CN108129404A - The synthetic method of chiral piperazine ketone derivatives - Google Patents
The synthetic method of chiral piperazine ketone derivatives Download PDFInfo
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- CN108129404A CN108129404A CN201810088386.4A CN201810088386A CN108129404A CN 108129404 A CN108129404 A CN 108129404A CN 201810088386 A CN201810088386 A CN 201810088386A CN 108129404 A CN108129404 A CN 108129404A
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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Abstract
The present invention relates to a kind of synthetic methods of chiral piperazine ketone derivatives, include the following steps：Oxidation reaction occurs for the ethanol amine with blocking group of formula (I), obtains the aminoacetaldehyde with blocking group of formula (II)；In alcoholic solvent; the aminoacetaldehyde with blocking group of formula (II) and amino-acid ester in the presence of a reducing agent under conditions of reduction amination occurs; obtain the chiral diamine derivative of formula (III); wherein; the temperature of reduction amination is 10 DEG C 0 DEG C, and amino-acid ester is the amino-acid ester of L-type or the amino-acid ester of D types；In alcoholic solvent, deprotection reaction and cyclization occur for the chiral diamine derivative of formula (III), obtain the chiral piperazine ketone derivatives of formula (IV)；Reaction route is as follows：
Description
Technical field
The present invention relates to chipal compounds synthesis technical field more particularly to a kind of synthesis sides of chiral piperazine ketone derivatives
Method.
Background technology
Piperazine (formula 1) and its derivative are highly useful pharmaceutical molecules segments, and are considered the medicine in drug molecule
Very important effect is played in terms of effect, pharmacology；Such as in anticancer drug Imatinib (Imatinib, formula 2), antibiosis prime ring third
All exist in the molecule of Sha Xing (Ciproloxacin, formula 3) and anti-Kieren Perkins medicine piribedil (Piribedil, formula 4)
Substituted piperazine structure, the molecular formula of above-mentioned each molecule are as follows：
In addition then have in some drug molecules and printed containing chiral piperazine structure or piperazinones structure, such as hiv inhibitor
Piperazine structure of that Wei (Indinavir, formula 5) of ground containing chirality, (-)-Nutlin-3 (formula 6) are above-mentioned containing piperazinones segment
The molecular formula of each molecule is as follows：
WO2013050424 reports the series compound with potential treatment nervous centralis or nerve ending, key
Synthesis material is then the chiral piperazine ketone compound shown in formula 7：
It is among a kind of crucial chiral drug that above example, which shows to have the chiral piperazine ketone derivatives shown in formula (IV),
Body develops its efficient synthetic method with realistic meaning, and wherein formula (IV) is as follows：
Synthesis for piperazine ring and bridged piperazine derivatives, document have some reports, but are all confined to achirality piperazine and spread out
The synthesis of biology；Chiral asymmetric syntheses is then less.For with the chiral piperazine ketone derivatives raceme shown in formula (IV)
Synthesis, the document (US2700668,1952) of early stage is to react to prepare by ethylenediamine, acetaldehyde and hydrogen cyanide, and the reaction is former
Expect that toxicity is high, process contamination is big, and reaction route is as follows：
Patent US2006/199817A1 is reported to be heated to synthesize in alcoholic solvent by ethylenediamine and 2 bromopropionic acid methyl esters
Its raceme, reaction route are as follows：
Also there is document (AngewandteChemie, International Edition, 2015,54,179-183) report
With 2- chloropropionates etc., but yield is all relatively low.
Synthesis for the chirality methyl piperazinones different isomer shown in formula (IV), document Chemical
Communications, 2012,48 (71), 8892-8894 and patent WO2013/7371A2 report the side of Kinetic Resolution
Method.Chiral piperazine ketone raceme shown in formula (IV) is in the presence of the chiral reagent (formula 14) of 5-10mol%, shown in formula 13
Compound occur some row selective reactions.R isomerization reactions are slower, and finally there are more, products in a free form
The selectivity of two kinds of configurations only has 90/10；And the reaction of S configurations is very fast, more exist in the form of amide, two kinds of product amide
The ratio of configuration is 79/21.Although above method provides a kind of new trial, but result is unsatisfactory, and needs to close
The resolution reagent shown in chiral reagent and formula 13 shown in an accepted way of doing sth 14, practicability are relatively low.
