CN102911106A - Preparation method of L-N-Boc-high tryptophan methyl ester - Google Patents
Preparation method of L-N-Boc-high tryptophan methyl ester Download PDFInfo
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Abstract
The invention discloses a preparation method of L-N-Boc-high tryptophan methyl ester, which can be mainly used for solving the problems that the reaction steps are more, the cost is low, the operation is difficult, and the single chirality of a final compound can not be ensured in an existing synthesizing method. The preparation method comprises the steps of conducting cyclization reaction to generate L-2-pyrrolidone-6-formic acid 1 by taking L-2-amino adipic acid as initial materials under the action of glacial acetic acid and water; 2. conducting an esterification reaction on the compound 1 and trimethyl silicon diazomethane to obtain L-2-pyrrolidone-6-methyl ester 2; 3. protecting N in the compound 2 by using Boc, then conducting the reduction reaction due to the action of a reducing agent, namely lithium triethylborohydride, and reducing carbonyl in the L-2-pyrrolidone-6-methyl ester protected by N-tert-butylcarbazate; and 4. finally synthesizing the high tryptophan methyl ester protected by the L-N-tert-butylcarbazate by two methods: synthesizing classical fisher benzazole in one method, and removing one molecular water by L-2-pyrrolidinol-6-methyl ester and iodoaniline, rearranging, and conducting Heck reaction under the action of a palladium catalyst to obtain the L-N-Boc-high tryptophan methyl ester in the other method.
Description
Technical field
The present invention relates to the preparation method of high tryptophan methyl esters, particularly the preparation method of a kind of L configuration-N-Boc-high tryptophan methyl esters.
Background technology
Preparation method's route of existing L configuration-N-Boc-high tryptophan methyl esters is as follows:
Above-mentioned synthetic method reaction step number is long, and raw material and human cost are high, and be not easy to operate, and final compound single chiral can't guarantee.
Summary of the invention
The objective of the invention is to be to provide a kind of preparation method of L-N-Boc-high tryptophan methyl esters, the reaction step number that mainly solves existing synthetic method existence is long, raw material and human cost are high, and be not easy to operate, the technical problem that the single chiral of final compound can't guarantee.
Technical scheme is: a kind of preparation method of L-N-Boc-high tryptophan methyl esters may further comprise the steps: the first step: take the L-2-aminoadipic acid as starting raw material, under the effect of Glacial acetic acid and water, carry out the cyclization reaction and generate L-2-pyrrolidone-6-formic acid; Then second step carries out esterification with the trimethyl silicane diazomethane and obtains L-2-pyrrolidone-6-methyl esters; In the 3rd step, in solvent, the N in the cyclic group protects with tertbutyloxycarbonyl L-2-pyrrolidone-6-methyl esters under alkaline condition; The 4th step, then under the effect of reductive agent lithium triethylborohydride, carry out reduction reaction, the carbonyl in the L-2-pyrrolidone of N-tertbutyloxycarbonyl protection-6-methyl esters is reduced and obtains alcohol; The 5th step, the synthetic method of the final step of L-N-tertbutyloxycarbonyl high tryptophan methyl esters has two kinds: first method is the Fischer(Fei Sheer by classics) indoles is synthetic, the L-2-pyrrolidinol that the second passes through-6-methyl esters and adjacent Iodoaniline are sloughed a part water, reset, under the effect of palladium catalyst, carry out again Heck(He Ke) reaction obtains.
Synthetic route is as follows:
Heck(He Ke) reaction mechanism is:
Wherein the used solvent of cyclization reaction is Glacial acetic acid and water in the first step molecule.Used temperature of reaction is 0 ~ 100 degree centigrade, take 80 degrees centigrade as optimum condition.The used reaction times is 8～40 hours, take 12 hours as preferred.
The second step esterification reaction of organic acid dropwise adds methylating reagent in the organic solvent of zero degrees celsius, in room temperature (20-30 degree centigrade) reaction, used methylating reagent is the trimethyl silicane diazomethane.Used solvent is a kind of in anhydrous methylene dichloride or the chloroform, and wherein methylene dichloride is preferred solvent.The used reaction times is 20～60 hours, take 36 hours as preferred.
