1. A 3-hydroxy-2, 6-disubstituted piperidine compound having the formula:

wherein R is¹Is benzyl, phenyl, p-trifluoromethylphenyl, n-butyl, ethyl;

R²is allylBenzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-trifluoromethylbenzyl, m-trifluoromethylbenzyl, p-trifluoromethylbenzyl, m-chlorobenzyl, m-bromobenzyl, p-cyanobenzyl, alpha-naphthyl.

2. A3-hydroxy-2, 6-disubstituted piperidine compound according to claim 1,

the compound is a compound 2-1-2-27 with the following structure:

3. a process for preparing a 3-hydroxy-2, 6-disubstituted piperidine compound according to claim 1, which comprises the following steps:

the method comprises the following steps:

dissolving the compound 1 in an organic solvent, adding a metal nucleophilic reagent at the temperature of between minus 78 and 25 ℃, stirring for 5 to 10 minutes, adding Lewis acid to react for 2 to 12 hours, and carrying out post-treatment to obtain a compound 2.

4. The method of claim 3, wherein the organic solvent is tetrahydrofuran, acetonitrile, dichloroethane, dichloromethane, cyclohexane, or n-hexane.

5. The process of claim 3 wherein said organic solvent is tetrahydrofuran.

6. The method of claim 3, wherein said one metal nucleophile is an aryl and alkyl substituted Grignard reagent or a monoalkyl zinc reagent.

7. The method of claim 3, wherein said one metal nucleophile is an aryl and alkyl substituted monoalkyl zinc reagent.

8. A process according to claim 3, wherein the lewis acid is zinc chloride, titanium tetrachloride, trimethylsilyl trifluoromethanesulfonate, boron trifluoride etherate or trimethylchlorosilane.

9. The process of claim 3 wherein said Lewis acid is titanium tetrachloride.

Background

The prior art discloses that 3-hydroxy-2, 6-disubstituted piperidine is an important component of alkaloid, the skeleton has three chiral centers on an N heterocyclic ring, and most of compounds have obvious physiological activity due to the special structure of the skeleton, and the skeleton is a key skeleton of a plurality of natural products and drug molecules. For example, (-) -cassine and (-) -spectaline, extracted from plant leaves, have anti-staphylococcus aureus and anti-trypanosomiasis effects, respectively. However, the introduction of substituents at the 2,6 positions of the piperidine ring is limited, and especially the introduction of a substituent at the C6 position is optional in the case where substituents are already present at the 2,3 positions. Recently, methods for introducing substituents at the adjacent N position of N-containing heterocycles have been reported: liuyue group realized the method of C-H functional group reaction of N-formyl piperidone and alkene, alkyne to construct 2, 6-disubstituted piperidine (Wang G, et al. org. Lett.,2016,18(24): 6476-9.); the Weibang topic group realizes a method for introducing a carbonyl-containing substituent at the C6 position of piperidine by nucleophilic substitution reaction of N, O-acetal and ketone (Liu Y.W.et al.Org.Biomol.chem.,2018,16, 771-779.); the sonwanze group achieved iridium-catalyzed introduction of ether substituents by allyl etherification of dihydropyridone at C6 position (song w.z.et al.j.org.chem.,2018,83(20), 12822-30.); research practice shows that the above known methods can only be used for introducing a specific type of substituent, and no report has been made on the ring introduction method of a benzyl type substituent.

Based on the current situation of the prior art, the inventor of the application intends to provide a new synthetic method to realize the synthesis of novel 2, 6-disubstituted piperidine, provide a new idea for the diversity synthesis of the alkaloids and provide a material basis for the research and development of new drug molecules; in particular to a 3-hydroxy-2, 6-disubstituted piperidine compound and a preparation method thereof.

Disclosure of Invention

The invention aims to provide a 3-hydroxy-2, 6-disubstituted piperidine new compound and a preparation method thereof based on the current situation of the prior art. The method has the characteristics of high efficiency, low cost, compatibility with various functional groups, capability of amplified preparation and the like.

The invention relates to a new 3-hydroxy-2, 6-disubstituted piperidine compound, which is characterized by having the following structural formula:

wherein R is¹Is benzyl, phenyl, p-trifluoromethylphenyl, n-butyl, ethyl.

R²Is allyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-trifluoromethylbenzyl, m-trifluoromethylbenzyl, p-trifluoromethylbenzyl, m-chlorobenzyl, m-bromobenzyl, p-cyanobenzyl, alpha-naphthyl.

Preferred compounds of the invention are those having the structure:

(1) 2-1 to 2-27 parts of a 3-hydroxy-2, 6-disubstituted piperidine compound.

