Preparation method of 1-BOC-2, 2-dimethylpiperidine-4-ketone

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a preparation method of 1-BOC-2, 2-dimethylpiperidine-4-ketone, which comprises preparation of a compound III, preparation of a compound shown as a formula IV, preparation of a compound shown as a formula V, preparation of a compound shown as a formula VI, preparation of a compound shown as a formula VII and preparation of a compound shown as a formula I. The method has the beneficial effects that the raw materials are easily available, the price is low, the operation is convenient, the reaction is easy to control, byproducts are avoided, the total yield is proper, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing 1-BOC-2,2-dimethylpiperidin-4-one. Background Art

[0002] 1-BOC-2,2-dimethylpiperidin-4-one is a widely used pharmaceutical intermediate, especially playing an important role in the research of new drugs. As recorded in the US patent publication with publication number US2004 / 0006229 A1, 1-BOC-2,2-dimethylpiperidin-4-one can be used as an intermediate to prepare 5-hydroxytryptamine (5-HT) agonists, which are used to inhibit neurogenic protein extravasation and treat or prevent migraine; as recorded in the international patent publication with publication number WO 2016 / 046755, 1-BOC-2,2-dimethylpiperidin-4-one can be used as an intermediate to prepare compounds that regulate RORyt activity, which are used to treat diseases such as immune and inflammatory disorders.

[0003] Regarding the synthesis of 1-BOC-2,2-dimethylpiperidin-4-one, the following preparation method is reported in patent US2005 / 239781:

[0004]

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

[0006] This method uses compound VIII as a raw material and a dangerous reagent, sodium hydride, and has isomeric by-products, a low yield, and is difficult to purify, and is therefore not suitable for large-scale production.

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

[0008]

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

[0010] This method uses compound IX as raw material, first undergoes ring closure, decarboxylation-removal of tert-butyloxycarbonyl protecting group, and tert-butyloxycarbonylation. The raw materials in the reaction process are expensive and difficult to obtain, and column chromatography purification is not suitable for large-scale preparation. The patent introduces 1-BOC-2,2-dimethylpiperidin-4-one, which is prepared using a similar method as above using compound Ⅻ as raw material. The raw materials are also expensive and difficult to obtain, and there is no yield report, so it needs to be tried. Its preparation method is roughly as follows:

[0011] Summary of the invention

[0012] In view of the problems in the prior art of the route and preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, such as expensive raw materials, low yield, and difficult separation and purification, the present invention provides a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, and the reaction formula is as follows:

[0013]

[0014] The following steps are involved:

[0015] S1. Dissolve the compound of formula II in a solvent, add benzylamine, raise the temperature to 60-65 degrees after the addition, stir for 32 hours, and concentrate to dryness under reduced pressure to obtain a colorless liquid, add methyl tert-butyl ether, add 10% citric acid solution to the mixture, separate the two layers, separate the organic layer, dry the organic layer over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a colorless liquid, i.e., the compound of formula III;

[0016] S2, dissolving the compound of formula III in tetrahydrofuran, protecting with nitrogen, adding base 1, controlling the temperature below 10°C, adding methyl chloroformyl acetate dropwise, naturally warming the reaction mixture to room temperature 20°C, then stirring for 12 hours, adding 10% sodium bicarbonate aqueous solution, separating the organic layer, washing the organic layer with 10% sodium chloride aqueous solution, separating the liquids, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain a brown solid, adding n-heptane / ethyl acetate to pulp, and suction filtering, and filtering the cake to obtain a yellow solid, i.e., the compound of formula IV;

[0017] S3, dissolve the compound of formula IV in methanol, protect with nitrogen, control the temperature at about 10 degrees, slowly add base 2 in batches, heat to 65-70 degrees, stir for 2 hours, concentrate under reduced pressure to remove methanol, add to 2N hydrochloric acid, add methyl tert-butyl ether, separate several layers, extract the aqueous phase with methyl tert-butyl ether, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain a yellow solid, i.e., the compound of formula V;

