CN110878042B - Preparation method of N-substituent piperidine-3-ketone - Google Patents
Preparation method of N-substituent piperidine-3-ketone Download PDFInfo
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- CN110878042B CN110878042B CN201811032204.8A CN201811032204A CN110878042B CN 110878042 B CN110878042 B CN 110878042B CN 201811032204 A CN201811032204 A CN 201811032204A CN 110878042 B CN110878042 B CN 110878042B
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
Abstract
The invention provides a preparation method of N-substituent piperidine-3-ketone, which comprises the steps of carrying out addition reaction on acrylonitrile (II) and nitromethane as raw materials to obtain 4-nitrobutyronitrile (III), then carrying out catalytic hydrogenation reduction on nitro to obtain 4-aminobutyronitrile (IV), carrying out twice substitution reaction to obtain N-substituent-N-alkoxycarbonyl methyl-4-aminobutyronitrile (V), and finally carrying out condensation cyclization reaction, hydrolysis reaction and decarboxylation to obtain N-substituent piperidine-3-ketone (I). The method has the advantages of cheap and easily-obtained raw materials, simple process route, simple and convenient operation, easy realization of reaction conditions, less waste water generation, environmental protection, high reaction selectivity and yield, and high purity of the prepared product, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of N-substituent piperidine-3-ketone, belonging to the technical field of pharmaceutical chemicals.
Background
The N-substituent piperidine-3-ketone (I) is an important organic synthesis intermediate, has wide application in the synthesis of medicines, pesticides and natural products, can be used for preparing (R) -3-aminopiperidine hydrochloride or (R) -3-aminopiperidine derivatives with optical activity, and then is used for synthesizing oral hypoglycemic drugs ALOGLIPTIN (1), trelagliptin (TRELAGLPTIN, 2) and linagliptin (LINAGLIPTIN, 3).
The synthesis of N-substituted piperidin-3-ones (I) reported so far mainly includes the following two types of methods:
1. condensation of benzylamine
In the literature, "Chinese medicine industry impurities 2004,35, 385-388" uses gamma-butyrolactone as a raw material and generates 1-benzyl-3-piperidone through six steps of benzylamine aminolysis, hydrolysis, esterification, substitution with ethyl bromoacetate, cyclization and decarboxylation; depicted as scheme 1 below. The synthetic route is long, and a lactam structure is easily formed in the third esterification step, so that the total yield of the whole route is influenced.
Synthesis scheme 1
Chinese patent document CN105622444A reports a reaction scheme similar to that of scheme 1 (see scheme 2); preparing N-benzyl glycine ethyl ester by taking 2-halogenated ethyl acetate and benzylamine as raw materials, then carrying out substitution reaction on the N-benzyl glycine ethyl ester and 4-halogenated butyric ester, and finally preparing 1-benzyl-3-piperidone through cyclization and decarboxylation. In the process, the gamma-butyrolactone in the synthetic route 1 is changed into 4-halogenated butyrate, so that the reaction steps are shortened; however, in practice, the reaction of the second step with 4-halobutanoic acid esters requires a long reaction time, the yield is not satisfactory, and purification is not easy, thus limiting the applicability of this process.
Synthesis scheme 2
2. 3-hydroxypyridine reduction process
The literature "Synlett, 2006, (7), 1440" uses 3-hydroxypyridine as raw material, and uses noble metal catalyst to catalyze hydrogenation reduction to obtain 3-hydroxypiperidine, which is introduced with protecting group to generate 1-substituted-3-hydroxypiperidine, and finally, hydroxyl is oxidized to carbonyl to obtain N-substituted piperidin-3-one (synthetic route 3). The raw material 3-hydroxypyridine used in the route is high in price, high pressure is needed for catalytic reduction of pyridine rings by the noble metal, equipment requirements are high, and the product cost is high.
Synthesis scheme 3
Chinese patent document CN103204801A discloses using 3-hydroxypyridine as a raw material, reacting with benzyl halide to generate a quaternary ammonium salt, reducing with sodium borohydride, debenzylating, introducing t-butyloxycarbonyl protection, and performing an oxidation reaction to generate 1-t-butyloxycarbonyl-3-piperidone (synthetic route 4); the Chinese patent document CN102351783A also reports the synthesis of 1-benzyl-3-piperidone by a similar method. Although noble metals are not used as catalysts for reducing pyridine rings, 3-hydroxypyridine and sodium borohydride are still used in the method, the route cost is high, and the oxidation step conditions are harsh, so that the method is not beneficial to industrial production.
Synthesis scheme 4
In conclusion, the existing method has the defects of long reaction route, strict requirements on reaction conditions, complex operation, high cost, low reaction selectivity, low yield and the like, and an industrial production method of N-substituent piperidine-3-ketone (I) with simple process, easy realization of reaction conditions, safe and simple operation, environmental protection, low cost, high purity and high yield is urgently needed to be established, and has important significance for the development of (R) -3-aminopiperidine hydrochloride and downstream products thereof, so the invention is provided.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of N-substituent piperidine-3-ketone (I) with low cost and high purity. The method has the advantages of cheap and easily-obtained raw materials, simple process route, simple and convenient operation, easy realization of reaction conditions, less waste water generation, environmental protection, high reaction selectivity and yield, and high purity of the prepared product, and is suitable for industrial production.
