CN111233750B - 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof - Google Patents

3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof Download PDF

Info

Publication number
CN111233750B
CN111233750B CN202010143683.1A CN202010143683A CN111233750B CN 111233750 B CN111233750 B CN 111233750B CN 202010143683 A CN202010143683 A CN 202010143683A CN 111233750 B CN111233750 B CN 111233750B
Authority
CN
China
Prior art keywords
formula
difluoro
tetrahydropiperidine
derivative
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010143683.1A
Other languages
Chinese (zh)
Other versions
CN111233750A (en
Inventor
吴香梅
于峰
晏飞军
刘井洲
卢艺
苏醒
卢寿福
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aqfluorotech Co ltd
Yangzhou Aqfluoropharma Co ltd
Shanghai Aqbiopharma Co ltd
Original Assignee
Aqfluorotech Co ltd
Yangzhou Aqfluoropharma Co ltd
Shanghai Aqbiopharma Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aqfluorotech Co ltd, Yangzhou Aqfluoropharma Co ltd, Shanghai Aqbiopharma Co ltd filed Critical Aqfluorotech Co ltd
Priority to CN202010143683.1A priority Critical patent/CN111233750B/en
Publication of CN111233750A publication Critical patent/CN111233750A/en
Application granted granted Critical
Publication of CN111233750B publication Critical patent/CN111233750B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative, which is characterized in that the structure of the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative is shown as a formula I, and R is hydrogen or C 1 ‑C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one of the OCOs; the R is 2 Is hydrogen, C 1 ‑C 9 Any one of alkyl, aryl or benzyl; the R is 3 Is C 1 ‑C 9 Any one of alkyl, aryl or benzyl: each of the foregoing groups is optionally unsubstituted or substituted with one or more substituents consisting of any one or more of free alkyl, haloalkyl, hydroxyalkyl, halogen, alkoxy, or hydroxy. The invention also discloses a preparation method of the catalyst. The invention discloses a method for synthesizing a difluoro substituted unsaturated piperidine structure for the first time, which has simple process, easy industrialized operation and low cost.

