind of strong drug action, side effect.Its drug effect is respectively 4～73 times of present clinical medicine haloperidol commonly used (haloperidol); 408 times and 10,000 times (10 of Sulpiride (sulpiride) of Cerucal (metachloride) 4).The 3-amino of enantiomer-pure-1-benzyl-2-crassitude is the key intermediate of synthetic emonapride.Because two enantiomorphs of chiral drug often show difference even opposite physiologically active, therefore develop the megatrend that single enantiomer (also claiming enantiomer-pure) medicine has become current drug development.
English Patent 2 037 740 (1980) discloses and has a kind ofly prepared 3-amino-1-benzyl-2-methyl-tetramethyleneimine by 1-benzyl-2-methyl-3-pyrrolidone, and then prepares the method for antipsychotics emonapride; Day disclosure speciallys permit 79 14 965, and 80 16 578, German publication Ger offen 2 855 853, French Patent 2 444 461 and United States Patent (USP) 4 210 660 (1980) also disclose similar method.Its making method is that 1-benzyl-2-methyl-3-pyrrolidone and the condensation of oxammonium hydrochloride amine get oxime, and latter's hydrogenation under Ra-Ni catalysis gets that 3-amino-the 1-benzyl-the 2-crassitude is suitable, 1: 1 mixture of trans isomer.Get the antipsychotics emonapride with benzoic acid after telling cis-isomeride.
Figure C9610833700061
(±)-emonapride
Subsequently, S.Iwanami etc. have also delivered The above results (J.Med.Chem., 24,1224-1230,1981).
Recently, day disclosure is speciallyyed permit 04 360 866,[92 360 866] (1992) disclose another kind of method by synthetic 3-amino-pyrrolidine derivatives of 3-(hydroxyl imines) pyrrolidin derivatives and analogue.Its method is in the presence of nickel borides or boronation cobalt, with sodium borohydride reduction 3-(hydroxyl imines) pyrrolidin derivatives, and synthetic 3-amino-pyrrolidine derivatives of Stereoselective and analogue.According to the catalyzer of selecting for use, suitable: reverse proportionality is not wait in 87: 13 to 94: 6.
Above-mentioned first method can only obtain suitable: the equivalent of trans isomer (1: 1) mixture, and be racemic modification; Though second method optionally obtains cis-product, what obtain is still racemic modification, is equivalent (1: the 1) mixture of levo-enantiomer and dextrorotation enantiomorph.
Purpose of the present invention be intended to develop a kind of Stereoselective synthesizing cis-(2R, 3R)-3-amino-1, the 2-disubstituted pyrrolidines and (2S, 3S)-method of single enantiomer.
Concrete synthetic route of the present invention is shown in accompanying drawing, and among narration below and the embodiment subsequently, specific synthetic product system is the numbering of middle structural formula with reference to the accompanying drawings, represents with Arabic numerals.R or S represent the absolute configuration of compound.Ph represents phenyl; Bn represents benzyl; Me represents methyl, and Ms represents methylsulfonyl.
It is feedstock production (2R, method 3R)-11 that accompanying drawing illustrates with (S)-oxysuccinic acid.
Step 1. compound 2 is to make from (S)-malic acid. Its method is that (S)-malic acid 1 at first reacted 2～4 hours under 40 ℃～52 ℃ with chloroacetic chloride; Behind the reduced pressure concentration with carrene dilution, then 30 ℃～40 ℃ lower and a kind of primary amine reactions 3～5 hours; Behind the reduced pressure concentration again with chloroacetic chloride 40 ℃～52 ℃ lower reactions 4～6 hours, concentrated by silica gel column chromatography separate 2. Said primary amine refers to fatty amine, aromatic amine, particularly methylamine, benzylamine and p-methoxybenzylamine.
Step 2. compound 2 is made solvent with alcohol under acid condition, 40 ℃～60 ℃ lower reactions 4～7 hours, preferably 45 ℃～55 ℃ lower reactions 5～6 hours with the benzene dilution, obtain compound 3 behind the reduced pressure concentration again concentrated rear the separation with silica gel column chromatography. The hydrogen chloride that said acid condition refers to direct adding hydrochloric acid or p-toluenesulfonic acid or produced by chloroacetic chloride and alcohol as solvent; Said alcohol refers to C1～C 4Monohydric alcohol particularly methyl alcohol and ethanol.
Step 3. compound 3 in a kind of ether, in the presence of silver suboxide with the benzyl bromine in 20 ℃～30 ℃ the reaction 36～60 hours, after the filtration, obtain compound 4.Said ether refers to C 2～C 4Ether, particularly ether and tetrahydrofuran (THF).
