CN107286202B - Chiral Ugi's amine, derivatives thereof, and synthesis method and application of optical isomers - Google Patents

Abstract

The invention discloses a method for synthesizing Ugi's amine shown in formula (I) and derivatives and optical isomers thereof, which takes chiral amine shown in formula (VI) and ferrocene shown in formula (V) as initial raw materials, and obtains the chiral Ugi's amine shown in formula (I) and derivatives and optical isomers thereof through reductive amination, reductive amination or amino alkylation, substitution reaction and amine substitution reaction in sequence; or through reductive amination, hydrogenation debenzylation, reductive amination or amine alkylation reaction to obtain chiral Ugi's amine of the formula (I) and derivatives and optical isomers thereof. The chiral Ugi's amine of the formula (I) and derivatives and optical isomers thereof can be used for synthesizing Josiphos ferrocene diphosphine ligands, are used as chiral ligands of various metal complex catalysts, are important chiral catalyst ligands for preparing medical intermediates and agricultural chemicals, have wide application in metal-catalyzed asymmetric reactions, and are suitable for industrial scale production.

Description

Chiral Ugi's amine, derivatives thereof, and synthesis method and application of optical isomers

Technical Field

The invention belongs to the technical field of chiral chemical synthesis, and particularly relates to chiral Ugi's amine, a synthesis method of a derivative and an optical isomer of the chiral Ugi's amine, and application of the chiral Ugi's amine in synthesis of Josiphos ferrocene diphosphine ligands.

Background

Chiral ferrocene has been extensively and extensively studied in the fields of asymmetric catalysis, material science, and biomedicine [ a) Hyashi, T.; togni, a., eds. in Ferrocenes; VCH Weinheim, Germany,1995.(b) Togni, A.; haloermann, r.l., eds. in Metallocenes; VCH Weinheim, Germany,1998, (c) Stepnicka, P., Ed. in Ferrocenes; wiley: chicchester, 2008 ], wherein the key intermediate chiral Ugi's amine begins with resolution of the racemate via (R) - (+) -tartaric acid [ a) Marquarding, d.; klusacek, h.; gokel, g.; hoffmann, p.; ugi, i.k., j.am.chem.soc.1970,92, 5389-5393; (b) battelle, l.f.; bau, R.; gokel, g.w.; oyakawa, r.t.; ugi, i.k., angel w.chem.int.ed.1972,11, 138-; (c) battelle, l.f.; bau, R.; gokel, g.w.; oyakawa, r.t.; ugi, i.k., j.am.chem.soc.1973,95, 482-486; (d) gokel, g.w.; ugi, i.k., j.chem.educ.1972,49, 294-; [ MEANS FOR solving PROBLEMS ] is provided. Since then, the preparation of chiral Ugi's amines by enzymatic catalysis has become the predominant method, namely the preparation of kilogram scale quantities using enzyme-selective esterification of racemic 1-ferrocenyl ethanol. To avoid the cumbersome recrystallization process, chiral centers are now introduced in the previous step when preparing Ugi's amine, i.e. chiral 1-ferrocenyl ethanol is prepared and then optically pure Ugi's amine is synthesized. However, the above methods often suffer from problems of chiral purity or low synthesis efficiency and the need to use expensive chiral catalysts in kilogram preparations [ a) blast, h.u.; pugin, b.; spindler, f.; thommen, m., acc, chem, res, 2007,40, 1240-; (b) schwink, l.; knochel, p.; tetrahedron lett.1996,37, 25-28; (c) blast, h.u.; spindler, f.; studer, m., appl.calal., a 2001,221, 119-; kok, s.h.l.; Au-Yeung, t.t.l.; wu, j.; cheung, h.y.; lam, F.L.; yeung, c.h.; chan, a.s.c., adv.syn.cata.2006,348,370-374. The characteristics of chiral Ugi's amine determine that it is a key intermediate in the preparation of chiral ferrocene ligands with high optical activity, and the preparation of chiral ferrocene derivatives with SFc configuration from Ugi's amine with R configuration is a common strategy for chiral ferrocene ligand synthesis [ Hayashi, t.; mise, t.; fukushima, m.; kagotani, m.; nagashima, n.; hamada, y.; matsumoto, a.; kawakami, s.; konishi, m.; yamamoto, k.; kumada, m.; bull. chem. Soc. Jpn.1980,53,1138-1151 ]. In view of the wide application of chiral ferrocene compounds but the lack of efficient synthesis technology to prepare a large amount of chiral Ugi's amine, researchers hope to find a method for efficiently and cheaply synthesizing chiral Ugi's amine without using a chiral resolution mode and further efficiently and cheaply synthesizing chiral Josiphos ferrocene diphosphine ligand.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides a brand-new chiral ferrocene compound key intermediate chiral Ugi's amine and a preparation method of a derivative and an optical isomer thereof. The invention utilizes the chiral amine which is easy to obtain commercially to efficiently synthesize the chiral Ugi's amine with high optical purity, and can utilize the chiral Ugi's amine to prepare a series of Josiphos ferrocene diphosphine ligands, and the Josiphos ferrocene diphosphine ligands have wide application in metal-catalyzed asymmetric reactions.

