Preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine

Abstract

The invention belongs to the technical field of drug synthesis, and in particular to a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The present invention provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, which uses Boc-L-pyroglutamate ethyl ester as raw material, and is prepared by seven-step reaction to obtain a final product. Through experiments, the preferred solvent and catalyst of step 2, the preferred temperature and reducing agent of step 7 are screened out, and the reaction does not require high pressure (less than 2MPa). The method has the advantages of easy availability of raw materials, simple and mild experimental conditions, low requirements for equipment, low energy consumption, and low cost, and has broad application prospects, which promotes the commercial production of piperidine derivatives.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. Background Art

[0002] Piperidine is a six-membered ring containing five carbon atoms and one nitrogen atom. Its derivatives are widely used as drugs and for other purposes. For example, it is used as a side chain in the synthesis of a quinolone antibiotic (3S,5S)-7-[3-amino-5-methyl-piperidine]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. The stereochemical configuration of the piperidine ring is crucial to the pharmaceutical activity of organic compounds containing piperidine. Therefore, the effective and stereoselective synthesis of piperidine derivatives has broad market prospects.

[0003] The prior art discloses a variety of methods for (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. Patent No. CN102093260A discloses Scheme 1 and Scheme 2. Scheme 1 specifically includes the following five steps:

[0004]

[0005] The above scheme uses commercially available L-glutamic acid as a raw material. First, the diacid is converted into a dimethyl ester under acidic conditions. Then, the amino group is protected with tert-butyloxycarbonyl (Boc). Then, LiHMDS is used as a base and iodomethane is used as a methylating agent to introduce a methyl group. Then, under DIBAL-H reduction, the dialdehyde compound 13 is obtained, which is further reacted with ammonia and NaBH4 to generate the piperidine compound 8.

[0006] The dialdehyde compound 13 can also be prepared from the diester by a reduction-oxidation sequence reaction. As shown in the following scheme 2, the diester compound 12 is reduced under LiA1H4 conditions to generate the diol compound 14, and then undergoes a Swern oxidation reaction to generate the dialdehyde compound 13.

[0007]

[0008] Patent publication number US2010 / 152452 discloses scheme three, which is to produce diamide compound 15 by amine ester exchange of diester compound 12, and then to produce dinitrile compound 16 by dehydration, and then to react ammonia or benzylamine with dinitrile compound 16 under one-pot catalytic hydrogenation conditions to produce piperidine compound 8.

[0009]

[0010] Scheme 4 is as follows. The dinitrile compound 16 can also be obtained by direct alkylation of the dicyano compound 18.

[0011]

[0012] The patent with publication number CN 107021916A discloses scheme 5, which uses 5-methylpiperidin-3-ol as a raw material, first reacts with a benzyl halide to obtain a quaternary ammonium salt, then performs catalytic hydrogenation, then reacts with a sulfonylating agent in the presence of a base, then performs nucleophilic substitution with benzylamine, and finally hydrolyzes in the presence of an acid to obtain the desired piperidine structure.

[0013]

[0014] However, the above schemes have the following problems: (1) The alkylation reaction of the C-4 position of compound 12 needs to be carried out at -78°C, which is a relatively harsh condition and has poor stereoselectivity, and needs to be purified by chemical resolution; (2) The methylation reagent iodomethane used in scheme 4 is expensive and genotoxic; (3) Step 2 of scheme 5 requires a high pressure of 7 MPa to react, which consumes a lot of energy; (4) There are few selectable raw materials, which is not conducive to the development of commercial production of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. Summary of the invention

[0015] In view of the problems of the prior art, the present invention provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

[0016] The present invention provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, comprising the following steps:

[0017]

[0018] Step 1, Boc-L-pyroglutamic acid ethyl ester reacts with formaldehyde or paraformaldehyde to generate compound 2;

[0019] Step 2, the compound 2 reacts with a reducing agent to generate a compound 3;

[0020] Step 3, the compound 3 is reacted to generate compound 4;

[0021] Step 4, the compound 4 reacts with an ammonia source to generate a compound 5;

[0022] Step 5, the compound 5 reacts with a dehydrating agent to generate a compound 6;

[0023] Step 6, the compound 6 reacts with a reducing agent to generate a compound 7;

[0024] Step 7, the compound 7 reacts with a reducing agent to generate a compound 8.

