Process for preparing acetonides

Details Process for preparing acetonides Process for preparing acetonides

2001-06-18

2002-11-19

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06482952

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the preparation of 2,2-dimethyloxazoles via the reaction of a carboxylic acid halide with a 1,2-aminoalcohol and 2-alkoxypropene or 2,2-dialkoxypropane. The 2,2-dimethyloxazoles described herein are more commonly referred to in the art as acetonides and are referred to as acetonides herein. The acetonides are useful as intermediates in the preparation of HIV protease inhibitors.
References are made throughout this application to various published documents in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,413,999 discloses N-substituted 2(R)-(substituted methyl)-4(S)-hydroxy-pentaneamide derivatives that are HIV protease inhibitors, including indinavir (referred to herein and in U.S. '999 as Compound J). The sulfate salt of indinavir is available from Merck under the tradename CRIXIVAN® for the treatment of HIV infection and AIDS. U.S. Pat. No. 5,646,148 discloses a class of N-substituted 2(R)-phenylmethyl-4(S)-hydroxy-pentaneamide derivatives which are potent HIV protease inhibitors, including N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl4(S)-hydroxy-5-(1 -(4-(2-benzo[b]furanylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide (referred to herein as Compound K).
Acetonides are useful as intermediates for the preparation of 2(R)-phenylmethyl4(S)-hydroxy-pentaneamide derivatives, as exemplified by the following scheme for the preparation of the indinavir penultimate 10:
In the scheme, acetonide 1 is allylated with allyl bromide in the presence of LHMDS to obtain the allyl acetonide 4, which is converted to the iodohydrin 6 by treatment with NCS and an aqueous solution of NaI in the presence of sodium bicarbonate. Iodohydrin 6 is converted to epoxide 7 by treatment with sodium methoxide. (Alternatively, the acetonide 1 can be reacted with (S)-glycidyl tosylate in the presence of LHMDS to obtain epoxide 7 directly.) Epoxide 7 is then coupled with N-protected piperazine 8 in methanol to provide the alkylated Boc-piperazine 9. Treatment of 9 removes the Boc and acetonide protecting groups to afford the indinavir penultimate 10. Alkylation of 10 with 3-picolyl chloride provides Compound J (indinavir). A variety of other protease inhibiting compounds can be obtained by alkylating 10 with a suitable alkyl halide. Compound K, for example, can be obtained by alkylating 10 with 2-chloromethylbenzofuran. Further description of the preparation of N-substituted 2(R)-(substituted methyl)-4(S)-hydroxy-pentaneamide derivatives from acetonides can be found in U.S. Pat. No. 5,491,238, 5,728,840, WO 97/47632, and Askin,
Drug Discovery
&
Development
1998, 1: 338-348.
Various methods for preparing acetonide 1 are known. The acetonide has been prepared in two steps by (1) treating hydrocinnamoyl chloride 2 with (−)-cis-1-aminoindan-2-ol 3 in a two-phase IPAc/aqueous potassium bicarbonate system at about 56-65° C. to give the corresponding hydrocinnamoyl amide 5, and then (2) drying 5 by distillation and reacting it in the same pot with 2-methoxypropene and methanesulfonic acid at about 40° C. to give the acetonide:
The acetonide-containing reaction product has then been distilled to remove by-product 2,2-dimethoxypropane and water, and solvent switched to THF for the allylation step.
Examples 24-26 of WO 97/47632 disclose two-step methods for preparing acetonide 1 which can be considered variations of the two-step method described in the preceding paragraph. A principal variation is the choice of solvent and reagent. The methods disclosed in Examples 24 and 25 employ diethoxymethane and sodium carbonate monohydrate instead of IPAc and aqueous potassium bicarbonate. In addition, Example 25 uses the tartrate salt methanol solvate of 3 instead of 3 per se. The method disclosed in Example 26 uses aqueous NaOH instead of aqueous potassium bicarbonate.
The above-described two-step methods have certain disadvantages. The reaction mixture in the first step consists of two phases—an aqueous phase and an organic phase. The phases must be separated at the conclusion of the reaction, and the organic phase containing the desired hydrocinnamoyl amide 5 must then be concentrated and dried (e.g., by atmospheric distillation) before it can be employed in the second step. Furthermore, the acetonide-containing mixture resulting from the second step cannot be used directly in the subsequent allylation. It must be solvent switched to a suitable solvent such as THF. Furthermore, the solvents employed in the two-step methods (i.e., IPAc and diethoxymethane) are relatively expensive compared to other organic solvents, and it would preferable to avoid their use in the large scale production of acetonide.
U.S. Pat. No. 5,491,238 (Example 1) discloses the preparation of acetonide 1 by reacting hydrocinnamoyl chloride 2 with (−)-cis-1-aminoindan-2-ol 3 at about 18-20° C. in THF and in the presence of triethylamine to provide hydroxyamide 3, and then treating the reaction mixture with pyridinium p-toluenesulfonate and then with 2-methoxypropene, and heating to 38-40° C. to afford 1. This method avoids the two-phase reaction system which characterizes the hydroxyamide formation step in the previously described methods, but it nonetheless has certain disadvantages. A by-product of hydroxyamide formation in the first step is the hydrochloride salt of Et
3
N, which must be removed prior to the allylation step, because its presence would otherwise degrade or destroy the base (e.g., LHMDS) used in the allylation. The removal of the amine salt necessitates a number of additional processing steps, such as solvent switching from THF to IPAc or EtOAc after acetonide formation, washing the IPAc layer with water to remove Et
3
N.HCl, and then isolating the acetonide by crystallization or solvent switching back to a solvent suitable for allylation (e.g., THF). Furthermore, the treatment of aqueous waste streams containing Et
3
N.HCl is costly, because direct disposal is precluded by environmental concerns. In addition to the problems posed by triethylamine, pyridinium p-toluenesulfonate is a very expensive reagent, and presents the same disposal problems as triethylamine.
U.S. Pat. No. 5,169,952 (Example 1) discloses reacting hydrocinnamic acid and cis-aminoindanol 3 in THF and in the presence of pivaloyl chloride and triethylamine at 25° C. to afford hydroxyamide 3, and then treating 3 slurried in methylene chloride with 2-methoxypropene and pyridinium p-toluenesulfonate at 25° C. to obtain acetonide 1. This preparative method is also disclosed in Askin et al.,
J. Org. Chem.
1992, 57: 2771-2773 (Supplemental Material). This method has the same disadvantages with respect to its use of triethylamine and pyridinium p-toluenesulfonate as the method of U.S. Pat. No. 5,491,238, as discussed in the preceding paragraph. An additional disadvantage is that methylene chloride is toxic and extremely expensive to use on a large scale due to environmental and reycling costs. Another disadvantage of the method is that it uses pivaloyl chloride to generate hydrocinamoyl chloride from the hydrocinnamic acid in situ. This results in the formation of pivalic acid as an additional by-product, which must also be removed from the acetonide product and disposed of.
Reaction of acetonide 1 in THF with allylating agents (particularly allyl bromide) in the presence of LHMDS to obtain allyl acetonide 4 has been disclosed in U.S. Pat. No. 5,728,840, WO 97/47632, and Askin,
Drug Discovery
&
Development
1998, 1: 338-348.
SUMMARY OF THE INVENTION
The present invention is directed to improved processes for preparing acetonides. The present invention includes a process for preparing an acetonide of Formula (I):
which comprises:
(A) reacting an acid halide of Formula (II):
with an alkoxy compound which is 2-alkoxypropene or 2,2-dialkoxypropane and an aminoalcohol of Formula (III):
i

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