CN102268029B - Preparation method of compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester - Google Patents
Preparation method of compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester Download PDFInfo
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Abstract
The invention discloses a preparation method of a compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester (shown in the structural formula 1). The preparation method comprises the following steps that L-phenylalanine and triphosgene undergo a reaction to produce a compound shown in the structural formula 8; the compound shown in the structural formula 8 and a compound shown in the structural formula 7 undergo a condensation reaction to produce a compound which has a single configuration and is shown in the structural formula 1; the compound shown in the structural formula 1 and pyrazinecarboxylic acid undergo a condensation reaction to produce a compound shown in the formula 10; and the compound shown in the formula 10 is hydrolyzed to form bortezomib which is an anticancer drug. The preparation method has the advantages of simple operation, high yield, easy acquirement of raw materials, and low pollution on the environment. The preparation method is suitable for industrialized production.
Description
Technical field
The present invention is a kind of Velcade intermediates preparation, particularly relates to a kind of yield height, and is easy and simple to handle, is fit to the Velcade intermediates preparation of suitability for industrialized production.
Background technology
Velcade (bortezomib) is by the Millennium drugmaker research and development of Massachusetts, United States Cambridge (Cambridge), Velcade is first two peptide boric acids proteinoid enzyme body inhibitor, be combined with the 26S proteasome to reversibility, the degraded of blocks protein prevents the malignant proliferation of tumour cell.Be mainly used in treating multiple myeloma.Its chemical being called [(1R)-the 3-methyl isophthalic acid-[[(2S)-and 1-oxygen-3-phenyl-2-[(pyrazine carbonyl) amino] propyl group] amino] butyl]-boric acid.Go on the market in the U.S. in May, 2003, go on the market in China in September, 2005.
Velcade by (1S, 2S, 3R, 5S)-pinine glycol-L-phenylalanine-L-leucine boric acid ester (compound of structural formula 1) and pyrazine-2-formic acid (compound of structural formula 9) condensation form.
Patent WO2005097809 and document Journal of Labelled Compound and Radiopharmaceuticals.2007; 50; 402-406 has described the synthetic of compound 1: (1R)-(S)-and pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester (compound 7) and BOC-L-phenylalanine; in the presence of TBTU; condensation generates (1S; 2S; 3R; 5S)-pinine glycol-N-BOC-L-phenylalanine-L-leucine boric acid ester (compound 12); compound 12 obtains compound 1 through the hydrolysis deprotection.This method yield is lower.And in synthetic, used condensing agent TBTU, it is many, big for environment pollution to produce the three wastes, is not suitable for industrial production.
Summary of the invention
In order to solve the industrialization problem that does not solve compound 1 in the prior art better, this patent has been invented one with low cost according to the constructional feature of compound 1, short route, the route of less environmental pollution synthetic compound 1.L-phenylalanine (compound 13) generates 4-benzyl-oxazolidine-2 with the triphosgene reaction, 5-diketone (compound 8), compound 8 and compound 7 direct condensations, generate target compound (1S, 2S, 3R, 5S)-pinine glycol-L-phenylalanine-L-leucine boric acid ester (compound 1).
Comprise the steps:
(1) L-phenylalanine and triphosgene reaction, 20 ℃-150 ℃ of temperature, time 1-50h; Obtain reaction solution and concentrate organic solvent dissolution; Described organic solvent is ether, tetrahydrofuran (THF), methylene dichloride, acetone, a kind of in 1, the 4-dioxane, preferred tetrahydrofuran (THF).
(2) under temperature-20 ℃-20 ℃, with alkali with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester dissolving, will the solution of the adding of the drips of solution in (1) (2) in, stirring reaction; Described temperature is preferably-5-0 ℃; Described alkali is N, the N-diisopropylethylamine, and triethylamine, a kind of in the diethylamine is preferably N, the N-diisopropylethylamine.
With respect to existing method, this synthetic route has following advantage:
1. easy and simple to handle, yield height (total recovery 85%);
2. reagent is easy to get, and cost is lower, is fit to industrial production;
3. do not use condensing agents such as TBTU, reduced the three wastes, be fit to suitability for industrialized production.
Embodiment
Embodiment 1
Triphosgene under the room temperature (3.6g, tetrahydrofuran (THF) 50ml liquid 12.1mmol), be added dropwise to the L-phenylalanine (2.0g, in tetrahydrofuran (THF) 12.1mmol) (50ml) solution, after dropwising, heating reflux reaction 4h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid 2.2g, yield 96%.
With (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester (4.3g, 11.3mmol), methylene dichloride 30ml adds in the reaction flask, is cooled to-5 ℃.With N, and the N-diisopropylethylamine (6ml, 34.5mmol) mixed solution with methylene dichloride 20ml is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 4h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 4.2g, total recovery 85%.MS(m/z):413(M+H)
+
Embodiment 2
Triphosgene under the room temperature (3.6g, ether 50ml solution 12.1mmol), be added dropwise to the L-phenylalanine (2.0g, in tetrahydrofuran (THF) 12.1mmol) (50ml) solution, after dropwising, heating reflux reaction 4h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid 1.8g, yield 78%.
(3.6g, 9.5mmol), methylene dichloride 20ml adds in the reaction flask, is cooled to-5 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.With N, and the N-diisopropylethylamine (4.5ml, 28.2mmol) mixed solution with methylene dichloride 20ml is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 40ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 4h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 3.5g, total recovery 70%.MS(m/z):413(M+H)
+
Embodiment 3
Triphosgene under the room temperature (7.2g, tetrahydrofuran (THF) 50ml solution 24.2mmol), be added dropwise to the L-phenylalanine (4.0g, in tetrahydrofuran (THF) 24.2mmol) (50ml) solution, after dropwising, heating reflux reaction 4h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid 3.7g, yield 85%
(7.4g, 19.4mmol), methylene dichloride 60ml adds in the reaction flask, is cooled to-5 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.With N, and the N-diisopropylethylamine (9.6ml, 58.2mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 4h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 6.6g, total recovery 71%.MS(m/z):413(M+H)
+
Embodiment 4
Triphosgene under the room temperature (7.2g, tetrahydrofuran (THF) 50ml solution 24.2mmol), be added dropwise to the L-phenylalanine (4.0g, in methylene dichloride 24.2mmol) (100ml) solution, after dropwising, heating reflux reaction 5h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid.2.1g, yield 45%.
(4.2g, 11.0mmol), methylene dichloride 60ml adds in the reaction flask, is cooled to-5 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.With N, and the N-diisopropylethylamine (5.5ml, 33.0mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 4h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 4.0g, total recovery 40%.MS(m/z):413(M+H)
+
Embodiment 5
Triphosgene under the room temperature (3.6g, tetrahydrofuran (THF) 50ml solution 12.1mmol), be added dropwise to the L-phenylalanine (2.0g, in tetrahydrofuran (THF) 12.1mmol) (50ml) solution, after dropwising, heating reflux reaction 4h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid.2.2g, yield 96%.
(4.3g, 11.3mmol), methylene dichloride 60ml adds in the reaction flask, and is cooled to-5 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.With N, and the N-diisopropylethylamine (5.0ml, 33.9mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 5h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 3.5g, total recovery 70%.MS(m/z):413(M+H)
+
Embodiment 6
Triphosgene under the room temperature (7.2g, tetrahydrofuran (THF) 50ml solution 24.2mmol), be added dropwise to the L-phenylalanine (4.0g, in tetrahydrofuran (THF) 24.2mmol) (100ml) solution, after dropwising, heating reflux reaction 5h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid.4.5g, yield 97%.
(7.4g, 19.4mmol), methylene dichloride 60ml adds in the reaction flask, and is cooled to-5 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.(6.0ml, 58.2mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution ,-5 ℃ of following 2h that stir with diethylamine.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 5h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 6.0g, total recovery 60%.MS(m/z):413(M+H)
+
Embodiment 7
Triphosgene under the room temperature (5.4g, tetrahydrofuran (THF) 50ml liquid 18.1mmol), be added dropwise to the L-phenylalanine (3.0g, in tetrahydrofuran (THF) 18.1mmol) (60ml) solution, after dropwising, heating reflux reaction 5h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid.3.3g, yield 97%.
(6.7,17.6mmol), methylene dichloride 60ml adds in the reaction flask, and is cooled to 0 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.With N, and the N-diisopropyl ethyl amine (8.7ml, 52.8mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution, and 0 ℃ is stirred 2h down.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 5h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 4.4g, total recovery 60%.MS(m/z):413(M+H)
+
Embodiment 8
Triphosgene under the room temperature (7.2g, tetrahydrofuran (THF) 50ml liquid 24.2mmol), be added dropwise to the L-phenylalanine (4.0g, in tetrahydrofuran (THF) 24.2mmol) (100ml) solution, after dropwising, heating reflux reaction 5h.
Reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid.4.5g, yield 97%.
(7.4,19.4mmol), methylene dichloride 60ml adds in the reaction flask, and is cooled to-10 ℃ with (1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester.(6.0ml, 58.2mmol) mixed solution with methylene dichloride 40ml is added dropwise in the above-mentioned dichloromethane solution ,-10 ℃ of following 2h that stir with diethylamide.4-benzyl-oxazolidine-2, the tetrahydrofuran (THF) 50ml of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 5h.The washing organic layer, the organic layer drying.Suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 6.0g, total recovery 60%.MS(m/z):413(M+H)
+
Claims (1)
1. one kind (1S, 2S, 3R, 5S)-and the preparation method of pinine glycol-L-phenylalanine-L-leucine boric acid ester, it is characterized in that step is as follows:
(1) under the room temperature, in the 50mL tetrahydrofuran solution that contains the 3.6g triphosgene, be added dropwise to the tetrahydrofuran solution that 50mL contains 2.0g L-phenylalanine, after dropwising, heating reflux reaction 4h, reaction finishes, concentration of reaction solution and cool off 4-benzyl-oxazolidine-2,5-diketone solid 2.2g, yield 96%;
(2) with 4.3g(1R)-(S)-pinine glycol-1-trifluoroacetate-3-methylbutane-1-boric acid ester, 30mL methylene dichloride add in the reaction flask, is cooled to-5 ℃; With 6mL N, the mixed solution of N-diisopropylethylamine and 20mL methylene dichloride is added dropwise in the above-mentioned dichloromethane solution, and-5 ℃ are stirred 2h down; To contain (1) gained 4-benzyl-oxazolidine-2 in steps, the tetrahydrofuran solution 50mL of 5-diketone is added dropwise in the above-mentioned dichloromethane solution, dropwises room temperature reaction 4h; The washing organic layer, the organic layer drying, suction filtration concentrates, obtain (1S, 2S, 3R, 5S)-and pinine glycol-L-phenylalanine-L-leucine boric acid ester 4.2g, total recovery 85%.
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| CN102492021B (en) * | 2011-12-13 | 2013-10-23 | 重庆泰濠制药有限公司 | Preparation process for bortezomib |
| CN103387566B (en) * | 2012-05-09 | 2015-09-09 | 上海医药工业研究院 | Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate |
| CN102887913B (en) * | 2012-10-08 | 2015-02-25 | 南京江原安迪科正电子研究发展有限公司 | Method for synthesizing 4-dihydroxyborane-2-fluorophenylalanine |
| CN103965231B (en) * | 2013-01-31 | 2016-06-08 | 江苏奥赛康药业股份有限公司 | For detecting the acid amides boric acid ester of bortezomib intermediate purity, preparation method and application thereof |
| CN103497233B (en) * | 2013-09-30 | 2015-04-08 | 哈药集团技术中心 | Preparation method for bortezomib |
Citations (2)
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| WO2005097809A2 (en) * | 2004-03-30 | 2005-10-20 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
| US7205385B2 (en) * | 2004-11-12 | 2007-04-17 | General Electric Company | Polymerization method for the synthesis of polypeptide imaging agents |
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| JP2002088097A (en) * | 2000-09-08 | 2002-03-27 | Kao Corp | Dipeptide derivative and method of producing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005097809A2 (en) * | 2004-03-30 | 2005-10-20 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
| US7205385B2 (en) * | 2004-11-12 | 2007-04-17 | General Electric Company | Polymerization method for the synthesis of polypeptide imaging agents |
Non-Patent Citations (3)
| Title |
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| JP特开2002-88097A 2002.03.27 |
| 两亲性二嵌段共聚物MPEG44- b-Phe 的合成及其在水溶液中的自组装;李丽颖等;《高分子学报》;20060228(第1期);124-128 * |
| 李丽颖等.两亲性二嵌段共聚物MPEG44- b-Phe 的合成及其在水溶液中的自组装.《高分子学报》.2006,(第1期),124-128. |
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