CN109721630A - A kind of synthetic method of Ugi ' s amine and its derivative - Google Patents

A kind of synthetic method of Ugi ' s amine and its derivative Download PDF

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CN109721630A
CN109721630A CN201711042263.9A CN201711042263A CN109721630A CN 109721630 A CN109721630 A CN 109721630A CN 201711042263 A CN201711042263 A CN 201711042263A CN 109721630 A CN109721630 A CN 109721630A
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formula
derivative
amine
primary amine
acid
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应永铖
姜雪峰
滕海鸽
俞斐
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Shanghai Maosheng Kaihui Technology Co Ltd
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Abstract

The invention discloses the synthetic methods of one kind Ugi's amine as shown in formula (I) and its derivative, the method is using Ferrocene and its derivative as raw material, racemic modification primary amine is obtained through reduction amination, then racemic modification primary amine is split through resolving agent, optical isomer primary amine is obtained, optical isomer primary amine obtains the Ugi's amine and its derivative through alkylated reaction or reductive amination process.The chirality Ugi's amine and its derivative can be used for synthesizing a series of Josiphos class ferrocene biphosphine ligands, using the chiral ligand as various metal complex catalysts, it is to prepare medicine intermediate, the important chiral catalyst ligand of agricultural chemicals, it has a wide range of applications in the asymmetric reaction of metal catalytic, and is suitable for industrial-scale production.Reaction condition of the present invention is mild, and raw material is easy to get inexpensive, and synthetic route is simple, and yield and chiral purity are higher.

Description

A kind of synthetic method of Ugi ' s amine and its derivative
Technical field
The invention belongs to chiral chemistry synthesis technical fields, and in particular to a kind of chirality Ugi ' s amine (Ugi ' s Amine) and The synthesis of its derivative.
Background technique
Chiral ferrocene has extensive research in asymmetry catalysis, material science and field of biomedicine [(a)Hyashi,T.；Togni,A.,Eds.In Ferrocenes；VCH:Weinheim,Germany,1995.(b)Togni, A.；Haltermann,R.L.,Eds.In Metallocenes；VCH:Weinheim,Germany,1998.(c) Stepnicka,P.,Ed.In Ferrocenes；Wiley:Chichester, 2008.], wherein key intermediate chirality Ugi ' s Amine is initially [(a) Marquarding, D. split by racemic modification by (R)-(+)-tartaric acid；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.,Angew.Chem.Int.Ed.1972,11,138- 140；(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- 296.].Hereafter, become main stream approach with the method preparation chirality Ugi ' s amine of enzymatic, i.e., disappear using enzyme selectivity esterification is outer Revolve the scale of 1- ferrocenyl ethyl alcohol preparation feather weight.In order to avoid cumbersome recrystallization process, when preparing Ugi ' s amine now all Chiral centre can be introduced before the step of, i.e., first prepare the chiral 1- ferrocenyl ethyl alcohol then pure Ugi ' s of synthesizing optical again Amine.But that chiral purity or combined coefficient are frequently encountered in feather weight preparation is not high and need using high for the above method The problems such as expensive chiral catalyst [(a) Blaser, H.U.；Pugin,B.；Spindler,F.；Thommen,M., Acc.Chem.Res.2007,40,1240-1250；(b)Schwink,L.；Knochel,P.；Tetrahedron Lett.1996,37,25-28；(c)Blaser,H.U.；Spindler,F.；Studer,M.,Appl.Catal.,A 2001, 221,119-143.(d)Lam,W.S.；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 characteristic of chiral Ugi ' s amine It determines that it becomes key intermediate in the chiral ferrocene ligands preparation of high optical activity, is prepared with Ugi ' the s amine of R configuration The chiral ferrocene derivative of SFc configuration is common strategy [Hayashi, the T. of chiral ferrocene ligands synthesis；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 hand Property the extensive purposes of ferrocene-containing compound, but lack efficient synthesis technology largely to prepare chiral Ugi ' s amine.