The preparation method of the compound related by the invention is according to the following specific technical route:

in the statements below, the intermediate formulae are indicated by Arabic numerals according to the numbering in the formulae. P represents a nitrogen atom protecting group, specifically-Fmoc, -Boc, -Cbz, -COOMe, -COOEt, -COPh, -COCH₂CH₂Ph, R represent different aryl or alkyl substituents.

More specifically, the process of the present invention for preparing 3-hydroxy-2, 6-disubstituted piperidine compounds follows the following technical scheme and steps:

step 1: dissolving the compound 1 in an organic solvent, adding a metal nucleophilic reagent at-78 ℃, stirring for 5-10 minutes, adding Lewis acid for reacting for 2-12 hours, and carrying out post-treatment to obtain a compound 2.

In the present invention, the organic solvent referred to in step 1 means tetrahydrofuran, acetonitrile, dichloroethane, dichloromethane, cyclohexane or n-hexane, particularly tetrahydrofuran. The metal nucleophilic reagent refers to aryl and alkyl substituted Grignard reagent, monoalkyl zinc reagent, especially monoalkyl zinc reagent. The Lewis acid refers to zinc chloride, titanium tetrachloride, trimethylsilyl trifluoromethanesulfonate, boron trifluoride diethyl etherate and trimethylchlorosilane, in particular to titanium tetrachloride.

The preparation technical route for preparing the 3-hydroxy-2, 6-disubstituted piperidine compound has the advantages of simple reaction condition, concise route and higher yield, and the used reagents are common reagents and can be prepared in large quantities.

Detailed Description

EXAMPLE 1 Synthesis of Compound 2-1

Under the protection of argon, compound 1-1(100mg,0.24mmol) is dissolved in dry tetrahydrofuran (1mL), a newly prepared benzyl zinc bromide reagent (1mL,1M in THF,4eq.) and titanium tetrachloride (0.05mL,2eq.) are slowly added dropwise at-78 ℃, and after 12 hours of reaction, saturated NaHCO is added into the reaction system₃(0.6mL) and warmed to room temperature, extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was subjected to silica gel column chromatography (PE/EA ═ 40:1) to give 2-1(116mg, 99%) as a colorless oily liquid.¹H NMR(400MHz,CDCl₃)δ7.43-7.26(m,7H),7.26-7.12(m,3H),4.48-4.14(m,2H),3.81-3.72(m,1H),3.02-2.63(m,4H),2.05-1.89(m,2H),1.52(s,9H),1.47-1.42(m,1H),1.27-124(m,1H),0.74(s,9H),-0.27(s,6H)ppm.

The preparation method of the compound 2-27 is the same as that of 2-1;

synthesis of Compound 2-2

A colorless oily liquid (107mg, 80%).¹H NMR(400MHz,CDCl₃)δ7.61-7.50(d,2H),7.47-7.43(d,1H),7.41-7.30(m,3H),7.29-7.10(m,3H),4.50-4.18(m,2H),3.75(brs,1H),3.06-2.81(m,3H),2.75-2.58(m,1H),2.05-1.92(dd,J＝8.4Hz,2H),1.51(s,9H),1.30-1.21(m,2H),0.74(s,9H),-0.27(s,6H)ppm.

Synthesis of Compounds 2-3

A colorless oily liquid (113mg, 90%).¹H NMR(400MHz,CDCl₃)δ7.39-7.26(m,4H),7.25-7.07(m,5H),4.48-4.12(m,2H),3.74(brs,1H),3.02-2.55(m,4H),2.07-1.88(dd,J＝8.0Hz,2H),1.52(s,9H),1.28-1.24(m,1H),0.74(s,9H),-0.27(s,6H)ppm.

Synthesis of Compounds 2 to 4

A colorless oily liquid (128mg, 96%).¹H NMR(400MHz,CDCl₃)δ7.80-7.64(m,1H),7.60-7.53(m,1H),7.45-7.41(m,1H),7.28-7.14(m,6H),4.55-4.36(m,1H),4.28-4.08(m,1H),3.70-3.63(m,1H),3.24-3.10(m,1H),2.97-2.79(m,2H),2.68-2.59(m,1H),1.97-1.86(m,2H),1.45-1.37(m,9H),1.37-1.32(m,1H),1.15-1.10(m,1H),0.67(s,9H),-0.12--0.43(m,6H)ppm.

