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WO2021043187A1 - Procédé de préparation de sel de bore de dipeptide de valine-proline - Google Patents

Procédé de préparation de sel de bore de dipeptide de valine-proline Download PDF

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Publication number
WO2021043187A1
WO2021043187A1 PCT/CN2020/113131 CN2020113131W WO2021043187A1 WO 2021043187 A1 WO2021043187 A1 WO 2021043187A1 CN 2020113131 W CN2020113131 W CN 2020113131W WO 2021043187 A1 WO2021043187 A1 WO 2021043187A1
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reaction
formula
acid
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Chinese (zh)
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赖桢
林增明
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Balmxy Pharmaceutic Co Ltd
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Balmxy Pharmaceutic Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the invention belongs to the technical field of compound synthesis, and relates to a preparation method of dipeptide valine boroproline salt.
  • the dipeptide valine boroproline salt is an important anti-cancer drug intermediate.
  • the existing synthetic routes all start from valine protected by tert-butoxycarbonyl or trifluoroacetyl, which leads to deprotection. Since the target product is easily soluble in water, it is difficult to be purified and separated from water.
  • the current method is generally to dechlorinate through ion exchange resin and then form salt. The steps are complicated, and the loss during the reaction process and post-treatment process is large, resulting in The final target product yield is very low.
  • the purpose of the present invention is to provide a method for preparing dipeptide valine boroproline salt.
  • the target configuration product obtained by the preparation method of the present invention has high yield and simple post-processing loss. small.
  • the present invention adopts the following technical solutions:
  • the present invention provides a preparation method of dipeptide valine boronproline salt, the preparation method comprising the following steps:
  • R 1 and R 4 groups are independently selected from any one of alkoxycarbonyl, acyl or aryl; R 2 and R 3 groups are independently selected from hydrogen, linear or branched alkyl;
  • the anion X is independently selected from any one of alkylsulfonate, halogen ion, sulfate ion, or carboxylate ion.
  • the pyrrolidine boronic acid protected by the R 1 group is used as a raw material to react with a diol to protect the two hydroxyl groups of the boronic acid and simultaneously induce chirality; in the second step, the compound represented by formula I After removing the protection of the R 1 group and adding a resolving agent for resolution, the compound shown in formula II is obtained.
  • This method of using a resolving agent to resolve the product can greatly increase the yield of the product with the target configuration;
  • the third step Using R 4 protected valine as the starting material, the purpose is to avoid product loss caused by complex post-processing during deprotection, and to ensure that the compound represented by formula V can be directly combined with acid HX in the last step.
  • Salt formation improves the total yield of dipeptide valine boroproline salt, simplifies the post-reaction processing steps, and reduces the loss of the final target product.
  • the invention provides a new process synthesis method of a new anticancer drug dipeptide valine boroproline methanesulfonate (Talabostat methanesulfonate).
  • the molar mass ratio of the pyrrolidine boronic acid protected by the R 1 group and the diol in step (1) is (1-1.2):1, for example, it can be 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.19, 1:1.2, preferably 1:1.
  • the R 1 group is selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (cbz), benzyl (Bn), 2,4-dimethoxybenzyl (Dmb) or trityl Any one of (Trt) is preferably tert-butoxycarbonyl (Boc).
  • the diol is (1S, 2S, 3R, 5S)-2,3-pinanediol or pinacol.
  • the reaction system in step (1) further includes a desiccant.
  • the desiccant in step (1) is anhydrous magnesium sulfate.
  • the molar mass ratio of the desiccant in step (1) to the pyrrolidine boronic acid protected by the R 1 group is (1-3):1, for example, it can be 1:1, 1.2:1, 1.3:1, 1.4 :1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1 , 2.7:1, 2.8:1, 2.9:1, 3:1, preferably 2:1.
  • the reaction time in step (1) is 1-5h, for example, it can be 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h.
  • the reaction temperature in step (1) is 10-30°C, for example, 10°C, 12°C, 14°C, 16°C, 18°C, 19°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C.
  • the solvent for the reaction in step (1) includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, Preferably it is tetrahydrofuran.
  • the reagent for removing the protection of the R 1 group in step (2) is an acid.
  • the acid in step (2) is hydrochloric acid and/or trifluoroacetic acid, preferably hydrochloric acid.
