Synthesis of sulfonamide intermediates

Enantioselective syntheses of (S)-6-chloro-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazin- 4-ol 1,1-dioxide and related compounds are described.

This invention is directed to the enantioselective synthesis of 
(S)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazin-4-ol 1, 
1-dioxide and related compounds. 
BACKGROUND OF THE INVENTION 
The 
chiral(S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c]1,3,2-oxaz 
aborole (oxazaborole.sub.1) catalyzed borane reduction and reduction using 
(+) or (-) B-chlorodiisopinocampheylborane are two of the most effective 
methods for the enantioselective reduction of ketones to alcohols. With 
both methods the degree of enantiomeric purity obtained is dependent on 
the structure of the ketone. 
The enantiomerically pure alcohol 1 is an important intermediate for the 
synthesis of 
(R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-th 
iazin-6-sulfonamide 1, 1-dioxide and related compounds, which are useful in 
the treatment of ocular hypertension and glaucoma as disclosed in U.S. 
Pat. Nos. 5,240,923 and 5,153,192. 
##STR1## 
wherein: R is H or Cl; and 
R' is C.sub.1-6 alkyl, CH.sub.2 (CH.sub.2).sub.n OR", wherein R" is 
CH.sub.3 or (CH.sub.2).sub.n CH.sub.3 and n is 1-4, CH.sub.2 
(CH.sub.2).sub.n X, wherein X is Br, Cl, or I, and n is 1-4, or 
(CH.sub.2).sub.n Ar, wherein Ar is unsubstituted phenyl, 3-methoxyphenyl, 
or 4-methoxyphenyl and n is 1 or 2. 
Synthesis of 1 can be accomplished via an enantioselective reduction of 3 
-(bromoacetyl)-2-thiophenesulfonamide 2 with 
(+)-B-chlorodiisopinocampheylborane [(+)-DIP-Chloride.TM.], followed by 
cyclization and N-alkylation with 3-bromo-1-methoxypropane. (See commonly 
assigned U.S. Pat. Nos. 5,240,923 and 5,153,192.) The method of the 
present invention has advantages over these procedures in that it is a 
catalytic reaction versus a reaction requiring a stoichiometric or excess 
amount of the reducing agent. 
Commonly assigned U.S. Pat. No. 5,344,929 discloses the synthesis of 1 via 
a (+)-DIP-Chloride.TM. reduction of the bromo ketone 2 followed by 
cyclization to the cyclic chiral alcohol 8 and alkylation to 1. The method 
of the present invention (Scheme 1) involves the preparation of a racemic 
cyclic alcohol 4 followed by N-alkylation, oxidation to ketone 6, and 
re-reduction with oxazaborole.sub.1 reagent to give 1. The present process 
avoids the use of (+)-DIP-Chloride.TM.. 
The same sequence of reaction steps using borane tetrahydrofuran and 
catalytic amounts of oxazaborole.sub.1 gives less enantiomerically pure 
compound 1 even with different amounts of catalyst and at lower reaction 
temperature. 
The present invention involves the synthesis of 1 with high 
enantioselectivity at about 30.degree. C. within a shortened reaction time 
and at a lower cost than prior methods. In addition, the precursor of the 
catalyst can be recovered by known procedures, see Jones, et al., J. Org. 
Chem. 56, 763-769 (1991) and Corey, J. Org. Chem. 53, 2861-2863 (1988). 
SUMMARY OF THE INVENTION 
This invention is concerned with a novel process for preparing 1 at a 
relatively low cost and with high enantiomeric purity. The process starts 
with ketone 2, which is converted to racemic 
3-(2-bromo-1-hydroxyethyl)-2-thiophenesulfonamide 3. Cyclization to 
racemic-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazin-4-ol 1, 1-dioxide 4 and 
N-alkylation with 3-bromo-1-methoxypropane leads to 5. 5 is then oxidized 
with chromic acid to achieve ketone 6. 6 is then treated with 
boran-tetrahydrofuran and catalytic amounts of either oxazaborole.sub.1, 
or (S)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo [1,2-c]1,3,2 oxazaborole 
(oxazaborole.sub.2) to provide 1. 
A second method (Scheme 2) starts with ketone 2, which is reduced with 
borane-tetrahydrofuran and oxazaborole.sub.1, to give enantiomeric 
enriched 9, which was not isolated, and cyclized with aqueous sodium 
hydroxide to give enantiomeric enriched 8, which is then N-alkylated with 
3-bromo-1-methoxypropane to give 1. 
A third method (Scheme 3) starts directly with oxidation of 4 to produce 7, 
which is reduced with oxazaborole.sub.1 catalyst to give 8, which is 
alkylated to give 1. 
DETAILED DESCRIPTION OF THE INVENTION 
The preferred method of the present invention is described by Scheme 1. 