[0025] Preferably, the step 1 includes the following contents:

[0026] Boc-L-pyroglutamic acid ethyl ester is mixed with a base and an acylating agent to generate an intermediate; the intermediate is then reacted with formaldehyde or polyformaldehyde to obtain the product.

[0027] Preferably, in step 1, the base is selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide; and / or, in step 1, the acylating agent is selected from diethyl oxalate, dimethyl oxalate;

[0028] And / or, in step 1, the mixed solvent is isopropyl ether, the temperature is 30-50° C., and the time is 24-48 hours;

[0029] And / or, in step 1, the molar equivalent ratio of the mixed Boc-L-pyroglutamate ethyl ester, acylating agent and base is 1:1.5-3:1-2.

[0030] Preferably, in step 1, the reaction is a reaction of the intermediate with paraformaldehyde;

[0031] And / or, in step 1, the reaction solvent is N,N-dimethylformamide, the temperature is 100-110° C., and the time is 10-12 hours;

[0032] And / or, in step 1, the molar equivalent ratio of Boc-L-pyroglutamate ethyl ester to formaldehyde or paraformaldehyde in the reaction is 1:2-4.

[0033] Preferably, in step 2, the reaction is carried out under catalyst conditions, and the catalyst is selected from Pd / C and Pt / C;

[0034] And / or, in step 2, the reducing agent of the reaction is H2, the pressure is 0.5-2.0 MPa, the temperature is 20-40°C, the time is 12-18 hours, and the solvent is selected from ethyl acetate, ethanol, tetrahydrofuran, and methanol.

[0035] Preferably, in step 2, the catalyst is 10% Pd / C; and / or, in step 2, the solvent is ethyl acetate.

[0036] Preferably, steps 3-6 include the following:

[0037] Step 3, the compound 3 is reacted with a base catalyst to obtain;

[0038] And / or, step 4, the compound 4 reacts with an organic base, an acid anhydride and an ammonia source to obtain;

[0039] And / or, step 5, the compound 5 is reacted with an organic base and a dehydrating agent to obtain;

[0040] And / or, step 6, the compound 6 is reacted with a base, a catalyst and a reducing agent to obtain.

[0041] Preferably, in step 3, the base catalyst is selected from sodium hydroxide or its hydrate, lithium hydroxide or its hydrate, the reaction solvent is a tetrahydrofuran aqueous solution with a volume ratio of 2:1-2, the temperature is 60-70°C, the time is 12-16 hours, and the molar equivalent ratio of compound 3 to the base catalyst is 1:2-4;

[0042] And / or, in step 4 and / or 5, the organic base is selected from 4-dimethylaminopyridine, pyridine, 2-fluoropyridine;

[0043] And / or, in step 4, the acid anhydride is di-tert-butyl dicarbonate, the ammonia source is ammonium bicarbonate, the reaction solvent is tetrahydrofuran, the temperature is 20-40° C., the reaction time is 12-16 hours, and the molar equivalent ratio of compound 4, organic base, acid anhydride and ammonia source is 1:1-3:2-3:1-3;

[0044] And / or, in step 5, the dehydrating agent is selected from trifluoromethanesulfonic anhydride and phosphorus oxychloride, the reaction solvent is tetrahydrofuran, the temperature is 20-40° C., the reaction time is 12-16 hours, and the molar equivalent ratio of compound 5, organic base and dehydrating agent is 1:1.5-6:2-4;

[0045] And / or, in step 6, the base is selected from triethylamine, N,N-diisopropylethylamine, the catalyst is selected from Raney nickel, palladium carbon, the reducing agent is H2, the solvent of the reaction is selected from ethanol, methanol, the temperature is 20-40°C, the pressure is 0.5-2.0 MPa, and the time is 12-16 hours.

[0046] Preferably, in step 7, the reducing agent is selected from DIBAL-H, sodium borohydride, sodium borohydride / boron trifluoride etherate, borane; and / or, in step 7, the reaction temperature is 20-60° C., the reaction time is 12-16 hours, and the solvent is selected from dichloromethane, dichloroethane, tetrahydrofuran.

