Preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride

Abstract

The present invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride. The preparation of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride uses methyl N-Boc-4-piperidinecarboxylate as the starting material, and undergoes four steps of reaction, namely substitution reaction, cyclization reaction, asymmetric reduction reaction, and deprotection and salt formation reaction, to obtain the finished product. The preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride provided by the present invention is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy scale-up production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride. Background Art

[0002] The structural formula of the existing (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride is as follows:

[0003]

[0004] After retrieval, the preparation method of the existing (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride is as shown below:

[0005]

[0006] The above-mentioned literature mainly uses 1-indanone as the starting material, and prepares intermediate 1 through a cyclization reaction, with a relatively low reaction yield (18%); in steps two to three, intermediate 3 is prepared by introducing chiral sulfonamide and reduction hydrogenation. The operation is relatively cumbersome. Titanium tetrachloride, which reacts violently with water, is used as a condensing agent, and the post-treatment is more dangerous. The subsequent removal of the double protecting group takes a long time (19 h). The overall conversion rate of the synthesis route is relatively low, and the process is relatively cumbersome, which is not conducive to large-scale preparation.

[0007] Therefore, it is necessary to provide a new, safe, environmentally friendly and easy-to-scale-up preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride. Summary of the Invention

[0008] The purpose of the present invention is to overcome the above problems existing in the traditional technology and provide a preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride.

[0009] To achieve the above technical purpose and reach the above technical effect, the present invention is realized through the following technical solutions:

[0010] A preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride. The preparation of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride uses methyl N-Boc-4-piperidinecarboxylate as the starting material, and obtains the finished product through four steps of reaction: substitution reaction, cyclization reaction, asymmetric reduction reaction, and deprotection and salt formation reaction.

[0011] Further, the reaction of the first step is as shown in formula (I), and intermediate A is obtained after the reaction:

[0012]

[0013] Further, the specific steps of the first-step reaction are as follows: Add dry tetrahydrofuran and methyl N-Boc-4-piperidinecarboxylate to the reaction kettle in sequence and stir to dissolve. Cool down to -10°C, and add a 60% mineral oil mixture of NaH to the reaction system in batches. After the addition, stir and react at 0°C for a period of time. Separately take benzyl bromide and add it dropwise to the reaction system. After the addition, heat up to 40°C and react for a period of time; Monitor the reaction of the raw materials to be complete by TLC, add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, and purify the crude product by flash column chromatography to obtain intermediate A.

[0014] Further, the second-step reaction is shown in formula (II), and intermediate B is obtained after the reaction:

[0015]

[0016] Further, the specific steps of the second-step reaction are as follows: Add methanol to the reaction kettle, add NaOH to the reaction kettle, stir and dissolve at room temperature, then add intermediate A, and keep warm and react for a period of time; Monitor the reaction of the raw materials to be complete by TLC, add 1N hydrochloric acid aqueous solution to adjust the pH to 3-4, extract with ethyl acetate for multiple times, combine the organic phases and dry with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure to remove the solvent, and obtain intermediate I;

[0017] Add nitrobenzene, intermediate I and aluminum trichloride to the reaction kettle in sequence and stir to dissolve, heat and stir at 130°C for a period of time; Detect that the reaction is completed by TLC, cool down to room temperature, add saturated sodium carbonate aqueous solution to quench the reaction, separate out the nitrobenzene organic phase, add cyclohexane to it and stir rapidly to precipitate solids, filter, wash the filter cake with cyclohexane, drain, and vacuum dry at 60°C for a period of time to obtain intermediate B.

