CN111233751B - Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof - Google Patents
Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
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- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of 3, 3-difluoro-4-aminopiperidine compounds shown in formula (I) and derivatives thereof, wherein the compounds have the following structures:
wherein R is hydrogen, C1‑C9Alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；R2Is C1‑C9Alkyl, aryl or benzyl, R3Is C1‑C9Alkyl, aryl or benzyl; the preparation method of the compounds and the derivatives thereof comprises the following steps of starting from a 3, 3-difluoro-4-hydroxypiperidine structure, introducing a sulfonyloxy leaving group, and then carrying out azide (N)3) The base substitution and the azide reduction. Wherein, the optical pure 3, 3-difluoro-4-hydroxypiperidine and derivatives thereof are used as starting materials, and the optical pure 3, 3-difluoro-4-aminopiperidine and derivatives thereof with reversed configuration are finally obtained after the conversion.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a 3, 3-difluoro-4-aminopiperidine compound and a derivative thereof.
Background
The piperidine structure is an important intermediate in the research and development of new drugs, and the piperidine structure is contained in a plurality of drugs. The introduction of fluorine atoms and fluorine-containing groups into piperidine molecules is a new direction for the development of new drugs. It is widely believed that the introduction of fluorine atoms into drugs can improve the metabolic stability and lipid solubility of drugs, regulate the acid-base property of functional groups, and improve the degree of binding between drug molecules and targets. The introduction of fluorine atoms into organic molecules can bring dramatic changes to the molecular activity and its pharmacological properties, thus having significant advantages in the development of new drugs. The synthesized fluorine substituted piperidine structure, especially the chiral product obtained by a chemical method, also has very wide application in drug molecules.
The 3, 3-difluoro-4-aminopiperidine structure is a very important structural unit in drug design, for example, the compound A with the 3, 3-difluoro-4-aminopiperidine structure is a very effective inhibitor of the activity of histone arginine transferase 1(CARM1), while CARM1 can methylate various protein substrates, is a co-activator of various tumor-associated transcription factors, and plays an important role in abnormal expression in various tumors, especially in the onset and development of breast cancer (WO2016/44641,2016, A2). For another example, a series of compounds B based on A3, 3-difluoro-4-aminopiperidine nucleus have been reported (WO2016/126869 a1) and further studies have shown that this class of compounds are potent NR2B receptor antagonists. Many studies have shown that the N-methyl-D-aspartate (NMDA) receptor plays an important role in synaptic plasticity and learning and memory, especially among them the type 2 receptor B subunit of the NMDA receptor (N-methyl-D-aspartate receptor 2B, NR 2B). Therefore, the compounds show good preliminary results in treating diseases caused by central nervous system disorder, such as Alzheimer's disease, depression and the like.
For the synthesis of 3, 3-difluoro-4-aminopiperidine structures, especially for the case where the amino group at the 4-position is chiral, few methods of synthesis have been reported. In the general synthesis, 3-difluoropiperidone is selected as a starting material, and the preparation (method 1) is realized by a way of reacting with benzylamine, reducing, ammoniating and then hydrogenating to remove benzylamine (WO2018/106818,2018, A1, WO2016/44641,2016, A2, WO2013/171694,2013 and A1).
The patent (EP2123651,2009, A1) also reports that a reduction of 3, 3-difluoropiperidone starting from a hydroxamic intermediate (method 2) gives moderate yields.
Correspondingly, for the preparation of 4-chiral amine products, a patent (WO2016/126869,2016, a1) reports a reductive amination process (process 3) using a chiral phenethylamine introduction process, and the resulting set of diastereomers is further separated by column chromatography, and finally hydrogenated to remove the benzyl group to obtain the desired product. A set of enantiomers can be obtained simultaneously with moderate to good yields. However, the amine of the intermediate diastereoisomer requires silica gel column purification and separation, and then crystallization purification is carried out to ensure the optical purity of the final product.