[0018] S4, dissolving the compound of formula V in a mixed solution of water and acetic acid, heating to 90-100 degrees, stirring for 12 hours, cooling to 20 degrees, slowly dropping a saturated sodium carbonate aqueous solution, stirring to precipitate a large amount of solid, suction filtering, rinsing the filter cake with water, filtering, suspending the solid in a mixed solution of n-heptane and methyl tert-butyl ether, stirring and slurrying to obtain a yellow solid, i.e., the compound of formula VI;

[0019] S5, dissolving the compound of formula VI in tetrahydrofuran, protecting with nitrogen, controlling the temperature at about 10 degrees, adding sodium borohydride in batches, slowly adding boron trifluoride ether dropwise, releasing heat and gas during the adding process, raising the temperature to 55 degrees after the addition is completed, stirring for 12 hours, lowering the temperature to 10 degrees, slowly adding methanol dropwise, releasing heat and gas, raising the temperature to reflux after the addition is completed, stirring for 6 hours, concentrating the reaction solution under reduced pressure, adding 2N hydrochloric acid aqueous solution, stirring for 30 minutes, adding methyl tert-butyl ether to the system for extraction, repeating this operation twice, combining the organic phases, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain an off-white solid, i.e., the compound of formula VII;

[0020] S6. Dissolve the compound of formula VII in methanol and add (Boc) 2 O and 10% palladium on carbon, hydrogen was introduced into the autoclave after the addition, and the reaction was stirred at 50°C for 16 hours. The system was filtered, the filtrate was concentrated, the solvent was removed, and n-heptane was added for slurrying to obtain a white solid, namely the compound of formula I.

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

[0022] Preferably, in S2, the molar ratio of the compound of formula III: base 1: methyl chloroformyl acetate is 1:1 to 1.5:1 to 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 formula VI, the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid.

[0026] Preferably, in the reaction of the compounds of formula VI to 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.

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

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

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

[0030] The invention has the beneficial effects of providing a preparation method of 1-BOC-2,2-dimethylpiperidin-4-one, which is prepared by using 3,3-dimethylacrylate and benzylamine as starting raw materials through the steps of addition, acylation, Dieckmann condensation, decarboxylation, reduction, hydrogenation and the like, and the raw materials are cheap and readily available with a high yield, the operation is simple, the controllability is good, the overall yield is appropriate, and the product is suitable for large-scale production. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] At the same time, the meaning of "and / or" or "and / or" appearing in the full text includes three options. Taking "A and / or B" as an example, it includes option A, or option B, or a option in which both A and B are satisfied.

[0033] In addition, in the present invention, descriptions such as "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0034] Example 1. This example provides a method for preparing 1-BOC-2,2-dimethylpiperidin-4-one, wherein the compound of formula III is prepared as follows:

[0035]

[0036] The compound of formula II (6000.0 g, 51.7 mol, 1.1 eq) was dissolved in 30 liters of methanol, and benzylamine (5120.4 g, 47.78 mol, 1.0 eq) was added. After the addition was completed, the temperature was raised to 60-65 degrees, and then stirred for 32 hours, and concentrated to dryness under reduced pressure to obtain a colorless liquid. 10 L of methyl tert-butyl ether was added, and 5 L of 10% citric acid solution was added to the mixture. The two layers were separated, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 6.95 kg of colorless liquid, i.e., the compound of formula III, with a yield of 65%.

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

[0038]

[0039] The compound of formula III (5000.0 g, 22.6 mol, 1.0 eq) was dissolved in 25 liters of tetrahydrofuran, and triethylamine (3430.3 g, 33.9 mol, 1.5 eq) was added under nitrogen protection. The temperature was controlled below 10°C, and methyl chloroformyl acetate (3393.5 g, 24.9 mol, 1.1 eq) was added dropwise. The reaction mixture was naturally heated to room temperature 20°C, and then stirred for 12 hours. 10 L of 10% sodium bicarbonate aqueous solution was added, and the organic layer was separated. The organic layer was washed with 10 L of 10% sodium chloride aqueous solution, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid. 9 L of n-heptane / ethyl acetate (volume ratio of 8:1) was added for slurrying, and suction was filtered. The filter cake obtained 6.53 kg of yellow solid, i.e., the compound of formula IV, with a yield of 90%.