[0047] Preferably, in step 7, the reducing agent is DIBAL-H; and / or, in step 7, the reaction temperature is 20-30°C.

[0048] The present invention provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The method uses Boc-L-pyroglutamate ethyl ester as a raw material and prepares a final product through seven-step reaction. Through experiments, the preferred solvent and catalyst of step 2, the preferred temperature and reducing agent of step 7 are screened, and the reaction does not require high pressure (less than 2MPa). The method has the advantages of easy availability of raw materials, simple and mild experimental conditions, low requirements for equipment, low energy consumption, and low cost, and has broad application prospects, which promotes the commercial production of piperidine derivatives.

[0049] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0050] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound 2: 4-methylene-5-oxo-Boc-L-pyroglutamate ethyl ester.

[0052] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound 3: (2S,4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester.

[0053] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 5: (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentamide.

[0054] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of compound 6: (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanonitrile.

[0055] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of compound 7: (3S,5S)-2-oxo-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

[0056] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of compound 8: (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

[0057] Figure 7 This is a graph showing the results of gas chromatography-mass spectrometry (GC-MS) analysis of compound 8. DETAILED DESCRIPTION

[0058] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0059] Paraformaldehyde: purity: 96%, acidity: <0.01%, manufacturer: Beijing Tianyu Kanghong Chemical Technology Co., Ltd., batch number: TY20240505.

[0060] The structures of the compounds were determined by H NMR spectroscopy ( 1 H NMR). 1 H NMR was measured using a 400 MHz nuclear magnetic spectrometer, and the solvent was deuterated chloroform (CDCl3).

[0061] Example 1 A method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine

[0062] This embodiment provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, which comprises the following steps:

[0063]

[0064] (1) Compound 2: Synthesis of 4-methylene-5-oxo-Boc-L-pyroglutamate ethyl ester

[0065] At 20-30°C, add isopropyl ether (1000mL) to a 3000mL three-necked flask equipped with a stirrer, cool to 0-5°C, and add NaH (40.4g, 60% purity, 1.3eq) in batches. After the addition, stir for 30min, and drop diethyl oxalate (227.2g, 2.0eq), and control the temperature during the addition process not to exceed 10°C. After the addition, stir for 30min, and drop Boc-L-pyroglutamic acid ethyl ester (200g, 1.0eq) isopropyl ether solution (isopropyl ether 1000mL). After the addition, slowly heat to 30-40°C, keep warm for 48h, and the raw material is basically converted by TLC detection. The reaction solution was concentrated under reduced pressure, and DMF (600 mL) was added to the concentrate to dissolve it. The temperature was raised to 70-75 ° C, and paraformaldehyde (46.7 g, 2.0 eq) was added in batches. Gas was generated during the addition, and it was better to release bubbles evenly. After the addition was completed, the temperature was raised to 100-110 ° C, and the reaction was kept warm for 12 hours. The TLC raw material was completely converted and dropped to 20-30 ° C. The reaction solution was slowly poured into a saturated sodium chloride solution to quench (2000 mL), stirred for 30 minutes, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate twice (1000 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness. Purification was performed by column chromatography, and the eluent was a petroleum ether: ethyl acetate solution with a volume ratio of 1:6, and 46.7 g (4-methylene-5-oxo-Boc-L-pyroglutamate ethyl ester) was obtained. The product was a yellow oily liquid with a yield of 23%.

[0066] like Figure 1 As shown, the product 1 The H NMR data are as follows:

[0067] δ6.23(t,J=3.3Hz,1H),5.50(q,J=1.9,1.1Hz,1H),4.60(dd,J=10.1,3.3,1H),4.25-4.16 (m,2H),3.13-3.00(m,1H),2.70(dd,J=17.4,2.7Hz,1H),1.51(s,9H),1.29-1.20(m,6H).

