CN111978215A - Benzyl-protected ortho-chiral amino alcohol compound and preparation method thereof - Google Patents

Benzyl-protected ortho-chiral amino alcohol compound and preparation method thereof Download PDF

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CN111978215A
CN111978215A CN201910424207.4A CN201910424207A CN111978215A CN 111978215 A CN111978215 A CN 111978215A CN 201910424207 A CN201910424207 A CN 201910424207A CN 111978215 A CN111978215 A CN 111978215A
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propyl
benzyl
amino alcohol
magnesium sulfate
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魏邦国
聂晓迪
刘艺雯
司长梅
林国强
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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Abstract

The invention belongs to the field of chemical synthesis, and relates to a benzyl-protected ortho-chiral amino alcohol compound shown in a formula 1 and a preparation method thereof. The technical route for preparing the benzyl protected chiral ortho-amino alcohol compound has the advantages of simple operation, concise route and higher yield, and the used reagents are common reagents. In particular, the technical route has low cost and high selectivity, and can be conveniently applied to the preparation of the benzyl-protected chiral ortho-amino alcohol compound.

Description

Benzyl-protected ortho-chiral amino alcohol compound and preparation method thereof
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a benzyl-protected ortho-chiral amino alcohol compound and a preparation method thereof.
Background
Research shows that the chiral amino alcohol compound has wide application value due to the special structure of the chiral amino alcohol compound and has important application value in the fields of medicinal chemistry, fine chemical industry and catalysis. In the medical field, the backbone structure of chiral amino alcohols is present in a variety of drug molecules, such as chloramphenicol and sulfoximine as broad-spectrum antibiotics; meanwhile, the chiral amino alcohol is used as a chiral resolving agent, so that chiral molecules with different configurations can be identified and efficiently resolved; in the field of asymmetric catalysis, chiral amino alcohol compounds are widely used as chiral ligands and auxiliaries; in addition, the chiral amino alcohol compound can be conveniently converted into the unnatural amino acid, and the unnatural amino acid has wide physiological activity due to structural diversity, so that the research on the field of new drug research and development can be promoted.
However, in the prior art, the synthesis of the ortho-chiral amino alcohol compound has the problems of high cost, low selectivity, long route or limited applicable groups, and based on the current situation of the prior art, the inventor of the application intends to provide a novel benzyl-protected ortho-chiral amino alcohol compound and a preparation method thereof, and the application has important significance for developing a novel method for synthesizing the ortho-chiral amino alcohol compound and chemically.
Disclosure of Invention
The invention aims to provide a novel benzyl-protected ortho-chiral amino alcohol compound and a preparation method thereof based on the current situation of the prior art, and the technical route of the invention aims at preparing chiral ortho-amino alcohol compounds with high efficiency, low cost and high selectivity, and provides a simple and convenient process technical route. The method has important significance for developing novel para-position chiral amino alcohol compounds and novel methods for chemical synthesis.
The invention synthesizes a benzyl-protected chiral ortho-amino alcohol compound with a chemical structure as follows:
Figure BDA0002066961910000021
wherein, the substituent R represents aryl or alkyl.
Further, the substituent R represents N-propyl, N-pentyl, N-heptyl, isopropyl, tert-butyl, 2, 2-dimethyl-propyl, (S) -1-methyl-propyl, 1-ethyl-propyl, 3-hexenyl, 1-allyl-propyl, phenylpropyl, 3-trifluoromethyl-phenylpropyl, 3- (5-methyl-2-furyl) propyl, 1-benzyl-propyl, 1- (3-fluorobenzyl) -propyl, 1- (4-methoxybenzyl) -propyl, 1- (4-tert-butylbenzyl) -propyl, 4-N-Boc-piperidinyl, cyclohexyl, cyclopentyl, cyclopropyl. The specific chemical structures of 21 benzyl-protected chiral ortho-amino alcohol compounds are given below, and the specific numbers are 1a to 1t in sequence.
Figure BDA0002066961910000022
Figure BDA0002066961910000031
The present invention provides a technical route (Scheme 1) for the preparation of benzyl protected chiral ortho amino alcohol compounds having the chemical structure of the above formula:
in the statements made hereinbelow, the general formula of the intermediates is according to the numbering in the formula, indicated by an Arabic number, P represents a protecting group for the nitrogen atom, in particular Boc, Cbz, COOMe or COOEt, P1Represents an oxygen atom protecting group, specifically TBS, TES, TBDPS, Bn, PMB, Ac, R represents different aryl or alkyl substituents.
