A process for the preparation of 1-boc-2,2-dimethylpiperidin-4-one

Abstract

The application belongs to the technical field of drug chemical synthesis, and particularly relates to a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, which comprises preparation of a compound of formula III, preparation of a compound of formula IV, preparation of a compound of formula V, preparation of a compound of formula VI, preparation of a compound of formula VII and preparation of a compound of formula I. The application has the advantages of easy availability and low price of raw materials, convenient operation, easy control of reaction, no by-product, suitable overall yield and suitability for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one. BACKGROUND

[0002] 1-BOC-2,2-dimethylpiperidin-4-one is a widely used pharmaceutical intermediate, and plays an important role in the research of new drugs. As disclosed in US2004 / 0006229 A1, 1-BOC-2,2-dimethylpiperidin-4-one can be used as an intermediate to prepare a 5-hydroxytryptamine (5-HT) agonist for inhibiting neuroprotein extravasation and treating or preventing migraine; as disclosed in WO 2016 / 046755, 1-BOC-2,2-dimethylpiperidin-4-one can be used as an intermediate to prepare a compound for regulating RORyt activity, and is used for treating diseases such as immune and inflammatory disorders.

[0003] As for the synthesis of 1-BOC-2,2-dimethylpiperidin-4-one, US2005 / 239781 reports a preparation method as follows:

[0004]

[0005] Reagents and yield: (a) sodium hydride, methyl iodide, tetrahydrofuran, 0-20℃, 12h, 32%.

[0006] The method uses sodium hydride as a hazardous reagent, has isomerization by-products, has low yield, and is difficult to purify, and thus is not suitable for large-scale production.

[0007] As for the synthesis of 1-BOC-2,2-dimethylpiperidin-4-one, US2003 / 232833 reports another similar preparation method as follows:

[0008]

[0009] Reagents: (a) potassium tert-butyrate, tetrahydrofuran, 0-20℃, 4.5h; (b) ethyl acetate, 5N HCl, reflux, 14.5h; (c) sodium hydroxide, di-tert-butyl dicarbonate, tetrahydrofuran, 20℃, 96h, pH=8-9.

[0010] The method takes compound IX as raw material, firstly undergoes ring closure, decarboxylate-removes tert-butyloxycarbonyl protective group, and then adds tert-butyloxycarbonyl. In the reaction process, the raw material is expensive and not easy to obtain, and the column chromatography purification is not suitable for large-scale preparation. The patent introduces 1-BOC-2, 2-dimethylpiperidin-4-one which is prepared by using the above-mentioned similar method with compound XII as raw material. The raw material is also expensive and not easy to obtain, and no yield is reported, which needs to be tried. The preparation method is as follows:

[0011] SUMMARY

[0012] In view of the problems of expensive and not easy to obtain raw material, low yield, and difficult separation and purification in the route and preparation method of 1-BOC-2, 2-dimethylpiperidin-4-one in the prior art, the present application provides a preparation method of 1-BOC-2, 2-dimethylpiperidin-4-one, and the reaction formula is as follows:

[0013]

[0014] The method comprises the following steps:

[0015] S1, the compound of formula II is dissolved in a solvent, benzylamine is added, after the addition is completed, the temperature is increased to 60-65 DEG C, then stirred for 32 hours, concentrated to dryness under reduced pressure, a colorless liquid is obtained, methyl tert-butyl ether is added, 10% citric acid solution is added to the mixture, two layers are separated, the organic layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a colorless liquid, which is the compound of formula III;

[0016] S2, the compound of formula III is dissolved in tetrahydrofuran, protected by nitrogen, and the temperature is controlled below 10 DEG C. Methyl chloroformate is added dropwise, the reaction mixture is naturally warmed to room temperature 20 DEG C, then stirred for 12 hours, 10% sodium bicarbonate aqueous solution is added, the organic layer is separated, washed with 10% sodium chloride aqueous solution, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid, which is the compound of formula IV;

[0017] S3, the compound of formula IV is dissolved in methanol, protected by nitrogen, and the temperature is controlled at about 10 DEG C. Base 2 is slowly added in batches, after the addition is completed, heated to 65-70 DEG C, stirred for 2h, the methanol is removed under reduced pressure, added to 2N hydrochloric acid, added with methyl tert-butyl ether, several layers are separated, the water phase is extracted with methyl tert-butyl ether, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid, which is the compound of formula V;

