CN109180564B - Preparation method of piperidine and derivatives thereof - Google Patents
Preparation method of piperidine and derivatives thereof Download PDFInfo
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- CN109180564B CN109180564B CN201811103546.4A CN201811103546A CN109180564B CN 109180564 B CN109180564 B CN 109180564B CN 201811103546 A CN201811103546 A CN 201811103546A CN 109180564 B CN109180564 B CN 109180564B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 discloses a preparation method of piperidine and derivatives thereof, and the preparation method comprises the steps ofCharacterized in that the piperidine is 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine by a series of redox reactions using 3, 3-difluoro-4-hydroxy-5-esterylpiperidine or a substituent-containing derivative thereof as a starting material to prepare 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine and derivatives thereof. The invention has the beneficial effects that: after the reaction in each step is finished, only conventional post-treatment and purification are needed, impurities are few and controllable, the method can be directly used for the next reaction, and the simplified operation can ensure that the reaction in each step can obtain higher yield. The initial raw materials and the used reagents related to the process route of the invention are 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 of pharmaceutical raw material medicines. No pollutant is generated in the preparation process, and the green and environment-friendly effect can be realized.
Description
Technical Field
The invention relates to the field of research and development of novel piperidine medicines, relates to a preparation method of piperidine and derivatives thereof, and particularly relates to 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine and derivatives 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 dramatically change the activity and pharmacological properties of the molecules, and particularly has significant advantages in developing safe and selective drug molecules. For example: compounds of formula (A) bind to 5-HT1D and 5-HT1D receptors to a comparable extent as compared to the parent without the fluoro group, but their oral absorption is much greater than the parent (Monique B. van Niel et al, J.Med.chem.1999,42, 2087-. Compounds of the formula (B) are T-type calcium channel antagonists and can be used for the treatment or prophylaxis of neurological or psychiatric disorders (Barrow J.C., Lindsley C.W., Shipe W.D., Yang Z.; WO 2007002361). The compounds of the formulae (C) and (D) have been found to have potent anti-senile dementia activity. Compounds of formula (E) are reported to have anti-cancer effects (Fatheree, P. et al, US 2006135764; John, V. et al, WO 2003043987; Stanton, M.G. et al, WO 2008030391; Burger, M. et al, WO 2008106692).
Based on the above research results for fluorochemical drugs, more and more pharmacologists and pharmaceutical companies are adding to the line of development of fluorine-containing drugs (e.p. gillis, k.j.eastman, m.d. hill, d.j.donnelly, n.a.meanwell, j.med.chem.,2015,58, 8315; j.wang et al, chem.rev.,2014,114,2432; s.purer, p.r.moore, s.swollow, v.gouverner, chem.soc.rev.,2008,37, 320; K.M muller, c.faeh, f.diederich, Science,2007,317,1881). Considering the outstanding role of fluorine substituted piperidine parent nucleus in medicinal chemistry, in order to further enrich the structural types of the fluoropiperidine, a method for synthesizing more fluorine substituted piperidine parent nucleus was also explored.
In general, the following strategy is generally employed for introducing a methyl group in the α -position to the ketone carbonyl group: the ketone carbonyl is activated by secondary amine to form an imine structure, further tautomerism is carried out to form active enamine, methyl iodide is taken as an electrophilic reagent to easily carry out electrophilic reaction with the enamine structure rich in electrons under the alkaline condition, and finally unstable imine is hydrolyzed to obtain the alpha-methyl substituted ketone.
Then N-tert-butyloxycarbonyl-3, 3-difluoro-4-carbonyl-piperidine is used as a template substrate, N-tert-butyloxycarbonyl-3, 3-difluoro-4-carbonyl-5-methylpiperidine is tried to be synthesized, and after repeated trials, the reaction is not successful.