As described above, the synthetic method of document report Split Method synthesis of chiral Ugi ' s amine has:
(1) it splits and prepares optically pure Ugi ' s amine method:
Gokel,G.W.,J.Chem.Edu.1972,49(4),294-296.
There is the problems such as fractionation is at high cost, and target product chiral purity ee value is low, needs recrystallization purifying repeatedly in this method.
(2) enzyme catalysis method prepares chiral ferrocene ethyl alcohol and photo-reduction ferrocenyl methyl ketone method, then synthesis of chiral Ugi ' s amine method:
Boaz,N-W.,Tetrahedron Lett.,1989,30,2061-2064.
Blaser,H-U.,Acc.Chem.,Res.,2007,40,1240-1250.
Enzyme catalysis method is there are resolution reagent valuableness, the problems such as synthesis yield is low low with optical purity.
The problems such as photoreduction met hod prepares the presence of chiral ferrocene ethyl alcohol and can not be mass produced, and optical purity is low.
Summary of the invention
The present invention provides the synthetic methods of a kind of new Ugi ' s amine (Ugi ' sAmine) and its derivative.This method with Ferrocene and its derivative shown in formula (V) is raw material, reacted to obtain racemic modification primary amine shown in formula (IV), then described Racemic modification primary amine is split through resolving agent, obtains optical isomer primary amine shown in formula (III) and formula (II), the optical isomer Primary amine obtains Ugi ' s amine and its derivative as shown in formula (I) through alkylation or reductive amination process.The reaction process is as follows Shown in reaction equation (1).
Wherein, R1For C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, aryl；
R2For C1-6Alkyl, aryl, halogen, hydrogen；
R3And R4It is each independently respectively hydrogen, C1-6Alkyl, aryl；R3And R44-8 member is formed with the nitrogen-atoms being connect Ring, being formed by ring may include 1-3 hetero atom.
Preferably, R1For Me, Bn, Et, Pr, i-Pr, t-Bu；
R2For Me, Et, Cl, Br, hydrogen；
R3And R4Respectively Me, Et, Pr, i-Pr, Bn, R3And R44-8 member ring is formed with the nitrogen-atoms being connect, is formed Ring may include 1-3 hetero atom, the hetero atom is N, O, S.
The synthetic method of Ugi ' s amine and its derivative proposed by the present invention specifically includes following reaction step:
1) under reducing agent effect, Ferrocene and its derivative shown in formula (V) and organic ammonium salt are through reductive amination process Afterwards, racemic modification primary amine shown in formula (IV) is obtained；
2) racemic modification primary amine shown in formula (IV) obtains shown in formula (III) and formula (II) after resolving agent is split Optical isomer primary amine；
3) optical isomer primary amine and alkylating reagent shown in formula (III) and formula (II) are through alkylated reaction, or and aldehyde With reducing agent after reductive amination process, Ugi ' s amine and its derivative shown in formula (I) are obtained；
Wherein, R1For C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, aryl；R2For C1-6Alkyl, aryl, halogen, hydrogen； R3And R4It is each independently respectively hydrogen, C1-6Alkyl, aryl, R3And R44-8 member ring is formed with the nitrogen-atoms being connect, is formed Ring may include 1-3 hetero atom.
In the present invention, the compound (III), (II), (I) are the optical isomer corresponding to it.
In step 1), ferrocene shown in the formula (V) includes ferrocenyl methyl ketone.
In step 1), the temperature of the reductive amination process is 0-150 DEG C；It preferably, is 80-120 DEG C.
In step 1), the time of the reductive amination process is 0-40h；It preferably, is 4-15h.
