Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-08
2002-06-25
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S334100
Reexamination Certificate
active
06410744
ABSTRACT:
The invention relates to certain carbonyldiimidazoles, esters derived therefrom, processes for their preparation and their use.
In the synthesis of peptides from amino acids, protection of the functional groups not involved in the reaction is absolutely necessary in order to obtain a homogeneous product. One of the most important protective groups, which is also used industrially, for the amino group of amino acids is the tert-butyloxycarbonyl group, which is usually abbreviated to BOC. In this case, the amino functionality is protected as urethane, and the protective group can be eliminated again under mild acidic conditions.
Urethanes are normally prepared by reacting amino groups with a chloroformate. However, tert-butyl chloroformate is extremely unstable and thus can be handled only with difficulty. It is therefore unsuitable for introducing the BOC protective group. Numerous compounds intended to be used to protect amino groups with BOC are described in the literature.
The compound used most often for introducing BOC protective groups is di-tert-butyl dicarbonate, also referred to as di-tert-butyl pyrocarbonate or BOC anhydride ((CH
3
)
3
C—O—CO—O—CO—O—C(CH
3
)
3
).Processes for preparing BOC anhydride are disclosed,for example, in U.S. Pat. Nos. 5,162,565 and 5,162,565 and EP-A-0 468 404. The processes for preparing BOC anhydride are multistage and include elaborate steps using costly chemicals. This is why BOC anhydride is very costly and is reluctantly employed as compound in industrial reactions.
One example of other compounds for introducing the BOC protective group is BOC fluoride as described in Liebigs Ann. Chem. 716 (1968) 175-185.
J. Org. Chem. 50 (1985) 3951-3953 describes the preparation of 1,2,2,2-tetrachloroethyl tert-butyl carbonate and its use for introducing BOC protective groups.
Helv. Chim. Acta 44 (1961), 2151, Spec. Chem. 13 (1993), 67-69 and EP-A-0 236 888 describe the preparation of tert-butyloxycarbonylimidazole from carbonyldiimidazole and its use for introducing the BOC protective group.
Whereas BOC fluoride can be synthesized only via carbonyl fluoride chloride, which is elaborate to prepare, and therefore has only minor importance, the two other compounds are solids which require elaborate techniques for isolation and purification. Other BOC-introducing reagents have no industrial importance because of their instability.
It is an object of the present invention to provide compounds for introducing BOC protective groups which can be obtained via less elaborate steps from compounds which are easy to obtain. The compounds should furthermore be liquid at room temperature and be amenable to distillation without decomposition under reduced pressure. They should furthermore have a long shelf life and avoid the disadvantages of known compounds.
We have found that this object is achieved by imidazolecarboxylic esters of the formulae IIIa and IIIb or mixtures thereof
where R
1
is C
1-4
-alkyl and R
2
is hydrogen or methyl.
The imidazolecarboxylic esters of the formulae IIIa, IIIb or mixtures thereof can be prepared by reacting carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof
where R
1
is C
1-4
-alkyl and R
2
is hydrogen or methyl, with tert-butanol in a substituted aromatic hydrocarbon as solvent, and extracting the resulting reaction mixture with water to remove imidazoles of the formulae IIa and IIb
where R
1
und R
2
have the abovementioned meanings, which are also formed.
The carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof can be obtained by reacting at least one imidazole of the formulae IIa and IIb with phosgene in a substituted aromatic hydrocarbon as solvent, wherein the hydrochloride, which is also formed, of the at least one imidazole of the formulae IIa and IIb is removed from the reaction mixture by phase separation as melt.
The preparation of carbonyldiimidazole from imidazole and phosgene is generally disclosed in EP-A-0 692 476. However, the reaction (see Example 1) results in imidazole hydrochloride as solid, which has to be filtered off. This requires a transfer of the reaction mixture, which is disadvantageous because the carbonyldiimidazole which is formed is very moisture-sensitive, and the workup is made difficult for this reason.
It has been found according to the invention that the hydrochlorides of the imidazoles of the formulae IIa and IIb result as liquids (melt) under the reaction conditions and can therefore be removed virtually completely from the product mixture by a simple phase separation. The hydrochlorides obtained in this way can be converted back by neutralization into the imidazoles of the formulae IIa and IIb and returned to the synthesis.
Thus, compared with the process described in EP-A-0 692 476, the removal of the hydrochloride is considerably simplified, and the risk of decomposition of the required carbonyldiimidazoles is reduced.
The carbonyldiimidazoles of the formulae Ia, Ib and Ic are formed as mixture on reaction of imidazoles of the formulae IIa and/or IIb. A shift of the double bonds and protons in the imidazoles is possible during the reaction, so that a product mixture is obtained even from a single compound of the formulae IIa and IIb. However, the product predominantly obtained is the one in which no shift of double bond and proton is necessary. The carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof can be isolated by precipitation by cooling the reaction mixture. However, they can also be further processed directly in the reaction mixture, after removal of the hydrochlorides of the imidazoles, without isolation being necessary. It is moreover possible to employ the hot crude solution without further workup.
The carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof can be employed for a large number of reactions, for example for preparing corresponding tert-butyl imidazole-1-carboxylates, for carbonyl group transfer, or for dehydration, especially for preparing esters and amides from carboxylic acids.
As a rule, phosgene is passed into the at least one imidazole of the formulae IIa and IIb in the solvent at from 60 to 130° C., preferably 80 to 130° C., in particular 90 to 130° C. Solvents which can be used are all substituted aromatic hydrocarbons suitable for this purpose. Examples of preferably employed solvents are chlorobenzene, xylene and o-dichlorobenzene. Unreacted phosgene can be removed by stripping with inert gases such as nitrogen. The resulting reaction mixture can if necessary be heated further until a liquid two-phase system forms and phase separation becomes possible.
Conversion of the carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof into the imidazolecarboxylic esters of the formulae IIIa and IIIb or mixtures thereof takes place by reaction with tert-butanol in a substituted aromatic hydrocarbon as solvent. This preferably entails employing a solvent as defined previously, which is, in particular, identical to the solvent used in the first reaction step. The reaction mixture obtained in the first reaction step can thus be used further without removing the solvent. The reaction with tert-butanol preferably takes place at from 50 to 140° C., particularly preferably 60 to 120° C., in particular 70 to 90° C. The yield can in this case be increased at a lower temperature. On reaction of carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof with tert-butanol there is formation not only of the required tert-butyl esters but also of imidazoles of the formulae IIa and IIb. These imidazoles can be removed by extracting the resulting reaction mixture with water. They can then be isolated from the aqueous imidazole phase and be returned to the process for preparing the carbonyldiimidazoles.
It has been found according to the invention that the resulting reaction mixture can be extracted with water without decomposition (hydrolysis) of the imidazolecarboxylic esters of the formulae IIIa, IIIb or mixtures thereof. Simple extraction with water is therefore possible, with the required imid
Botzem Jörg
Henningsen Michael
Julius Manfred
Kindler Alois
Stamm Armin
Higel Floyd D.
Keil & Weinkauf
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