##STR2## 
wherein: R is H or Cl; and 
R' is C.sub.1-6 alkyl, CH.sub.2 (CH.sub.2).sub.n OR", wherein R" is 
CH.sub.3 or (CH.sub.2).sub.n CH.sub.a and n is 1-4, CH.sub.2 
(CH.sub.2).sub.n X, wherein X is Br, Cl, or I, and n is 1-4, or 
(CH.sub.2).sub.n Ar, wherein Ar is unsubstituted phenyl, 3-methoxyphenyl, 
or 4-methoxyphenyl and n is 1 or 2. 
Compound 1 can also be prepared according to the following two procedures 
set forth in Schemes 2 and 3 with R, R', and R" as defined above. 
##STR3## 
In the following examples, melting points were determined on a Gallenkamp 
melting point apparatus and are uncorrected. IR spectra were recorded on a 
Perkin-Elmer-297 infrared spectrometer. NMR-Spectra were recorded in 
CDCl.sub.3 and D.sub.6 -acetone (.sup.13 C, .sup.1 H) on a Bruker ARX 400 
spectrometer. .sup.1 H chemical shifts are reported in ppm from internal 
standard of residual chloroform (7.27 ppm) and acetone (2.01 ppm). .sup.13 
C chemical shifts are reported in ppm from the central peak of 
deuterochloroform (77.0 ppm) or deuteroacetone (29.8 ppm). 
Tris-[3-(trifluormethylhydroxymethylene)-d-camphorato]-europium-(III) was 
used as chemical shift reagent and purchased from Fluka. Specific 
rotations were determined on a Schmidt & Haensch polarimeter from the pure 
liquids. Analytical gas chromatography (GC) was carried out on a 
Perkin-Elmer 8700 gas chromatograph equipped with a split mode injector 
for capillary columns, an on-column injector for packed columns, and a 
flame-ionization detector, with helium as carrier gas. The following 
columns were used: 25 m.times.0.32 mm FS-OV-1-0.25 (Macherey & Nagel) and 
5'1/8'2 mm GE SE-52 (Macherey & Nagel). Analytical high-performance 
liquid chromatography (HPLC) was carried out on a Merck Hitachi model D 
6000 with a D 6000 Interface using the following columns: 4.times.125 mm 
LiChroCart 250-4(Merck) Spherisorb ODS-2 (5 mm) and 4.times.250 mm 
LiChroCart 250-4 (Merck) ChiraDex (5 mm). Analytical thin layer 
chromatography (TLC) was carried out with TLC-aluminum sheets silica 60 
F.sub.254 using the following solvent system: n-hexane/ethyl acetate 1:1 
or n-hexane/acetone 1:1. Visualization was accomplished with UV-light. 
(S)-Tetrahydro-1 
-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole was obtained 
from Callery Chemical Company U.S.A. or prepared according to the 
literature. 3-Bromoacetyl-5-chloro-2-thiophensulfonamide 2 (R=Cl) was 
obtained from Amcis AG, Switzerland. 
In the following examples R is Cl and R' is CH.sub.2 (CH.sub.2).sub.2 
OCH.sub.3.

EXAMPLE 1 
6-chloro-3,4-dihydro-2H-thien[3,2-e]-1,2-thiazin-4-ol 1, 1-dioxide 4 
In a 4.5 L three necked flask fitted with a reflux condenser, thermometer 
and dropping funnel 159 g ketone 2 were dissolved in 1.5 L ethanol. To the 
stirred solution, which retains some undissolved ketone 2, were added in 
small portions 10.7 g sodium borohydride. During this time the reaction 
mixture first became red-brown and then a clear yellow solution. At the 
same time H.sub.2 evolved and the temperature rose to 40.degree. C. 
Stirring was continued for 1 h during which the temperature dropped to 
28.degree. C. Then 1.5 L of 1N aqueous sodium hydroxide solution were 
added within 15 min. During this time the temperature rose again to 
35.degree. C. and a small amount of sodium hydroxide separated at the 
bottom of the flask (saturation). After a further 5 min. the ethanol was 
evaporated under vacuum and the residual aqueous solution was acidified 
with about 1.1 L of 1N hydrochloric acid to pill. The separating brown oil 
was 1.times. extracted with 600 mL ethyl acetate and 1.times. with 300 mL. 
The clear aqueous solution was discarded and the extracts dried over 
sodium sulfate. After filtration the solvent was evaporated and 
crystallization induced by dissolving and stirring in 250 mL of 
dichloromethane. The solid was separated by filtration and washed with 
dichloromethane. After drying the residue weighed 94 g (88%). This raw 
material was used without further purification. The identity of this 
racemic 4 was elucidated by comparison with IR-spectra and TLC of 
enantiomerically pure 8. 