  • the molar mass ratio of the acid in step (2) to the compound represented by formula I is (1-3):1, for example, it can be 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5 :1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1 , 2.8:1, 2.9:1, 3:1.
  • the reaction time for removing the R 1 group protection in step (2) is 0.5-2h, for example, it can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6 h, 1.8h, 2h.
  • the reaction temperature for removing the protection of the R 1 group in step (2) is -10 to 5°C, for example, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C. °C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C.
  • the reaction solvent for removing R 1 group protection in step (2) includes any one of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran or A combination of at least two, preferably diethyl ether.
  • the resolving agent in step (2) is L-dibenzoyltartaric acid monohydrate, L-dibenzoyltartaric acid anhydrate, L-mandelic acid, L-oxy-acetylmandelic acid, L -Either bis-p-toluoyl tartaric acid monohydrate or L- bis-p-toluoyl tartaric acid anhydrate, preferably L-dibenzoyl tartaric acid monohydrate.
  • the molar mass ratio of the resolving agent in step (2) to the compound represented by formula I is (0.9-1):1, for example, it can be 0.9:1, 0.91:1, 0.92:1, 0.93:1 , 0.94:1, 0.95:1, 0.96:1, 0.97:1, 0.98:1, 0.99:1, 1:1, preferably 0.95:1.
  • the conditions for the resolution in step (2) are: first react at 50-60°C (for example, 50°C, 52°C, 54°C, 56°C, 58°C, 60°C) for 0.5-2h (for example It can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, 2h), and then at -10 ⁇ 5°C (for example, it can be -10°C,- 9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, React at 5°C for 0.5-2h (for example, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, 2h).
  • 50-60°C for example, 50°C,
  • the solvent for the resolution in step (2) includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran , Preferably ethyl acetate.
  • the molar mass ratio of the compound represented by formula II and the L-valine protected by the R 4 group in step (3) is (1-1.5):1, for example, it may be 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, preferably 1:1.
  • the R 4 group is selected from the group consisting of benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-methoxybenzyl (Pmb) or benzyl (Bn) Any one, preferably benzyloxycarbonyl (Cbz);
  • the reaction system in step (3) further includes an organic base.
  • the organic base in step (3) is diisopropylethylamine.
  • the molar mass ratio of the organic base in step (3) to the L-valine protected by the R 4 group is (1-1.5):1, for example, it can be 1:1, 1.2:1, 1.3:1 , 1.4:1, 1.5:1.
  • the reaction temperature in step (3) is -10 to 5°C, for example, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C,- 3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, preferably 0°C.
  • the reaction time in step (3) is 6-10h, for example, it can be 6h, 7h, 8h, 9h, 10h, preferably 8h.
  • the reaction solvent in step (3) includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably It is dichloromethane.
  • the reaction system in step (3) further includes an activator.
  • step (3) are: first use an activator to activate L-valine protected by the R 4 group, and then react with the compound represented by formula II to obtain the compound represented by formula III.
  • the activator in step (3) is isobutyl chloroformate.
  • the molar mass ratio of the activator in step (3) to the L-valine protected by the R 4 group is (1-1.5):1, for example, it can be 1:1, 1.2:1, 1.3:1 , 1.4:1, 1.5:1.
  • the activation reaction system in step (3) further includes an organic base.
  • the organic base in step (3) is diisopropylethylamine.
  • the molar mass ratio of the organic base in step (3) to the L-valine protected by the R 4 group is (1-1.5):1, for example, it can be 1:1, 1.2:1, 1.3:1 , 1.4:1, 1.5:1.
  • the activation reaction temperature in step (3) is -10 to 5°C, for example, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, preferably 0°C.
  • the activation reaction time in step (3) is 0.5-2h, for example 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, 2h .
  • the solvent for the activation reaction in step (3) includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran , Preferably dichloromethane.
  • the molar mass ratio of the acid in step (4) to the compound represented by formula III is (10-15):1, for example, it can be 10:1, 11:1, 12:1, 13:1, 14: 1, 15:1.
  • the acid in step (4) is phenylboronic acid and hydrochloric acid.
  • the molar mass ratio of the phenylboronic acid in step (4) to the compound represented by formula III is (10-15):1, for example, it may be 10:1, 11:1, 12:1, 13:1, 14 :1, 15:1.
  • the molar mass ratio of the hydrochloric acid in step (4) to the compound represented by formula III is (1-1.5):1, for example, it can be 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5: 1.
  • the reaction time in step (4) is 10-20h, for example, it can be 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, preferably 12h.
  • the reaction temperature in step (4) is 10-30°C, for example, 10°C, 12°C, 14°C, 16°C, 18°C, 19°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C.
  • the reaction solvent in step (4) includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran , Preferably methanol.
  • the deprotection reaction of the R 4 group in step (5) is a catalytic hydrogenolysis reaction.
  • the catalyst for catalyzing the hydrogenolysis reaction in step (5) is palladium on carbon.
  • the addition amount of the catalyst for the catalytic hydrogenolysis reaction in step (5) is 1-10% of the mass of the compound represented by formula IV, for example, it can be 1%, 2%, 3%, 4%, 5%, 6% , 7%, 8%, 9%, 10%, preferably 5%.
  • the pressure at which hydrogen is fed into the catalytic hydrogenolysis reaction in step (5) is 0.3-0.7 MPa, for example, it can be 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, preferably 0.5 MPa.
  • the catalytic hydrogenolysis reaction time in step (5) is 2-6h, for example, it can be 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, preferably 4h.
  • the solvent for the catalytic hydrogenolysis reaction in step (5) includes any one of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, ethanol, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran or A combination of at least two, preferably methanol.
  • the molar mass ratio of the compound represented by formula V to the acid HX in step (6) is 1:(1-1.2), for example, it can be 1:1, 1:1.02, 1:1.04, 1:1.06, 1 :1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.19, 1:1.2.
  • the acid HX in step (6) is any one of methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid or benzoic acid, preferably methanesulfonic acid.
  • the reaction time in step (6) is 1-3h, for example, it can be 1h, 1.5h, 2h, 2.5h, 3h, preferably 2h.
  • the reaction temperature in step (6) is 10-30°C, for example, 10°C, 12°C, 14°C, 16°C, 18°C, 19°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C.
  • the reaction solvent in step (6) includes any one or at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, acetone, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran.
  • the combination of these is preferably acetone.
  • the preparation method specifically includes the following steps:
  • the compound represented by formula I reacts with an acid to deprotect the R 1 group, the molar mass ratio of the acid to the compound represented by formula I is (1-3):1, and the deprotected R 1 group
  • the reaction time is 0.5-2h, and the reaction temperature for removing the protection of the R 1 group is -10 to 5°C; then a resolving agent is added for resolution, and the molar mass ratio of the resolving agent to the compound represented by formula I It is (0.9-1):1, first react at 50-60°C for 0.5-2h, and then at -10 ⁇ 5°C for 0.5-2h, to obtain the compound represented by formula II;
  • the compound represented by formula IV undergoes catalytic hydrogenolysis reaction to remove the protection of the R 4 group to obtain the compound represented by formula V.
  • the added amount of the catalyst is 1-10% of the mass of the compound represented by formula IV, and the catalytic hydrogen
  • the pressure of hydrogen introduced into the decomposition reaction is 0.3-0.7 MPa, and the hydrogenation reaction time is 2-6 hours;
  • the present invention has the following beneficial effects:
  • the preparation method of the present invention uses R 1 group-protected pyrrolidine boronic acid and R 4 group-protected valine as starting materials, avoiding the problem of product loss caused by complex post-processing during deprotection.
  • the preparation process is simple and the total yield is high, which is conducive to large-scale industrial production and has economic benefits and market value.
  • the preparation method of the present invention uses a resolving agent for resolution in the second step, avoiding the problem of high product loss using resolution methods with different solubility, thereby greatly improving the product yield of the target configuration. It can reach more than 33%.
  • N-Boc-2-pyrrolidine boronic acid (215g, 1mol) is dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) is added with stirring, and then (1S, 2S, 3R, 5S) -2,3-Pinanediol (170g, 1mol), after two hours of reaction, filtered, washed, the organic phase was concentrated and dried, 331g of intermediate A1 was obtained.
  • Steps (1), (2), (3), (4) and (5) are the same as the preparation method of Example 1, except that the raw material acid HX in step (6) is hydrochloric acid.
  • N-Boc-2-pyrrolidine boronic acid (215g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added with stirring, and then pinacol (118g, 1mol) was added, After reacting for two hours, it was filtered, washed, and the organic phase was concentrated and dried to obtain 276 g of Intermediate A2.
  • N-Trt-2-pyrrolidine boronic acid (357g, 1mol) is dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) is added with stirring, and then (1S, 2S, 3R, 5S) -2,3-Pinanediol (170g, 1mol), after two hours of reaction, filtered, washed, and the organic phase was concentrated and dried, 466g to obtain Intermediate A3.
  • the present invention uses the above examples to illustrate a method for preparing a dipeptide valine boroproline salt of the present invention, but the present invention is not limited to the above examples, which does not mean that the present invention must rely on The above-mentioned embodiment can be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de préparation d'un sel de bore d'un dipeptide de valine-proline. Le procédé utilise de l'acide pyrrolidine-borique protégé par un groupe R1 et une valine protégée par un groupe R4 en tant que matières premières initiales et évite le problème de perte de produit provoquée par un post-traitement complexe pendant la déprotection, ce qui permet d'améliorer considérablement le rendement en un produit cible et de faciliter considérablement la production en masse correspondante ; et ledit procédé utilise également un procédé de résolution au moyen d'un agent de résolution et évite le problème de perte excessive d'un produit présentant une configuration cible provoquée par l'utilisation de procédés de résolution avec différentes solubilités, ce qui permet d'améliorer considérablement le rendement en produit présentant la configuration cible.
PCT/CN2020/113131 2019-09-03 2020-09-03 Procédé de préparation de sel de bore de dipeptide de valine-proline Ceased WO2021043187A1 (fr)

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CN201910829098.4 2019-09-03
CN201910829098.4A CN110452258B (zh) 2019-09-03 2019-09-03 一种二肽缬氨酸硼脯氨酸盐的制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4313033A4 (fr) * 2021-03-24 2025-04-23 Trustees Of Tufts College Composés d'acide boronique, compositions et méthodes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016339A1 (fr) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
CN1073946A (zh) * 1991-11-22 1993-07-07 博灵格英格海母制药公司 制备脯氨酸硼酸酯的方法
WO2008066729A2 (fr) * 2006-11-22 2008-06-05 Dara Biosciences, Inc. Compositions contenant de l'acide boronique
WO2018187698A2 (fr) * 2017-04-07 2018-10-11 Trustees Of Tufts College Polythérapies utilisant des agents anticancéreux dépendant de la caspase-1 et des antagonistes de pge2

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062914A1 (fr) * 1998-06-05 1999-12-09 Point Therapeutics, Inc. Composes cycliques de boroproline
CN102286011B (zh) * 2010-03-16 2017-10-03 美德（江西）生物科技有限公司 吡咯烷硼酸酯二肽基肽酶抑制剂及其药物组合物
CN108047257B (zh) * 2017-12-17 2020-03-13 沧州普瑞东方科技有限公司 一种手性n-boc-吡咯烷-2-硼酸的制备工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016339A1 (fr) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
CN1073946A (zh) * 1991-11-22 1993-07-07 博灵格英格海母制药公司 制备脯氨酸硼酸酯的方法
WO2008066729A2 (fr) * 2006-11-22 2008-06-05 Dara Biosciences, Inc. Compositions contenant de l'acide boronique
WO2018187698A2 (fr) * 2017-04-07 2018-10-11 Trustees Of Tufts College Polythérapies utilisant des agents anticancéreux dépendant de la caspase-1 et des antagonistes de pge2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GIBSON FRANK S., SINGH AMBARISH K., SOUMEILLANT MAXIME C., MANCHAND PERCY S., HUMORA MICHAEL, KRONENTHAL DAVID R.: "-Valyl-pyrrolidine-(2 R )-boronic Acid: Efficient Recycling of the Costly Chiral Auxiliary (+)-Pinanediol", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 6, 1 November 2002 (2002-11-01), US, pages 814 - 816, XP055789568, ISSN: 1083-6160, DOI: 10.1021/op025587b *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4313033A4 (fr) * 2021-03-24 2025-04-23 Trustees Of Tufts College Composés d'acide boronique, compositions et méthodes

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