Document Tetrahedron:Asymmetry 2008, (19) 1689-1697 is reported to be induced with chiral structure
Carry out the piperazinones of synthesis of chiral.In document since compound 15, selective deprotection is carried out to it and obtains two differences
The compound 16 and 17 of configuration, the latter can selectively induce introducing R substituent, form the piperazinones of two various configurations.
But the method route is tediously long, first has to multi-step synthesis compound 15, and compound 18,19 will be deprotected.
Patent EP3144307A1 also describes the piperazine reacted to prepare other chiralitys with ternary azacyclo- using amino acid
Piperazine ketone.But this method will use the thiophenol of stench, and cyclization yield is not also high, and only 42%, reaction route is as follows：
In short, the big or tediously long effect of route is polluted there are material toxicity height in the preparation method of existing chiral piperazine ketone
The shortcomings that rate is low, the method for not occurring also solving problem above at present.
Invention content
In order to solve the above technical problems, the object of the present invention is to provide a kind of synthetic method of chiral piperazine ketone derivatives,
Its raw material is easy to get, is at low cost, safe operation, pollution less, high income, product purity and ee values it is equal>99%.
To achieve the above object, present invention employs following technical solutions：
The present invention provides a kind of synthetic methods of chiral piperazine ketone derivatives, include the following steps：
(1) oxidation reaction occurs for the ethanol amine with blocking group of formula (I), obtains the amino with blocking group of formula (II)
Acetaldehyde；
(2) in alcoholic solvent, the aminoacetaldehyde with blocking group of formula (II) and amino-acid ester are in the presence of a reducing agent
Under the conditions of reduction amination occurs, obtain the chiral diamine derivative of formula (III), wherein, the temperature of reduction amination for-
10 DEG C -0 DEG C, amino-acid ester is the amino-acid ester of L-type or the amino-acid ester of D types；
(3) in alcoholic solvent, deprotection reaction and cyclization occur for the chiral diamine derivative of formula (III), obtain formula (IV)
The chiral piperazine ketone derivatives；
Reaction route is as follows：
Wherein, blocking group X is benzyloxycarbonyl group (Cbz yls) or tertbutyloxycarbonyl (Boc yls)；
R is methyl, ethyl, isopropyl, isobutyl group, ethoxy, benzyl or to hydroxybenzyl；
R ' is methyl, ethyl or isopropyl.
Further, in step (1), amino-acid ester is methyl lactamine, alanine ethyl ester, valine methyl ester, figured silk fabrics ammonia
Acetoacetic ester, leucine methyl ester, leucinethylester, Isoleucine methyl ester, isoleucine ethyl ester, phenyalanine methyl ester, phenylalanine
Ethyl ester, methyl-P-tyrosine or tyrosine ethyl ester.Preferably, amino-acid ester is the methyl lactamine of L-type or the alanine first of D types
Ester.
Further, in step (1), oxidation reaction is carried out using TEMPO oxidation reactions system, reaction temperature is -10
℃-10℃.Preferably, reaction temperature is -5 DEG C -0 DEG C.TEMPO oxidation reaction system conditions are most mild, and environmental-friendly, should
Reaction often carries out at a lower temperature.
Further, the reaction dissolvent of TEMPO oxidation reactions system is acetonitrile, in ethyl acetate, acetic acid second propyl ester, THF
A kind of mixed system with water.Preferably, reaction dissolvent is ethyl acetate/water or acetic acid second propyl ester/water.
Further, in step (1), can also use Qiong Shi oxidation reactions system, manganese dioxide reaction system,
DCC oxidation reactions system, the architecture of Swern oxidation reactions or IBX oxidation reactions system carry out oxidation reaction.
Further, in step (2), reducing agent is sodium triacetoxy borohydride (NaBH (OAc)3) or Raney's nickel.
Further, in step (2) and step (3), alcoholic solvent is methanol, ethyl alcohol, ethylene glycol, glycerine, n-butanol
One or more of with the common alcohols solvent such as n-hexyl alcohol.Preferably, alcohol is methanol and/or ethyl alcohol.
Further, in step (3), deprotection reaction and cyclization occur under the action of Pd/C and hydrogen, wherein, instead
It is 10-30 DEG C to answer temperature.