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

[0041]

[0042] The compound of formula IV (6500.0 g, 20.2 mol, 1.0 eq) was dissolved in 30 liters of methanol, and the temperature was controlled at about 10 degrees under nitrogen protection. Sodium methoxide (1309.4 g, 24.2 mol, 1.2 eq) was slowly added in batches. After the addition was completed, the temperature was raised to 65-70 degrees, stirred for 2 hours, and the methanol was concentrated under reduced pressure to remove the methanol. The mixture was added to 20L of 2N hydrochloric acid, and 15L of methyl tert-butyl ether was added to separate the layers. The aqueous phase was extracted with 10L of methyl tert-butyl ether, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5.2 kg of a yellow solid, i.e., 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 mixed solution of 20 L of water and 2 L of acetic acid, heated to 90-100 degrees, stirred for 12 hours, cooled to 20 degrees, and 10 L of saturated sodium carbonate aqueous solution was slowly added dropwise. A large amount of solid was precipitated by stirring, and the filter cake was rinsed with water and filtered. The solid was suspended in a mixed solution of 10 L of n-heptane and 2 L of methyl tert-butyl ether, stirred and slurried to obtain 3.68 kg of yellow solid, i.e., the compound of formula VI, with a yield of 90%.

[0046] The preparation of the compound of formula VII is as follows:

[0047]

[0048] The compound of formula VI (3600.0 g, 15.6 mol, 1.0 eq) was dissolved in 20 liters of tetrahydrofuran, protected by nitrogen, and the temperature was controlled at about 10 degrees. 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. Heat and gas were released during the addition process. After the addition was completed, the temperature was raised to 55 degrees and stirred for 12 hours. The temperature was lowered to 10 degrees, and 15 L of methanol was slowly added dropwise. Heat and gas were released. After the addition was completed, the temperature was raised to reflux and stirred for 6 hours. The reaction solution was concentrated under reduced pressure, 10 L of 2N hydrochloric acid aqueous solution was added, stirred for 30 minutes, 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 an off-white solid, namely the compound of formula VII, with a yield of 82.5%. 1 HNMR (400 MHz, CDCl 3 )δ(ppm): δ7.39-7.40(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 preparation of the compound of formula I is as follows:

[0050]

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

[0052] 1 HNMR (400 MHz, CDCl 3 )δ(ppm): δ3.93(t,2H),2.61(br s,2H),2.47(t,2H),1.53(s,9H),1.49(s,6H).

[0053] In this embodiment, the molar ratio of the compound of formula III: base 1: methyl chloroformyl acetate is 1:1 to 1.5:1 to 2:1.

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

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

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

[0057] In this embodiment, in the reaction of the compounds of formula VI to 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 embodiment, in the reaction of the compounds of formula VI to formula VII, the molar ratio of the compound of formula VI to the reducing agent is 1:1 to 1:1.5.

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

[0060] Example 2, which differs from Example 1, is that the compound of formula I is prepared 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 and (Boc) 2 O (1204.7 g, 5.52 mol, 1.2 eq) and 10% palladium on carbon (100.0 g), hydrogen (4 MPa) was introduced into the autoclave, and the reaction was stirred at 20°C for 16 h. The system was filtered and the filtrate was concentrated. The solvent was removed and 5 L of n-heptane was added for slurrying to obtain 950 g of a white solid, i.e., the yield of the compound of formula I was 90.8%.

[0063] 1 HNMR (400 MHz, CDCl 3)δ(ppm): δ3.91(t,2H),2.59(br s,2H),2.46(t,2H),1.51(s,9H),1.47(s,6H).

[0064] Example 3, which differs from Example 1, is that the compound of formula I is prepared 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 and (Boc) 2 O (1204.7 g, 5.52 mol, 1.2 eq) and 10% palladium hydroxide on carbon (80.0 g), hydrogen (2 MPa) was introduced into the autoclave, and the reaction was stirred at 50°C for 16 h. The system was filtered and the filtrate was concentrated. The solvent was removed and 5 L of n-heptane was added for slurrying to obtain 900 g of a white solid, i.e., the compound of formula I, with a yield of 86%.