Description

3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof
Technical Field
The invention relates to the field of pharmacy, in particular to a 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and a preparation method thereof.
Background
In the field of pharmaceutical chemistry research, methods for introducing fluorine atoms are commonly used to improve the metabolic stability of drugs, to improve the lipid solubility, to regulate the acid-base properties of functional groups, and to improve the degree of binding of drug molecules to targets. The unique fluorine atom can be introduced into organic molecules to bring dramatic changes to the activity and the pharmaceutical properties of the molecules, and the method has obvious advantages in the aspect of developing drug molecules with safety and selectivity. Thus attracting more and more pharmaceutical chemists and companies to add lines of fluorine-containing drug development (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.Purser,P.R.Moore,S.Swallow,V.Gouverneur,Chem.Soc.Rev, 2008,37,320; K.Muller, C.Faeh, F.Diederich, science,2007,317,1881.)
Piperidine structures are an important class of intermediates in the development of new drugs. The structure is contained in many medicines, and the introduction of fluorine atoms and fluorine-containing groups into piperidine molecules is a new direction for developing new medicines.
The prior art shows that the compounds of the formula (A) are compared with the 5-HT 1D And 5-HT 1D The receptor binding capacity is comparable, but the oral absorption is much higher than that of the parent (Monique B.van Niel, et al, J.Med. Chem.1999,42, 2087-2104). The compounds of formula (B) are T-type calcium channel antagonists useful for the treatment or prevention of neurological or psychiatric disorders (Barrow J.C., lindsley C.W., shipe W.D., yang Z.; WO 2007002361). Compounds of structural formulae (C) and (D) have been found to have potent anti-Alzheimer's disease activity. Compounds of formula (E) are reported to have anticancer effects (Fatheree, P. Et al, U.S. Pat. No. 2006135764; john, V. Et al, WO2003043987; stanton, M.G. et al, WO2008030391; burger, M. Et al, WO 2008106692).
However, in the existing structure, difluoro structures on unsubstituted unsaturated piperidine rings have not been reported.
Disclosure of Invention
In order to overcome the above-mentioned drawbacks of the prior art, an object of the present invention is to provide 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivatives.
The second object of the present invention is to provide a method for producing the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivatives.
Compared with the existing method, the method has the advantages of milder reaction conditions, convenient industrial production operation and low cost.
In order to achieve one of the purposes of the invention, the technical scheme of the invention is as follows:
3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivatives, wherein the structure of the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivatives is shown as formula I, and R is hydrogen or C 1 -C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one of the OCOs;
the R is 2 Is hydrogen, C 1 -C 9 Any one of alkyl, aryl or benzyl;
the R is 3 Is C 1 -C 9 Any one of alkyl, aryl or benzyl;
each of the above groups is unsubstituted or substituted with one or more substituents consisting of any one or more of free alkyl, haloalkyl, hydroxyalkyl, halogen, alkoxy or hydroxy.
In order to achieve the second object of the invention, the technical scheme adopted is as follows:
the preparation method of the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative comprises the steps of taking the 3, 3-difluoro-4-hydroxypiperidine derivative shown in a formula II as a raw material, introducing a sulfonyloxy leaving group to obtain an intermediate product shown in a formula III, and then carrying out elimination reaction under alkaline conditions to obtain the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative shown in a formula I finally, wherein the specific typical reaction formula is shown in a reaction formula 1:
in a preferred embodiment of the present invention, the reaction formula 1 specifically includes the following steps:
step one, an intermediate product preparation step:
in a first organic solvent, 3-difluoro-4-hydroxy piperidine derivatives shown in formula II and sulfonyloxy compounds are mixed according to the formula 1: the ratio of 0.8 to 5.0 is in a temperature range of-78 ℃ to 100 ℃ under first alkaline conditions to produce an intermediate product shown as a formula III.
The first organic solvent comprises any one or more of ether solvents or halogenated hydrocarbon solvents;
the sulfonyloxy compound is sulfonyl chloride or sulfonic anhydride, the sulfonylating agent is used for introducing sulfonyloxy leaving group, and the sulfonyloxy leaving group is substituted C 1 -C 6 Fluoroalkyl sulfonyloxy groups of (a);
the first alkaline condition is an alkaline condition using a first organic alkaline reagent.
Step two, a final product preparation step:
the intermediate of formula III with a base reagent under second organic solvent and second alkaline conditions at 1: removing the sulfonyloxy leaving group by an elimination reaction at a ratio of 0.8-5.0 to produce a 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative represented by formula I;
the second organic solvent comprises any one or more of ethers, hydrocarbons, halogenated hydrocarbons, benzene or polysubstituted benzene solvents;