In the above methods, the introduction of amino groups is achieved by conversion of functional groups from carbonyl groups to amino groups, all starting from 3, 3-difluoropiperidone. However, the methods of reductive amination by introducing benzyl group and reduction by introducing hydroxamic acid in method 1 are limited to laboratory scale preparations, and only the preparation of racemic compound is finally achieved. Although the method 3 can realize the preparation of optical pure products, the separation is carried out by adopting a column-passing purification and separation method in the process, and the mass production of the products is also greatly restricted.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a novel synthetic method of a 3, 3-difluoro-4-aminopiperidine compound and a derivative thereof. The method has the advantages of mild reaction conditions, convenient operation, low cost and good yield, is suitable for preparing chiral and racemic 3, 3-difluoro-4-aminopiperidine, and is suitable for industrial production.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
a3, 3-difluoro-4-aminopiperidine compound or a derivative thereof represented by formula I, wherein the structural formula is as follows:
wherein R is hydrogen, C1-C9Alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；
R2Is C1-C9An alkyl group, an aryl group or a benzyl group,
R3is C1-C9Alkyl, aryl or benzyl.
The invention also provides a preparation method of the 3, 3-difluoro-4-aminopiperidine compound and the derivatives thereof shown in the formula I, which comprises the following steps:
wherein R is1Is C1-C9A fluoroalkyl group;
(1) dissolving a compound shown in a formula (II) and a sulfonylation reagent in an organic solvent, and reacting at-78-100 ℃ in the presence of an organic base to generate a compound shown in a formula (III);
(2) dissolving the compound shown in the formula (III) in an organic solvent, and generating S at 0-150 ℃ under the action of an azidation reagentN2, obtaining a compound shown in a formula (IV) through substitution reaction;
(3) dissolving the compound shown in the formula (IV) in a solvent, carrying out reduction reaction, and reducing N3The radical is amino to obtain the compound shown in the formula (I).
Preferably, the organic solvent in step (1) is selected from ethers or halogenated hydrocarbon solvents; the organic base is any one of triethylamine, diisopropylethylamine, triethylene diamine, DBU and pyridine;
preferably, the weight ratio of the compound represented by the formula (II) in the step 1 to the sulfonylating agent is 0.5 to 5.0.
Preferably, the sulfonyloxy leaving group in step (1) is a trifluoromethylsulfonyloxy group or a perfluoroethylsulfonyloxy group.
Preferably, the sulfonylation reagent in step (1) is fluoroalkyl sulfonyl chloride or fluoroalkyl sulfonic anhydride.
Preferably, the organic solvent in step (2) is a nucleophilic substitution reaction solvent, and the nucleophilic substitution reaction solvent is any one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and HMPA.
Preferably, the azide reagent in the step (2) is selected from sodium azide and TMSN3Either one of them; the feeding weight ratio of the compound shown in the formula (III) to the azidation reagent is 0.8-5.0.
Further, Pd/C, H is selected for the reduction reaction in the step (3)2Any one of a reduction system, a sodium borohydride/Lewis acid reduction system, a lithium aluminum hydrogen reduction method, a Staudinger reduction method and a hydrazine reduction method. The compound shown in the formula (II) and the derivative thereof are (R) -3, 3-difluoro-4-hydroxypiperidine and the derivative thereof, and the final product shown in the formula (I) and the derivative thereof are (S) -3, 3-difluoro-4-aminopiperidine compounds and the derivative thereof; or the compound shown in the formula (II) and the derivative thereof are (S) -3, 3-difluoro-4-hydroxypiperidine and the derivative thereof, and the final product shown in the formula (I) and the derivative thereof are preparedThe compound is (R) -3, 3-difluoro-4-aminopiperidine compound and derivatives thereof.
As follows:
wherein R is hydrogen, C1-C9Alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；
R2Is C1-C9An alkyl group, an aryl group or a benzyl group,
R3is C1-C9Alkyl, aryl or benzyl.
The invention uses 3, 3-difluoro-4-hydroxypiperidine or derivatives thereof containing substituent groups as starting materials to prepare the 3, 3-difluoro-4-aminopiperidine derivatives, and the provided technical scheme has the following technical effects: first, the present invention provides a novel method for the synthesis of 3, 3-difluoro-4-aminopiperidine structures and the preparation of the corresponding optically pure products; secondly, reagents used in each step of reaction are cheap and easy to obtain, the technical scheme of the synthesis reaction is reasonable, and the method can be used for mass production to meet the production requirement of pharmaceutical raw material medicines. Thirdly, the reaction yield of each step is high, the treated and purified impurities are few and controllable, the method can be directly used for the next reaction, the simplified operation can ensure that no pollutant is produced in the preparation process, and the method can be used for mass production to meet the production requirement of pharmaceutical raw material medicines.