In step 1), the reducing agent is selected from sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), borine (BH3), triethylsilane (Et3SiH), zinc borohydride (Zn (BH4)2), lithium aluminium hydride reduction (LiAlH4), potassium borohydride (KBH4), Vitride red aluminum solution, zinc amalgam, tetramethyl disiloxane, one of three tert-butyl alcohol lithium aluminium hydride reductions etc. or a variety of；It is preferred that Ground is sodium borohydride (NaBH4) or sodium cyanoborohydride (NaBH3CN)。
In step 1), the dosage of the reducing agent is the 1.0- of Ferrocene and its derivative dosage shown in formula (V) 10.0eq；It preferably, is 3.0-6.0eq.
In step 1), the organic ammonium salt be selected from ammonium acetate, ammonium formate, ammonium oxalate, fluorenes methoxy carbonyl amide, fluoroacetic acid ammonium, One of trifluoroacetic acid ammonium, dihydroxy aluminium ammonium acetate, 2- hydroxyacetic acid ammonium, naphthalene -1- ammonium acetate etc. are a variety of；Preferably, it is Ammonium acetate.
In step 1), the dosage of the organic ammonium salt is the 1.0- of Ferrocene and its derivative dosage shown in formula (V) 30.0eq；It preferably, is 2.0-15.0eq.
In step 2), the resolving agent is acid resolving agent, is selected from tartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, apple Tartaric acid, acetyl tartaric acid acid anhydride, two toluoyl tartaric acid, aspartic acid, glutamic acid, pyroglutamic acid, quininic acid, methylbenzyl One of isocyanates etc. is a variety of；It preferably, is tartaric acid.
In step 2), the dosage of the resolving agent is the 0.1-10.0eq of racemic modification primary amine dosage shown in formula (IV)； It preferably, is 0.8-3.0eq.
In step 2), the temperature of the split process is 10-190 DEG C；It preferably, is 60-120 DEG C.
In step 2), the time of the split process is 0.2-12h；It preferably, is 0.5-3h.
In step 3), the alkylating reagent be selected from formaldehyde, paraformaldehyde, iodoethane, bromoethane, iodopropane, N-Propyl Bromide, One of formic acid, dimethyl suflfate, dithyl sulfate, dibutyl sulfate, p-methyl benzenesulfonic acid ester etc. are a variety of；Preferably, it is Iodoethane, bromoethane.
In step 3), the dosage of the alkylating reagent is optical isomer primary amine dosage shown in formula (III) or (II) 0.1-20.0eq.
In step 3), the temperature of the alkylated reaction is 0-200 DEG C；It preferably, is 25-120 DEG C.
In step 3), the time of the alkylated reaction is 0.5-40h；It preferably, is 1-5h.
In step 3), the reductive amination process is that optical isomer primary amine shown in formula (III) or (II) and aldehyde are condensed Afterwards, then through reducing agent reduction reaction Ugi ' s amine and its derivative shown in formula (I) is made.
Wherein, aldehyde used in the reductive amination process is in formaldehyde, acetaldehyde, paraformaldehyde, fatty aldehyde, aromatic aldehyde It is one or more；It preferably, is formaldehyde, paraformaldehyde；
Wherein, the dosage of the aldehyde is the 0.1- of optical isomer primary amine dosage shown in formula (III) or formula (II) 20.0eq。
Wherein, the reducing agent is selected from sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), triacetoxy borohydride Sodium hydride (NaBH (OAc)3), 2- picoline-N- monoborane, lithium aluminium hydride reduction (LiAlH4), potassium borohydride (KBH4One of) Or it is a variety of；It preferably, is sodium cyanoborohydride (NaBH3CN), sodium triacetoxy borohydride (NaBH (OAc)3), 2- methyl pyrrole One of pyridine-N- monoborane is a variety of.
Wherein, the dosage of the reducing agent is the 0.1- of optical isomer primary amine dosage shown in formula (III) or formula (II) 20.0eq；It preferably, is 1-20.0eq；It is further preferred that being 1.0-6.0eq.
In step 3), the temperature of the reductive amination process is 10-200 DEG C；It preferably, is 60-150 DEG C.