[0018] S4, the compound of formula V is dissolved in a mixture of water and acetic acid, heated to 90-100 degrees, stirring for 12 hours, cooling to 20 degrees, slowly drop saturated sodium carbonate aqueous solution, stirring to precipitate a large amount of solid, suction filtration, filter cake is rinsed with water, filtration, solid suspended in a mixture of n-heptane and methyl tert-butyl ether, stirring to pulp, to get yellow solid, compound of formula VI;

[0019] S5, the compound of formula VI is dissolved in tetrahydrofuran, nitrogen protection, temperature control about 10 degrees, batch adding sodium borohydride, after adding, slowly drop boron trifluoride ether, during the process, exothermic gas, after adding, heating to 55 degrees, stirring for 12 hours, cooling to 10 degrees, slowly drop methanol, exothermic gas, after drop, heating to reflux, stirring for 6h, the reaction solution is concentrated under reduced pressure, adding 2N hydrochloric acid aqueous solution, stirring for 30 minutes, to the system, adding methyl tert-butyl ether extraction, repeat the operation twice, the organic phase is combined, dried over anhydrous magnesium sulfate, filtration, concentrated under reduced pressure to get white solid, compound of formula VII;

[0020] S6, the compound of formula VII is dissolved in methanol, adding (Boc)2O and 10% palladium carbon, after adding, autoclave hydrogen, stirring at 50 degrees for 16h, the system is filtered, the filtrate is concentrated, removing the solvent, adding n-heptane to pulp, to get white solid, compound of formula I.

[0021] Preferably, in S1, the solvent is selected from one or a mixture of two of methanol, ethanol or water.

[0022] Preferably, in S2, the molar ratio of the compound of formula III: base 1: methyl chloroformate is 1:1-1.5:1-2:1.

[0023] Preferably, in S2, base 1 is triethylamine, N,N'-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0024] Preferably, in S3, base 2 is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or sodium hydride.

[0025] Preferably, in the reaction of the compound of formula V to the compound of formula VI, the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid.

[0026] Preferably, in the reaction of the compound of formula VI to the compound of formula VII, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, boron trifluoride ether, borane tetrahydrofuran complex, borane dimethyl sulfide complex or red aluminum.

[0027] Preferably, in the reaction of the compound of formula VI to the compound of formula VII, the molar ratio of the compound of formula VI to the reducing agent is 1:1-1:1.5.

[0028] Preferably, in the reaction of the compound of formula VII to the compound of formula I, the catalyst is selected from Pd / C, Pd(OH)2 / C or Raney nickel.

[0029] More preferably, in the reaction of the compound of formula VII to the compound of formula I, the hydrogen pressure is 2-4 atmospheres.

[0030] The present application has the beneficial effect of providing a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, which is prepared from 3,3-dimethyl methacrylate and benzylamine as starting materials through addition, acylation, dieckmann condensation, decarboxylation, reduction, hydrogenation and other steps. The raw materials are cheap and easy to obtain, the yield is high, the operation is simple, the controllability is good, the overall yield is suitable, and it is suitable for large-scale production. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0032] Meanwhile, "and / or" or "and / or" appearing throughout the text means that it includes three schemes. Taking "A and / or B" as an example, it includes A scheme, or B scheme, or A and B schemes.

[0033] In addition, the description of "first", "second" and the like in the present application is only for the purpose of description, and cannot be understood as indicating or implying the relative importance of the indicated technical features or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first", "second" can explicitly or implicitly include at least one of the features. In addition, the technical solutions of each embodiment can be combined with each other, but it must be based on the realization of those of ordinary skill in the art. When the combination of technical solutions appears contradictory or unachievable, it should be considered that the combination of technical solutions does not exist, and is not within the scope of protection required by the present application.

