Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF AMINOALCOHOLS"

Abstract The present invention relates to a process for opening of diverse epoxides by amines using zirconium compound as catalyst in the presence or absence of a solvent at an appropriate temperature to yield optically active or racemic 2-aminoalcohols, also the ratio of possible regioisomers formed by using unsymmetrical epoxide as substrate can be controlled by the selection of suitable catalyst, solvent and/or reaction temperature.
Full Text An improved process for the preparation of aminoalcohols
Field of present invention
The present invention relates to a process for opening of diverse epoxides by amine using a Zirconium compound as catalysts in the presence or absence of a solvent at an appropriate temperature to give 2-aminoalcohols. In case of unsymmetrical epoxides, the ratio of regioisomeric product obtained can be altered by an appropriate selection of zirconium (IV) compound as a catalyst, solvent and/or reaction temperature.
Background of the Invention
2-Aminoalcohols are well known in the art as a class of cardiovascular agents in the
treatment of hypertension e.g., propranolol. The most general method for the synthesis of
2-aminoalcohols involves reaction of epoxide and amine. The reaction is generally
carried out at high temperature, under high pressure or under the influence of a catalyst.
Various synthetic methods are known where epoxide-opening reaction by amines
constitutes a key step.
Most of the methodologies involve unsymmetrical epoxide i.e. different substitutions on
two carbons constituting the epoxide ring. The reaction leads to the formation of two
regioisomers. Nucleophilic opening of epoxide in regioselective fashion is a key issue in
these transformations. In the synthesis of propranolol, 1-naphthyl glycidyl ether is
reacted with 2-propyl amine.
Various processes are known for opening of epoxides by amines.
Opening of the epoxide ring takes place on heating the epoxide with amine at high
temperature.
Posner et al (J. Am. Chem. Soc. 1977, 99, 8208-8214) described an investigation for
epoxide opening with amines using alumina. Alumina works well with aliphatic amines.
However, large excess of reagent and alumina is required for completion of reaction and
hence the process is not useful for large-scale synthesis.
Crotti et al (Tet. Lett. 1990, 31, 4661-4664) described an investigation for epoxide
opening with amines using various salts such as lithium perchlorate, magnesium
perchlorate, lithium tetrafluoroborate etc. The report describes lithium perchlorate to be
the best candidate among these salts. With LiClO4, the reaction works for aliphatic,
^enzylic and aromatic amines. For reaction of benzylamine, using lithium perchlorate for
2 h, the ratio of compounds 3 and 4 (see figure 1) is 60:40. The major disadvantage of
this protocol is the use of stoichiometric amounts of lithium perchlorate. The strong
oxidizing properties and the potential explosion hazourds of perchlorates are also notable
drawbacks of this methodology.
Auge et al (Tet. Lett. 1996, 7715-7716) described an investigation using LiOTf (lithium
trifluoromethanesulphonate) for aminolysis of epoxides. The reaction of styrene oxide
with benzylamine carried out in acetonitrile for 3.5 h gave 83% yield with regioisomers
in the ratio of 60:40 selectivity. The use of large amounts (0.5 equivalent) of the costly
catalyst is considered to be the notable disadvantage for industrial applications.
Singh et al (J. Org. Chem. 1999, 64, 287-289) described an investigation using Cu(OTf)2
and Sn(OTf)2. However, the process describes reactions with symmetrical except 1-
dodecene oxide and the issue of regioselectivity remains unanswered. Requirement of
extended reaction time (20 h) and the use of costly and water sensitive catalysts do not
make this invention attractive for industrial applications.
Akamanchi et al (Synthesis 2000, 78-80) described a method using DIPAT
(diisopropoxyaluminium trifluoroacetate) in which compound 4 was formed as the only
product at room temperature in 1.5 h. However, DIPAT was used in stoichiometric
amounts, it is moisture sensitive and its preparation involves tedious steps.
Chandrasekar et al (Synthesis 2000, 1817-1818) described an investigation using TaCls.
The reaction was reported for symmetrical epoxides. The reaction time is not mentioned.
Ramarao et al (Synthesis 2001, 831-832) described an investigation using CeC^. The
reaction is carried out for 12 h with 30-mol% of the catalyst. In the reaction of styrene
oxide with aniline, compound 6 (see figure 2) was obtained in 76% yield but the amount
of compound 5 formed is not reported. However, the catalyst works only in case of
aromatic amines.
The zirconium catalysts have been used for epoxide opening reaction with other
nucleophiles are described as under.
Whittaker et al (J. Chem. Soc. Chem. Comm. 1993, 1427-1428) had earlier described a
process where crystalline polymeric zirconium phosphate was used as heterogeneous
catalyst for epoxide opening reaction using methanol and acetic acid.
Curini et al (Eur. J. Org. Chem. 2001, 4149-4152) described a process where zirconium
sulfophenyl phosphate is used as heterogeneous catalyst for the synthesis of P-amino
cohols from epoxides. The reaction of styrene oxide and aniline carried out at 40°C for 24 h gives 83% yields of the mixture of products 5 and 6 in the percentage ratio of 88:12. Nugent et al (J. Org. Chem. 1998, 6656-6666) describes a process where the complex [(L*)Zr]2(OH)(02CCF3) in which L* = (+)-(S,S,S) -triisopropanolamine was used for the diastereoselective epoxide opening reaction with trialkylsilyl azide to give 2-azidoalkanol trialkylsilyl ether.
