Phenylpropanolamine To Speed
Phenylpropanolamine To Speed
Phenylpropanolamine To Speed
NHR
Scheme 2
()----, i i
e A. 2S-(+)-amphetamine (RFH)
HX -ss 2S-(+)-methamphetamine (RFCH)
Sa
Sa
R2
II
OCOR H NHR
/
R2
e
Sa.
e
Sa
NHR
HX 1 - |
B
R2
e
S.
Sa
|
NHR
OX 15 ()----, H. H.
1S,2S-(+)-norpseudoephedrine (RFH)
R2 R2 1S,2S-(+)-pseudoephedrine (RFCH3)
III I
OH OAc
NH NH
A 100 mL round bottom flask with a magnetic stirrer was 2 Ac2O 2
charged with thionyl chloride (24.47g, 15 mL) and norephe 55 HCI co- OHCI
drine hydrochloride (5.38 g). The mixture was stirred and
heated at reflux temperature for about 1 hour and allowed to
cool to ambient temperature. The excess thionyl chloride
was removed by evaporation on a rotary evaporator. The A three-necked 100 mL round bottom flask equipped with
residue in the flask was triturated with ether (50 mL) and the 60 thermocontroller, Stirrer, condenser, and gas bubbler was
solid collected. The crude solid product was recrystallized charged with 18.77 g (0.10 mol) d.1-norephedrine
from methanol-isopropyl ether and the purified Solid col hydrochloride, acetic acid (18 mL), and acetic anhydride
lected (2.83 g, 48%). The purified 2-amino-1-chloro-1- (12.24 g., 0.12 mol). The reaction mixture was warmed with
phenylpropane hydrochloride was then Subjected to hydro a heating mantle with thermocontroller set for 80 C. After
genolysis as follows. A Solution of 2-amino-1-chloro-1- 65 the reaction mixture cleared, it was held at 80° C. for 2
phenylpropane hydrochloride (2.38 g., 0.0137 mol) in a hours. Heptane (36 mL) was added to the 80° C. reaction
mixture of 50 mL ethanol/16 mL water was prepared and mixture slowly with rapid Stirring, then the mixture was
US 6,399,828 B1
10
allowed to cool to ambient temperature. The slurry was norephedrine hydrochloride) in a mildly exothermic reaction
Stirred overnight at ambient temperature and the Solid was at 50-80 C. for 2 hours, although exothermic reaction
collected by filtration. The granular solid was dried under temperatures could exceed 80 C. Generally, when less than
ambient conditions overnight to obtain 18.13 g of product a 20% excess of acetic anhydride is used, Some unreacted
(89.99% yield). norephedrine remains, for example, when a 10% excess of
B. Preparation of 2-Amino-1-acetoxy-1-phenylpropane
Hydrochloride (O-Acetylnorephedrine) from Norephedrine acetic anhydride was used, it reacted with only about 80%
Hydrochloride and Reduction to Amphetamine without Iso of the norephedrine hydrochloride. It was found that the
lation of the Intermediate amount of acetic acid used does not appear to be critical, as
the reaction proceeded well with either 1 or 2 mL/g of
OH norephedrine hydrochloride and could be agitated without
NH2 difficulty at 1 mL/g. When no acetic acid was used, however,
Ac2O the product obtained consisted of a mixture 16.71%
HCl Ao norephedrine, 67.08% O-acetylnorephedrine, and 14.43%
15 O,N-diacetylnorephedrine. Results of other laboratory
OAc
preparations are Summarized in Table 1.
NH2
OCI H2, Pd/C TABLE 1.
Summary on Acetylations of Norephedrine Hydrochloride
NH2
Experiment Yield AcNE Amp AcNE NE AcAmp diAcNE
A. : 90.8 - <1 6.3
25 C 80.1 92.98 - 3.74
D 52.2 98.43 - 1.57 -
E 26.8 97.5 2.5
The following method is an example wherein the reduc F 85.5 95.7
tion of the intermediate O-acetylnorephedrine is performed G 56.9 100
without isolating the O-acetylnorephedrine. H
I
95.2
90.O
A 100 mL 3-necked round bottom flask equipped with a L 82.7 89.44 0.832 - 9.06
magnetic Stirrer, condenser, and thermocontroller, was Z. 99.18 8939 -
charged with d.l-norephedrine hydrochloride (9.39 g, 0.050
mol), acetic anhydride (6.12 g, 0.060 mol), and acetic acid * Product was not isolated: reaction mixture carried on to reduction step
(Experiment B, Tables 3, 4, and 7).
