Process for the preparation of 2-hydroxyalkyl halophenones

Details Process for the preparation of 2-hydroxyalkyl halophenones Process for the preparation of 2-hydroxyalkyl halophenones

2000-11-29

2001-10-09

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S322000, C568S323000, C568S386000, C568S391000, C568S393000, C568S397000

Reexamination Certificate

active

06300522

ABSTRACT:

This invention relates to processes for the preparation of certain chiral compounds and to novel compounds used in the processes.
1(2,4-dihalophenyl)-2-hydroxy-1-propanones are key intermediates for the synthesis of a variety of pharmaceuticals and agrochemicals, particularly antifungal compounds and medicines used in the treatment of AIDS. For example Sch 42427/SM9164 and ER-30346 are made from these intermediates.
The chiral 2-hydroxy group in these compounds has been prepared by chiral &agr;-hydroxylation of the corresponding 2′,4′-difluoropropiophenone. One such method is described in Tetrahedron Letters, Vol 37, No. 45, pp8117-8120 (1996). An alternative method involves the regioselective ring opening of a 2′,4′-fluorophenyl propylene oxide, as described in Tetrahedron Letters, Vol 35, No. 45, pp8299-8302 (1994). We have now devised a process for preparing 2′,4′-dihalo-2-hydroxypropiophenones with good enantiomeric purity from readily available L- or D-2-chloropropionic acid.
According to one aspect of the present invention there is provided a process for the preparation of a compound of Formula (1):
wherein:
X
1
and X
2
are each independently H, Cl or F, provided that at least one of X
1
and X
2
is Cl or F;
one of R
1
and R
2
is H and the other is OH; and
R
5
is an unsubstituted alkyl, preferably a C
1-6
alkyl, group comprising the steps:
(a) condensing a 2-chloroalkanoic acid with an optionally substituted benzyl alcohol to form a 2-(optionally substituted benzyloxy) alkanoic acid;
(b) converting the product from step (a) to the corresponding acid chloride; then either:
(c) reacting the product of step (b) with a compound of the Formula (2) in the presence of a source of copper (I) to give a compound of Formula (3) wherein one of R
3
and R
4
is H and the other is optionally substituted benzyloxy;
or
(d) reacting the product of step (b) with a compound of Formula (4):
A—NH—B
wherein A and B independently represent substituted alkyl, alkoxy, aryl or oxyaryl groups, or are linked to form a heterocyclic ring to form an amide, and then reacting the amide with a compound of Formula (2) to give a compound of Formula (3); and
(e) removing the optionally substituted benzyl group from the compound of Formula (3) by hydrogenation, thereby giving the compound of Formula (1).
The process steps a) to d) above for the production of a compound of Formula (3) form another aspect of the present invention.
In step (a) the reaction of the 2-chloroalkanoic acid with an optionally substituted benzyl alcohol proceeds with an inversion of configuration. Accordingly, the choice of which enantiomer of the 2-chloroalkanoic acid will be made on the basis of the desired configuration of the desired compound of Formula (1) or Formula (3). 2-chloroalkanoic acids which can be employed in the present invention have the general formula: R
5
—CR
6
R
7
—CO
2
H, wherein R
5
is an alkyl group, preferably a C
1-6
alkyl group, and most preferably a methyl group, and one of R
6
or R
7
is Cl, the other being H. The most preferred 2-chloroalkanoic acids are L- and D-2-chloropropionic acid.
The optionally substituted benzyl alcohol is preferably benzyl alcohol or a benzyl alcohol having from 1 to 5 substituents, often selected from the group consisting of halo, preferably F, Cl or Br; nitro; C
1-4
-alkyl, preferably methyl or ethyl; C
1-4
-alkoxy, preferably methoxy or ethoxy; carboxy; sulpho and amino. Benzyl alcohol is most preferred.
The condensation in step (a) is preferably performed in the presence of a strong base, preferably an inorganic base. Examples of suitable organic bases include alkyl lithium salts such as butyl lithium, and alkali metal, especially lithium, alkylamide salts such as lithium diisopropylamide. Examples of suitable inorganic bases include alkali metals, especially lithium, sodium and potassium metal, alkali metal hydrides such as lithium, sodium or potassium hydride, alkali metal hydroxides, carbonates and bicarbonates, especially sodium hydroxide, potassium hydroxide and mixtures thereof.