Shibasaki et al (J. Am. Chem. Soc. 2000, 1245-1246) described a process in which Zr iPro 4 was used for synthesis of (3-acetoxy alcohols from olefins in presence of bis(trimethylsilyl) peroxide (BTSP) and trimethylsilylacetate. The reaction involves formation of epoxide followed by opening of the epoxide ring. The protocol was extended by Shibasaki et al (J. Am. Chem. Soc. 2001, 1256-1257) for synthesis of p-cyano alcohols from olefins using BTSP and trimethylsilylcyanide. The reaction was found to be sluggish and required the use of triphenylphosphine oxide to increase the rate of the reaction.
Thus, the epoxide opening reaction with amine as nucleophile using any zirconium compound as catalyst described in this invention is not known in the prior art. The epoxide opening reaction, when carried out in the presence of strong acids, bases or alkoxides results in less yield of the desired product. In these cases, the major reaction is polymerization, rearrangement, nucloephilic opening etc. leading to undesired by-products. The various byproducts could be characterized as alcohol, aldehyde or ketone and 1,2-diols. Polymerization can occur when the un-reacted epoxide gets activated due to presence of promoter or catalyst and undergoes reaction with another epoxide molecule. Due to the presence of these byproducts, the isolation of the desired product becomes a tedious job.
In order to obviate all the drawbacks existing with the prior art processes, it is necessary to develop an efficient process for the preparation of 2-aminoalcohols. This has been achieved in the present invention by reacting, an epoxide with amine as a nucleophile using Zirconium compound as a catalyst in the absence or presence of a solvent, preferable at an appropriate temperature.
Thus, the epoxide opening reaction with amine as a nucleophile using any zirconium compound as catalyst as described in the present invention is not reported earlier.
that is needed is an efficient and improved procedure for nucleophillic ring opening 01 diversely functionalised epoxides which gives higher yield, reduces formation of alcohol and/or carbonyl compound that are side products obtained from rearrangement of epoxide, and in case of unsymmetrical epoxides, used as a substrate, the choice of reaction parameters such as solvent, catalyst and/or reaction temperature can be altered for obtaining regioselectivity of the required product.
Object of the Invention
An objective of the invention is to provide an improved process for epoxide opening reaction by amines in the presence of various zirconium (IV) compounds as a catalyst. Another object of the present invention provides the use of unsymmetrical epoxides where the ratio of regioisomers of the product can be controlled by the selection of zirconium compounds used as a catalyst, solvent and/or reaction temperature. Yet, another objective of the invention provides the use of various solvents to control the ratio of regioisomers in the product.
Yet another object of the present invention provides the use of a solvent for carrying out the reaction is selected from a group consisting of chlorinated solvents such as methylene chloride chloroform and 1,2-dichloroethane aprotic polar solvents such as acetonitrile aromatic solvents such as benzene, toluene, xylene and ethereal solvents such as diethyl ether, diisopropylether and tetrahydrofuran (THF).
Still another objective of the invention provides temperature in the range of 0°C to 150°C to perform the reaction.
Still yet another objective of the present invention uses an epoxide is mono-substituted epoxide, a di-substituted epoxide, a tri-substituted epoxide., or a tetra-substituted epoxide.
Another objective of the invention provides use of a catalyst in the concentration range of 0.01 to 1.0-mol % of overall concentration.
SUMMARY OF THE INVENTION
The present invention describes a process for the preparation of 2-aminoalcohol by the reaction of an epoxide, an amine using Zirconium compound as a catalyst in the presence or absence of a solvent at an appropriate temperature under inert atmosphere.
The invention is related to a process that does not lead to any of the above-mentioned byproducts.
In case of the unsymmetrical epoxides, the two carbon centers constituting the epoxide ring can lead to two isomers. The invention is related to the use of the catalyst and reaction conditions that can alter the ratio of these regioisomers. More particularly there are three aspects of controlling the ratio of regioisomers
1. Catalyst;
2. Solvent; and
3. Reaction temperature
DETAILED DESCRIPTION OF THE INVENTION
A process for the preparation of an optically active or racemic 2-aminoalcohols (formula
wherein, R] R2 R3 and R4 is independently defined as H, unsubstituted alkyl, alkylaryl, aryl or hetroaryl group, and R5 is defined as H, unsubstituted alkyl, alkylaryl, aryl or hetroaryl group; the said process comprising steps of:
a) adding Zirconium (IV) compound catalyst to an epoxide in the presence or absence of a solvent,
b) adding an amine to step (a) mixture in an inert atmosphere,
c) stirring the mixture of step (b) at a temperature ranging between 0° to 150°C for a time period of 15 minutes to 12 hours, and
d) isolating the required product 2-aminoalcohol from step (c) reaction mixture by conventional methods.
An embodiment of the present invention provides the use of symmetrically or
unsymmetrically substituted epoxides.
Another embodiment of the present invention provides the use of monosubstituted
epoxides.
Yet another embodiment of the present invention provides the use of di-substituted
epoxides.
^till another embodiment of the present invention provides the use of tri-substituted epoxides.
Yet another embodiment of the present invention provides the use of tetrasubstituted epoxides.
In yet another embodiment of the present invention, the Zirconium (IV) catalyst used may be an organo or inorgano zirconium (IV) compound.