EXAMPLE 2 
6-chloro-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazin-4-ol 
1, 1-dioxide 5 
Into a 250 mL three necked flask fitted with thermometer and reflux 
condenser 19.6 g of alcohol 4 were dissolved in 100 mL dimethylsulfoxide, 
then 33.9 g potassium carbonate and 15.3 g of 1-bromo-3-methoxypropane 
were added. During this period the temperature rose to about 30.degree. C. 
and stirring was continued through the night. After 22 h the mixture was 
poured into 960 mL of saturated sodium chloride solution and then twice 
extracted with 220 mL of t-butyl methyl ether. The combined extracts were 
then washed with 100 mL of 10% aqueous sodium hydroxide solution, 80 mL of 
2.5% sodium hypochlorite solution and then with 60 mL of saturated sodium 
chloride solution. After drying with sodium sulfate and filtration the 
solvent was evaporated in vacuum. The residue was used without further 
purification; yield 23.5 g (92%). Identification was made by comparison 
between the IR-spectra of compounds 5 and 1. 
EXAMPLE 3 
6-chloro-2,3 
-dihydro-2-(3-methoxypropyl)-4H-thieno[3,2-e]-1,2-thiazin-4-one 1, 
1-dioxide 6 
243 g of alcohol 5 were dissolved in 1.56 L t-butyl methyl ether and 
charged into a 4-L three necked flask fitted with a reflux condenser and a 
thermometer. With stirring and cooling with an ice bath a mixture 
consisting of 155 g of sodium dichromate and 206 g sulfuric acid dissolved 
in 546 mL of water was added. The temperature was maintained below 
20.degree. C. during the addition. After the addition of chromic acid, the 
biphasic mixture was stirred for further 90 min at 25.degree. C. until the 
TLC indicated complete consumption of the racemic alcohol 5. Then the 
aqueous layer was separated and 4.times. extracted with 390 mL of t-butyl 
methyl ether. The combined etheral solutions were successively washed with 
624 mL of saturated sodium bicarbonate and sodium chloride solution, 
respectively. After drying with sodium sulfate and filtration the solvent 
was evaporated. Crystallization of the residual oil was induced by 
addition of a few crystals of authentic ketone 6 and about 25 mL of 
diethyl ether. To complete the crystallization 400 mL of n-hexane were 
added. An analytical sample was recrystallized from diethyl ether, mp: 
48.degree.-52.degree. C., yield: 194 g (80%). 
EXAMPLE 4 
6-Chloro-2,3-dihydro-4H-thieno[3,2-e]-1,2-thiazin-4-one 1, 1-dioxide 7 
Ketone 7 was prepared from 4 in the same manner as mentioned for ketone 6, 
yield 61%. 
EXAMPLE 5 
(S)-6-Chloro-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazin-4 
-ol 1, 1-dioxide 1 
Into a thoroughly dried four necked flask (750 mL) fitted with two dropping 
funnels, a reflux condenser, and a thermometer trader an argon atmosphere 
were placed 2.07 g of oxazaborole.sub.1 and 15 mL of tetrahydrofuran. From 
one of the dropping funnels, which was filled with 250 mL of borane 
tetrahydrofuran complex solution, 25 mL of this solution were released 
into the reaction vessel. The second dropping funnel contained 116 g of 
ketone 6 dissolved in 250 mL of tetrahydrofuran. Simultaneously from both 
dropping funnels these prepared solutions were then added dropwise to the 
reaction vessel within 1/2 h. The temperature of the reaction mixture was 
held below 33.degree. C. with an ice water bath. The mixture was stirred 
for another 5 min and then quenched with 55 mL of methanol. Then the 
solution was washed with sodium chloride, sodium bicarbonate, and then 
again with sodium chloride (190 mL of saturated solutions, respectively). 
The etheral solution was then dried with sodium sulfate, filtered, and the 
solvent evaporated in vacuum. The residue was purified on a silica (1 kg) 
column with n-hexane/ethyl acetate 1:1 as eluent; yield: 112 g (90%); 
[.alpha.].sup.22.sub.D =+20.97.degree. (91.6% ee). The enantiomeric purity 
determined by HPLC and .sup.1 H-NMR with chemical shift reagent was 
greater than 94% ee. 
EXAMPLE 6 
(S)-6-chloro-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazin-4 
-ol 1, 1-dioxide 1 
Starting with 9.3 g of ketone 6 and following the same procedure as 
mentioned in Example 5 except using a stock solution of 1M 
(S)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole as 
catalyst led to 1, 4.9 g (52%) yield, ee=65%. 
EXAMPLE 7 
(S)-6-Chloro-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazin-4-ol 1, 1-dioxide 8 
Starting with 7.13 g of ketone 7, following the same procedure as mentioned 
in Example 5, led to 5.84 g (81%) of alcohol 8; ee 71.5% determined by 
HPLC. 
EXAMPLE 8 
Starting with ketone 2 and following the same procedure mentioned in 
Example 5 except that variable amounts of the catalyst (1.0, 2.0, 5.0, and 
10.0 mol %) were used at different temperatures, after cyclization 
according the method using (+)-B-chlorodiisopinocampheylborane, gave 
ee-values less than 59%.