CN1289480C - Process for chiral synthesis of (2S,6R)-2,6-dialkyl piperidine hydrochloride - Google Patents
Process for chiral synthesis of (2S,6R)-2,6-dialkyl piperidine hydrochloride Download PDFInfo
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- CN1289480C CN1289480C CN 200410083625 CN200410083625A CN1289480C CN 1289480 C CN1289480 C CN 1289480C CN 200410083625 CN200410083625 CN 200410083625 CN 200410083625 A CN200410083625 A CN 200410083625A CN 1289480 C CN1289480 C CN 1289480C
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Abstract
The present invention discloses a method for chiral synthesis of (2S, 6R)-2, 6-dialkyl piperidine hydrochloride. The synthesis method provided by the present invention comprises the following steps: step 1, 1-(alpha-aminobenzyl)-2-naphthol, 1, 5-glutaraldehyde and benzotriazole react, which generates a compound V; step 2, the compound V obtained in the step 1 and organometallic reagent react in the temperature of-78 DEG C to 20 DEG C, which generates a compound VI; step 3, the compound VI obtained in the step 2 and organometallic reagent react in the temperature of-10 DEG C to 20 DEG C, which generates a compound VII; step 4, the compound VII obtained in the step 3 has a catalytic hydrogenolysis N-debenzylation reaction with the existence of dichloromethane, which generates a product (2S, 6R)-2, 6-dialkyl piperidine hydrochloride. The synthesis method of the present invention has high stereoselectivity and high yield rate. The synthesis method is suitable for preparing (2S, 6R)-2, 6-dialkyl piperidine hydrochloride in a large-scale mode. The synthesis method has a wide application prospect.
Description
Technical field
The present invention relates to the synthetic method of chipal compounds, particularly relate to a kind of chirality synthetic (2S, 6R)-2, the method for 6-dialkyl piperidine hydrochloride.
Background technology
Chirality 2, the 6-dialkyl piperidine is the alkaloidal feature structure of small molecule, as among Dihydropinidine (formula I), Solenopsin A (formula II), Isosolenopsin A (formula III) and the Precoccinelline (formula IV) chirality 2 being arranged all, 6-dialkyl piperidine structure.Many chiralitys (cis)-2,6-dialkyl piperidine compound are to be found in the intravital natural product of some animals and plants, and have important biologic activity (M.S.Blum, J.R.Walker, P.S.Callahan, A.F.Novak, Science 1958,128,306-307; G.B.Yi, D.McClendon, D.Desaiah, J.Goddard, A.Lister, J.Moffitt, R.K.Vander Meer, R.deShazo, K.S.Lee, R.W.Rockhold, Int.J.Toxicol., 2003,22,81-86.).But be subjected to the resource abundance restriction by in animal and plant body, extracting this compounds of acquisition, and the cost height, make the biology of these compounds and pharmacology research be subjected to restriction seriously.
At present, there have been some to use method of asymmetric synthesis and carried out synthetic chirality 2, the report of 6-dialkyl piperidine compound.But these synthetic methods because have complicated operation, shortcoming such as the product optical purity is lower or productive rate is low, do not have actual application value.For example: use the intermediate 1 that chirality 2-phenyl-the 2-monoethanolamine generates with glutaraldehyde, 3-Yang Dan oxazole, using this intermediate then, to carry out product synthetic, this synthetic method has the short and derivative variation flexible characteristic of route of synthesis, but it has two shortcomings: the one, and intermediate 1, the alkylated reaction of 3-Yang Dan oxazole lacks the stereoselectivity of height; Another be lost before volatile products through generating behind traditional N-debenzylation are being converted to hydrochloride many, lower (the H.Poerwono of productive rate, K.Higashiyama, T.Yamauchi, H.Kubo, S.Ohmiya, H.Takahashi, Tetrahedron 1998,54,13955-13970; A.R.Katrizky, G.Qiu, B.Yang, P.J.Steel, J.Org.Chem., 1998,63,6699-6703; H-P.Husson, J.Royer, Chem.Soc.Rev., 1999,28,383.).