(18 mL). The reaction mixture is heated with heating mantle
with a thermocontroller set at 80 C. When the temperature 35
reached about 60° C., the reaction mixture became exother (i). Side Products
mic and the temperature rose to 84 C. The reaction mixture
was cooled to 80° C. and held at 80° C. for 2 hours. HPLC Table 1 lists the side products found in various acetylation
analysis of reaction mixture at this point showed 90.69% experiments. Small amounts of unreacted norephedrine and
O-acetyln ore phe drine and 6.88% O, N 40 O,N-diacetylnorephedrine, were found as Side products in
diacetylnorephedrine. The reaction mixture was stirred over the isolated products. The Signal for amphetamine in experi
night at ambient temperature and then diluted with 20 mL ment L. may be an artifact.
ethanol. The resulting solution was transferred to a Parr
bottle, which was purged with nitrogen gas and about 1 g of (ii). Crystallization Solvent
10% palladium-carbon catalyst (50% water) was added. The 45
Parr bottle was installed on a Parr shaker apparatus and To increase the rate of crystallization of the
inerted with nitrogen. The Parr bottle was then pressurized O-acetylnorephedrine hydrochloride Salt and aid in remov
with hydrogen to 45 psi and then shaken under hydrogen ing acetic acid and any exceSS acetic anhydride that may be
preSSure at ambient temperature. In 10 minutes a 3 psi present, the reaction mixture was treated with heptane
pressure drop was observed. The Parr bottle temperature 50
(Experiment I), methyl tert-butyl ether (Experiments F and
controller was set to 55° C. and the pressure increased from H), ethanol (Experiment G), isopropanol, methyl isobutyl
42 psi to 47 psi. The pressure changes over the next 5 to 6
hours were recorded. The heat was then turned off and the ketone, acetonitrile, ethyl acetate, tetrahydrofuran, or other
reaction mixture was allowed to cool to ambient tempera solvent in which the product has little solubility. The solid
ture. The final pressure was recorded and the Parr bottle was 55 product that formed was collected by filtration. Heptane is a
depressurized and purged with nitrogen gas. The mixture preferred Solvent, as the Solid produced was dense and did
was filtered to remove the catalyst and the filtrate was not appear to be Solvated as much as with other Solvents
analyzed and found to consist of 2.45% norephedrine, tried.
57.59% amphetamine, 20.71% O-acetylnorephedrine, 10%
N-acetyl ampheta mine, and 3.75% O, N 60 (iii). Rate of the Acetylation Reaction
diacetylnorephedrine. The calculated yield was 3.89 g (57%)
C. Further Examples of Acetylation of Norephedrine Hydro The rate of the acetylation reaction is demonstrated by the
chloride results of high performance liquid chromatography analyses
As illustrated above, O-acetylnorephedrine hydrochloride (HPLC) of a reaction at various time intervals (Experiment
can be prepared in good yield from norephedrine hydro 65 A). These results are given in Table 2 and show that the
chloride by heating with acetic anhydride (preferably 1.2 to reaction is almost complete within 20 minutes of the reac
2.0 equivalents) in acetic acid (preferably 1 to 2 mL/g of tion mixture becoming clear.
US 6,399,828 B1
12
ammonium formate Solution was added in 2 mL increments
TABLE 2 to the reaction mixture at 5 minute intervals. When evolution
O-Acetylation of (t)-Norephedrine Hydrochloride of gas began to Subside, the remainder of ammonium
formate Solution was added dropwise and the reaction
Time mixture Stirred in the water bath for approximately 1 hour.
(minutes) % NE % N-AcNE % O-AcNE % O,N-diAcNE The water bath temperature controller was then turned off
O: 21.14 71.68 4.79 and the reaction mixture was allowed to cool to ambient
2O 3.48 89.53 5.49 temperature while Stirring overnight. The cooled reaction
40 <2 91.91 6.11
90 <1 90.92 6.47
mixture was then filtered to remove the catalyst and the
12O <1 90.80 6.30 filtrate was treated with 26 mL (0.50 mol) of 50% sodium
hydroxide solution. The basified reaction mixture was then
*zero time: point at which the heated reaction mixture was observed to transferred to a separatory funnel and allowed to Stand for
become clear
0.5 hour. The bottom aqueous layer was separated from the
(iv). Chemical Reactivities of Norephedrine Free Base 15 top oily layer and the oily layer was recovered (40.83 g). The
and Salts oil was analyzed and the analysis had the following results:
The commercially available precursor to dextroamphet GLC weight-% assay: 60.18% amphetamine; Karl Fischer
amine is 1R,2S-(-)-norephedrine. Attempts were made to titration: 23.15% water; HPLC analysis: 79.03%
O-acetylate the norephedrine free base, but produced mostly amphetamine, 14.6% N-acetylnorephedrine, 5.49%
N-acetylamphetamine according to an analysis of the car
bonyl region of the infrared Spectra. In one experiment, N-acetylamphetamine, and 0.76% norephedrine; calculated
norephedrine free base in acetic acid was treated with 0.5 yield: 24.6 g amphetamine (88.8%).