Step 4. compound 4 in tetrahydrofuran (THF) with a kind of Grignard reagent in-78 ℃～-68 ℃ down reactions 2-4 hour, dichloromethane extraction, concentrate and silica gel column chromatography after obtain compound 5 by the R definition.Said R is C 1～C 8Alkyl, benzyl or right-methoxy-benzyl, particularly methyl, benzyl and right-methoxy-benzyl; Said Grignard reagent refers to by C 1～C 8Iodo, bromo or hydrochloric ether, benzyl halide or right-methoxy-benzyl halogen, particularly methyl iodide, methyl chloride or monobromethane and the Grignard reagent made of MAGNESIUM METAL;
The dichloromethane solution of step 5. compound 5 under anhydrous titanium tetrachloride or etherate of trifluoroboron catalysis, with triethyl silicane-78 ℃ of down reduction 15～24 hours, dichloromethane extraction, concentrate and silica gel column chromatography after obtain compound 6.Trans with this method products therefrom: the ratio of cis-isomeride can obtain pure trans-isomer(ide) greater than 95: 5 after the separation.
Step 6. compound 6 is under palladium carbon catalysis, at a kind of C 1～C 4Monohydroxy-alcohol particularly in methyl alcohol or the alcohol solvent, the nitrogen atmosphere of 1～3atm and 15 ℃～32 ℃ reaction 15～30 hours down is preferably in 1atm nitrogen atmosphere, 20 ℃～25 ℃ reaction 24 hours down.Filter, concentrate and silica gel column chromatography after obtain compound 7.
Step 7. compound 7 and Lithium Aluminium Hydride reacted 2～15 hours down at 35 ℃～67 ℃ in a kind of ether solvents, and preferably in tetrahydrofuran (THF), 65 ℃ were reacted 3 hours down.After adding entry and aqueous sodium hydroxide solution successively, with dichloromethane extraction, concentrate and silica gel column chromatography after, obtain compound 8.Said solvent is C 2～C 4Ether, especially ether and tetrahydrofuran (THF).
Step 8. compound 8 with a kind of SULPHURYL CHLORIDE, reacted 15～28 hours down in 15 ℃～35 ℃ in the presence of a kind of alkali and esterifying catalyst DMAP in methylene dichloride.Dichloromethane extraction, concentrate and silica gel column chromatography after obtain by 9 of X definition.Said alkali is tertiary amine, particularly pyridine and triethylamine; Said SULPHURYL CHLORIDE is p-toluenesulfonyl chloride, benzene sulfonyl chloride, particularly methylsulfonyl chloride; Said X refers to ptoluene-sulfonyl, benzenesulfonyl, particularly methylsulfonyl.
(2R 3S)-9 reacted 30～60 hours down in 40 ℃～80 ℃ in a kind of non-proton property polar solvent with a kind of nitrogen nucleophile step 9. compound, preferably reacted 42～44 hours down at 50 ℃～60 ℃.Use extracted with diethyl ether after adding saturated aqueous common salt, concentrate with silica gel column chromatography after obtain compound (2R, 3R)-10.The compound of gained is pure cis-isomeride.Said non-proton property polar solvent is methyl-sulphoxide (DMSO) or dimethyl formamide (DMF); Said nitrogen nucleophile refers to Lithium Azide or sodiumazide.
Step 10. compound (2R, 3R)-10 in ether or tetrahydrofuran (THF), under 35 ℃～67 ℃ with Lithium Aluminium Hydride reduction 3～15 hours, preferably in tetrahydrofuran (THF), 65 ℃ of reactions 4 hours down.After adding entry and aqueous sodium hydroxide solution successively, filter, concentrate and silica gel column chromatography after obtain target compound (2R, 3R)-11.
According to the identical characteristics of different enantiomorph chemical reactivities, according to above-mentioned with (S)-oxysuccinic acid be the raw material synthetic compound (2R, method 3R)-11 and condition, from (R)-oxysuccinic acid 1, through (4R, 5S)-6 synthesized (2S, 3S)-11.Two sequences (S and R) selectivity and productive rate in steps close, have only the optically-active opposite in sign.
The present invention is a raw material from (S)-oxysuccinic acid inexpensive, that be easy to get, highly-solid selectively (＞95: 5) synthesis of trans-(4S, 5R)-1,5-dialkyl group-4-hydroxyl-2-Pyrrolidone; The cis of synthetic enantiomer-pure-(2R, 3R)-3-amino-1-benzyl-2-crassitude and analogue thereof.This compound again by the antipsychotics of currently known methods one-step synthesis enantiomer-pure (2R, 3R)-emonapride.From (R)-oxysuccinic acid, synthesized another enantiomorph, that is: (2S, 3S)-3-amino-1-benzyl-2-crassitude.
