Note: Descriptions are shown in the official language in which they were submitted.
1060013
The present invention relates to a process for converting alcohols,
which have heretofore found little or no utility, into ketones which are val-
uable intermediates in the preparation of compounds which display analgesic
activity. More precisely, the present invention relates to a process for
the conversion of the ~-1 and ~dl diastereoisomeric aminobutanols of formula
II
OH R2 R
C - CH - CH2 - N II
~H2 Rl
~ .,
. . .
i wherein R and Rl represent lower alkyl of 1 to 4 carbon atoms or, taken to- -
. gether with the adjacent nitrogen atom may represent a pyrrolidino, piper-
idino or morpholino radical and R2 represents lower alkyl of 1 to 4 carbon
atoms, into a ketone of formula I
~, .
O R2 R -
C-CH-CH2-N
~r Rl
1wherein R, Rl and R2 are as defined above.
~1
According to Pohland et al. - J.Am.Chem.Soc. ~ 4458(1953), the
~-dl-1,2-diphenyl-2-hydroxy-3-lower alkyl-4-substituted-aminobutanes (C2-C5)
alkanoyl derivatives possess marked analgesic activity whereas the ~-dl-dia-
stereoisomers are substantially devoid of this pharmacological activity -
more particularly in the case of ~-dl-1,2-diphenyl-2-hydroxy-3-methyl 1-dime-
~j thylaminobutane propionate (dl-propoxyphene) it was demonstrated that all of
the analgesic activity resided in the dextrorotatory (~-d) enantiomer which
is now widely employed as analgesic drug (d-propoxyphene). It is known from
the chemical literature that the analgesic 1,2-diphenyl-2-(C2-C5)alkanoyloxy-
j 3-lower alkyl 4-substituted-aminobutanes may be advantageously prepared
according to the following schemes: -
.1 -- 1 -- . .
:. ~ ' ':
. . .
11~)60013
Scheme a)
/R 1) ~ CH2MgCl ~ ,OH
CO-CH-CH2-N~R J ~ /C\ / R
CH2 CH-CH2-N
(d,l) 2)Separation of diaste- ~ I ~ R
reoisomers (~ and ~ l J R2
form)
3)Separation of the enan- (~-d-enan-
tiomers ( form) tiomer
, ~.''
~ alkanoylation
(Alkanoyl = C2-Csalkanoyl) ~ ~ ~OAlkanoyl
C 2 ~ Cn-C~2-N~
(~-d-enantiomer)
Scheme b)
I O 3 R2
¦ ~ 3 2 ~ R H2=S~CR ~ CH2-C-CR-CR2-N~ R
-3 ~ (d,l)
1) ~ Li
2)Separation of the
: diastereoisomers
~-1 3)Separ.ation of the enan-I tiomers of the ~form
:~ : OAlkanoyl OH R2
CH ~ -CR2-N~ R Alk~noyl~tior ~ CR ~ ~-C~2-N~
-d enantio~er)
(Alcanoyl = C2-C5aIkanoyl) (~-d enantiomer~ ::
- 2 -
: .
-' :,
~1~60013
According to scheme a) the racemic l-phenyl-2-lower alkyl-3-sub-
stituted amino-l-propanone undergoes an usual Grignard reaction leading pre-
dominantly, about 85-90%, to the ~-diastereoisomer. The mixture is separated
into the ~ and ~ components by fractional crystallization from aqueous ethan-
ol, being defined as diastereoisomer ~ the less soluble component. In
accordance with the usual practice the ~-diastereoisomer is then resolved
into the d and 1 enantiomers by reaction with an optically active acid, such
as for instance dibenzoyl-l-tartaric acid, dibenzoyl-d-tartaric acid, 1-
; camphorsulfonic acid or d-camphorsulfonic acid to form two diastereoisomeric
salts which are in turn readily separable by fractional crystalli~ation. The
two salt fractions can be separately decomposed to yield the individual ~-1
and a-d enantiomers of the base compound. The ~-d enantiomer when esterified
with alkanoyl anhydride, such as for instance propionic anhydride, does not
change its configuration (Pohland et al.-J. Am. Chem. Soc.-77, 3400, (1955)
, and United States Patent No. 2.728.779).
i According to scheme b) the ~ and ~ components of 1,2-diphenyl-2-
hydroxy-3-lower alkyl-4-substituted-aminobutane are obtained by regiospecific
opening of the epoxide formed by reaction of dl-l-phenyl-2-lower alkyl-3-
substituted amino-l-propanone and dimethylsulfaxonium methyl;de (Donetti et
al.-Il Farmaco (Sci), 24, 900(1969).
