Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-02-01
2004-01-13
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S509000, C562S840000, C549S483000, C549S484000, C548S562000
Reexamination Certificate
active
06677487
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates in general to the field of &agr;-haloenamine chemistry, processes for the preparation of &agr;-haloenamines and, in one embodiment, to &agr;-haloenamine reagents supported by an organic or inorganic material which, under a defined set of conditions, renders the supported reagent sufficiently insoluble to enable separation of the reagent from a mixture.
&agr;-Haloenamine reagents are used in a number of synthetic reactions. For example, they are used to convert carboxylic acids to acid halides, alcohols to halides, sugars to sugar halides, and thiophosphoryl compounds to the corresponding phosphoryl halides. &agr;-haloenamine reagents offer advantages over other reagents for such conversions, particularly under neutral conditions and in those instances in which the substrate for the reaction contains one or more sensitive functionalities.
Despite these advantages, haloenamines are not being used to their full potential for a variety of reasons. Among these reasons are synthetic challenges. Ghosez et al. (
Angew. Chem. Int. Ed. Engl
. 1969, 8, 454) disclosed a route which involved the reaction of tertiary amides with phosgene followed by the dehydrochlorination of the intermediate &agr;-chloroiminium salts with triethylamine. According to Ghosez et al., the hazard associated with the use of large amounts of phosgene as well as the ban on phosgene in many laboratories led them to re-examine the preparation of &bgr;-disubstituted-&agr;-chloroenamines; more recently, Ghosez et al. (
Tetrahedron
54 (1998) 9207-9222) reported a synthetic route which was said to be conceptually the same as the previous one: it involved the reaction of a tertiary amide with a chlorinating agent followed by the elimination of hydrochloric acid from the resulting &agr;-chloroiminium salt. The halogenating agents tried by Ghosez et al. were thionyl chloride, diphosgene, triphosgene, phosphorous oxychloride, and phosphorous oxybromide. Of these, only phosphorous oxychloride was said to be suitable for the preparation of large amounts of &agr;-chloroenamines. Thionyl chloride was said to be unsuitable. Diphosgene and triphosgene were said to be suitable although in both cases a minor by-product was produced. As a result, Ghosez et al. stated that phosphorous oxychloride would probably supersede phosgene as the halogenating agent. Ghosez et al. also reported that they succeeded in preparing the corresponding &agr;-bromoenamines which, until then, they said were only available by halide exchange. Despite the advances reported by Ghosez et al., the conversion of a tertiary amide to an &agr;-chloroiminium salt, particularly when the nitrogen substituents are bulky can be difficult.
Recent advances in molecular biology, chemistry and automation have resulted in the development of rapid, high throughput screening (HTS) protocols to synthesize and screen large numbers of compounds for a desired activity or other desirable property in parallel. These advances have been facilitated by fundamental developments in chemistry, including the development of highly sensitive analytical methods, solid state chemical synthesis, and sensitive and specific biological assay systems. As a result, it is now common to carry out such reactions, in parallel, in a multi-well micro titer plate or other substratum having a plurality of wells for containing a reaction mixture, e.g., 96, 384 or even a greater number of wells. To date, however, &agr;-haloenamine reagents have not been provided in a form which would enable rapid, automated use and purification from such reaction mixtures.
SUMMARY OF THE INVENTION
One aspect of the present invention, therefore, is an improved process for the preparation of &agr;-haloenamines. The resulting &agr;-haloenamines may be used in a wide variety of synthetic schemes, such as the conversion of hydroxy-containing compounds and thiol-containing compounds to the corresponding halides. If immobilized onto a support, the resulting &agr;-haloenamines are particularly useful in high-throughput, automated and other systems where ease of separation is desired.
Briefly, therefore, the present invention is directed to an immobilized haloenamine reagent having the formula:
wherein
R
1
and R
4
are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy;
R
2
and R
3
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro, and
X is halo,
provided at least one of R
1
, R
2
, R
3
and R
4
comprises a support which enables physical separation of the reagent from a liquid mixture.
The present invention is further directed to a process for the preparation of an &agr;-haloenamine. The process comprises combining a tertiary amide with a pentavalent phosphorous halide in a solvent to form an &agr;-haloiminium salt and converting the &agr;-haloiminium salt to the &agr;-haloenamine with a base, the pentavalent phosphorous halide having at least two halogen atoms bonded to the pentavalent phosphorous atom.
The present invention is further directed to a process for dehydrating a non-aqueous solvent. The process comprises combining the solvent with an immobilized &agr;-haloenamine reagent.
The present invention is further directed to a process for converting a hydroxy-containing compound or a thiol-containing compound to the corresponding halide. The process comprises contacting the hydroxy-containing compound or thiol-containing compound with an immobilized &agr;-haloenamine. The hydroxy-containing compound may be selected, for example, from the group consisting of alcohols, carboxylic acids, silanols, sulfonic acids, sulfinic acids, phosphinic acids, phosphoric acids, and phosphates.
The present invention is further directed to an immobilized tertiary amide reagent having the formula:
wherein
R
1
and R
4
are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; and
R
2
and R
3
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro,
provided at least one of R
1
, R
2
, R
3
and R
4
comprises a support which enables physical separation of the reagent
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A. Preparation of &agr;-Haloenamines
In accordance with one aspect of the present invention, &agr;-haloenamines may be prepared from tertiary amides and pentavalent phosphorous halides. The tertiary amide reacts with the pentavalent phosphorous halide to produce a haloiminium salt which is then converted to the &agr;-haloenamine with a base.
In general, the tertiary amide may be any tertiary amide having a hydrogen atom bonded to the carbon which is in the alpha position relative to the carbonyl group of the tertiary amide and which does not interfere with the synthesis of or react with the &agr;-haloenamine. In one embodiment, the tertiary amide has the general formula:
wherein
R
1
and R
4
are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; and
R
2
and R
3
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro.
Ordinarily, it will be preferred that R
2
and R
3
are other than hydrogen, such as alkyl or aryl to increase the stability of the reagent to a variety of conditions. Nevertheless, under some circumstances, provided one of R
2
and R
3
is sufficiently electron-withdrawing, the other may be hydrogen. Und
Kumar Shailendra
Pharmacia Corporation
Senniger Powers Leavitt & Roedel
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