In step 3), the time of the reductive amination process is 0.5-30h；It preferably, is 1-10h.
The invention also provides Ugi ' s amine and its derivative as shown in formula (I),
Wherein, R1For C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, aryl；
R2For C1-6Alkyl, aryl, halogen, hydrogen；
R3And R4It is each independently respectively hydrogen, C1-6Alkyl, aryl, R3And R44-8 member is formed with the nitrogen-atoms being connect Ring, being formed by ring may include 1-3 hetero atom.
Preferably, R1For Me, Bn, Et, Pr, i-Pr, t-Bu；
R2For Me, Et, Cl, Br, hydrogen；
R3And R4Respectively Me, Et, Pr, i-Pr, Bn, R3And R44-8 member ring is formed with the nitrogen-atoms being connect, is formed Ring may include 1-3 hetero atom, the hetero atom is N, O, S；
The invention also provides Ugi ' s amine and its derivatives as shown in formula (I) being prepared as above-mentioned synthetic method.
The invention also provides Ugi ' the s amine and its derivatives to synthesize a series of Josiphos class ferrocene pair in preparation Application in Phosphine ligands, wherein a series of Josiphos class ferrocene biphosphine ligands can be used as various complex catalysts Chiral ligand has a wide range of applications in the asymmetric reaction of metal catalytic.
The beneficial effects of the present invention are: the chiral Ugi ' s amine and its derivative that the present invention is prepared can be used for synthesizing A series of Josiphos class ferrocene biphosphine ligands are to prepare medicine using the chiral ligand as various metal complex catalysts Intermediate, the important chiral catalyst ligand of agricultural chemicals, has a wide range of applications in the asymmetric reaction of metal catalytic, And it is suitable for industrial-scale production.Reaction condition of the present invention is mild, and raw material is easy to get inexpensive, and synthetic route is simple, yield and Chiral purity is higher.
Referred to as corresponding full name is used in specification corresponds to table
Entry Abbreviation Full name
1 D-DBTA D- dibenzoyl tartaric acid
2 D-DTTA D- bis- is to toluyl tartaric acid
3 DMF Dimethylformamide
4 TA Tartaric acid
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition, Experimental method etc. is among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, and the present invention does not have Especially limitation content.
The present invention is explained in detail below with reference to specific example, so that those skilled in the art more fully Xie Benfa Bright, specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
Embodiment 1
Ferrocenyl methyl ketone V-1 (23.00g, 0.10mol, 1.0eq) is weighed in 500mL round-bottomed flask, is added 230.0mL MeOH dissolution.Be added under nitrogen environment ammonium acetate (77.00g, 1.00mol, 10.0eq) and acetic acid (3.00g, 0.05mol, 0.5eq), sodium cyanoborohydride (12.60g, 0.20mol, 2.0eq), be heated to 90 DEG C under stirring, reaction 4h, vacuum distillation removal methanol, is added water, methylene chloride, extracting and demixing, and methylene chloride is concentrated under reduced pressure out in organic layer, and water is added With hydrochloric acid, after the back extraction of PE:EA=5:1 mixed liquor, methylene chloride is added in water phase, adjusts PH > 10 with sodium hydrate solid, point Layer, methylene chloride phase anhydrous sodium sulfate is dry, methylene chloride is concentrated under reduced pressure out obtains red liquid IV-1 (20.40g, 0.089mol) Y=89.1%.