In step (2), reaction needs to control temperature between -10 DEG C -0 DEG C, in case aldehyde radical is reduced directly to alcohol.Step
Suddenly the amino acid with various configuration may be selected to obtain chiral diamine derivative in (2), when the amino-acid ester for selecting L-type, most
Whole target product is S configurations, and when the amino-acid ester for selecting D types, final target product is R configurations.
In step (3), after sloughing blocking group, the direct attack ester group of amino and cyclization obtains target product, the reaction
It usually carries out, and reacts more environmentally friendly in the low-carbons alcoholic solvent such as methanol or ethyl alcohol.
Further, after the step (2) and after step (3), the step of further including purified product.Step (2) and step
Suddenly the product that (3) obtain can be purified by column chromatography.
Further, it is further comprising the steps of before step (1)：
(S1) in organic solvent, upper protection reaction occurs in the presence of a base for ethanol amine, and the band for obtaining formula (I) is protected
Protect the ethanol amine of group；
Reaction route is as follows：
Wherein, blocking group X is benzyloxycarbonyl group or tertbutyloxycarbonyl.
Further, in step (S1), blocking group X is benzyloxycarbonyl group, wherein upper protection reaction temperature is 0 DEG C -25
℃。
Further, in step (S1), when blocking group X is benzyloxycarbonyl group, protection examination used in upper protection reaction
Agent is benzene methoxy carbonyl acyl succinimide (Z-OSu) or benzyl chloroformate (Cbz-Cl).
Further, in step (S1), alkali is inorganic base, and inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, carbon
One or more of sour potassium, sodium bicarbonate and saleratus.
Further, in step (S1), alkali is organic base, and organic base is in triethylamine, pyridine and dimethylamino pyridine
One or more.
Further, in step (S1), organic solvent is tetrahydrofuran (THF), dichloromethane, acetonitrile, toluene and N, N
One or more of dimethylformamide.
The reaction temperature of step (S1) is relatively low, and the reaction product of the step is not required to purification and can be used as reacting in next step.
Further, when blocking group is benzyloxycarbonyl group (Cbz group), before step (2), include the following steps：
(S1) in organic solvent, ethanol amine and the protection reagent containing benzyloxycarbonyl group occur in the presence of a base on protect
Shield reaction obtains the ethanol amine of the benzyloxycarbonyl group protection of formula (Ia), and wherein reaction temperature is 0 DEG C -25 DEG C；Guarantor containing benzyloxycarbonyl group
It is benzene methoxy carbonyl acyl succinimide (Z-OSu) or benzyl chloroformate (Cbz-Cl) to protect reagent；
(1) oxidation reaction occurs for the ethanol amine of the benzyloxycarbonyl group protection of formula (Ia), obtains the benzyloxycarbonyl group protection of formula (IIa)
Aminoacetaldehyde；
Reaction route is as follows：
Wherein, Cbz represents benzyloxycarbonyl group.
Specifically, when blocking group is benzyloxycarbonyl group, amino-acid ester is alanine methyl ester hydrochloride, the chirality of R configurations
The synthetic route of Piperazinone derivs is as follows：
Specifically, when blocking group is benzyloxycarbonyl group, amino-acid ester is alanine methyl ester hydrochloride, the chirality of S configurations
The synthetic route of Piperazinone derivs is as follows：
According to the above aspect of the present invention, the present invention has at least the following advantages：
The present invention overcomes material toxicity present in the preparation method of existing chiral piperazine ketone high, and pollution is big, Huo Zhelu
The shortcomings that tediously long efficiency of line is low, provides a kind of new preparation method of chiral piperazine ketone derivatives, the raw material of this method is easy to get,
At low cost, safe operation, pollution less, high income, product purity and ee values be above 99%, suitable for industrialized production.
Above description is only the general introduction of technical solution of the present invention, in order to better understand the technological means of the present invention,
And can be implemented in accordance with the contents of the specification, below with presently preferred embodiments of the present invention and after coordinating detailed description such as.
Specific embodiment
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but be not limited to the scope of the present invention.
In following embodiment of the present invention, the synthetic route of the chiral piperazine ketone derivatives of R configurations is as follows：
The synthetic route of the chiral piperazine ketone derivatives of S configurations is as follows：
Its specific preparation method is referring to following embodiment.