Still another embodiment of the present invention, the Zirconium (IV) compounds used is represented by the formula Zr(IV)X.
Yet another embodiment of the present invention, X is represented by a group F4, CI4, Br4,14, 0(C104)2, Si04, (CH3COCH2COCH3)4 and OCl2.
Another embodiment of the present invention, wherein the catalyst used is ZrCl4. Still another embodiment of the present invention provides a solvent selected from a group consisting of chlorinated solvent such as methylene chloride, chloroform and 1,2-dichloroethane, aprotic polar solvent such as acetontrile, aromatic hydrocarbon solvent such as benzene, toluene, xylene and etheral solvent such as diethyl ether, diisopropylether and tetrahydrofuran (THF).
Yet another embodiment of the present invention, the amine used may be ammonia substituted or unsubstituted alkyl amine, aromatic amine, alkylaryl amine or hetroarylamine
Still another embodiment of the present invention, the substitution on the alphatic amine used is selected from fluoro chloro, bromo, iodo, cyano, nitro, amino, alkoxy, akjtk sulphonic or mixtures thereof.
Yet another embodiment of the present invention, the substitution on the alkyl aryl amine used is selected from fluoro chloro, bromo, iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or mixtures thereof.
Still another embodiment of the present invention, the substitution on the aryl amine used is selected from fluoro chloro, bromo, iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or mixtures thereof.
Yet another embodiment of the present invention, the substitution on the hetro aryl amine used is selected from fluoro, chloro, bromo, iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or mixtures thereof.
Yet in another embodiment of the present invention, provide an inert atmosphere for the reaction by flushing dry nitrogen gas.
Still another embodiment of the present invention, the concentration of the catalyst used is in the range of 0.01 to 1.0-mol % of overall concentration.
One more embodiment of the present invention provides the addition of reactants in any sequence to perform the reaction.
Yet another embodiment of the present invention provides a reaction temperature in the range of 0 to 150°C.
In another embodiment of the present invention, the preferred reaction temperature is in the range of0° to 110° C.
Yet in another embodiment of the present invention, the use of unsymmetrical epoxide provides a mixture of regioisomeric products.
Still in another embodiment of the present invention, the ratio of regioisomers formed is controlled by the selection of catalyst, catalyst concentration, solvent and/or reaction temperature.
Another embodiment of the present invention provides an improved process for the preparation of optically active or racemic 3-substituted-l-amino-propane-2-ol. Yet another embodiment of the present invention, provides an improved process for the preparation of optically active or recemic 3-aryloxy-l-alkylamino-propane-2-ol as (3 adrenergic blockers such as propranolol and atenolol
Yet another embodiment of the present invention provides an improved process for the preparation of optically active or recemic 3-heteroaryloxy-l-alkylamino-propane-2-ol as P adrenergic blockers such as carvedilol.
Another embodiment of the present invention provides a process of a type wherein a reaction mixture formed by mixing an epoxide, an amine using Zirconium compound as a catalyst in the presence or absence of a solvent at an appropriate temperature under inert atmosphere to yield required 2-aminoalcohols.
DESCRIPTION OF FIGURES
Figure 1: represents the reaction of styrene oxide with benzylamine.
Figure 2: represents the reaction of styrene oxide with various amines.
Figure 3: represents various epoxides and the corresponding products arising from
the reaction with aniline.
Figure 4: represents methyl naphthyl glycidyl ether and the corresponding product,
propranolol, arising from the reaction with isopropylamine.
Brief description of examples
In examples cyclohexene oxide and aniline were used as substrates for the invention of
catalytic activity of zirconium (IV) compounds. The yield of 2-anilinocyclohexanol was
found to be excellent. The earlier mentioned by-products like the ketone or alcohol
related to cyclohexene oxide was not obtained. In case of entries 7-9, the starting
materials were recovered unreacted.
In example 2, the effect of equivalents of the catalyst is discussed. In example 3, the
reaction of cyclohexene oxide with various amines in the presence of ZrCl4 as the
catalyst is given.
In example 4 Styrene oxide is used as substrate to study the effect on regioselectivity.
various catalysts are used for the reaction of styrene oxide with aniline.
In example 5, various amines were used for the reaction with styrene oxide in the
presence of ZrCl4 as the catalyst to establish generality.
In example 6, the effect of reaction temperature on regioselectivity during the reaction of
styrene oxide with aniline in the presence of ZrCl4 has been discussed.
In example 7, various solvents have been used for the reaction of styrene oxide with
aniline in the presence of ZrCU.
In example 8, the reaction of other epoxides is carried out with aniline in the presence of
ZrCU (figure 3).
In example 9, the reaction of naphthyl glycidyl ether is performed with 2-propyl amine
(figure 4) in the presence of ZrCl4 and the reaction product is propranolol.
The invention is illustrated with following examples and should not be construed to limit
the scope of the present invention.
EXAMPLES
Example 1:
The reaction of cyclohexene oxide (1 equivalent) and aniline (1 equivalent) was carried out in an inert atmosphere in the presence of catalyst (0.1 equivalent) in the absence of solvent. The results are summarized in table 1.
(Table Removed)