The used protecting group of three-step reaction is tertbutyloxycarbonyl.Used alkali is triethylamine; Used organic solvent is one or more in alcoholic solvent or the tetrahydrofuran solvent, and described solvent is take methyl alcohol as preferred; Used temperature of reaction is 20 ~ 50 degrees centigrade, take 25 degrees centigrade as optimum condition, the used reaction times is 5 ~ 35 hours; Take 10 hours as optimum condition.
The used reductive agent of four-step reaction is lithium triethylborohydride.Used organic solvent is one or more in ether solvent or the tetrahydrofuran solvent, take ether as optimum condition; Used temperature of reaction is-100-0 ℃, and preferable reaction temperature is subzero 78 degrees centigrade; The used reaction times is 1 ~ 30 hour; The preferred reaction time is ~ 12 hours.
The 5th step is by classical Fischer(Fei Sheer) the used solvent of high tryptophan methyl esters protected of the synthetic L-N tertbutyloxycarbonyl of indoles is alcoholic solvent, and take Virahol as optimum condition, used temperature of reaction is 10-100 ℃, and preferable reaction temperature is 90 degrees centigrade; The used reaction times is 10 ~ 30 hours; The preferred reaction time is ~ 12 hours.
By Heck(He Ke) the used metal catalyst of high tryptophan methyl esters of the synthetic L-N tertbutyloxycarbonyl protection of reaction is palladium; Used alkali is triethylene diamine; Used solvent is aprotic polar solvent, take DMF as optimum condition.
Beneficial effect of the present invention: compare with existing method, have obvious advantage, the present invention is simple to operate, and reaction easily detects, and aftertreatment is simple, is easy to obtain sterling; Starting material cheaply are easy to get, and cost is low, and used reaction reagent is comparatively safe, do not have large potential safety hazard.React step number short (reaction of 5 steps), can obtain the product of high yield and single chiral, the ee value can reach 96%.
Embodiment
Enumerate embodiment so that the present invention is described in detail, but the present invention is not limited to these embodiment.
The preparation of L-2-pyrrolidone-6-formic acid
Operation steps:
Embodiment 1: L-2-aminoadipic acid (1.61 grams, 10 mmoles) is joined in acetic acid (30 milliliters) and the water (5 milliliters).The mixture of gained was general 12 hours of 80 ℃ of reactions.After complete with LC-MS monitoring raw material reaction, reactant is concentrated obtain L-2-pyrrolidone-6-formic acid (1.21 grams, yield: 84.6%), the not purified the next step that both can be used for.
Embodiment 2: L-2-aminoadipic acid (1.61 grams, 10 mmoles) is joined in acetic acid (30 milliliters) and the water (5 milliliters).The mixture of gained was general 12 hours of 50 ℃ of reactions.After complete with LC-MS monitoring raw material reaction, reactant is concentrated obtain L-2-pyrrolidone-6-formic acid (0.20 gram, yield: 14.0%), the not purified the next step that both can be used for.
1HNMR?(DMSO,?Bruker?Avance?400?MHz):δ?1.623?(m,?2H),?1.749?(t,?J=7.2Hz,?1H),?1.902?(dd,?
J=8.8?Hz,?
J=4.4?Hz,?1H),?2.110?(m,?2H),?3.924?(m,?2H),?7.4(s,?1H)。
The preparation of L-2-pyrrolidone-6-methyl esters
Operation steps:
Embodiment 3: L-2-pyrrolidone-6-formic acid (1.43 grams, 10 mmoles) is dissolved in anhydrous methylene chloride (20 milliliters) and the methyl alcohol (10 milliliters).Then trimethyl silicane diazomethane (1.14 gram, 10 mmoles) dropwise adds at 0 ℃, and reaction mixture was room temperature reaction 36 hours.Reaction detects raw material without after remaining by LC-MS, water (2 milliliters) cancellation, the concentrated crude product that obtains (S)-2-Pyrrolidone-6-methyl esters.Crude product obtains sterling (0.56 gram, the yield: 36%) of L-2-pyrrolidone-6-methyl esters by silica gel chromatography.
Embodiment 4: L-2-pyrrolidone-6-formic acid (1.43 grams, 10 mmoles) is dissolved in anhydrous methylene chloride (20 milliliters) and the methyl alcohol (10 milliliters).Then trimethyl silicane diazomethane (1.14 gram, 10 mmoles) dropwise adds at 0 ℃, and reaction mixture was room temperature reaction 20 hours.After reaction detects by LC-MS, water (2 milliliters) cancellation, the concentrated crude product that obtains (S)-2-Pyrrolidone-6-methyl esters.Crude product obtains sterling (0.2 gram, the yield: 12.9%) of L-2-pyrrolidone-6-methyl esters by silica gel chromatography.
