CN101328136B - Aminoacid acidamide compounds and preparation thereof - Google Patents
Aminoacid acidamide compounds and preparation thereof Download PDFInfo
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- CN101328136B CN101328136B CN2008100297050A CN200810029705A CN101328136B CN 101328136 B CN101328136 B CN 101328136B CN 2008100297050 A CN2008100297050 A CN 2008100297050A CN 200810029705 A CN200810029705 A CN 200810029705A CN 101328136 B CN101328136 B CN 101328136B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses an amino acid amide compound and a preparation method thereof. Amino acid protected by FMOC and an acyl chloride reagent react to produce amino acid acyl chloride which is dissolved into a solvent with an appropriate polarity and reacts with a simple compound with primary amine and secondary amine so that the prepared amino acid amide compound can precipitate once forming in the reaction process, thereby reducing the contact of the FMOC and the amine; the whole process is short in the reaction time and fast in speed, thereby preventing the de-protection and realizing that the amino acid protected by the FMOC reacts with the simple amine on the premise without removing protective group; and the yield is up to more than 93 percent. The reaction method is simple, and has high efficiency and clean products as well as easy post treatment.
Description
Technical field
The present invention relates to the organic synthesis field, particularly a kind of aminoacid acidamide compounds and preparation method thereof.
Background technology
Aminoacid acidamide compounds is very important pharmaceutical intermediate of a class and synthetic agent, can derive by it and to synthesize the multiple compound that has the sterilization anti-tumor activity, strengthens living organism immunity and fatigue resistance, it is the synthetic proteinic important source material of sophisticated functions, also be the important carrier of selecting the absorption chipal compounds, be subjected to extensive concern always in fields such as chemistry, biology, medical science.
The main method of synthesizing amino acid acid amides has two kinds at present: a kind of is that the amino acid carboxyl is converted into the active stronger group that ammonia is separated that more helps, and as ester, acid anhydrides etc., ammonia is separated and made then; Another kind is dehydration preparation under the effect of amidation coupling catalyst.In patent usp5723646, people such as Seitz utilize the Xie Ansuan of isopropyl carbonyl protection, with the chloroformic acid tert-butyl ester methyl piperidine as the condition of acid absorber under back flow reaction, preparation anhydrides compound, and then with alpha-amino group ditane reaction, prepared amides; In patent usp 4996358, people such as Handa earlier the amino acid of protection is converted to ester again with contain the aminocompound back flow reaction and prepare acid amides; In patent usp5506362, people such as Callens utilize the amino acid of benzene methoxycarbonyl protection, with other amino acid or the compound that contains active amino under alkaline conditions such as triethylamine, in alcohol solvent, reflux, prepared amides or other amides of peptide; In patent CN1294121, the quick man of virtue and ability in island etc. utilizes boron compound as catalyzer and under the condition of organic alcohols as solubility promoter, and N-acylamino acid and amine or ammoniac compounds are carried out dehydration condensation, preparation amino acid amide analog derivative; In patent usp6335468, people such as Hatajima have set forth and have utilized boride can realize the dehydrating condensation of amino acid carboxyl and simple aminated compounds.In above-mentioned these preparation process, be used for amino protecting group and mainly contain BOC (tertbutyloxycarbonyl), CBZ (benzene methoxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl) etc.But protecting group BOC and CBZ can not can not make the amino acid of protection generate acyl chlorides at stable existence under the strong acidic condition; And the amino acid of protecting group Fmoc protection can form acyl chlorides; but in homogeneous system during with simple amine reaction; can take off protection; make reaction efficiency very low, if can realize directly the reaction with amine, will overcome BOC, CBZ need be in the constraint of deprotection under the system strongly such as strong acid or palladium-carbon reduction; taking off protecting group Fmoc can be simple aminated compounds (piperidines, methylamine etc.) taking off of quick gentleness down; method is simple, the efficient height, and aftertreatment is easy.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the prior art, provide that a kind of technology is simple, reaction efficiency is high, the simple aminoacid acidamide compounds of aftertreatment.