Summary of the invention
The purpose of this invention is to provide the high chirality of a kind of stereospecificity height, productive rate synthetic (2S, 6R)-2, the method for 6-dialkyl piperidine hydrochloride.
Chirality provided by the present invention is synthetic, and (25,6R)-2, the method for 6-dialkyl piperidine hydrochloride comprises the steps: (1) with 1-(alpha-amino group benzyl)-beta naphthal and 1,5-glutaraldehyde and benzotriazole reacting generating compound V; (2) compound V that step (1) is obtained and organometallic reagent obtain compound VI-78 ℃ of-20 ℃ of reactions, and described organometallic reagent is RMgX or RLi; (3) step (2) gained compound VI and organometallic reagent are obtained compound VI I-10 ℃ of-20 ℃ of reactions, described organometallic reagent is R
1MgX or R
1Li; (4) with step (3) gained compound VI I in the presence of methylene dichloride through catalytic hydrogenolysis N-debenzylation obtain product (2S, 6R)-2, the 6-dialkyl piperidine hydrochloride; Wherein, described R and R
1Contain the alkyl that aryl or substituted aryl replace or the alkylene or the alkynes base of 1-6 carbon atom for the cycloalkyl of the alkyl of 1-20 carbon atom, a 1-20 carbon atom, a 1-20 carbon atom; X is Cl, Br or I.
Step (1) uses (S)-1-(alpha-amino group benzyl)-beta naphthal to be raw material, and with 1,5-glutaraldehyde productive rate with 91% in the presence of benzotriazole generates midbody compound V.The temperature of reaction of step (1) is-2 ℃-20 ℃, wherein preferably 0 ℃.(S)-1-(alpha-amino group benzyl)-beta naphthal can obtain with reference to the method for splitting described in Chinese patent ZL01127170.1 and the Chinese invention patent application 02157261.5.
Then organometallic reagents such as refined reagent or organolithium in the midbody compound V dative are carried out alkylated reaction, obtain an alkylated compound VI and dialkyl group compound VI I.Reaction solvent is an ether, tetrahydrofuran (THF), or the mixture of ether and benzene or toluene, or the mixture of tetrahydrofuran (THF) and benzene or toluene; The mol ratio of described RMgX of step (2) or RLi and compound V is 1-20: 1; The described R of step (3)
1MgX or R
1The mol ratio of Li and compound VI is 1-20: 1.
R and R among the gained alkylate compound VI I
1Can be identical, also can be different.When with step (2) gained one alkylated compound VI being raw material when reacting, can obtain R and R with Ge Liya reagent with identical group or organolithium compound
1Identical cis dialkyl group substitution compound VII; When being raw material with step (2) gained one alkylated compound VI and have not isoplastic Ge Liya reagent or organolithium compound when reacting, then can obtain R and R
1Cis dialkyl group substitution compound VII inequality.When introducing two alkyl that vary in size, at first introduce less group, and then introduce bigger group, help improving productive rate.Wherein, the physical and chemical parameter of more common compound VI, VII is as shown in table 1.
Productive rate and the physical and chemical parameter of common compound VI of table 1. and compound VI I
R | R 1 | Productive rate (%) | Fusing point (℃) | Specific rotation [α] D 25 |
VI Me n-C 3H 7 n-C 4H 9 n-C 6H 13 n-C 12H 25VII Me n-C 3H 7 Ph n-C 4H 9 | n-C 3H 7 Me Me n-C 5H 11 | 94 92 87 88 70 98 85 69 77 | 120-122 110-111 113-114 73-75 155-156.5 102-103 95-96 146-147 113-114.5 | +161.6°(c0.2,CHCl 3) +177.5°(c0.3,CHCl 3) +202.3°(c0.3,CHCl 3) +98.1° (c0.2,CHCl 3) +334.3°(c0.3,CHCl 3) +134.8°(c0.2,CHCl 3) +54.5° (c0.25,CHCl 3) +29.5° (c0.1,CHCl 3) +12.3° (c0.1,CHCl 3) |
I carries out hydrogenolysis N-debenzylation under catalyst action with step (3) gained compound VI, can generate corresponding cis-2 quantitatively, the 6-dialkyl piperidine hydrochloride.Wherein, catalyzer commonly used is the Pd/C catalyzer, and the quality percentage composition of Pd is 1-20% in this Pd/C catalyzer, is preferably 10%; Reaction solvent is the alcohol of 1-6 carbon atom, and tetrahydrofuran (THF), or the ester of the alcohol of 1-6 carbon atom and acetate or propionic acid generation are preferably methyl alcohol; Temperature of reaction is-10 ℃-40 ℃, preferably carries out at ambient temperature; The pressure that increases hydrogen in the reaction process can improve speed of response, can reach good reaction result usually under synthesis under normal pressure.