'H NMR (CDC13, 8): 1.03-1.42 (m, 4H), 1.72-1.78 (m, 2H), 2.10-2.16 (me, 2H), 2.9 (m, 2H, D20 exchangeable), 3.11 (m, 1H), 3.33 (m, 1H), 6.7-7.2 (m, 5H) TR (neat, cm-1): 3354, 2931, 2858, 1067, 1601, 1500, 1448
Example 2:
The reaction of cyclohexene oxide (1 equivalent) and aniline (1 equivalent) was carried out in the presence of ZrCl4 in an inert atmosphere in the absence of solvent. The results are summerised in table 2.
(Table Removed)
IR and NMR are identical to those of compound obtained in the example 1.
Example 3:
The reaction of cyclohexene oxide (1 equivalent) and various amines (1 equivalent) was carried out in the presence of ZrCl4 (0.1 equivalent) in inert atmosphere in the absence of solvent for 15 min.
Entry AmineYield (%) of product
(Table Removed)
'H NMR (CDC13, 5): 0.94-1.06 (m, 1H), 1.23-1.42 (m, 3H), 1.67-1.75 (m, 2H), 2.07-2.12
(m, 2H), 2.23 (s, 3H), 3.01-3.10 (m, 1H), 3.26-3.34 (m, 1H), 6.62 (d,J= 7.7 Hz, 2H),
6.98 (d, J= 1.1 Hz, 2H)
IR(neat, cm"'): 3389, 2932, 2859, 1616, 1517, 1298, 1067,908,811
Entry 2:
'H NMR (CDCI3, 6): 1.03-1.07 (m, 1H), 1.26-1.42 (m, 3H), 1.71-1.78 (m, 2H), 2.06-
2.10 (m, 2H), 2.67 (bs, D20 exchangeable, 2H), 3.05-3.13 (m, 1H), 3.33-3.40 (m, 1H),
6.63-6.65 (d, J= 8.6 Hz, 2H), 7.10-7.13 (d, J= 8.6 Hz, 2H)
IR (neat, cm"1): 3386, 2931, 2858, 1511, 1242, 1035, 818
Entry 3:
'H NMR (CDCI3, 5): 1.02- 1.23 (m, 4H), 1.65-1.72 (m, 2H), 1.98 (m, 1H), 2.11- 2.16 (m,
1H), 2.34- 2.41 (m, 1H), 3.21-3.24 (m, 1H), 3.73 (d, J = 12.9 Hz, 1H), 4.00 (d, J = 12.9
Hz, 1H), 7.26- 7.35 (m, 5H)
IR (neat, cm"1): 3294, 3059, 2931, 2855, 1602, 1451, 1352, 1079, 910, 732
Entry 4:
1H NMR (CDCI3, 5): 1.24-1.30 (m, 4H), 1.61-2.12 (m, 8H), 2.44-2.69 (m, 2H), 2.83-2.92
(m, 2H), 3.28- 3.32 (m, 1H), 3.43- 3.50 (m, 1H)
IR (neat, cm"1): 3422, 2938, 1640, 1484, 1085, 738
Example 4:
Styrene oxide (1 equivalent) was treated with aniline (1 equivalent) in the presence of the catalyst (0.1 equivalent) at room temperature under nitrogen in absence of solvent for 15 min. The results are summerised below:
(Table Removed)