Further specify the present invention with embodiment below.Embodiment 1
Step 1, (S)-3-acetoxyl group-1-benzyl-2,5-pyrrolidine-diones (S)-2:
Figure C9610833700091
Get 1.5g (S)-oxysuccinic acid and 6mL Acetyl Chloride 98Min. one and arise from 50 ℃ of following stirrings 2.5 hours.Be chilled to concentrating under reduced pressure after the room temperature, a water white transparency oily thing, add the dilution of 5mL exsiccant methylene dichloride, add the dichloromethane solution 5mL that contains the 2.0mL benzylamine again, stirred 4 hours down in 40 ℃.After being chilled to room temperature, concentrating under reduced pressure gets orange-yellow transparent thick thing, adds the 6mL Acetyl Chloride 98Min. again, stirs 5 hours down in 50 ℃.Separate (ethyl acetate: sherwood oil=1: 3), get 2.35g white solid 2, productive rate 87%, m.p.64.5-65.0 ℃ with silica gel column chromatography behind the concentrating under reduced pressure.
Step 2, (S)-1-benzyl-3-hydroxyl-2,5-pyrrolidine-diones (S)-3:
2.35g (11.9mmol) compound 2 is dissolved in the 90mL dehydrated alcohol, drips 3.6mL (54.2mmol) Acetyl Chloride 98Min., be heated to 50 ℃ of reactions 5 hours, remove solvent under reduced pressure.Crude product removes benzene under reduced pressure with the dissolving of 6mL benzene, triplicate like this, the crude product of gained purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 1.5) get 1.83g white needle-like crystals 3, productive rate 90%, m.p.101-102 ℃.
Step 3, (S)-3-benzyloxy-1-benzyl-2,5-pyrrolidine-diones (S)-4:
Figure C9610833700093
1.83g (9.27mmol) 3 is dissolved in the 70mL ether, add 2.77mL (28.07mmol) benzyl bromine and 6.50g (28.07mmol) silver suboxide, after stirring 48 hours under 25 ℃, filter, concentrating under reduced pressure separates with silica gel column chromatography [ethyl acetate: sherwood oil=1: (5～3)], get a transparent oily matter, separate out 2.33g white solid 4 after the placement, productive rate 87%, m.p.:76-77.5 ℃.
Step 4, (4S, 5RS)-1-benzyl-4-benzyloxy-5-hydroxy-5-methyl base--2-Pyrrolidone (4S, 5RS)-5:
Figure C9610833700101
Get 2.33g compound 4 and be dissolved in the 30mL exsiccant tetrahydrofuran (THF), be cooled to-78 ℃, under nitrogen atmosphere, add 15.8mL methyl Grignard reagent (CH 3MgI) diethyl ether solution (2.5mol/L) reacted after 4 hours, added 6mL saturated ammonium chloride solution and 100mL methylene dichloride, told organic layer; Water 70mL dichloromethane extraction three times; The organic phase anhydrous sodium sulfate drying that merges; Filter, concentrating under reduced pressure with flash chromatography method separated product (petrol ether/ethyl acetate=1: 4), obtains two isomer of 5, is white solid, is total to 1.73g, productive rate 70%.M.p.:132-133 ℃ and m.p.:131-132 ℃.
Step 5, (4S, 5R)-1-benzyl-4-benzyloxy-5-N-methyl-2-2-pyrrolidone N-(4S, 5R)-6:
Figure C9610833700102
Get 1.73g (5.57mmol) 5 and be dissolved in the 20mL exsiccant methylene dichloride, under nitrogen atmosphere, be cooled to-78 ℃; Add 8.89mL (55.67mmol) triethyl silicane and 0.83mL (6.12mmol) boron trifluoride ethyl ether complex solution successively.Reaction mixture stirred 15 hours down at-78 ℃, dripped 2mL saturated sodium bicarbonate aqueous solution and 7mL water then in reaction flask, used 50mL dichloromethane extraction four times.Anhydrous sodium sulfate drying is washed, used to the organic phase that merges with the 5mL salt solution; Behind filtration, the concentrating under reduced pressure, obtain the trans product 6 of 938mg, productive rate 57% with rapid column chromatography (petrol ether/ethyl acetate=1: 4) separation.
Step 6, (4S, 5R)-1-benzyl-4-hydroxy-5-methyl base-2-Pyrrolidone (4S, 5R)-7:
Figure C9610833700103
Get 678mg (2.30mmol) compound 6 and be dissolved in the ethanol of 8mL 95%, add 244mg 10% palladium carbon catalyst, 25 ℃ were stirred 24 hours down under the 1atm nitrogen atmosphere; The reaction mixture diatomite filtration, filter residue washs three times with the 16ml ethyl acetate.Merging filtrate, concentrating under reduced pressure separates (sherwood oil: ethyl acetate=1: 2) obtain 356mg colorless oil 7, productive rate 76% with silica gel column chromatography.
