Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-10-12
2001-12-11
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S187000
Reexamination Certificate
active
06329542
ABSTRACT:
BACKGROUND OF THE INVENTION
Robl in U.S. Pat. No. 5,508,272 discloses compounds of the formula
wherein A can be
X can be S, Y can be CH
2
, m can be one, and n can be two as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity. Among these compounds is [4S-[4&agr;(R*),7&agr;, 10a&bgr;]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl-amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid which is currently undergoing clinical evaluation. This compound is reported in the literature as BMS 186,716 and as omapatrilat.
Robl discloses that the amino lactam portion of BMS 186,716, i.e. the intermediate
can be prepared by coupling (S)-2-amino-6,6-di-methoxyhexanoic acid, methyl ester with the N-protected amino acid
wherein P
1
is an amino protecting group and P
2
is a sulfur protecting group to give the dipeptide of the formula
Removal of the P
2
protecting group, followed by acid catalyzed cyclization, and removal of the P
1
protecting group gives [4S-(4&agr;,7&agr;, 10a&bgr;)]-octahydro-4-amino-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid, methyl ester.
Robl discloses preparing (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester by converting N-protected L-&egr;-hydroxynorleucine to its methyl ester, oxidizing to the aldehyde of the formula
then reacting with trimethyl orthoformate in the presence of a strong acid catalyst, and removing the P
3
protecting group.
SUMMARY OF THE INVENTION
This invention is directed to an improved chemical synthesis of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester and novel dioxolane intermediates from this synthesis.
According to the process of this invention the glycinamide of the formula
is reacted with the dioxolane of the formula
wherein L is a leaving group such as iodo, bromo, alkylsulfonyloxy, or arylsulfonyloxy to give the dioxolane of the formula
The dioxolane of formula III is treated under aqueous refluxing conditions to give the dioxolane pentanoic acid of the formula
The dioxolane pentanoic acid of formula IV is then treated to exchange the dioxolane acetal with a dimethoxy acetal and convert the carboxylic acid to the methyl ester resulting in the desired compound (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester. This can be achieved by reacting compound IV with thionyl chloride in methanol or by reacting compound IV with anhydrous HCl such as HCl gas and dimethyl sulfite in methanol or by the in situ generation of HCl such as by reacting compound IV with chlorotrimethylsilane or an acid chloride such as acetyl chloride and dimethyl sulfite in methanol.
Another aspect of this invention is the preparation of storage stable salts of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X. Such salts can be converted to the free amine for ultimate conversion to the desired product. This affords added flexibility in scheduling production runs and enables different stages of the reaction to be carried out at different manufacturing facilities.
DETAILED DESCRIPTION OF THE INVENTION
(S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester of the formula
is useful as an intermediate in the preparation of [4S-[4&agr;(R*),7&agr;, 10a⊖]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-5-oxo-7H-pyrido[2,1-b]-[1,3]thiazepine-7-carboxylic acid of the formula
as described by Robl in U.S. Pat. No. 5,508,272.
According to the process of this invention (S)-2- amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X is prepared by a chemical synthesis that avoids the need for an oxidation reaction and for an optical resolution. In this process, the glycinamide of formula I is reacted with the dioxolane of formula II to give the dioxolane of formula III. This reaction is performed in the presence of lithium diisopropylamide in an organic solvent such as tetrahydrofuran, which is preferred, diethoxymethane, tert-butyl methyl ether, 2-methyl tetrahydrofuran, or diethyl ether. The reaction is carried out at a temperature of from about−78° C. to about 0°C.
The glycinamide of formula I is prepared as described by Myers et al.,
Tetrahedron Letters
, Vol. 36, p. 4555-4558 (1995).
The leaving group L in the dioxolane reagent of formula II can be an alkylsulfonyloxy such as methane sulfonyloxy, an arylsulfonyloxy such as p-toluenesulfonyloxy, bromo, or iodo with iodo being preferred. Such dioxolane reagents of formula II are known in the art or can be prepared from commercially available compounds. For example, the dioxolane of formula II wherein L is iodo can be prepared by reacting 2-(3-chloropropyl)-1,3-dioxolane with sodium iodide in the presence of sodium bicarbonate.
The dioxolane intermediate of formula III is then treated under aqueous refluxing conditions to give the dioxolane pentanoic acid of formula IV. The dioxolane pentanoic acid of formula IV is then reacted to give (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X by exchanging the dioxolane acetal with a dimethoxy acetal and introducing the methyl ester group. For example, the dioxolane pentanoic acid of formula IV can be reacted with thionyl chloride in methanol or reacted with anhydrous HCl such as HCl gas and dimethyl sulfite in methanol or reacted with HCl generated in situ such as by reacting the compound of formula IV with chlorotrimethylsilane or an acid chloride such as acetyl chloride and dimethyl sulfite in methanol to give the desired compound of formula X. These reactions can be performed at a temperature of from about 40° C. to about 45° C.
(S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester can be converted to a storage stable salt. This provides added flexibility to the overall process as the process steps leading up to the (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester salt can be performed separately from the process steps for converting (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester to the desired final product. The term storage stable salt refers to a salt of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester which can be maintained for a period of at least about 30 days under conditions of low temperature and the absence of moisture and then converted to (S)-2-amino-6,6-dimethoxy-hexanoic acid, methyl ester in high yields. Salts of (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X suitable for this purpose include the oxalic acid salts (1:1) and (2:1), the diphenylacetic acid salt (1:1), and the phosphoric acid salt (1:1).
The salt is treated with a base such as potassium bicarbonate to give the (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X.
As described by Robl in U.S. Pat. No. 5,508,272, (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester of formula X can be coupled with the N-protected amino acid of the formula
to give the dipeptide of the formula
wherein P
1
is an amino protecting group such as benzyloxycarbonyl or t-butoxycarbonyl or a group which together with the. N-atom forms a protecting group such as phthalimido and P
2
is a mercapto protecting group such as acetyl or benzoyl. This coupling reaction is preferably performed in the presence of a coupling reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, ethyl-3-(3-dimethylamino)propyl carbodiimide, methanesulfonyloxybenzotriazole, or dicyclohexylcarbodiimide.
The P
2
protecting group is selectively removed from the dipeptide of formula VI such as by treatment with sodium methoxide in methanol or by treatment with p-toluenesulfonic acid in methanol. The resulting mercaptan compound is then subjected to an acid catalyzed cyclization reaction preferably by treating with a strong acid such as trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or a commercially available polystyrene sulfonate polymer type ion exchange resin such as Amberlyst15®. This cyclization reaction can be performed in a non-protic solvent such as methylene chloride or chloroform to give the l
Dillon, Jr. John L.
Godfrey Jr. Jollie D.
Jass Paul A.
Kotnis Atul S.
Kronenthal David R.
Bristol-Myers Squibb Co.
Davis Stephen B.
Owens Amelia
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