1H NMR (400MHz, CHLOROFORM-d) ppm 1.28 (d, J=6.53Hz, 3H) 1.57 (br.s., 2H) 3.73 (q, J=6.53Hz, 1H) 4.05 (s, 2H) 4.06-4.14 (m, 7H)
Embodiment 2
Ferrocenyl methyl ketone V-1 (11.40g, 0.05mol, 1.0eq) is weighed in 500mL round-bottomed flask, is added 60.0mLMeOH dissolution.Ammonium chloride (15.00g, 0.15mol, 3.0eq) and tetraisopropyl titanate are added under nitrogen environment (28.40g, 0.10mol, 2.0eq), after being stirred overnight at room temperature, sodium borohydride (8.0g, 0.15mol, 3.0eq) is added portionwise, adds Finish, stirring 2 hours or more, rotary evaporation removed solvent.Residue adds MTBE to dissolve, and then adds 2N hydrochloric acid, stirs 2h, uses After the back extraction of PE:EA=5:1 mixed liquor, methylene chloride is added in water phase, adjusts PH > 10, layering, dichloro with sodium hydrate aqueous solution Methane phase anhydrous sodium sulfate is dry, methylene chloride is concentrated under reduced pressure out obtains red liquid IV-1 (8.40g, 0.037mol) y= 74.0%.
1H NMR (400MHz, CHLOROFORM-d) ppm 1.28 (d, J=6.53Hz, 3H) 1.57 (br.s., 2H) 3.73 (q, J=6.53Hz, 1H) 4.05 (s, 2H) 4.06-4.14 (m, 7H)
Embodiment 3
IV-1 (15.00g, 0.0655mol) and 90% ethyl alcohol 750ml are weighed in the three-necked flask of 1000mL, adds D- wine Stone acid (9.80g, 0.0655mol), is heated to whole dissolutions under stirring, Temperature fall is precipitated solid, II-1 is filtered to obtain, by II- 1 with after 90% ethyl alcohol recrystallization rufous liquid II-1 (4.70g, 0.0205mol) y=31.3%, ee 99.5%
Filtrate merging will be crystallized twice, be added after decompression 20% sodium carbonate liquor (200ml), methylene chloride 200ml extraction Three times, dry precipitation obtains 10.90g red liquid.By 10.90g red liquid, 90% ethyl alcohol (550mL) is added tri- mouthfuls of 1000ml It in flask, is added L-TARTARIC ACID (7.13g, 0.0476mol, 1.00eq), is heated to complete molten rear Temperature fall, 60 DEG C are precipitated admittedly Body, 40 DEG C are filtered to obtain 14.20g yellow solid wet product.14.20 solids are added in 500ml there-necked flask, 90% ethyl alcohol is added (430mL), 60 DEG C of heating complete molten 55 DEG C latter, and 45 DEG C of filterings obtain yellow solid wet product, add methylene chloride, 10% sodium hydroxide water Solution, extracting and demixing, dichloromethane layer is dry with anhydrous sodium sulfate, precipitation obtain rufous liquid III-1 (4.95g, 0.0216mol), y=33.0%, ee 99.6%.
Embodiment 4
IV-1 (23.0g, 1.00mol) and methanol 460ml are weighed in the three-necked flask of 1000mL, adds D-DBTA (35.8g, 1.00mol), is heated to whole dissolutions under stirring, Temperature fall, and solid is precipitated, filter III-1 crude product, will Rufous liquid III-1 (5.75g, 0.025mol) y=25.0%, ee is obtained after 90% recrystallizing methanol of the crude product of III-1 99.2%
Embodiment 5
IV-1 (23.0g, 1.00mol) and methanol 460ml are weighed in the three-necked flask of 1000mL, adds D-DTTA (33.0g, 1.00mol), is heated to whole dissolutions under stirring, Temperature fall, and solid is precipitated, filter III-1 crude product, will Rufous liquid III-1 (5.93g, 0.026mol) y=25.8%, ee is obtained after 90% recrystallizing methanol of the crude product of III-1 99.0%
Embodiment 6
III-1 (0.74g, 3.23mmol) is weighed in the round-bottomed flask of 100mL, 10mL methanol, cyano hydroboration is added Sodium (0.61g, 9.69mmol), paraformaldehyde (0.48g, 16.15mmol), is heated to flowing back under stirring.3h end of reaction, decompression Methylene chloride, water is added in concentration removal methanol, and layering, the washing of organic phase saturated brine, anhydrous sodium sulfate is dry, is concentrated under reduced pressure Methylene chloride obtains bronzing liquid I-1 (0.81g, 3.15mmol) y=97.0%, ee 99.5% out.
Mass spectral analysis MS (ESI, m/s): 256.8.
1H NMR(400MHz,CHLOROFORM-d)ppm 1.35-1.46(m,3H)1.98-2.10(m,6H)3.48- 3.63(m,1H)4.01-4.11(m,9H)
Embodiment 7
III-1 (2.29g, 0.01mol) is weighed in the round-bottomed flask of 100mL, 25mL methanol, sodium borohydride is added (0.95g, 0.25mol), paraformaldehyde (0.90g, 0.03mol), is heated to flowing back under stirring.1.5h end of reaction depressurizes dense Methylene chloride, water is added in contracting removal methanol, and layering, the washing of organic phase saturated brine, anhydrous sodium sulfate is dry, is concentrated under reduced pressure out Methylene chloride obtains bronzing liquid I-1 (2.30g, 0.01mol) y=89.5%, ee 99.2%.
Mass spectral analysis MS (ESI, m/s): 256.8.
1H NMR(400MHz,CHLOROFORM-d)ppm 1.35-1.46(m,3H)1.98-2.10(m,6H)3.48- 3.63(m,1H)4.01-4.11(m,9H)
Embodiment 8
III-1 (250mg, 1.09mmol) is weighed in the round-bottomed flask of 25mL, is added 5mLDMF, iodoethane (511mg, 3.27mmol), potassium carbonate (603mg, 4.37mmol), is stirred at room temperature, 3h end of reaction, and removal DMF is concentrated under reduced pressure, is added two Chloromethanes, water, layering, the washing of organic phase saturated brine, anhydrous sodium sulfate is dry, and methylene chloride is concentrated under reduced pressure out and obtains bronzing liquid Body I-2 (300mg, 1.05mmol) y=96.5%.
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect Protect range.

Claims (12)

  1. The synthetic method of 1.Ugi ' s amine and its derivative, which is characterized in that be with Ferrocene and its derivative shown in formula (V) Raw material, reacted to obtain racemic modification primary amine shown in formula (IV), then the racemic modification primary amine is split through resolving agent, obtains formula (III) and optical isomer primary amine shown in formula (II), the optical isomer primary amine are anti-through alkylated reaction or reduction amination It should obtain Ugi ' s amine and its derivative as shown in formula (I)；Shown in the reaction process following reaction formula (1)；
    Wherein, R1For C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, aryl；
    R2For C1-6Alkyl, aryl, halogen, hydrogen；
    R3And R4It is each independently respectively hydrogen, C1-6Alkyl, aryl；R3And R44-8 member ring, institute are formed with the nitrogen-atoms being connect The ring of formation may include 1-3 hetero atom.
  2. 2. synthetic method as described in claim 1, which is characterized in that the described method comprises the following steps:
    1) under reducing agent effect, Ferrocene and its derivative shown in formula (V) and organic ammonium salt obtain after reductive amination process To racemic modification primary amine shown in formula (IV)；
    2) racemic modification primary amine shown in formula (IV) obtains optics shown in formula (III) and formula (II) after resolving agent is split Isomers primary amine；
    3) optical isomer primary amine and alkylating reagent shown in formula (III) and formula (II) be through alkylated reaction, or with aldehyde and also Former agent obtains Ugi ' s amine and its derivative shown in formula (I) after reductive amination process.