equivalents of Sulfuric acid and then treated with 1.1 equiva E. Catalytic Hydrogenation of O-Acetylnorephedrine
lents of acetic anhydride with heating to 63 C. to obtain a Hydrochloride
clear solution. Catalytic reduction followed by basification 25
OAc
gave an oil that was composed of 13.96% amphetamine and
68% norephedrine, an indication that the acetylation proce NH2
dure on a Sulfate Salt was only partially Successful. In Pd/C, H2
another experiment, a 10 mol portion of norephedrine OCI
hydrochloride was acetylated with a 20% excess of acetic
anhydride in 2 mL acetic acid/g of Salt and progreSS of the
reaction followed fours (Table 2). The reaction mixture was
diluted with 130 mL water and subjected to catalytic hydro
genation for 22 hours to obtain 10.4 g of oil. The long 35
reaction time is attributed to the presence of acetic acid in
the reduction mixture. Yield of amphetamine from norephe A Parr bottle was charged with O-acetylnorephedrine
drine hydrochloride based on the weight of product and hydrochloride (11.43 g) and 75 mL of water. The Parr bottle
HPLC analysis is 66% (Experiments A and B). For these was flushed with nitrogen and the catalyst added. The bottle
experiments, it can be seen that the best results were 40 was then Shaken on a Parr apparatus with an initial preSSure
obtained with the Salts of phenylpropylamine or of 55 psi. After 2 hours, the pressure drop was 4 psi (on
norephedrine, particularly the hydrochloride Salt. tank). The Parr bottle was shaken for another hour to ensure
D. Catalytic Transfer Hydroge nation of completion of hydrogenolysis and then depressurized and
O-Acetylnorephedrine flushed with nitrogen. The contents of the Parr bottle was
45
then filtered to remove the catalyst and the filtrate was
OAc basified with 15 mL of 50% sodium hydroxide solution and
NH2 the mixture was allowed to stand overnight. The mixture
HCOONH4, H2O
He
was then transferred to a separatory funnel to Separate the
OCI PdAC 50 bottom aqueous layer from the top oily layer, the oily layer
was recovered (7.00 g). The oil was analyzed and the
NH2 analysis had the following results: GLC weight-% assay:
63.02% amphetamine; HPLC analysis: 87.22%
amphetamine, 10.8% N-acetylnorephedrine, 0.37%
55 N-acetylamphetamine; Karl Fischer analysis: 23.699%
water; calculated yield: 4.41 g amphetamine (65.33%).
A 500 mL 3-necked round bottom flask equipped with F. Further Examples of the Reduction of
Stirrer, addition funnel, condenser, and thermocontroller was O-Acetylnorephedrine Hydrochloride to Amphetamine
charged with O-acetylnorephedrine hydrochloride (47.0 g, 60
Reduction of O-acetylnorephedrine hydrochloride to
0.205 mol), 131 mL of water, and 1.0 g of 10% palladium amphetamine is accomplished by either catalytic hydroge
on carbon (50% water) catalyst. A solution of ammonium nation or catalytic transfer hydrogenation. Catalytic hydro
formate (HCOONH; 15.50 g, 0.246 mol) in 20 mL water genation can be achieved in about four hours at room
was then prepared. The reaction mixture in the 3-necked temperature in water using 10% palladium on carbon cata
round bottom flask was then heated in a water bath tem 65 lyst (50% wet with water) at 50-55 psi hydrogen pressure on
perature controlled to 71 C. When the reaction mixture a Parr Shaker. Using this method, most of the hydrogen
temperature reached 68 C., approximately 6 mL of the uptake occurs within 2 hours. Catalytic transfer hydrogena
US 6,399,828 B1
13 14
tion using ammonium formate and 10% palladium on carbon and thus may require a larger Volume of Solvent for hydro
(50% wet with water) in water is complete in 20–30 minutes genation to proceed readily (Experiment BB). If either acetic
from initiation of the reaction if the ammonium formate acid or ethanol is used, an extra Step in the work-up to
Solution is added in one portion. remove the organic Solvent is necessary. This makes water
1. Catalytic Hydrogenation 5 an excellent Solvent for the catalytic reduction as the Volume
Results of laboratory hydrogenation Experiments are is not excessive, it is not flammable, and it is inexpensive.