Another object of the present invention is to provide a kind of preparation method of above-mentioned aminoacid acidamide compounds.
Purpose of the present invention is achieved through the following technical solutions:
A kind of preparation method of aminoacid acidamide compounds comprises the steps:
(1) amino acid with the protection of 1 mass parts fluorenylmethyloxycarbonyl (FMOC) is dissolved in the organic solvent that dewaters of 5～50 mass parts, adding consumption is the chloride reagent of 2～20 times of amino acid molar weights, after the back flow reaction, organic solvent and chloride reagent are removed in distillation, and vacuum-drying, obtain the acyl chlorides solid reaction product;
(2) add the organic solvent that dewaters that consumption is 10～60 times of acyl chlorides solid reaction product quality then, after treating dissolving fully, adding consumption is the aminated compounds of 3～10 times of acyl chlorides solid reaction product molar weights, be settled out aminoacid acidamide compounds, aminated compounds and organic solvent are removed in the water flushing then, and vacuum-drying obtains the aminoacid acidamide compounds of FMOC protection;
(3) with the aminoacid acidamide compounds of the above-mentioned FMOC protection dissolution with solvents with 10～70 mass parts, the amine reagent that adds 2%～20% volume parts is taken off protective material FMOC, and the mistake silicagel column obtains aminoacid acidamide compounds behind the rotation evaporate to dryness.
In the step 1, described amino acid is meant α, β, γ, δ ... ω etc. contain acidity, neutrality or the alkaline amino acid of mono amino and carboxyl; Preferred Padil, L-Ala, Xie Ansuan, Isoleucine, methionine(Met), L-LEU, phenylalanine, halfcystine, proline(Pro) or tryptophane.
In the step 1, the described organic solvent that dewaters is an aprotic solvent, preferred methylene dichloride, tetrahydrofuran (THF), chloroform or acetone.
In the step 1, described chloride reagent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride.
In the step 1, the time of described back flow reaction is 2～8 hours.
In the step 2, the described organic solvent that dewaters is can dissolve the acyl chlorides solid reaction product but the aprotic solvent that do not dissolve acid amides, preferred ether, benzene, toluene, methylene dichloride or tetracol phenixin.
In the step 2, described aminated compounds is meant and contains amino aliphatics or aromatic amine compounds, preferred ammoniacal liquor, methylamine, ethamine, propylamine, Isopropylamine, butylamine, isobutylamine, TERTIARY BUTYL AMINE, aniline, o-toluidine, to monomethylaniline, benzene methanamine, quadrol, propylene diamine or diisopropylethylamine.
In the step 3, described solvent is that polarity is strong and can dissolve organic aprotic solvent of aminoacid acidamide compounds, preferred tetrahydrofuran (THF), N, dinethylformamide (DMF), pyridine, acetonitrile or acetone.
In the step 3, described amine reagent is piperidines, methylamine, Isopropylamine, ethamine, butylamine, N-methyl piperidine or 4-Dimethylamino pyridine.
Synthetic general formula of the present invention is:
R wherein
0Expression:
Deng α, β, γ, δ ... omega amino acid;
R
1Expression
R
2, R
3Represent simple amine such as ammoniacal liquor, methylamine, ethamine, quadrol, propylamine, Isopropylamine, butylamine, isobutylamine, TERTIARY BUTYL AMINE etc.
A kind of aminoacid acidamide compounds adopts method for preparing to obtain.
The present invention compared with prior art has following advantage and effect:
(1) the present invention utilizes the amino acid of FMOC protection and chloride reagent reaction to form the amino acid acyl chlorides; select the dissolution with solvents of suitable polarity then; again with the simple compounds reaction that contains primary amine, secondary amine; aminoamide compound formation in a single day in reaction process of preparation just is precipitated out immediately; minimizing Fmoc contacts with amine; the whole process reaction time is short; speed is fast; thereby the carrying out that stops deprotection; the amino acid of having realized the Fmoc protection under the prerequisite of not taking off protecting group with the reaction of simple amine, productive rate is up to more than 93%.
(2) this reaction method is simple, the efficient height, and product is pure, aftertreatment is easy.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) N-Fmoc-L-valyl chlorine is synthetic
15.0g N-Fmoc-L-Xie Ansuan (44.2mmol) is dissolved in 250ml CH
2Cl
2In, feed N
2Protection drips 32.1ml SOCl
2(442.0mmol), be heated to 50 ℃, behind the back flow reaction 4h, change water distilling apparatus into, normal pressure boils off most of CH
2Cl
2Back evaporated under reduced pressure and at 60 ℃ of following vacuum-drying 2h obtains the N-Fmoc-L-valyl chlorine of little yellow solid 15.5g, productive rate 98%.
(2) N-Fmoc-N '-methyl-L-valine amide is synthetic
With above-mentioned solid product 15.5g (44.2mmol), be dissolved in the 465g anhydrous diethyl ether, dissolving is quick 25%～30% methylamine (221.0mmol) aqueous solution 26.0g that adds 5 times of above-mentioned solid product molar weights in back fully, concuss 3min, suction filtration places 800ml water to wash solid, suction filtration, use the 800ml water washing again, suction filtration, repeatable operation 6 times, obtain white solid, room temperature vacuum-drying 48h obtains N-Fmoc-N '-methyl-L-valine amide of 14.4g, and productive rate is 93.6%.m.p.211～212℃；
1H?NMR(CDCl
3，400MHz)δ：0.92(d，J＝7.8Hz，6H，)，2.05～2.18(m，1H)，2.81(d，J＝4.0Hz，3H)，3.88(t，J＝7.6，7.2Hz，1H)，4.20(t，J＝6.4，6.8Hz，1H)，4.40(d，J＝8.7Hz，2H)，5.32(d，J＝7.6Hz，1H)，5.81(brs，1H)，7.30(t，J＝7.2，7.2Hz，2H)，7.38(t，J＝7.2，7.6Hz，2H)，7.57(d，J＝7.6Hz，2H)，7.76(d，J＝7.6Hz，2H)
(3) L-valyl methylamine is synthetic
12.0g (34.1mmol) N-Fmoc-N '-methyl valine amide is placed 200ml THF, the piperidines of disposable adding 5% volume (10ml), behind the stirring reaction 4h, rotation concentrates removes THF, vacuum is drained, and gained solid dissolve with methanol filters, remove the Fmoc impurity that major part is taken off, use CH at last
2Cl
2The 5ml dissolving is crossed silicagel column, elutriant CH
2Cl
2: Methanol=100: 5, rotation obtains colourless oil liquid 3.6g's after doing) and L-valyl methylamine, productive rate 81.5%.
1H NMR (CDCl
3, 400MHz) δ: 0.79 (d, J=6.8Hz, 3H), 0.97 (d, J=7.2Hz, 3H), 2.27～2.32 (m, 1H), 2.80 (d, J=5.2Hz, 3H), 3.21 (d, J=3.6Hz, 1H), 3.37 (brs, 2H), 7.25 (brs, 1H).
Embodiment 2
(1) N-Fmoc-L-valyl chlorine is synthetic
15.0g N-Fmoc-L-Xie Ansuan (44.2mmol) is dissolved in 250ml CH
2Cl
2In, feed N
2Protection drips 32.1ml SOCl
2(442.0mmol), be heated to 50 ℃, behind the back flow reaction 4h, change water distilling apparatus into, normal pressure boils off most of CH
2Cl
2Back evaporated under reduced pressure and at 60 ℃ of following vacuum-drying 2h obtains the N-Fmoc-L-valyl chlorine of little yellow solid 15.5g, productive rate 98%.