Step 7, (2R, 3S)-1-benzyl-3-hydroxy-2-methyl tetramethyleneimine (2R, 3S)-8:
Figure C9610833700111
The adding of the 6mL tetrahydrofuran solution of 356mg (1.73mmol) compound 7 is placed with in the exsiccant reaction flask of 455mg (12.17mmol) Lithium Aluminium Hydride.Finish, be heated to 65 ℃, stirred 3 hours with oil bath.Then, be cooled to 0 ℃, stir down and slowly splash into 0.9mL water, 0.9mL (3mmol/mL) aqueous sodium hydroxide solution and 0.9mL water successively toward reaction flask.With 90mL dichloromethane extraction four times, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, (ethyl acetate: purifying methyl alcohol=100: 2) obtains the faint yellow oily thing 8 of 303mg, productive rate 91% to crude product with silica gel column chromatography.
Step 8, (2R, 3S)-1-benzyl-2-methyl-3-mesyloxy-tetramethyleneimine (2R, 3S)-9:
Figure C9610833700112
303mg (1.59.mmol) 8 is dissolved in the 6mL methylene dichloride, and (364mg, 3.19mmol) methylsulfonyl chloride reacted 20 hours down in 20 ℃ to add 0.3mL pyridine and 30mg4-Dimethylamino pyridine (DMAP) and 0.26ml.Add the 15mL saturated sodium bicarbonate aqueous solution behind the concentrating under reduced pressure, with 30mL dichloromethane extraction four times, the organic phase that merges is used anhydrous magnesium sulfate drying after the 3mL saturated sodium-chloride water solution is washed, use purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 2) get 262mg yellow oil 9, productive rate 61% behind the concentrating under reduced pressure.
Step 9, (2R, 3R)-3-azido--1-benzyl-2-crassitude (2R, 3R)-10:
Figure C9610833700113
262mg (0.97mmol) 9 and 524mg (8.05mmol) sodiumazide are dissolved in the 12mL exsiccant dimethyl formamide, under nitrogen atmosphere, reacted 28 hours in 55 ℃, add 374mg (5.61mmol) sodiumazide again, continue under identical conditions, to react 16 hours.Add the 7mL saturated aqueous common salt under the room temperature, use 20mL extracted with diethyl ether four times.The organic phase anhydrous magnesium sulfate drying that merges is used purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 7) get 153mg yellow oil 10, productive rate 73% behind filtration, the concentrating under reduced pressure.
Step 10, (2R, 3R)-3-amino-1-benzyl-2-crassitude (2R, 3R)-11:
Figure C9610833700121
Get 153mg (0.73mmol) 10 and be dissolved in the 4mL dry tetrahydrofuran, join at the bottom of the garden that 84mg (2.18mmol) Lithium Aluminium Hydride is housed in the flask.In nitrogen atmosphere, reacted 4 hours in 65 ℃.Then, be cooled to 0 ℃, carefully be added dropwise to 0.8mL sodium hydroxide (3mmol/mL) aqueous solution and 2mL water successively.With 20mL dichloromethane extraction five times, merge organic phase, anhydrous sodium sulfate drying filters, concentrating under reduced pressure.Crude product is through purification by silica gel column chromatography (ethyl acetate: methyl alcohol: ammoniacal liquor=100: 10: 1) get 99mg compound 11, productive rate 74%.Embodiment 2
Step 1, (S)-3-acetoxyl group-1-benzyl-2,5-pyrrolidine-diones (S)-2:
Compound 2 makes by the method for example 1.Promptly (S)-oxysuccinic acid 1 at first reacted 4 hours down at 40 ℃ with Acetyl Chloride 98Min.; With methylene dichloride dilution, reacted 5 hours with benzylamine down at 30 ℃ then behind the concentrating under reduced pressure; Behind the concentrating under reduced pressure again with Acetyl Chloride 98Min. 40 ℃ of down reactions 6 hours, concentrate after silica gel column chromatography separate 2, productive rate 76%.
Step 2, (S)-1-benzyl-3-hydroxyl-2,5-pyrrolidine-diones (S)-3:
According to the method for embodiment 1 by preparation (S)-3, (S)-2, make solvent with methyl alcohol, use by Acetyl Chloride 98Min. and the hydrogenchloride that produces as the methyl alcohol of solvent and make catalyzer, reacted 4 hours down at 60 ℃, dilute with benzene behind the concentrating under reduced pressure, concentrate the back once more and obtain compound 3, productive rate 81% with the silica gel column chromatography separation.
Step 3, (S)-3-benzyloxy-1-benzyl-2,5-pyrrolidine-diones (S)-4:
According to the method for embodiment 1 by preparation (S)-4, (S)-3, make solvent with tetrahydrofuran (THF), in the presence of silver suboxide, made (S)-4, productive rate 71% in 60 hours in 20 ℃ of reactions with the benzyl bromine.