shown in Tables 3 and 4. In Table 4, the weight-% amphet Rigorous purging of the hydrogenation vessel with an inert
amine was determined by GLC and the 96 composition was gas before charging the palladium catalyst is not required
determined by HPLC. 1O with water, as it would be with a flammable solvent. The
TABLE 3
amphetamine obtained from Experiments T, V, and Y was
Separated from the aqueous Solution after basification rather
Reaction Conditions used in the Catalytic Hydrogenation of O than extracting with a Solvent. The crude amphetamine was
Acetylnorephedrine Hydrochloride shown by Karl Fischer water analysis to contain 23–24%
15
Experi- Time Crude yield water. This accounts for yields greater than 100% and lower
ment g (mol) Solvent (mL) mL/g (hours) g (%) weight-% amphetamine values.
AA 10.04 (0.044) HO (100) 4.96 3.75 6.9 (>100%) 2. Catalytic Transfer Hydrogenation
BB 6.00 (0.026) HO (50) 25 1.5 3.44 (98)
EtOH (100) For catalytic transfer hydrogenation, a mixture of
CC 11.48 (0.05) HO (100) 8.7 4.5 2O O-acetylnorephedrine hydrochloride, water, and 10% palla
B 22.95 (0.10)** HO (114) 6.54 23 10.4 (77)
HOAc (36) dium on carbon (50% wet with water) can be treated with 1.2
N 11.48 (0.050) HO (50) 4.36 4 equivalents of ammonium formate and heated until an
5.18(76.7)
T 22.95 (0.10) HO (70) 3.05 22.5 13.65 (>100)
exothermic reaction accompanied by evolution of gas
V 11.45 (0.050) HO (75) 6.55 2. 7.00 (>100)
Y 22.95 (0.10) HO (137) 5.97 2 + 2* 14.66 (>100) 25 occurs. The reaction is completed when the evolution of gas
Subsides. Results of Experiments using catalytic transfer
* Reduction judged to be >95% complete in 2 hours but given another 2 hydrogenation are shown in Table 5. These reactions were
hours on Parr apparatus to make sure hydrogen uptake was complete.
**From Experiment A done at temperatures between 60 C-80 C. except for the
higher temperature attained in the exotherm.
TABLE 4
Analysis of Catalytic Hydrogenation Products
% Yield Wt 2% % % % % %
Experiment (crude) Amp O-AcNE Amp N-AcNE NE N-AcAmp diAcNE
B 773. 75.23 86.3 6.7 1.3 2.7 2.67
N 76.7 83.07 82.7 15.73 O.8 O.21
T 101 68.86 91.16 4.65 O.26 2.55
V 104 63.02 87.72 10.8 O.O7 O.37
Y 109 73.12 O.32 93.92 4.79 O.63 O.24
Wt (7% % % % % % % O.N-
Experiment Yield Amp O-AcNE Amp N-AcNE NE N-AcAmp diAcNE
DD 81.9 57.40
67.O 81.8O 86.23 9.57 1.9
73.4 92.18 91.75 4.76 1.05 1.87
45.9 - 96.16 2.64 O.43 0.59
83.6 - 90.19 7.91 O.63 O.84
89.3 71.52 88.86 7.87 O.92 1.97
90.4 7.O.O 81:19 13.84 O.43 4.22
1. 47.O 60.18 79.03 14.60 O.76 5.49
US 6,399,828 B1
15 16
The quantities of reactants for the catalytic transfer hydro ammonium formate added. Samples were taken at intervals
genation reactions presented in Table 5 are shown in Table 6. for HPLC analyses. At room temperature, the percentage of
TABLE 6
Reactant Quantities in Catalytic Transfer Hydrogenolysis
Grams o Crude
Ammonium Yield
Experiment O-AcNE.HCl Solvent Formate (mol) (% yield) % Amp.