(2) N-Fmoc-N '-sec.-propyl-L-valine amide is synthetic
With above-mentioned solid product 15.5g (44.2mmol), be dissolved in the 310g dry toluene, dissolving is quick Isopropylamine (176.8mmol) the solution 10.1g that adds 4 times of above-mentioned solid product molar weights in back fully, concuss 4min, suction filtration places 600ml water to wash solid, suction filtration, use the 600ml water washing again, suction filtration, repeatable operation 6 times, obtain white solid, room temperature vacuum-drying 48h obtains N-Fmoc-N '-sec.-propyl-L-valine amide of 15.8g, and productive rate is 94.2%.m.p.206～208℃；
1H?NMR(CDCl
3，400MHz)δ：0.93(d，J＝7.2Hz，6H)，1.13(d，J＝7.3Hz，6H)，2.04～2.09(m，1H)，3.85(t，J＝7.6，7.6Hz，1H)，4.03～4.8(m，1H)，4.19(t，J＝6.8，7.2Hz，1H)，4.35～4.40(m，2H)，5.42(d，J＝8.4Hz，1H)，5.63(brs，1H)，7.27(t，J＝7.2，7.6Hz，2H)，7.38(t，J＝7.6，7.6Hz，2H)，7.58(d，J＝7.6Hz，2H)，7.75(d，J＝7.6Hz，2H).
(3) L-valyl Isopropylamine is synthetic
12.0g (31.6mmol) N-Fmoc-N '-sec.-propyl-L-valine amide is placed 100ml CH
2Cl
2In, the triethylamine of disposable adding 5% volume (5ml), behind the stirring reaction 4h, rotation concentrates removes CH
2Cl
2, vacuum is drained, and gained solid dissolve with methanol filters, and removes the Fmoc impurity that major part is taken off, and uses CH at last
2Cl
2The 5ml dissolving is crossed silicagel column, elutriant CH
2Cl
2: Methanol=100: 4, obtain the L-valyl Isopropylamine of colourless oily mater 4.1g, productive rate 80.5%.
1H NMR (CDCl
3, 400MHz) δ: 0.84 (d, J=7.2Hz, 6H), 0.92 (d, J=6.8Hz, 6H), 1.98～2.03 (m, 1H), 3.31 (dd, J=3.2,4.8Hz, 1H), 3.91 (m, 1H), 4.04 (brs, 2H), 6.72 (d, J=8.4Hz, 1H).
Embodiment 3
(1) N-Fmoc-L-leucyl chlorine is synthetic
10.0g N-Fmoc-L-leucine (28.3mmol) is dissolved in 75ml CH
2Cl
2In, feed N
2Protection drips 20.6ml SOCl
2(283.0mmol), be heated to 50 ℃, behind the back flow reaction 2h, change water distilling apparatus into, normal pressure boils off most of CH
2Cl
2Back evaporated under reduced pressure and at 60 ℃ of following vacuum-drying 2h obtains the N-Fmoc-L-leucyl chlorine of little yellow solid 10.3g, productive rate 98%.
(2) N-Fmoc-N '-methyl-L-leucyl amine is synthetic
With above-mentioned solid product 10.0g (26.9mmol), be dissolved in the 400g dry toluene, dissolving is quick aqueous methylamine solution (80.7mmol) 9.5g that adds 3 times of above-mentioned solid product molar weights in back fully, concuss 2min, suction filtration places 600ml water to wash solid, suction filtration, use the 600ml water washing again, suction filtration, repeatable operation 8 times, obtain white solid, room temperature vacuum-drying 72h obtains N-Fmoc-N '-methyl-L-leucyl amine of 9.3g, and productive rate is 94.2%.m.p.167～168 ℃;
1HNMR (CDCl
3, 400MHz) δ: 0.92 (d, J=7.6Hz, 6H), 1.48～1.52 (m, 1H), 1.62 (s, 2H), 2.78 (s, 3H), 4.10 (d, J=4.0Hz, 1H), 4.18 (t, J=6.8,6.4Hz, 1H), 4.42 (d, J=6.0Hz, 2H), 5.13 (d, J=7.2Hz, 1H), 5.95 (brs, 1H), 7.28 (t, J=7.8,7.6Hz, 2H), 7.38 (t, J=7.6,7.6Hz, 2H), 7.56 (d, J=7.6Hz, 2H), 7.75 (d, J=7.6Hz, 2H).