1HNMR?(CDCl
3,?Bruker?Avance?400?MHz):δ?1.859?(m,?3H),?2.177?(m,?1H),?2.393?(t,?
J=6.4?Hz,?2H),?2.110?(m,?2H),?3.787?(s,?3H),?4.110(t,
?J=6?Hz,?1H),?6.421(s,?1H)。
The preparation of the L-2-pyrrolidone of N-tertbutyloxycarbonyl protection-6-methyl esters
Operation steps:
Embodiment 5:L-2-pyrrolidone-6-methyl esters (1.57 grams, 10 mmoles) and triethylamine (2 grams, 20 mmoles) are dissolved in the methyl alcohol (20 milliliters), and then Boc acid anhydrides (2.3 grams, 11 mmoles) joins in the reaction system.Reaction was carried out 10 hours at 25 ℃, until detect raw material less than after remaining with LC-MS, the concentrated crude product that obtains of reaction mixture.After separating by column chromatography, crude product obtains the L-2-pyrrolidone of N-Boc protection-6-methyl esters (2.41 grams, yield: 94%).
Embodiment 6: L-2-pyrrolidone-6-methyl esters (1.57 grams, 10 mmoles) and triethylamine (2 grams, 20 mmoles) are dissolved in the methyl alcohol (20 milliliters), and then Boc acid anhydrides (2.3 grams, 11 mmoles) joins in the reaction system.Reaction was carried out 2 hours at 25 ℃, after detecting with LC-MS, and the concentrated crude product that obtains of reaction mixture.After separating by column chromatography, crude product obtains the L-2-pyrrolidone of N-Boc protection-6-methyl esters (0.8 gram, yield: 31.2%)
1HNMR?(CDCl
3,?Bruker?Avance?400?MHz):δ?1.507（s,?9H）,1.775?(m,?2H),?2.066?(m,?1H),?2.160?(m,?1H),?2.519?(m,?2H),?3.778?(s,?3H),?4.717(dd,
?J=5.6?Hz,?
J=4?Hz,?1H)。
The preparation of L-2-pyrrolidinol-6-methyl esters
Operation steps:
Embodiment 7: lithium triethylborohydride (the THF solution of 1 mol/L, 10 milliliters, 10 mmoles) is dissolved in the ether (200 milliliters).At-78 ℃, join lentamente through mentioned solution in the solution of THF (60 milliliters) of the L-2-pyrrolidone of N-tertbutyloxycarbonyl protection-6-methyl esters (1.2 grams, 5 mmoles), feed time is five minutes.After raw material consumption was complete, reaction solution was with the careful cancellation of the aqueous hydrochloric acid of 1 N.Organic phase is with 1.0 N HCI(100 milliliters) wash twice, wash with saturated common salt again.Obtain the product L-2-pyrrolidinol of oily-6-methyl esters (0.26 gram, yield: 20%) after organic phase is concentrated.
Embodiment 8: lithium triethylborohydride (the THF solution of 1 mol/L, 10 milliliters, 10 mmoles) is dissolved in the ether (200 milliliters).At-78 ℃, join lentamente through mentioned solution in the solution of THF (60 milliliters) of the L-2-pyrrolidone of N-tertbutyloxycarbonyl protection-6-methyl esters (1.2 grams, 5 mmoles), feed time is two minutes.After raw material consumption was complete, reaction solution was with the careful cancellation of the aqueous hydrochloric acid of 1 N.Organic phase is with 1.0 N HCI(100 milliliters) wash twice, wash with saturated common salt again.Obtain the product L-2-pyrrolidinol of oily-6-methyl esters (0.1 gram, yield: 7.7%) after organic phase is concentrated.
1HNMR?(CDCl
3,?Bruker?Avance?400?MHz):δ?1.547（s,?9H）,1.701?(m,?2H),?1.907?(m,?1H),?2.175?(m,?1H),?3.536?(m,?1H),?3.746?(s,?3H),?4.442(m,?1H),?4.777(m,?1H),?5.632(m,?1H)。
The preparation of L-N-Boc high tryptophan methyl esters
Operation steps by Heck (He Ke) reaction preparation is as follows:
Embodiment 9: under nitrogen protection, with 2-Iodoaniline (2.19 grams, 10 mmoles); triethylene diamine (12.2 grams; 11 mmoles) and palladium (0.4 gram, 0.2 mmole) be added to the DMF(50 milliliter of L-2-pyrrolidinol-6-methyl esters (2.59 grams, 10 mmoles)) in the solution.Then reaction system nitrogen vacuum displacement three times are heated to 85 ℃ of reaction overnight.After reaction is finished, cool to room temperature, then thin up uses ethyl acetate extraction (50 milliliters of * 3).