Embodiment 1
The synthesis of N-Cbz- ethanol amines (shown in Formulas I)
45g ethanol amines and 91g triethylamines are dissolved in 400mL THF, 206g Z-OSu are added portionwise under stirring, room temperature is stirred
It mixes overnight.It filters after the reaction was complete, filtrate decompression concentration, product cures after slightly placing, and obtains solid 157g, yield 106%,
HPLC purity 73.6%.The crude product that the present embodiment is obtained does not purify to direct plunge into react in next step.
Embodiment 2
The synthesis of N-Cbz- aminoacetaldehydes (shown in Formula II)
The N-Cbz- ethanol amines of 57g are dissolved in 700mL isopropyl acetates, are cooled to -5~0 DEG C.Under stirring, to solution
It is middle addition 51g sodium bromides, 31g sodium bicarbonates, the TEMPO (tetramethyl piperidine nitrogen oxides) of 0.4g, 31g sodium bicarbonates and
250mL water.The liquor natrii hypochloritis of 320mL is slowly added dropwise, temperature of reaction system is kept to be less than 0 DEG C.TLC is monitored, and is reacted to original
After material conversion completely, add in sodium thiosulfate and reaction, liquid separation is quenched.Organic phase is collected, adds in anhydrous sodium sulfate drying 4h.It crosses
Filter, filtrate decompression concentration, obtains colourless liquid 40g, yield 70%.The crude product that the present embodiment is obtained, which does not purify, to be direct plungeed into down
Single step reaction.
Embodiment 3
(R) synthesis of -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl propionate (shown in formula a)
The D-alanine methyl ester hydrochloride of 33g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove salt.
Filtrate is collected, adds in the 300mL methanol solutions of 40g N-Cbz- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g tri-
87g sodium triacetoxy borohydrides are added portionwise in ethamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.TLC
Monitoring is complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation, water layer 200mL is quenched
DCM is extracted once again, is merged organic phase, is concentrated to give transparency liquid.Silica gel column chromatography separating purification (uses normal heptane/acetic acid second
Make eluant, eluent in ester=1/2), obtain 40.7g colourless viscous liquids, the as product shown in formula a, yield 83%, to product
Nuclear-magnetism characterization is carried out, test result is as follows：
1H NMR(400MHz,CDCl3):δ=7.35~7.28 (m, 5H), 5.37 (s, 1H), 5.14 (s, 1H), 5.11 (s,
1H), 3.72 (s, 3H), 3.36~3.31 (m, 2H), 3.24~3.21 (m, 1H), 2.81~2.75 (m, 1H), 2.64~2.58
(m, 1H), 1.30~1.28 (d, 3H).
Embodiment 4
(R) synthesis of -3- methyl piperazines -2- ketone (shown in formula c)
(R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl propionate of 10g is added in 100mL methanol,
3g palladium carbons are added in, hydrogen is added in 1.8MPa, reaction is stirred at room temperature overnight.HPLC monitors that the reaction was complete to raw material.By reaction solution
Filtering, filtrate decompression concentration.Crude product is obtained through silica gel column chromatography separating purification (making eluant, eluent with ethyl acetate/methanol=9/1)
White solid 3.71g, the as product shown in formula c, yield 91%, HPLC purity 98.2%, ee values 98.3%.To product
Nuclear-magnetism characterization, mass spectral characteristi and optical activity test are carried out, it is as a result as follows：
1H NMR(400MHz,CDCl3):δ=6.48 (s, 1H), 3.58~3.52 (m, 1H), 3.49~3.42 (m, 1H),
3.35~3.29 (m, 1H), 3.19~3.14 (m, 1H), 3.06~2.99 (m, 1H), 2.12 (s, 1H), 1.42~1.40 (d,
3H)。
MS(ES+)m/z:137.15[M+Na+],115.16[M+H+]。
[α]D 28=+36 (c=0.2g/100mL, CHCl3).(R) -3- first that WO2013/7371A2 report ee values are 80%
The optically-active data of base piperazine -2- ketone are [α]D 28=+/- 0 (c=0.2g/100mL, CHCl3).The above result shows that the present embodiment
Products therefrom is R configurations.
