Synthesis method of spiro indoline piperidine salt compound
By reacting compound 4 with trifluoroacetic acid to form spirocyclic indoline piperidine compound 1 of trifluoroacetate, the problems of slow precipitation speed and poor process stability in the prior art were solved, and the preparation effect of high yield and high purity was achieved.
Patent Information
- Application Number
- CN202311685091.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-11
- Publication Date
- 2025-06-13
AI Technical Summary
In the prior art, the spirocyclic indoline piperidine hydrochloride is slow during the salt formation process, which affects the yield and has the problem of poor process stability.
By reacting compound 4 with trifluoroacetic acid, removing the tert-butoxycarbonyl protecting group to form trifluoroacetate, the spirocyclic indoline piperidine compound 1 is prepared using specific process steps and conditions.
The yield and purity of the spirocyclic indoline piperidine salt compound is improved, the process stability is significantly improved, and the problems of slow material precipitation speed and poor process stability are overcome in the prior art.
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Figure FT_1 
Figure BDA0004597476460000011 
Figure BDA0004597476460000012
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthetic pharmaceuticals, and particularly to a method for synthesizing spiroindoline piperidine salt compounds. Background Art
[0002] The common structures of spiroindoline piperidine compounds are as follows:
[0003]
[0004] They have wide applications in the pharmaceutical field, especially for the synthesis of the drug Ibutamoren.
[0005] Ibutamoren is a drug applicable to patients with normal hypothalamic-pituitary hormone (HP-GH) axis function, which stimulates the secretion of endogenous growth hormone by activating the patient's GHSR. The above intermediate structure compounds 5 and 6 are spiroindoline piperidine compounds with known structures.
[0006] During the synthesis of Ibutamoren, compound 5, as an important intermediate, can be prepared by reacting its hydrochloride compound 6 with a base according to the reports in the existing literature and the common knowledge of those skilled in the art. The reaction formula is:
[0007] According to the reports in the existing literature and the common knowledge of those skilled in the art, compound 6 can also be prepared by existing technologies. However, through experiments, it is found that in the process of forming the salt, compound 6 has the disadvantages of slow precipitation rate, affecting the yield, and poor process stability. Once there are defects and technical obstacles in obtaining compound 6, it further leads to the difficulty in preparing compound 5.
[0008] Considering the wide applications of spiroindoline piperidine compounds in the pharmaceutical field and their use in the preparation of the drug Ibutamoren, it is necessary to overcome the technical obstacles existing in the prior art and develop a preparation method for spiroindoline piperidine compounds with high yield and high purity. Summary of the Invention
[0009] Aiming at the disadvantages and problems existing in the prior art, the present invention has developed a spiroindoline piperidine salt compound and its preparation method. To achieve the above object, the present invention provides the following solutions:
[0010] The spiroindoline piperidine salt compound provided by the present invention is a compound in the form of trifluoroacetate, which can be used for the final synthesis of the drug Ibutamoren. Its structural formula is as follows:
[0011]
[0012] The trifluoroacetate salt of the spiroindoline piperidine compound of the present invention is prepared from compound 4 through deprotection and salt formation reactions.
[0013]
[0014] Among them, Pg is a common amino protecting group such as tert-butoxycarbonyl, Cbz, etc.
[0015] Through experiments, it was found that the above-mentioned compound 1 is a spiroindoline piperidine salt compound with better properties than the hydrochloride salt. This was accidentally discovered by the R & D personnel of the present invention and achieved unexpected technical effects.
[0016] The preparation process of the above-mentioned compound 1 of the present invention includes the following steps:
[0017] Step 1: N-Pg-4-piperidinecarboxaldehyde and phenylhydrazine are reacted under the action of trifluoroacetic acid through an indole synthesis reaction to obtain compound 2, and compound 2 is reduced with sodium borohydride to obtain compound 3;
[0018] Step 2: Compound 3 reacts with methanesulfonyl chloride to protect the amino group to obtain compound 4;
[0019] Step 3: Compound 4 reacts with trifluoroacetic acid to be deprotected by removing Pg and then form a salt to obtain compound 1.
[0020] In the above-mentioned step 1, the reaction temperature is 30 - 35 °C. In the above-mentioned step 1, the solvent is toluene or acetonitrile.