Step 4, according to embodiment 1 by (S)-4 preparations (4S, method 5RS)-5 is made solvent with tetrahydrofuran (THF) ,-68 ℃ down reaction making 5, productive rate 62% in 2 hours.
Step 5, according to embodiment 1 by (4S, 5RS)-5 preparation (4S, method 5R)-6 is made catalyzer with titanium tetrachloride ,-78 ℃ down reaction made in 24 hours (4S, 5R)-6, productive rate 52%.
Step 6, (4S, 5R)-1-benzyl-4-hydroxy-5-methyl base-2-Pyrrolidone (4S, 5R)-7:
According to embodiment 1 by 6 preparations, 7 method, compound 6 under palladium carbon catalysis, do solvent reaction 30 hours under 15 ℃, 1atm nitrogen atmosphere with methyl alcohol, filter, concentrate and silica gel column chromatography after make 7, productive rate 65%.
Step 7, (2R, 3S)-1-benzyl-3-hydroxy-2-methyl-tetramethyleneimine (2R, 3S)-8:
According to embodiment 1 by 7 preparations, 8 method, in anhydrous diethyl ether, under 35 ℃ with Lithium Aluminium Hydride reduction 15 hours.After being cooled to 0 ℃, carefully drip entry and aqueous sodium hydroxide solution successively after, with dichloromethane extraction, concentrate and silica gel column chromatography make (2R, 3S)-8, productive rate 83%.
Step 8, (2R, 3S)-1-benzyl-2-methyl-3-phenylsulfonyloxy-tetramethyleneimine (2R, 3S)-9
By 8 preparations, 9 method, compound 8 is made alkali with triethylamine and was reacted 15 hours down at 35 ℃ with benzene sulfonyl chloride in methylene dichloride according to embodiment 1.Dichloromethane extraction, concentrate and silica gel column chromatography after make (2R, 3S)-9, productive rate 56%.
Step 9, (2R, 3R)-3-azido--1-benzyl-2-crassitude (2R, 3R)-10:
According to embodiment 1 by 9 preparations, 10 method, (2R, 3S)-1-benzyl-2-methyl-3-phenylsulfonyloxy-tetramethyleneimine and Lithium Azide in dimethyl formamide (DMF), reacted 30 hours down in 80 ℃.Use extracted with diethyl ether after adding saturated aqueous common salt, concentrate with silica gel column chromatography after make (2R, 3R)-10, productive rate 61%.
Step 10, (2R, 3R)-3-amino-1-benzyl-2-crassitude (2R, 3R)-11:
According to the method for embodiment 1 by 10 preparations 11, (2R 3R)-10 in anhydrous diethyl ether, reduced 15 hours with Lithium Aluminium Hydride under 35 ℃ compound.After being cooled to 0 ℃, carefully drip entry and aqueous sodium hydroxide solution successively after, with filter, concentrate and silica gel column chromatography after make (2R, 3R)-11, productive rate 70%.Embodiment 3
Compound 2 makes by the method for example 1.
According to the method for embodiment 1 by (S)-2 preparations (S)-3, with methyl alcohol make solvent, 10% tosic acid is made acid catalyst, in 40 ℃ down reaction made (S)-3 in 7 hours.
According to the method for embodiment 1 by preparation (S)-4, (S)-3, reaction made (S)-4 in 36 hours under 30 ℃.
Compound 5 and 6 methods by embodiment 1 make.
According to embodiment 1 by (4S, 5R)-6 preparation (4S, method 5R)-7, under the 3atm nitrogen atmosphere, 32 ℃ down reaction made in 15 hours (4S, 5R)-7.
Compound 8 makes by the method for embodiment 1.
According to embodiment 1 by (2R, 3S)-8 preparation (2R, method 3S)-9,15 ℃ down reaction made in 28 hours (2R, 3S)-9.
According to embodiment 1 by (2R, 3S)-9 preparation (2R, method 3R)-10,40 ℃ down reaction made in 60 hours (2R, 3R)-10.