The reaction formula of building-up reactions of the present invention is as follows:
The present invention adopt compound V (1,3-Yang Dan oxazine) that (S)-1-(alpha-amino group benzyl)-beta naphthal (Betti alkali) and glutaraldehyde reaction generate for intermediate carry out (2S, 6R)-2, the synthesizing of 6-dialkyl piperidine hydrochloride.This intermediate can carry out alkylated reaction in the alpha-position and the α '-position of piperidine ring with the organometallic reagent substep, and the height stereospecificity generates alpha-position cis dialkyl compound VII identical with α '-position or inequality with high productivity.This compound is carried out catalytic hydrogenolysis N-debenzylation through the Pd/C catalyzer in containing the solvent of methylene dichloride, can almost directly generate accordingly quantitatively (2S, 6R)-2, the 6-dialkyl piperidine hydrochloride.Wherein the hydrogenchloride in the hydrochloride comes from the methylene dichloride dechlorination reaction of Pd/C catalyst.Because the generation of hydrochloride is to finish in the process of hydrogenolysis N-debenzylation He in the closed system, the volatile amine of generation not loss just is converted to the solid salt hydrochlorate.Therefore this reaction has not only been eliminated hydrochloride that traditional method prepares amine fully in operational trouble, and is particularly suitable for improving the productive rate of small molecules volatile amine.Synthetic method of the present invention has highly-solid selectively and high yield, is fit to prepare in a large number that (2S, 6R)-2, the 6-dialkyl piperidine hydrochloride is with a wide range of applications.
Embodiment
Embodiment 1: synthetic (7aR, 11R, 13S)-and 13-phenyl-11-(1-benzotriazole base)-8,9,10,11-tetrahydrochysene-7aH, 13H-naphtho-[1,2-e] piperidine ring is [2,1-b] [1,3] oxazine (compound V) also
0 ℃ down slowly with the tartrate mixture of the aqueous solution (25%, 4.8g 12mmol) is added drop-wise to S-Betti alkali (S)-1-(alpha-amino group benzyl)-beta naphthal) of glutaraldehyde (4.0g, 10mmo1) and benzotriazole (1.43g, CH 12mmol)
2Cl
2(40mL) in the solution, use solid K then
2CO
3Transfer to pH8-9.Continued stirring reaction 20 minutes, and followed the tracks of level of response until reacting completely with TLC.(1.0M 20mL) and stirred 15 minutes, uses diatomite filtration to add the NaOH aqueous solution.Tell organic phase from filtrate, water layer is used CH again
2Cl
2Extraction.The organic phase that merges is used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Dry.Boil off the crude product that obtains behind the solvent through CH
2Cl
2-CH
3The OH recrystallization obtains midbody compound V3.93g, and productive rate is 91.0%.
This compound is a clear crystal, and its fusing point is 180-182 ℃; Specific rotation [α]
D 25=+164.8 ° of (c0.2, CHCl
3);
1H NMR(300MHz,CDCl
3):6.75-8.16(m,15H),5.83-5.87(m,1H),5.21-5.29(m,1H),4.72(s,1H),2.58-2.66(m,1H),2.12-2.22(m,3H),1.85-1.89(m,2H);
13C NMR(100MHz,CDCl
3):152.3,147.2,141.8,132.7,132.4,130.1,129.9(2C),129.6,128.9,128.5(2C),127.8,127.6,127.2,124.7,123.8,122.8,120.8,119.0,118.5,112.1,110.1,81.8,56.5,31.2,29.7,18.2.