The invention provides a method for synthesizing chiral Ugi's amine shown in formula (I) and derivatives and optical isomers thereof, wherein the reaction process is shown in a scheme (1);

specifically, the method comprises the following reaction steps:

1) carrying out reductive amination reaction on the ferrocene derivative shown in the formula (V) and chiral amine shown in the formula (VI) to obtain a compound shown in the formula (IV);

2) carrying out reductive amination reaction or alkylation reaction on the amino group of the compound in the formula (IV) to obtain a compound in a formula (III);

3) a compound of the formula (III) with an acid anhydride (R)⁶CO)₂Carrying out substitution reaction on O to obtain a compound shown in a formula (II);

4) a compound of formula (II) with an amine HNR³R⁴The chiral Ugi's amine of formula (I) and its derivatives and optical isomers are obtained by amine substitution.

Wherein, in the step (1):

the reductive amination reaction is to perform condensation reaction on a compound shown as a formula (V) serving as a raw material and chiral amine shown as a formula (VI) under a Lewis acid condition to generate imine; and then carrying out reduction imine reaction under the action of a reducing agent to obtain the compound shown in the formula (IV).

Wherein the Lewis acid is tetraisopropyl titanate Ti (Oi-Pr)₄Aluminum trioxide Al₂O₃And the like.

Wherein the reducing agent is sodium borohydride NaBH₄Borane BH₃Triethylsilane Et₃SiH, zinc borohydride Zn (BH)₄)₂And the like.

Wherein the condensation reaction is carried out in a solvent such as ethanol or toluene; the imine reduction reaction is carried out in methanol and/or ethanol.

Wherein, the molar ratio of the compound shown in the formula (V) to the Lewis acid and the chiral amine shown in the formula (VI) is respectively 1: (1-3): (1-3).

Wherein the reaction temperature of the condensation reaction is 35-45 ℃.

Wherein the reaction time of the condensation reaction is 8-24 h.

Wherein the reaction temperature of the reduction imine reaction is 25 ℃;

wherein the reaction time of the reduction imine reaction is 1-24 h.

Wherein, in the step (2):

the reductive amination reaction is to react a compound shown in a formula (IV) with aldehyde in a protic organic solvent under the action of sodium cyanoborohydride to generate a compound shown in a formula (III).

The alkylation reaction of the amido is to react a compound shown in a formula (IV) with alkyl halide to generate a compound shown in a formula (III).

Wherein, in the reductive amination reaction:

wherein the protic organic solvent is methanol or ethanol.

The aldehyde includes formaldehyde, acetaldehyde.

The alkyl halides include methyl iodide, ethyl iodide and ethyl bromide.

Wherein the molar ratio of the compound shown in the formula (IV) to the cyano sodium borohydride and the aldehyde is 1: (0.5-2.0): (2.0-6.0).

Wherein the reaction temperature of the reductive amination reaction is 15-50 ℃.

Wherein the reaction time of the reductive amination reaction is 1-24 h.

Wherein, in the alkylation reaction of the amino:

wherein the molar ratio of the compound shown in the formula (IV) to the alkyl halide is 1 (1-10).

Wherein the reaction temperature of the reductive amination reaction of the amine group is 15-50 ℃;

wherein the reaction time of the reductive amination reaction of the amine group is 1-24 h.

Wherein, in the step (3),

the substitution reaction is that the compound shown as the formula (III) is in acid anhydride (R)⁶CO)₂And reacting in O to obtain the compound shown in the formula (II).

