WO2006027788A1 - Process for the preparation of n-carboxyanhydrides - Google Patents
Process for the preparation of n-carboxyanhydrides Download PDFInfo
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- WO2006027788A1 WO2006027788A1 PCT/IN2004/000275 IN2004000275W WO2006027788A1 WO 2006027788 A1 WO2006027788 A1 WO 2006027788A1 IN 2004000275 W IN2004000275 W IN 2004000275W WO 2006027788 A1 WO2006027788 A1 WO 2006027788A1
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- 0 CC1(C)C2=C1C(C1)CC1C2CC* Chemical compound CC1(C)C2=C1C(C1)CC1C2CC* 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
- C07D263/44—Two oxygen atoms
Definitions
- the invention relates to an improved process for the preparation of N-carboxyanhydrides from the corresponding amino acids and phosgene, diphosgene or triphosgene using unsaturated organic compounds e.g. cyclohexene.
- N-Carboxyanhydrides obtained from .alpha.-, .beta.- or .gamma.-amino acids are very useful compounds due to the activation of their acid functional group. This is because they make possible the reaction of this acid functional group with any nucleophilic entity. Thus, the preparation of the amide functional group, by reaction with an amine functional group is facilitated. For this reason, they readily polymerize and are used to form peptides. The ester bond is also easily formed by reaction with alcohol. They are also advantageous when it is desired to reduce an acid functional group.
- NCA N-Carboxyanhydrides
- N-carboxyanhydrides Several processes are known for preparing N-carboxyanhydrides. One of the commonest and most direct is the process according to which an amino acid or its hydrochloride is reacted with phosgene, diphosgene or triphosgene in a solvent medium.
- the process according to US 6,479,665 corresponds to a process by which N-carboxyanhydrides are prepared by reaction of the corresponding .alpha.-, .beta.- or .gamma.-amino acid or of one of its salts with phosgene, diphosgene and/or triphosgene in a solvent medium in the presence, during the entire or a portion of the duration of the reaction, of an unsaturated organic compound which has one or more double bonds of ethylenic type, the remainder of the molecule of which is inert with respect to compounds present in the medium and one of the carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms.
- the instant invention- relates to the process for the preparation of a compound of Formula I , where in G 1 is Alkyl C 1 -C 8 , aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
- Formula I comprising of : treating a compound of Formula II or salts thereof, where in G 1 is Alkyl C 1 - C 8 , aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others.
- the instant invention discloses the process for the preparation of a compound of Formula I , wherein G 1 is Alkyl C 1 -C 8 , aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
- Formula I comprising of : treating a compound of Formula II or salts thereof, wherein G 1 is Alkyl C 1 - C 8 , aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
- Formula II with phosgene, in the presence of an unsaturated organic compound which has one or more ethylenic double bonds.
- the compound of Formula II is optionally reacted with phosgene, diphosgene and/ or triphosgene.
- the unsaturated organic compound is selected from hydrocarbons.
- the unsaturated organic compound is cyclohexene.
- the phosgenation is carried out in a solvent selected from aliphatic esters and chlorinated or non-chlorinated aliphatic esters and chlorinated or non-chlorinated aliphatic or aromatic hydrocarbons.
- the solvent is ethyl acetate.
- the compound of Formula II is selected from leucine, alanine, N- (ttifluoroacetyl)lysine, the .gamma. -benzyl ester or .gamma.-methyl ester of glutamic acid, or N-(l-ethoxycarbonyl-3-phenyrpropyl) alanine, or salts thereof.
- the salt of compound of Formula II is a sulphate, an acetate, a toluenesulphonate or a methanesulphonate.
- the salt of compound of Formula II is a hydrohalide.
- the process according to the invention makes it possible to obtain the
- EXAMPLE 6 To a solution of 2Og L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml of 1,4-Dioxane, 2.5 equivalents of phosgene was purged at 60-65°C in one hour. After Phosgenation stirred at reflux temp for ⁇ hours. The contents were allowed to cool to room temperature, chilled to — 10°C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 7
Abstract
The invention relates to a process for the preparation of N-carboxyanhydrides by reaction of the corresponding amino acid with phosgene, diphosgene and/or triphosgene in a solvent medium, characterized in that the reaction is a least partially carried out in the presence of an unsaturated organic compound which has one or more ethylenic double bonds. The N-carboxyanhydrides are thus obtained with better yields and an improved purity.
Description
TITLE OF THE INVENTION
Process for the preparation of N-carboxyanhydrides FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of N-carboxyanhydrides from the corresponding amino acids and phosgene, diphosgene or triphosgene using unsaturated organic compounds e.g. cyclohexene. BACKGROUND OF THE INVENTION
N-Carboxyanhydrides (abbreviation NCA) obtained from .alpha.-, .beta.- or .gamma.-amino acids are very useful compounds due to the activation of their acid functional group. This is because they make possible the reaction of this acid functional group with any nucleophilic entity. Thus, the preparation of the amide functional group, by reaction with an amine functional group is facilitated. For this reason, they readily polymerize and are used to form peptides. The ester bond is also easily formed by reaction with alcohol. They are also advantageous when it is desired to reduce an acid functional group.
Several processes are known for preparing N-carboxyanhydrides. One of the commonest and most direct is the process according to which an amino acid or its hydrochloride is reacted with phosgene, diphosgene or triphosgene in a solvent medium.
Another process for the preparation of NCA is also claimed in US 6,479,665 which claims process for the preparation of N-carboxyanhydrides by reaction of the corresponding .alpha.-, .beta.- or .gamma.-amino acid or of one of its salts with phosgene, diphosgene and/or triphosgene in a solvent medium, wherein the reaction is at least during a portion of its duration carried out in the presence of an unsaturated organic compound which has one or more ethylenic double bonds, the remainder of the molecule of which is inert with respect to compounds present in the medium and one of the
carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms.
It is also disclosed in US 6,479,665 that, in addition to the N- carboxyanhydride, a large amount of hydrochloric acid is also formed, that is to say 2 mol per mole of NCA. Hydrochloric acid is highly reactive. Its presence in the medium leads to side reactions and the appearance of chlorinated by-products. These chlorinated impurities, which remain in the NCAs produced, are entirely undesirable, both in terms of quality and in terms of yield. This is because they strongly interfere with the polymerization reaction of the NCAs. In order for this polymerization to be carried out suitably, it is necessary for the amount of chlorinated compounds present in the NCA monomers to be sufficiently low. Thus, the level of hydrolysable chlorine must generally be less than 0.05% by weight.
In point of fact, according to known processes, when the reaction is carried out without the presence of a basic compound, it is difficult to repeatably obtain such a low level of hydrolysable chlorine. On the other- hand, when a basic compound is added to neutralize the hydrochloric acid, the polymerization of the NCAs, undesired at this stage, is activated and there is then the risk of it taking place in the medium.
Furthermore, one of the other difficulties of the prior processes is the choice of the solvent. This is because it has been found that, in solvents such as aliphatic esters, for example ethyl acetate, or non-polar aprotic solvents, for example dichloromethane or toluene, the reaction for the formation of the NCAs is generally very slow and incomplete. In a solvent from the family of the ethers, such as tetrahydrofuran or dioxane, the reaction is faster but these. solvents are not completely inert with respect to phosgene and hydrochloric acid, which generates other impurities.
There consequently existed a need to improve the existing process in which the amino acid is reacted directly with phosgene, diphosgene or
triphosgene, in order to obtain the NCAs with better yields and an improved purity, in particular having a level of hydrolysable chlorine of less than 0.05%. The decrease in the duration of the reaction, in the most inert solvents, was also highly desirable.
The process according to US 6,479,665 corresponds to a process by which N-carboxyanhydrides are prepared by reaction of the corresponding .alpha.-, .beta.- or .gamma.-amino acid or of one of its salts with phosgene, diphosgene and/or triphosgene in a solvent medium in the presence, during the entire or a portion of the duration of the reaction, of an unsaturated organic compound which has one or more double bonds of ethylenic type, the remainder of the molecule of which is inert with respect to compounds present in the medium and one of the carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms.
The process of US 6,479,665 needs special reagents like unsaturated organic compound containing one of the carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms e.g. Pinene.
Use of alpha pinene as disclosed in US 6,479,665 makes the process very expensive since 2 equivalents are used, it has a high boiling point and as such complete removal of the said reagent may be difficult that would result in contamination in the final product. Pinene also has a very strong sweet odour that is not desirable.
The novel process of instant invention employs any unsaturated organic compound even without any substitution. Being economical in comparison, its ready availability and also the ease of its removal results in a purer final product. SUMMARY OF INVENTION
The instant invention- relates to the process for the preparation of a
compound of Formula I , where in G1 is Alkyl C1-C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
Formula I comprising of : treating a compound of Formula II or salts thereof, where in G1 is Alkyl C1- C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention discloses the process for the preparation of a compound of Formula I , wherein G1 is Alkyl C1-C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
Formula I comprising of : treating a compound of Formula II or salts thereof, wherein G1 is Alkyl C1- C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
Formula II with phosgene, in the presence of an unsaturated organic compound which has one or more ethylenic double bonds. The compound of Formula II is optionally reacted with phosgene, diphosgene and/ or triphosgene.
The unsaturated organic compound is selected from hydrocarbons.
The unsaturated organic compound is cyclohexene.
The phosgenation is carried out in a solvent selected from aliphatic esters and chlorinated or non-chlorinated aliphatic esters and chlorinated or non-chlorinated aliphatic or aromatic hydrocarbons.
The solvent is ethyl acetate.
The compound of Formula II is selected from leucine, alanine, N- (ttifluoroacetyl)lysine, the .gamma. -benzyl ester or .gamma.-methyl ester of glutamic acid, or N-(l-ethoxycarbonyl-3-phenyrpropyl) alanine, or salts thereof.
The salt of compound of Formula II is a sulphate, an acetate, a toluenesulphonate or a methanesulphonate.
The salt of compound of Formula II is a hydrohalide. The process according to the invention makes it possible to obtain the
N-carboxyanhydrides of the majority of cyclic or non-cyclic and natural or synthetic .alpha.-amino acids and their derivatives, the amine functional group of which is primary or secondary, and in particular of all those already known to react with phosgene, diphosgene and/or triphosgene. Likewise, it is very useful for obtaining the N-carboxyanhydrides of
.beta.- and .gamma.-amino acids and their derivatives comprising a primary
or secondary amine functional group. This is because these compounds are regarded as difficult to prepare according to the prior processes.
The examples which follow illustrate the invention without, however, limiting it. EXAMPLES EXAMPLE 1
To a solution of 2Og L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml Ethyl acetate, 2.5 equivalents of phosgene was purged at 60-650C in one hour. After Phosgenation stirred at reflux temp for 6hours. The contents were allowed to cool to room temperature, chilled to - 100C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 2
To a solution of 2Og L-Glutamic acid methyl ester, 3 equivalents of cyclohexene and 150ml Ethyl acetate, 2.5 equivalents of phosgene was purged 60-650C in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, chilled to — 100C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 3
To a solution of 2Og L-Leucine, 2 equivalents of cyclohexene and 150ml Ethyl acetate, 2.5 equivalents of phosgene was purged at 60-650C in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, chilled to —10°C and precipitated the desired carboxy anhydride by the addition of hexane. The . precipitated solid was filtered under inert atmosphere, dried and stored.
EXAMP-LE 4
To a solution of 2Og L- Valine, 2 equivalents of cyclohexene and 150ml Ethyl acetate, 2.5 equivalents of phosgene was purged at 60-650C in one hour. After Phosgenation stirred at reflux temp for 6hours. The contents were allowed to cool to room temperature, chilled to — 10°C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 5
To a solution of 2Og L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml of THF, 2.5 equivalents of phosgene was purged at 60-65°C in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, chilled to — 100C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 6 To a solution of 2Og L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml of 1,4-Dioxane, 2.5 equivalents of phosgene was purged at 60-65°C in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, chilled to — 10°C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored. EXAMPLE 7
To a solution of 20g L-Phenyl alanine, 2 equivalents of cyclohexene and 150ml of 1,4-Dioxane, 2.5 equivalents of phosgene was purged at 60- 65αC in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, chilled to — 100C and precipitated the desired carboxy anhydride by the addition of hexane. The precipitated solid was filtered under inert atmosphere, dried and stored.
EXAMPLE 8
To a solution of 2Og L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml of THF, 2.5 equivalents of phosgene was purged at 60-650C in one hour. After Phosgenation stirred at reflux temp for όhours. The contents were allowed to cool to room temperature, solvent was removed under reduced pressure and hesane was added to precipitate the solid, which was filtered and dried. EXAMPLE 9
To a solution of 2Og of L-Glutamic acid methyl ester, 2 equivalents of cyclohexene and 150ml of ethyl acetate was added followed by 2.5 equivalents of triphosgene. The reaction mixture was heated to 60-650C until the solids went into a clear solution. Continue reflux for 3h and allow the contents to cool to room temperature, chilled to -10 °C and precipitated the desired NCA, which was filtered, washed with hexanes and dried. Comparative Example Preparation of the N-carboxyanhydride of the .gamma. -benzyl ester of glutamic acid (H-GIu(OBzI)-NCA)
100 g Of H-GIu(OBzI)-OH (0.42 mol) are suspended in 885 ml of ethyl acetate. The suspension is cooled to +5. degree. C. and then 90 g (0.91 mol, 2.16 eq.) of gaseous phosgene are introduced. The reaction medium is brought to reflux. Despite the presence of a greater excess of phosgene in comparison with the preceding example, the reaction is slow and it is necessary to leave the reaction medium under stationary conditions at the reflux temperature for 6 hours instead of 3 hours, as in the preceding example. Distillation is subsequently carried out in order to separate 600 ml of a mixture of ethyl acetate and of phosgene. 600 ml of industrial-grade heptane are added under warm conditions and the mixture is cooled to -lO.degree. C. over 2 hours. The crystallized product is separated by filtration and washed
with industrial-grade heptane.
