CN111377850B - Chiral N-substituted-3,3-difluoro-4-hydroxypiperidine derivative and preparation method thereof - Google Patents
Chiral N-substituted-3,3-difluoro-4-hydroxypiperidine derivative and preparation method thereof Download PDFInfo
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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
Abstract
The invention discloses chiral N-substituted-3,3-difluoro-4-hydroxypiperidine, which is characterized in that the chiral N-substituted-3,3-difluoro-4-hydroxypiperidine is a product of (I) or (II). The invention also discloses a preparation method of the composition. The method realizes the asymmetric reduction of 3,3-difluoro-4,4-dihydroxy structure for the first time, has simple and convenient operation and low cost, is beneficial to the industrial production of the optical pure 3,3-difluoro-4-hydroxypiperidine derivative, and has the characteristics of environmental protection.
Description
Technical Field
The invention relates to the field of chemical synthesis, and in particular relates to a chiral 3,3-difluoro-4-hydroxypiperidine derivative and a preparation method thereof.
Background
1.1 chiral drug overview
Chirality refers to the characteristic of structural asymmetry of a carbon-containing compound molecule due to the three-dimensional arrangement of tetravalent carbon atoms. Chiral drugs refer to a pair of drug enantiomers whose molecular structures are in mirror image relationship with each other and cannot coincide, and are also called drugs containing chiral factors.
In addition, since most of the important structural components constituting a living body are chiral compounds, the pharmacological and physiological effects of chiral drugs after entering the living body are mostly related to the molecular matching and molecular recognition ability between them and receptors. Therefore, the absorption, distribution and metabolism of enantiomers of chiral drugs in organisms all show stereoselectivity and often show different pharmacological effects.
For example, L-dopamine can treat Parkinson's disease, but because dopamine cannot cross blood brain barrier to enter an action site, prodrug dopamine racemate must be taken, enzyme in a human body only reacts with the L-dopamine to generate the L-dopamine, and the D-dopamine accumulates in the human body to cause harm to the human body. Therefore, it is a major issue to be focused on the resolution of chiral drugs to provide single enantiomers with pharmacological activity, thereby controlling the quality of pharmaceutical products.
1.2 preparation of chiral secondary alcohols by asymmetric reduction
Asymmetric reduction of carbonyl compounds involves two broad classes of methods, metal hydride reduction and direct catalytic hydrogenation of carbonyl groups. Asymmetric hydrogenation of carbonyl compounds under the catalysis of transition metal complexes is one of the most effective methods for preparing chiral secondary alcohols, and the reactions generally show very good selectivity, but the catalysts are generally expensive because precious metals such as Rh, ru, ni and Ir are generally selected as metal sources, and chiral ligands with complex structures are often used to control the stereoselectivity.
In addition, considering the issue of chemoselectivity, it is required that other functional groups (e.g., C = C, C-X) in the molecule are not affected.
For the reduction of metal hydrides, the best known method is the asymmetric reduction of carbonyl compounds with boranes modified with chiral ligands. Kagen reported in 1969 that reduction of acetophenone by borane modified with the chiral ligand amphetamine, or borane modified with methamphetamine, unfortunately resulted in very low ee (< 5% ee) (Fiaud j.c., kagan h.b., bull.soc. The successful borane derivatizing reagent oxazaborolidine was first reported by Hirao in 1981, and was later improved by Itsuno and Corey and gradually became an effective method for chiral reduction of carbonyl compounds. (Hirao A., itsuno S., nakahama S., et al.J.Chem., soc.Chem.Commun.,1981,315, itsuno S., hirao A., nakahama S., et al.J.Chem.Soc.Perkin Trans.,1983,1,1673, wallbaum S., maetens J., tetrahedron: asym.1992,3,1475 Corey E.J., link J.O.tetrahedron Lett.,1989,30,6275.