DD 4.98 g 100 mL methanol 4.98 g 2.4 g 57.4 Area-%
(0.0217 mol) (0.08 mol) (81.9%)
M 4.98 g 10 mL water (AF) 5.03 g 1.97g 86.2 Area-%
(0.0217 mol) 10 mL MeOH (0.08 mol) (67%)
(OACNE)
O 5.74 g 20 mL water 3.15g 2.48 g 92.18 Wt-%
(0.025 mol) (OAcNE) (0.05 mol) (73.4%)
10 mL water (AF)
P 5.74 g 20 mL watcr 2.36 g 1.55g 96.16Area-%
(0.025 mol) (OAcNE) (0.0375 mol) (45.9%)
10 mL water (AF)
O 5.74 g 20 mL water 1.58 g 2.82 g 90.2 Area-%
(0.025 mol) (OAcNE) (0.025 mol) (83.6%)
10 mL water (AF)
R 11.48g 33 mL water 3.78 g 6.03 g 71.5 Witez, * *
(0.05 mol) (OAcNE) (0.06 mol) (89.3%)
20 mL water (AF)
S 22.95 g 69 mL water 7.56 g 12.2g 7O.O Witez, * *
(0.10 mol) (OAcNE) (0.12 mol) (90.4%)
10 mL water (AF)
U 47.0 g 131 mLwater 15.50 g 40.87 g 60.18 Wt2%**
(0.205 mol) (OAcNE) (0.246 mol) (147%)
20 mL water (AF)
*2 volumes of solvent shown where ammonium formate (AF) solution is added to OAcNE.HCl
solution separately
**amphetamine layer was separated without extraction into ether after basification
When a large excess of ammonium formate is used, a white O-acetylnorephedrine hydrochloride decreased from 99.30
Solid Sublimes into the condenser. Sublimation was not 35
to 99.12% over a period of 6 hours and the percentage of
observed with only a 10-20% excess of ammonium formate. N-acetylnorephedrine increased from 0.10% to 0.21%. At
A 10-20% excess of ammonium formate appears to be 60° C., the percentage of O-acetylnorephedrine hydrochlo
Sufficient for complete reaction. The exotherm and evolution
of gas were also seen at about 52 C. in Experiment DD that ride decreased from 99.18 to 97.79 with the percentage of
was conducted in methanol. 40 N-acetylnorephedrine increasing from 0.21% to 1.1% over a
3. Comparison of Hydrogenolysis Reactions 6 hour period. With the ammonium formate mixture at 60
In both types of the hydrogenolysis reactions, workup, C., the percentage of O-acetylnorephedrine hydrochloride
with one exception, consists of filtering the reaction mixture dropped to 91.23% within 30 minutes and to 77.20% by 6
to remove the palladium on carbon catalyst, basifying the 45 hours while the amount of N-acetylnorephedrine increased
filtrate to pH 14, Separation of the aqueous layer from the
amphetamine layer, and distillation of the amphetamine. from 7.51% to 20.95%. The catalytic hydrogenation route
That exception was Experiment DD where the filtered therefore appears to be preferable to catalytic transfer hydro
reaction mixture was concentrated and the residue taken up genation in View of the induction period, gas evolution, and
in water and basified. The two types of hydrogenolysis 50 rearrangement potential.
reactions are comparable in efficiency, with the catalytic
transfer hydrogenation being the faster. However, there is a
question of Safety as there is an induction period with the The amphetamine obtained from several of the hydro
catalytic transfer hydrogenation reaction accompanied by genolysis reactions of both types was analyzed by HPLC
considerable evolution of gas when the reaction begins. The 55 and/or GLC and the results Summarized in Table 7. The
reaction can be partially controlled by initial addition of only products of Experiments Experiment P and Experiment Q
about 25% of the ammonium formate as an aqueous Solution were obtained by extraction into ether and drying of the
and heating the mixture until the reaction begins. The extract to remove any water. The product obtained in Experi
remainder of the ammonium formate Solution can then be
added at a Suitable rate. 60 ments R, S, and U were shown by Karl Fischer analyses to
Ammonium formate appears to catalyze the rearrange contain water and is compensated for in the Weight-%
ment of O-acetylnore phe drine hydrochloride to amphetamine analyses. The percent yield of amphetamine is
N-acetyln ore phe drine. Three samples of calculated from the actual weight of the product isolated and
O-acetylnorephedrine hydrochloride (Experiment Z 65 the percentage of amphetamine in the product as determined
recrystallized) were stirred with water for six hours respec by GLC or HPLC weight-% analyses. The composition of
tively at room temperature, at 60° C., and at 60° C. with the product is the area-% analysis.
US 6,399,828 B1
17 18
from a phenylpropanolamine Salt of formula II
TABLE 7
II
Crude and Actual Yields of OH
Amphetamine from Both Reduction Methods R2
e NHR
Reaction Crude e
Experiment
Size
(mol)
Yield
(g)
Wt. 2%
Amp.