(3) L-leucyl methylamine is synthetic
8.0g (21.9mmol) N-Fmoc-N '-methyl-L-leucyl amine is placed 60ml CH
2Cl
2In, the ethamine of disposable adding 7% volume (4.2ml), behind the stirring reaction 3h, rotation concentrates removes CH
2Cl
2, vacuum is drained, and gained solid dissolve with methanol filters, and removes the Fmoc impurity that major part is taken off, and uses CH at last
2Cl
2The 3ml dissolving is crossed silicagel column, elutriant CH
2Cl
2: Methanol=100: 4, obtain the L-leucyl methylamine of colourless oily mater 2.7g, productive rate 84.3%.
1H NMR (CDCl
3, 400MHz) δ: 0.90 (d, J=6.8Hz, 3H), 0.95 (d, J=7.2Hz, 3H), 1.80 (m, 1H), 2.13 (m, 2H), 2.78 (d, J=5.6Hz, 3H), 3.57 (brs, 2H), 3.90 (dd, J=8.4,8.8Hz, 1H), 7,39 (brs, 1H).
Embodiment 4
(1) N-Fmoc-L-methinyl chlorine is synthetic
10.0g N-Fmoc-L-methionine(Met) (26.9mmol) is dissolved in 75ml CH
2Cl
2In, feed N
2Protection drips 19.6ml SOCl
2(269mmol), be heated to 50 ℃, behind the back flow reaction 3h, change water distilling apparatus into, normal pressure boils off most of CH
2Cl
2Back evaporated under reduced pressure and at 50 ℃ of following vacuum-drying 4h obtains the N-Fmoc-L-methinyl chlorine of little yellow solid 10.4g, productive rate 99%.
(2) N-Fmoc-N '-methyl-L-methinyl amine is synthetic
With above-mentioned solid product 5.0g (12.8mmol), be dissolved in the 300g anhydrous diethyl ether, dissolving is quick aqueous methylamine solution (128mmol) 15.1g that adds 10 times of above-mentioned solid product molar weights in back fully, concuss 4min, suction filtration places 100ml water to wash solid, suction filtration, use the 100ml water washing again, suction filtration, repeatable operation 5 times, obtain white solid, room temperature vacuum-drying 12h obtains N-Fmoc-N '-methyl-L-methinyl amine of 4.7g, and productive rate is 96.2%.m.p.181～182℃；
1HNMR(CDCl
3，400MHz)δ：1.92～1.96(m，2H)，2.08(s，3H)，2.49～2.54(m，2H)，2.80(d，J＝4.0Hz，3H)，4.18(t，J＝6.8，6.4Hz，1H)，4.30(d，J＝7.6Hz，1H)，4.39(d，J＝6.0Hz，2H)，5.53(d，J＝8.0Hz，1H)，6.14(brs，1H)，7.27(t，J＝7.2，7.6Hz，2H)，7.38(t，J＝7.7，7.6Hz，2H)，7.56(d，J＝7.6Hz，2H)，7.75(d，J＝7.6Hz，2H).
(3) L-methinyl methylamine is synthetic
4.0g (10.4mmol) N-Fmoc-N '-methyl-L-methinyl amine is placed 40ml THF, the piperidines of disposable adding 7% volume (2.8ml), behind the stirring reaction 1h, rotation concentrates removes CH
2Cl
2, vacuum is drained, and gained solid dissolve with methanol filters, and removes the Fmoc impurity that major part is taken off, and uses CH at last
2Cl
2The 2ml dissolving is crossed silicagel column, elutriant CH
2Cl
2: Methanol=100: 5, the L-methinyl methylamine of colorless oil 1.5g, productive rate 88.6%.
1H NMR (CDCl
3, 400MHz) δ: 1.69 (t, J=5.6,5.6Hz, 2H), 2.18 (s, 3H), 2.36 (t, J=6.8,6.4Hz, 2H), 2.79 (s, 3H), 3.39 (brs, 2H), 4.19 (t, J=6.4,3.6Hz, 1H), 6.58 (s, 1H).