The oxazaborolidine has the functions of Lewis acid and Lewis base, and is released after the reduction reaction caused by drawing ketone and borane. The oxazole borane catalyst behaves like an enzyme, and thus is referred to as a "chemoenzyme", i.e., a small molecule that behaves as an enzyme. Through continuous improvement, the application of the catalyst in the method for preparing the chiral alcohol is also increasingly wide. Corey named this class of catalysts as CBS catalysts, consisting of the first letter of the inventor's name Corey-Bakshi-Shibata.
However, the asymmetric reduction of the geminal bishydroxy structure in the present invention to a hydroxy structure by all of the above reagents has not been reported in the literature.
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 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.
Disclosure of Invention
One of the purposes of the present invention is to provide a method for synthesizing 3,3-difluoro-4-hydroxypiperidine derivatives with high optical activity.
The second purpose of the invention is to provide a preparation method for synthesizing 3,3-difluoro-4-hydroxypiperidine derivatives with high optical activity.
In order to realize one of the purposes of the invention, the adopted technical scheme is as follows:
a chiral N-substituted-3,3-difluoro-4-hydroxypiperidine, wherein said chiral N-substituted-3,3-difluoro-4-hydroxypiperidine is the product of (I) or (II):
wherein R is 1 Including hydrogen, C1-C9 alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one of OCO; wherein, the first and the second end of the pipe are connected with each other,
said R is 2 Including any one of C1-C9 alkyl, aryl or benzyl;
the R is 3 Including any one of C1-C9 alkyl, aryl or benzyl;
in a preferred embodiment of the invention, the ee value of the product is not less than 98%.
In order to realize the second purpose of the invention, the adopted technical scheme is as follows:
a preparation method of chiral N-substituted-3,3-difluoro-4-hydroxypiperidine, wherein the chemical reaction formula of the steps of the overall preparation method is as follows:
namely, the crude product of the formula (IV) is obtained by the catalytic reduction reaction of the formula (III), and then the product of the formula (I) or (II) is obtained by the recrystallization step.
In a preferred embodiment of the present invention, the catalytic reduction step is: the compound (III) reacts under the catalysis of chiral oxazaborolidine catalyst at-80-100 ℃ in the presence of reducing agent to generate a crude compound shown as a formula (IV) -R or (IV) -S.
In a preferred embodiment of the present invention, the reducing agent comprises any one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, DIBAL-H, and lithium aluminum hydride.
In a preferred embodiment of the present invention, the chiral oxazaborolidine catalyst comprises any one or more of the structures shown in the following chemical formula:
in a preferred embodiment of the present invention, the recrystallization step is: putting the crude product (IV) obtained in the step into a solvent, dissolving and clarifying under a heating condition, standing, cooling, separating out a solid, and filtering to obtain a product with higher optical activity; and carrying out secondary recrystallization according to the recrystallization step, and drying the obtained solid product under vacuum condition to obtain the product with high optical activity.
In a preferred embodiment of the present invention, the temperature range of the operation in the recrystallization step is-20 to 100 ℃.
In a preferred embodiment of the present invention, the solvent is selected from any one or more of ethers, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, o-xylene, p-xylene or m-xylene.
In a preferred embodiment of the invention, the preparation method of chiral N-substituted-3,3-difluoro-4-hydroxypiperidine comprises the following specific steps:
a catalytic reduction reaction step: mixing a catalytic amount of chiral 2-methyl-CBS-oxazaborolidine catalyst and a borane tetrahydrofuran solution with the concentration of 1.00M at low temperature, adding the tetrahydrofuran solution of the raw material under the protection of nitrogen, heating and stirring overnight after finishing dropwise addition, and performing post-treatment to obtain a chiral product crude product shown as a formula (IV);
a recrystallization step: putting the crude product (IV) obtained in the step into a solvent, dissolving and clarifying under a heating condition, standing, cooling, separating out a solid, and filtering to obtain a product with higher optical activity; and carrying out secondary recrystallization according to the recrystallization step, and drying the obtained solid product under vacuum condition to obtain the product with high optical activity.
In a preferred embodiment of the present invention, the catalytic reduction step is specifically:
under the protection of nitrogen, 39-41 parts of (S) - (-) -2-methyl-CBS-oxazaborolidine is added into a reaction vessel, the temperature of a reaction system is reduced to be below 0 ℃, and 386-388 parts of borane tetrahydrofuran is slowly added dropwise to prepare a catalytic reaction system solution;
then dissolving 59-61 parts of N-Boc-3,3-difluoro-4,4-dihydroxy piperidine shown in formula (V) in 290-310 parts of tetrahydrofuran to prepare the raw material tetrahydrofuran solution, slowly dripping the raw material tetrahydrofuran solution into the catalytic reaction system solution, slowly heating the reaction system to a temperature higher than room temperature, and stirring overnight; dropwise adding 29-31 parts of methanol at the temperature of below 0 ℃ until no obvious gas is released from the reaction solution, and continuously stirring for 25-35 minutes;
and adding 190-210 parts of ice water into the reaction system, concentrating the reaction solution, adding 290-310 parts of ethyl acetate for dissolving, dropwise adding 47-49 parts of dilute hydrochloric acid, vigorously stirring, carrying out solid-liquid separation and filtration, washing the solid with ethyl acetate, washing the organic phase with a sodium bicarbonate aqueous solution and a saturated saline solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a solid crude product.
In a preferred embodiment of the invention, the aqueous sodium bicarbonate solution is saturated sodium bicarbonate.
In a preferred embodiment of the invention, the dilute hydrochloric acid has a concentration of 1.00M.
In a preferred embodiment of the present invention, the recrystallization step is specifically:
and (2) heating and refluxing a mixture of 55-57 parts of the solid crude product and 139-141 parts of petroleum ether-4-6 parts of ethyl acetate until the system is clear, slowly cooling to room temperature, standing to separate out a solid, standing in a freezer at-10 ℃ for 2.5-3.5 hours, filtering to obtain a first recrystallization product solid, recrystallizing the first recrystallization product solid again according to the conditions, filtering, and drying to obtain the product.
The principle of the invention is as follows:
the method uses a chiral boron reagent catalytic auxiliary reduction method for asymmetric reduction of 3,3-difluoro-4,4-dihydroxy piperidine for the first time. The reaction can realize certain stereoselectivity, and the 3,3-difluoro-4-hydroxypiperidine derivatives with high optical purity (ee is more than 98%) can be finally obtained by further screening conditions for recrystallization and purification. It is important to point out that the substrate 3,3-difluoro-4,4-dihydroxypiperidine structure related by the patent has a special structure of C4-dihydroxy, but not carbonyl in the traditional sense, which is also a pioneering expansion to the application range of the chiral boron reagent catalytic auxiliary reduction method. Has novelty.
The main innovation points of the invention are as follows:
the preparation method is disclosed for the first time, and the preparation method is mild in reaction conditions, convenient to operate, low in cost, good in yield, good in optical purity and suitable for industrial production.
Detailed Description
The invention provides a method for preparing a compound shown as formulas (I) and (II). The preparation of the compounds of the invention is described herein.