For this reason, we speculate that this is directly related to the fluorine substitution structure on the piperidine ring. Fluorine atoms have strong electronegativity, and after the fluorine atoms are introduced into molecules, bonding electrons are strongly attracted, so that a strong electron-attracting induction effect is shown, the electron distribution and dipole moment of the whole molecule are obviously changed, and the chemical property and the physical property of the organic molecules are further influenced. It is further speculated that the electron cloud density in the enamine structure in which the substrate participates is strongly induced by the presence of adjacent fluorine atoms, and is significantly lower than that of the non-fluorinated ketone, thereby leading to increased difficulty in electrophilic attack and difficulty in reaction.
Disclosure of Invention
In order to overcome the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a 1-R1A process for the preparation of (E) -3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine and derivatives thereof, which enables an efficient method for introducing an alkyl group in the alpha-position of a fluoropiperidinone.
In order to achieve the above purpose of the present invention, the adopted technical scheme is as follows:
preparation method of piperidine and derivatives thereof, wherein piperidine is 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine, wherein 1-R1-3, 3-difluoro-4-hydroxy-5-methylpiperidine is a compound of the following formula (I), 1-R1-the derivative of 3, 3-difluoro-4-carbonyl-5-methylpiperidine is a compound of formula (II):
wherein R is1Is hydrogen, C1-C9 alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；
R2Is C1-C9Alkyl, aryl or benzyl;
R3is C1-C9Alkyl, aryl or benzyl;
the R is1、R2、R3Each of which is optionally unsubstituted or substituted by oneOne or more substituents optionally consisting of alkyl, haloalkyl, hydroxyalkyl, halogen, alkoxy or hydroxy;
the preparation method of the 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine and derivatives thereof comprises the following steps:
wherein R is1As defined above, R4Is hydrogen, alkyl, R5Is phenyl, substituted aryl or alkyl.
In a preferred embodiment of the invention, when R1Is tert-butyloxycarbonyl, and the preparation method comprises the following steps:
(1) reacting a compound shown as a formula (VI) in a solvent at-20 ℃ to 100 ℃ under a reduction condition to generate a compound shown as a formula (VII);
(2) reacting a compound shown as a formula (VII) with sulfonyl chloride in a certain ratio in a solvent at 0-100 ℃ under the conditions of conventional organic base and inorganic base aqueous solution (pH 8-12) to generate a compound shown as a formula (VIII);
(3) reducing the compound shown in the formula (IV) into alkyl in a solvent in the presence of a reducing agent at the reaction temperature of 0-50 ℃; further protection of alcoholic hydroxyl group occurs to produce a compound of formula (IX)
In a preferred embodiment of the present invention, the reaction in step (1) is carried out in a solvent, wherein the solvent comprises one or a mixture of two or more of tetrahydrofuran, water, alcohols, 1, 4-dioxane, N-dimethylformamide, ethylene glycol monomethyl ether, and halogenated hydrocarbons.
In a preferred embodiment of the present invention, in step (1), the reducing conditions are achieved by adding a reducing agent, wherein the reducing agent is selected from any one or a mixture of two or more of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane solution, catechol borane, 9-BBN, diisobutyl aluminum hydride, (DIBAL-H), lithium tri-sec-butylborohydride (L-Selectride), and potassium tri-sec-butylborohydride (K-Selectride).
In a preferred embodiment of the present invention, the reaction in step (2) is carried out in a solvent, and the solvent in step (2) includes any one or a mixture of two or more of ethers, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, o-xylene, p-xylene, and m-xylene.
In a preferred embodiment of the present invention, the basic conditions in step (2) are achieved by a base, which includes one or a mixture of two or more of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.
In a preferred embodiment of the present invention, the molar ratio of the sulfonyl chloride in the step (2) to the compound represented by the formula (VII) is 1.0-3.0: 3.0-1.0.
In a preferred embodiment of the present invention, the sulfonyl chloride in step (2) is any one or a mixture of two or more of methanesulfonyl chloride, cyclopropane sulfonyl chloride and benzenesulfonyl chloride.
In a preferred embodiment of the present invention, the reaction in step (3) is carried out in a solvent selected from any one or a mixture of any two or more of water, dimethylsulfoxide, ethers, alcohols, toluene, and esters.