[0018] Further, the third-step reaction is shown in formula (III), and intermediate C is obtained after the reaction:

[0019]

[0020] Further, the specific steps of the third-step reaction are as follows: Add intermediate B to the reaction kettle, add ethyl acetate, 30% ammonia water, and concentrated hydrochloric acid and stir evenly, heat under reflux and react for a period of time; Monitor the reaction of the raw materials to be complete by TLC, cool down, precipitate solids, filter, wash the filter cake with ethanol, drain, and vacuum dry at 60°C for a period of time to obtain intermediate II;

[0021] Add intermediate II, dry tetrahydrofuran, methanol, and (R)-1,1'-bi-2,2'-naphthol into a reaction kettle, stir to dissolve, cool to -20 °C for standby. Add sodium borohydride to the reaction system in batches. After adding, warm up to 0 °C and keep stirring and reacting for a period of time. Monitor the reaction by TLC until completion. Then add saturated sodium sulfate aqueous solution to quench the reaction. Extract with ethyl acetate for multiple times. Combine the organic phases and dry with anhydrous magnesium sulfate. Filter to remove the desiccant, evaporate to dryness, and purify by flash column chromatography to obtain intermediate C.

[0022] Furthermore, the reaction in the fourth step is shown in Formula (IV), and the finished product is obtained after the reaction:

[0023]

[0024] Furthermore, the specific steps of the reaction in the fourth step are as follows: Add intermediate C into a reaction kettle, add dichloromethane and stir to dissolve. Cool down to 0 °C, introduce dry hydrogen chloride gas and stir to react. React at room temperature for a period of time. Monitor the reaction by TLC until the raw materials are completely reacted. Filter the precipitated crystals. Wash the filter cake with dichloromethane, drain, and dry in vacuum at 40 °C for a period of time to obtain the finished product of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride.

[0025] The beneficial effects of the present invention are:

[0026] In the present invention, the preparation of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride uses methyl N-Boc-4-piperidinecarboxylate as the starting material, and undergoes four steps of reaction, namely substitution reaction, cyclization reaction, asymmetric reduction reaction, and deprotection and salt formation reaction, to obtain the finished product; this is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy scale-up production.

[0027] Of course, it is not necessary for any product implementing the present invention to achieve all the above advantages simultaneously. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0029] Figure 1 It is a schematic diagram of the NMR detection result of the finished product of the present invention;

[0030] Figure 2 It is a schematic diagram of the LCMS detection result of the finished product of the present invention;

[0031] Figure 3Schematic diagram of the HPLC test result of the finished product of the present invention;

[0032] Figure 4 Schematic diagram of the HPLC-ee test result of the finished product of the present invention. Detailed implementation mode

[0033] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work belong to the scope of protection of the present invention.

[0034] The specific references of the abbreviations in this embodiment are as follows:

[0035] SM: Methyl N-Boc-4-piperidinecarboxylate

[0036] THF: Tetrahydrofuran

[0037] Me: Methyl

[0038] MeOH: Methanol

[0039] EA: Ethyl acetate

[0040] (R)-BINOL: (R)-1,1'-Bi-2,2'-naphthol

[0041] DCM: Dichloromethane

[0042] The specific embodiment of the present invention is as follows:

[0043] Example 1

[0044] A preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride. The preparation of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride uses methyl N-Boc-4-piperidinecarboxylate as the starting material and undergoes a substitution reaction, a cyclization reaction, an asymmetric reduction reaction, and a deprotection and salt formation reaction, a total of four steps of reaction to obtain the finished product.

[0045] The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0046]

[0047] The specific steps of the first-step reaction are as follows: Add dry THF (5.0 L) and SM (500.0 g, 1.0 eq) to the reaction kettle in sequence and stir to dissolve. Cool down to -10 °C for standby. Take 60% mineral oil mixture of NaH (86.3 g, 1.05 eq) and add it to the reaction system in batches. After adding, stir and react at 0 °C for 1 h. Take another benzyl bromide (387 g, 1.1 eq) and add it dropwise to the reaction system. After adding, heat up to 40 °C and react for 8 h. Monitor the reaction of raw materials by TLC until it is complete. Add saturated ammonium chloride aqueous solution (5 L) to quench the reaction. Extract twice with ethyl acetate (3 L). Combine the organic phases and dry with anhydrous sodium sulfate for 2 h. Filter to remove the desiccant. Concentrate the filtrate under reduced pressure. Purify the crude product by flash column chromatography to obtain 603.8 g of intermediate A product, with a yield of 88.1%.