[0067] 1 HNMR (400 MHz, CDCl 3 )δ(ppm): δ3.96(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 embodiments is only to illustrate the present invention and is not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and / or variations to the present invention, and all of these equivalent forms also fall within the protection scope defined by the appended claims of this application.

Claims

1. A method for preparing 1-BOC-2,2-dimethylpiperidin-4-one, characterized in that: The reaction formula is as follows: The following steps are involved: S1. Dissolve the compound of formula II in a solvent, add benzylamine, raise the temperature to 60-65 degrees after the addition, stir for 32 hours, and concentrate to dryness under reduced pressure to obtain a colorless liquid, add methyl tert-butyl ether, add 10% citric acid solution to the mixture, separate the two layers, separate the organic layer, dry the organic layer over anhydrous magnesium sulfate, and concentrate 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°C, adding methyl chloroformyl acetate dropwise, naturally warming the reaction mixture to room temperature 20°C, then stirring for 12 hours, adding 10% sodium bicarbonate aqueous solution, separating the organic layer, washing the organic layer with 10% sodium chloride aqueous solution, separating the liquids, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain a brown solid, adding n-heptane / ethyl acetate to pulp, and suction filtering, and filtering the cake to obtain a yellow solid, i.e., the compound of formula IV; S3, dissolve the compound of formula IV in methanol, protect with nitrogen, control the temperature at about 10 degrees, slowly add base 2 in batches, heat to 65-70 degrees, stir for 2 hours, concentrate under reduced pressure to remove methanol, add to 2N hydrochloric acid, add methyl tert-butyl ether, separate several layers, extract the aqueous phase with methyl tert-butyl ether, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate 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, stirring for 12 hours, cooling to 20 degrees, slowly dropping a saturated sodium carbonate aqueous solution, stirring to precipitate a large amount of solid, suction filtering, rinsing the filter cake with water, filtering, suspending the solid in a mixed solution of n-heptane and methyl tert-butyl ether, stirring and slurrying 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, slowly adding boron trifluoride ether dropwise, releasing heat and gas during the adding process, raising the temperature to 55 degrees after the addition is completed, stirring for 12 hours, lowering the temperature to 10 degrees, slowly adding methanol dropwise, releasing heat and gas, raising the temperature to reflux after the addition is completed, stirring for 6 hours, concentrating the reaction solution under reduced pressure, adding 2N hydrochloric acid aqueous solution, stirring for 30 minutes, adding methyl tert-butyl ether to the system for extraction, repeating this operation twice, combining the organic phases, drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain an off-white solid, i.e., the compound of formula VII; S6. Dissolve the compound of formula VII in methanol, add (Boc)2O and 10% palladium on carbon, introduce hydrogen into the autoclave, stir and react at 50°C for 16 hours, filter the system, concentrate the filtrate, remove the solvent, add n-heptane to slurry, and obtain a white solid, i.e., the compound of formula I.

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

3. A method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In S2, the molar ratio of the compound of formula III: base 1: methyl chloroformyl acetate is 1:1 to 1.5:1 to 2:

1.

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

5. A method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In S3, base 2 is potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide or sodium hydride.

6. The method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In the reaction of the compound of formula V to formula VI, the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid.

7. The method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In the reaction of the compound of formula VI to 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.

8. The method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In the reaction of the compounds of formula VI to formula VII, the molar ratio of the compound of formula VI to the reducing agent is 1:1 to 1:1.

5.

9. The method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In the reaction of the compounds of formula VII to formula I, the catalyst is selected from Pd / C, Pd(OH)2 / C or Raney nickel.

10. The method for preparing 1-BOC-2,2-dimethylpiperidin-4-one according to claim 1, characterized in that: In the reaction of the compounds of formula VII to formula I, the hydrogen pressure is 2 to 4 atmospheres.

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