Ultimate analysis (C
28H
24N
4O): calculated value C, 77.75%; H, 5.59%; N, 12.95%; Measured value C, 77.77%; H, 5.7%; N, 12.91%.
V is correct for proof gained compound.
Embodiment 2: synthetic (7aR, 11S, 13S)-and 13-phenyl-11-methyl-8,9,10,11-tetrahydrochysene-7aH, 13H-naphtho-[1,2-e] piperidine ring be [2,1-b] [1,3] oxazine (compound VI, wherein R is a methyl) also
Under 0 ℃ and nitrogen protection; THF (tetrahydrofuran (THF)) drips of solution of MeMgCl (12mmol) is added in the anhydrous THF solution (5mmol is dissolved in 50mL) of step 1 gained compound V; drip off the back and continue to stir 2 hours down, follow the tracks of level of response until reacting completely with TLC at 0 ℃.Add saturated NH then
4The Cl aqueous solution is told organic phase.Water layer is used CH again
2Cl
2Extraction merges organic interdependent time and uses distilled water, saturated NaCl solution washing and anhydrous MgSO
4The thick product that drying, removal of solvent under reduced pressure obtain gets compound VI (R is a methyl) through column chromatography (silica gel, petrol ether/ethyl acetate), and productive rate is 94%.
120-122 ℃ of this melting point compound; Specific rotation [α]
D 25=+161.6 ° of (c0.2, CHCl
3);
13C NMR(100MHz,CDCl
3):154.2,143.8,131.5,129.0(2C),128.8,128.6,128.5,128.0(2C),126.9,126.2,123.1,122.8,119.0,114.2,81.6,60.5,54.4,32.1,29.6,18.4,14.1.
Ultimate analysis (C
23H
23NO): calculated value C, 83.85%; H, 7.04%; N, 4.25%; Measured value C, 83.89%; H, 7.11%; N, 4.31%.
Proof gained compound VI (R is a methyl) is correct.
Embodiment 3: synthetic (1S, 2S, 6R)-[α-(2-methyl-6-n-propyl piperidyl)-benzyl]-(compound VI I, wherein R is methyl, R to beta naphthal
1Be n-C
3H
7)
Under-10 ℃ and nitrogen protection; to make Grignard reagent n-PrMgBr in anhydrous diethyl ether (40mL) by Mg (15mmol) and n-PrBr (15mmol) is added drop-wise to step 2 gained compound VI (wherein R is a methyl) (0.5g is in anhydrous ether solution 1.5mmol) (15mL).Dropwise afterreaction and finish (TLC tracking).And then add saturated NH
4Cl solution, the organic phase of telling are used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Dry.Removal of solvent under reduced pressure gets thick product compound VII, and (wherein R is methyl, R
1Be n-C
3H
7), productive rate is 98%.
This compound is a weak yellow foam shape solid; Fusing point 102-103 ℃; Specific rotation [α]
D 25=+134.8 ° of (c0.2, CHCl
3);
MS m/z(%):372(M
+-H,0.28),233(24),232(85),231(100),203(31),202(73),201(31),116(15),115.5(27),101(34);
Ultimate analysis (C
26H
31NO): calculated value C, 83.60%; H, 8.37%; N, 3.75%. measured value: C, 83.78%; H, 8.17%; N, 3.70%.
(wherein R is methyl, R to proof gained compound VI I
1Be n-C
3H
7) correct.