Organic layer anhydrous sodium sulfate drying after the merging concentrates and obtains thick product.Crude product obtains the high tryptophan methyl esters of the finished product L-N-tertbutyloxycarbonyl protection with the silica gel column chromatography purifying, and (1.12 grams, yield: 34%), sterling is white solid.
Embodiment 10: under nitrogen protection, with 2-Iodoaniline (2.19 grams, 10 mmoles); triethylene diamine (12.2 grams; 11 mmoles) and palladium (0.4 gram, 0.2 mmole) be added to the DMF(50 milliliter of L-2-pyrrolidinol-6-methyl esters (2.59 grams, 10 mmoles)) in the solution.Then reaction system nitrogen vacuum displacement three times are heated to 85 ℃ of reactions 8 hours.After reaction is finished, cool to room temperature, then thin up uses ethyl acetate extraction (50 milliliters of * 3).
Organic layer anhydrous sodium sulfate drying after the merging concentrates and obtains thick product.Crude product obtains the high tryptophan methyl esters of the finished product L-N-tertbutyloxycarbonyl protection with the silica gel column chromatography purifying, and (0.5 gram, yield: 15.2%), sterling is white solid.
By Fischer(Fei Sheer) the synthetic operation steps of indoles is as follows:
Embodiment 11: L-2-pyrrolidinol-6-methyl esters (2.59 grams, 10 mmoles) and hydrazinobenzene hydrochloride salt (1.44 grams, 10 mmoles) refluxed 12 hours in Virahol (50 milliliters).After complete by LC-MS detection raw material reaction, the concentrated crude product that obtains of reaction solution.Crude product obtains high tryptophan methyl esters (0.7 gram, the yield: 21%) of the finished product L-N tertbutyloxycarbonyl protection with the silica gel column chromatography purifying.
Embodiment 12: L-2-pyrrolidinol-6-methyl esters (2.59 grams, 10 mmoles) and hydrazinobenzene hydrochloride salt (1.44 grams, 10 mmoles) are heated to 40 ℃ of reactions 12 hours in Virahol (50 milliliters).After complete by LC-MS detection raw material reaction, the concentrated crude product that obtains of reaction solution.Crude product obtains high tryptophan methyl esters (0.2 gram, the yield: 6.0%) of the finished product L-N tertbutyloxycarbonyl protection with the silica gel column chromatography purifying.
1HNMR?(CDCl
3,?Bruker?Avance?400?MHz):δ?1.483（s,?9H）,?2.066?(dd,
?J=14?Hz,?
J=7.6?Hz,?1H),?2.066?(dd,
?J=13.2?Hz,?
J=5.6?Hz,?1H),?2.852?(t,?
J=8?Hz,?2H),?3.688?(s,?3H),?4.428?(d,?
J=4.8?Hz,?1H),?5.152?(d,?J=7.2?Hz,?1H),?7.027(s,?1H),?7.133(t,?
J=7.6?Hz,?1H),?7.199(d,?J=7.6?Hz,?1H),?7.280(s,?1H),?7.372(d,?
J=8?Hz,?1H),?7.589(d,?
J=8?Hz,?1H),?8.079(s,?1H)。
By these two kinds of methods, can obtain at last the high tryptophan methyl esters of the L-N tertbutyloxycarbonyl protection of single configuration, ee value 96%.