Embodiment 5～9 related conditional parameters see Table 1, and other steps are with embodiment 1
Reaction conditions and the parameter of table 1 embodiment 1-9
Claims (6)
1. the preparation method of an aminoacid acidamide compounds is characterized in that comprising the steps:
(1) amino acid with 1 mass parts fluorenylmethyloxycarbonyl FMOC protection is dissolved in the organic solvent that dewaters of 5～50 mass parts, adding consumption is the chloride reagent of 2～20 times of amino acid molar weights, after the back flow reaction, organic solvent and chloride reagent are removed in distillation, and vacuum-drying, obtain the acyl chlorides solid reaction product;
(2) add the organic solvent that dewaters that consumption is 10～60 times of acyl chlorides solid reaction product quality then, after treating dissolving fully, adding consumption is the aminated compounds of 3～10 times of acyl chlorides solid reaction product molar weights, be settled out aminoacid acidamide compounds, aminated compounds and organic solvent are removed in the water flushing then, and vacuum-drying obtains the aminoacid acidamide compounds of FMOC protection; Described aminated compounds is methylamine, ethamine, propylamine, Isopropylamine, butylamine, isobutylamine, TERTIARY BUTYL AMINE, aniline, o-toluidine, to monomethylaniline, benzene methanamine, quadrol, propylene diamine; The described organic solvent that dewaters is ether, benzene, toluene, methylene dichloride or tetracol phenixin;
(3) with the aminoacid acidamide compounds of the above-mentioned FMOC protection dissolution with solvents with 10～70 mass parts, the amine reagent that adds 2%～20% volume parts is taken off protective material FMOC, and the mistake silicagel column obtains aminoacid acidamide compounds behind the rotation evaporate to dryness.
2. the preparation method of aminoacid acidamide compounds according to claim 1, it is characterized in that: step 1, described amino acid are acidity, neutrality or the alkaline amino acid that contains mono amino and carboxyl.
3. the preparation method of aminoacid acidamide compounds according to claim 1, it is characterized in that: in the step 1, the described organic solvent that dewaters is methylene dichloride, tetrahydrofuran (THF), chloroform or acetone.
4. the preparation method of aminoacid acidamide compounds according to claim 1, it is characterized in that: in the step 1, described chloride reagent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride.
5. the preparation method of aminoacid acidamide compounds according to claim 1, it is characterized in that: in the step 3, described solvent is tetrahydrofuran (THF), N, dinethylformamide, pyridine, acetonitrile or acetone.
6. the preparation method of aminoacid acidamide compounds according to claim 1, it is characterized in that: in the step 3, described amine reagent is piperidines, methylamine, Isopropylamine, ethamine, butylamine, N-methyl piperidine or 4-Dimethylamino pyridine.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5079260A (en) * | 1989-06-22 | 1992-01-07 | Nova Pharmaceutical Corporation | Method for treating inflammation and compounds and compositions suitable for use therein |
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|---|---|---|---|---|
| US5079260A (en) * | 1989-06-22 | 1992-01-07 | Nova Pharmaceutical Corporation | Method for treating inflammation and compounds and compositions suitable for use therein |
Non-Patent Citations (4)
| Title |
|---|
| Louis A.Carpino.((9-Fluorenylmethyl)oxy)carbonyl(Fmoc) Amino Acid Chlorides. Synthesis,Characterization,and Application to the Rapid Synthesis of Short Peptide Segments.J.Org.Chem..1986,51(19),3732-3734. * |
| Yoji Aoki,et al..Development of a Reductive Alkylation Method Using p-Benzyloxybenzylamine(BOBA) Resin for the Synthesis of N-Alkylated Amides.J.Comb.Chem..1999,1(5),371-372. * |
| 黄世俊，等.氨基酸N-羧酸内酸酐与胺反应的位阻效应.厦门大学学报（自然科学版）.2005,44(4),511-514. |
| 黄世俊等.氨基酸N-羧酸内酸酐与胺反应的位阻效应.厦门大学学报(自然科学版).2005,44(4),511-514. * |
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