[0034] Embodiment 1 provides a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, wherein the preparation of the compound of formula III is as follows:

[0035]

[0036] Dissolve the compound of formula II (6000.0 g, 51.7 mol, 1.1 eq) in 30 L of methanol, add benzylamine (5120.4 g, 47.78 mol, 1.0 eq), after the addition is completed, warm to 60-65 degrees, then stir for 32 hours, concentrate to dryness under reduced pressure, to obtain a colorless liquid, add 10 L of methyl tert-butyl ether to the mixture, add 5 L of 10% citric acid solution to the mixture, separate the two layers, separate the organic layer, dry the organic layer with anhydrous magnesium sulfate, concentrate under reduced pressure to obtain 6.95 kg of a colorless liquid, which is the compound of formula III, with a yield of 65%.

[0037] The compound of formula IV is prepared as follows:

[0038]

[0039] Dissolve the compound of formula III (5000.0 g, 22.6 mol, 1.0 eq) in 25 L of tetrahydrofuran, protect with nitrogen, add triethylamine (3430.3 g, 33.9 mol, 1.5 eq), control the temperature below 10 degrees, drop methyl chloroformate (3393.5 g, 24.9 mol, 1.1 eq), naturally warm the reaction mixture to room temperature 20 degrees, then stir for 12 hours, add 10 L of 10% sodium bicarbonate aqueous solution, separate the organic layer, wash the organic layer with 10 L of 10% sodium chloride aqueous solution, separate the layers, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure to obtain a brown solid, add 9 L of n-heptane / ethyl acetate (volume ratio 8:1) to make a slurry, filter, and obtain 6.53 kg of a yellow solid, which is the compound of formula IV, with a yield of 90%.

[0040] The compound of formula V is prepared as follows:

[0041]

[0042] Dissolve the compound of formula IV (6500.0 g, 20.2 mol, 1.0 eq) in 30 L of methanol, protect with nitrogen, control the temperature at about 10 degrees, slowly add sodium methoxide (1309.4 g, 24.2 mol, 1.2 eq) in batches, after the addition is completed, warm to 65-70 degrees, stir for 2 hours, concentrate the methanol under reduced pressure, add to 20 L of 2N hydrochloric acid, add 15 L of methyl tert-butyl ether, separate the layers, extract the water phase with 10 L of methyl tert-butyl ether, combine the organic phases, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure to obtain 5.2 kg of a yellow solid, which is the compound of formula V, with a yield of 88.9%.

[0043] The compound of formula VI is prepared as follows:

[0044]

[0045] The compound of formula V (5100.0 g, 17.6 mol, 1.0 eq) was dissolved in a mixture of 20 L water and 2 L acetic acid, heated to 90-100 °C, stirred for 12 h, cooled to 20 °C, slowly added 10 L saturated sodium carbonate aqueous solution, stirred to precipitate a large amount of solid, filtered, the filter cake was washed with water, filtered, and the solid was suspended in a mixture of 10 L n-heptane and 2 L methyl tert-butyl ether, stirred to form a slurry, to obtain 3.68 kg of yellow solid, which was the compound of formula VI, with a yield of 90%.

[0046] The compound of formula VII was prepared as follows:

[0047]

[0048] The compound of formula VI (3600.0 g, 15.6 mol, 1.0 eq) was dissolved in 20 L tetrahydrofuran, protected by nitrogen, controlled to about 10 °C, and sodium borohydride (708.2 g, 18.7 mol, 1.2 eq) was added in batches. After the addition was completed, boron trifluoride ether (3321.2 g, 23.4 mol, 1.5 eq) was slowly added dropwise. During the addition process, heat and gas were released. After the addition was completed, the temperature was increased to 55 °C, and stirred for 12 h. The temperature was decreased to 10 °C, and 15 L of methanol was slowly added dropwise. Heat and gas were released. After the addition was completed, the temperature was increased to reflux, and stirred for 6 h. The reaction solution was concentrated under reduced pressure, 10 L of 2 N hydrochloric acid aqueous solution was added, stirred for 30 min, 10 L of methyl tert-butyl ether was added to the system for extraction, and the operation was repeated twice. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.8 kg of white solid, which was the compound of formula VII, with a yield of 82.5%. 1 HNMR (400 MHz, CDCl3) δ (ppm): δ 7.39-7.40 (d, 2H), 7.33-7.35 (t, 2H), 7.25 (t, 1H), 3.63 (s, 2H), 2.76 (t, 2H), 2.39 (s, 2H), 2.34-2.31 (m, 2H), 1.19 (s, 6H).