Claims (12)
1.L-N-Boc-the preparation method of high tryptophan methyl esters is characterized in that, may further comprise the steps:
The first step: take the L-2-aminoadipic acid as starting raw material, under the effect of Glacial acetic acid and water, carry out the cyclization reaction and generate L-2-pyrrolidone-6-formic acid;
Second step: L-2-pyrrolidone-6-formic acid carries out esterification at the trimethyl silicane diazomethane and obtains L-2-pyrrolidone-6-methyl esters;
The 3rd step: in organic solvent, the N in the cyclic group protects with tertbutyloxycarbonyl L-2-pyrrolidone-6-methyl esters under alkaline condition;
The 4th step: in organic solvent, carry out reduction reaction under the effect of reductive agent lithium triethylborohydride, the carbonyl in the L-2-pyrrolidone of N-tertbutyloxycarbonyl protection-6-methyl esters is reduced and obtains alcohol;
The 5th step: the synthetic method of the final step of the high tryptophan methyl esters of L-N tertbutyloxycarbonyl protection is selected from following a kind of: first method is that the L-2-pyrrolidinol that passes through-6-methyl esters and adjacent Iodoaniline are sloughed a part water, reset, under the effect of palladium catalyst, carry out again the He Ke reaction and obtain; The second is synthetic by the Fei Sheer indoles,
Synthetic route is as follows:
2. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1 is characterized in that, described the first step reaction is carried out in solvent, and solvent is Glacial acetic acid and water, and temperature of reaction is 0 ~ 100 degree centigrade, and the reaction times is 8～40 hours.
3. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 2 is characterized in that, temperature of reaction is 80 degrees centigrade, 12 hours reaction times.
4. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1, it is characterized in that, described second step reaction is in the organic solvent of zero degrees celsius, dropwise add methylating reagent trimethyl silicane diazomethane, at room temperature reaction, used solvent is anhydrous methylene dichloride or chloroform, and the used reaction times is 20～60 hours.
5. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 4 is characterized in that, solvent is anhydrous methylene chloride, 36 hours reaction times.
6. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1 is characterized in that, the used alkali of described three-step reaction is triethylamine; Used organic solvent is one or more in alcoholic solvent or the tetrahydrofuran solvent, and temperature of reaction is 20 ~ 50 degrees centigrade, and the reaction times is 5 ~ 35 hours.
7. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 6 is characterized in that, organic solvent is methyl alcohol, 25 degrees centigrade of temperature of reaction, 10 hours reaction times.
8. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1, it is characterized in that, the used organic solvent of described four-step reaction is one or more in ether solvent or the tetrahydrofuran solvent, temperature of reaction is-and 100-0 ℃, the reaction times is 1 ~ 30 hour.
9. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 8 is characterized in that, organic solvent is ether, and temperature of reaction is subzero 78 degrees centigrade, 12 hours reaction times.
10. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1 is characterized in that, described the 5th step He Ke reaction palladium catalyst is palladium; The He Ke reaction is carried out in solvent under alkaline condition, and used alkali is triethylene diamine; Used solvent is the aprotic polar solvent DMF.
11. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 1 is characterized in that, described the 5th step Fei Sheer carries out in alcoholic solvent, and temperature of reaction is 10-100 ℃, and the reaction times is 10 ~ 30 hours.
12. the preparation method of L-N-Boc-high tryptophan methyl esters according to claim 11 is characterized in that, solvent is Virahol, and temperature of reaction is 90 degrees centigrade, and the reaction times is 12 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106810467A (en) * | 2017-01-03 | 2017-06-09 | 苏州昊帆生物股份有限公司 | Diamine compounds list Boc guard methods |
| CN107337573A (en) * | 2017-07-06 | 2017-11-10 | 台州学院 | A kind of green new method of disubstituted amide derivative decarbonylation hydrogenation |
| CN115286554A (en) * | 2022-08-22 | 2022-11-04 | 常州吉恩药业有限公司 | Preparation method of N-alpha-9-fluorenylmethoxycarbonyl-N-in-tert-butoxycarbonyl-L-tryptophan |
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2012
- 2012-11-13 CN CN 201210451473 patent/CN102911106A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810467A (en) * | 2017-01-03 | 2017-06-09 | 苏州昊帆生物股份有限公司 | Diamine compounds list Boc guard methods |
| CN107337573A (en) * | 2017-07-06 | 2017-11-10 | 台州学院 | A kind of green new method of disubstituted amide derivative decarbonylation hydrogenation |
| CN107337573B (en) * | 2017-07-06 | 2020-09-01 | 台州学院 | Green and novel decarbonylation and hydrogenation method for disubstituted amide derivative |
| CN115286554A (en) * | 2022-08-22 | 2022-11-04 | 常州吉恩药业有限公司 | Preparation method of N-alpha-9-fluorenylmethoxycarbonyl-N-in-tert-butoxycarbonyl-L-tryptophan |
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Application publication date: 20130206 |