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 crude N-tert-Butoxycarbonyl-3,3-difluoro-4-hydroxypiperidine (VI)
Under the protection of nitrogen, (S) - (-) -2-methyl-CBS-oxazaborolidine (40mL, 0.15eq,1.00Min Toluene) is added into a 1L three-mouth reaction bottle, the reaction system is cooled to below zero centigrade, and borane tetrahydrofuran (387mL, 1.50eq,1.00M in THF) is slowly added dropwise. The substrate N-Boc-3,3-difluoro-4,4-dihydroxypiperidine represented by formula (V) (60.0g, 258mmol, 1.00eq) was dissolved in tetrahydrofuran THF (300 mL) to prepare a solution, which was slowly added dropwise to the above reaction system, and the reaction system was slowly warmed to a temperature higher than room temperature and stirred overnight. Methanol (30 mL) was added dropwise at 0 ℃ until no significant gas was evolved in the reaction mixture, stirring was continued for 30 minutes, 200mL of ice water was added to the reaction system, and the reaction mixture was concentrated. 300mL of ethyl acetate was added to dissolve, 1.00M diluted hydrochloric acid (48 mL) was added dropwise, the mixture was stirred vigorously, filtered, and the solid was washed with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 56.2g of crude solid.
EXAMPLE 2 preparation of (R) -N-tert-Butoxycarbonyl-3,3-difluoro-4-hydroxypiperidine (VII)
And heating and refluxing a mixture of crude product (R) -N-tert-butoxycarbonyl-3,3-difluoro-4-hydroxypiperidine (56.0 g) and petroleum ether (140 mL) -ethyl acetate (5 mL) until the system is clear, slowly cooling to room temperature, standing to separate out a solid, placing in a freezer at-10 ℃ for 3 hours, and filtering to obtain a first recrystallization product solid. The solid was recrystallized again according to the above conditions, filtered and dried to obtain the product as a white solid (36.0 g, 98% ee, 64% total yield over two steps starting from the starting material (V)).
A compound of formula (VII): [ alpha ] to] D20 ＝-15.4(c＝1.00,CHCl 3 )； 1 HNMR (400MHz, DMSO-d 6), delta (ppm): 5.69 (d, J =5.2hz, 1h), 3.83-3.65 (m, 2H), 3.55-3.43 (m, 2H), 3.27 (brs, 1H), 1.77-1.69 (m, 1H), 1.58-1.51 (m, 1H), 1.38 (s, 9H); MS-ESI theoretical value (M): 237.1; actual values: 260.1 (M + Na) + )。
EXAMPLE 3 preparation of optically pure (S) -N-t-butyloxycarbonyl-3,3-difluoro-4-hydroxypiperidine (VIII)
According to the same preparation process of the compound (VII), the other chiral enantiomer (S) -N-tert-butyloxycarbonyl-3,3-difluoro-4-hydroxypiperidine (VIII) is obtained by using (R) - (+) -2-methyl-CBS-oxazaborolidine as a chiral catalyst:
a compound of formula (VIII): [ alpha ] to] D20 ＝+15.8(c＝1.00,CHCl 3 )； 1 HNMR (400MHz, DMSO-d 6), delta (ppm): 5.69 (d, J =5.2hz, 1h), 3.83-3.65 (m, 2H), 3.55-3.43 (m, 2H), 3.27 (brs, 1H), 1.77-1.69 (m, 1H), 1.58-1.51 (m, 1H), 1.38 (s, 9H); MS-ESI theoretical value (M): 237.1; actual values: 260.1 (M + Na) + )。
EXAMPLE 4 preparation of optically pure (R) -N-methyl-3,3-difluoro-4-hydroxypiperidine (X)
By the same preparation process as in the case of the compound (VII), optically pure (R) -N-methyl-3,3-difluoro-4-hydroxypiperidine (IX) was obtained as a white solid (ee: 98%,55% total yield).
A compound of formula (IX): [ alpha ] to] D20 ＝+0.5(c＝1.00,CHCl 3 )； 1 HNMR (400MHz, DMSO-d 6), delta (ppm): 5.44 (d, J =5.2Hz, 1H), 3.66-3.56 (m, 1H), 2.76-2.70 (m, 1H), 2.52-2.46 (m, 1H), 2.42-2.34 (m, 1H), 1.77-1.69 (m, 1H), 1.64-1.55 (m, 1H); MS-ESI theoretical value (M): 151.1; actual values: 174.1 (M + Na) + )。
EXAMPLE 5 preparation of optically pure (R) -N-benzyl-3,3-difluoro-4-hydroxypiperidine (XI)
By the same preparation process as in the case of the compound (VII), optically pure (R) -N-benzyl-3,3-difluoro-4-hydroxypiperidine (X) was obtained as a white solid (ee: 98%,63% total yield).
A compound of formula (X): [ alpha ] of] D20 ＝+1.9(c＝1.00,CHCl 3 )； 1 HNMR (400MHz, DMSO-d 6), delta (ppm): 7.35-7.24 (m, 5H), 5.46 (d, J =5.2hz, 1h), 3.69-3.59 (m, 1H), 3.53 (s, 2H), 2.80-2.71 (m, 1H), 2.60-2.55 (m, 1H), 2.46-2.38 (m, 1H), 2.25 (t, J =4.8hz, 1h), 1.77-1.70 (m, 1H), 1.64-1.54 (m, 1H); MS-ESI theoretical value (M): 227.1; actual values: 250.1 (M + Na) + )。
Claims (3)
1. A preparation method of chiral N-substituted-3,3-difluoro-4-hydroxypiperidine is characterized in that,
the preparation method comprises the following steps:
reacting a compound shown in a formula (III) in the presence of a reducing agent under the catalysis of a chiral oxazaborolidine catalyst at-80-100 ℃ to generate a crude compound shown in a formula (IV) -R or (IV) -S;
a recrystallization step: putting a crude compound shown as a formula (IV) -R or (IV) -S into a solvent, dissolving and clarifying under a heating condition, standing, cooling, precipitating a solid, and filtering to obtain a product with optical activity;
performing secondary recrystallization according to the recrystallization step, and pumping the obtained solid product under vacuum condition to obtain the product with optical activity as shown in formula (I) or (II), wherein the ee value of the product is not lower than 98%;
formula (III);
formula (IV) -R or (IV) -S;
formula (I);
formula (II);
wherein R is 1 Is hydrogen, C1-C9 alkyl, benzyl, CF 3 CO、R 2 CO or R 3 Any one of OCO;
the R is 2 Is C1-C9 alkyl;
the R is 3 Is C1-C9 alkyl;
the reducing agent is borane tetrahydrofuran;
the chiral oxazaborolidine catalyst is any one or more of structures shown in the following chemical formulas:
2. the process for preparing chiral N-substituted-3,3-difluoro-4-hydroxypiperidine according to claim 1 wherein the temperature range of operation in said recrystallization step is-20 to 100 ℃.
3. The method for preparing chiral N-substituted-3,3-difluoro-4-hydroxypiperidine according to claim 1, wherein the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, o-xylene, p-xylene or m-xylene.
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| CN106715419A (en) * | 2014-09-26 | 2017-05-24 | 吉利德科学公司 | Aminotriazine derivatives useful as TANK-binding kinase inhibitor compounds |
| CN108069946A (en) * | 2016-11-08 | 2018-05-25 | 威尚（上海）生物医药有限公司 | With the substituted quinazoline compound through blood-brain barrier ability |
| CN108430993A (en) * | 2015-12-17 | 2018-08-21 | 吉利德科学公司 | TANK- combination kinase inhibitor compounds |
| CN108727157A (en) * | 2018-07-06 | 2018-11-02 | 大连理工大学 | The preparation method of glucagon receptor antagonist intermediate |
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| CN106715419A (en) * | 2014-09-26 | 2017-05-24 | 吉利德科学公司 | Aminotriazine derivatives useful as TANK-binding kinase inhibitor compounds |
| CN108430993A (en) * | 2015-12-17 | 2018-08-21 | 吉利德科学公司 | TANK- combination kinase inhibitor compounds |
| CN108069946A (en) * | 2016-11-08 | 2018-05-25 | 威尚（上海）生物医药有限公司 | With the substituted quinazoline compound through blood-brain barrier ability |
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