Detailed Description
The following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention. In particular, the synthesis of chiral compounds in the examples is understood to be the opposite configuration of intermediates and products, and is within the scope of this patent.
Unless otherwise stated, substituents and groups are as defined in formula (I).
Unless otherwise indicated, the terms "room temperature" and "ambient temperature" mean a temperature between 16 ℃ and 25 ℃.
The present invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Proportions and percentages are by weight unless otherwise indicated.
EXAMPLE 1 preparation of (S) -N-tert-Butoxycarbonyl-3, 3-difluoro-4-trifluoromethylsulfonyloxypiperidine (VI)
Under the protection of nitrogen, the compound (S) -N-tert-butoxycarbonyl-3, 3-difluoro-4-hydroxypiperidine (100g, 0.42mol, 1.00eq) shown in the formula (V) is dissolved in 800mL of dichloromethane, pyridine (100.0g, 1.26mol, 3.00eq) is added, the mixed solvent is cooled to minus 40 ℃, and trifluoromethanesulfonic anhydride (177.7g, 0.63mol, 1.50eq) is slowly added. The resulting pale yellow clear liquid was slowly returned to room temperature and the reaction was monitored for completion after 2 hours of continued stirring at room temperature. The reaction solution was quenched with 600mL of water and separated into layers. The separated organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain 155.0g of a pale yellow solid, which was then subjected to the next reaction without purification of the crude product.
A compound of formula (VI):1H NMR(400MHz,CDCl3)，δ(ppm)：5.02～4.98(m,1H),3.86～3.63(m,3H),3.54～3.47(m,1H),2.17～2.11(m,1H),1.49(s,9H)。
MS-ESI theoretical value (M): 369.3; actual values: 369.7(M + H)+)。
EXAMPLE 2 preparation of (S) -N-benzyl-3, 3-difluoro-4-trifluoromethylsulfonyloxypiperidine (VIII)
Under the protection of nitrogen, a compound (R) -N-benzyl-3, 3-difluoro-4-hydroxypiperidine (100g, 0.44mol, 1.00eq) shown in formula (VII) is dissolved in 800mL of dichloromethane, pyridine (104.4g, 1.32mol, 3.00eq) is added, the temperature of the mixed solvent is reduced to minus 40 ℃, and trifluoromethanesulfonic anhydride (186.1g, 0.66mol, 1.50eq) is slowly added. The resulting pale yellow clear liquid was slowly returned to room temperature and the reaction was monitored for completion after continued stirring at room temperature for 1.5 hours. The reaction solution was quenched with 600mL of water and separated into layers. The separated organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 159.2g of a pale yellow solid, which was then subjected to the next reaction without purification of the crude product.
A compound of formula (VIII):1H NMR(400MHz,CDCl3)，δ(ppm)：7.36～7.26(m,5H),4.95～4.80(m,1H),3.63(s,2H),3.95～3.85(m,1H),2.75～2.65(m,2H),2.60～2.48(m,1H),2.21～2.18(m,2H)。
MS-ESI theoretical value (M): 359.3, respectively; actual values: 359.5(M + H)+)。
It should be noted that the sulfonylation reagent according to the present invention includes, but is not limited to, trifluoromethanesulfonic anhydride described in examples 1 and 2, and may also include fluoroalkyl sulfonyl chloride or fluoroalkyl sulfonic anhydride. The fluoroalkyl sulfonyl chloride or fluoroalkyl sulfonic anhydride can be trifluorofluoroalkyl sulfonyl chloride or trifluoroalkyl sulfonic anhydride; or a perfluoroalkyl sulfonyl chloride or perfluoroalkyl sulfonic anhydride.
Wherein the feeding weight ratio of the compound shown in the formula (V) or the formula (VII) to the sulfonylation reagent is 0.5-5.0. Preferably, the feeding weight ratio is 0.5-2, and the yield of the product prepared in the preferable range is higher.
EXAMPLE 3 preparation of (R) -N-tert-Butoxycarbonyl-3, 3-difluoro-4-azidopiperidine (IX)
The compound N-tert-butoxycarbonyl-3, 3-difluoro-4-trifluoromethylsulfonyloxypiperidine (20g,54.2mmol, 1.00eq) represented by the formula (VI) was dissolved in anhydrous DMF (150mL), and after adding sodium azide (5.28g, 81.2mmol, 1.5eq), the mixture was stirred uniformly. The resulting mixture was warmed to 40 ℃ and stirred for 12 hours. After the reaction is detected to be complete, the reaction is cooled to room temperature, 200mL of saturated sodium chloride and 200mL of ethyl acetate are added for separating, the aqueous phase is extracted for 1 time by ethyl acetate, the combined organic phase is washed by saturated saline (200mL of X2), dried by anhydrous sodium sulfate and filtered, and the crude product is obtained by concentration and can be directly used for the next reaction (light yellow oily matter, 12.78g, 48.8mmol, purity 95 percent and yield 90 percent).