Embodiment 5
(S) synthesis of -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl propionate (shown in formula b)
The l-Alanine methyl ester hydrochloride of 33g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove salt.
Filtrate is collected, adds in the 300mL methanol solutions of 40g N-Cbz- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g tri-
87g sodium triacetoxy borohydrides are added portionwise in ethamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.TLC
Monitoring is complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation, water layer 200mL is quenched
DCM is extracted once again, is merged organic phase, is concentrated to give transparency liquid.Silica gel column chromatography separating purification (uses normal heptane/acetic acid second
Make eluant, eluent in ester=1/2), obtain 41.5g colourless viscous liquids, the as product shown in formula b, yield 85%, to product
Nuclear-magnetism characterization is carried out, test result is as follows：
1H NMR(400MHz,CDCl3):δ=7.35~7.28 (m, 5H), 5.37 (s, 1H), 5.14 (s, 1H), 5.11 (s,
1H), 3.72 (s, 3H), 3.36~3.31 (m, 2H), 3.24~3.21 (m, 1H), 2.81~2.75 (m, 1H), 2.64~2.58
(m, 1H), 1.30~1.28 (d, 3H).
Embodiment 6
(S) synthesis of -3- methyl piperazines -2- ketone (shown in formula d)
(S) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl propionate of 10g is added in 100mL methanol,
3g palladium carbons are added in, hydrogen is added in 1.8MPa, reaction is stirred at room temperature overnight.HPLC monitors that the reaction was complete to raw material.By reaction solution
Filtering, filtrate decompression concentration.Crude product is obtained through silica gel column chromatography separating purification (making eluant, eluent with ethyl acetate/methanol=9/1)
White solid 3.67g, the as product shown in formula d, yield 90%, HPLC purity 98.1%, ee values 98.0%.To product into
Row nuclear-magnetism characterization, mass spectral characteristi and optical activity test, it is as a result as follows：
1H NMR(400MHz,CDCl3):δ=6.48 (s, 1H), 3.58~3.52 (m, 1H), 3.49~3.42 (m, 1H),
3.35~3.29 (m, 1H), 3.19~3.14 (m, 1H), 3.06~2.99 (m, 1H), 2.12 (s, 1H), 1.42~1.40 (d,
3H)。
MS(ES+)m/z:137.15[M+Na+],115.16[M+H+]。
[α]D 28=-34 (c=0.2g/100mL, CHCl3).The above result shows that the present embodiment products therefrom is S configurations.
Embodiment 7
The synthesis of N-Cbz- ethanol amines
45g ethanol amines and 32.5g sodium hydroxides are dissolved in 400mL THF and 120mL water, 206g is added portionwise under stirring
Z-OSu is stirred overnight at room temperature.It is filtered after the reaction was complete, filtrate decompression concentration is extracted with ethyl acetate, and organic phase concentration is slightly put
Product curing is postponed, obtains solid 157g.The crude product that the present embodiment is obtained does not purify to direct plunge into react in next step.
Embodiment 8
The synthesis of N-Boc- ethanol amines
45g ethanol amines and 91g triethylamines are dissolved in 400mL THF, 180g Boc acid anhydrides, room temperature are added portionwise under stirring
It is stirred overnight.It is filtered after the reaction was complete, filtrate decompression concentration, product cures after slightly placing, and obtains solid 120g.The present embodiment institute
The crude product of acquisition does not purify to direct plunge into react in next step.
Embodiment 9
The synthesis of N-Boc- aminoacetaldehydes
The N-Boc- ethanol amines of 43g are dissolved in 700mL isopropyl acetates, are cooled to -5~0 DEG C.Under stirring, to solution
It is middle addition 51g sodium bromides, 31g sodium bicarbonates, the TEMPO (tetramethyl piperidine nitrogen oxides) of 0.4g, 31g sodium bicarbonates and
250mL water.The liquor natrii hypochloritis of 320mL is slowly added dropwise, temperature of reaction system is kept to be less than 0 DEG C.TLC is monitored, and is reacted to original
After material conversion completely, add in sodium thiosulfate and reaction, liquid separation is quenched.Organic phase is collected, adds in anhydrous sodium sulfate drying 4h.It crosses
Filter, filtrate decompression concentration, obtains colourless liquid 30g.The crude product that the present embodiment is obtained does not purify to direct plunge into react in next step.