In a preferred embodiment of the present invention, the reducing agent in step (3) is selected from any one or a mixture of two or more of hydrogen (Pd/C, Pt/C, etc.), sodium borohydride and potassium borohydride.
The invention has the following main innovation points:
1. the invention uses 3, 3-difluoro-4-hydroxy-5-ester piperidine or derivatives containing substituent groups as starting materials to prepare 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methyl piperidine and derivatives thereof, and after the reaction in each step is finished, only routine post-treatment and purification are needed, impurities are few and controllable, the method can be directly used for the next reaction, and the simplified operation can ensure that each reaction step obtains higher yield.
2. The initial raw materials and the used reagents related to the process route of the invention are 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 of pharmaceutical raw material medicines.
3. No pollutant is generated in the preparation process, and the green and environment-friendly effect can be realized.
Detailed Description
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.
The invention provides a method for preparing a compound shown as a formula (I). The preparation of the compounds of the invention is described herein.
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 ℃.
Example 1
Preparation of N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy-5-hydroxymethylpiperidine (VII)
N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy 5-carboxylic acid ethyl ester piperidine (VI) (100g, 0.32mol, 1.00eq) was dissolved in 800 ml of methanol, calcium chloride (10.0g, 0.09mol, 0.27eq) was added, and sodium borohydride (37.0g, 1.00mol, 3.00eq) was added in portions under nitrogen. The reaction was monitored for completion after stirring the resulting colorless clear liquid at room temperature for 12 hours. Slowly adjusting the pH of the reaction liquid to 4-5 by using 1.00 mol/L diluted hydrochloric acid, removing most of methanol solution by rotary evaporation, extracting the reaction liquid by using ethyl acetate (300 ml x2), combining organic phases, washing the organic phases once by using saturated saline (500 ml), drying the organic phases by using anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 75.0g of light yellow oily matter, wherein the crude product can be directly subjected to the next reaction without purification.
A compound of formula (VII): 1H NMR (300MHz, CDCl3), δ (ppm): 3.98-3.73 (m,5H), 3.03-2.97 (m,2H),2.65(brs,1H), 2.05-2.00 (m,2H),1.46(s, 9H).
MS-ESI theoretical value (M): 267.1, respectively; actual values: 289.9(M + Na +).
Example 2
Preparation of N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy-5-p-toluenesulfonyloxymethylpiperidine (VIII)
N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy-5-hydroxymethylpiperidine (23.5g, 88.0mmol, 1.0eq) was dissolved in 100 ml of dry dichloromethane, the reaction was allowed to cool to room temperature, and triethylamine (13.3g, 132mmol, 1.50eq) was added. P-toluenesulfonyl chloride (17.6g, 92.4mmol, 1.05eq) was dissolved in anhydrous dichloromethane (100 ml) and the resulting colorless solution was added dropwise to the above reaction solution. As the dropwise addition proceeded, the reaction solution gradually appeared as a white solid suspension. After the mixture was slowly warmed to room temperature and stirred for further 12 hours, the reaction was checked to be complete. And (3) adjusting the pH of the reaction solution to 4-5 of an aqueous phase by using dilute hydrochloric acid (0.50 mol/L) at low temperature, separating the solution, extracting the aqueous phase once by using dichloromethane, combining organic phases, washing in a saturated laboratory, drying, filtering, and evaporating the solvent to dryness under reduced pressure to obtain a crude product. The crude product was recrystallized from methyl tert-butyl ether to give 33.3g of white solid (VIII), 90% yield
A compound of formula (VII):1HNMR(400MHz,CDCl3)，δ(ppm)：7.79(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),4.15～3.90(m,5H),3.20～3.15(m,1H),2.70～2.65(m,1H),2.45(s,3H),2.43-2.05(m,2H),1.42(s,9H)。
MS-ESI theoretical value (M): 421.1, respectively; actual values: 444.1(M + Na +).
Example 3
Preparation of N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy 5-methylpiperidine (IX)
N-tert-Butoxycarbonyl-3, 3-difluoro-4-hydroxy-5-p-toluenesulfonyloxymethylpiperidine (VIII) (17.0g, 38.0mmol, 1.00eq) was dissolved in 80 ml of dimethyl sulfoxide, and after stirring uniformly, the reaction system was placed in an ice-water bath. Sodium borohydride solid (6.20g, 114mmol, 3.00eq) was added in portions over 30 minutes and the resulting pale yellow reaction solution was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with 200 ml of water, the aqueous phase was extracted three times with 100 ml of ethyl acetate, and the combined organic phases were washed twice with 200 ml of saturated brine. The obtained organic phase is dried by anhydrous sodium sulfate and then filtered, and the solvent is removed by reduced pressure distillation to obtain a crude product. The product was purified by simple chromatography using ethyl acetate, petroleum ether, to give 6.00g of the target product (IX) in 60% yield.
A compound of formula (VII):1HNMR (400MHz, CDCl3), δ (ppm): 4.32(brs,1H),4.15 to 3.80(M,2H),3.48 to 3.30(M,1H),3.05(dd, J ═ 1.2,12.8Hz,1H),2.80 to 2.45(M,1H),2.25 to 1.95(M,1H),1.70(s,9H),1.00(d, J ═ 6.8Hz,3H), MS-ESI theoretical value (M): 251.1 of a base material; actual values: 274.1(M + Na +).
Example 4:
preparation of N-tert-Butoxycarbonyl-3, 3-difluoro-5-methyl-4-piperidone (X)
The product (IX) was oxidized by Dess-Martin to give N-t-butyloxycarbonyl-3, 3-difluoro-4-carbonyl-5-methylpiperidine (X) in 70% yield as an off-white solid.
1HNMR (400MHz, CDCl3), δ (ppm): 6.12(s,2H),3.95(brs,1H),3.75(brs,1H),2.95 to 2.65(M,2H),1.85(brs,1H),1.36(s,9H),0.84(d, J ═ 6.8Hz,3H), MS-ESI theoretical value (M): 249.1, actual value: 167.9(M + H + -Boc).
Claims (9)
1. The preparation method of the piperidine and the derivatives thereof is characterized in that the piperidine is 1-R1-3, 3-difluoro-4-hydroxy or carbonyl-5-methylpiperidine; wherein 1-R1-3, 3-difluoro-4-hydroxy-5-methylpiperidine is a compound of the following formula (I), 1-R1-the derivative of 3, 3-difluoro-4-carbonyl-5-methylpiperidine is a compound of formula (II):
wherein R is1Is hydrogen, C1-C9 alkyl, aryl, benzyl, CF3CO、R2CO or R3OCO；
R2Is C1-C9Alkyl, aryl or benzyl;
R3is C1-C9Alkyl, aryl or benzyl;
the R is1、R2、R3Each of which is optionally unsubstituted or substituted with one or more substituents optionally consisting of alkyl, haloalkyl, hydroxyalkyl, halogen, alkoxy or hydroxy;
the preparation method of the piperidine and the derivatives thereof comprises the following steps:
wherein R is1As defined above, R4Is hydrogen or alkyl, R5Is phenyl, substituted aryl or alkyl;
the reducing agent adopted for reducing the compound of the formula (III) into the compound of the formula (IV) is any one or mixture of more than two of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane solution, catechol borane, 9-BBN, diisobutylaluminum hydride, DIBAL-H, lithium tri-sec-butylborohydride and potassium tri-sec-butylborohydride;
the hydroxyl protecting reagent used in the selective protection of the primary alcohol is sulfonyl chloride;
the reducing agent adopted for reducing the compound of the formula (V) into the compound of the formula (I) is any one or mixture of more than two of hydrogen and Pd/C, hydrogen and Pt/C, sodium borohydride and potassium borohydride;
the oxidation adopts Dess-Martin reagent as an oxidation reagent.