Ratio of 3a: 4a was determined on the basis of 1H NMR of the product without separation.
1HNMR(CDCI3): 8 3.6- 4.0 (m, 4H), 4.5 (m, 1H), 6.4- 7.5 (m, 10H) IR (neat): 3400, 3070, 1600, 1500, 760 cm"1
1H NMR (CDC13): δ 3.3 ( m, 2H), 4.60 (brs, 2H), 5.0 (m, 1H), 6.5 - 7.8 (m, 10H) IR (neat): 3360, 3010, 1600, 1500, 760 cm-1
Example 5:
Styrene oxide (1 equivalent) was treated with different amines (1 equivalent) in the presence of ZrCI4 (0.1 equivalent) at room temperature under nitrogen in the absence of solvent for 15 min. The results are summerised below.
(Table Removed)
Entry 1:
Compound 4b:
1H NMR (CDC13, δ): 2.18 (s,3H), 3.65-3.71 (dd, 7=7.4, 11.1 Hz, 1H), 3.85-3.90 (dd, 7=
4.2, 11.1 Hz, 1H), 4.42- 4.46 (dd, 7= 4.2, 7.4 Hz, 1H), 6.47 (d,J= 8.1 Hz, 2H), 6.90 (d, 7
= 8.1 Hz, 2H), 7.18-7.32 (m, 5H)
IR(Neat, cm-1): 3390, 3026, 2922, 2868, 1617, 1517, 1453, 1067
Entry 2
Compound 4 Q
1H NMR (CDC13, δ): 3.71- 3.77 (dd, J = 6.9, 10.8 Hz, 1H), 3.90- 3.95 (dd, 7= 4.1, 10.8
Hz, 1H), 4.41- 4.45 (dd, 7= 4.1, 6.9 Hz, 1H), 6.46 (d, 7= 8.8 Hz, 2H), 7.00 (d, 7= 8.8
Hz, 2H), 7.13-7.39 (m,5H)
IR(Neat, cm-1): 3396, 2931, 1600, 1496, 1314, 813, 701
Entry 3
Compound 4d:
1H NMR (CDC13, δ): 2.28 (s, 3H), 3.84- 3.90 (dd, 7= 7.2, 11.2 Hz, 1H), 3.96- 4.01 (dd,
7= 4.0, 11.1 Hz, 1H), 4.52- 4.56 (dd, 7= 4.1, 6.9 Hz, 1H), 6.43 (d, 7= 7.9 Hz, 1H), 6.67 (t,
7= 7.3 Hz, 1H), 6.94 (t, 7= 7.5 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 7.22- 7.35 (m, 5H)
IR(Neat, cm-1): 3303, 3059, 1603, 1509, 1447, 1314, 1053, 749
Entry 4
Compound 4e:
1H NMR (CDC13, δ): 3.75-3.81 (dd,7 =6.9, 11.1 Hz, 1H), 3.91- 3.96 (dd,7= 4.0, 11.1
Hz, 1H), 4.50- 4.54 (dd, 7= 4.4, 6.2 Hz, 1H), 6.42 (d, 7= 7.9 Hz, 1H), 6.58 (t, 7= 7.5 Hz,
1H), 6.93 (t, J= 7.2 Hz, 1H), 7.22- 7.46 (m, 6H)
IR (Neat, cm-1): 3404, 3065, 2993, 1593, 1508, 1321, 1033, 787
Entry 5
Determined on the basis 1H NMR without separation as discussed by S. R. Anderson et
al (Jet. Asymmetry, 1999,10, 2655-2663)
3f
1H NMR (CDCI3, 5): 1.34- 1.59 (m, 2H), 1.59-1.88 (m, 4H), 2.20- 2.56 (m, 4H), 3.59 -
3.71 (m, 2H), 3.99 (t/lH, 9.98 Hz), 7.18- 7.60 (m, 5H).
'H NMR (CDCb, 5): 1.36- 1.58 (m, 2H), 1.59-1.93 (m, 4H), 2.18- 2.62 (m, 4H), 2.72
(bs, 2H), 4,75 (dd, 1H, J = 10.4, 3.5 Hz), 7.18- 7.60 (m, 5H).
Example 6:
Styrene oxide (1 equivalent) was treated with aniline (1 equivalent) in the presence of