Compound 11 makes by the method for embodiment 1.Embodiment 41, (R)-3-acetoxyl group-1-benzyl-2,5-pyrrolidine-diones (R)-2:
According to the method for embodiment 1,, make (R)-2 from (R)-oxysuccinic acid by (S)-oxysuccinic acid preparation (S)-2.2, (R)-1-benzyl-3-hydroxyl-2,5-pyrrolidine-diones (R)-(3):
According to the method for embodiment 1,, make (R)-3 from (R)-2 by preparation (S)-3, (S)-2.3, (R)-3-benzyloxy-1-benzyl-2,5-pyrrolidine-diones (R)-4:
According to the method for embodiment 1,, make (R)-4 from (R)-3 by preparation (S)-4, (S)-3.4, (4R, 5SR)-1-benzyl-4-benzyloxy-5-hydroxy-5-methyl base--2-Pyrrolidone (4R, 5SR)-5:
According to embodiment 1 by (S)-4 preparations (4S, method 5RS)-5 from (R)-4, make (4R, 5SR)-5.5, (4R, 5S)-1-benzyl-4-benzyloxy-5-N-methyl-2-2-pyrrolidone N-(4R, 5S)-6:
According to embodiment 1 by (4S, 5RS)-5 the preparation (4S, method 5R)-6, from (4R 5SR)-5 sets out, make (4R, 5S)-6.6, (4R, 5S)-1-benzyl-4-hydroxy-5-methyl base-2-Pyrrolidone (4R, 5S)-7:
According to embodiment 1 by (4S, 5R)-6 the preparation (4S, method 5R)-7, from (4R 5S)-6 sets out, make (4R, 5S)-7.7, (2S, 3R)-1-benzyl-3-hydroxy-2-methyl tetramethyleneimine (2S, 3R)-8:
According to embodiment 1 by (4S, 5R)-7 the preparation (2R, method 3S)-8, from (4R 5S)-7 sets out, make (2S, 3R)-8.8, (2S, 3R)-1-benzyl-2-methyl-3-mesyloxy-tetramethyleneimine (2S, 3R)-9:
According to embodiment 1 by (2R, 3S)-8 the preparation (2R, method 3S)-9, from (2S 3R)-8 sets out, make (2S, 3R)-9.9, (2S, 3S)-3-azido--1-benzyl-2-crassitude (2S, 3S)-10:
According to embodiment 1 by (2R, 3S)-9 the preparation (2R, method 3R)-10, (2S 3R)-9 sets out, make (2S, 3S)-10.10, (2S, 3S)-3-amino-1-benzyl-2-crassitude (2S, 3S)-11:
According to embodiment 1 by (2R, 3R)-10 the preparation (2R, method 3R)-11, by (2S 3S)-10 sets out, make (2S, 3S)-11.
Embodiment 5～8
Compound 1～4,6～11 press the method preparation of embodiment 1, and compound 5 is also pressed the method preparation of embodiment 1, is conversion Grignard reagent (RMgX), and the result is as follows:
Figure C9610833700141
Embodiment RMgX R 5 productive rates (%) 6 productive rates (%)
5 n-C 4H 9MgBr n-C 4H 9 90 78
6 i-C 4H 9MgBr i-C 4H 9 71 78
7 C 6H 5CH 2MgCl C 6H 5CH 2 83 75
8 p-CH 3OC 6H 5CH 2MgCl p-CH 3OC 6H 5CH 2 89 83

Claims (8)

1.一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，结构式为
Figure C9610833700021
，R为C1～C8烃基、苄基或对-甲氧基苄基，其特征在于反应步骤如下：1. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidines, the structural formula is
Figure C9610833700021
, R is C 1 ~C 8 hydrocarbon group, benzyl or p-methoxybenzyl, characterized in that the reaction steps are as follows: 步骤1：(S)-苹果酸与乙酰氯在40℃～52℃下反应2～4小时，减压浓缩后用二氯甲烷稀释，然后在30℃～40℃下与一种伯胺反应3～5小时，减压浓缩后再与乙酰氯在40℃～52℃下反应4～6小时，浓缩后经硅胶柱层析分离得化合物(2)
Figure C9610833700022
，所说的伯胺为甲胺、苄胺或对-甲氧基苄胺；Step 1: (S)-malic acid reacts with acetyl chloride at 40°C to 52°C for 2 to 4 hours, concentrates under reduced pressure and dilutes with dichloromethane, then reacts with a primary amine at 30°C to 40°C 3 ~ 5 hours, concentrated under reduced pressure and then reacted with acetyl chloride at 40 ° C ~ 52 ° C for 4 ~ 6 hours, concentrated and separated by silica gel column chromatography to obtain compound (2)
Figure C9610833700022
, said primary amine is methylamine, benzylamine or p-methoxybenzylamine; 步骤2：化合物(2)在酸性条件下用甲醇或乙醇作溶剂，在40℃～60℃下反应4～7小时，减压浓缩后用苯稀释，再次浓缩后用硅胶柱层析分离得化合物(3)
Figure C9610833700023
，所说的酸性条件指的是直接加入盐酸或对-甲苯磺酸或由乙酰氯与作为溶剂的醇产生的氯化氢；Step 2: Compound (2) uses methanol or ethanol as a solvent under acidic conditions, reacts at 40°C to 60°C for 4 to 7 hours, concentrates under reduced pressure, dilutes with benzene, concentrates again and separates the compound by silica gel column chromatography (3)
Figure C9610833700023