[0048] Mass spectrometry: MS-ESI: 334.4 [M+H] +

[0049] The reaction of the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0050]

[0051] The specific steps of the second-step reaction are as follows: Add methanol (4 L) to the reaction kettle. Add NaOH (100 g) to the reaction kettle. After stirring and dissolving at room temperature, add intermediate A (603.8 g, 1.0 eq), and keep the temperature for reaction for 2 h. Monitor the reaction of raw materials by TLC until it is complete. Add 1N hydrochloric acid aqueous solution to adjust the pH to 3-4. Extract 3 times with ethyl acetate (3 L). Combine the organic phases and dry with anhydrous sodium sulfate. Filter. Concentrate the filtrate under reduced pressure to remove the solvent to obtain the intermediate. Add nitrobenzene (5 L), the intermediate and aluminum trichloride (313.9 g, 1.3 eq) to the reaction kettle in sequence and stir to dissolve. Heat to 130 °C and stir and react for 2 h. Detect the reaction by TLC until it is complete. Cool to room temperature. Add saturated sodium carbonate aqueous solution to quench the reaction. Separate the nitrobenzene organic phase. Add cyclohexane (5 L) to it and stir rapidly to precipitate solids. Filter. Wash the filter cake with cyclohexane, drain, and dry in vacuum at 60 °C for 12 h to obtain 462.2 g of intermediate B product, with a yield of 84.7%.

[0052] Mass spectrometry: MS-ESI: 302.4 [M+H] +

[0053] The reaction of the third step is shown in formula (III), and intermediate C is obtained after the reaction:

[0054]

[0055] The specific steps of the reaction in the third step are as follows: Add intermediate B (462.2 g, 1.0 eq.) into the reaction kettle, add EA (5 L), 30% ammonia water, and concentrated hydrochloric acid (10 ml), stir evenly, and heat under reflux for 4 h. Monitor the reaction of the raw materials by TLC until it is complete, cool down, precipitate solids, filter, wash the filter cake with ethanol, drain, and dry in vacuum at 60 °C for 6 h to obtain the intermediate. Add the intermediate, dry tetrahydrofuran (5 L), methanol (1 L), and (R)-BINOL (87.8 g, 0.2 eq) into the reaction kettle, stir to dissolve, cool to -20 °C for standby, add sodium borohydride (69.6 g, 1.2 eq) into the reaction system in batches, and after adding, warm up to 0 °C and keep stirring for 8 h. Monitor the reaction by TLC until it is complete, add saturated sodium sulfate aqueous solution (3 L) to quench the reaction, extract twice with ethyl acetate (5 L), combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, evaporate to dryness, and purify by flash column chromatography to obtain 396.9 g of intermediate C product, yield: 85.6%.

[0056] Mass spectrometry: MS-ESI: 303.4 [M+H] + 。

[0057] The reaction in the fourth step is shown in formula (IV), and the finished product is obtained after the reaction:

[0058]

[0059] The specific steps of the reaction in the fourth step are as follows: Add intermediate C (396.9 g, 1.0 eq.) into the reaction kettle, add DCM (4 L), stir to dissolve, cool down to 0 °C, introduce dry hydrogen chloride gas, stir and react, and react at room temperature for 4 h. Monitor the reaction of the raw materials by TLC until it is complete, filter the precipitated crystals, wash the filter cake with DCM, drain, and dry in vacuum at 40 °C for 12 h to obtain 255.0 g of the pure target product, yield: 96.3%, purity 97.7%, and ee value 99.5%.

[0060] Mass spectrometry: MS-ESI: 203.2 [M+H] + 。

[0061] The relevant tests and results of the finished product are as Figures 1 to 4 shown.

[0062] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to only the specific implementation manners. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principle and practical application of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride, characterized in that: The preparation of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride starts from methyl N-Boc-4-piperidinecarboxylate and is obtained through four steps of reactions: substitution reaction, cyclization reaction, asymmetric reduction reaction, and deprotection and salt formation reaction. The reaction of the first step is shown in Formula (I), and intermediate A is obtained after the reaction: The reaction of the second step is shown in Formula (II), and intermediate B is obtained after the reaction: The specific steps of the second step are as follows: Add methanol to the reaction kettle, add NaOH to the reaction kettle, stir and dissolve at room temperature, then add intermediate A, and keep the temperature for a certain period of time. Monitor the reaction of the raw materials by TLC until it is complete. Add 1N hydrochloric acid aqueous solution to adjust the pH to 3-4, extract with ethyl acetate for multiple times, combine the organic phases and dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to remove the solvent to obtain intermediate I. Add nitrobenzene, intermediate I, and aluminum trichloride to the reaction kettle in sequence, stir and dissolve, and stir and react at 130 °C for a certain period of time. Detect the completion of the reaction by TLC, cool to room temperature, add saturated sodium carbonate aqueous solution to quench the reaction, separate the nitrobenzene organic phase, add cyclohexane to it and stir rapidly to precipitate solids, filter, wash the filter cake with cyclohexane, drain, and dry in vacuum at 60 °C for a certain period of time to obtain intermediate B. The reaction of the third step is shown in Formula (III), and intermediate C is obtained after the reaction: The reaction of the fourth step is shown in Formula (IV), and the finished product is obtained after the reaction:

2. The preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride according to claim 1, characterized in that, The specific steps of the first step are as follows: Add dry tetrahydrofuran and methyl N-Boc-4-piperidinecarboxylate to the reaction kettle in sequence, stir and dissolve, cool to -10 °C, add a 60% mineral oil mixture of NaH to the reaction system in batches. After adding, stir and react at 0 °C for a certain period of time. Then, add benzyl bromide dropwise to the reaction system. After adding, warm up to 40 °C and react for a certain period of time. Monitor the reaction of the raw materials by TLC until it is complete. Add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, and purify the crude product by flash column chromatography to obtain intermediate A.

3. The preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride according to claim 2, characterized in that, The specific steps of the third step are as follows: Add intermediate B to the reaction kettle, add ethyl acetate, 30% ammonia water, and concentrated hydrochloric acid, stir evenly, and heat to reflux for a certain period of time. Monitor the reaction of the raw materials by TLC until it is complete, cool down, precipitate solids, filter, wash the filter cake with ethanol, drain, and dry in vacuum at 60 °C for a certain period of time to obtain intermediate II. Add intermediate II, dry tetrahydrofuran, methanol, and (R)-1,1'-bi-2,2'-naphthol to the reaction kettle, stir and dissolve, cool to -20 °C for standby, add sodium borohydride to the reaction system in batches. After adding, warm up to 0 °C and keep stirring and reacting for a certain period of time. Monitor the completion of the reaction by TLC, add saturated sodium sulfate aqueous solution to quench the reaction, extract with ethyl acetate for multiple times, combine the organic phases and dry with anhydrous magnesium sulfate, filter to remove the desiccant, evaporate to dryness, and purify by flash column chromatography to obtain intermediate C.

4. The preparation method of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride according to claim 3, characterized in that, The specific steps of the reaction in the fourth step are as follows: Add intermediate C to the reaction kettle, add dichloromethane and stir to dissolve, cool down to 0 °C, introduce dry hydrogen chloride gas and stir to react, and react at room temperature for a period of time; Monitor the reaction of the raw materials completely by TLC, filter the precipitated crystals, wash the filter cake with dichloromethane, drain, and vacuum dry at 40 °C for a period of time to obtain the finished product of (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride.

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