Synthesis of Compounds 2 to 5

A colorless oily liquid (116mg, 87%).¹H NMR(400MHz,CDCl₃)δ7.69-7.42(m,4H),7.40-7.30(m,3H),7.29-7.16(m,2H),4.56-4.17(m,2H),3.80(brs,1H),3.09-2.87(m,3H),2.81-2.65(m,1H),2.09-1.96(d,J＝8.0,2H),1.55(s,9H),1.29-1.26(m,1H),0.77(s,9H),-0.24(s,6H)ppm.

Synthesis of Compounds 2 to 6

A colorless oily liquid (92mg, 71%).¹H NMR(400MHz,CDCl₃)δ8.67-8.50(s,0.52H),8.32-8.19(s,0.36H),7.90-7.80(m,1H),7.77-7.70(m,1H),7.66-7.50(m,1H),7.50-7.44(m,1H),7.43-7.28(m,6H),7.26-7.23(m,1H),4.66(brs,1H),4.41-4.19(m,1H),3.88-3.76(m,1H),3.51-3.34(m,1H),3.33-3.18(m,1H),3.17-2.96(m,1H),2.90-2.80(m,1H),2.17-1.80(m,2H),1.57-1.41(m,9H),1.30-1.16(m,1H),0.72(s,9H),-0.28(s,6H)ppm.

Synthesis of Compounds 2 to 7

A colorless oily liquid (117mg, 97%).¹H NMR(400MHz,CDCl₃)δ7.38-7.29(m,3H),7.27-7.21(m,3H),7.19-7.09(m,3H),4.49-4.15(m,2H),3.76(brs,1H),3.02-2.59(m,4H),2.34(s,3H),2.07-1.88(m,2H),1.54(s,9H),1.50-1.45(m,1H),1.35-1.29(m,1H),0.76(s,9H),-0.25(s,6H)ppm.

Synthesis of Compounds 2 to 8

A colorless oily liquid (83mg, 69%).¹H NMR(400MHz,CDCl₃)δ7.82-7.49(m,3H),7.41-7.25(m,5H),7.24-7.21(m,1H),4.63-4.18(m,2H),3.75(brs,1H),3.34-3.19(m,1H),3.03-2.87(m,2H),2.76-2.69(m,1H),2.05-1.95(m,2H),1.52(s,9H),1.45-1.40(m,1H),1.24-1.20(m,1H),0.75(s,9H),-0.24--0.3(m,6H)ppm.

Synthesis of Compounds 2 to 9

A colorless oily liquid (89mg, 72%).¹H NMR(400MHz,CDCl₃)δ7.60(brs,2H),7.46(brs,2H),7.33(brs,3H),7.26-7.20(m,2H),4.46-4.16(m,2H),3.75(brs,1H),2.99-2.84(m,3H),2.76-2.64(m,1H),2.09-1.92(m,2H),1.52-1.48(m,9H),1.44-1.42(m,1H),1.26-1.21(m,1H),0.74(s,9H),-0.27(s,6H)ppm.

Synthesis of Compounds 2 to 10

A colorless oily liquid (85mg, 72%).¹H NMR(400MHz,CDCl₃)δ7.36-7.30(m,4H),7.25-7.17(m,3H),7.15-7.10(m,1H),7.04(d,2H),5.31(brs,1H),4.60-4.52(m,2H),2.71-2.65(dd,J＝4.0,13.2Hz,1H),2.23-2.14(dd,J＝11.2,12.8Hz,1H),1.59-1.52(m,1H),1.49(s,9H),1.25-1.19(m,1H),0.89(s,9H),0.07-0.06(m,6H)ppm.

Synthesis of Compounds 2 to 11

A colorless oily liquid (101mg, 75%).¹H NMR(400MHz,CDCl₃)δ7.47-7.41(d,2H),7.35-7.30(d,4H),7.24-7.15(m,1H),7.14-1.10(d,2H),5.32(brs,1H),4.59(brs,2H),2.76-2.67(dd,J＝4.8,13.2Hz,1H),2.31-2.22(dd,J＝10.4,12.8Hz,1H),2.10-2.00(m,2H),1.62-1.55(m,1H),1.48(s,9H),1.22-1.16(m,1H),0.89(s,9H),0.08(s,6H)ppm.

Synthesis of Compounds 2 to 12

A colorless oily liquid (92mg, 73%).¹H NMR(400MHz,CDCl₃)δ7.34-7.30(d,4H),7.28-7.25(m,1H),7.13-7.08(m,2H),6.97-6.94(s,1H),6.92-6.90(m,1H),5.32(brs,1H),4.61-4.53(m,2H),2.76-2.60(dd,J＝4.8,13.2Hz,1H),2.21-2.12(dd,J＝10.4,13.2Hz,1H),2.09-1.95(m,2H),1.61-1.54(m,1H),1.48(s,9H),1.24-1.19(m,1H),0.90(s,9H),0.07(s,6H)ppm.