Calc. Yield
Amp. (g)
2% Yield
Amp. C OX
B1. O.10 10.4 75.23 7.82 58.0
Sás
R2
N1 O.OS 6.75 83.7 4.34 64.2
T1 O.10 13.65 68.86 9.35 69.6
V1 O.OS 7.00 63.02 4.41 66.1 through the intermediate compound of formula III
Y1 O.10 14.66 73.32 10.7O 79.3
M2 O.O22 1.97 81.8 1.61 55.0 III
O2 O.O25 2.48 81.8 1.61 55.0 OCOR
P2 O.O25 1.55% 96.16 1.44 42.8 15
Q? O.10 2.82% 90.2 2.54 75.4 R2
e NHR
R2 O.OS 6.03 71.52 4.31 63.9 e
S2
U2
O.10
O.205
12.2
40.83
7O.O
60.18
8.54
24.57
6.3.3
88.8 C OX
'catalytic hydrogenation
Sás
R2
°catalytic transfer hydrogenation
*product obtained in these reactions by extraction into ether and drying wherein:
extract
R is hydrogen or a lower alkyl group;
Instead of having wt % amphetamine data, area % of each R is independently a hydrogen, halogen, lower alkyl
amphetamine in product mixture was used to calculate 25 group, lower alkoxy groups, lower alkyl group Substi
expected yield of amphetamine. In other reactions, the tuted with 1 to 5 halogens, lower alkoxy groups Sub
product obtained was not dry. stituted with 1 to 5 halogens, or both R together when
on adjacent carbons constitute a -O(CH2).O- where
All publications, patent applications, patents, and other X is 1 to 4, thereby forming a ring structure fused with
references mentioned herein are incorporated by reference in the phenyl group;
their entirety. Furthermore, unless otherwise defined, all R is a C-C-alkyl group, a C-C-aralkyl group,
technical and Scientific terms used herein have the same
C-C2-alkaryl group, or a phenyl group, each option
ally substituted by 1 to 5 substituents selected from
meaning as commonly understood by one of ordinary skill halogen, hydroxy, or C-C-alkyl, and
in the art to which this invention belongs. 35
HX is an equivalent of an organic or inorganic acid,
AS required, the above description includes the best mode the proceSS comprising:
presently contemplated for carrying out the invention. It will (a) acylating the phenylpropanolamine Salt of formula II
be noted that the invention has been described with refer with an acylating agent in a Solvent at elevated tem
ence to numerous Specific embodiments and examples, it is perature to make a reaction mixture containing an
O-acylated phenylpropanolamine Salt of formula III
emphasized that these embodiments and examples are not to 40
which can be isolated by the addition of a crystalliza
be construed as limiting the invention but are made merely tion Solvent, or optionally this mixture can be used in
for the purpose of describing the general principles of the the next Step; and
invention and illustrating the invention. Therefore, although (b) hydrogenating the O-acylated phenylpropanolamine
Suitable methods, apparatus, and materials for the practice or 45 Salt to make the compound of formula I in the presence
testing of the present invention are described above, other of a catalyst.
Suitable methods, apparatus, and materials similar or equiva 2. The process of claim 1, wherein the acylating agent is
lent to those described herein, which are well known in the Selected from the group consisting of acetic anhydride,
art or will hereinafter be developed, can also be used without acetyl chloride, propionic anhydride, propionyl chloride,
departing from the Spirit or Scope of the invention. AS these 50 butyric anhydride, and butyryl chloride.
various equivalents and Substitutions will be recognized by 3. The process of claim 1, wherein the acylating agent is
those of ordinary skill in the art in View of the foregoing a compound of formula RC(O)x, wherein:
disclosure, they are contemplated to be within the Scope of X is a halogen; and
Ra is a C-Cs-alkyl group, a C-C2-aralkyl group,
the present invention as defined by the appended claims. The 55 C-C2-alkaryl group, or a phenyl group, each option
appended claims Solely define the Scope of the invention. ally substituted by 1 to 5 substituents selected from
We claim: halogen, hydroxy, or C-C-alkyl.
1. A process for making compound of formula I 4. The process of claim 3, wherein R is a methyl group.
5. The process of claim 1, wherein the acylating agent is
60 a compound of formula RC(O)O(O)CR, wherein:
R
NHR R and R are independently a C-C-alkyl group, a
C-C2-aralkyl group, C-C2-alkaryl group, or a phe
nyl group, each optionally Substituted by 1 to 5 Sub
Stituents Selected from halogen, hydroxy, or C-C-
^ 65 alkyl.