, said acidic condition refers to directly adding hydrochloric acid or p-toluenesulfonic acid or hydrogen chloride produced by acetyl chloride and alcohol as solvent; 步骤3：化合物(3)在乙醚或四氢呋喃中，在氧化银存在下与苄溴于20℃～30℃反应36～60小时，过滤后得化合物(4) Step 3: Compound (3) is reacted with benzyl bromide in ether or tetrahydrofuran at 20°C to 30°C for 36 to 60 hours in the presence of silver oxide, and compound (4) is obtained after filtration 步骤4、化合物(4)在四氢呋喃中与格氏试剂于-78℃～-68℃下反应2～4小时，二氯甲烷萃取、浓缩和硅胶柱层析后得由R定义的化合物(5)
Figure C9610833700031
其中R的定义同上，所说的格氏试剂为由C1-C8的碘代、溴代或氯代烃、苄基卤或对-甲氧基苄基卤与金属镁制成的格氏试剂；Step 4, compound (4) reacts with Grignard reagent in tetrahydrofuran at -78°C to -68°C for 2 to 4 hours, extracts with dichloromethane, concentrates and silica gel column chromatography to obtain compound (5) defined by R
Figure C9610833700031
Wherein R is as defined above, and said Grignard reagent is a Grignard reagent made of C 1 -C 8 iodo, bromo or chlorinated hydrocarbons, benzyl halides or p-methoxybenzyl halides and metal magnesium. Reagent; 步骤5、化合物(5)的二氯甲烷溶液在无水四氯化钛或三氟化硼合乙醚催化下，用三乙基硅烷在-78℃下还原15～24小时，二氯甲烷萃取、浓缩和硅胶柱层析后得化合物(6)
Figure C9610833700032
，其中R的定义同上；Step 5, the dichloromethane solution of compound (5) is catalyzed by anhydrous titanium tetrachloride or boron trifluoride diethyl ether, reduced with triethylsilane at -78°C for 15 to 24 hours, extracted with dichloromethane, Compound (6) was obtained after concentration and silica gel column chromatography
Figure C9610833700032
, where R is as defined above; 步骤6：化合物(6)在钯-碳催化下、在甲醇或乙醇中，1～3atm的氢气氛和15℃～32℃下反应15～30小时，过滤、浓缩和硅胶柱层析后得到化合物(7)
Figure C9610833700033
，其中R的定义同上；Step 6: Compound (6) reacts under palladium-carbon catalysis in methanol or ethanol in a hydrogen atmosphere of 1 to 3 atm at 15°C to 32°C for 15 to 30 hours, and obtains the compound after filtration, concentration and silica gel column chromatography (7)
Figure C9610833700033
, where R is as defined above; 步骤7：化合物(7)与四氢铝锂在乙醚或四氢呋喃中，在35℃～67℃下反应2～15小时，依次加入水和氢氧化钠水溶液后，用二氯甲烷萃取、浓缩和硅胶柱层析后，得到化合物(8)
Figure C9610833700034
，其中R的定义同上；Step 7: Compound (7) reacts with lithium aluminum tetrahydride in diethyl ether or tetrahydrofuran at 35°C to 67°C for 2 to 15 hours. After adding water and aqueous sodium hydroxide solution in sequence, extract with dichloromethane, concentrate and dissolve on silica gel After column chromatography, compound (8) was obtained
Figure C9610833700034
, where R is as defined above; 步骤8：化合物(8)在二氯甲烷中，在一种碱和酯化催化剂4-二甲氨基吡啶存在下与一种磺酰氯于15℃～35℃下反应15～28小时，二氯甲烷萃取、浓缩和硅胶柱层析后得由R和X定义的化合物(9)
Figure C9610833700041
，其中R的定义同上，所说的磺酰氯为对-甲苯磺酰氯、苯磺酰氯或甲磺酰氯，X为对-甲苯磺酰基、苯磺酰基、甲磺酰基，所说的碱是叔胺；Step 8: Compound (8) reacts with a sulfuryl chloride at 15°C to 35°C for 15 to 28 hours in the presence of a base and an esterification catalyst 4-dimethylaminopyridine in dichloromethane, and dichloromethane Compound (9) defined by R and X is obtained after extraction, concentration and silica gel column chromatography
Figure C9610833700041
, wherein R is defined as above, said sulfonyl chloride is p-toluenesulfonyl chloride, benzenesulfonyl chloride or methanesulfonyl chloride, X is p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, and said base is a tertiary amine ; 步骤9：化合物(9)与叠氮化锂或叠氮化钠在二甲基甲酰胺中于40℃～80℃下反应30～60小时，加入饱和食盐水后用乙醚萃取，浓缩和硅胶柱层析后得到化合物(10)
Figure C9610833700042
，其中R的定义同上；Step 9: react compound (9) with lithium azide or sodium azide in dimethylformamide at 40°C to 80°C for 30 to 60 hours, add saturated saline, extract with ether, concentrate and use a silica gel column Compound (10) was obtained after chromatography
Figure C9610833700042
, where R is as defined above; 步骤10：化合物(10)在乙醚或四氢呋喃中，35℃～67℃下用四氢铝锂还原3～15小时，依次加入水和氢氧化钠水溶液后，经过滤、浓缩和硅胶柱层析后得到目标化合物(11)
Figure C9610833700043
