A preparation method of (R)-3-aminopiperidine dihydrochloride

Abstract

The invention discloses a method for preparing (R)-3-aminopiperidine dihydrochloride, and belongs to the field of pharmaceutical intermediates. With N-Boc-3-piperidone as a raw material, in the presence of a dehydrating agent, it is condensed with (S)-α-methylbenzylamine, reduced by a reducing agent, and then diastereoisomerized in fumaric acid, and then split and debenzylated by D-di-p-methylbenzoyltartaric acid to obtain the target product (R)-3-aminopiperidine dihydrochloride. The preparation method has easy-to-obtain raw materials, a yield much higher than that of traditional chemical splitting, simple operation, high chiral purity, and is suitable for process production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing (R)-3-aminopiperidine dihydrochloride. Background Art

[0002] (R)-3-aminopiperidine dihydrochloride, English name: (R)-3-aminopiperidinedihydro chloride, CAS: 334618-23-4, white to off-white crystals, is an important intermediate for the preparation of anti-type 2 diabetes drugs linagliptin and alogliptin. Alogliptin is a selective DPP-IV inhibitor developed by Takeda Corporation of Japan. It was approved for marketing by the US FDA in December 2010 under the trade name Nesina. Another new type of highly selective DPP-IV inhibitor, Linagliptin, is an oral hypoglycemic drug developed by Boehringer Ingelheim Pharmaceuticals of Germany. It was approved for marketing by the FDA in May 2011 under the trade name Tradjenta.

[0003] There are three main methods for preparing (R)-3-aminopiperidine dihydrochloride:

[0004] The first is the chemical splitting method: Patents WO2007075630 and WO2008028654 use 3-aminopyridine as a raw material, catalytically hydrogenate under the action of a metal catalyst to obtain 3-aminopiperidine, and then split it with a chiral splitting agent to obtain (R)-3-aminopiperidine dihydrochloride. This method requires a high-pressure reactor and an expensive catalyst, and has disadvantages such as low yield. Patent WO2011160037 discloses a method of using 3-acetylaminopyridine as a raw material, catalytically hydrogenating under high pressure, and hydrolyzing with a strong base to split (R)-3-aminopiperidine dihydrochloride. This method requires a high-pressure reactor and an expensive catalyst, and the hydrogenation and alkaline hydrolysis reactions are incomplete, which affects the splitting effect. Patent CN103319399 uses 3-piperidinecarboxamide as a raw material, and obtains (R)-3-aminopiperidine dihydrochloride through Hofmann rearrangement and splitting under the action of 1-fluoronaphthalene, hydrogen peroxide and fluoroboric acid. This method uses fluoroboric acid and requires the use of special equipment, which is not conducive to industrial production.

[0005] The second method is enzymatic resolution: the literature Adv.Synth.Catal.2008,350,807-812 discloses a method for resolving N-protected-3-aminopiperidine using transaminase. Patent US8338142 uses piperidine-3-carboxamide to selectively hydrolyze and resolve, and obtains optically pure 3-aminopiperidine through Hofmann degradation. Although the product obtained by the enzymatic resolution method has high optical purity, the enzyme is difficult to obtain, the source is limited, and the cost is high, making it difficult to achieve industrial production.

[0006] The third method is the chiral source synthesis method: Patents JP2007262040 and CN101955457 both require D-glutamic acid as a raw material and utilize natural chiral centers to obtain a chiral source. This method has the following disadvantages: 1) There are many steps and the operation is cumbersome; 2) The intermediate is highly water-soluble and difficult to purify; 3) Special impurities are difficult to remove and require column chromatography purification. Patent WO2007112368 uses D-ornithine hydrochloride as a raw material and obtains the target product through esterification, cyclization, reduction and salt formation. The first step of this method requires ultra-low temperature conditions and uses lithium aluminum tetrahydride, which is expensive, highly dangerous and difficult to post-process. The operation is cumbersome and is not conducive to industrial production. Patent CN105111134 uses N-Boc-3-piperidone as a raw material, reacts with enantiomerically pure (R) or (S)-tert-butylsulfenamide, and obtains (R)-3-aminopiperidine dihydrochloride through reduction and hydrolysis to form a salt. The second step yield of the method is 48-55%, and the used (R) or (S)-tert-butylsulfenamide is expensive and has low atomic utilization, resulting in high production costs. Summary of the invention

[0007] In order to overcome the above problems, the present invention discloses a method for preparing (R)-3-aminopiperidine dihydrochloride. N-Boc-3-piperidone is used as a raw material, and in the presence of a dehydrating agent, it is condensed with (S)-α-methylbenzylamine, reduced with a reducing agent, and then diastereomerized in fumaric acid, and then split and debenzylated with D-di-p-methylbenzoyltartaric acid to obtain the target product (R)-3-aminopiperidine dihydrochloride. The raw materials of the preparation method are easy to obtain, the yield is much higher than that of traditional chemical splitting, the operation is simple, the chiral purity is high, and it is suitable for process production.

