Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-05
2003-05-06
Rotman, Alan L. (Department: 1628)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06559318
ABSTRACT:
This application is a 371 of PCT/EP99/10159 Dec. 21, 1999.
The present invention relates to a process for the preparation of (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid and intermediates, which can be used during the process. (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid has the formula
(2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid is an important intermediate product for the manufacture of inhibitors for angiotensinase (DE 3322530, EP 267098). It is in particular a key product for the manufacture of Trandolapril (EP 84164).
The synthesis processes for (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid so far known in the art are very costly (DE 3322530, EP 267098). Now a simpler and cheaper process for the preparation of this substance has been found.
The present invention relates to a process for the preparation of (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid, consisting of the following steps
a) reacting a compound of the formula I
(R
1
O)
2
CH—CH
2
—CH(OR
2
)
2
I
wherein R
1
and R
2
may be the same or different and represent each a C
1-4
-alkyl group, with water in the presence of an acidic catalyst,
b) subjecting the obtained 3,3-dialkoxypropionaldehyde of formula II
(R
1
O)
2
CH—CH
2
—CHO II
to a Henry-reaction with nitromethane,
c) subjecting the obtained 4,4-dialkoxy-1-nitro-4-butanol of formula III
(R
1
O)
2
CH—CH
2
—CHOH—CH
2
—NO
2
III
to a dehydration
d) converting the obtained nitroolefin IV with the aid of a Diels-Alder reaction into the corresponding trans-4-(2,2-dialkoxyethyl)-5-nitro-1-cyclohexene V
e) hydrogenating the obtained substance V into the corresponding trans-4-(2,2-dialkoxyethyl)-5-amino-1-cyclohexane VI
f) subjecting the compound VI to an racemate resolution and obtaining the (1S, 2R)-1-amino-2-(2,2-dialkoxyethyl)-cyclohexane VII,
in enantiomerical pure form
g) hydrolyzing the obtained compound VII to the corresponding aldehyde VIII
h) converting the obtained aldehyde into the corresponding nitrile IX by reaction with cyanide ions
and
i) saponifying this nitrile to the (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid
The hydrolysis of the 1,1,3,3-tetraalkoxyalkanes (I) to the corresponding 3,3-dialkoxypropionaldehydes (=malone dialdehyde monoacetales) (II) is effected by converting the educt with water with an acidic catalyst. As catalyst generally all catalysts known for the hydrolysis of acetates are usable. In particular suitable are strong protonic acids or strong acidic ion exchange materials, such as for example sulfuric acid, hydrochloric acid, phosphoric acid, toluenesulfonic acid, Nafion, ion exchange materials with sulfonic acid groups and the like.
Step b, the Henry reaction of the malone dialdehyde monoacetale with nitromethane to the 4,4-dialkoxy-1-nitro-butanol (III) is carried out under the usual conditions for this type of addition reaction (M.Shvekhgeimer, Russ.Chem.Rev. 67, 35-68 (1998)). As catalyst all catalysts described for those type of reaction can be envisaged, such as nitrogen containing bases, such as aliphatic amines or guanidine, basic ion exchange materials, Potassium fluoride, potassium fluoride supported on aluminium oxide, alkali or alkaline earth hydroxides or alkali or alkaline earth alcoholates, such as sodium methylate. Step b is carried out usually under basic conditions. As bases suitable are in particular tertiary amines, such as trimethylamine, triethylamine, tetramethylenediamine, tetramethyl-1,3-propanediamine, DBN and DABCO. The malone dialdehyde monoacetale can be employed as crude product, as obtained after hydrolysis, without any further purification.
In step c the 4,4-dialkoxy-1-nitro-2-butanol (III) is dehydrated to the 4,4-dialkoxy-1-nitro-2-butene (IV). For the dehydration all methods known for the dehydration of nitroalcoholes may be employed. The following are enumerated here: 1.direct dehydration with aluminium oxide (J.Org.Chem. 57, 2160-2162 (1992)), 2. Dehydration with methane sulfochloride and triethylamine (J.Org.Chem. 40, 2138-2139 (1975)) and 3. Dehydration using phthalic anhydride (Org.Synth. 60, 101 (1981)).