[0068] (2) Compound 3: Synthesis of (2S,4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester

[0069] At 20-30°C, add ethyl acetate (100 mL) as the reaction solvent to a 300 mL hydrogenation kettle (Shanghai Yanzheng Experimental Instrument Co., Ltd., model: YZPR-300MX) equipped with a stirrer, 4-methylene-5-oxo-Boc-L-pyroglutamate (20.0 g, 1.0 eq), wet palladium carbon (4.5 g, 10% purity, 0.05 eq) as the catalyst, replace with nitrogen 3 times, replace with hydrogen 3 times, maintain the hydrogen pressure at 1.0 MPa, heat to 40°C, and keep the temperature and pressure for 16 hours. Release the pressure, take a sample, and the TLC raw material is completely converted. Filter the reaction solution with diatomaceous earth, wash with anhydrous ethanol until there is no product residue, collect the filtrate, and concentrate to dryness to obtain 23.0 g of a light yellow oily liquid. Column chromatography was performed for purification, and the eluent was a petroleum ether:ethyl acetate solution with a volume ratio of 1:3, to obtain 13.0 g ((2S,4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester). The product was a colorless oily liquid, and the yield was 64%.

[0070] like Figure 2 As shown, the product 1 The H NMR data are as follows:

[0071] δ4.46(dd,J=8.4,7.0Hz,1H),4.20(q,J=7.1Hz,2H),2.67-2.43(m,2H),1.68-1.54(m,1H),1.47(s,9H),1.24(dt,J=15.9,6.8Hz,6H).

[0072] (3) Compound 4: Synthesis of (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanoic acid

[0073] At 20-30°C, tetrahydrofuran (150 mL), purified water (150 mL), and lithium hydroxide monohydrate (2.30 g, 2.0 eq) were added to a 1000 mL three-necked flask equipped with a stirrer and stirred for 30 min. (2S, 4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester (15.0 g, 1.0 eq) was added, the temperature was raised to 60-70°C, and the reaction was kept warm for 16 h. The TLC raw material was basically converted completely. The pH was adjusted to 2-3 with 0.1 M dilute hydrochloric acid, and ethyl acetate was added to extract twice (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phases were concentrated to dryness. Column chromatography was performed for purification, and the eluent was a petroleum ether: ethyl acetate solution with a volume ratio of 1:3 to obtain 4.61 g ((2S, 4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanoic acid). The product was a yellow oily liquid with a yield of 29%.

[0074] (4) Compound 5: Synthesis of (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentylamide

[0075] At 20-30°C, tetrahydrofuran (32 mL), (2S, 4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanoic acid (4.0 g, 1.0 eq), and pyridine (1.49 g, 1.3 eq) were added to a 250 mL three-necked flask equipped with a stirrer. The mixture was stirred and cooled to 0-10°C. Di-tert-butyl dicarbonate (4.12 g, 1.0 eq) was added dropwise. After the addition was completed, the mixture was stirred for 30 min. Ammonium bicarbonate (1.72 g, 1.5 eq) was added in batches. The mixture was heated to 20-30°C and kept warm for 16 h. The TLC showed that the raw material was basically converted. The pH was adjusted to 1-2 with 0.1M dilute hydrochloric acid, and methyl tert-butyl ether was added for extraction twice (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The organic phase was purified by column chromatography, and the eluent was a petroleum ether: ethyl acetate solution with a volume ratio of 1:5, to obtain 3.0 g ((2S, 4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentylamide). The product was a white powdery solid with a yield of 75%.

[0076] like Figure 3 As shown, the product 1 The H NMR data are as follows:

[0077] δ5.93(s,1H),5.65(s,1H),5.29(dd,J=67.0,8.5Hz,1H),4.32-4.23(m,1H),4.18(q,J=7.1Hz,2 H),2.45(q,J=7.1Hz,1H),2.08-1.98(m,1H),1.87-1.80(m,1H),1.42(s,9H),1.30-1.19(m,6H).

[0078] (5) Compound 6: Synthesis of (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanonitrile

[0079] To a 100mL three-necked flask equipped with a stirrer at 20-30°C, add tetrahydrofuran (15mL), (2S,4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentamide (3.0g, 1.0eq), and pyridine (3.69g, 4.5eq), and stir while cooling to 0-10°C. Add trifluoromethanesulfonic anhydride (4.36g, 2.0eq) dropwise. After the addition is complete, stir and heat to 20-30°C. Keep the reaction warm for 16h. TLC shows that the raw material is basically converted. Saturated sodium bicarbonate (100 mL) was added to quench, methyl tert-butyl ether was added to extract twice (100 mL×2), the organic phases were combined, washed twice with 0.1 M dilute hydrochloric acid (50 mL×2), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, and purified by column chromatography, the eluent was a petroleum ether: ethyl acetate solution with a volume ratio of 1:1, and 2.13 g ((2S, 4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanonitrile) was obtained. The product was a colorless transparent liquid with a yield of 72%.