Description of terms:
a compound of formula II: acrylonitrile (II);
a compound of formula III: 4-nitrobutyronitrile (III);
a compound of formula IV: 4-aminobutyronitrile (IV);
a compound of formula V: N-substituent-N-alkoxycarbonylmethyl-4-aminobutyronitrile (V); in the structural formula, a substituent P is benzyl or benzoyl, and R is methyl, ethyl, isopropyl, n-propyl or tert-butyl;
a compound of formula I: n-substituted piperidin-3-ones (I); in the structural formula, a substituent P is the same as that of the compound of the formula V.
In the specification, the compound numbers are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a process for the preparation of an N-substituted piperidin-3-one of formula i, comprising the steps of:
(1) preparing a compound of formula III by subjecting a compound of formula II and nitromethane to an addition reaction;
(2) preparing a compound of formula IV by subjecting a compound of formula III to a catalytic hydrogenation reaction;
(3) preparing a compound of formula v by subjecting a compound of formula iv to a substitution reaction;
in the structural formula of the compound shown in the formula V, R is methyl, ethyl, isopropyl, n-propyl or tert-butyl, and P is benzyl or benzoyl;
(4) the N-substituted piperidin-3-ones (I) are prepared by subjecting the compounds of formula V to condensation cyclization, hydrolysis, acidification and decarboxylation with hydrochloric acid.
According to the invention, in step (1), the addition reaction of the compound of formula II and nitromethane is preferably carried out in solvent A and under the action of catalyst B.
Preferably, the solvent A is one or the combination of more than two of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene or toluene; the mass ratio of the solvent A to the compound shown in the formula II is (0-15) to 1; further preferably, the mass ratio of the solvent A to the compound of the formula II is (3-8): 1.
Preferably, the catalyst B is potassium fluoride/aluminum oxide with potassium fluoride content of 2 wt%, triethylamine, tri-n-butylammonium, 4-dimethylaminopyridine, DBU, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, wherein the potassium fluoride/aluminum oxide means that potassium fluoride is loaded on aluminum oxide; the mass ratio of the catalyst B to the compound shown in the formula II is (0.5-5.0): 100; more preferably, the mass ratio of the catalyst B to the compound of the formula II is (1.0-2.0): 100.
Preferably, the addition reaction of the compound of formula ii and nitromethane comprises the steps of: uniformly mixing the solvent A, the catalyst B and nitromethane, dropwise adding the compound of the formula II at 0-80 ℃, and carrying out addition reaction after dropwise adding is completed within 0.5-3 hours.
According to the invention, in step (1), the molar ratio of nitromethane to the compound of formula II is (1-10): 1; preferably, the molar ratio of the nitromethane to the compound of formula II is (3-5): 1.
Preferably, according to the invention, in step (1), the addition reaction temperature is 0-80 ℃; preferably, the addition reaction temperature is 20-40 ℃. The addition reaction time is 1-10 hours; preferably, the addition reaction time is 3 to 5 hours.
Preferably, according to the invention, in step (2), the catalytic hydrogenation of the compound of formula III is carried out in solvent C, under the action of catalyst D.
Preferably, the solvent C is one or a combination of more than two of methanol, ethanol, isopropanol, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetic acid, benzene or toluene; the mass ratio of the solvent C to the compound shown in the formula III is (3-15) to 1; further preferably, the mass ratio of the solvent C to the compound of the formula III is (4-8): 1.
Preferably, the catalyst D is palladium carbon or raney nickel, and more preferably is palladium carbon; the mass of the catalyst D is 0.5-25% of that of the compound shown in the formula III; further preferably, the mass of the palladium-carbon catalyst is 0.5-5.0% of that of the compound shown in the formula III, and the mass of the Raney nickel catalyst is 5-25% of that of the compound shown in the formula III; most preferably, the mass of the palladium-carbon catalyst is 1-3% of the mass of the compound of formula III, and the mass of the Raney nickel catalyst is 10-15% of the mass of the compound of formula III.
Preferably, in step (2), the temperature of the catalytic hydrogenation reaction is 10-70 ℃, and the hydrogen pressure is 0.1-0.5 MPa; preferably, the temperature of the catalytic hydrogenation reaction is 20-50 ℃, and the hydrogen pressure is 0.2-0.4 MPa. The catalytic hydrogenation reaction time is 2-10 hours; preferably, the catalytic hydrogenation reaction time is 3 to 6 hours.