6. The process of claim 5, wherein R and Rare methyl
groupS.
US 6,399,828 B1
19 20
7. The process of claim 1, wherein HX is selected from the 32. The process of claim 26, wherein the hydrogenation
group consisting of hydrofluoric acid, hydrochloric acid, agent is Selected from the group consisting of ammonium
hydrobromic acid, hydroiodic acid, Sulfuric acid, phosphoric formate, formic acid, ammonium or metal Salts of hypo
acid, nitric acid, formic acid, acetic acid, propionic acid, phosphite.
benzoic acid, tartaric acid, Succinic acid, oxalic acid, aspar 33. The process of claim 1, wherein the acetylated phe
tic acid, Saccharic acid, and malic acid. nylpropanolamine Salt obtained from Step (a) is isolated
8. The process of claim 1, wherein HX is a carboxylic before step (b) is performed.
acid, dicarboxylic acid, or tricarboxylic acid. 34. The process of claim 33, wherein the acylated phe
9. The process of claim 1, wherein the compound of nylpropanolamine Salt obtained from Step (a) is isolated by
formula I is amphetamine. adding a crystallization Solvent to the reaction mixture
10. The process of claim 9, wherein the amphetamine is containing the acylated phenylpropanolamine Salt.
d.1-amphetamine.
11. The process of claim 9, wherein the amphetamine is 35. The process of claim 34, wherein the crystallization
S-(+)-amphetamine. Solvent is Selected from the group consisting of pentane,
12. The process of claim 9, wherein the amphetamine is hexane, heptane, octane, methyl tert-butyl ether, methyl
R-(-)-amphetamine. 15 isobutyl ketone, ethanol, propanol, isopropanol, butanol, and
13. The process of claim 1, wherein the compound of mixtures thereof.
formula I is methamphetamine. 36. The process of claim 35, wherein the crystallization
14. The process of claim 13, wherein the methamphet Solvent is heptane.
amine is S-(+)-methamphetamine. 37. The process of claim 1, wherein the acylated phenyl
15. The process of claim 13, wherein the methamphet propanolamine Salt obtained from Step (a) is not isolated
amine is R-(-)-methamphetamine. before step (b) is performed.
16. The process of claim 1, wherein acetic acid, propionic 38. The process of claim 1, wherein the carbon bearing the
acid, or butyric acid is added to the phenylpropanolamine amino group in the phenylpropanolamine Salt has the race
Salt as Solvent before or at the same time as the acylating mic configuration.
agent. 25 39. The process of claim 1, wherein the carbon bearing the
17. The process of claim 1, wherein the hydrogenation amino group in the phenylpropanolamine Salt has the S
Step (b) is performed using catalytic hydrogenation. configuration.
18. The process of claim 17, wherein the catalytic hydro 40. The process of claim 1, wherein the phenylpropano
genation is performed using a precious metal catalyst. lamine Salt is Selected from the group consisting of 1R,2S
19. The process of claim 18, wherein the precious metal (-)-norephedrine, 1S,2S-(+)-norpseudoephedrine, 1R,2S
catalyst is Selected from the group consisting of platinum, (-)-ephedrine, and 1S,2S-(+)-pseudoephedrine.
palladium, ruthenium, osmium, iridium, rhodium, and mix 41. The process of claim 1, wherein the compound of
tures thereof.
20. The process of claim 19, wherein the precious metal formula I is S-(+)-methamphetamine and the phenylpro
catalyst is in the form of a finely divided or high Surface area panolamine Salt is Selected from the group consisting of:
metal or alloy. 35 1R,2S-(-)-ephedrine and 1S,2S-(+)-pseudoephedrine.
21. The process of claim 19, wherein the precious metal 42. The process of claim 1, wherein the amount of
catalyst is obtained by converting a precursor compound acylating agent used is between about 1.0 equivalents and
into the active catalyst before or during hydrogenation. 3.0 equivalents based on the amount of phenylpropanola
22. The process of claim 19, wherein the precious metal mine Salt.
catalyst is distributed on an inorganic Support. 40 43. The process of claim 42, wherein the amount of
23. The process of claim 20, wherein the inorganic acylating agent used is between about 1.1 equivalents and
Support is Selected from the group consisting of carbon, 2.5 equivalents based on the amount of phenylpropanola
activated carbon, metal oxides, metal carbonates, and metal mine Salt.