A compound of formula (IX):1H NMR(400MHz,CDCl3)，δ(ppm)：3.79～3.70(m,3H),3.50～3.42(m,2H),1.94(brs,1H),1.81(brs,1H),1.45(s,9H).
MS-ESI theoretical value (M): 262.3; actual values: 285.2(M + Na)+)。
EXAMPLE 4 preparation of (S) -N-benzyl-3, 3-difluoro-4-azidopiperidine (X)
The compound (R) -N-benzyl 3, 3-difluoro-4-trifluoromethylsulfonyloxypiperidine (20g,55.7mmol, 1.00eq) represented by the formula (VIII) was dissolved in anhydrous DMA (150mL), added with sodium azide (5.43g, 83.5mmol, 1.5eq) and stirred uniformly. The mixture was heated to 40 ℃ and stirred for 12 hours to check the completion of the reaction. The reaction was cooled to room temperature, and saturated sodium chloride (200mL) and methyl tert-butyl ether (150mL) were added to separate the layers. The resulting aqueous phase was extracted with methyl tert-butyl ether and the combined organic phases were washed with saturated brine (200mL X2), dried over anhydrous sodium sulfate and filtered and concentrated to remove the solvent to give the crude product (pale yellow solid, 13.07g, 51.8mmol, 95% purity, 93% yield).
A compound of formula (X):1H NMR(400MHz,CDCl3)，δ(ppm)：7.39～7.29(m,5H),3.70(s,2H),3.79～3.50(m,5H),1.97～1.91(m,1H),1.85～1.80(m,1H),
MS-ESI theoretical value (M): 252.3; actual values: 275.3(M + Na)+)。
It is to be noted that the azidation reagent of the present invention includes, but is not limited to, sodium azide, TMSN, described in examples 3 and 43Azide reagents may also effect S as described aboveN2, substitution reaction.
Wherein the feeding weight ratio of the compound shown in the formula (VI) or the formula (VIII) to the azidation reagent is 0.5-5.0. Preferably, the feeding weight ratio is 2-4, and the yield of the product prepared in the preferable range is higher.
EXAMPLE 5 preparation of (R) -N-tert-Butoxycarbonyl-3, 3-difluoro-4-aminopiperidine (XI)
The compound (R) -N-tert-butoxycarbonyl-3, 3-difluoro-4-azidopiperidine (10g,38.1mmol, 1.00eq) represented by the formula (IX) was dissolved in ethyl acetate (100mL), and Pd/C (1.0g, 10% wet) was added under nitrogen protection. The mixture was purged with hydrogen three times and stirred at room temperature for 12 hours. After completion of the detection reaction, the reaction solution was filtered through a small piece of celite to remove the palladium carbon. The resulting colorless mother liquor was concentrated to give the crude product as a pale yellow solid. Recrystallization gave the product of formula (XI) as white crystals (7.92g, 99% purity, ee-99%, yield 88%)
A compound of formula (XI):1H NMR(400MHz,DMSO-d6)，δ(ppm)：3.89(q,J＝8.4Hz，1H),3.64(d,J＝13.6Hz,1H),3.30(brs,1H),3.18～2.98(m,2H),1.72～1.68(m,2H),1.37(s,9H)；
19F NMR(376MHz,DMSO-d6)，δ(ppm)：-111(dd,JFF＝160Hz,234Hz),-121(dd,JFF＝142Hz,234Hz)；
MS-ESI theoretical value (M): 236.3; actual values: 259.3(M + Na)+)。
Example 6: preparation of (S) -N-benzyl-3, 3-difluoro-4-aminopiperidine (XII)
The compound (S) -N-benzyl-3, 3-difluoro-4-aminopiperidine (10g,39.6mmol, 1.00eq) represented by the formula (X) was dissolved in tetrahydrofuran (100mL), and water (3.56g,198mmol,5.0eq) and triphenylphosphine (15.58g,59.4mmol,1.5eq) were added thereto and stirred uniformly. The resulting pale yellow mixture was warmed to 50 ℃ for 12 hours and the reaction was checked to be complete. The reaction was cooled to room temperature, and 100mL of 2M diluted hydrochloric acid and 100mL of ethyl acetate were added to separate the solutions. The aqueous phase was washed with ethyl acetate (100mL X2) and made basic, whereupon a white product precipitated. The cake was collected by filtration and dried, and the crude product obtained was recrystallized to give the compound represented by the formula (XII) (white crystal, 7.44g, 32.9mmol, purity 98%, yield 83%).