Figure BDA0002066961910000032
Dissolving compound 1 in an organic solvent, adding a free radical initiator (or conditions), adding a pyridine sulfone, reacting for 0.5-1 hr, quenching, adding a water absorbent, and post-treating to obtain compound 3.
In the present invention, the organic solvent refers to tetrahydrofuran, acetonitrile, dichloroethane, dichloromethane, cyclohexane or n-hexane, particularly tetrahydrofuran.
In the present invention, said one radical initiator (or condition) means Cl2，Br2Cyclohexanone peroxide, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptonitrile, samarium diiodide and light conditions, particularly samarium diiodide.
In the present invention, the pyridine sulfone refers to methyleneoxybenzylpyridine sulfone, methyleneoxyalkylpyridine sulfone, especially methyleneoxybenzylpyridine sulfone. The water absorbent is anhydrous magnesium sulfate, anhydrous sodium sulfate, molecular sieve, anhydrous copper sulfate, especially anhydrous magnesium sulfate.
The technical route for preparing the benzyl protected chiral ortho-amino alcohol compound has the advantages of simple operation, concise route and higher yield, and the used reagents are common reagents. In particular, the technical route has low cost and high selectivity, and can be conveniently applied to the preparation of the benzyl-protected chiral ortho-amino alcohol compound.
Detailed Description
Example 1
Synthesis of Compound 3a
Compound 1a (150mg,0.87mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 35mL) and then 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (457.6mg,2mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by silica gel column chromatography to give compound 3 as a colorless oil, (135mg, 56%).1H NMR(400MHz,CDCl3,rotamers)7.37-7.27(m,5H),4.62-4.51(m,1H),4.51-4.46(m,1H),3.67-3.61(m,0.75H),3.56-3.48(m,1H),3.48-3.43(m,0.75H),3.43-3.33(m,1.5H),1.71-1.65(m,1H),1.62-1.49(m,0.9H),1.49-1.41(m,1.1H),1.40-1.37(m,1H),1.25-1.16(m,9H),0.97-0.88(m,3H)ppm.
Synthesis of Compound 3b
Under the protection of nitrogen, compound 1b (200mg,1mol) is dissolved in tetrahydrofuran (2mL), and added with fresh samarium diiodide (0.1M, 40mL), then 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (516mg,2mol) is dropped, stirred for 40 minutes at room temperature and then quenched with water, added with anhydrous magnesium sulfate and stirred, filtered through a silica gel funnel, and then common salt is added The reaction mixture was washed once with water, dried over anhydrous magnesium sulfate, filtered, concentrated and subjected to silica gel column chromatography to give compound 3b (182mg, 56%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.39-7.28(m,5H),4.61-4.56(m,0.6H),4.55-4.51(m,0.8H),4.50-4.46(m,0.6H),3.67-3.62(m,1H),3.55-3.49(m,1H),3.48-3.43(m,0.55H),3.43-3.38(m,1H),3.38-3.33(m,0.45H),1.68-1.59(m,1H),1.58-1.46(m,1H),1.44-1.35(m,1H),1.33-1.24(m,5H),1.23-1.20(s,4.7H),1.20-1.17(m,4.3H)ppm.
Synthesis of Compound 3c
Compound 1c (102mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3c (92mg, 52%) as a colorless oil.1H NMR(400MHz,CDCl3)7.40-7.27(m,5H),4.57-4.48(m,2H),3.53-3.43(m,2H),3.42-3.39(m,1H),3.38-3.33(m,1H),1.71-1.59(m,2H),1.33-1.25(s,10H),1.21-1.18(s,9H),0.92-0.83(m,3H)ppm.
Synthesis of Compound 3d
Compound 1d (95mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3d (86mg, 55%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.39-7.28(m,5H),4.64-4.52(m,1H),4.52-4.45(m,1H),3.68-3.61(m,1.5H),3.65-3.48(m,1H),3.48-3.44(m,1H),3.44-3.33(m,0.5H),1.84-1.65(m,1H),1.62-1.46(m,2H),1.23-1.18(m,9H),0.94-0.86(m,6H)ppm.