After drying, 88 g Of H-GIu(OBzI)-NCA are obtained, i.e. a yield of 74.6%. The level of hydrolysable chlorine is 0.13%.
Claims
1. The process for the preparation of a compound of Formula I , wherein G1 is Alkyl C1-C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
Formula I comprising of : 2. treating a compound of Formula II or salts thereof, wherein G1 is
Alkyl C1-C8, aryl, arylalkyl, heteroaryl that may be optionally substituted with ester, amides, nitriles, thiol, thiol ethers and others
Formula II with phosgene, in the presence of an unsaturated organic compound which has one or more ethylenic double bonds.
2. The process according to claim 1, wherein the compound of Formula II is optionally reacted with phosgene, diphosgene and/or triphosgene.
3. Process according to claim 1, wherein the unsaturated organic compound is selected from hydrocarbons.
4. Process according to claim 1, wherein the unsaturated organic compound is cyclohexene.
5. Process according to claim 1, wherein the phosgenation is carried out in a solvent selected from aliphatic esters and chlorinated or non- chlorinated aliphatic esters and chlorinated or non-chlorinated aliphatic or aromatic hydrocarbons.
6. Process according to claim 5, wherein the solvent is ethyl acetate.
7. Process according to claim 1, wherein the compound of Formula II is selected from leucine, alanine, N-(trifluoroacetyl)lysine, the .gamma.- benzyl ester or .gamma.-methyl ester of glutamic acid, or N-(I- ethoxycarbonyl-3-phenylpropyl) alanine, or salts thereof.
8. Process according to claim 1, wherein the salt of compound of Formula II is a sulphate, an acetate, a toluenesulphonate or a methanesulphonate.
9. Process according to claim 1, wherein the salt of compound of Formula II is a hydrohalide.
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| PCT/IN2004/000275 WO2006027788A1 (en) | 2004-09-06 | 2004-09-06 | Process for the preparation of n-carboxyanhydrides |
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| PCT/IN2004/000275 WO2006027788A1 (en) | 2004-09-06 | 2004-09-06 | Process for the preparation of n-carboxyanhydrides |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020064904A1 (en) * | 2018-09-28 | 2020-04-02 | Lonza Ltd | Method for preparation of n-carboxyanhydrides |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3369026A (en) * | 1963-07-23 | 1968-02-13 | Mori Shigeo | Process for preparing gamma-methyl glutamate n-carboxy anhydride |
| GB1189261A (en) * | 1967-01-21 | 1970-04-22 | Kyowa Hakko Kogyo Kk | Process for Producing N-Carboxy Anhydrides of Glutamic Acid-gamma-Esters |
| US6479665B2 (en) * | 2000-10-30 | 2002-11-12 | Isochem | Process for the preparation of N-carboxyanhydrides |
| US6603016B2 (en) * | 2001-05-31 | 2003-08-05 | Isochem | Process for the preparation of N-carboxyanhydrides |
-
2004
- 2004-09-06 WO PCT/IN2004/000275 patent/WO2006027788A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3369026A (en) * | 1963-07-23 | 1968-02-13 | Mori Shigeo | Process for preparing gamma-methyl glutamate n-carboxy anhydride |
| GB1189261A (en) * | 1967-01-21 | 1970-04-22 | Kyowa Hakko Kogyo Kk | Process for Producing N-Carboxy Anhydrides of Glutamic Acid-gamma-Esters |
| US6479665B2 (en) * | 2000-10-30 | 2002-11-12 | Isochem | Process for the preparation of N-carboxyanhydrides |
| US6603016B2 (en) * | 2001-05-31 | 2003-08-05 | Isochem | Process for the preparation of N-carboxyanhydrides |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020064904A1 (en) * | 2018-09-28 | 2020-04-02 | Lonza Ltd | Method for preparation of n-carboxyanhydrides |
| CN112912369A (en) * | 2018-09-28 | 2021-06-04 | 隆萨有限公司 | Process for preparing N-carboxyanhydrides |
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