[0049] The compound of formula I was prepared as follows:

[0050]

[0051] The compound of formula VII (500.0 g, 2.3 mol, 1.0 eq) was dissolved in 3 L of methanol, (Boc)2O (602.4 g, 2.76 mol, 1.2 eq) and 10% palladium on carbon (50.00 g) were added, the autoclave was purged with hydrogen (2 MPa), and stirred at 50 °C for 16 h. The system was filtered, the filtrate was concentrated to remove the solvent, 1 L of n-heptane was added to form a slurry, to obtain 460 g of white solid, which was the compound of formula I, with a yield of 88%.

[0052] 1HNMR (400 MHz, CDC13) δ (ppm): δ 3.93 (t, 2H), 2.61 (br s, 2H), 2.47 (t, 2H), 1.53 (s, 9H), 1.49 (s, 6H).

[0053] In this example, the molar ratio of the compound of formula III: base 1: chloroformic methyl ester is 1:1-1.5:1-2:1.

[0054] In this example, base 1 is triethylamine, N,N'-diisopropylethylamine or 1,8- diazabicyclo[5.4.0]undec-7-ene.

[0055] In this example, base 2 is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or sodium hydride.

[0056] In this example, in the reaction of the compound of formula V to the compound of formula VI, the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid.

[0057] In this example, in the reaction of the compound of formula VI to the compound of formula VII, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, boron trifluoride etherate, borane tetrahydrofuran complex, borane dimethyl sulfide complex or red aluminum.

[0058] In this example, in the reaction of the compound of formula VI to the compound of formula VII, the molar ratio of the compound of formula VI to the reducing agent is 1:1-1:1.5.

[0059] In this example, in the reaction of the compound of formula VII to the compound of formula I, the catalyst is selected from Pd / C, Pd(OH)2 / C or Raney nickel.

[0060] Example 2, which differs from example 1 in that the preparation of the compound of formula I is as follows:

[0061]

[0062] The compound of formula VII (1000.0 g, 4.6 mol, 1.0 eq) was dissolved in 6 liters of methanol, (Boc)20 (1204.7 g, 5.52 mol, 1.2 eq) and 10% palladium on carbon (100.0 g) were added, the autoclave was purged with hydrogen (4 MPa), and the system was stirred at 20°C for 16 h. The system was filtered under suction, the filtrate was concentrated, 5 L of n-heptane was added to the system to form a slurry, and white solid 950 g was obtained, which was the compound of formula I with a yield of 90.8%.

[0063] 1 HNMR (400 MHz, CDC13) δ (ppm): δ 3.93 (t, 2H), 2.61 (br s, 2H), 2.47 (t, 2H), 1.53 (s, 9H), 1.49 (s, 6H).

[0064] Example 3, except that the preparation of the compound of formula I is as follows:

[0065]

[0066] The compound of formula VII (1000.0 g, 4.6 mol, 1.0 eq) was dissolved in 6 liters of methanol, (Boc)2O (1204.7 g, 5.52 mol, 1.2 eq) and 10% palladium hydroxide on carbon (80.0 g) were added, the autoclave was purged with hydrogen (2 MPa), and the reaction was stirred at 50°C for 16 h. The system was filtered, the filtrate was concentrated, 5 L of n-heptane was added to the system to form a slurry, and 900 g of a white solid was obtained, which was the compound of formula I, with a yield of 86%.

[0067] 1 HNMR (400 MHz, CDC13) δ (ppm): δ 3.96 (t, 2H), 2.63 (br s, 2H), 2.50 (t, 2H), 1.55 (s, 9H), 1.52 (s, 6H).

[0068] It should be understood that the purpose of these examples is merely to illustrate the present application and is not intended to limit the scope of protection of the present application. Furthermore, it should also be understood that after reading the above technical content of the present application, those skilled in the art can make various modifications, changes and / or variations to the present application, and all of these equivalent forms are also within the scope of protection defined by the claims of the present application.