[0080] like Figure 4 As shown, the product 1 The H NMR data are as follows:

[0081] δ5.40-5.17(m,1H),4.35(q,J=7.3Hz,1H),4.20(q,J=7.1Hz,2H),2.74(q,J=7.2Hz,1H), 2.03(dd,J=12.0,5.1Hz,2H),1.41(s,9H),1.35(d,J=7.1Hz,3H),1.27(t,J=7.1Hz,3H).

[0082] (6) Compound 7: Synthesis of (3S,5S)-2-oxo-3-(tert-butoxycarbonylamino)-5-methylpiperidine

[0083] At 20-30°C, add anhydrous ethanol (30 mL), (2S, 4S)-4-(tert-butylcarbonylamino)-5-ethoxy-2-methyl-5-oxopentanonitrile (2.0 g, 1.0 eq), triethylamine (1.5 g, 2.0 eq), Raney nickel (2.17 g, 5.0 eq) to a 100 mL autoclave equipped with a stirrer (Shanghai Yanzheng Experimental Instrument Co., Ltd., model: YZPR-100MX), replace with nitrogen 3 times, replace with hydrogen 3 times, maintain the hydrogen pressure at 2.0 MPa, heat to 40°C, and keep the temperature and pressure for 16 hours. Release the pressure, take a sample, and the TLC raw material is completely converted. Filter the reaction solution with diatomaceous earth, wash with anhydrous ethanol until there is no product residue, collect the filtrate, and concentrate to dryness to obtain 2.3 g of light yellow oily liquid. Column chromatography was performed for purification, and ethyl acetate was used as the eluent to obtain 1.5 g ((3S,5S)-2-oxo-3-(tert-butoxycarbonylamino)-5-methylpiperidine). The product was a white solid, and the yield was 88%.

[0084] like Figure 5 As shown, the product 1 The H NMR data are as follows:

[0085] δ7.20(s,1H),5.52(s,1H),4.26-3.94(m,1H),3.33-3.21(m,1H),2.88(dd,J=12.7,8 .1Hz,1H),2.13-1.92(m,2H),1.80-1.68(m,1H),1.39(s,9H),1.02(d,J=6.7Hz,3H).

[0086] (7) Compound 8: Synthesis of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine

[0087] At 20-30°C, add dichloromethane (20 mL) and (3S,5S)-2-oxo-3-(tert-butoxycarbonylamino)-5-methylpiperidine (1.5 g, 1.0 eq) to a 50 mL three-necked flask equipped with a stirrer, stir and cool to 0-10°C, slowly drop the reducing agent DIBAL-H (48.0 mL, 1.0 M in toluene, 10.0 eq), and control the temperature not to exceed 10°C. After the addition, keep warm and stir for 1 hour, raise the reaction temperature to 20-30°C, keep warm and react for 16 hours, and the TLC raw material is basically converted completely. Saturated potassium sodium tartrate solution (100 mL) was added to quench the reaction, and the mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane twice (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The organic phase was purified by column chromatography, and the eluent was a methanol: dichloromethane solution with a volume ratio of 1:10, to obtain 1.12 g (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The product was a white solid with a yield of 80%.

[0088] like Figure 6 As shown, the product 1 The H NMR data are as follows:

[0089] δ5.44(s,1H),3.72(br s,1H),3.00-2.77(m,2H),2.66(dd,J=11.9,2.7Hz,1H),2.16(t,J=10.8Hz,1 H),1.80-1.62(m,3H),1.40(s,9H),1.22-1.04(m,1H),0.80(d,J=6.5Hz,3H).

[0090] The GC-MS results are as follows Figure 7 shown.

[0091] The technical solution of the present invention is further illustrated by experiments below.