[0021] In the above-mentioned step 2, the reaction temperature is -5 - 5 °C.
[0022] In the above-mentioned step 3, the solvent is dichloromethane.
[0023] In the above-mentioned step 3, the reaction temperature is 35 - 45 °C.
[0024] The above also includes the process of purifying compound 1 by post-treatment with activated carbon.
[0025] The reaction equation of the whole process of the present invention is:
[0026]
[0027] The most preferred process route is:
[0028]
[0029] The present invention overcomes the disadvantages of the existing spiroindoline piperidine hydrochloride, such as slow precipitation rate and affecting the yield. Compared with the existing technology, it has the advantage of greatly improving the process stability. It is an invention accidentally discovered by the R & D personnel without technical inspiration, achieving substantial features and significant progress, and having unexpected technical effects. Brief Description of the Drawings
[0030] Attached Figure 1 1H NMR spectrum of Compound 1 prepared for the example. Detailed Description of the Invention
[0031] To better understand the present invention, the following further details the above-designed content of the present invention through specific implementation examples. The experimental methods described in the following examples are all conventional methods unless otherwise specified.
[0032]
[0033] Example 1:
[0034] 58.64 g of phenylhydrazine, 2073.90 g of toluene, 44.02 g of acetonitrile, and 198.96 g of trifluoroacetic acid were charged into a reaction flask. The temperature was adjusted to 30 - 35 °C under nitrogen protection, and a mixed solution of 429.32 g of toluene / 8.40 g of acetonitrile containing 104.70 g of N-BOC-4-piperidinecarboxaldehyde was added. After the reaction solution was qualified, 199.04 g of ethanol was added to quench the reaction. The temperature was adjusted to -5 - 5 °C, and 28.30 g of sodium borohydride was added. After the reaction was completed, 209.40 g of ammonia water / 837.62 g of aqueous solution was added to quench the reaction. It was filtered, layered, washed with water, the organic layer was separated, concentrated under reduced pressure, recrystallized with 314.16 g of methyl tert-butyl ether, filtered, and the filter cake was dried in a vacuum oven at 45 °C to obtain Compound 3, with a yield of 106.25 g and a yield of 75.0%.
[0035] 51.70 g of DIPEA, 646.20 g of dichloromethane, and 71.80 g of Compound 3 were charged into a reaction flask. The temperature was adjusted to -5 - 5 °C, and a solution of 43.02 g of methanesulfonyl chloride / 287.40 g of dichloromethane was added dropwise, and the reaction was carried out under insulation; after the reaction was sufficient, 57.48 g of sodium carbonate / 517.60 g of purified aqueous solution was added to quench the reaction, allowed to stand for layering, washed with water, and the organic phase was separated; the organic layer was concentrated until no liquid dripped out, recrystallized with 359.60 g of ethanol, filtered, and the filter cake was dried in a vacuum oven at 55.0 °C to obtain Compound 4, with a yield of 84.90 g and a yield of 93.1%.
[0036] 225.60 g of dichloromethane, 47.56 g of trifluoroacetic acid, and 25.00 g of Compound 4 were charged into a reaction flask. The internal temperature was adjusted to 35 - 45 °C, and the reaction was carried out under insulation; after the reaction was complete, it was distilled under reduced pressure until the distillate did not distill linearly, recrystallized with 75.38 g of ethanol, filtered, and dried at 45 °C to obtain the crude product of Compound 1; the crude product of Compound 1 was mixed with 12.56 g of purified water and 250.60 g of ethanol, recrystallized, filtered, and the filter cake was dried in a vacuum oven at 55 °C to obtain Compound 1, with a yield of 20.86 g and a yield of 80.4%.
[0037] Example 2:
[0038] 14.06 g of phenylhydrazine, 495.08 g of toluene, 10.58 g of acetonitrile, and 47.60 g of trifluoroacetic acid were charged into a reaction flask. The temperature was adjusted to 15 - 25°C under nitrogen protection, and 25.00 g of N-BOC-4-piperidinecarboxaldehyde and a mixed solution of 102.60 g of toluene / 2.06 g of acetonitrile were added. After the reaction solution passed the in-process control, 47.56 g of ethanol was added to quench the reaction. The temperature was adjusted to 0°C, 6.76 g of sodium borohydride was added, and the reaction was carried out at -5 - 5°C with heat preservation. After the reaction solution passed the in-process control, 50.40 g of ammonia water / 200.08 g of aqueous solution was added to quench the reaction. The mixture was filtered, and the filtrate was allowed to stand for layering, washed with water, the organic layer was separated, concentrated under reduced pressure, recrystallized with 75.42 g of methyl tert-butyl ether, filtered, and the filter cake was dried in a vacuum oven at 45.6°C to obtain 20.14 g of Compound 3, with a yield of 60.1%.
[0039] 10.80 g of DIPEA, 135.66 g of dichloromethane, and 15.00 g of Compound 3 were charged into a reaction flask. The temperature was adjusted to 5 - 15°C, and a solution of 9.08 g of methanesulfonyl chloride / 60.24 g of dichloromethane was added dropwise, followed by heat preservation reaction. After the reaction was complete, 12.00 g of sodium carbonate / 108.40 g of purified aqueous solution was added to quench the reaction, and the mixture was allowed to stand for layering to separate the organic phase. The organic phase was added with 120.40 g of purified water and stirred for 20 minutes, then allowed to stand for layering to separate the organic phase. The organic layer was concentrated until no liquid dripped out, recrystallized with 75.50 g of ethanol, filtered, and the filter cake was dried in a vacuum oven at 55.1°C to obtain 13.23 g of Compound 4, with a yield of 69.4%.
[0040] 90.30 g of dichloromethane, 19.10 g of trifluoroacetic acid, and 10.00 g of Compound 4 were charged into a reaction flask. The internal temperature was adjusted to 35 - 45°C for heat preservation reaction. After the reaction was complete, it was distilled under reduced pressure until the distillate did not distill linearly. Then 30.10 g of ethanol was added for recrystallization, filtered, and dried at 45°C to obtain the crude product of Compound 1. The crude product of Compound 1 was mixed with 5.10 g of purified water and 100.22 g of ethanol for recrystallization, filtered, and the filter cake was dried in a vacuum oven at 55.3°C to obtain 8.20 g of Compound 1, with a yield of 79.1%.
[0041] Example 3:
[0042] 12.76 g of phenylhydrazine, 495.10 g of toluene, 10.60 g of acetonitrile, and 47.58 g of trifluoroacetic acid were added to a reaction flask. Under nitrogen protection, the temperature was adjusted to 30 - 35 °C, and 25.00 g of N-BOC-4-piperidinecarboxaldehyde and a mixed solution of 102.50 g of toluene / 2.02 g of acetonitrile were added. After the reaction solution passed the in-process control, 47.52 g of ethanol was added to quench the reaction. The temperature was adjusted to -5 - 5 °C, 6.75 g of sodium borohydride was added, and the reaction was carried out under insulation at -5 - 5 °C. After the reaction solution passed the in-process control, 50.10 g of ammonia water / 200.20 g of aqueous solution was added to quench the reaction. The mixture was filtered, and the filtrate was allowed to stand for phase separation, washed with water, and the organic layer was separated. The organic layer was concentrated under reduced pressure. When the distillate no longer showed a linear distillation, 75.30 g of methyl tert-butyl ether was added for recrystallization. The mixture was filtered, and the filter cake was dried in a vacuum oven at 45.1 °C to obtain Compound 3, with a yield of 21.18 g and a yield of 63.1%.
[0043] 10.78 g of DIPEA, 135.50 g of dichloromethane, and 15.00 g of Compound 3 were added to a reaction flask. The temperature was adjusted to -5 - 5 °C, and a solution of 7.50 g of methanesulfonyl chloride / 60.10 g of dichloromethane was added dropwise, and the reaction was carried out under insulation. After the reaction was complete, 12.00 g of sodium carbonate / 108.20 g of purified aqueous solution was added to quench the reaction, and the mixture was stirred for 1.0 hour, allowed to stand for phase separation, and the organic phase was separated. The organic phase was added with 120.10 g of purified water and stirred for 20 minutes, allowed to stand for phase separation, concentrated until no liquid dripped out, 75.30 g of ethanol was added for recrystallization. The mixture was filtered, and the filter cake was dried in a vacuum oven at 55.3 °C to obtain Compound 4, with a yield of 14.77 g and a yield of 77.5%.
