Selective sulphonation of the primary alcohol of a diol...

Details Selective sulphonation of the primary alcohol of a diol... Selective sulphonation of the primary alcohol of a diol...

1998-02-25

2001-02-27

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S336000, C558S044000, C558S051000, C558S056000, C558S061000

Reexamination Certificate

active

06194586

ABSTRACT:

This invention relates to the fields of pharmaceutical and organic chemistry and provides a new catalytic process for the selective sulfonylation of a primary alcohol in the presence of a secondary or unactivated alcohol.
An efficient process for selectively sulfonating a primary alcohol in a substrate that also contains a secondary alcohol is desired for the synthesis of key intermediates to important pharmaceutical agents. Normal methods of sulfonating such a diol use a base with toluenesulfonyl chloride. As shown in Equation 1, the normal method results in a mixture of the desired primary tosylate (2), a secondary tosylate (3), and a bis-tosylate (4), as well as the starting diol (1) (eq 1).
The present invention provides an improved process for preparing a compound of formula I
wherein
R
1
is H or R
2
; and
R
2
is C
1
-C
12
alkyl; C
2
-C
12
alkenyl, C
3
-C
8
-cycloalkyl, aryl, aryl-(C
1
-C
6
alkyl), aryl-Z—(C
1
-C
6
alkyl), heteroaryl, heteroaryl-(C
1
-C
6
alkyl), or heteroaryl-Z—(C
1
-C
6
alkyl), any of which may have up to three R
5
substituents; or
R
1
and R
2
together complete a 5-6-membered ring that may have up to three R
5
substituents;
R
5
is C
1
-C
12
alkyl, halo, hydroxy or C
1
-C
3
alkoxy;
n is 0, 1 or 2;
Z is 0 or S; and
R
p
is C
1
-C
6
alkylsulfonyl or arylsulfonyl comprising contacting
a) a compound of formula II
with
b) a compound of formula R
p
SO
2
X or (R
p
SO
2
)
2
O
wherein X is halo or imidazolyl;
c) a tertiary amine; and
d) a catalytic quantity of a compound of formula (R
a
)
2
Sn (X
a
) m;
wherein
R
a
is C
1
-C
12
alkyl;
X
a
is O, Cl, Br, OAc or OR
b
;
m is 1 or 2; and
R
b
is C
1
-C
6
alkyl or aryl.
A preferred aspect of this invention is a process for selectively tosylating a primary alcohol in the presence of a secondary alcohol comprising reacting the primary alcohol with tosyl chloride in the presence of a catalytic quantity of Sn(IV).
The use of tin(IV) in a catalytic amount rather than in a stoichiometric amount provides important advantages. Reactions using a stoichiometric amount of tin require extensive chromatography to remove unwanted, lipophilic tin oxide. Even after such purification steps, about one to ten mole percent (1-10%) of tin contaminants remain. Such compromised product quality significantly limits the use of stannylene methodology in the preparation of pharmaceuticals.
Products produced by the process of this invention can be purified using a brief rinse and solvent removal. Additionally, the product contains dramatically less tin contaminant (less than 0.1 mole percent).
Thus, the present process provides the needed selectivity and gives a pharmaceutically acceptable intermediate that has <0.1 mole percent tin contaminant.
Preferred diol intermediates are those that are useful for preparing cryptophycin compounds.
Preferred tin catalysts are tin oxides. Particularly useful tin oxides are dibutyltin oxide and dibutyltin dimethoxide.
The present invention also provides a process for deracemizing a meso-diol comprising reacting such a diol with a chiral tin (IV) reagent.
The phrase “catalytic quantity” is understood in the art. It refers to an amount that is less than a stoichiometric amount, but is sufficient to achieve the desired results.
The term “alkyl” refers to an alkyl group with the designated number of carbon atoms. It may be saturated or unsaturated, branched or straight chain. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like.
The term “alkenyl” refers to an alkyl group having from one to three double bonds. “Cycloalkyl” refers to a saturated C
3
-C
12
cycloalkyl group.
The term, “alkoxy” means a straight or branched alkyl group bonded to an oxygen atom.