Sulfates. 44. The process of claim 43, wherein the amount of
24. The process of claim 18, wherein the precious metal 45 acylating agent used is between about 1.1 equivalents and
catalyst is palladium on carbon. 2.0 equivalents based on the amount of phenylpropanola
25. The process of claim 1, wherein the hydrogenation mine Salt.
Step (b) is performed using catalytic transfer hydrogenation 45. The process of claim 44, wherein the amount of
with a hydrogenation agent. acylating agent used is between about 1.2 equivalents and
26. The process of claim 25, wherein the catalytic transfer 50 1.5 equivalents based on the amount of phenylpropanola
hydrogenation is performed using a precious metal catalyst. mine Salt.
27. The process of claim 26, wherein the precious metal 46. The process of claim 1, wherein the temperature of the
catalyst is Selected from the group consisting of platinum, reaction mixture of step (a) is between 50° C. and 100° C.
palladium, ruthenium, osmium, iridium, rhodium, and mix 47. The process of claim 46, wherein the temperature of
tures thereof. 55 the reaction mixture of step (a) is between 60° C. and 90° C.
28. The process of claim 27, wherein the precious metal 48. The process of claim 47, wherein the temperature of
catalyst is in the form of a finely divided or high Surface area the reaction mixture of step (a) is between 70° C. and 85°C.
metal or alloy. 49. The process of claim 1, wherein the phenylpropano
29. The process of claim 28, wherein the precious metal lamine Salt is made from phenylpropanolamine free base.
catalyst is obtained by converting a precursor compound 60 50. The process of claim 1, wherein the phenylpropano
into the active catalyst before or during hydrogenation. lamine Salt is a Salt of phenylpropylamine and an acid
30. The process of claim 27, wherein the precious metal Selected from the group consisting of hydrofluoric acid,
catalyst is palladium on carbon. hydrochloric acid, hydrobromic acid, hydroiodic acid, Sul
31. The process of claim 25, wherein the hydrogenation furic acid, phosphoric acid, nitric acid, formic acid, acetic
agent is Selected from the group consisting of ammonium 65 acid, propionic acid, benzoic acid, tartaric acid, Succinic
formate, formic acid, ammonium or metal Salts of hypo acid, Oxalic acid, malic acid, aspartic acid, and Saccharic
phosphite. acid.
US 6,399,828 B1
21 22
51. The process of claim 1, wherein the phenylpropano the proceSS comprising acylating the phenylpropanolamine
lamine Salt is a Salt of phenylpropylamine and an acid Salt with an acylating agent to make a reaction mixture
Selected from the group consisting of carboxylic acid, dicar containing the O-acylated phenylpropanolamine Salt.
boxylic acid, and tricarboxylic acid. 54. A process for making compound of formula I
52. The process of claim 1, wherein the phenylpropano
lamine Salt is a Salt of phenylpropylamine and hydrochloric
acid. R2
53. A process for making an O-acylated phenylpropano e
e NHR
lamine Salt of formula III useful in the manufacture of
amphetamines C OX
Sás
R2
III
OCOR
R2 from an O-acylated phenylpropanolamine Salt of formula III
NHR
e 15
C OX III
Sás
R2 R2
OCOR
2) NHR
e
e
e NHR 25 wherein:
C OX R is hydrogen or a lower alkyl group;
Sás
R2
each R is independently a hydrogen, halogen, lower alkyl
group, lower alkoxy groups, lower alkyl group Substi
tuted with 1 to 5 halogens, lower alkoxy groups Sub
wherein: stituted with 1 to 5 halogens, or both R together
R is hydrogen or a lower alkyl group; constitute a -O(CH)O- where X is 1 to 4, thereby
each R2 is independently a hydrogen, halogen, lower alkyl forming a ring Structure fused with the phenyl group;
group, lower alkoxy groups, lower alkyl group Substi Ra is a C-Cs-alkyl group, a C-C2-aralkyl group,
tuted with 1 to 5 halogens, lower alkoxy groups Sub 35 CC2-alkaryl group, or a phenyl group, each option
stituted with 1 to 5 halogens, or both R together ally substituted by 1 to 5 substituents selected from
constitute a -O(CH)O- where X is 1 to 4, thereby halogen, hydroxy, or C-C-alkyl, and
forming a ring Structure fused with the phenyl group;
Ra is a C-Cs-alkyl group, a C-C2-aralkyl group, HX is an equivalent of an organic or inorganic acid,
C-C2-alkaryl group, or a phenyl group, each option 40 the proceSS comprising: hydrogenating the O-acylated phe
ally substituted by 1 to 5 substituents selected from nylpropanolamine Salt to make the compound of formula I.
halogen, hydroxy, or C-C-alkyl, and
HX is an equivalent of an organic or inorganic acid,