Synthesis of Compounds 2 to 13

A colorless oily liquid (88mg, 70%).¹H NMR(400MHz,CDCl₃)δ7.34-7.30(m,4H),7.27-7.24(m,2H),7.11(s,2H),7.08-7.03(m,1H),6.98-6.92(d,1H),5.32(brs,1H),4.62-4.53(m,2H),2.67-2.59(dd,J＝4.8,13.2Hz,1H),2.21-2.12(dd,J＝10.4,13.2Hz,1H),2.09-1.96(m,2H),1.61-1.56(m,1H),1.48(s,9H),1.30-1.28(m,1H),0.90(s,9H),0.07(s,6H)ppm.

Synthesis of Compounds 2 to 14

A colorless oily liquid (102mg, 88%).¹H NMR(400MHz,CDCl₃)δ7.60-7.56(m,2H),7.48-7.42(d,2H),7.24-7.19(m,2H),7.17-7.13(m,1H),7.06-7.02(d,2H),5.30(brs,1H),4.61-4.50(m,2H),2.76-2.68(dd,J＝4.4,13.2,1H),2.27-2.18(dd,J＝10.8,12.8,1H),2.06-1.90(m,2H),1.62-1.56(m,1H),1.60(s,9H),1.26-1.23(m,1H),0.90-0.88(m,9H),0.09-0.04(m,6H)ppm.

Synthesis of Compounds 2 to 15

A colorless oily liquid (126mg, 97%).¹H NMR(400MHz,CDCl₃)δ7.60-7.55(m,2H),7.47-7.42(m,3H),7.16-7.09(m,2H),5.31(brs,1H),4.78-4.47(m,2H),2.82-2.73(dd,J＝4.8,13.2,1H),2.36-2.26(dd,J＝10.8,13.2,1H),2.08-1.87(m,2H),1.66-1.61(m,1H),1.48(s,9H),1.24-1.19(m,1H),0.90(s,9H),0.14-0.06(m,6H)ppm.

Synthesis of Compounds 2 to 16

A colorless oily liquid (120mg, 98%).¹H NMR(400MHz,CDCl₃)δ7.60-7.57(d,2H),7.45-7.40(d,2H),7.15-7.10(d,2H),7.00(s,1H),6.91-6.86(m,1H),5.30(brs,1H),4.61-4.52(m,2H),2.70-2.63(dd,J＝5.2,13.2,1H),2.35-2.16(dd,J＝10.4,13.2,1H),2.12-2.02(m,1H),1.99-1.90(m,1H),1.65-1.60(m,1H),1.48(s,9H),1.28-1.23(m,1H),0.89(s,9H),0.08-0.05(m,6H)ppm.

Synthesis of Compounds 2 to 17

A colorless oily liquid (111mg, 92%).¹H NMR(400MHz,CDCl₃)δ7.25-7.12(m,5H),4.36(brs,1H),3.92(brs,1H),3.78(brs,1H),2.87-2.80(m,1H),2.70-2.61(m,1H),1.90-1.81(m,2H),1.54-1.49(m,2H),1.46(s,9H),1.42-1.39(m,1H),1.21-1.16(m,1H),0.98-0.92(m,3H),0.88-0.82(m,9H),0.06--0.02(m,6H)ppm.

Synthesis of Compounds 2 to 18

A colorless oily liquid (107mg, 77%).¹H NMR(400MHz,CDCl₃)δ7.56-7.50(d,2H),7.43-7.30(m,2H),4.40(d,2H),4.03-4.70(m,2H),2.96-2.88(m,1H),2.81-2.69(m,1H),2.00-1.80(m,2H),1.60-1.49(m,3H),1.47(s,9H),1.21-1.13(m,1H),1.02-0.96(m,3H),0.86(s,9H),0.08-0.03(m,6H)ppm.

Synthesis of Compounds 2 to 19

A colorless oily liquid (96mg, 74%).¹H NMR(400MHz,CDCl₃)δ7.24-7.08(m,4H),4.36(brs,1H),4.01-3.77(m,2H),2.88-2.81(m,1H),2.71-2.61(m,1H),1.98-1.72(m,3H),1.55-1.51(m,2H),1.48(s,9H),1.23-1.16(m,1H),1.00-0.95(m,3H),0.86(s,9H),0.08-0.03(m,6H)ppm.