Synthesis of Compound 3e
Compound 1e (93mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh diiodo was added Samarium (0.1M, 30mL) was added dropwise to a 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes, quenched with water, added with anhydrous magnesium sulfate, stirred, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give compound 3e (101mg, 65%) as a colorless oil.1H NMR(400MHz,CDCl3)7.38-7.27(m,5H),4.67-4.57(m,1H),4.52-4.38(m,1H),4.02-3.90-(m,1H),3.83-3.77(m,1H),3.72-3.63(m,1H),3.10-2.96(m,1H),1.30-1.24(s,9H),1.01-0.89(s,9H)ppm.
Synthesis of Compound 3f
Compound 1f (100mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3f (105mg, 65%) as a colorless oil.1H NMR(400MHz,CDCl3)7.38-7.27(m,5H),4.67-4.57(m,1H),4.52-4.38(m,1H),4.02-3.90-(m,1H),3.83-3.77(m,1H),3.72-3.63(m,1H),3.10-2.96(m,1H),1.30-1.24(s,9H),1.01-0.89(s,9H)ppm.
Synthesis of Compound 3g
Under nitrogen protection, compound 1g (99mg,0.5mol) was dissolved in tetrahydrofuran (2mL) and added to fresh samarium diiodide (0.1M, 30mL), followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration, and chromatographed on a silica gel column to give compound 3g (141mg, 93%) as a colorless oil. 1H NMR(400MHz,CDCl3)7.38-7.28(m,5H),4.64-4.55(m,1H),4.50-4.43(m,1H),3.73-3.65(m,1H),3.65-3.61(m,2H),3.29-3.17(m,1H),1.83-1.72(m,1H),1.57-1.48(m,1H),1.25-1.21(s,9H),1.15-1.05(m,1H),0.97-0.88(m,6H)ppm.
Synthesis of Compound 3h
Under the protection of nitrogen, the nitrogen gas is used for protecting the reaction vessel,compound 1h (100mg,0.5mol) was dissolved in tetrahydrofuran (2mL) and freshly prepared samarium diiodide (0.1M, 30mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 min and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated by silica gel column chromatography to give compound 3h (102mg, 63%) as a colorless oil.1H NMR(400MHz,CDCl3)7.38-7.28(m,5H),4.64-4.55(m,1H),4.50-4.43(m,1H),3.73-3.65(m,1H),3.65-3.61(m,2H),3.29-3.17(m,1H),1.83-1.72(m,1H),1.57-1.48(m,1H),1.25-1.21(s,9H),1.15-1.05(m,1H),0.97-0.88(m,6H)ppm.
Synthesis of Compound 3i
Compound 1i (100mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3i (102mg, 63%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.37-7.26(m,5H),5.42-5.34(m,1H),5.33-5.25(m,1H),4.62-4.56(m,0.7H),4.55-4.51(m,0.5H),4.51-4.44(m,0.8H),2.19-2.08(m,2H),2.08-1.96(m,2H),1.77-1.72(m,0.7H),1.67-1.57(m,1.3H),1.25-1.21(m,6.4H),1.21-1.18(m,2.6H),0.98-0.91(m,2.8H)ppm.
Synthesis of Compound 3j
Under nitrogen protection, compound 1j (108mg,0.5mol) was dissolved in tetrahydrofuran (2mL), and added to fresh samarium diiodide (0.1M, 30mL), followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration, and chromatographed on a silica gel column to give compound 3j (98mg, 58%) as a colorless oil. 1H NMR(400MHz,CDCl3,rotamers)7.39-7.27(m,5H),5.86-5.66(m,1H),5.16-5.46(m,2H),5.59-5.46(m,2H),3.65-3.57(m,1H),3.52-3.49(m,2H),2.23-2.08(m,1.6H),2.05-1.96(m,0.4H),1.83-1.77(m,0.6H),1.74-1.64(m,0.4H),1.59-1.34(m,2H),1.27-1.21(s,3.5H),1.21-1.16(s,5.5H),0.97-0.87(m,3H)ppm.
Synthesis of Compound 3k
Compound 1k (117mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3k (114mg, 64%) as a colorless oil.1H NMR(400MHz,CDCl3)7.37-7.26(m,7H),7.23-7.14(m,3H),4.64-4.57(m,0.7H),4.57-4.51(m,0.3H),4.51-4.42(m,1H),3.80-.3.73(m,0.65H),3.72-3.64(m,0.9H),3.61-3.53(m,1H),3.52-3.48(m,0.35H),3.47-3.39(m,1.1H),2.78-2.69(m,1H),2.67-2.54(m,1H),2.07-1.99(m,0.3H),1.93-1.80(m,1.7H),1.28-1.23(m,7.4H),1.22-1.19(m,1.6H)ppm.