Preferably, according to the present invention, the step (3) of converting the compound of formula IV into the compound of formula V comprises the steps of: in a solvent E, under the catalysis of alkali F, the compound of the formula IV sequentially reacts with a compound with a general formula PX and a halogenated acetate for twice substitution reaction to prepare a compound of the formula V, or the compound of the formula IV sequentially reacts with the halogenated acetate and the compound with the general formula PX for twice substitution reaction to prepare the compound of the formula V; wherein in the general formula PX, X is chlorine or bromine, and the meaning of P is the same as that of P in the structural formula of the compound of the formula V.
Preferably, the solvent E is one or the combination of more than two of water, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane or toluene; the mass ratio of the solvent E to the compound shown in the formula IV is (5-35) to 1; further preferably, the mass ratio of the solvent E to the compound of the formula IV is (9-20): 1.
Preferably, the base F is an inorganic base or an organic base, the inorganic base is selected from one or a combination of sodium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate or calcium acetate, and the organic base is selected from one or a combination of triethylamine, tri-n-butylamine or pyridine; the molar ratio of the base F to the compound of formula IV is (2.0-3.0): 1.
Preferably, the haloacetate is a bromoacetate or a chloroacetate.
Preferably, the molar ratio of the compound having the general formula PX, the haloacetate, and the compound having the formula IV is (1.0-1.2): 1; further preferably, the molar ratio of the compound having the general formula PX, the haloacetate, and the compound having the formula IV is (1.0-1.05): (1.0-1.1): 1. The slightly excessive amount of the substitution reagent of the present invention is to allow the substitution reaction to proceed completely, to allow the compound of formula IV to react completely, and to allow the excessive amount of the substitution reagent to be easily removed.
Preferably, the compound having the general formula PX and the haloacetate are added dropwise to the reaction system, and then the substitution reaction is performed.
Preferably, the temperature of the twice substitution reaction of the compound of formula IV and the compound of general formula PX and the haloacetate in turn and the temperature of the twice substitution reaction of the compound of formula IV and the haloacetate and the compound of general formula PX in turn are both 10-90 ℃; further preferably, the substitution reaction temperature is 30-60 ℃. The substitution reaction time is 1-9 hours; more preferably, the substitution reaction time is 3 to 5 hours.
According to a preferred embodiment of the present invention, in step (4), the condensation cyclization reaction of the compound of formula V is carried out in a solvent G under the action of a base H.
Preferably, the solvent G is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane or toluene; the mass ratio of the solvent G to the compound of the formula V is (3-20) to 1; further preferably, the mass ratio of the solvent G to the compound of the formula V is (4-10): 1.
Preferably, the base H is sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the molar ratio of the base H to the compound of formula V is (1.0-2.0): 1; further preferably, the molar ratio of the base H to the compound of the formula V is (1.1-1.3): 1.
Preferably, the condensation cyclization reaction of the compound of formula v comprises the steps of: mixing solvent G and alkali H, dripping formula V compound at (-20) -10 deg.C, and performing condensation cyclization reaction. In order to ensure safe feeding and prevent overtemperature, the temperature is controlled not to exceed 10 ℃ when the compound of the formula V is dripped.
Preferably, according to the invention, the condensation and cyclization reaction temperature in the step (4) is (-20) to 80 ℃; preferably, the condensation cyclization reaction temperature is 20-40 ℃. The condensation cyclization reaction time is 2-5 hours.
Preferably, according to the invention, the hydrolysis reaction in step (4) is carried out in the presence of water; the mass ratio of the water to the compound of the formula V is 3-5: 1; the hydrolysis reaction temperature is 20-100 ℃; preferably, the hydrolysis reaction temperature is 50-80 ℃. The hydrolysis reaction time is 1-6 hours; preferably, the hydrolysis reaction time is 2 to 3 hours.
Preferably, in step (4), the decarboxylation by acidification with hydrochloric acid is performed by using a pH of a hydrochloric acid acidification system with a mass concentration of 20-30 wt% to 2.0-3.0; the decarboxylation reaction temperature is 0-60 ℃; preferably, the decarboxylation reaction temperature is 20-30 ℃. The decarboxylation reaction time is 0.5-2 hours; preferably, the decarboxylation reaction time is 0.5 to 1 hour.
The reaction process of the present invention is depicted as the following synthetic scheme 5:
synthesis scheme 5
Wherein X is chlorine or bromine; p is benzyl or benzoyl; r is methyl, ethyl, isopropyl, n-propyl or tert-butyl.
The invention has the following technical characteristics and beneficial effects:
1. the invention provides a novel preparation method of N-substituent piperidine-3-ketone, which comprises the steps of carrying out addition reaction on acrylonitrile (II) and nitromethane serving as raw materials to obtain 4-nitrobutyronitrile (III), then carrying out catalytic hydrogenation reduction on nitro to obtain 4-aminobutyronitrile (IV), carrying out substitution reaction twice to obtain N-substituent-N-alkoxycarbonyl methyl-4-aminobutyronitrile (V), and finally carrying out condensation cyclization reaction, hydrolysis reaction and decarboxylation to obtain N-substituent piperidine-3-ketone (I).
2. The synthetic route is short, and the target product can be prepared only by 4 steps; the operation is simple, the reaction does not need harsh conditions, and the method is easy to realize; the method has the advantages of less waste water generation amount, environmental protection; the invention does not use strong irritant raw materials such as thionyl chloride and the like, and the used raw materials are safe, good in stability, cheap and easily available, and low in cost; the method has the advantages of less side reaction, high reaction selectivity, high yield and purity of the target product, and suitability for industrial production.
3. The reaction route of the invention fully embodies the concept that the quality of API is from design, and the related steps have high reaction activity, strong specificity, easy reaction and high product purity. Nitromethane and acrylonitrile are easy to perform an addition reaction under the catalysis of a weakly alkaline substance, and then the nitro is reduced to be amino to prepare 4-aminobutyronitrile; the selectivity of the two-step reaction is 100%, the products in each step are stable, the catalyst and the solvent are easy to recover or reuse, and the atom economy is high. Then preparing N-substituent-N-alkoxycarbonyl methyl-4-amino butyronitrile by using two substitution reactions, and then obtaining N-substituent piperidine-3-ketone by condensation cyclization reaction, hydrolysis reaction and decarboxylation; in the operation process, the concentration is controlled by dripping N-substituent-N-alkoxycarbonyl methyl-4-aminobutyronitrile, so that intermolecular condensation side reactions are reduced, and the guarantee is provided for high selectivity, high product purity and high yield of the reaction.
4. The invention utilizes the acrylonitrile to replace the ester compound in the prior art, and has unexpected advantages; not only the amidation side reaction of intermolecular amino and ester group is avoided, but also the generation of polymer is avoided; in addition, the activation strength of the cyano group to the ortho methylene group is higher than that of the ester, so that the condensation cyclization reaction is easy to carry out, the condensation reaction can be carried out at a lower temperature, the side reaction is reduced, and the yield and the purity of the target product are further improved.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified. The yields are all molar yields.
Example 1: preparation of 4-nitrobutyronitrile (III)
100 g of dichloromethane, 122.0 g (2.0 mol) of nitromethane and 0.4 g of potassium fluoride/aluminum trichloride (the catalyst can be prepared by the prior art) with the potassium fluoride content of 2 percent are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a condenser and a constant pressure dropping funnel, 26.5 g (0.5 mol) of acrylonitrile is dripped between 20 ℃ and 25 ℃, the dripping is finished for about 1 hour, then the mixture is stirred and reacted for 4 hours at the temperature of 20 ℃ to 25 ℃, the reaction of the acrylonitrile is detected by GC to be complete, the mixture is filtered, the dichloromethane and the nitromethane are recovered from the filtrate obtained by normal pressure distillation, and then 53.2 g of colorless liquid 4-nitrobutyronitrile is obtained by reduced pressure distillation (50 ℃ to 65 ℃/5mmHg), the yield is 93.3 percent, and the GC purity is 99.7.
Example 2: preparation of 4-nitrobutyronitrile (III)
100 g of tetrahydrofuran, 122.0 g (2.0 mol) of nitromethane and 0.3 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a condenser and a constant pressure dropping funnel, 26.5 g (0.5 mol) of acrylonitrile is dripped between 30 ℃ and 35 ℃ until the dripping is finished for about 1 hour, then the mixture is stirred and reacted for 4 hours at 30 ℃ to 35 ℃, the reaction is detected by GC to be complete, the mixture is filtered, the tetrahydrofuran and the nitromethane are recovered from filtrate by normal pressure distillation, and then 52.8 g of colorless liquid 4-nitrobutyronitrile is obtained by reduced pressure distillation (50 ℃ to 65 ℃/5mmHg), the yield is 92.6 percent, and the GC purity is 99.5 percent.
Example 3: preparation of 4-aminobutyronitrile (IV)
220 g of methanol, 45.6 g (0.4 mol) of 4-nitrobutyronitrile obtained in example 1, 0.6 g of a 5% palladium on carbon catalyst (containing 50% water) were charged into a 500 ml autoclave, and after 3 times of replacement with nitrogen, the mixture was stirred at an internal temperature of 20 to 25 ℃ under a hydrogen pressure of 2 to 4 atmospheres for reaction for 4 hours, the catalyst was recovered by filtration, the cake was washed with 20 g of methanol, the filtrate was distilled to recover methanol, and then, 32.0 g of colorless liquid, 4-aminobutyronitrile, was obtained by distillation under reduced pressure (60 to 70 ℃ C./5 mmHg), the yield was 95.2%, and the GC purity was 99.6%.
Example 4: preparation of 4-aminobutyronitrile (IV)
220 g of isopropanol, 45.6 g (0.4 mol) of 4-nitrobutyronitrile obtained in example 2, 5.0 g of a 50% Raney nickel catalyst (containing 50% of water) were charged into a 500 ml autoclave, and after 3 times of nitrogen substitution, the mixture was stirred at an internal temperature of 40 to 45 ℃ under a hydrogen pressure of 2 to 4 atmospheres for reaction for 6 hours, cooled to room temperature, filtered to recover the catalyst, the filter cake was washed with 20 g of isopropanol, the isopropanol was recovered from the filtrate by distillation, and the residue was subjected to reduced pressure distillation (60 to 70 ℃/5mmHg) to obtain 31.2 g of colorless liquid, 4-aminobutyronitrile, the yield was 92.9%, and the GC purity was 99.3%.
Example 5: preparation of N-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V1)
A500 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser was charged with 80 g of tetrahydrofuran, 8.4 g (0.1 mol) of 4-aminobutyronitrile prepared in example 3, 34.5 g (0.25 mol) of potassium carbonate, and a mixture of 13.0 g (0.103 mol) of benzyl chloride and 20 g of tetrahydrofuran was added dropwise at 40 to 45 ℃ after completion of the dropwise addition for 1 hour, followed by stirring at 50 to 55 ℃ for reaction for 3 hours to detect completion of the 4-aminobutyronitrile reaction. Cooling to 30-35 ℃, dropwise adding a mixture of 11.5 g (0.105 mol) of methyl chloroacetate and 20 g of tetrahydrofuran, finishing dropwise adding for 1 hour, and then stirring and reacting for 3 hours at 45-50 ℃. Filtering, washing the filter cake with 20 g of tetrahydrofuran for 1 time, combining the filtrates, distilling and recovering the tetrahydrofuran, and distilling the residue under reduced pressure (110-.
Example 6: preparation of N-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 80 g of tetrahydrofuran, 8.4 g (0.1 mol) of 4-aminobutyronitrile prepared in example 3, 34.5 g (0.25 mol) of potassium carbonate, 30 to 35 ℃ were added, a mixture of 16.1 g (0.105 mol) of methyl bromoacetate and 20 g of tetrahydrofuran was dropped for 1 hour, and then stirred at 45 to 50 ℃ for reaction for 3 hours, and the completion of the 4-aminobutyronitrile reaction was detected. And (3) dropwise adding a mixture of 17.5 g (0.102 mol) of benzyl bromide and 20 g of tetrahydrofuran, after dropwise adding for 1 hour, and then stirring and reacting for 3 hours at 50-55 ℃. Filtering, washing the filter cake with 20 g of tetrahydrofuran for 1 time, combining the filtrates, distilling and recovering the tetrahydrofuran, and distilling the residue under reduced pressure (110-.
Example 7: preparation of N-benzoyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V2)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 90 g of dichloromethane, 8.4 g (0.1 mol) of 4-aminobutyronitrile prepared in example 4, 25.5 g (0.25 mol) of triethylamine, 30 to 35 ℃ were added, a mixture of 14.5 g (0.103 mol) of benzoyl chloride and 20 g of dichloromethane was added dropwise thereto, the dropwise addition was completed within 1 hour, and then the reaction was stirred at 35 to 40 ℃ for 3 hours, and the completion of the 4-aminobutyronitrile reaction was detected. Cooling to 30-35 ℃, dropwise adding a mixture of 11.5 g (0.105 mol) of methyl chloroacetate and 20 g of dichloromethane, finishing dropwise adding for 1 hour, and then stirring and reacting for 4 hours at 35-40 ℃. Filtering, washing the filter cake with 20 g of dichloromethane for 1 time, combining the filtrates, distilling and recovering dichloromethane, and distilling the residue under reduced pressure (115 ℃ C./2-3 mmHg) to obtain 24.3 g of viscous liquid N-benzoyl-N-methoxycarbonylmethyl-4-aminobutyronitrile, wherein the yield is 93.5 percent and the GC purity is 99.3 percent.
Example 8: preparation of N-benzoyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V2)
A500 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser was charged with 70 g of methylene chloride, 20 g of water, 8.4 g (0.1 mol) of 4-aminobutyronitrile prepared in example 4, 26.5 g (0.25 mol) of sodium carbonate, 30 to 35 ℃ and a mixture of 16.1 g (0.105 mol) of methyl bromoacetate and 20 g of methylene chloride was dropped for 1 hour, and then stirred at 35 to 40 ℃ for reaction for 4 hours, and the completion of the 4-aminobutyronitrile reaction was detected. Then, a mixture of 14.5 g (0.103 mol) of benzoyl chloride and 20 g of methylene chloride was added dropwise thereto, and after the dropwise addition was completed for 1 hour, the mixture was stirred at 35 to 40 ℃ for reaction for 3 hours. Filtering, washing the filter cake with 20 g of dichloromethane for 1 time, combining the filtrates, distilling and recovering the dichloromethane, and distilling the residue under reduced pressure (115 ℃ C./2-3 mmHg) to obtain 24.6 g of viscous liquid N-benzoyl-N-methoxycarbonylmethyl-4-aminobutyronitrile, wherein the yield is 94.6 percent and the GC purity is 99.5 percent.