Synthesis of Compounds 2 to 20

A colorless oily liquid (126mg, 90%).¹H NMR(400MHz,CDCl₃)δ7.86-7.55(m,2H),7.50-7.47(m,1H),7.31-7.26(m,1H),4.56(brs,1H),4.05-3.72(m,2H),3.21-3.08(m,1H),2.88-2.80(m,1H),1.99-1.82(m,2H),1.63-1.53(m,2H),1.48(s,9H),1.43-1.39(m,1H),1.16-1.10(m,1H),1.02-0.98(m,3H),0.86(s,9H),0.07-0.02(m,6H)ppm.

Synthesis of Compounds 2 to 21

A colorless oily liquid (112mg, 80%).¹H NMR(400MHz,CDCl₃)δ7.48-7.37(m,4H),4.40(brs,1H),4.10-3.79(m,2H),2.97-2.89(m,1H),2.80-2.71(m,1H),2.00-1.82(m,2H),1.56-1.51(m,2H),1.48(s,9H),1.46-1.41(m,1H),1.20-1.13(m,1H),1.01-0.96(m,3H),0.86(s,9H),0.08-0.03(m,6H)ppm.

Synthesis of Compounds 2 to 22

A colorless oily liquid (126mg, 99%).¹H NMR(400MHz,CDCl₃)δ7.60-7.55(d,2H),7.43-7.32(m,2H),4.39(brs,1H),3.95(brs,1H),3.83(brs,1H),2.96-2.88(m,1H),2.82-2.70(m,1H),2.03-1.91(m,1H),1.88-1.81(m,1H),1.57-1.49(m,3H),1.47(s,9H),1.19-1.09(m,1H),1.01-0.95(m,3H),0.91-0.85(m,9H),0.08-0.02(m,6H)ppm.

Synthesis of Compounds 2 to 23

A colorless oily liquid (87mg, 73%).¹H NMR(400MHz,CDCl₃)δ7.28-7.16(m,5H),4.40(brs,1H),4.02(brs,1H),3.81(brs,1H),2.90-2.81(m,1H),2.75-2.64(m,1H),1.94-1.83(m,2H),1.59-1.50(m,2H),1.49(s,9H),1.45-1.30(m,6H),0.94-0.90(m,3H),0.86(s,9H),0.07-0.01(m,6H)ppm.

Synthesis of Compounds 2 to 24

A colorless oily liquid (102mg, 75%).¹H NMR(400MHz,CDCl₃)δ7.53-7.47(m,2H),7.42-7.30(m,2H),4.39(brs,1H),3.97(brs,1H),3.77(brs,1H),2.92-2.85(m,1H),2.77-2.67(m,1H),1.93-1.79(m,2H),1.49-1.47(m,1H),1.45(s,9H),1.40-1.27(m,6H),1.17-1.11(m,1H),0.97-0.87(m,3H),0.83(s,9H),0.09-0.02(m,6H)ppm.

Synthesis of Compounds 2 to 25

White solid (93mg, 73%).¹H NMR(400MHz,CDCl₃)δ7.26-7.13(m,4H),4.38(brs,1H),4.00(brs,1H),3.79(brs,1H),2.87-2.79(m,1H),2.71-2.63(m,1H),1.95-1.81(m,2H),1.48(s,9H),1.46-1.44(m,1H),1.42-1.30(m,6H),1.22-1.17(m,1H),0.94-0.90(m,3H),0.86(s,9H),0.09-0.01(m,6H)ppm.

Synthesis of Compounds 2 to 26

White solid (53mg, 50%).¹H NMR(400MHz,CDCl₃)δ5.84-5.69(m,1H),5.06-4.99(m,1H),4.26(brs,1H),3.97(brs,1H),3.75(m,1H),2.33-2.15(m,2H),2.10-1.97(m,1H),1.81-1.72(m,1H),1.50-1.46(m,1H),1.44(s,9H),1.43-1.42(m,1H),1.38-1.30(m,6H),0.93-0.89(m,3H),0.87(s,9H),0.06-0.03(m,6H)ppm.

Synthesis of Compounds 2 to 27

A colorless oily liquid (74mg, 70%).¹H NMR(400MHz,CDCl₃)δ7.30-7.27(m,2H),7.25-7.07(m,3H),5.82(brs,1H),5.11-5.00(m,2H),4.40-4.10(m,2H),3.69(brs,1H),2.93-2.76(m,1H),2.70-2.54(m,1H),2.42-2.30(m,1H),2.15-2.00(m,1H),1.94-1.82(m,1H),1.49(s,9H),1.45-1.40(m,2H),0.75(s,9H),-0.29(s,6H)ppm.。