Embodiment 4: synthetic (2S, 6R)-2-methyl-6-n-propyl piperidine hydrochlorate (natural product Dihydropinidine)
(wherein R is methyl, R with embodiment 3 gained compound VI I
1Be n-C
3H
7) (1.5mmol) be dissolved in MeOH (20mL) and CH
2Cl
2In the mixing solutions (10mL).Add the 10%Pd/C catalyzer (0.23g, 0.15mmol) after, feed hydrogen stirring reaction 48 hours under normal pressure, room temperature.Reaction finishes after-filtration and goes out catalyzer, and the solvent in the filtrate is removed in decompression.Add ether then, just obtain white solid, obtain the clear crystal product through the MeOH recrystallization again, productive rate is 96%.
240-242 ℃ of product fusing point; Specific rotation [α]
25 D=-13.2 ° (c0.2, EtOH).
13C NMR(300MHz,CDCl
3):58.4,54.5,35.1,30.7,27.4,22.8,19.4,18.8,13.7.
Ultimate analysis (C
9H
19N.HCl): calculated value C, 60.83%; H, 11.34%; N, 7.88%; Measured value C, 60.87%; H, 11.43%; N, 7.76%.
The proof products therefrom (2S, 6R)-2-methyl-6-n-propyl piperidine hydrochlorate is correct.
Embodiment 5: synthetic (2S, 6R)-2-methyl-6-n-nonyl piperidine hydrochlorate (natural product Isosolenopsin) under 0 ℃ and nitrogen protection, will be by Mg (15mmol) and n-C
9H
19Br (15mmol) makes Grignard reagent n-C in anhydrous diethyl ether (40mL)
9H
19MgBr is added drop-wise to embodiment 2 gained compound VI (wherein R is a methyl), and (0.5g is in anhydrous ether solution 1.5mmol) (15mL).Dropwise afterreaction and finish (TLC tracking), and then add saturated NH
4Cl solution, the organic phase of telling are used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Dry.Removal of solvent under reduced pressure gets thick product compound VII, and (wherein R is methyl, R
1Be n-C
9H
19), productive rate is 93%.Thick product is not purified to be directly used in next step reaction.
The thick product that previous step is obtained is dissolved in MeOH (20mL) and CH
2Cl
2In the mixing solutions (10mL).Add the 15%Pd/C catalyzer (0.23g, 0.15mmol) after, feed hydrogen stirring reaction 48 hours under normal pressure, room temperature.Reaction finishes after-filtration and goes out catalyzer, and the solvent in the filtrate is removed in decompression.Add ether, just obtain white solid, obtain the clear crystal product through the MeOH recrystallization again, productive rate is 95%.
M.p.176-177 ℃ of product fusing point; Specific rotation [α]
25 D=-12.5 ° of (c0.2, CHCl
3);
13C NMR(300MHz,CDCl
3):58.6,54.5,33.2,31.8,30.7,29.6,29.5,29.3,29.2,27.4,25.7,22.9,22.6,19.4,14.0.
Ultimate analysis (C
15H
31N.HCl): calculated value C, 68.80%; H, 12.32%; N, 5.35%; Measured value C, 68.96%; H, 12.46%; N, 5.42%.
The proof products therefrom (2S, 6R)-2-methyl-6-n-nonyl piperidine hydrochlorate is correct.
Embodiment 6: synthetic (2S, 6R)-2-methyl-6-n-undecane phenylpiperidines hydrochloride (natural product Isosolenopsin A)
Under-10 ℃ and nitrogen protection, will be by Mg (20mmol) and n-C
11H
23Br (20mmol) makes Grignard reagent n-C in anhydrous diethyl ether (40mL)
11H
23MgBr is added drop-wise to embodiment 2 gained compound VI (wherein R is a methyl), and (0.5g is in anhydrous ether solution 1.5mmol) (15mL).Dropwise afterreaction and finish (TLC tracking).And then add saturated NH
4Cl solution, the organic phase of telling are used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Drying, removal of solvent under reduced pressure get thick product compound VII, and (wherein R is methyl, R
1Be n-C
11H
23), productive rate is 90%.Thick product is not purified to be directly used in next step reaction.