[0092] Experimental Example 1 Effect of different reaction solvents on the yield of synthetic compound 3

[0093] 1. Experimental Methods

[0094] The method of step 2 of Example 1 was followed, except that the reaction solvent was replaced with anhydrous ethanol, tetrahydrofuran and anhydrous methanol respectively.

[0095] 2. Experimental Results

[0096] The results are shown in Table 1: When the reaction solvent is ethyl acetate, the yield of synthesizing (2S, 4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester is the highest. The results show that the preferred reaction solvent for synthesizing (2S, 4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester is ethyl acetate.

[0097] Table 1 Effect of reaction solvent on reaction yield of step 2

[0098]

[0099]

[0100] Experimental Example 2 Effect of Different Catalysts on the Synthesis of Compound 3: (2S,4S)-4-Methyl-5-oxo-Boc-pyroglutamate ethyl ester

[0101] 1. Experimental Methods

[0102] The method of step 2 of Example 1 was followed, except that the catalysts were replaced with 5% Pd / C and 10% Pt / C, respectively.

[0103] 2. Experimental Results

[0104] The results are shown in Table 2: When 10% Pd / C is used as the catalyst, the yield of synthesizing (2S, 4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester is the highest. The results show that the preferred catalyst for synthesizing (2S, 4S)-4-methyl-5-oxo-Boc-pyroglutamate ethyl ester is 10% Pd / C.

[0105] Table 2 Effect of catalyst on reaction yield of step 2

[0106]

[0107] Experimental Example 3 Effects of different reaction temperatures and reducing agents on the synthesis of compound 8: (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine

[0108] 1. Experimental Methods

[0109] The method of step 7 of Example 1 was followed, except that the reaction temperature was adjusted to 50-60°C, and the reducing agent was replaced with NaBH4 / Et2O·BF3 and BH3·THF, respectively.

[0110] 2. Experimental Results

[0111] The results are shown in Table 3: When the reaction temperature is 20-30°C and the reducing agent is DIBAL-H, the yield of synthesizing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine is the highest. The results show that the preferred reaction temperature for synthesizing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine is 20-30°C and the preferred reducing agent is DIBAL-H.

[0112] Table 3. Effect of reducing agent type and temperature on the reaction yield of step 7

[0113]

[0114]

[0115] The above experimental results show that through screening and comparative experiments, the preferred solvent for step 2 is ethyl acetate, the preferred catalyst is 10% Pd / C, the preferred temperature for step 7 is 20-30° C., and the preferred reducing agent is DIBAL-H.

[0116] The invention uses Boc-L-pyroglutamic acid ethyl ester as a raw material, develops a method for introducing a chiral methyl group by means of Aldol condensation-catalytic hydrogenation with the aid of chiral induction, then hydrolyzing the ring to open the ring, obtaining a valeronitrile intermediate by condensation-dehydration, catalytically hydrogenating the ring to close the ring, and reducing the amide to generate (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The method can successfully prepare the target compound.

[0117] Through the above embodiments and experimental examples, it can be seen that the present invention provides a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, which uses Boc-L-pyroglutamate ethyl ester as a raw material and prepares the final product through seven steps of reaction. Through experiments, the preferred solvent and catalyst of step 2, the preferred temperature and reducing agent of step 7 are screened, and the reaction does not require high pressure (less than 2MPa). The method has the advantages of easy availability of raw materials, simple and mild experimental conditions, low equipment requirements, low energy consumption, and low cost, and has broad application prospects, which promotes the commercial production of piperidine derivatives.

Claims

1. A method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, characterized in that: The steps include: Step 1, Boc-L-pyroglutamic acid ethyl ester reacts with formaldehyde or paraformaldehyde to generate compound 2; Step 2, the compound 2 reacts with a reducing agent to generate a compound 3; Step 3, the compound 3 reacts to generate compound 4; Step 4, the compound 4 reacts with an ammonia source to generate a compound 5; Step 5, the compound 5 reacts with a dehydrating agent to generate a compound 6; Step 6, the compound 6 reacts with a reducing agent to generate a compound 7; Step 7, the compound 7 reacts with a reducing agent to generate a compound 8.