[0044] 90.30 g of dichloromethane, 19.08 g of trifluoroacetic acid, and 10.00 g of Compound 4 were added to a reaction flask. The internal temperature was adjusted to 35 - 45 °C, and the reaction was carried out under insulation. After the reaction was complete, the mixture was distilled under reduced pressure until the distillate no longer showed a linear distillation, and 30.10 g of ethanol was added for recrystallization. The mixture was filtered, and the crude product of Compound 1 was obtained after drying at 45.6 °C. The crude product of Compound 1 was mixed with 7.56 g of purified water and 150.22 g of ethanol for recrystallization, and the filter cake was dried in a vacuum oven at 55.8 °C to obtain Compound 1, with a yield of 8.29 g and a yield of 80.0%.
[0045] Example 4:
[0046] 12.78 g of phenylhydrazine, 495.18 g of toluene, 10.66 g of acetonitrile, and 47.60 g of trifluoroacetic acid were charged into a reaction flask. Under nitrogen protection, the temperature was adjusted to 30 - 35 °C, and a mixed solution of 28.95 g of N-Cbz-4-piperidinecarboxaldehyde in 102.58 g of toluene / 2.00 g of acetonitrile was added. After the reaction solution passed the in-process control, 47.58 g of ethanol was added to quench the reaction. The temperature was adjusted to -5 - 5 °C, 6.78 g of sodium borohydride was added, and the reaction was carried out under insulation at -5 - 5 °C. After the reaction solution passed the in-process control, 50.14 g of ammonia water / 200.10 g of aqueous solution was added to quench the reaction. The filtrate was allowed to stand for layer separation, washed with water, and the organic layer was separated. It was concentrated under reduced pressure. When the distillate no longer showed a linear distillation, 75.20 g of methyl tert-butyl ether was added for recrystallization. After filtration, the filter cake was placed in a vacuum oven at 45.9 °C for drying to obtain Compound 3, with a yield of 25.65 g and a yield of 68.4%.
[0047] 10.76 g of DIPEA, 135.40 g of dichloromethane, and 16.78 g of Compound 3 were charged into a reaction flask. The temperature was adjusted to -5 - 5 °C, and a solution of 9.06 g of methanesulfonyl chloride in 60.08 g of dichloromethane was added dropwise, and the reaction was carried out under insulation; after the reaction was complete, 12.06 g of sodium carbonate / 108.10 g of purified aqueous solution was added to quench the reaction. After standing for layer separation, the organic phase was separated; the organic phase was added with 120.40 g of purified water and stirred for 20 minutes, then allowed to stand for layer separation and concentrated until no liquid dripped out. 75.34 g of ethanol was added for reflux dissolution and recrystallization. After filtration, the filter cake was placed in a vacuum oven at 55.5 °C for drying to obtain Compound 4, with a yield of 17.32 g and a yield of 83.1%.
[0048] 90.30 g of dichloromethane, 19.12 g of trifluoroacetic acid, and 10.92 g of Compound 4 were charged into a reaction flask. The internal temperature was adjusted to 35 - 45 °C, and the reaction was carried out under insulation; after the reaction was complete, it was distilled under reduced pressure until the distillate no longer showed a linear distillation, and 30.12 g of ethanol was added for recrystallization; after filtration, it was dried at 45.6 °C to obtain the crude product of Compound 1; the crude product of Compound 1 was mixed with 5.10 g of purified water and 100.10 g of ethanol for recrystallization, and the filter cake was placed in a vacuum oven at 55.7 °C for drying to obtain Compound 1, with a yield of 8.21 g and a yield of 79.1%.
[0049] Example 5:
[0050] 12.75 g of phenylhydrazine, 495.10 g of toluene, 10.60 g of acetonitrile, and 47.60 g of trifluoroacetic acid were added to a reaction flask. Under nitrogen protection, the temperature was adjusted to 30 - 35 °C, and 28.96 g of N-CBZ-4-piperidinecarboxaldehyde and a mixed solution of 102.60 g of toluene / 2.00 g of acetonitrile were added. After the reaction solution passed the in-process control, 47.56 g of ethanol was added to quench the reaction. The temperature was adjusted to -5 - 5 °C, 6.76 g of sodium borohydride was added, and the reaction was carried out under insulation at -5 - 5 °C. After the reaction solution passed the in-process control, 50.10 g of ammonia water / 200.20 g of aqueous solution was added to quench the reaction. The mixture was filtered, and the filtrate was allowed to stand for phase separation, washed with water, and the organic layer was separated. The organic layer was concentrated under reduced pressure. When the distillate no longer showed a linear distillation, 75.10 g of methyl tert-butyl ether was added for recrystallization. The mixture was filtered, and the filter cake was dried in a vacuum oven at 45.9 °C to obtain 25.60 g of Compound 3 with a yield of 68.3%.
[0051] 10.74 g of DIPEA, 135.10 g of dichloromethane, and 16.72 g of Compound 3 were added to a reaction flask. The temperature was adjusted to -5 - 5 °C, and a solution of 9.00 g of methanesulfonyl chloride / 60.10 g of dichloromethane was added dropwise, followed by reaction under insulation. After the reaction was complete, 12.00 g of sodium carbonate / 108.08 g of purified aqueous solution was added to quench the reaction. The mixture was allowed to stand for phase separation, and the organic phase was separated. The organic phase was stirred with 120.60 g of purified water for 20 minutes, allowed to stand for phase separation, and the organic phase was separated. The mixture was concentrated until no liquid dripped out, 75.64 g of ethanol was added for reflux dissolution and recrystallization. The mixture was filtered, and the filter cake was dried in a vacuum oven at 55.7 °C to obtain 17.10 g of Compound 4 with a yield of 82.1%.
[0052] 96.04 g of 1.67 mol / L hydrochloric acid ethyl acetate solution and 10.88 g of Compound 4 were added to a reaction flask. The internal temperature was adjusted to 35 - 45 °C, and the reaction was carried out under insulation. After the reaction was complete, the mixture was distilled under reduced pressure until the distillate no longer showed a linear distillation. 30.18 g of ethanol was added for recrystallization. The mixture was filtered and dried at 45.0 °C to obtain the crude product of Compound 1. The crude product of Compound 1 was mixed with 5.2 g of purified water and 100.60 g of ethanol for recrystallization. The filter cake was dried in a vacuum oven at 55.4 °C to obtain 4.60 g of Compound 1 with a yield of 56.00%.
Claims
1. A spiroindoline piperidine compound trifluoroacetate, with the structural formula:
2. A preparation method of a spiroindoline piperidine compound trifluoroacetate salt, characterized in that, it is prepared from compound 4 through deprotection and salt formation reactions, wherein, Pg is an amino protecting group.
3. The preparation method according to claim 2, characterized in that, Pg is tert-butoxycarbonyl or Cbz.
4. The preparation method according to claim 2, characterized in that, it includes the steps: Step 1: N-Pg-4-piperidinecarboxaldehyde and phenylhydrazine react under the action of trifluoroacetic acid to obtain compound 2, and compound 2 is reduced by sodium borohydride to obtain compound 3; Step 2: Compound 3 reacts with methanesulfonyl chloride to obtain compound 4; Step 3: Compound 4 reacts with trifluoroacetic acid to remove the amino protection and then form a salt to obtain compound 1, 5. The preparation method according to claim 4, characterized in that, Pg is tert-butoxycarbonyl, and the reaction equation is:
6. The preparation method according to claim 4, characterized in that, in the said Step 1, the solvent is toluene or acetonitrile, and in the said Step 3, the solvent is dichloromethane.
7. The preparation method according to claim 4, characterized in that, in the said Step 1, the reaction temperature is 30 - 35 °C.
8. The preparation method according to claim 4, characterized in that, in the said Step 2, the reaction temperature is -5 - 5 °C.
9. The preparation method according to claim 4, characterized in that, in the said Step 3, the reaction temperature is 20 - 30 °C.
10. The preparation method according to claim 4, characterized in that, it includes the process of purifying compound 1 by post-treatment with activated carbon.