Claims

1. A process for the preparation of 1-BOC-2,2-dimethylpiperidin-4-one, characterized in that: The reaction formula is as follows: ; The method comprises the following steps: S1, dissolving the compound of formula II in a solvent, adding benzylamine, after the completion of feeding, heating to 60-65 degrees, then stirring for 32 hours, concentrating to dryness under reduced pressure, obtaining a colorless liquid, adding methyl tert-butyl ether, adding a 10% citric acid solution to the mixture, separating the two layers, separating the organic layer, drying the organic layer with anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain a colorless liquid, i.e. the compound of formula III; S2, dissolving the compound of formula III in tetrahydrofuran, protecting with nitrogen, adding base 1, controlling the temperature below 10 degrees, dropwise adding methyl chloroformate, naturally heating the reaction mixture to room temperature 20 degrees, then stirring for 12 hours, adding a 10% sodium bicarbonate aqueous solution, separating the organic layer, washing the organic layer with a 10% sodium chloride aqueous solution, separating the liquid, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain a brown solid, adding n-heptane / ethyl acetate to make a slurry, and extracting the filter cake to obtain a yellow solid, i.e. the compound of formula IV; S3, dissolving the compound of formula IV in methanol, protecting with nitrogen, controlling the temperature at about 10 degrees, adding base 2 in batches slowly, after the completion of feeding, heating to 65-70 degrees, stirring for 2 hours, concentrating the methanol under reduced pressure, adding to 2N hydrochloric acid, adding methyl tert-butyl ether, separating the organic layer, extracting the aqueous phase with methyl tert-butyl ether, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain a yellow solid, i.e. the compound of formula V; S4, dissolving the compound of formula V in a mixed solution of water and acetic acid, heating to 90-100 degrees, controlling the temperature and stirring for 12 hours, cooling to 20 degrees, slowly dropwise adding saturated sodium carbonate aqueous solution, stirring to precipitate a large amount of solid, extracting the filter cake, washing the filter cake with water, filtering, and suspending the solid in a mixed solution of n-heptane and methyl tert-butyl ether, stirring to make a slurry, to obtain a yellow solid, i.e. the compound of formula VI; S5, dissolving the compound of formula VI in tetrahydrofuran, protecting with nitrogen, controlling the temperature at about 10 degrees, adding sodium borohydride in batches, after the completion of feeding, slowly dropwise adding boron trifluoride ether, during the feeding process, releasing heat and gas, after the completion of feeding, heating to 55 degrees, stirring for 12 hours, cooling to 10 degrees, slowly dropwise adding methanol, releasing heat and gas, after the completion of dropwise adding, heating to reflux, stirring for 6 hours, concentrating the reaction liquid under reduced pressure, adding 2N hydrochloric acid aqueous solution, stirring for 30 minutes, adding methyl tert-butyl ether to extract the system, repeating the operation twice, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain a white solid, i.e. the compound of formula VII; S6, dissolving the compound of formula VII in methanol, adding (Boc)2O and 10% palladium carbon, after feeding, introducing hydrogen into the autoclave, stirring at 50 degrees for 16 hours, extracting the system, concentrating the filtrate to remove the solvent, adding n-heptane to make a slurry, and obtaining a white solid, i.e. the compound of formula I.

2. A process for the preparation of l-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In S1, the solvent is selected from one or a mixture of two of methanol, ethanol or water.

3. A process for the preparation of l-BOC-2,2-dimethylpiperidin-4-one according to claim 2, characterized in that: In S2, base 1 is triethylamine, N,N'-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

4. The process for the preparation of l-BOC-2,2-dimethylpiperidin-4-one as claimed in claim 1, wherein: In S3, base 2 is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or sodium hydride.

5. A process for the preparation of 1-BOC-2,2-dimethylpiperidin-4-one, characterized in that: The reaction formula is as follows: ; wherein base 1 is triethylamine, N,N'-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; base 2 is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or sodium hydride; the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid; the reducing agent is selected from borane tetrahydrofuran complex, borane dimethyl sulfide complex; the catalyst is selected from Pd / C, Pd(OH)2 / C or Raney nickel.

6. A process for the preparation of l-BOC-2,2-dimethylpiperidin-4-one according to claim 5, characterized in that: The molar ratio of the compound of formula VI to the reducing agent is 1:1 to 1:1.

5.

7. A process for the preparation of l-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized by: In the reaction of the compound of formula VII to the compound of formula I, the hydrogen pressure is 2 to 4 atmospheres.

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