[0008] The present invention provides a method for preparing (R)-3-aminopiperidine dihydrochloride, comprising the following steps:

[0009] In the first step, N-Boc-3-piperidone, a dehydrating agent and (S)-α-methylbenzylamine undergo a condensation reaction in an organic solvent A. After the reaction is completed, the intermediate I is obtained by filtering and concentrating.

[0010] In the second step, intermediate I reacts with a reducing agent in alcohol, and intermediate II is obtained after quenching, extraction, and concentration;

[0011] The third step is to salt the intermediate II with fumaric acid in acetone, adjust the pH to neutral with an alkaline aqueous solution, and then salt it with D-di-p-methylbenzoyltartaric acid, and perform alkaline hydrolysis to obtain the intermediate III;

[0012] In the fourth step, the intermediate III is deprotected with palladium carbon in a mixed solvent of organic solvent B, and then salified in concentrated hydrochloric acid to prepare (R)-3-aminopiperidine dihydrochloride.

[0013] The equation is expressed as follows:

[0014]

[0015] Furthermore, in the first step, the organic solvent A is selected from toluene or tetrahydrofuran.

[0016] Furthermore, in the first step, the dehydrating agent is selected from anhydrous magnesium sulfate, 3 molecular sieve or 4A molecular sieve.

[0017] Furthermore, in the first step, the molar ratio of N-Boc-3-piperidone to (S)-α-methylbenzylamine is 1:1.0-1.1; the weight ratio of N-Boc-3-piperidone to the dehydrating agent is 1:2-3.

[0018] Furthermore, in the second step, the reducing agent is selected from NaBH4, NaBH3CN or NaBH(OAc)3.

[0019] Furthermore, in the second step, the molar ratio of the intermediate I to the reducing agent is 1.0:1.0-1.5.

[0020] Furthermore, in the third step, the molar ratio of intermediate II, fumaric acid and D-di-p-methylbenzoyltartaric acid is 1:1:1.

[0021] Furthermore, in the third step, the base used twice is selected from KOH or NaOH.

[0022] Furthermore, in the fourth step, the organic solvent B is selected from ethanol or isopropanol.

[0023] Furthermore, in the fourth step, the weight ratio of intermediate III, palladium carbon, concentrated hydrochloric acid and organic solvent B is 1:0.03-0.05:2.0-2.5:7.0-9.0.

[0024] The present invention has the following advantages:

[0025] 1. Reductive amination was carried out using (S)-α-methylbenzylamine and N-Boc-3-piperidone. The obtained intermediate II was diastereomerized in acetone under the action of fumaric acid to obtain a fumarate with a (S, 3R) / (S, 3S) value of >9 / 1. The intermediate III was then resolved and alkaline hydrolyzed with D-di-p-methylbenzoyltartaric acid to obtain the intermediate III. The yield of this step was as high as 80-85%, which was much higher than the theoretical yield of 50% of traditional chemical resolution.

[0026] 2. This method has mild reaction conditions, simple operation, safety and controllability, and cheap and readily available raw materials. It has cost and route advantages and is suitable for industrial scale-up production. Specific embodiments

[0027] Example 1 Synthesis of Intermediate I

[0028] Under nitrogen protection, 400 mL of toluene, N-Boc-3-piperidone (49.8 g, 0.25 mol), anhydrous magnesium sulfate (99.6 g) and (S)-α-methylbenzylamine (30.3 g, 0.25 mol) were added to the reaction bottle and stirred at 20-30° C. for 16 hours. The raw material N-Boc-3-piperidone was controlled to be less than 2% by HPLC. The filtrate was filtered and concentrated under reduced pressure to obtain 72.0 g of yellow oily intermediate I, HPLC: 94.7%, yield 90.2%, LC-MS (m / z) 303.2 (M+H + ).

[0029] Example 2 Synthesis of Intermediate I

[0030] Under nitrogen protection, 400 mL of tetrahydrofuran, N-Boc-3-piperidone (49.8 g, 0.25 mol), 3A molecular sieves (149.4 g) and (S)-α-methylbenzylamine (33.3 g, 0.275 mol) were added to the reaction bottle, and stirred at 20-30° C. for 16 hours. The raw material N-Boc-3-piperidone was controlled to be less than 2% by HPLC. The filtrate was filtered and concentrated under reduced pressure to obtain 74.8 g of yellow oily intermediate I, HPLC: 92.2%, yield 91.3%, LC-MS (m / z) 303.2 (M+H + ).