Embodiment 10
(R) synthesis of -2- ((2- (((tertiary fourth oxygen) carbonyl) amino) ethyl) amino) methyl propionate
The D-alanine methyl ester hydrochloride of 33g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove salt.
Filtrate is collected, adds in the 300mL methanol solutions of 30g N-Boc- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g tri-
87g sodium triacetoxy borohydrides are added portionwise in ethamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.TLC
Monitoring is complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation, water layer 200mL is quenched
DCM is extracted once again, is merged organic phase, is concentrated to give transparency liquid.Silica gel column chromatography separating purification (uses normal heptane/acetic acid second
Make eluant, eluent in ester=1/2), obtain 30g colourless viscous liquids.
Embodiment 11
(R) synthesis of -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) ethyl propionate
The D-alanine carbethoxy hydrochloride of 36g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove salt.
Filtrate is collected, adds in the 300mL methanol solutions of 40g N-Cbz- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g tri-
87g sodium triacetoxy borohydrides are added portionwise in ethamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.TLC
Monitoring is complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation, water layer 200mL is quenched
DCM is extracted once again, is merged organic phase, is concentrated to give transparency liquid.Silica gel column chromatography separating purification (uses normal heptane/acetic acid second
Make eluant, eluent in ester=1/2), obtain 42g colourless viscous liquids.
Embodiment 12
(R) synthesis of -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) 4- methylbutanoic acid methyl esters
The D-Val methyl ester hydrochloride of 40g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove salt.
Filtrate is collected, adds in the 300mL methanol solutions of 40g N-Cbz- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g tri-
87g sodium triacetoxy borohydrides are added portionwise in ethamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.TLC
Monitoring is complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation, water layer 200mL is quenched
DCM is extracted once again, is merged organic phase, is concentrated to give transparency liquid.Silica gel column chromatography separating purification (uses normal heptane/acetic acid second
Make eluant, eluent in ester=1/2), obtain 49g colourless viscous liquids.
Embodiment 13
(R) synthesis of -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl phenylpropionate
The D-phenylalanine methyl ester hydrochloride of 48g is dissolved in 200mL DCM, 25g triethylamines is added to neutralize, are filtered to remove
Salt.Filtrate is collected, adds in the 300mL methanol solutions of 40g N-Cbz- aminoacetaldehydes, 15min is stirred, is cooled to 0 DEG C.Add in 48g
87g sodium triacetoxy borohydrides are added portionwise in triethylamine.After adding, continue to stir, be slowly increased to room temperature, be stirred overnight.
TLC monitors complete to reaction conversion.Saturated sodium bicarbonate solution is added in into reaction system, reaction, liquid separation is quenched, water layer is used
200mL DCM are extracted once again, are merged organic phase, are concentrated to give transparency liquid.Silica gel column chromatography separating purification (with normal heptane/
Make eluant, eluent in ethyl acetate=1/2), obtain 58g colourless viscous liquids.
Embodiment 14
(R) synthesis of -3- methyl piperazines -2- ketone
(R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) ethyl propionate of 10g is added in 100mL methanol,
3g palladium carbons are added in, hydrogen is added in 1.8MPa, reaction is stirred at room temperature overnight.HPLC monitors that the reaction was complete to raw material.By reaction solution
Filtering, filtrate decompression concentration.Crude product is obtained through silica gel column chromatography separating purification (making eluant, eluent with ethyl acetate/methanol=9/1)
White solid 3.6g.
Embodiment 15
(R) synthesis of -3- isopropyls piperazine -2- ketone
(R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) 4- methylbutanoic acid methyl esters of 11g is added into 100mL
In methanol, 3g palladium carbons are added in, hydrogen is added in 1.8MPa, reaction is stirred at room temperature overnight.HPLC monitors that the reaction was complete to raw material.It will
Reaction solution filters, filtrate decompression concentration.Crude product (is eluted through silica gel column chromatography separating purification with ethyl acetate/methanol=9/1
Agent), obtain white solid 4.6g.