Synthesis of Compound 3l
Under nitrogen protection, compound 1l (151mg,0.5mol) was dissolved in tetrahydrofuran (2mL), and added to fresh samarium diiodide (0.1M, 30mL), followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration, and chromatographed on a silica gel column to give compound 3l (119mg, 56%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.47-7.39(m,3H),7.39-7.36(m,1H),7.35-7.28(m,5H),4.63-4.58(m,0.6H),5.53-4.50(m,0.7H),4.50-4.45(m,0.7H),3.79-3.74(m,0.6H),3.71-3.67(m,0.6H),3.60-3.55(m,0.8H),3.55-3.46(m,1H),3.44-3.36(m,1H),2.87-2.80(m,0.5H),2.80-2.73(m,0.9H),2.70-2.67(m,0.6H),2.07-1.97(m,0.8H),1.95-1.84(m,1.2H),1.27-1.24(s,6H),1.22-1.20(s,3H)ppm.
Synthesis of Compound 3m
Compound 1m (119mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh dioxane was addedSamarium iodide (0.1M, 30mL) was added dropwise to a 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes, quenched with water, added with anhydrous magnesium sulfate, stirred, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and chromatographed on a silica gel column to give 3M (98mg, 54%) as a colorless oily compound. 1H NMR(400MHz,CDCl3,rotamers)7.38-7.25(m,5H),5.92-5.89(s,0.3H),5.85-5.81(s,1.45H),4.63-4.56(m,0.6H),4.56-4.51(m,0.4H),4.51-4.49(m,0.65H),4.48-4.44(m,0.35H),3.72-3.65(m,1.2H),3.59-3.52(m,1H),3.51-3.39(m,1.8H),2.78-2.68(m,0.9H),2.68-2.53(m,1.1H),2.26-2.21(s,3H),2.10-1.92(m,0.9H),1.91-1.85(m,1.1H),1.25-1.21(s,5.5H),1.20-1.17(s,3.5H)ppm.
Synthesis of Compound 3n
Compound 1n (131mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and added to fresh samarium diiodide (0.1M, 30mL) and 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol) was added dropwise thereto, stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3M (145mg, 75%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.40-7.24(m,7.2H),7.23-7.12(m,2.8H),4.57-4.39(m,2H),3.66-363(m,1H),3.62-3.60(s,0.3H),3.56-3.54(s,1H),3.52-3.47(m,0.7H),2.81-2.73(m,1H),2.58-2.42(m,1H),2.11-2.03(m,0.4H),2.02-1.94(m,0.6H),1.58-1.46(m,0.28H),1.45-1.33(m,1H),1.33-1.26(m,0.72H),1.26-1.19(s,5.6H),1.19-1.09(s,3.4H),0.94-0.86(m,3H)ppm.
Synthesis of Compound 3o
Compound 1o (140mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh samarium diiodide (0.1M, 30mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and silica gel column chromatography to give compound 3o (131mg, 65%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.39-7.27(m,5H),7.27-7.18(m,1H),6.98-6.82(m,3H),4.57-4.41(m,2H),3.66-3.59(m,2.5H),3.57-3.51(m,0.5H),3.49-3.40(m,1H),2.83-2.65(m,1H),2.52-2.42(m,1H),2.09-1.98(m,1H),1.58-1.36(m,1H),1.27-1.23(s,7.5H),1.19-1.17(s,1.5H),0.94-0.84(m,3H)ppm.
Synthesis of Compound 3p
Compound 1p (131mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh samarium diiodide (0.1M, 30mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and silica gel column chromatography to give compound 3p (170mg, 82%) as a colorless oil. 1H NMR(400MHz,CDCl3,rotamers)7.38-7.26(m,5H),7.10-7.01(m,2H),6.87-6.77(m,2H),4.56-4.40(m,2H),3.82-3.76(s,3H),3.64-3.62(m,1H),3.61-3.58(m,0.5H),3.53-3.51(m,1H),3.50-3.47(m,0.5H),3.74-3.60(m,1H),3.51-3.36(m,1H),3.04-1.96(m,0.4H),1.95-1.89(m.0.6H),1.56-1.47(m,0.4H),1.44-1.34(m,1H),1.32-1.27(m,0.6H),1.26-1.20(s,6H),1.18-1.16(s,3H),0.95-0.85(m,3H)ppm.
Synthesis of Compound 3q
Compound 1q (200mg,0.62mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh samarium diiodide (0.1M, 22mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (328mg,1.25mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and silica column chromatography to give compound 3q (145mg, 66%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.36-7.25(m,7H),7.10-7.04(m,2H),4.57-4.38(m,2H),3.67-3.63(m,1.5H),3.62-3.57(m,1H),3.56-3.46(m,1.5H),2.79-2.61(m,0.87H),2.54-2.43(m,1H),2.07-1.98(m,1H),1.43-1.37(m,1H),1.32-1.29(s,9H),1.26-1.21(s,9H),1.20-1.19(m,1H),1.15-1.13(m,1H),0.95-0.88(m,3H)ppm.
Synthesis of Compound 3r
Compound 1r (158mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh samarium diiodide (0.1M, 60mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and silica gel column chromatography to give compound 3r (148mg, 68%) as a colorless oil.1H NMR(400MHz,CDCl3,rotamers)7.39-7.28(m,5H),4.63-4.55(m,1H),4.50-4.42(m,1H),4.25-3.97(m,1H),3.73-3.60(m,3H),3.18-3.02(m,1H),2.72-2.54(m,2H),1.86-1.73(m,2H),1.62-1.51(m,1H),1.47-1.42(s,9H),1.25-1.21(s,9H),1.19-1.04(m,2H)ppm.
Synthesis of Compound 3s
Compound 1s (106mg,0.5mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and fresh samarium diiodide (0.1M, 60mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (394mg,1.5mol), stirred at room temperature for 40 minutes and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and silica gel column chromatography to give compound 3s (101mg, 60%) as a colorless oil. 1H NMR(400MHz,CDCl3,rotamers)7.38-7.28(m,5H),4.65-4.54(m,1H),4.50-4.44(m,1H),3.69-3.60(m,3H),3.19-3.09(m,1H),1.87-1.80(m,1H),1.78-1.59(m,4H),1.27-1.22(s,9H),1.21-1.06(m,4H),1.02-0.86(m,2H)ppm.
Synthesis of Compound 3t
Under nitrogen protection, compound 1t (99mg,0.5mol) was dissolved in tetrahydrofuran (2mL), and fresh samarium diiodide (0.1M, 60mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (328mg,1.5mol), stirring at room temperature for 40 minutes, quenching with water, addition of anhydrous magnesium sulfate, stirring, filtration through a silica gel funnel, followed by washing once with brine, drying over anhydrous magnesium sulfate, filtration and concentration, and silica gel column chromatography to give compound 3t (106mg, 66%) as a colorless oil.1H NMR(400MHz,CDCl3)7.38-7.27(m,5H),4.66-4.58(m,1H),4.50-4.40(m,1H),3.81-3.73(m,1H),3.71-3.66(m,1H),3.65-3.61(m,1H),3.19-3.11(m,1H),2.21-2.06(m,0.9H),1.85-1.71(m,1H),1.62-1.56(m,2H),1.56-1.50(m,2H),1.25-1.22(s,9H),1.22-1.20(m,1H),1.20-1.10(m,2H)ppm.
Synthesis of Compound 3u
Under nitrogen protection, compound 1u (85mg,0.5mol) was dissolved in tetrahydrofuran (2mL), and fresh samarium diiodide (0.1M, 60mL) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (328mg,1.5mol), stirred at room temperature for 40 minutes, quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration, and chromatographed on a silica gel column to give compound 3u (83mg, 56%) as a colorless oil.1H NMR(400MHz,CDCl3)7.38-7.28(m,5H),4.60-4.52(m,2H),3.64-3.58(m,3H),2.60-2.53(m,1H),1.22-1.19(s,9H),1.10-1.03(m,1H),0.67-0.59(m,2H),0.46-0.40(m,1H),0.36-0.27(m,1H)ppm.。
Example 2
The preparation of compounds 3b-u is the same as in example 1.
Synthesis of Compound 3a
Compound 1a (150mg,0.87mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and azobisisobutyronitrile (428mg, 2.6mol) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (457mg,2mol), stirring at room temperature for 1h and quenching with water, addition of anhydrous magnesium sulfate and stirring, filtration through a silica gel funnel, followed by one-time washing with saline, drying with anhydrous magnesium sulfate, filtration and concentration, and silica gel column chromatography to give compound 3a (95mg, 42%) as a colorless oil.
Example 3
The preparation of compounds 3b-u is the same as in example 1.
Synthesis of Compound 3a
Compound 1a (150mg,0.87mol) was dissolved in tetrahydrofuran (2mL) under nitrogen and dibenzoyl peroxide (629mg, 2.6mol) was added, followed by dropwise addition of 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (457mg,2mol), stirred at room temperature for 1h and quenched with water, stirred with anhydrous magnesium sulfate, filtered through a silica gel funnel, washed once with brine, dried over anhydrous magnesium sulfate, filtered, concentrated by filtration and chromatographed on a silica gel column to give compound 3a as a colorless oil (112mg, 50%).
Example 4
The preparation of compounds 3b-u is the same as in example 1.
Synthesis of Compound 3a
Compound 1a (150mg,0.87mol) was dissolved in tetrahydrofuran (2mL) under a nitrogen atmosphere, followed by dropwise addition of a 2- (phenoxymethyl) pyridylsulfone tetrahydrofuran solution (457mg,2mol), followed by stirring at room temperature under blue light for 36 hours, and then subjected to silica gel column chromatography to give compound 3a (106mg, 47%) as a colorless oil.

Claims (8)

1. A benzyl protected ortho-chiral amino alcohol compound with a structure shown in formula 1,
Figure FDA0002066961900000011
wherein, the substituent R represents an aromatic group or an alkyl group.
2. The benzyl-protected ortho-chiral amino alcohol compound of the structure of formula 1, as claimed in claim 1, wherein the substituent R is N-propyl, N-pentyl, N-heptyl, isopropyl, tert-butyl, 2, 2-dimethyl-propyl, (S) -1-methyl-propyl, 1-ethyl-propyl, 3-hexenyl, 1-allyl-propyl, phenylpropyl, 3-trifluoromethyl-phenylpropyl, 3- (5-methyl-2-furyl) propyl, 1-benzyl-propyl, 1- (3-fluorobenzyl) -propyl, 1- (4-methoxybenzyl) -propyl, 1- (4-tert-butylbenzyl) -propyl, 4-N-Boc-piperidinyl, cyclohexyl, cyclopentyl or cyclopropyl.
3. The benzyl protected ortho-chiral amino alcohol compound of formula 1 according to claim 1, wherein the benzyl protected ortho-chiral amino alcohol compound has the following structure:
Figure FDA0002066961900000012
Figure FDA0002066961900000021
4. a preparation method of benzyl-protected ortho-chiral amino alcohol compound with a structure shown in a formula 1 is characterized by adopting the following reaction route:
Figure FDA0002066961900000022
wherein, the substituent R represents aryl or alkyl;
dissolving compound 1 in an organic solvent, adding a free radical initiator or condition, adding a pyridine sulfone compound 2, reacting for 0.5-36 hr, quenching, adding a water absorbent, and post-treating to obtain compound 3.
5. The process according to claim 4, wherein the organic solvent is tetrahydrofuran, acetonitrile, dichloroethane, dichloromethane, cyclohexane or n-hexane, in particular tetrahydrofuran.
6. The method of claim 4 wherein said free radical initiator or condition is Cl2，Br2Cyclohexanone peroxide, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptonitrile, samarium diiodide or light conditions, especially samarium diiodide.
7. The process according to claim 4, wherein the pyridine sulfone is methyleneoxybenzylpyridine sulfone or methyleneoxyalkylpyridine sulfone, in particular methyleneoxybenzylpyridine sulfone.
8. The method of claim 4, wherein the water absorbent is anhydrous magnesium sulfate, anhydrous sodium sulfate, molecular sieves, or anhydrous copper sulfate, particularly anhydrous magnesium sulfate.
CN201910424207.4A 2019-05-21 2019-05-21 Benzyl-protected ortho-chiral amino alcohol compound and preparation method thereof Pending CN111978215A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085372A (en) * 2014-05-12 2015-11-25 上海交通大学 Preparation method of chiral gamma-aminoalcohol compound

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
CN105085372A (en) * 2014-05-12 2015-11-25 上海交通大学 Preparation method of chiral gamma-aminoalcohol compound

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Title
CHARLOTTE L. HUMES等: ""Bis{( R )- N -[( R)-2-benzyloxy-1-(4- tert -butylphenyl)ethyl]-2-methylpropane-2-sulfinamide} monohydrate"", 《ACTA CRYST.》 *
NATHAN D. COLLETT等: ""Stereoselective Synthesis of the Eastern Quinolizidine Portion of Himeradine A"", 《ORGANIC LETTERS》 *
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