  3. 3. synthetic method as claimed in claim 2, which is characterized in that in step 1), the reducing agent is selected from sodium borohydride NaBH4, sodium cyanoborohydride NaBH3CN, borine BH3, triethylsilane Et3SiH, zinc borohydride Zn (BH4)2, lithium aluminium hydride reduction LiAlH4, potassium borohydride KBH4, Vitride red aluminum solution, zinc amalgam, tetramethyl disiloxane, in three tert-butyl alcohol lithium aluminium hydride reductions It is one or more；And/or the dosage of the reducing agent is the 1.0- of Ferrocene and its derivative dosage shown in formula (V) 10.0eq。
  4. 4. synthetic method as claimed in claim 2, which is characterized in that in step 1), the organic ammonium salt is selected from ammonium acetate, first Sour ammonium, ammonium oxalate, fluorenes methoxy carbonyl amide, fluoroacetic acid ammonium, trifluoroacetic acid ammonium, dihydroxy aluminium ammonium acetate, 2- hydroxyacetic acid ammonium, naphthalene- One of 1- ammonium acetate is a variety of；And/or the dosage of the organic ammonium salt is Ferrocene and its derivative shown in formula (V) The 1.0-30.0eq of dosage；And/or the temperature of the reductive amination process is 0-150 DEG C.
  5. 5. synthetic method as claimed in claim 2, which is characterized in that in step 2), the resolving agent is acid resolving agent, choosing From tartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, malic acid, acetyl tartaric acid acid anhydride, two toluoyl tartaric acid, asparagus fern One of propylhomoserin, glutamic acid, pyroglutamic acid, quininic acid, methylbenzyl based isocyanate are a variety of；And/or the use of the resolving agent Amount is the 0.1-10.0eq of racemic modification primary amine dosage shown in formula (IV).
  6. 6. synthetic method as claimed in claim 2, which is characterized in that in step 2), the temperature of the split process is 10- 190℃；The time of the split process is 0.2-12h.
  7. 7. synthetic method as claimed in claim 2, which is characterized in that in step 3), the alkylating reagent is selected from formaldehyde, more Polyformaldehyde, iodoethane, bromoethane, iodopropane, N-Propyl Bromide, formic acid, dimethyl suflfate, dithyl sulfate, dibutyl sulfate, to first Benzene sulfonate it is one or more；And/or the dosage of the alkylating reagent is that optics shown in formula (III) or formula (II) is different The 0.1-20.0eq of structure body primary amine dosage.
  8. 8. synthetic method as claimed in claim 2, which is characterized in that in step 3), the temperature of the alkylated reaction is 0- 200℃；The time of the alkylated reaction is 0.5-40h.
  9. 9. synthetic method as claimed in claim 2, which is characterized in that in step 3), the aldehyde is selected from formaldehyde, acetaldehyde, poly One of formaldehyde, fatty aldehyde, aromatic aldehyde are a variety of；And/or the dosage of the aldehyde is light shown in formula (III) or formula (II) Learn the 0.1-20.0eq of isomers primary amine dosage；And/or the reducing agent is selected from sodium borohydride NaBH4, sodium cyanoborohydride NaBH3CN, sodium triacetoxy borohydride NaBH (OAc)3, 2- picoline-N- monoborane, lithium aluminium hydride reduction LiAlH4, hydroboration Potassium KBH4One of or it is a variety of；The dosage of the reducing agent is that optical isomer primary amine shown in formula (III) or formula (II) is used The 0.1-20.0eq of amount.
  10. 10. synthetic method as claimed in claim 2, which is characterized in that in step 3), the temperature of the reductive amination process is 10-200℃；The time of the reductive amination process is 0.5-30h.
  11. 11.Ugi ' s amine and its derivative, which is characterized in that shown in its structure such as formula (I),
    Wherein, R1For C1-6Alkyl, C3-6Naphthenic base, C3-6Heterocyclylalkyl, aryl；
    R2For C1-6Alkyl, aryl, halogen, hydrogen；R3And R4It is each independently respectively hydrogen, C1-6Alkyl, aryl；R3And R4With connect The nitrogen-atoms connect forms 4-8 member ring, and being formed by ring may include 1-3 hetero atom, and the hetero atom is N, O, S.
  12. 12. Ugi ' s amine as claimed in claim 11 and its derivative are in preparing Josiphos class ferrocene biphosphine ligand Using.
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