The thick product that previous step is obtained is dissolved in MeOH (20mL) and CH
2Cl
2In the mixing solutions (10mL).Add the 5%Pd/C catalyzer (0.23g, 0.15mmol) after, feed hydrogen stirring reaction 48 hours under normal pressure, room temperature.Reaction finishes after-filtration and goes out catalyzer, and the solvent in the filtrate is removed in decompression.Add ether, just obtain white solid, obtain the clear crystal product through the MeOH recrystallization again, productive rate is 95%.
M.p.147-148 ℃ of product fusing point; Specific rotation [α]
25 D=-9.9 ° of (c0.2, CHCl
3);
13C NMR(300MHz,CDCl
3):58.6,54.5,33.2,31.8,30.7,29.6(3C),29.5,29.3,29.2,27.4,25.6,22.8,22.6,19.4,14.1.
Ultimate analysis (C
17H
35N.HCl): calculated value C, 70.43%; H, 12.52%; N, 4.83%; Measured value C, 70.44%; H, 12.46%; N, 4.80%.
The proof products therefrom (2S, 6R)-2-methyl-6-n-undecane phenylpiperidines hydrochloride is correct.
Embodiment 7: synthetic (2S, 6R)-2-methyl-6-n-tridecane phenylpiperidines hydrochloride (natural product IsosolenopsinB)
Under 0 ℃ and nitrogen protection, will be by Mg (10mmol) and n-C
13H
27Br (10mmol) makes Grignard reagent n-C in anhydrous diethyl ether (40mL)
13H
27MgBr is added drop-wise to embodiment 2 gained compound VI (wherein R is a methyl), and (0.5g is in anhydrous ether solution 1.5mmol) (15mL).Dropwise afterreaction and finish (TLC tracking).And then add saturated NH
4Cl solution, the organic phase of telling are used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Dry.Removal of solvent under reduced pressure gets thick product compound VII, and (wherein R is methyl, R
1Be n-C
13H
27), productive rate is 93%.Thick product is not purified to be directly used in next step reaction.
The thick product that previous step is obtained is dissolved in MeOH (20mL) and CH
2Cl
2In the mixing solutions (10mL), add the 20%Pd/C catalyzer (0.23g, 0.15mmol) after, feed hydrogen stirring reaction 48 hours under normal pressure, room temperature.Reaction finishes after-filtration and goes out catalyzer, and the solvent in the filtrate is removed in decompression.Add ether, just obtain white solid, obtain the clear crystal product through the MeOH recrystallization again, productive rate is 94%.
140-142 ℃ of product fusing point; Its specific rotation [α]
25 D=-9.4 ° of (c0.2, CHCl
3);
13C NMR(300MHz,CDCl
3):58.6,54.5,33.2,31.8,30.7,29.6,29.5,29.3,29.2,27.4,25.7,22.9,22.6,19.4,14.0;
Ultimate analysis (C
19H
39N.HCl): calculated value C, 71.77%; H, 12.68%; N, 4.40%; Measured value C, 71.60%; H, 12.48%; N, 4.41%.
The proof products therefrom (2S, 6R)-2-methyl-6-n-tridecane phenylpiperidines hydrochloride is correct.
Embodiment 8: synthetic (2S, 6R)-2-methyl-6-Pentadecane phenylpiperidines hydrochloride (natural product IsosolenopsinC)
Under-10 ℃ and nitrogen protection, will be by Mg (20mmol) and n-C
15H
31Br (20mmol) makes Grignard reagent n-C in anhydrous diethyl ether (40mL)
15H
31MgBr is added drop-wise to embodiment 2 gained compound VI (wherein R is a methyl), and (0.5g is in anhydrous ether solution 1.5mmol) (15mL).Dropwise afterreaction and finish (TLC tracking).And then add saturated NH
4Cl solution, the organic phase of telling are used distilled water, saturated NaCl solution washing and anhydrous MgSO successively
4Drying, removal of solvent under reduced pressure get thick product compound VII, and (wherein R is methyl, R
1Be n-C
15H
31), productive rate is 90%.Thick product is not purified to be directly used in next step reaction.