the second alkaline condition is an alkaline condition using a second organic alkaline reagent.
In a preferred embodiment of the present invention, the first organic base reagent comprises any one or more of triethylamine, diisopropylethylamine, tripropylamine, tributylamine, N-methylmorpholine, 1, 8-diazabicyclo undec-7-ene (DBU), pyridine or substituted pyridine.
In a preferred embodiment of the present invention, the second organic base reagent comprises any one or more of N-methylmorpholine, tetramethylguanidine (TMG), 1, 8-diazabicyclo undec-7-ene (DBU) or triethylenediamine (DABCO).
In a preferred embodiment of the present invention, the polysubstituted aromatic hydrocarbon solvent comprises any one or more of toluene, xylene or halogenated benzene.
In a preferred embodiment of the invention, the substitution C 1 -C 6 The fluoroalkyl sulfonyloxy group of (a) includes any one of a trifluoromethyl sulfonyloxy group and a perfluoroethyl sulfonyloxy group.
The invention has the beneficial effects that:
firstly, the invention provides a method for synthesizing a difluoro substituted unsaturated piperidine structure, which provides a new idea for enriching a fluorine-containing piperidine medical mother nucleus structure;
secondly, after each step of reaction is finished, only conventional post-treatment and purification are needed, the method can be directly used for the next step of reaction, and the simplified operation can basically ensure that each step of reaction obtains higher yield;
thirdly, the starting materials and the used reagents related to the process route are easy to obtain, the technical scheme of the synthesis reaction is reasonable, and the process route can be used for mass production to meet the production of the medical raw materials. The environmental impact is controllable in the preparation process, and the green and environment-friendly effects can be realized.
Detailed Description
The invention will be better understood by the following examples, which are not intended to limit the scope of the invention.
Unless otherwise indicated, substituents and groups are defined as in formula (I).
The terms "room temperature" and "ambient temperature" refer to temperatures between 16 ℃ and 25 ℃ unless otherwise indicated.
The principle of the invention is as follows:
in the prior art, due to the strong electron withdrawing property of fluorine atoms, particularly the presence of difluoromethylene, the ortho-position leaving group is not easy to leave, and even elimination reaction is difficult.
When a common methanesulfonyloxy group is used as a leaving group, elimination reaction does not occur under the preparation conditions described in the present invention, and only a fluoroalkyl sulfonyloxy group which is more easily removed can be smoothly carried out.
The invention is further illustrated below in conjunction with specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The proportions and percentages are by weight unless otherwise indicated.
EXAMPLE 1 preparation of N-Boc-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (V)
Under the protection of nitrogen, the compound N-tertiary Ding Yang carbonyl-3, 3-difluoro-4-hydroxy piperidine (100 g,0.42mol,1.00 eq) shown in formula (IV) is dissolved in 800mL of dichloromethane, pyridine (100.0 g,1.26mol,3.00 eq) is added, the mixed solvent is cooled to minus 40 ℃, and trifluoromethanesulfonic anhydride (177.7 g,0.63mol,1.50 eq) is slowly added. The resulting pale yellow clear liquid slowly returned to room temperature, and after stirring at room temperature for 2 hours, the reaction was monitored to end. The reaction mixture was quenched with 600mL of water and separated. The separated organic phase was washed once with saturated laboratory, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 155.0g of pale yellow solid, and the crude product was directly subjected to the next reaction without purification.
A compound of formula (V): 1 H NMR(400MHz,CDCl 3 )，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 value: 369.7 (M+H) + )。
EXAMPLE 2 preparation of N-benzyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (VII)
Under the protection of nitrogen, the compound N-benzyl-3, 3-difluoro-4-hydroxy piperidine (100 g,0.44mol,1.00 eq) shown in formula (VII) is dissolved in 800mL dichloromethane, pyridine (104.4 g,1.32mol,3.00 eq) is added, the mixed solvent is cooled to minus 40 ℃, and trifluoromethanesulfonic anhydride (186.1 g,0.66mol,1.50 eq) is slowly added. The resulting pale yellow clear liquid slowly returned to room temperature, and after stirring at room temperature for 1.5 hours, the reaction was monitored to end. The reaction mixture was quenched with 600mL of water and separated. The separated organic phase was washed once with saturated laboratory, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 159.2g of pale yellow solid, and the crude product was directly subjected to the next reaction without purification.
A compound of formula (VIII): 1 H NMR(400MHz,CDCl 3 )，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; actual value: 359.5 (M+H) + )。
Example 3: preparation of N-methyl-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine (X)