Dehydration c can also be effected by acylation of the alcohol with an acid anhydride and subsequent cleaving of the acid with bases, such as alkali carbonates or alkali hydrogen carbonates or nitrogen containing bases or aluminium oxide, see J.Am.Chem.Soc. 76, 2716 (1954), J.Am.Cem.Soc. 69, 1048 (1947), Synthesis 1983, 920, Liebigs Ann.Chem. 1994, 1235 and Tetrahedron Lett. 35, 5731 (1994). Further possibilities for dehydration are those using dicyclocarbodiimide with copper catalysis (Sythesis 1982, 1017) and those using triphenylphosphine/carbon tetrachloride/triethylamine (Synthesis 1994, 685).
In particular suitable for the dehydration c is the acylation of the nitroalcohol with acetanhydride and subsequent cleavage of acetic acid. Acetic acid is already partially cleaved off during acylation. Complete cleavage can be achieved thermally at temperatures of from 120 to 500° C. or with bases, such as alkali or alkaline earth carbonates, hydrogen carbonates or hydroxides of the aliphatic amines. For the acylation it is preferred to employ catalysts (for example 4-(dimethylamino)pyridine). During dehydration the thermodynamically more stable trans-product is formed mainly.
In step d the nitroolefin is reacted with butadiene in an Diels-Alder reaction. Pure thermal Diels-Alder reactions without catalysts are carried out at temperatures of from 50 to 200° C., preferably from 90 to 120° C., in aromatic hydrocarbons, such as benzene, toluene or xylene. With the use of catalysts the reaction temperature can be reduced. The trans-nitroolefin gives the trans-4-(2,2-dialkoxyethyl)-5-nitro-1-cyclohexene.
In step e the double bonds and the nitro group are hydrogenated. The hydrogenation may be effected in one step or in two steps. As catalysts all hydrogenation catalysts are suitable, preferably Raney nickel or Pd or Pt catalysts, such as Pd/C or Pt/C. The hydrogenation is carried out at from 20 to 150° C. As solvent suitable are alcoholes such ass methanol and ethanol or acetic acid.
The preparation of the enantiomerically pure form of (1S, 2R)-1-amino-2-(2,2-dialkoxyethyl)-cyclohexane (step f) can be effected by resolution of racemates in the usual manner. In particular suitable is the encymatic resolution of racemates. Therein the racemic mixture of (1S, 2R)— and (1R, 2S)-1-amino-2-(2,2-dialkoxyethyl)-cyclohexane is reacted with acylating agents, such as alkoxy acetic acid isopropyl ester, in the presence of hydrolases, in particular lipases. In this reaction the (1R, 2S)-enantiomer is acylatetd selectively while the desired (1S, 2R)-enantiomer does not react and can be separated from the reaction mixture by means of destination or chromatography. Suitable as lipase is in particular Novozym 435. Resolution occurs suitably at from 20 to 40° C.
The hydrolysis of the acetale (step g) to the aldehyde takes place suitably by boiling the acetate in an aqueous acid, such as hydrochloric acid, sulfuric acid or phosphoric acid.
The conversion of the aldehyde to the nitrile (step h) can be effected in particular by reaction with sodium cyanide under alkaline conditions, at a pH>9, wherein the nitrile is saponified directly into the sodium salt of the (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid (step i). The acid is obtaines by acidifying the reaction solution.
The present invention also relates to new compounds, used in the above described synthesis. These are the following:
2. 4,4-Dialkoxy-1-nitro-2-butenes of Formula IV
(R
1
O)
2
CH—CH═CH—CH
2
—NO
2
IV
3. trans-4-(2,2-Dialkoxyethyl)-5-nitro-1-cyclohexenes of Formula V
4. trans-4-(2,2-Dialkoxyethyl)-5-amino-1-cyclohexanes of Formula VI
5. (1S, 2R)-1-amino-2-(2,2-dialkoxyethyl)-cyclohexanes of Formula VII
The aldehyde of formula VIII
and the acid addition salts.
The new process for the preparation of (2S, 4R, 9S)-octahydro-1H-indole-2-carboxylic acid yields the substance in an higher yield, compared with the process
Ebel Klaus
Nübling Christoph
Ohlbach Frank
BASF - Aktiengesellschaft
Shameem Golam M. M.
Wood Phillips Katz Clark & Mortimer
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