ZrCl4 (0.1 equivalent) at different temperatures under nitrogen in the absence of solvent.
The results are summerised below.
(Table Removed)
The ratio of isomers was calculated on the basis of H NMR.
Example 7:
Styrene oxide (1 equivalent) was treated with aniline (1 equivalent) in presence of the ZrCl4 (0.1 equivalent) at room temperature under nitrogen in presence of various solvents for 30 min. The results are summerised below.
(Table Removed)
The ratio of isomers was calculated on the basis of lH NMR.
Example 8:
Epoxide (1 equivalent) was treated with aniline (1 equivalent) in the presence of ZrCl4
(0.1 equivalent) at room temperature under nitrogen in the absence of solvent for lh. The
(Table Removed)
'H NMR (CDC13, 5): 3.25- 3.35 (m, 1H), 3.41- 3.46 (m, 1H), 3.57- 3.64 (m, 1H), 3.96-
4.04 (m, 2H), 6.69- 6.78 (m, 2H), 6.86- 6.99 (m, 4H), 7.16- 7.31 (m, 4H)
3391, 3056, 2926, 2872, 1600, 1495, 1243, 1041, 753
IR (Neat, cm'1):
Entry 2
1H NMR (CDCI3, 5): 1.20 (s, 9H), 3.09- 3.15 (dd, J= 6.9, 12.5 Hz, 1H), 3.24- 3.30 (dd,
J= 4.2, 12.5 Hz, 1H), 3.35- 3.41 (dd, J= 6.3, 8.9 Hz, 1H), 3.44- 3.49 (dd, J= 3.9, 8.9 Hz,
1H), 3.93 (m, 1H), 6.62 (d, J= 8.2 Hz, 2H), 6.70 (t, J= 7.3 Hz, 1H), 7.16 (t, J= 7.6 Hz,
2H)
IR (Neat, cm"1): 3385, 3051, 2973, 1601, 1500, 1243, 1078, 751
Entry 3
'H NMR (CDCb, 5): 3.20- 3.27 (dd, J=l.\, 13.3 Hz, 1H), 3.36- 3.41 (dd, J= 4.4, 13.3
Hz, 1H), 3.61 (m, 2H), 4.05- 4.10 (m, 1H), 6.66 (d, J= 7.9 Hz, 2H), 6.75 (t, J= 7.3 Hz,
1H), 7.19 (t, 7=7.6 Hz, 2H)
IR (Neat, cm"1): 3404, 3062, 2952, 1602, 1505, 1318, 1259, 1090, 753
Example 9:
Naphthyl glycidyl ether (1 equivalent) was treated with 2-propylamine (1 equivalent) in
the presence of ZrCl4 (0.1 equivalent) at room temperature under nitrogen in the
absence of solvent for 15 min. 3-(2-naphthyl)oxy-l-(2-propyl) propane-2-ol [Check the
normal feature of the product. There is no amino function in this] was obtained in 100%
yield after usual work up.
1H NMR (CDCI3, 5): 1.18 (d, J= 6.2 Hz, 6H), 2.89- 3.00 (m, 2H), 3.06- 3.11 (dd, J= 3.6,
12.2 Hz, 1H), 4.11-4.23 (m,2H), 4.26-4.31 (m, 1H), 6.81 (d, J= 7.4 Hz, 1H), 7.35 (t, J=
/ Hz, 1H), 7.42- 7.51 (m, 3H), 7.78- 7.81 (m, 1H), 8.22- 8.26 (m, 1H) IR (Neat, cm"1): 3405, 3270, 3056, 2965, 2924, 2664, 1580, 1459, 1399, 1209, 1102