Under nitrogen protection, the compound N-methyl-3, 3-difluoro-4-hydroxypiperidine (10 g,66.2mmol,1.00 eq) of formula (X) was dissolved in 100mL of dichloromethane, pyridine (28.0 g,198.6mmol,3.00 eq) was added, the mixed solvent was cooled to-40℃and trifluoromethanesulfonic anhydride (186.1 g,99.3mmol,1.50 eq) was slowly added. The resulting pale yellow clear liquid slowly returned to room temperature, and after stirring at room temperature for 1.5 hours, the reaction was monitored to end. The reaction mixture was quenched with 100mL of water and separated. The separated organic phase was used in a saturated laboratoryWashing once, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a pale yellow oily substance, and purifying the crude product by a silica gel column to obtain a compound (9.37 g,50% yield) shown in the formula (XI): 1 H NMR(400MHz,CDCl 3 )，δ(ppm)：4.92～4.86(m,1H),2.89～2.81(m,2H),2.78～2.48(m,2H),2.38(s,3H),2.21～2.18(m,2H)。
EXAMPLE 4 preparation of N-Boc-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine (VI)
The compound N-t-butoxycarbonyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (100 g,0.27mol,1.00 eq) of formula (V) was dissolved in anhydrous toluene (800 mL), and 1, 8-diazabicyclo undec-7-ene (DBU) (61.8 g,0.41mol,1.5 eq) was added thereto and stirred well. The resulting pale yellow mixture was heated to 100℃and reacted for 12 hours, and the reaction was detected to be complete. The reaction was cooled to room temperature, washed with saturated sodium chloride and separated. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated to dryness to obtain crude product. The product was purified by distillation under reduced pressure to give the compound of formula (VI) (53.4 g,24.4mmol, purity 98%, yield 90%).
A compound of formula (VII): 1H NMR (400 MHz, CDCl) 3 )，δ(ppm)：6.16(brs,1H),5.90(brs,1H),3.98(s,2H),3.79(t,J＝10.8Hz,2H),1.44(s,9H).
MS-ESI theoretical value (M): 219.2; actual value: 242.1 (M+Na) + )。
EXAMPLE 5 preparation of N-Boc-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine (VI)
The compound N-t-butoxycarbonyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (100 g,0.27mol,1.00 eq) of formula (V) was dissolved in xylene (800 mL), and triethylenediamine (DABCO) (45.6 g,0.41mol,1.5 eq) was added thereto and stirred well. The resulting pale yellow mixture was heated to 120℃and reacted for 6 hours, and the reaction was detected to be complete. The reaction was cooled to room temperature, washed with saturated sodium chloride and separated. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated to dryness to obtain crude product. The product was purified by distillation under reduced pressure to give the compound of formula (VI) (50.3 g,0.23mol, purity 98%, yield 85%).
Example 6: preparation of N-benzyl-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine (IX)
The compound N-benzyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (100 g,0.28mol,1.00 eq) of formula (VIII) was dissolved in anhydrous toluene (800 mL), and 1, 8-diazabicyclo undec-7-ene (DBU) (63.5 g,0.42mol,1.50 eq) was added thereto and stirred well. The resulting pale yellow mixture was heated to 100℃and reacted for 12 hours, and the reaction was detected to be complete. The reaction was cooled to room temperature, washed with saturated sodium chloride and separated. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated to dryness to obtain crude product. The product was purified by distillation under reduced pressure to give the compound of formula (VI) (53.9 g,25.8mmol, purity 98%, yield 92%).
A compound of formula (VII): 1 H NMR(400MHz,CDCl 3 )，δ(ppm)：7.39～7.29(m,5H),6.21～6.15(m,1H),5.90～5.80(m,1H),3.70(s,2H),3.10～3.07(m,2H),2.90(t,J＝11.6Hz,2H)。
MS-ESI theoretical value (M): 209.2; actual value: 232.2 (M+Na) + )。
Example 7: preparation of N-benzyl-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine (IX)
The compound N-benzyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (100 g,0.28mol,1.00 eq) of formula (VIII) was dissolved in anhydrous xylene (800 mL), and triethylenediamine (DABCO) (47.1 g,0.42mol,1.50 eq) was added thereto and stirred well. The resulting pale yellow mixture was heated to 120℃and reacted for 6 hours, and the reaction was detected to be complete. The reaction was cooled to room temperature, washed with saturated sodium chloride and separated. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated to dryness to obtain crude product. The product was purified by distillation under reduced pressure to give the compound of formula (IX) (50.9 g,24.4mmol, purity 98%, yield 87%).
Example 8: preparation of N-methyl-3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine hydrochloride (XII)
The compound N-benzyl-3, 3-difluoro-4-trifluoromethylsulfonyloxy piperidine (10.0 g,35.3mmol,1.00 eq) of formula (XI) was dissolved in anhydrous toluene (80 mL), and 1, 8-diazabicyclo undec-7-ene (DBU) (8.06 g,53.0mmol,1.50 eq) was added and stirred well. The resulting pale yellow mixture was heated to 100℃and reacted for 12 hours, and the reaction was detected to be complete. The reaction was cooled to room temperature, washed with saturated sodium chloride and separated. The organic phase is dried by anhydrous sodium sulfate and filtered, and the organic phase is communicated with hydrogen chloride gas to separate out salt from the product. The filter cake was collected by filtration and washed with ethyl acetate, and after drying, the compound (2.99 g,17.7mmol, purity 98%, yield 50%) shown in (XII) was obtained.
A compound of formula (XII): 1 H NMR(400MHz,DMSO-d6)，δ(ppm)：6.43～6.39(m,1H),6.21～6.16(m,1H),3.80(brs,2H),3.70(brs,2H),2.75(s,3H)。
the invention has the advantages that:
the implementation of the method enriches the types of the fluoropiperidine structures, and provides a new idea for obtaining more derivatives and bioactive molecules of the fluoropiperidine structures from unsaturated bonds in the follow-up process.