[0031] Example 3 Synthesis of Intermediate II

[0032] 300 mL of methanol and intermediate I (72.0 g, HPLC 94.7%, 0.226 mol) were added to the reaction bottle, stirred until fully dissolved, cooled to -10-0 ° C, and NaBH4 (10.2 g, 0.27 mol) was added in batches. The feeding speed was controlled according to the amount of gas released. After the addition was completed, -10-0 ° C was kept warm for 2 hours. The raw material reaction was controlled to be complete in HPLC. 100 mL of water was dropped at -10-0 ° C. After methanol was concentrated under reduced pressure, dichloromethane (200 mL × 3) was added, the organic layers were combined, washed with saturated brine, and the organic layer was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure to obtain 67.6 g of intermediate II, HPLC: 94.9%, yield 93.7%, LC-MS (m / z) 305.2 (M+H + ).

[0033] Example 4 Synthesis of Intermediate II

[0034] 300 mL of methanol and intermediate I (74.8 g, HPLC 92.2%, 0.228 mol) were added to the reaction bottle, stirred until fully dissolved, cooled to -10-0 ° C, and NaBH3CN (21.5 g, 0.342 mol) was added in batches. The feeding speed was controlled according to the amount of gas released. After the addition was completed, -10-0 ° C was kept warm for 2 hours. The raw material reaction was controlled to be complete in HPLC. 100 mL of water was dropped at -10-0 ° C. After methanol was concentrated under reduced pressure, dichloromethane (200 mL × 3) was added, the organic layers were combined, washed with saturated brine, and the organic layer was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure to obtain 70.3 g of intermediate II, HPLC: 92.6%, yield 94.2%, LC-MS (m / z) 305.2 (M+H + ).

[0035] Example 5 Synthesis of Intermediate III

[0036] Add 400 mL of acetone and fumaric acid (24.6 g, 0.212 mol) to the reaction flask, stir for 10 minutes, add intermediate II (67.6 g, HPLC 94.9%, 0.212 mol) / 600 mL acetone solution, heat to reflux and stir for 4-5 hours, distill off about 700 mL of acetone at normal pressure, control the diastereomer (S, 3R) / (S, 3S) ratio to 67 / 33 in HPLC, slowly reduce to room temperature and stir for 10-12 hours, control the diastereomer (S, 3R) / (S, 3S) ratio to 79 / 21 in HPLC, then reduce to 0-5 ° C and stir for 2 hours, filter, rinse the filter cake with cold acetone, and dry to obtain 80.4 g of white solid fumarate, (S, 3R) / (S, 3S) ratio 92 / 8;

[0037] Fumarate (80.4g) was mixed with 400mL isopropanol, 60mL 10% NaOH solution was added dropwise to adjust pH=7, D-di-p-methylbenzoyltartaric acid (81.9g, 0.212mol) was added, heated under reflux for 2 hours, slowly reduced to 0-5°C, filtered, and 131.5g of white solid was obtained. The obtained white solid was neutralized with 200mL dichloromethane and mixed, 20% NaOH was added dropwise to adjust pH=10-12, stirred at room temperature for 30 minutes, separated, extracted with dichloromethane (200mL×2), the organic layers were combined, washed with saturated brine, and the organic layer was concentrated under reduced pressure to obtain 54.5g of intermediate III, HPLC 99.4%, yield 84.5%.

[0038] Example 6 Synthesis of Intermediate III

[0039] Add 400 mL of acetone and fumaric acid (24.9 g, 0.214 mol) to the reaction flask, stir for 10 minutes, add intermediate II (70.3 g, HPLC 92.6%, 0.214 mol) / 600 mL acetone solution, heat to reflux and stir for 4-5 hours, distill off about 700 mL of acetone at normal pressure, control the diastereomer (S, 3R) / (S, 3S) ratio to 65 / 35 in HPLC, slowly reduce to room temperature and stir for 10-12 hours, control the diastereomer (S, 3R) / (S, 3S) ratio to 77 / 23 in HPLC, then reduce to 0-5 ° C and stir for 2 hours, filter, rinse the filter cake with cold acetone, and dry to obtain 81.6 g of white solid fumarate, (S, 3R) / (S, 3S) ratio 91 / 9;

[0040] Fumarate (81.6 g) was mixed with 400 mL of isopropanol, 65 mL of 10% NaOH solution was added dropwise to adjust pH=7, D-di-p-methylbenzoyltartaric acid (82.6 g, 0.214 mol) was added, heated under reflux for 2 hours, slowly reduced to 0-5°C, filtered, and 132.1 g of white solid was obtained. The obtained white solid was neutralized with 200 mL of dichloromethane and mixed, 20% NaOH was added dropwise to adjust pH=10-12, stirred at room temperature for 30 minutes, separated, extracted with dichloromethane (200 mL×2), the organic layers were combined, washed with saturated brine, and the organic layer was concentrated under reduced pressure to obtain 53.8 g of intermediate III, HPLC 99.2%, yield 82.7%.

[0041] Example 7 Synthesis of (R)-3-aminopiperidine dihydrochloride

[0042] Add intermediate III (54.5 g, 0.179 mol), 10% palladium carbon (1.6 g) and 450 mL of anhydrous ethanol to the hydrogenation reactor, replace with nitrogen 3 times, introduce hydrogen to 1.0 MPa, stir at 40-50 ° C for 12 hours, cool to room temperature, filter after nitrogen breaks through, drop 109 g of concentrated hydrochloric acid into the filtrate, heat and reflux for 1 hour until completely dissolved, slowly cool to 0 ° C and stir for 1 hour, filter, and dry to obtain 28.1 g of white solid (R)-3-aminopiperidine dihydrochloride, HPLC 99.6%, yield 90.7%, 1 HNMR(400HMz,D2O): δ3.76(m,2H),3.50-3.46(m,1H),3.23-3.20(m,1H),3.09-3.07 (m,1H),2.32-2.30(m,1H),2.17-2.14(m,1H),1.99-1.95(m,1H),1.87-1.84(m,1H).

[0043] Example 8 Synthesis of (R)-3-aminopiperidine dihydrochloride

[0044] Add intermediate III (53.8 g, 0.177 mol), 10% palladium carbon (2.7 g) and 485 mL of isopropanol into a hydrogenation reactor, replace with nitrogen three times, introduce hydrogen to 1.0 MPa, stir at 40-50 ° C for 12 hours, cool to room temperature, filter after nitrogen breaks through, drop 134.5 g of concentrated hydrochloric acid into the filtrate, heat under reflux for 1 hour until completely dissolved, slowly cool to 0 ° C and stir for 1 hour, filter, and dry to obtain 27.2 g of (R)-3-aminopiperidine dihydrochloride as a white solid, HPLC 99.5%, yield 88.2%.

[0045] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing (R)-3-aminopiperidine dihydrochloride, characterized in that: The steps include: In the first step, N-Boc-3-piperidone, a dehydrating agent and (S)-α-methylbenzylamine undergo a condensation reaction in an organic solvent A. After the reaction is completed, the intermediate I is obtained by filtration and concentration. The dehydrating agent is selected from anhydrous magnesium sulfate, 3A molecular sieve or 4A molecular sieve; In the second step, intermediate I reacts with a reducing agent in alcohol, and intermediate II is obtained after quenching, extraction, and concentration. The reducing agent is selected from NaBH4, NaBH3CN or NaBH(OAc)3; In the third step, intermediate II is salified with fumaric acid in acetone, the pH is adjusted to neutral with an alkaline aqueous solution, and then salified with D-di-p-methylbenzoyltartaric acid, and alkaline hydrolysis is performed to obtain intermediate III. The base used twice is selected from KOH or NaOH; In the fourth step, the intermediate III is deprotected with palladium carbon in a mixed solution of an organic solvent B, and then salified in concentrated hydrochloric acid to prepare (R)-3-aminopiperidine dihydrochloride.

2. The method for preparing (R)-3-aminopiperidine dihydrochloride according to claim 1, wherein: In the first step, the organic solvent A is selected from toluene or tetrahydrofuran.

3. The preparation method of (R)-3-aminopiperidine dihydrochloride according to claim 1, wherein: In the first step, the molar ratio of N-Boc-3-piperidone to (S)-α-methylbenzylamine is 1:1.0-1.1; the weight ratio of N-Boc-3-piperidone to the dehydrating agent is 1:2-3.

4. The method for preparing (R)-3-aminopiperidine dihydrochloride according to claim 1, wherein: In the second step, the molar ratio of intermediate I to reducing agent is 1.0:1.0-1.

5.

5. The preparation method of (R)-3-aminopiperidine dihydrochloride according to claim 1, characterized in that: In the third step, the molar ratio of intermediate II, fumaric acid and D-di-p-methylbenzoyltartaric acid is 1:1:

1.

6. The method for preparing (R)-3-aminopiperidine dihydrochloride according to claim 1, wherein: In the fourth step, the organic solvent B is selected from ethanol or isopropanol.

7. The method for preparing (R)-3-aminopiperidine dihydrochloride according to claim 1, wherein: In the fourth step, the weight ratio of intermediate III, palladium carbon, concentrated hydrochloric acid and organic solvent B is 1:0.03-0.05:2.0-2.5:7.0-9.0.

Images