Embodiment 16
(R) synthesis of -3- benzyl diethylenediamines -2- ketone
(R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) methyl propionate of 12g is added in 100mL methanol,
3g palladium carbons are added in, hydrogen is added in 1.8MPa, reaction is stirred at room temperature overnight.HPLC monitors that the reaction was complete to raw material.By reaction solution
Filtering, filtrate decompression concentration.Crude product is obtained through silica gel column chromatography separating purification (making eluant, eluent with ethyl acetate/methanol=9/1)
White solid 5.7g.
The above is only the preferred embodiment of the present invention, is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of chiral piperazine ketone derivatives, which is characterized in that include the following steps：
(1) oxidation reaction occurs for the ethanol amine with blocking group of formula (I), obtains the amino second with blocking group of formula (II)
Aldehyde；
(2) in alcoholic solvent, the aminoacetaldehyde with blocking group and the condition of amino-acid ester in the presence of a reducing agent of formula (II)
Issue raw reduction amination, obtain the chiral diamine derivative of formula (III), wherein, the temperature of the reduction amination for-
10 DEG C -0 DEG C, the amino-acid ester is the amino-acid ester of L-type or the amino-acid ester of D types；
(3) in alcoholic solvent, deprotection reaction and cyclization occur for the chiral diamine derivative of formula (III), obtain the institute of formula (IV)
State chiral piperazine ketone derivatives；
Reaction route is as follows：
Wherein, blocking group X is benzyloxycarbonyl group or tertbutyloxycarbonyl；
R is methyl, ethyl, isopropyl, isobutyl group, ethoxy, benzyl or to hydroxybenzyl；
R ' is methyl, ethyl or isopropyl.
2. the synthetic method of chiral piperazine ketone derivatives according to claim 1, it is characterised in that：In step (1), institute
Amino-acid ester is stated as methyl lactamine, alanine ethyl ester, valine methyl ester, valinate, leucine methyl ester, leucine second
Ester, Isoleucine methyl ester, isoleucine ethyl ester, phenyalanine methyl ester, phenylalanine ethyl ester, methyl-P-tyrosine or tyrosine second
Ester.
3. the synthetic method of chiral piperazine ketone derivatives according to claim 1, it is characterised in that：In step (1), adopt
Oxidation reaction is carried out with TEMPO oxidation reactions system, reaction temperature is -10 DEG C -10 DEG C.
4. the synthetic method of chiral piperazine ketone derivatives according to claim 1, it is characterised in that：In step (2), institute
Reducing agent is stated as sodium triacetoxy borohydride and/or Raney's nickel.
5. the synthetic method of chiral piperazine ketone derivatives according to claim 1, it is characterised in that：In step (2) and step
Suddenly in (3), the alcoholic solvent is one or more of methanol, ethyl alcohol, ethylene glycol, glycerine, n-butanol and n-hexyl alcohol.
6. the synthetic method of chiral piperazine ketone derivatives according to claim 1, it is characterised in that：In step (3),
Deprotection reaction and cyclization occurs under the action of Pd/C and hydrogen, wherein, reaction temperature is 10-30 DEG C.
7. the synthetic method of chiral piperazine ketone derivatives according to claim 1, which is characterized in that before step (1),
It is further comprising the steps of：
(S1) in organic solvent, upper protection reaction occurs in the presence of a base for ethanol amine, obtains the band protecting group of formula (I)
The ethanol amine of group；
Reaction route is as follows：
Wherein, blocking group X is benzyloxycarbonyl group or tertbutyloxycarbonyl.
8. the synthetic method of chiral piperazine ketone derivatives according to claim 7, it is characterised in that：In step (S1),
The blocking group X is benzyloxycarbonyl group, wherein upper protection reaction temperature is 0 DEG C -25 DEG C.
9. the synthetic method of chiral piperazine ketone derivatives according to claim 8, it is characterised in that：In step (S1),
The alkali is inorganic base, and the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and saleratus
One or more of.
10. the synthetic method of chiral piperazine ketone derivatives according to claim 8, it is characterised in that：In step (S1),
The alkali is organic base, and the organic base is one or more of triethylamine, pyridine and dimethylamino pyridine.
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| CN109438180A (en) * | 2018-12-29 | 2019-03-08 | 凯瑞斯德生化(苏州)有限公司 | The preparation method of one kind (S) -1- (the chloro- 3- fluorophenyl of 2,6- bis-) ethyl alcohol |
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