The thick product that previous step is obtained is dissolved in MeOH (20mL) and CH
2Cl
2In the mixing solutions (10mL), add the 15%Pd/C catalyzer (0.23g, 0.15mmol) after, feed hydrogen stirring reaction 48 hours under normal pressure, room temperature.Reaction finishes after-filtration and goes out catalyzer, and the solvent in the filtrate is removed in decompression.Add ether, just obtain white solid, obtain the clear crystal product through the MeOH recrystallization again, productive rate is 96%.
137-139 ℃ of product fusing point; Specific rotation [α]
25 D=-8.0 ° of (c0.2, CHCl
3);
13C NMR(300MHz,CDCl
3):58.5,54.4,33.2,31.8,30.7,29.6(7C),29.5,29.3,29.2,27.4,25.6,22.8,22.6,19.4,14.0;
Ultimate analysis (C
19H
39N.HCl): calculated value C, 72.89%; H, 12.82%; N, 4.05%; Measured value C, 72.83%; H, 12.66%; N, 4.08%.
The proof products therefrom (2S, 6R)-2-methyl-6-Pentadecane phenylpiperidines hydrochloride is correct.
Claims (11)
1, a kind of chirality synthetic (2S, 6R)-2, the method for 6-dialkyl piperidine hydrochloride comprises the steps: (1) with 1-(alpha-amino group benzyl)-beta naphthal and 1,5-glutaraldehyde and benzotriazole reacting generating compound V; (2) compound V that step (1) is obtained and organometallic reagent obtain compound VI-78 ℃ of-20 ℃ of reactions, and described organometallic reagent is RMgX or RLi; (3) step (2) gained compound VI and organometallic reagent are obtained compound VI I-10 ℃ of-20 ℃ of reactions, described organometallic reagent is R
1MgX or R
1Li; (4) with step (3) gained compound VI I in the presence of methylene dichloride through catalytic hydrogenolysis N-debenzylation obtain product (2S, 6R)-2, the 6-dialkyl piperidine hydrochloride; Wherein, described R and R
1Contain the alkyl that aryl or substituted aryl replace or the alkylene or the alkynes base of 1-6 carbon atom for the cycloalkyl of the alkyl of 1-20 carbon atom, a 1-20 carbon atom, a 1-20 carbon atom; X is Cl, Br or I.
2, method according to claim 1 is characterized in that: the described 1-of step (1) (alpha-amino group benzyl)-beta naphthal is the S-configuration; The temperature of reaction of step (1) is-2 ℃-20 ℃.
3, method according to claim 2 is characterized in that: the reaction solvent of step (2) and step (3) is an ether, tetrahydrofuran (THF), or the mixture of ether and benzene or toluene, or the mixture of tetrahydrofuran (THF) and benzene or toluene.
4, method according to claim 3 is characterized in that: the mol ratio of described RMgX of step (2) or RLi and compound V is 1-20: 1; The described R of step (3)
1MgX or R
1The mol ratio of Li and compound VI is 1-20: 1.
5, according to claim 1 or 2 or 3 or 4 described methods, it is characterized in that: the catalyzer of step (4) is the Pd/C catalyzer.
6, method according to claim 5 is characterized in that: the quality percentage composition of Pd is 1-20% in the described Pd/C catalyzer.
7, method according to claim 6 is characterized in that: the quality percentage composition of Pd is 10% in the described Pd/C catalyzer.
8, according to claim 1 or 2 or 3 or 4 described methods, it is characterized in that: the reaction solvent of step (4) is the alcohol of 1-6 carbon atom, tetrahydrofuran (THF), or the ester of the alcohol of 1-6 carbon atom and acetate or propionic acid generation.
9, method according to claim 8 is characterized in that: described solvent is a methyl alcohol.
10, according to claim 1 or 2 or 3 or 4 described methods, it is characterized in that: the temperature of reaction of step (4) is-10 ℃-40 ℃.
11, method according to claim 10 is characterized in that: the described temperature of reaction of step (4) is a room temperature.
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