2. The process for the preparation of piperidines and their derivatives as claimed in claim 1, wherein when R is1Is tert-butyloxycarbonyl, and the preparation method comprises the following steps:
(1) reacting a compound shown as a formula (VI) in a solvent at-20 ℃ to 100 ℃ under a reduction condition to generate a compound shown as a formula (VII);
(2) reacting a compound shown in a formula (VII) with paratoluensulfonyl chloride according to a certain proportion in a solvent at 0-100 ℃ in the presence of a conventional organic base or inorganic base aqueous solution to generate a compound shown in a formula (VIII);
(3) reducing the compound shown in the formula (VIII) into alkyl in a solvent in the presence of a reducing agent at the reaction temperature of 0-50 ℃; to produce a compound represented by the formula (IX)
3. The process for preparing piperidine and its derivatives as claimed in claim 2, wherein the reaction in step (1) is carried out in a solvent selected from tetrahydrofuran, water, alcohols, 1, 4-dioxane, N-dimethylformamide, ethylene glycol monomethyl ether and halogenated hydrocarbons.
4. The method for preparing piperidine and derivatives thereof according to claim 2, wherein in step (1), the reducing conditions are achieved by adding a reducing agent, wherein the reducing agent is any one or a mixture of two or more of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane solution, catechol borane, 9-BBN, diisobutylaluminum hydride, DIBAL-H, lithium tri-sec-butylborohydride and potassium tri-sec-butylborohydride.
5. The method for preparing piperidine and derivatives thereof according to claim 2, wherein the reaction in step (2) is carried out in a solvent, and the solvent in step (2) is one or a mixture of more than two of tetrahydrofuran, ethylene glycol dimethyl ether, toluene, o-xylene, p-xylene or m-xylene.
6. The method of claim 2, wherein the organic or inorganic base in step (2) is one or more of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
7. The method for preparing piperidine and derivatives thereof according to claim 2, wherein the molar ratio of p-toluenesulfonyl chloride to the compound of formula (VII) in step (2) is 1.0-3.0: 3.0-1.0.
8. The process for preparing piperidine and its derivatives according to claim 2, wherein the reaction in step (3) is carried out in a solvent selected from the group consisting of water, dimethylsulfoxide, ethers, alcohols, toluene, and esters.
9. The method for preparing piperidine and derivatives thereof according to claim 2, wherein the reducing agent in step (3) is any one of hydrogen and Pd/C, hydrogen and Pt/C, sodium borohydride and potassium borohydride.
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| CN102731368A (en) * | 2012-07-10 | 2012-10-17 | 扬州氟药科技有限公司 | Preparation method of 5,5-difluoro-3-substituted piperidine derivative |
| CN103936662A (en) * | 2013-01-23 | 2014-07-23 | 艾琪康医药科技（上海）有限公司 | 1-R1-3, 3-difluoro-4-R2-piperidine and its derivatives and its prepn |
| CN103965096A (en) * | 2014-05-09 | 2014-08-06 | 湖南华诚生物资源有限公司 | 1-deoxynojirimycin preparing method suitable for industrial production |
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| CN102731368A (en) * | 2012-07-10 | 2012-10-17 | 扬州氟药科技有限公司 | Preparation method of 5,5-difluoro-3-substituted piperidine derivative |
| CN103936662A (en) * | 2013-01-23 | 2014-07-23 | 艾琪康医药科技（上海）有限公司 | 1-R1-3, 3-difluoro-4-R2-piperidine and its derivatives and its prepn |
| CN103965096A (en) * | 2014-05-09 | 2014-08-06 | 湖南华诚生物资源有限公司 | 1-deoxynojirimycin preparing method suitable for industrial production |
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Effective date of registration: 20210913 Address after: Room 708, No. 780 Cailun Road, pilot Free Trade Zone, Pudong New Area, Shanghai 201200 Patentee after: SHANGHAI AQBIOPHARMA Co.,Ltd. Address before: 323000 No. 8, Jinting Road, Shuige Industrial Park, Liandu District, Lishui City, Zhejiang Province Patentee before: AQFLUOROTECH Co.,Ltd. |