，其中R的定义同上。Step 10: Compound (10) is reduced in diethyl ether or tetrahydrofuran with lithium aluminum tetrahydrogen for 3 to 15 hours at 35°C to 67°C, after adding water and aqueous sodium hydroxide solution in sequence, after filtration, concentration and silica gel column chromatography Obtain the target compound (11)
Figure C9610833700043
, where R is as defined above. 2.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤1中所述的伯胺为苄胺。2. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidine as claimed in claim 1, characterized in that the primary amine described in step 1 is benzylamine. 3.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤2的反应条件为45℃～55℃下反应5～6小时。3. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidine as claimed in claim 1, characterized in that the reaction condition of step 2 is to react at 45°C to 55°C 5-6 hours. 4.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤5中所述的格氏试剂为碘甲烷或氯甲烷或溴甲烷与金属镁制成的格氏试剂；且化合物(5)中的R为甲基。4. a kind of stereoselective synthesis enantiomerically pure 3-amino-1, the method for 2-disubstituted pyrrolidines as claimed in claim 1 is characterized in that the Grignard reagent described in step 5 is methyl iodide or A Grignard reagent made of methyl chloride or methyl bromide and magnesium metal; and R in the compound (5) is a methyl group. 5.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤6的反应条件为1atm氢气氛、20℃～25℃下反应24小时。5. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidine as claimed in claim 1, characterized in that the reaction conditions in step 6 are 1atm hydrogen atmosphere, 20°C～ React at 25°C for 24 hours. 6.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤7中的反应条件为在四氢呋喃中，65℃下反应3小时。6. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidine as claimed in claim 1, characterized in that the reaction conditions in step 7 are in tetrahydrofuran, 65°C The reaction was carried out for 3 hours. 7.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤8中所述的碱为吡啶或三乙胺，所说的磺酰氯为甲磺酰氯，化合物(9)中的X为甲磺酰基。7. a kind of stereoselective synthesis enantiomerically pure 3-amino-1, the method for 2-disubstituted pyrrolidine as claimed in claim 1, it is characterized in that the base described in step 8 is pyridine or triethylamine , said sulfonyl chloride is methanesulfonyl chloride, and X in compound (9) is methanesulfonyl. 8.如权利要求1所述的一种立体选择性合成对映体纯3-氨基-1，2-二取代吡咯烷的方法，其特征在于步骤9的反应条件为在50℃～60℃下反应42～44小时；步骤10中化合物(10)在四氢呋喃中，65℃下反应4小时。8. A method for stereoselectively synthesizing enantiomerically pure 3-amino-1,2-disubstituted pyrrolidines as claimed in claim 1, characterized in that the reaction conditions in step 9 are at 50°C to 60°C Reaction for 42-44 hours; in step 10, compound (10) was reacted in tetrahydrofuran at 65°C for 4 hours.
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US4210660A (en) * 1978-12-20 1980-07-01 Yamanouchi Pharmaceutical Co., Ltd. Benzamide derivatives
DE2855853A1 (en) * 1978-12-22 1980-07-10 Yamanouchi Pharma Co Ltd N-(3-Pyrrolidine)-substd. benzamide derivs. - have CNS depressant activity, providing use as psychotropic drugs
GB2037740A (en) * 1978-12-21 1980-07-16 Yamanouchi Pharma Co Ltd Benzamide derivatives
JPH04360866A (en) * 1991-06-06 1992-12-14 Sankyo Kagaku Kk Production of 3-aminopyrrolidines

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US4210660A (en) * 1978-12-20 1980-07-01 Yamanouchi Pharmaceutical Co., Ltd. Benzamide derivatives
GB2037740A (en) * 1978-12-21 1980-07-16 Yamanouchi Pharma Co Ltd Benzamide derivatives
DE2855853A1 (en) * 1978-12-22 1980-07-10 Yamanouchi Pharma Co Ltd N-(3-Pyrrolidine)-substd. benzamide derivs. - have CNS depressant activity, providing use as psychotropic drugs
JPH04360866A (en) * 1991-06-06 1992-12-14 Sankyo Kagaku Kk Production of 3-aminopyrrolidines

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