The term “aromatic group” and “heteroaromatic group” refer to common aromatic rings having 4n+2 pi electrons in a monocyclic conjugated system or a bicyclic conjugated system. The term “aryl” refers to an aromatic group. Examples of aromatic groups are phenyl, benzyl and naphthyl. Heteroaromatic groups will contain one or more oxygen, nitrogen and/or sulfur atoms in the ring. Examples of heteroaromatic groups include furyl, pyrrolyl, thienyl, pyridyl and the like. When the aromatic or heteroaromatic groups are substituted, the substituents may be attached at any available carbon atom.
The term “halo” refers to Cl, Br, F, or I.
One example of the process of this invention is shown in Equation 2
Product
6
was tosylated selectively and cleanly under the catalytic tin conditions (<1% bis-tosylate), wherein in the absence of tin, the reaction was neither selective nor clean (>10% bis-tosylate).
Thus, tin in catalytic amounts efficiently accelerates the regioselective protection of primary alcohols. This method obviates the need for extensive chromatographic purification and provides a product with minimal tin contamination.
The process of this invention is applicable to a variety of alcohol substrates and is particularly useful for the synthesis of a key intermediate for the production of cryptophycin compounds.
Examples of formula II substrates include:
In these examples, Ar is as defined supra, and
The process of this invention is carried out in the presence of a tertiary amine. The tertiary amine can be represented by R
3
N, wherein R can be alkyl or aryl or the R
3
unit together with the N represents a ring, such as pyridine or piperidine. Trialkylamines are preferred, and triethylamine is especially preferred. Diisopropylethylamine and pyridine can also be used.
The process of this invention is preferably carried out in the presence of a solvent, such as an inert organic solvent. Dichloromethane is an especially preferred solvent. Other solvents that can be used are acetonitrile, which is better than tetrahydrofuran, which is better than toluene, which is still better than methanol.
The specificity of the process of this invention is illustrated in Table 1, which compares the tosylation of diol 5 with and without tin as a catalyst:
TABLE 1
Comparison of Bis-Tosylate Formation with Tin Catalysis
Without Tin
With Tin
Reagent
Catalysis
Catalysis
diol 5
1.0 mole
1.0 mole
TsCl
1.0 mole
1.0 mole
Et
3
N
1.0 mole
1.0 mole
Bu
2
Sn = O
0
0.001 mole
% bis tosylate
>10%
<1%
An especially preferred feature of the improved process is that it makes possible a shorter and more efficient synthesis of cryptophycin compounds than the known synthetic method. See Barrow, et al. J. Am. Chem. Soc. 1995, 117, 2479-2490. The process also is useful in preparing modified cryptophycin compounds of formula I
wherein
G is C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl or Ar;
Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
R
1
is halo, SR, OR, amino, mono or di-(C
1
-C
6
-alkyl)amino, tri (C
1
-C
6
-alkyl) ammonium, C
1
-C
6
-alkylthio, di (C
1
-C
6
-alkyl)sulfonium, C
l
-C
6
-alkylsulfonyl, or C
1
-C
6
-alkylphosphonyl and
R
2
is OH or SH; or
R
1
and R
2
taken together form a second bond between C-18 and C-19 or together form an epoxide, aziridine, episulfide, or cyclopropyl ring;
R is H, C
1
-C
6
alkyl, C
1
-C
6
alkanoyl or Ar;
R
3
is C
1
-C
6
alkyl;
R
4
and R
5
are H; or
R
4
and R
5
taken together form a second bond between C-13 and C-14;
R
7
is H, C
1
-C
6
alkyl NR
51
R
52
, -(C
1
-C
3
-alkyl)NR
51
R
52
, or OR
51
; and
R
8
is H or C
1
-C
6
alkyl; or
R
7
and R
8
together form a cyclopropyl ring;
R
51
and R
52
independently are C
1
-C
3
alkyl;
R
9
is H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
-alkynyl or (C
1
-C
6
alkyl) C
3
-C
5
cycloalkyl;
R
10
is H or C
1
-C
6
alkyl;
R
14
is H or a lower alkyl group;
X is O, NH or (C
1
-C
3
alkyl)N—;
Y is C, O, NH, S, SO, SO
2
or (C
1
-C
3
alkyl)N—;
R
6
is C
1
-C
6
alkyl, substituted (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, substituted C
3
-C
8
cycloalkyl, a heteroaromatic or substituted heteroaromatic group, or a

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