Example 9: preparation of N-benzylpiperidin-3-one (I1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 100 g of tetrahydrofuran and 6.5 g (0.12 mol) of sodium methoxide were charged, and the mixture was cooled to 0 to 5 ℃ and 24.6 g (0.1 mol) of N-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile) (obtained in example 5) was added dropwise thereto at the temperature1) And 20 g of tetrahydrofuran solution, and stirring and reacting for 4 hours at 20-25 ℃ after dripping. Filtering, washing a filter cake twice with tetrahydrofuran, 20 g each time, combining filtrates, distilling at normal pressure to recover tetrahydrofuran, adding 100 g of water into the obtained solid, and stirring at 70-80 ℃ for hydrolysis reaction for 3 hours. Then cooling to 20-25 ℃, adjusting the pH value of the system to 2.0-3.0 by using 30% hydrochloric acid, stirring at 20-30 ℃ for decarboxylation reaction for 1 hour, neutralizing the pH value of the system to 8.0-9.0 by using 20% sodium carbonate aqueous solution, adding 100 g of dichloromethane, layering, extracting a water layer for 2 times by using dichloromethane, 30 g of each time, combining dichloromethane layers, distilling and recovering dichloromethane, and distilling the residue under reduced pressure (75-90 ℃/2-3mmHg) to obtain 17.9 g of viscous liquid N-benzyl piperidine-3-ketone (I1), wherein the yield is 94.7%, and the GC purity is 99.8%.
The nuclear magnetic data of the obtained target product are as follows:
1HNMR (400MHz, deuterated DMSO) δ (ppm):
7.25–7.32(m,5H),3.56(s,2H),3.01(s,2H),2.62(m,2H),2.35(t,2H),1.92(m,2H)。
example 10: preparation of N-benzoylpiperidin-3-one (I2)
100 g of tetrahydrofuran and 12.3 g (0.11 mol) of potassium tert-butoxide are added into a 500 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, cooled to 0 to 5 ℃, and 26.0 g (0.1 mol) of a solution of N-benzoyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V2) obtained in example 7 and 20 g of tetrahydrofuran are added dropwise at the temperature, and after the addition, the mixture is stirred and reacted at 20 to 25 ℃ for 4 hours. Filtering, washing a filter cake twice with tetrahydrofuran, 20 g each time, combining filtrates, distilling at normal pressure to recover tetrahydrofuran, adding 120 g of water into the obtained solid, and stirring at 70-80 ℃ for hydrolysis reaction for 2 hours. Then cooling to 20-25 ℃, adjusting the pH value of the system to 2.0-3.0 by using 30% hydrochloric acid, stirring at 20-30 ℃ for decarboxylation reaction for 0.5 hour, neutralizing the pH value of the system to 8.0-9.0 by using 20% sodium carbonate aqueous solution, adding 100 g of dichloromethane, layering, extracting a water layer for 2 times by using the dichloromethane, 30 g each time, combining dichloromethane layers, distilling and recovering the dichloromethane, and carrying out reduced pressure distillation (75-90 ℃/2-3mmHg) on the remainder to obtain 18.9 g of viscous liquid N-benzoyl piperidine-3-ketone (I2), wherein the yield is 93.2%, and the GC purity is 99.7%.
The nuclear magnetic data of the obtained target product are as follows:
1HNMR (400MHz, deuterated DMSO). delta. (ppm) 7.36-7.43 (m,5H),3.62-3.75(m,2H),3.18(m,1H),3.02(dd,1H),1.92(m,1H),1.76(m,1H), 1.38-1.52 (m, 2H).
Comparative example 1: preparation of 4-nitrobutyronitrile (III)
100 g of methylene chloride, 122.0 g (2.0 mol) of nitromethane, 26.5 g (0.5 mol) of acrylonitrile, 0.4 g of potassium fluoride/aluminum trichloride with the potassium fluoride content of 2% are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a condenser and a constant pressure dropping funnel, the mixture is stirred and reacted for 3 hours at the temperature of 20-25 ℃, the acrylonitrile is detected to be completely reacted by GC, the methylene chloride and the nitromethane are recovered by distilling the filtrate at normal pressure, then 22.6 g of colorless liquid 4-nitrobutyronitrile is obtained by reduced pressure distillation (50-65 ℃/5mmHg), the yield is 39.6%, the GC purity is 98.1%, 49.3 g of residue is obtained, and the 4-nitroheptadinitrile is analyzed by GC-MS.
Comparative example 1 shows that the addition of acrylonitrile is beneficial to reducing the side reaction of 4-nitrobutyronitrile and acrylonitrile and improving the yield and purity of the target product.
Comparative example 2: preparation of N-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V1)
In a 500 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 120 g of tetrahydrofuran, 8.4 g (0.1 mol) of 4-aminobutyronitrile prepared in example 3, 34.5 g (0.25 mol) of potassium carbonate and 13.0 g (0.103 mol) of chlorobenzyl were charged, and the reaction was stirred at 50 to 55 ℃ for 3 hours to detect the completion of the 4-aminobutyronitrile reaction. Cooling to 30-35 ℃, adding 11.5 g (0.105 mol) of methyl chloroacetate, and then stirring and reacting at 45-50 ℃ for 3 hours. Filtering, washing the filter cake with 20 g of tetrahydrofuran for 1 time, combining the filtrates, distilling and recovering the tetrahydrofuran, and distilling the residue under reduced pressure (110-.
Comparative example 2 shows that the dropwise addition of the raw materials is beneficial to controlling concentration effect factors of the reaction, reducing side reactions and improving the yield and purity of the target product.
Comparative example 3: preparation of N-benzylpiperidin-3-one (I1)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser were charged 120 g of tetrahydrofuran, 6.5 g (0.12 mol) of sodium methoxide, 24.6 g (0.1 mol) of N-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile (V-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile) (V-benzyl-N-methoxycarbonylmethyl-4-aminobutyronitrile obtained in example 51) And stirring and reacting for 4 hours at the temperature of 20-25 ℃. Filtering, washing a filter cake twice with tetrahydrofuran, 20 g each time, combining filtrates, distilling at normal pressure to recover tetrahydrofuran, adding 100 g of water into the obtained solid, and stirring at 70-80 ℃ for hydrolysis reaction for 3 hours. Then cooling to 20-25 ℃, adjusting the pH value of the system to 2.0-3.0 by using 30% hydrochloric acid, stirring at 20-30 ℃ for decarboxylation reaction for 1 hour, neutralizing the pH value of the system to 8.0-9.0 by using 20% sodium carbonate aqueous solution, adding 100 g of dichloromethane, layering, extracting a water layer for 2 times by using dichloromethane, 30 g of each time, combining dichloromethane layers, distilling and recovering dichloromethane, and distilling the residue under reduced pressure (75-90 ℃/2-3mmHg) to obtain 11.6 g of viscous liquid N-benzyl piperidine-3-ketone (I1), wherein the yield is 61.4%, and the GC purity is 98.6%.
Comparative example 3 shows that the dropwise addition of the intermediate material is beneficial to controlling concentration effect factors of the reaction, reducing side reactions and improving the yield and purity of the target product.
Claims (12)
1. A process for the preparation of an N-substituted piperidin-3-one of formula i, comprising the steps of:
(1) preparing a compound of formula III by subjecting a compound of formula II and nitromethane to an addition reaction; the addition reaction of the compound of formula II and nitromethane comprises the following steps: uniformly mixing the solvent A, the catalyst B and nitromethane, dropwise adding a compound shown in a formula II at 0-80 ℃, and carrying out addition reaction after dropwise adding is completed within 0.5-3 hours;
(2) preparing a compound of formula IV by subjecting a compound of formula III to a catalytic hydrogenation reaction; the catalytic hydrogenation reaction of the compound shown in the formula III is carried out in a solvent C under the action of a catalyst D;
(3) preparing a compound of formula v by subjecting a compound of formula iv to a substitution reaction; converting the compound of formula iv to the compound of formula v comprises the steps of: in a solvent E, under the catalysis of alkali F, the compound of the formula IV sequentially reacts with a compound with a general formula PX and a halogenated acetate for twice substitution reaction to prepare a compound of the formula V, or the compound of the formula IV sequentially reacts with the halogenated acetate and the compound with the general formula PX for twice substitution reaction to prepare the compound of the formula V; wherein in the general formula PX, X is chlorine or bromine, and the meaning of P is the same as that of P in the structural formula of the compound of the formula V; the compound with the general formula PX and the haloacetate are dripped into a reaction system in a dripping mode and then subjected to substitution reaction;
in the structural formula of the compound shown in the formula V, R is methyl, ethyl, isopropyl, n-propyl or tert-butyl, and P is benzyl or benzoyl;
(4) preparing N-substituent piperidine-3-ketone (I) by subjecting a compound of formula V to condensation cyclization, hydrolysis reaction, acidification and decarboxylation with hydrochloric acid; the condensation cyclization reaction of the compound of formula v comprises the steps of: uniformly mixing a solvent G and a base H, dropwise adding a compound of the formula V at (-20) -10 ℃, and then carrying out condensation cyclization reaction after dropwise adding;
2. the method of claim 1, wherein step (1) comprises one or more of the following conditions:
a. the solvent A is one or the combination of more than two of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene or toluene; the mass ratio of the solvent A to the compound shown in the formula II is (0-15) to 1;
b. the catalyst B is potassium fluoride/aluminum oxide with potassium fluoride content of 2 wt%, triethylamine, tri-n-butylammonium, 4-dimethylaminopyridine, DBU, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, wherein the potassium fluoride/aluminum oxide means that the potassium fluoride is loaded on the aluminum oxide; the mass ratio of the catalyst B to the compound of the formula II is (0.5-5.0): 100.