A compound represented by the formula (XII):1H NMR(400MHz,DMSO-d6)，δ(ppm)：7.39～7.29(m,5H),3.90(q,J＝8.0Hz,1H),3.75(s,2H),3.60～3.40(m,2H),3.28～2.95(m,2H),1.72～1.68(m,2H)；
19F NMR(376MHz,DMSO-d6)，δ(ppm)：-110(dd,JFF＝160Hz,238Hz),-122(dd,JFF＝140Hz,238Hz)；
MS-ESI theoretical value (M): 226.3; actual values: 249.3(M + Na +).
In the present invention, N is reduced3The method of amino group includes but is not limited to Pd/C, H described in example 5 and example 62Reduction system, Staudinger reduction method, sodium borohydride/Lewis acid reduction system, lithium aluminum hydrogen reduction method, hydrazine reduction method and other commonly used azide reduction methods. The above methods can all realize the reduction of N3The radical is amino.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A preparation method of 3,3, -difluoro-4-aminopiperidine compounds and derivatives thereof shown in formula I is characterized by comprising the following steps:
wherein R is1Is trifluoromethyl;
r is hydrogen, C1-C9Alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；
R2Is C1-C9An alkyl group, an aryl group or a benzyl group,
R3is C1-C9An alkyl group, an aryl group or a benzyl group,
(1) under the protection of nitrogen, dissolving a compound shown as a formula (II) and a sulfonylation reagent in an organic solvent, and reacting at-40 ℃ in the presence of an organic base to generate a compound shown as a formula (III);
(2) dissolving the compound shown in the formula (III) in an organic solvent, and generating S at 40 ℃ under the action of an azidation reagentN2, obtaining a compound shown in a formula (IV) through substitution reaction;
(3) dissolving the compound shown in the formula (IV) in a solvent, carrying out reduction reaction, and reducing N3The radical is amino to obtain the compound shown in the formula (I).
2. The method according to claim 1, wherein the organic solvent in step (1) is selected from ethers or halogenated hydrocarbon solvents; the organic base is selected from any one of triethylamine, diisopropylethylamine, triethylene diamine, DBU and pyridine.
3. The process according to claim 1, wherein the weight ratio of the compound represented by the formula (II) to the sulfonylating agent used in the step (1) is 0.5 to 5.0.
4. The method according to claim 1, wherein the sulfonylating agent in the step (1) is fluoroalkyl sulfonyl chloride or fluoroalkyl sulfonic anhydride.
5. The method according to claim 1, wherein the organic solvent in step (2) is a nucleophilic substitution reaction solvent, and the nucleophilic substitution reaction solvent is any one of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, and HMPA.
6. The method according to claim 1, wherein the azide reagent in the step (2) is selected from the group consisting of sodium azide and TMSN3Either one of them; the feeding weight ratio of the compound shown in the formula (III) to the azidation reagent is 0.8-5.0.
7. The method according to claim 1, wherein the reduction reaction in step (3) is carried out using Pd/C, H2Any one of a reduction system, a sodium borohydride/Lewis acid reduction system, a lithium aluminum hydrogen reduction method, a Staudinger reduction method and a hydrazine reduction method.
8. The preparation method of claim 1, wherein the compound represented by formula (II) and the derivative thereof are (R) -3, 3-difluoro-4-hydroxypiperidine and the derivative thereof, and the final product obtained by the preparation is (S) -3,3, -difluoro-4-aminopiperidine and the derivative thereof; or the compound shown in the formula (II) and the derivative thereof are (S) -3, 3-difluoro-4-hydroxypiperidine and the derivative thereof, and the final product shown in the formula (I) and the derivative thereof are (R) -3, 3-difluoro-4-aminopiperidine compounds and the derivative thereof.
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