The condensation of step (a) is preferably performed at an elevated temperature, more preferably 30° C. to 150° C., especially 40° C. to 120° C.
Condensation step (a) can be performed in the presence of an organic solvent which is unreactive towards the reagents employed. Examples of suitable solvents include halocarbons, especially chlorocarbons such as dichloromethane, chloroform, dichloroethane, chlorobenzene, and ethers, particularly C
1-6
alkylethers such as t-butyl methyl ether and tetrahydrofuran. It is preferred that the benzyl alcohol serves as its own solvent, and in many embodiments, a molar excess of benzyl alcohol over the chloropropionic acid is employed, such as a mole ratio of benzyl alcohol to 2-chloroalkanoic acid of from 2:1 to 15:1, and commonly from 5:1 to 10:1.
Conversion of the product of step (a) to the corresponding acid chloride (i.e. —COCl) is preferably performed using oxalyl chloride, thionyl chloride, or a phosphorus halide, such as PCL
3
or PCL
5
. Elevated temperatures are preferred, especially 30° C. to 110° C., more preferably 35° C. to 90° C. The reaction is commonly carried out neat, but an organic solvent which is unreactive towards the reagents may be employed. Examples of suitable solvents include halocarbons, especially chlorocarbons such as dichloromethane, chloroform, dichloroethane, chlorobenzene; ethers, particularly C
1-6
alkylethers such as t-butyl methyl ether and tetrahydrofuran; and aromatic solvents such as toluene.
The source of copper (I) used in step (c) is preferably a Cu (I) salt, such as CuNO
3
, CuCN or a copper (I) halide, especially CuCl, CuBr or Cul. The amount of copper (I) source used is preferably between 80 and 200 mole % relative to the number of moles of the acid chloride product of step (b), more preferably from 85 to 150 mole %, especially 90 to140 mole %.
Step (c) is commonly carried out in the presence of an organic solvent which is unreactive towards the reagents is commonly employed. Examples of suitable organic solvents include ethers, particularly C
1-6
alkylethers such as t-butyl methyl ether and tetrahydrofuran; and aromatic solvents such as toluene. The reaction temperature of step (c) is commonly in the range of from −78° C. to 30° C., and preferably from −40° C. to 0° C.
The compound of Formula (2) is commonly prepared by reacting the appropriately substituted phenyl bromide with magnesium metal in the presence of a suitable solvent, often the solvent employed in step (c). Preferably, a stoichiometric ratio or moderate molar excess of phenyl bromide to magnesium is employed, often a molar ratio of from 1:1 to 2:1, and advantageously from 1.25:1 to 1.75:1. The preparation often takes place at a temperature of from ambient temperature (20-25° C.) to about 35° C. It will be recognised that the preparation of compounds of Formula (2) can be exothermic, and so appropriate cooling is advantageously provided to control such exotherms.
In the amine compound of Formula (4) employed in step (d), when A or B represents an alkyl or alkoxy group, it is preferably a C
1-4
alkyl or alkoxy group, and particularly a methyl or methoxy group. When A or B represents an aryl or aryloxy group, it is preferably a phenyl or phenoxy group. When A and B are linked to form a ring, the ring preferably contains from 5 to 8 members, and 1, 2 or 3 heteroatoms. In addition to the amine nitrogen, other heteroatoms, especially oxygen may be present in the ring. Examples of preferred amines include morpholine, pyrrolidine and N-methoxy-N-methylamine. The amine can be employed as a free amine or in the form of a salt, especially a hydrochloride salt. The mole ratio of amine to acid chloride is commonly from 1:1 to 2:1. Step (d) is commonly carried out in the presence of an organic solvent which is unreactive towards the reagents is commonly employed. Advantageously, the solvent employed is substantially water insoluble. Examples of suitable organic solvents include halocarbons, especially

Affiliated with

Also associated with

Rating

Process for the preparation of 2-hydroxyalkyl halophenones does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of 2-hydroxyalkyl halophenones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of 2-hydroxyalkyl halophenones will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2582035