Wherein the molar ratio of the compound shown in the formula (III) to the acid anhydride is 1: (1-20).

Wherein the reaction temperature of the substitution reaction is 60-80 ℃;

wherein the reaction time of the substitution reaction is 1-8 h.

Wherein, in the step (4),

the amine substitution reaction is that in methanol, a compound shown as a formula (II) and amine HNR³R⁴The compound shown in the formula (I) is prepared by reaction.

Wherein, the compound shown as the formula (II) reacts with amine HNR³R⁴In a molar ratio of 1: (1.0-6.0).

Wherein the reaction temperature of the amine substitution reaction is 15-50 ℃;

wherein the reaction time of the amine substitution reaction is 2-24 h.

Wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r³And R⁴Each independently is hydrogen or C_1-6Alkyl, aryl, R³And R⁴Form a 4-8 membered ring with the nitrogen atom to which it is attached, the ring formed may contain 1-3 heteroatoms; r⁵Is C_1-6An alkyl group; r⁶Is C_1-6Alkyl, aryl; ar is aryl.

In a preferred embodiment of the present invention, said R, R¹、R³、R⁴、R⁵、R⁶Are respectively Me, R²Is H, Ar is phenyl or substituted phenyl.

In another preferred embodiment of the present invention, said R, R¹、R³、R⁴、R⁵、R⁶Are respectively Me, R²In the form of Et (ethyl acetate),ar is phenyl or substituted phenyl.

Wherein the compound of formula (IV), the compound of formula (III), the compound of formula (II) and the compound of formula (I) are optical isomers corresponding to the compounds.

In a preferred embodiment of the present invention, a method for synthesizing chiral Ugi's amines of formula (Ia) and optical isomers thereof comprises the following reaction steps:

1) performing a condensation reaction on acetyl ferrocene shown in a formula (Va) and chiral R (+) - α -methylbenzylamine shown in a formula (VIa), and then performing a reduction reaction to obtain a compound shown in a formula (IVa);

2) reacting the compound shown in the formula (IVa) with formaldehyde, and then carrying out reduction reaction to obtain a compound shown in a formula (IIIa); or reacting the compound shown in the formula (IVa) with methyl iodide to obtain a compound shown in a formula (IIIa);

3) a compound represented by the formula (IIIa) with acetic anhydride (MeCO)₂O reaction to obtain a compound shown as a formula (IIa);

4) a compound of formula (IIa) with an amine HNMe₂Obtaining chiral Ugi's amine shown in a formula (Ia) and derivatives and optical isomers thereof after substitution reaction;

the reaction process is shown in scheme 1-a:

the invention also provides a method for synthesizing the chiral compound of the formula (III) and the derivative and the optical isomer thereof, wherein the compound of the formula (IV) is subjected to reductive amination of amino or alkylation reaction of amino to obtain the compound of the formula (III); the reaction process is shown as a reaction formula (1):

wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r⁵Is C_1-6An alkyl group; ar is aryl。

The invention also provides a method for synthesizing the chiral compound shown in the formula (II) and an optical isomer thereof, which specifically comprises the following reaction steps:

a compound represented by the formula (III) below and an acid anhydride (R)⁶CO)₂And O reaction to obtain the compound shown in the formula (II).

Wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r⁵Is C_1-6An alkyl group; r⁶Is C_1-6Alkyl, aryl; ar is aryl.

Preferably, said R is Me, said R¹Is Me or Bn, said R²Is hydrogen, Me, Et, Cl or Br, said R⁵Is Me, said R⁶Me, Ar is phenyl or substituted phenyl.

The compound represented by the formula (III) and the acid anhydride (R) of the present invention⁶CO)₂O to give the compound of formula (II), in a preferred embodiment R, R¹、R⁵、R⁶Are respectively Me, R²Is H, Ar is phenyl or substituted phenyl.

The compound represented by the formula (III) and the acid anhydride (R) of the present invention⁶CO)₂O to give R, R in another preferred embodiment, in the compound of formula (II)¹、R⁵、R⁶Are respectively Me, R²Is Et, Ar is phenyl or substituted phenyl.