We Claim:
1. A process for the preparation of optically active or racemic 2-aminoalcohols
(formula I).
(Formula Removed)

wherein, R1, R2, R3 and R4 is independently defined as H, unsubstituted or substituted alkyl, alkylaryl, aryl or hetroaryl group, and R5 is defined as H, unsubstituted or substituted alkyl, alkylaryl, aryl or hetroaryl group the said process comprising steps of:
a) adding Zirconium (IV) compound as catalyst to an epoxide in the presence or absence of a solvent,
b) adding an amine to step (a) mixture under an inert atmosphere,
c) stirring the mixture of step (b) at a temperature ranging between 0° to 150° C for a time period of 15 min to 12 h, and
d) isolating the required product 2-aminoalcohols from step ( c ) reaction mixture by conventional methods.

2. A process as claimed in claim 1, wherein in step (a) the epoxide is symmetrically or unsymmetrically substituted epoxide.
3. A process as claimed in claim 2, wherein the epoxide is a monosubstituted epoxide.
4. A process as claimed in claim 2, wherein the epoxide is a disubstituted epoxide.
5. A process as claimed in claim 2, wherein the epoxide is a trisubstituted epoxide.
6. A process as claimed in claim 2, wherein the epoxide is a tetrasubstituted epoxide.
7. A process as claimed in claim 1, wherein in step (a) the Zirconium (IV) compound as catalyst is an organo or inorgano zirconium (IV) compound.

8. A process as claimed in claim 7, wherein the Zirconium (IV) compound is
represented by formula Zr(IV)X.
9. A process as claimed in claim 8, wherein X is represented by a group selected
from F4, Cl4, Br4,I4,O(C1O4)2, SiO4, OCI2 or (acac)4.
10. A process as claimed in claim 1 wherein in step (a) the Zr(IV) compound as
catalyst is selected from a group consisting of ZrF4- ZrCl4, ZrBr4, Zrl4-ZrO(CIO4)2, xH2O; ZrSio4, Zr(acac)4 and ZrOCI2 xH2O.
11. A process of claim 10, wherein the catalyst is ZrCl4.
12. A process of claim 1, wherein in step (a) the solvent is selected from a group
consisting of chlorinated solvent such as methylene chloride, chloroform, and 1,2-dichloroethane, aprotic polar solvent such as acetontrile (CH3CN), aromatic solvent such as benzene, toluene xylene, and ethereal solvent such as diethylether, diisopropylether and tetrahydrofuran(THF).
13. A process of claim 1, wherein in step (b) the amine is ammonia, substituted or
unsubstituted alkyl amine, aromatic amine, alkylaryl amine or heteroarylamine.
14. A process of claim 13, wherein the alkyl amine is saturated or unsaturated.
15. A process of claim 14, whrein the amine is linear, branched for cyclic.
16. A process of claim 13, wherein the substitution on the alkyl (alphatic) amine is
an aliphatic amine selected from a group consisting of fluoro chloro, bromo,
iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or combination thereof.
17. A process of claim 13, wherein the substitution on the alkyl aryl amine is selected from a group consisting of fluoro chloro, bromo, iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or combination thereof.
18. A process of claim 13, wherein the substitution on the aryl amine is selected from a group consisting of fluoro chloro, bromo, iodo, cyano, nitro, amino, alkoxy, alkyl, sulphonic or combination thereof.
19. A process of claim 13, wherein the substitution on the hetro aryl amine is selected
from a group consisting of fluoro chloro, bromo, iodo, cyano, nitrol, amino,
alkoxy, alkyl, sulphonic or combination thereof.