The separation of the ~ and ~ components, the resolution of the ~
fraction and the esterification of the ~-d-enantiomer are carried out follow-
ing the already mentioned procedures.
, As it is obvious from the above schemes, the ~-dl-diastereoisomers
and substantial quantities of the ~-l-isomer are unuseful by-products whose
formation is responsible for the low overall yields of analgesically active
substance. Practically, the yields of both processes a) and b) above describ-
ed are ranging between 40 and 45%. Higher yields (about 60%) may be obtained
with a stereoselective synthesis which follows scheme a), wherein the start-
ing material is the appropriate optically active isomer (Pohland et al. J.
~`
`~ ''
'
'
-............................. . . , . . - .
1060013
Org. Chem. 28, 2483 (1963)).
In any case, low percent yields raise many important problems con-
cerned with both the layout of the waste matter and the cost of the process,
particularly when working on industrial scale.
We have now discovered a new and useful process which allows util-
; ization of the undesired side-products ~-1 and ~-dl-1,2-diphenyl-2-hydroxy-
3-lower alkyl-4-substituted-aminobutanes by restoring the starting l-phenyl-
2-lower alkyl-3-substituted-amino-1-propanones in yields higher than 89% and
at low cost.
The process of the invention comprises treating the starting amino-
butanols with a suitable oxidi~ing agent in an acidic medium. If optical
active forms of aminobutanols are employed, the corresponding oxidation
products may be easily racemi~ed by refluxing in aqueous mineral acid solu-
tions.
The present invention provides a process for the preparation of a
compound of formula
~ ~ O
R2-CH-CH2-N
` 20 ~1
"1 :
wherein R and Rl each independently represent a lower alkyl group of 1 to 4
carbon atoms or, taken together with the adjacent nitrogen atom, may repre-
sent a pyrrolidino, piperidino or morpholino radical and R2 represents a
lower alkyl of 1 to 4 carbon atoms, which comprises treating an a-l or ~-dl
aminobutanol of formula
OH II
C / R
CH2 1 _ GH2 - N\
~ R2 R
... .. - , , ., . :. . . .
106()013
wherein R, Rl and R2 have the same meaning as before, with an oxidi~ing agent
selected from the group consisting of derivatives of hexavalent chromium,
derivatives of trivalent cobalt, manganese dioxide, alkali metal manganates,
permanganates, bismuthates and periodates and lead tetraacetate in an acidic
medium.
A specific embodiment of the present invention provides for the
preparation of a compound of formula
~ 1 ~ / GN3
CH3-CH-CH2-N~
CH
:;3
, which comprises treating an ~-1 or B-dl butanol of formula
11 ~
r ~ OH
~ C ~ CH3
- CH CH - CH -
2 1 2
~ CH3 3
:~ 20
with from about 0.6 to about 4 molecular proportion of a hexavalent chromium -
:' .
derivative selected from chromic anhydride and alkali metal dichromates in an
acidic mediu~, selected from aqueous diluted sulfuric acid and concentrated :
acetic acid, at a temperature comprised between about 20C and about 110C,
~~ removing the co-products of the reaction and recovering the resulting 1-
.,
phenyl-2-methyl-3-dimethylamino-1-propanone.
For practical purposes the oxidizing agent, in the suitably select-
ed conditions, must break the C-C bond which l;nks the benzyl radical to the
group
:, :
`' _ 5 ~
' ., : .
; .: ' ' ' `"'' ' j .. ' ' ' : `'i'` ': . '
. .
1060013
~ / OH
/ \
1 2 \
~` R2 Rl .
leading to benzoic acid or benzaldehyde (which in turn is transformed into
benzoic acid by the oxidizing agent excess) and the aminoketone of formula
II, without further demolition. Ben~oic acid may be recovered at the end of
the reaction by means of the usual techniques or, in order to save part of
the oxidizing agent, benzaldehyde may be stripped out from the reaction
medium by steam distillation before further oxidative step to benzoic acid
takes place.