The invention provides another method for synthesizing chiral Ugi's amine shown in formula (I) and derivatives thereof and optical isomers thereof, the reaction process is shown in a scheme (2),

specifically, the method comprises the following reaction steps:

1) carrying out hydrogenolysis reaction (or called as hydrodebenzyl) on the compound shown in the formula (IV) to obtain a compound shown in a formula (VII);

2) the compound shown in the formula (VII) is subjected to reductive amination reaction or amine alkylation reaction to obtain chiral Ugi's amine shown in the formula (I) and derivatives and optical isomers thereof.

Wherein, in the step (1),

the hydrogenolysis reaction is carried out by reacting the compound shown as the formula (IV) in Pd/C or Pd (OH) in a protonic organic solvent₂Under the action of H₂The reaction takes place to give the compound of formula (VII).

Wherein the protic solvent is methanol or ethanol.

Wherein the compound of formula (IV) is reacted with the Pd/C or Pd (OH)₂The mass ratio of (1): (1% to 20%).

Wherein the reaction temperature of the hydrogenolysis reaction is 25-55 ℃.

Wherein the reaction time of the hydrogenolysis reaction is 4-48 h.

Wherein, in the step (2),

the reductive amination reaction is carried out in a protic organic solvent in hydrogen H₂Under the action, the compound of the formula (VII) reacts with aldehyde to prepare the compound of the formula (I). The amine alkylation reaction is to react a compound shown in a formula (VII) with halogenated hydrocarbon in a protic organic solvent to prepare a compound shown in a formula (I).

Wherein, in the reductive amination reaction,

wherein the protic solvent is methanol or ethanol.

Wherein the aldehyde comprises formaldehyde and acetaldehyde.

Wherein the molar ratio of the compound of formula (VII) to aldehyde is 1: (2-10).

Wherein the reaction temperature of the reductive amination reaction is 25-60 ℃.

Wherein the reaction time of the reductive amination reaction is 2-24 h.

Wherein, in the amine alkylation reaction,

wherein the protic solvent is methanol or ethanol.

Wherein the halogenated hydrocarbon is R³X and/or R⁴X comprises methyl iodide, ethyl iodide and ethyl bromide.

Wherein the molar ratio of the compound of formula (VII) to the halogenated hydrocarbon is 1: (1-10).

Wherein the reaction temperature of the amine alkylation reaction is 25-35 ℃.

Wherein the reaction time of the amine alkylation reaction is 1-12h ℃.

Wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r³And R⁴Each independently is hydrogen or C_1-6Alkyl, aryl, R³And R⁴Form a 4-8 membered ring with the nitrogen atom to which it is attached, the ring formed may contain 1-3 heteroatoms; ar is aryl.

In a preferred embodiment of the present invention, said R, R¹、R³、R⁴Are respectively Me, R²Is H, Ar is phenyl or substituted phenyl.

In another preferred embodiment of the present invention, said R, R¹、R³、R⁴Are respectively Me, R²Is Et, Ar is phenyl or substituted phenyl.

In a specific embodiment of the present invention, the method for synthesizing chiral Ugi's amine represented by formula (Ia) and optical isomers thereof comprises the following reaction steps:

1) compounds of formula (IVa) in Pd/C or Pd (OH)₂Under the action of an isocatalyst with H₂Reaction occurs to produce a compound of formula (VIIa).

2) Reacting the compound shown in the formula (VIIa) with formaldehyde, and then carrying out reduction reaction to obtain a compound shown in a formula (Ia); or reacting the compound shown in the formula (VIIa) with methyl iodide to obtain a compound shown in a formula (Ia); the reaction is shown in scheme 2-a;

the invention also provides a method for synthesizing chiral amine shown in the formula (VII) and optical isomers thereof, which specifically comprises the following reaction steps:

compounds of formula (IV) in Pd/C or Pd (OH)₂Under the action of an isocatalyst with H₂Reacting to generate a compound shown in a formula (VII); the reaction is as described in the reaction formula (3)

Wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; ar is aryl.

In the present invention, the R, R is a preferred embodiment in the preparation of the compound of formula (VII) from the compound of formula (IV)¹Are respectively Me, R²Is H, Ar is phenyl or substituted phenyl.

In the present invention, the R, R is another preferred embodiment in the preparation of the compound of formula (VII) from the compound of formula (IV)¹Are respectively Me, R²Is Et, Ar is phenyl or substituted phenyl.

The invention also provides a method for synthesizing chiral Ugi's amine shown in formula (I) and derivatives thereof and optical isomers thereof,

specifically, the method comprises the following reaction steps:

carrying out reductive amination or alkylation reaction on the compound shown in the formula (VII) to obtain chiral Ugi's amine shown in the formula (I) and derivatives and optical isomers thereof; the reaction is shown in the reaction formula (4).

Wherein R is¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r³And R⁴Each independently is hydrogen or C_1-6Alkyl, aryl, R³And R⁴Form a 4-8 membered ring with the nitrogen atom to which it is attached, and the ring formed may contain 1-3 heteroatoms.

In the preparation of the compound of formula (I) from the compound of formula (VII) according to the present invention, in a preferred embodiment, said R, R¹、R³、R⁴Are respectively Me, R²Is H.

In the present invention, R, R is described in the preparation of the compound of formula (I) from the compound of formula (VII)¹、R³、R⁴Are respectively Me, R²Is Et.

The invention also provides chiral ferrocene compounds shown as formulas (IV '), (VII '), (I ').

Wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r³And R⁴Each independently is hydrogen or C_1-6Alkyl, aryl, R³And R⁴Form a 4-8 membered ring with the nitrogen atom to which it is attached, the ring formed may contain 1-3 heteroatoms; ar is aryl.

Wherein, the compounds (IV '), (VII '), (I ') are corresponding optical isomers.

The invention also provides application of the chiral ferrocene compounds shown as the formulas (IV '), (VII'), (I ') in preparing chiral Ugi's amine

The invention also provides an application of the chiral ferrocene compound shown as formulas (IV '), (VII '), (I ') in preparing Josiphos ferrocene diphosphine ligand, which comprises the following steps: directly carrying out substitution reaction to prepare different types of Josiphos ferrocene diphosphine ligands.

The synthetic method has the advantages of mild conditions, easily obtained and cheap raw materials, simple synthetic route and higher yield, and the product of the compound shown in the formula (I) is used as an important intermediate of the chiral ferrocene Josiphos diphosphine ligand and is widely suitable for industrial scale production. The synthetic method of the invention efficiently synthesizes chiral Ugi's amine with high optical purity and derivatives thereof by utilizing commercially available chiral amine, improves the yield of the whole route and the optical purity of the product, has simple and easily-removed impurities and controllable cost.

The terms used in the present invention have the following meanings, unless otherwise stated:

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.

"aryl" refers to 6 to 10 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups, polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

Abbreviation table:

Detailed Description

The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Example 1

Va (100.0g, 438.4mmol), tetraisopropyl titanate [ Ti (OiPr)₄](263.0mL, 876.9mmol) and R- (+) - α -methylbenzylamine (113.1mL, 876.9mmol) in a 2000mL round bottom flask, dissolved in 500.0mL EtOH, stirred for 14h and then NaBH was weighed₄(24.9g, 657.7mmol) were added portionwise to the reaction flask, which was then stirred for a further 2h and the solvent was removed by rotary evaporation. The residue was dissolved in 2400.0mL of methyl tert-butyl ether (MTBE), followed by addition of 1200.0mL of 2N hydrochloric acid, stirring for 2h, and filtration to give a yellow solid which was freed with base to give 86.0g of the title compound IVa, yield: 58.9% yellow solid. Mass spectrometric analysis MALDI-TOF-MS M/z 333 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.26-7.33(m,4H),7.19-7.23(m,1H),4.09(br. s.,1H),4.05(d,J＝6.8Hz,2H),4.01(s,5H),3.95(s,1H),3.72-3.79(m,1H),3.26(q,J＝6.4Hz, 1H),1.33(d,J＝6.3Hz,3H),1.16(d,J＝6.3Hz,3H)。

Route 1:

example 2

IVa (68.0g, 240.1mmol) and NaBH were weighed₃CN (10.3g, 163.2mmol) was dissolved in 340.0mL of MeOH in a 1000mL round-bottom flask, and an aqueous formaldehyde solution (58.0g, 714.2mmol, 37%) was weighed and added dropwise to the flask with stirring. After 2h the reaction was complete and quenched by addition to 3400.0mL of water to precipitate a large amount of yellow solid which was filtered to give 57.1 g of the title compound IIIa, yield: 80.6% and yellow solid. Mass spectrometric analysis MALDI-TOF-MS M/z:347 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.26-7.34(m,4H),7.18-7.22(m,1H),4.04(m,4H),3.95(s,5H),3.72(d,J＝6.8Hz,1H),3.43(d,J＝6.5Hz,1H),1.85(s,3H),1.31(d,J＝6.8Hz, 3H),1.17(d,J＝6.5Hz,3H)。

Example 3

IIIa (25.0g, 72.0mmol) was weighed into a 250mL round bottom flask, dissolved with 125.0mL acetic anhydride and heated to 65 ℃. After 16h the reaction was complete, the acetic anhydride was removed by rotary evaporation, the residue was dissolved in 140.0mL of methanol, and aqueous dimethylamine (24.4g, 216.0mmol, 40%) was weighed out and added dropwise to the reaction flask with stirring. After 16h the reaction was complete and the reaction solution was rotary evaporated to remove MeOH, the residue was diluted with 400.0mL ethyl acetate, washed with water, dried and rotary evaporated to remove ethyl acetate to give 16.1g of the title compound Ia, yield: 87.0% and yellow oil. Mass Spectrometry MALDI-TOF-MS M/z:257 (M)⁺)。

¹H-NMR(CDCl3/TMS,400MHz):δ(ppm)4.02-4.07(m,9H),3.52(d,J＝6.8Hz,1H),2.00(s,6H),1.37(d,J＝7.0Hz,3H)。

Route 2:

practice ofExample 4

Weighing IIIa (44.0g, 132.0mmol) in a 1000mL round bottom flask, adding 300.0mL methanol to dissolve, weighing Pd/C (8.8g, w% ═ 10%), adding into a reaction bottle with stirring, heating to 50 ℃ under hydrogen atmosphere, and finishing the reaction after 16 h. Cooling the reaction liquid to room temperature, measuring a formaldehyde aqueous solution (70.5mL, 868.1mmol, 37%), adding the aqueous solution into a reaction bottle while stirring, heating the reaction liquid to 50 ℃ in a hydrogen environment, after 20 hours of reaction, cooling the reaction liquid to room temperature, filtering to remove Pd/C, performing rotary evaporation to remove methanol, extracting the residue with ethyl acetate, drying, and performing rotary evaporation to remove ethyl acetate to obtain 32.4g of a target compound Ia, wherein the yield is as follows: 95.3% yellow oil. Mass Spectrometry MALDI-TOF-MS M/z:257 (M)⁺)。

Example 5

The procedure is as in example 1, yield: 78.6% and IVb as a brown solid. Mass spectrometric analysis MALDI-TOF-MS M/z 333 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.29(d,J＝4.5Hz,4H),7.18-7.23(m,1H),4.03 -4.11(m,3H),3.99-4.02(m,5H),3.95(s,1H),3.75(d,J＝6.8Hz,1H),3.26(d,J＝6.5Hz,1H), 1.33(d,J＝6.5Hz,3H),1.16(d,J＝6.8Hz,3H)。

Example 6

The procedure is as in example 2, yield: 86.4% and yellow solid IIIb. Mass spectrometric analysis MALDI-TOF-MS M/z:347 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.27-7.32(m,4H),7.18-7.21(m,1H),4.04(s,4H),3.95(s,5H),3.72(d,J＝6.8Hz,1H),3.43(q,J＝6.5Hz,1H),1.85(s,3H),1.31(d,J＝6.8Hz, 3H),1.16-1.19(m,3H)。

Example 7

The procedure is as in example 3, yield: 86.7% and yellow oil Ib. Mass Spectrometry MALDI-TOF-MS M/z:257 (M)⁺)。

¹H-NMR(CDCl3/TMS,400MHz):δ(ppm)4.02-4.07(m,9H),3.52(d,J＝6.8Hz,1H),2.00(s,6H),1.37(d,J＝7.0Hz,3H)。

Example 8

The procedure is as in example 4, yield: 92.0% yellow oil Ib, MALDI-TOF-MSm/z Mass Spectrometry 257 (M)⁺)。

Example 9

VI' a (2.5g, 11.7mmol), acetic anhydride (12.0g, 117.8mmol) were weighed into a 100mL round-bottomed flask, phosphoric acid (3.5g, 35mmol) was weighed into the reaction flask and after the addition was complete, the temperature was raised to 50 ℃. After the reaction is finished after 2h, cooling the reaction liquid to room temperature, adding ice water for quenching, extracting with ethyl acetate, drying, performing rotary evaporation to remove ethyl acetate, and performing column chromatography on the residue to obtain 2.0g of a target compound V' a, wherein the yield is as follows: 67% red brown oil. Mass spectrometric analysis MALDI-TOF-MS M/z: 256 (M)⁺)。

1H-NMR(CDCl3/TMS,300MHz):δ(ppm)4.63(br.s.,2H),4.39(br.s.,2H),4.03(br.s.,4H), 2.32(br.s.,2H),2.21(m,J＝7.3Hz,3H),1.02-1.10(m,J＝7.2Hz,3H)。

Table one: examples 10A to 10E

Examples 10A-10E the same procedure as in example 1 was followed.

Example 10A

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.21(d,J＝8.5Hz,2H),6.83(d,J＝8.8Hz,2H),4.08(s,1H),4.02-4.06(m,2H),4.01(s,5H),3.95(s,1H),3.75(s,3H),3.67-3.72(m,1H),3.24 (q,J＝6.5Hz,1H),1.32(d,J＝6.5Hz,3H),1.13(d,J＝6.5Hz,3H)。

Example 10B

¹H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.18-7.26(m,4H),3.86-4.09(m,9H),3.70(q, J＝6.5Hz,1H),3.11-3.24(m,1H),1.30(d,J＝6.8Hz,3H),1.08-1.12(d,J＝6.5Hz,3H).

Example 10D

¹H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.70-7.88(m,4 H),7.34-7.53(m,3 H),3.95- 4.14(m,9 H),3.89-3.95(m,1 H),3.23-3.36(m,1 H),3.09-3.19(m,1 H),1.37(d,J＝6.5 Hz,3 H),1.20-1.27(d,J＝6.5 Hz,3H).

Example 10E

¹H-NMR(CDCl3/TMS,400MHz):7.35-7.46(m,4H),7.21-7.34(m,1H),4.03-4.20(m,5H),3.99(d,J＝1.5 Hz,3H),3.87(d,J＝6.4 Hz,1H),3.22-3.67(m,1H),2.31(d,J＝7.5Hz,2H), 1.45(d,J＝4.6 Hz,3H),1.29(d,J＝6.4 Hz,3H),1.09-1.25(m,3H)。

Table two: examples 11A to 11E

Examples 11A-11E the same procedure as in example 2 was followed.

Example 11A

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.22(d,J＝8.5Hz,2H),6.82(d,J＝8.5Hz,2H), 4.02-4.05(m,4H),3.96(s,5H),3.76(s,3H),3.69-3.75(m,1H),3.38(d,J＝6.5Hz,1H),1.84(s， 3H),1.30(d,J＝6.8Hz,3H),1.16(d,J＝6.5Hz,3H)。

Table three: examples 12A to 12E

Examples 12A-12E the same procedure as in example 3 was followed.

Table four: examples 13A to 13E

Examples 13A-13E the same procedure as in example 4 was followed.

Example 14

Weighing I (5.0g, 19.4mmol) in a 100mL reaction bottle, dissolving with 50.0mL diethyl ether, dropwise adding sec-butyl lithium (44.9mL, 58.3mmol, 1.3M) into the reaction bottle under the protection of nitrogen, stirring at room temperature for 2h, weighing diphenyl phosphine chloride (4.2mL, 23.3mmol) into the reaction bottle, heating to reflux, after 4h, pouring the reaction liquid into water to quench, extracting with ethyl acetate, drying, removing ethyl acetate by rotary evaporation, and purifying the residue by column chromatography to obtain 7.5g of target compound VIII, wherein the yield is: 87.4% and yellow solid. Mass spectrometric analysis MALDI-TOF-MS M/z:441 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.51(dt,J＝7.3,3.0Hz,2H),7.25-7.31(m,3H), 7.10-7.16(m,5H),4.31(br.s.,1H),4.19(br.s.,1H),4.02-4.13(m,1H),3.87(s,5H),3.80(br.s., 1H),1.71(br.s.,6H),1.20(d,J＝7.3Hz,3H)。

Table five: examples 14A to 14E

Examples 14A-14E example 14 was performed.

Example 15

VIII (4.5g, 11.3mmol) was weighed into a 100mL reaction vialTo this solution, 45.0mL of acetic acid was added and dissolved, and di-tert-butylphosphine (2.3mL, 12.46mmol) was weighed out and added dropwise to the reaction flask and heated to 100 ℃. After 1h the reaction was complete, the reaction was rotary evaporated to remove acetic acid and the residue was purified by column chromatography to give 4.7g of the title compound IX, yield: 76.5% yellow solid. Mass spectrometric analysis MALDI-TOF-MS M/z:542 (M)⁺)。

¹H-NMR(CDCl₃/TMS,400MHz):δ(ppm)7.52-7.60(m,2H),7.24-7.30(m,3H),7.06-7.18(m,5H),4.30(br.s.,1H),4.16(t,J＝2.3Hz,1H),3.93(s,1H),3.77(s,5H),3.31-3.42(m, 1H),1.77(dd,J＝7.3,3.0Hz,3H),1.12(d,J＝10.5Hz,9H),0.92(d,J＝10.5Hz,9H)。

Table six: examples 15A to 15E

Examples 15A-15E example 15 was performed.

The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.

Claims (9)

1. A method for synthesizing chiral Ugi's amine shown in formula I and its derivatives and optical isomers thereof, which is characterized in that the method comprises the following steps:

1) carrying out reductive amination reaction on the ferrocene derivative shown in the formula V and chiral amine shown in the formula VI to obtain a compound shown in the formula IV;

2) carrying out reductive amination reaction or alkylation reaction on the amino group of the compound shown in the formula IV to obtain a compound shown in a formula III;

3) compounds of formula III with anhydrides (R)⁶CO)₂Obtaining a compound shown in a formula II after the O reaction;

4) a compound of formula II with an amine HNR³R⁴Carrying out substitution reaction to obtain chiral Ugi's amine of the formula I, a derivative thereof and an optical isomer thereof;

the reaction process is shown as a scheme (1);

wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r³And R⁴Each independently is hydrogen or C_1-6Alkyl, aryl, R³And R⁴Form a 4-8 membered ring with the nitrogen atom to which it is attached, the ring formed may contain 1-3 heteroatoms; r⁵Is C_1-6An alkyl group; r⁶Is C_1-6Alkyl, aryl; ar is aryl.

2. The synthetic method of claim 1 wherein R is Me and R is¹Is Me or Bn, said R²Is hydrogen, Me, Et, Cl or Br, said R³And R⁴Are each Me, R⁵Is Me, said R⁶Me, Ar is phenyl or substituted phenyl.

3. The synthesis method according to claim 1 or 2, wherein in the step (1), the reductive amination is a condensation reaction of the compound of formula V and the chiral amine of formula VI under the condition of Lewis acid, and then reduction imine reaction is carried out under the action of a reducing agent to obtain the compound of formula IV.

4. The method of claim 3, wherein the Lewis acid is selected from the group consisting of tetraisopropyl titanate Ti (Oi-Pr)₄Or aluminum trioxide Al₂O₃(ii) a The reducing agent is sodium borohydride NaBH₄Borane BH₃Triethylsilane Et₃SiH or zinc borohydride Zn (BH)₄)₂。

5. The synthesis method of claim 1 or 2, wherein in the step (2), the reductive amination is carried out by reacting the compound shown in formula IV with aldehyde in a protic organic solvent under the action of sodium cyanoborohydride to produce the compound shown in formula III; the alkylation reaction of the amido is that the compound shown in the formula IV and alkyl halide react to generate the compound shown in the formula III.

6. The synthesis method according to claim 1 or 2, wherein in the step (3), the molar ratio of the compound represented by the formula III to the acid anhydride is 1 (1-20).

7. The synthesis process according to claim 1 or 2, wherein in step (4), the compound of formula II is reacted with an amine HNR³R⁴In a molar ratio of 1: (1.0-6.0).

8. A method for synthesizing chiral compound of formula II, its derivative and its optical isomer is characterized by that, the compound of formula III and acid anhydride (R)⁶CO)₂O reaction to obtain a compound shown in a formula II;

wherein R is C_1-6An alkyl group; r¹Is C_1-6Alkyl, aryl; r²Is hydrogen, C_1-6Alkyl, aryl, halogen; r⁵Is C_1-6An alkyl group; r⁶Is C_1-6Alkyl, aryl; ar is aryl.

9. The synthetic method of claim 8 wherein R is Me and R is¹Is Me or Bn, said R²Is hydrogen, Me, Et, Cl or Br, said R⁵Is Me, said R⁶Me, Ar is phenyl or substituted phenyl.