2. The preparation method according to claim 1, characterized in that: The step 1 includes the following contents: Boc-L-pyroglutamic acid ethyl ester is mixed with a base and an acylating agent to generate an intermediate; the intermediate is then reacted with formaldehyde or polyformaldehyde to obtain the product.

3. The preparation method according to claim 2, characterized in that: In step 1, the base is selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide; and / or, in step 1, the acylating agent is selected from diethyl oxalate, dimethyl oxalate; And / or, in step 1, the mixed solvent is isopropyl ether, the temperature is 30-50° C., and the time is 24-48 hours; And / or, in step 1, the molar equivalent ratio of the mixed Boc-L-pyroglutamate ethyl ester, acylating agent and base is 1:1.5-3:1-2.

4. The preparation method according to claim 2, characterized in that: In step 1, the reaction is a reaction between the intermediate and paraformaldehyde; And / or, in step 1, the reaction solvent is N,N-dimethylformamide, the temperature is 100-110° C., and the time is 10-12 hours; And / or, in step 1, the molar equivalent ratio of Boc-L-pyroglutamate ethyl ester to formaldehyde or paraformaldehyde in the reaction is 1:2-4.

5. The preparation method according to claim 1, characterized in that: In step 2, the reaction is carried out under catalyst conditions, and the catalyst is selected from Pd / C and Pt / C; And / or, in step 2, the reducing agent of the reaction is H2, the pressure is 0.5-2.0 MPa, the temperature is 20-40°C, the time is 12-18 hours, and the solvent is selected from ethyl acetate, ethanol, tetrahydrofuran, and methanol.

6. The preparation method according to claim 5, characterized in that: In step 2, the catalyst is 10% Pd / C; and / or, in step 2, the solvent is ethyl acetate.

7. The preparation method according to claim 1, characterized in that: Steps 3-6 include the following: Step 3, the compound 3 is reacted with a base catalyst to obtain; And / or, step 4, the compound 4 reacts with an organic base, an acid anhydride and an ammonia source to obtain; And / or, step 5, the compound 5 is reacted with an organic base and a dehydrating agent to obtain; And / or, step 6, the compound 6 is reacted with a base, a catalyst and a reducing agent to obtain.

8. The preparation method according to claim 7, characterized in that: In step 3, the base catalyst is selected from sodium hydroxide or its hydrate, lithium hydroxide or its hydrate, the reaction solvent is a tetrahydrofuran aqueous solution with a volume ratio of 2:1-2, the temperature is 60-70° C., the time is 12-16 hours, and the molar equivalent ratio of compound 3 to the base catalyst is 1:2-4; And / or, in step 4 and / or 5, the organic base is selected from 4-dimethylaminopyridine, pyridine, 2-fluoropyridine; And / or, in step 4, the acid anhydride is di-tert-butyl dicarbonate, the ammonia source is ammonium bicarbonate, the reaction solvent is tetrahydrofuran, the temperature is 20-40° C., the reaction time is 12-16 hours, and the molar equivalent ratio of compound 4, organic base, acid anhydride and ammonia source is 1:1-3:2-3:1-3; And / or, in step 5, the dehydrating agent is selected from trifluoromethanesulfonic anhydride and phosphorus oxychloride, the reaction solvent is tetrahydrofuran, the temperature is 20-40° C., the reaction time is 12-16 hours, and the molar equivalent ratio of compound 5, organic base and dehydrating agent is 1:1.5-6:2-4; And / or, in step 6, the base is selected from triethylamine, N,N-diisopropylethylamine, the catalyst is selected from Raney nickel, palladium carbon, the reducing agent is H2, the solvent of the reaction is selected from ethanol, methanol, the temperature is 20-40°C, the pressure is 0.5-2.0 MPa, and the time is 12-16 hours.

9. The preparation method according to claim 1, characterized in that: In step 7, the reducing agent is selected from DIBAL-H, sodium borohydride, sodium borohydride / boron trifluoride etherate, borane; and / or, in step 7, the reaction temperature is 20-60° C., the reaction time is 12-16 hours, and the solvent is selected from dichloromethane, dichloroethane, tetrahydrofuran.

10. The preparation method according to claim 9, characterized in that: In step 7, the reducing agent is DIBAL-H; and / or, in step 7, the reaction temperature is 20-30°C.

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