3. The method of preparing an N-substituted piperidin-3-one according to claim 2, characterized by comprising one or more of the following conditions:
a. the mass ratio of the solvent A to the compound shown in the formula II is (3-8) to 1;
b. the mass ratio of the catalyst B to the compound of the formula II is (1.0-2.0): 100.
4. The method of claim 1, wherein step (2) comprises one or more of the following conditions:
a. the solvent C is one or the combination of more than two of methanol, ethanol, isopropanol, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, acetic acid, benzene or toluene; the mass ratio of the solvent C to the compound shown in the formula III is (3-15) to 1;
b. the catalyst D is palladium carbon or Raney nickel; the mass of the catalyst D is 0.5-25% of the mass of the compound of the formula III.
5. The method of claim 4, wherein the method comprises one or more of the following conditions:
a. the mass ratio of the solvent C to the compound shown in the formula III is (4-8) to 1;
b. the mass of the palladium-carbon catalyst is 0.5-5.0% of that of the compound shown in the formula III, and the mass of the Raney nickel catalyst is 5-25% of that of the compound shown in the formula III.
6. The method of claim 5, wherein the palladium-carbon catalyst is present in an amount of 1% to 3% by weight of the compound of formula III, and the Raney nickel catalyst is present in an amount of 10% to 15% by weight of the compound of formula III.
7. The method of claim 1, wherein step (3) comprises one or more of the following conditions:
a. the solvent E is one or the combination of more than two of water, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane or toluene; the mass ratio of the solvent E to the compound shown in the formula IV is (5-35) to 1;
b. the alkali F is inorganic alkali or organic alkali, the inorganic alkali is selected from one or the combination of sodium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate or calcium acetate, and the organic alkali is selected from one or the combination of triethylamine, tri-n-butylamine or pyridine; the molar ratio of the base F to the compound of formula IV is (2.0-3.0) to 1;
c. the molar ratio of the compound with the general formula PX, the haloacetate and the compound with the general formula IV is (1.0-1.2): (1.0-1.2): 1;
d. the twice substitution reaction of the compound of formula IV with the compound of general formula PX and haloacetate in turn and the twice substitution reaction of the compound of formula IV with haloacetate and the compound of general formula PX both have a temperature of 10-90 ℃.
8. The method of claim 7, wherein the method comprises one or more of the following conditions:
a. the mass ratio of the solvent E to the compound shown in the formula IV is (9-20) to 1;
b. the molar ratio of the compound with the general formula PX, the haloacetate and the compound with the general formula IV is (1.0-1.05): (1.0-1.1): 1;
c. the temperature of the twice substitution reaction of the compound of formula IV and the compound of general formula PX and the haloacetate in turn and the twice substitution reaction of the compound of formula IV and the haloacetate and the compound of general formula PX are both 30-60 ℃.
9. The method of claim 1, wherein step (4) comprises one or more of the following conditions:
a. the solvent G is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane or toluene; the mass ratio of the solvent G to the compound of the formula V is (3-20) to 1;
b. the alkali H is sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the molar ratio of the base H to the compound of the formula V is (1.0-2.0): 1.
10. The method of preparing an N-substituted piperidin-3-one according to claim 9, characterized by comprising one or more of the following conditions:
a. the mass ratio of the solvent G to the compound of the formula V is (4-10) to 1;
b. the molar ratio of the base H to the compound of formula V is (1.1-1.3): 1.
11. the method of claim 1, wherein the method comprises one or more of the following conditions:
a. in the step (1), the molar ratio of the nitromethane to the compound shown in the formula II is (1-10) to 1;
b. in the step (1), the temperature of the addition reaction is 0-80 ℃;
c. in the step (2), the temperature of the catalytic hydrogenation reaction is 10-70 ℃, and the hydrogen pressure is 0.1-0.5 MPa;
d. in the step (4), the temperature of the condensation cyclization reaction is (-20) to 80 ℃;
e. in the step (4), the hydrolysis reaction is carried out in the presence of water; the mass ratio of the water to the compound of the formula V is 3-5: 1; the hydrolysis reaction temperature is 20-100 ℃;
f. in the step (4), the acidification and decarboxylation of hydrochloric acid is to perform decarboxylation reaction by using the pH value of a hydrochloric acid acidification system with the mass concentration of 20-30 wt% to 2.0-3.0; the decarboxylation reaction temperature is 0-60 ℃.
12. The method of claim 11, wherein the one or more of the following conditions are included:
a. in the step (1), the molar ratio of the nitromethane to the compound shown in the formula II is (3-5) to 1;
b. in the step (1), the temperature of the addition reaction is 20-40 ℃;
c. in the step (2), the temperature of the catalytic hydrogenation reaction is 20-50 ℃, and the hydrogen pressure is 0.2-0.4 MPa;
d. in the step (4), the temperature of the condensation cyclization reaction is 20-40 ℃;
e. in the step (4), the hydrolysis reaction temperature is 50-80 ℃;
f. in the step (4), the decarboxylation reaction temperature is 20-30 ℃.
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