Suitable oxidizing agents are selected from derivatives of hexa-
~ valent chromium, derivatives of trivalent cobalt, manganese dioxide, alkali -
J~ metal manganates, permanganates, bismuthates and periodates and lead tetra- -
acetate.
Jl A preferred group of oxidizing agents comprises the hexavalent'~ 20 chromium derivatives such as for instance alkali metal chromates and dichrom- -
~ ates, chromic anhydride, chromyl acetate, chromyl chloride, piridinium
`1 chlorochromate. The best reaction conditions, such as temperature range,
proportion of the axidizing agent to the butanol, solvent and acidic medium,
vary withln a wide range depending on the selected oxidizing agent. When
derivatives of hexavalent chromium are employed as oxidizing agents, accord-
ing to a preferred embodiment of the invention, the molar ratio between Cr
and the butanol substrate may range from about 0.6 to about 4. Accordingly
water is employed as the most convenient solvent and mineral acids or lower ~-
aliphatic acids (which may act also as the solvent) are advantageously
1 30 employed as the acidic medium.
'~ ' '' . '
1 - 6 -
:'.,: '' '
. 1 ,
'' '
10600~3
The reaction temperature ranges from about the room temperature to
about 150C, preferably fram about 20C to about 110C.
The concentration of the acid may vary within a wide range without
considerably affecting the final yields. However, when working with mineral
; acids at high temperatures, it is generally preferred to keep the concentra-
tion of said mineral acid lower than about 60 per cent, in order to avoid
side reactions such as ~-eliminations, rearrangements and fragmentations.
The reaction time may vary between about one to about 24 hours, depending on
the selected Z~xidizing agent and the other chemico-physical reaction condi-
tions.
The following examples are illustrative of the ways in which the
invention may be performed but by no means are intended to constitute a
limitation of the scope of the invention.
Example 1
s
A solution containing 0.2 mole of Z~-1-1~2-diphenyl-2-hydraxy-3-
methyl-4-dimethylaminobutane in 100 ml. of diluted H2S04 was heated to 50C
during the dropwise addition of 0.21 mole of sodium dichromate in 150 ml.
of 5~% H2S04. After the addition was completed the mixture was heated to
100-105C for three hours and then cooled to room temperature. Benzoic acid
was separated by filtration and the filtrate was made basic with diluted
ammonium hydroxide and then extracted with ethyl ether. By concentrating to
dryness, 36.5 g. of dl-1-phenyl-2-methyl-3-dimethylaminZ~-l-propanone were
obtained (95% yield).
E ample 2
. ::
A solution of 71 g. of ~-1-1,2-diphenyl-2-hydroxy-3-methyl-4-di- ~ -
meth~laminobutane in 1500 ml. of glacial acetic acid was maintained at 45-
50C during the gradual addition of 110 g. of chromic anhydride. The mixture
was then concentrated under vacuum, the residue poured into 1500 ml. of water
and made basic by addition of 10% NaOH. The aqueous solution was extracted
i 30 with ethyl ether and after concentration under vacuum of the dried organic
, i .
I - 7 -
:'
:. . ~ , .. : ~
16~60013
extract, 45.5 g. of d-1-phenyl-2-methyl-3-dimethylamino-1-propanone,/~ /;D
(1% HCl O.lN)=+49.4; were obtained (yield 94%).
Example 3
0.14 mole of sodium dichromate in 110 ml. of 50% H2S04 was added
dropwise to a solution containing 0.2 mole of a-1-1,2-diphenyl-2-hydroxy-3-
methyl-4-dimethylaminobutane in 110 ml. of diluted sulfuric acid, while the
reaction mixture was refluxed. During the reaction, benzaldehyde and smaIl
amount of benzoic acid were stripped out from the reaction medium by steam
distillation. The reaction mass, treated according to the previous examples,
: 10 yielded 34 g. of 1-phenyl-2-methyl-3-dimethylamino-1-propanone raceme (89%).
, ~
.1 '
(
'.
'
~ .
',
. ~ .
... .
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. :
,.1 .
',
- 8 -