Claims (1)

1. The preparation method is characterized in that a raw material shown in a formula II is adopted to obtain a raw material shown in a formula III by introducing a sulfonyloxy leaving group, the raw material shown in the formula III is subjected to elimination reaction under alkaline conditions to obtain a 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative shown in a formula I finally, and a specific typical reaction formula is shown in a reaction formula 1:
the raw materials shown in the formula III are subjected to elimination reaction under alkaline conditions to obtain the final 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative shown in the formula I, the final 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative is carried out under organic solvents and organic alkaline conditions, and the intermediate product shown in the formula III and an alkaline reagent forming the organic alkaline conditions are prepared by the following steps: removing the sulfonyloxy leaving group by an elimination reaction at a ratio of 0.8-5.0 to produce a 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative represented by formula I;
any one or more of ethers, hydrocarbons, halogenated hydrocarbons, benzene or substituted aromatic hydrocarbon solvents are used as the solvent for the elimination reaction;
the organic alkali reagent is any one of 1, 8-diazabicyclo undec-7-ene (DBU) or triethylene Diamine (DABCO);
in the 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivatives shown in the formula I, R is hydrogen, C1-C9 alkyl, aryl, benzyl and CF 3 CO、R 2 CO or R 3 Any one of the OCOs;
R 1 is a C1-C6 fluoroalkyl group;
r2 is any one of hydrogen, C1-C9 alkyl, aryl or benzyl;
and R3 is any one of C1-C9 alkyl, aryl or benzyl.
CN202010143683.1A 2020-03-04 2020-03-04 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof Active CN111233750B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010143683.1A CN111233750B (en) 2020-03-04 2020-03-04 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010143683.1A CN111233750B (en) 2020-03-04 2020-03-04 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof

Publications (2)

Publication Number Publication Date
CN111233750A CN111233750A (en) 2020-06-05
CN111233750B true CN111233750B (en) 2023-12-05

Family

ID=70871686

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010143683.1A Active CN111233750B (en) 2020-03-04 2020-03-04 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof

Country Status (1)

Country Link
CN (1) CN111233750B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010638B (en) * 2022-05-09 2024-02-13 杭州国瑞生物科技有限公司 Synthesis method of Nemactetvir intermediate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105073746A (en) * 2012-12-20 2015-11-18 默沙东公司 Substituted imidazopyridines as HDM2 inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105073746A (en) * 2012-12-20 2015-11-18 默沙东公司 Substituted imidazopyridines as HDM2 inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN检索报告;王沙沙;《STN检索报告》;20220922;第5页 *
王沙沙.STN检索报告.《STN检索报告》.2022,第5页. *

Also Published As

Publication number Publication date
CN111233750A (en) 2020-06-05

Similar Documents

Publication Publication Date Title
JP2022553230A (en) 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6 by resolution of the racemate with diastereomeric tartaric esters - a method for preparing naphthyridine-3-carboxylates
JP2021504418A (en) Method for producing 2- (5-methoxyisochroman-1-yl) -4,5-dihydro-1H-imidazole and its hydrogen sulfate
JP2022552713A (en) 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6- was obtained by racemate separation with diastereomeric tartaric esters. Method for preparing naphthyridine-3-carboxylate
CN111233750B (en) 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof
CN105949118A (en) Preparation method of 2-aryl quinoline derivatives
JP7205059B2 (en) Method for producing evodiamine
CN102731368B (en) Preparation method of 5,5-difluoro-3-substituted piperidine derivative
JP6676146B2 (en) Novel production method of chromanol derivative
JP5133704B2 (en) Production method
CN109180564B (en) Preparation method of piperidine and derivatives thereof
JP2012502984A (en) Improved process for producing adefovir dipivoxil
WO2002085858A1 (en) Process for producing purified piperidine derivative
WO2014126008A1 (en) Catalyst and method for producing optically active anti-1,2-nitroalkanol compound
JP2002510699A (en) Preparation of phosphine ligand
JP5270549B2 (en) Method for producing HI-6 dimethanesulfonate
CN111233751B (en) Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof
CN100408577C (en) Process for the preparation of imidazo(1,2-A)pyridine-3-acetamides
CN109265407B (en) Synthesis method of bislinezolid
KR20170080190A (en) Method for preparing eight-membered heterocycles using catalytic cycloaddition of 1,5-dipole and eight-membered heterocycles prepared thereby
JP5279449B2 (en) Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride
CN116947924A (en) Camptothecin biphosphate compound and preparation method thereof
CN115626895A (en) Biaryl bridged eight-membered, nine-membered or ten-membered nitrogen-containing heterocyclic compound and synthetic method thereof
JPH06228103A (en) New octahydroacridine derivative and its production
CN112778198A (en) Synthesis method of dihydroquinolinone compound
US692437A (en) Hydrochlorid of cinnamyl-quinin and process of making same.

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant