WO1999052897A1 - Nouveaux reactifs utiles en tant qu'activateurs et reactifs de couplage dans des syntheses organiques - Google Patents

Nouveaux reactifs utiles en tant qu'activateurs et reactifs de couplage dans des syntheses organiques Download PDF

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Publication number
WO1999052897A1
WO1999052897A1 PCT/US1999/008022 US9908022W WO9952897A1 WO 1999052897 A1 WO1999052897 A1 WO 1999052897A1 US 9908022 W US9908022 W US 9908022W WO 9952897 A1 WO9952897 A1 WO 9952897A1
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Prior art keywords
coupling
substituted
cbdci
carboxylic acid
compound
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PCT/US1999/008022
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English (en)
Inventor
Chandra Vargeese
Venkata Palle
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Nexstar Pharmaceuticals, Inc.
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Priority to AU35562/99A priority Critical patent/AU3556299A/en
Publication of WO1999052897A1 publication Critical patent/WO1999052897A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention describes versatile, easily synthesized reagents that can be used as coupling activators and coupling reagents in a wide variety of organic synthetic reactions.
  • CDI as a coupling activator has several drawbacks.
  • One limitation is that imidazole is a relatively poor leaving group, and therefore the nucleophilic displacement of imidazole from the intermediate acyl imidazolide 2 is the rate-limiting step in this reaction.
  • Esterification of carboxylic acids in particular, suffer from poor yields and long reaction times, since the intermediate acyl imidazolides are sluggish toward nucleophilic attack by alcohols, which are relatively poor nucleophiles (Staab (1962) Angew. Chem., Int. Ed. Engl. 1:351).
  • CDI carboxylic acid activator
  • racemization-suppressing additives such as 1- hydroxybenzotriazole (HOBT) (Sieber et al. (1977) Helv. Chim. Acta 60:27) or the simultaneous use of HOBT and copper(II) chloride (Miyazawa et al. (1988) J. Chem. Soc, Chem. Commun. 419) in the CDI activation method have been suggested.
  • HOBT 1- hydroxybenzotriazole
  • copper(II) chloride Miyazawa et al. (1988) J. Chem. Soc, Chem. Commun. 419)
  • the present invention is directed to novel reagents that are useful as coupling activators for the synthesis of carboxylic acid derivatives and as coupling reagents in organic synthesis.
  • the novel reagents of the present invention are derivatives of 1,1'- carbonyldiimidazole (CDI) comprising substituted imidazole moieties.
  • CDI 1,1'- carbonyldiimidazole
  • the substituted imidazole moieties of the novel reagents described herein provide characteristics which offer improvements over the use CDI in the syntheses of carboxylic acid derivatives and in organic coupling reactions.
  • the substituents on the imidazoles make the substituted imidazole moieties of the novel reagents better leaving groups than the unsubstituted imidazole moiety of CDI.
  • nucleophilic displacement of the intermediate acyl imidazolide 2 in Scheme 1 proceeds much faster when the novel reagents of the present invention are used as coupling activators. Therefore, the novel reagents described herein increase the overall reaction rate of carboxylic acid derivatization by increasing the rate of nucleophilic displacement (Scheme 1, Step 2) in the coupling reaction.
  • the substituted imidazole by-products formed during coupling reactions using the improved reagents of the present invention are non-basic, having pKa's between 5.0 and 6.8. As such, the novel reagents will not cause racemization of the product of the coupling reaction, and further are compatible with acid-labile protecting groups. Therefore, using the novel reagents of the present invention in organic coupling reactions results in increased coupling rates, higher product yields and maintenance of the chiral integrity of the product.
  • novel reagents of the invention include 1,1 '-carbonyldiimidazole derivatives comprising substituted imidazole moieties, wherein the substituted imidazole moieties have pKa's between 5.0 and 6.8, and wherein the substituted imidazole moieties are more facile leaving groups than unsubstituted imidazole.
  • the most preferred coupling activator and coupling reagent is l,l'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI) (4).
  • the present invention further includes an improved method of synthesizing carboxylic acid derivatives using the novel reagents of the invention as coupling activators.
  • the present invention further includes the use of the novel reagents of the invention as coupling reagents.
  • the present invention encompasses novel reagents that are useful as coupling activators for the synthesis of carboxylic acid derivatives and as coupling reagents in organic synthesis.
  • the novel reagents of the present invention are derivatives of 1,1'- carbonyldiimidazole (CDI) comprising substituted imidazole moieties.
  • the novel reagents of the invention include 1,1 '-carbonyldiimidazole derivatives comprising substituted imidazole moieties, wherein the substituted imidazole moieties have pKa' s between 5.0 and 6.8, and wherein the substituted imidazole moieties are better leaving groups than unsubstituted imidazole.
  • the most preferred coupling activator and coupling reagent is l,r-carbonylbis-(4,5-dicyanoimidazole) (CBDCI) (4).
  • CBDCI The preparation of CBDCI (4) following the literature procedure for the preparation of CDI (Staab and Wendel Organic Synthesis 48:44) was unsuccessful.
  • CBDCI was synthesized in the presence of pyridine.
  • CBDCI can be easily prepared by reacting two equivalents of DCI with one 6 equivalent of phosgene in the presence of two equivalents of pyridine in tetrahydrofuran, to afford the desired product in quantitative yield (Example 1).
  • CBDCI can be isolated as a solid, however, for synthetic purposes CBDCI is most conveniently generated in solution just prior to use. In addition, CBDCI is soluble in most organic solvents routinely used in organic syntheses, making it a very versatile reagent.
  • the present invention further includes an improved method of synthesizing carboxylic acid derivatives using the novel reagents of the invention as coupling activators.
  • the synthesis of carboxylic acid derivatives is performed by activating a carboxylic acid with CBDCI, as illustrated in Scheme 2.
  • a carboxylic acid reacts with CBDCI (4), leading to rapid evolution of CO 2 to give the activated form of the carboxylic acid, the acyl 4,5-dicyanoimidazolide intermediate 7, and one equivalent of 4,5-dicyanoimidazole (DCI) (6).
  • the acyl 4,5-dicyanoimidazide intermediate 7 is then reacted with a nucleophile resulting in formation of a carboxylic acid derivative 3, along with another equivalent of DCI.
  • Coupled activator means a reagent which will react with a carboxylic acid to make the carbonyl group more reactive towards nucleophilic attack.
  • the most preferred coupling activator is l,l'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI) (4).
  • nucleophile as used herein is defined as an electron-rich compound that reacts with the carbonyl carbon of an acyl imidazolide.
  • Suitable nucleophiles for use in the present invention include, but are not limited to, alcohols, amines, thiols, carboxylic acids and other nucleophiles known by those of skill in the art to undergo nucleophilic attack at a carbonyl carbon.
  • peptide refers to a polymer of amino acids chemically bound by amide linkages (CONH).
  • An "amino acid” is defined as an organic molecule containing both an amino group (NH 2 ) and a carboxylic acid (COOH).
  • an “amino acid” is any compound of the general formula RCH(NH 2 )COOH ( ⁇ -amino acid), wherein R is selected from the group consisting of H or any suitably protected known amino acid side chain. Suitable protection for amino acid side chains is know to those skilled in the art.
  • peptide includes peptides, polypeptides and proteins. The peptides synthesized by the method of this invention are depicted generally as follows:
  • Suitable N-protecting groups may be selected from the many reported N-protecting groups which are known to those in the art, including but not limited to urethanes, such as FMOC and t-BOC, benzyl groups, acyl groups or triphenylmethyl groups.
  • the N- protecting group may also be a solid support.
  • Suitable COOH-protecting groups may be selected from the many reported
  • COOH-protecting groups which are know to those in the art, including but not limited to ester protecting groups.
  • the COOH-protecting group may also be a solid support.
  • solid support as used herein is defined as a solid support which can be covalently coupled to an amino acid or peptide, in such a fashion that the amino acid or peptide can be further modified using the chemistry disclosed herein, and subsequently removed using conventional chemistry.
  • Suitable solid supports for use in the present invention include, but are not limited to, controlled pore glass (CPG) of various pore size and loading, polystyrene beads and polystyrene-polyethylene glycol copolymer support (TentaGel).
  • Coupled reagent means a reagent that will couple two compounds having the structures R ⁇ H and R 2 Y 2 H to form a compound having the structure R,Y r C(O)-Y 2 R 2 , wherein Y, and Y 2 are independently selected from the group consisting of O, NH, S or C(O)O-; and R, and R 2 are independently selected from the group consisting of alkyl, alkenyl, alkynyl or aryl.
  • the term “coupling reagent” further includes a reagent that will form a cyclic compound having the structure 9
  • R 2 . and R 2 ' are independently selected from the group consisting of H, alkyl. alkynyl or aryl, or together R, and R 2 are part of a carbocyclic or heterocyclic ring.
  • the novel reagents of the present invention offer several advantages over the use of CDI as a coupling activator.
  • the by-products of coupling reactions using the novel reagents described herein are weakly acidic, substituted imidazoles, having pKa's between 5.0 and 6.8.
  • the by-product of a coupling reaction in which a carboxylic acid is activated with CBDCI is 4,5-dicyanoimidazole (DCI), which has a pKa of 5.2.
  • DCI 4,5-dicyanoimidazole
  • This DCI by-product is an innocuous by-product in the synthesis of carboxylic acid derivatives via CBDCI activation for several reasons.
  • DCI since DCI is non-basic, no loss of optical activity is observed with chiral compounds.
  • novel reagents of the present invention rather than CDI as a coupling activator is that the substituted imidazole moieties of these novel reagents are more facile leaving groups than the unsubstituted imidazole moieties of CDI.
  • novel reagent CBDCI as an example, the presence of the two cyano groups on the imidazole moieties make the 4,5-dicyanoimidazole (DCI) moiety of this reagent a better leaving group than imidazole.
  • nucleophilic displacement of the intermediate 4,5-dicyanoimidazolide 7 proceeds much faster than nucleophilic displacement of the unsubstituted acyl imidazolide 2 (Scheme 1), resulting in shorter reaction times and higher product yields.
  • Esters and amides were synthesized via CBDCI activation to illustrate the usefulness of the novel reagents of the present invention.
  • the yields and reaction rates were found to be superior to those obtained using CDI.
  • the results of the coupling reactions are summarized in Table 1. 10
  • Entries 1 and 2 of Table 1 summarize the reaction times and yields of an amide synthesized from benzoic acid and n-butyl amine using CBDCI and CDI, respectively.
  • the reaction activated by CBDCI (entry 1) is clearly superior to the reaction activated by CDI (entry 2).
  • the reaction activated by CBDCI afforded the amide product in quantitative yield in only 2 hours, whereas the reaction activated by CDI was only 50% complete after 2 hours.
  • a coupling reaction to be particularly noted is entry 5 of Table 1, in which L-CBZ- phenylalanine (CBZ - carbobenzoxy) was esterified with the sterically hindered long chain alcohol octadecanol.
  • This reaction is significant in that amino acid esters of long-chain C- 18 alcohols are of pharmacological value (Penney et al. (1985) J. Org. Chem. 50:1457V
  • N-stearoyl amino acids possess nutritional value and stearyl amino acids are effective immunoadjuvants for vaccine production and allergy desensitization therapy. To date, the synthesis of these compounds has been problematic.
  • the present invention demonstrates that the octadecyl ester of CBZ-phenylalanine can be easily prepared in quantitative yield in two hours by activating CBZ-phenylalanine with CBDCI (entry 5).
  • This coupling reaction is in sharp contrast to the analogous coupling reaction utilizing CDI as the coupling agent (entry 6) in which the product was obtained in only 30% yield after 2 hours.
  • novel reagents of the present invention are also useful as coupling activators in peptide synthesis.
  • the novel reagents described herein are utilized in the solid phase synthesis of peptides.
  • solid phase peptide synthesis proceeds from the C-terminal to the N-terminal amino acid.
  • the carboxyl-terminal amino acid of the peptide to be synthesized is protected and covalently attached to a solid support.
  • the subsequent amino acid monomers (which have been N-protected and side-chain protected) are then sequentially added in the form of a activated acyl imidazolides, such as acyl 4,5- dicyanoimidazolides formed by activation of protected amino acids with the novel reagent CBDCI.
  • the solid phase peptide synthesis proceeds from the N- terminal to the C-terminal amino acid.
  • the amino-terminal amino acid of the peptide is covalently attached to a solid support.
  • the free carboxyl group is activated with a novel reagent of the present invention, and the subsequent amino acid monomer (which has been COOH-protected and side-chain protected) is then added.
  • the COOH-protecting group is then removed, the free COOH is activated with a novel reagent of the present invention, and the procedure is repeated until the desired peptide is obtained.
  • the novel reagents described herein are utilized in solution phase synthesis of peptides.
  • One method of solution phase peptide synthesis is described in United States Patent Application Serial No.
  • This method is characterized by the utilization of an anchor group attached to the N-terminal amino acid end of the growing peptide product.
  • the method comprises the reaction of an amino acid, protected with a suitable N-protecting group, with the N- terminal end of a growing peptide chain (whose C-terminal end is suitably protected with a standard COOH protecting group) in solution in the presence of a carboxylic acid activator.
  • Entry 7 in Table 1 demonstrates the utility of CBDCI in solution phase peptide synthesis.
  • the esterification of the racemization sensitive L-CBZ- phenylalanine with valine methyl ester using CBDCI as the activator gave the peptide product in 90% yield in only 30 minutes.
  • the analogous reaction employing CDI as the carboxylic acid activator afforded only 70% of the peptide product. 12
  • novel reagents of the present invention may also be utilized as coupling reagents.
  • novel reagents of the instant invention may be used for the synthesis of ureas, carbonates, anhydrides, carbamates, thiocarbamates and thicarbonates. The synthesis of these compound is achieved by reacting a compound having the structure
  • R,Y,H with, for example, a novel reagent of the invention such as CBDCI to form a acyl
  • CN 8 followed by reacting the acyl 4,5-dicyanoimidazolide intermediate 8 with a compound having the structure R 2 Y 2 H to form the compound having the structure R,Y 1 -C(O)-Y 2 R 2 , wherein Y, and Y 2 are independently selected from the group consisting of O, NH, S or C(O)O-; and R, and R 2 are independently selected from the group consisting of alkyl, alkenyl, alkynyl or aryl. 13
  • Example 2 Synthesis of n-butyl benzamide via CBDCI activation (Table 1, entry 1)
  • a solution of CBDCI (10 mL) was cannulated into a solution of benzoic acid (488 mg, 4 mmol) in anhydrous THF and the mixture was stirred for 30 minutes.
  • n-butylamine 0.5 mL
  • TLC 10% ethyl acetate in hexanes
  • the reaction mixture was then concentrated and applied to a silica gel column. Elution with 10% ethyl acetate in hexanes gave pure product in quantitative yield.
  • Example 4 Preparation of ethyl benzoate via CBDCI activation (Table 1 , entry 3) A solution of CBDCI (17.5 mL) was cannulated into a solution of benzoic acid (854 mg, 7 mmol) in anhydrous THF and the mixture was stirred. After 30 minutes 14 ethanol (0.4 mL) was added and mixture was stirred for 3 hours. TLC showed the completion of reaction. (10% ethyl acetate in hexanes). The reaction mixture was then concentrated and applied to a silica gel column. Elution with 10% ethyl acetate in hexanes gave pure ethyl benzoate in 80% yield.
  • CBDCI 2.6 mL
  • L-CBZ- phenylalanine 598 mg, 2 mmol
  • octadecyl alcohol 260 mg, lmmol
  • the reaction was determined to be complete by TLC (10% ethyl acetate in hexanes).
  • the reaction mixture was concentrated and applied to a silica gel column. Elution with 10% ethyl acetate in hexanes gave pure CBZ-phenylalanyl octadecanoate (m.p. 71 °C) in quantitative yield.
  • Example 8 Synthesis of CBZ-phenylalanyl valine methyl ester via CBDCI activation
  • CBDCI a solution of CBDCI (5 mL) was cannulated into a solution of CBZ-phenylalanine (600 mg, 2 mmol) in anhydrous THF and the mixture was stirred for 30 minutes. To this was added L-valine methyl ester (162 mg, liberated from its hydrochloride with N-methyl morpholine) and the mixture was stirred for 2 hours. The reaction was determined to be complete by TLC (20% ethyl acetate in hexanes). The reaction mixture was concentrated and applied to a silica gel column. Elution with 20% ethyl acetate in hexanes gave pure product (m.p 81°C) in 90% yield.
  • Example 8 The reaction described in Example 8 was repeated using CDI (1 eq.) as the coupling activator in THF (10 mL). After 2 hours only 70% of product could be isolated by column chromatography (20% ethyl acetate in hexanes).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des nouveaux réactifs, utiles en tant qu'activateurs et agents de couplage, et comprenant des dérivés 1,2-carbonyldiimidazole comportant des fractions imidazoles substituées. Ces fractions possèdent des pKa compris entre 5,0 et 6,8 et elles constituent des groupes labiles plus faciles que des imidazoles non substituées. On a trouvé qu'un réactif préféré, le 1,1'-carbonylbis-(4,5-dicyano-imidazole) (CBDCI) constituait un activateur et agent de couplage efficace. On a également trouvé que des couplages d'acide carboxylique mettant en oeuvre CBDCI permettaient d'obtenir un bon rendement en esters et amides (notamment des peptides), avec des temps de réaction courts et sans racémisation.
PCT/US1999/008022 1998-04-14 1999-04-13 Nouveaux reactifs utiles en tant qu'activateurs et reactifs de couplage dans des syntheses organiques WO1999052897A1 (fr)

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AU35562/99A AU3556299A (en) 1998-04-14 1999-04-13 Novel reagents for use as coupling activators and coupling reagents in organic synthesis

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US8169398P 1998-04-14 1998-04-14
US60/081,693 1998-04-14

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3113134A (en) * 1961-07-29 1963-12-03 Boehringer & Soehne Gmbh Process for the production of reserpic acid diesters
US3121707A (en) * 1960-11-23 1964-02-18 American Cyanamid Co Peptide synthesis using n-n' carbonyldiimidazole activator

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3121707A (en) * 1960-11-23 1964-02-18 American Cyanamid Co Peptide synthesis using n-n' carbonyldiimidazole activator
US3113134A (en) * 1961-07-29 1963-12-03 Boehringer & Soehne Gmbh Process for the production of reserpic acid diesters

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