20. A process as claimed in claim 1, wherein in step (b), the inert atmosphere is
provided by flushing with nitrogen gas.
21. A process as claimed in claim 1, wherein in step ( c ) the temperature of the
reaction is preferably in the range of 0° to 110°C.
22. A process as claimed in claim 1, wherein in step ( c ) the time period of the
reaction is preferably in the range of l hour to 8hour.
23. A process as claimed in claim 1, wherein the concentration of the catalyst is in the range of 0.01 to 1.0-mol % of overall concentration.
24. A process of claim 1 provides any sequence of addition of reactants to perform the reaction.
25. A process of claim 2, wherein the unsymmetrical epoxide provides a mixture of regioisomeric product.
26. A process of claim 25, wherein the ratio of regioisomers formed is dependent on
the nature of catalyst, catalyst concentration, solvent and/or reaction temperature.
27. A process of claim 25, wherein the product obtained is enriched with one
regioisomer.
28. A process of claim 25, wherein the product obtained is exclusively a single regioisomer.
29. A process of claim 1 provides an improved process for the preparation of optically active or recemic 3-subsituted-l-amino-propane-2-ol.
30. A process of claim 29 provides an improved process for the preparation of optically active or racemic 3-aryloxy-l-alkylamino-propane-2-ol.
31. A process of claim 29 provides an improved proess for the preparation of ß adrenergic blockers such as propranolol and atenolol.
32. A process of claim 29 provides an improved process for the preparation of optically active or racemic 3-heteroaryloxy-l-alkylamino-propane-2-ol.
33. A process of claim 32 provides an improved process for the preparation of beta adrenergic blockers carvedilol.
34. A process of claim 1, wherein the yield of 2-amino alcohol obtained is in the range of 75 to l00%.

Documents:

337-del-2003- Abstract-(08-12-2011).pdf

337-del-2003- Claims-(08-12-2011).pdf

337-del-2003- Correspondence Others-(08-12-2011).pdf

337-del-2003- Description (Complete)-(08-12-2011).pdf

337-del-2003- Drawings-(08-12-2011).pdf

337-del-2003- Form-1-(08-12-2011).pdf

337-del-2003- Form-13-(08-12-2011)-1.pdf

337-del-2003- Form-3-(08-12-2011).pdf

337-del-2003-abstract.pdf

337-del-2003-claims.pdf

337-del-2003-correspondence-others.pdf

337-del-2003-correspondence-po.pdf

337-del-2003-description (complete).pdf

337-del-2003-drawings.pdf

337-del-2003-form-1.pdf

337-del-2003-Form-13-(08-12-2011).pdf

337-del-2003-form-18.pdf

337-del-2003-form-2.pdf

337-del-2003-form-3.pdf

337-del-2003-form-5.pdf

337-del-2003-GPA-(08-12-2011).pdf

337-del-2003-gpa.pdf


Patent Number 252277
Indian Patent Application Number 337/DEL/2003
PG Journal Number 19/2012
Publication Date 11-May-2012
Grant Date 04-May-2012
Date of Filing 21-Mar-2003
Name of Patentee NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)
Applicant Address SECTOR 67, S.A.S. NAGAR (MOHALI), DISTRICT ROPAR, PUJAB 160062, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 ASIT KUMAR CHAKRABORTI NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, SECTOR 67, S.A.S. NAGAR, PHASE X, MOHALI PUJAB 160062, INDIA.
2 ATUL KODASKAR NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, SECTOR 67, S.A.S. NAGAR, PHASE X, MOHALI PUJAB 160062, INDIA.
PCT International Classification Number A61K 31/045
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA