This article was downloaded by: [University of Illinois Chicago]On: 18 October 2014, At: 20:31Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Synthetic Communications: AnInternational Journal for RapidCommunication of Synthetic OrganicChemistryPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/lsyc20

A Practical Preparation of ThiolCarboxylic Esters of 2-(Isoxazolyl)Acetic AcidsJaan A. Pesti a , Jianguo Yin a & Jihchin Chung aa The DuPont Pharmaceuticals Company, Chemical ProcessResearch and Development , Experimental Station, BuildingE336, Wilmington, Delaware, 19880-0336Published online: 17 Sep 2007.

To cite this article: Jaan A. Pesti , Jianguo Yin & Jihchin Chung (1999) A Practical Preparationof Thiol Carboxylic Esters of 2-(Isoxazolyl) Acetic Acids, Synthetic Communications: AnInternational Journal for Rapid Communication of Synthetic Organic Chemistry, 29:21,3811-3820, DOI: 10.1080/00397919908086021

To link to this article: http://dx.doi.org/10.1080/00397919908086021

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information(the “Content”) contained in the publications on our platform. However, Taylor& Francis, our agents, and our licensors make no representations or warrantieswhatsoever as to the accuracy, completeness, or suitability for any purpose of theContent. Any opinions and views expressed in this publication are the opinions andviews of the authors, and are not the views of or endorsed by Taylor & Francis. Theaccuracy of the Content should not be relied upon and should be independentlyverified with primary sources of information. Taylor and Francis shall not be liablefor any losses, actions, claims, proceedings, demands, costs, expenses, damages,

and other liabilities whatsoever or howsoever caused arising directly or indirectly inconnection with, in relation to or arising out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden.Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

SYNTHETIC COMMUNICATIONS, 29(21), 381 1-3820 (1999)

A PRACTICAL PREPARATION OF THIOL CARBOXYLIC ESTERS OF

2-(ISOXAZOLYL) ACETIC ACIDS.

Jaan A. Pesti,* Jianguo Yin, and Jihchin Chung

The DuPont Pharmaceuticals Company, Chemical Process Research and Development, Experimental Station, Building E336,

Wilmington, Delaware 19880-0336

Abstract: High yields of several thiolesters of 2-[3-(4-cyanophenyl)-4,5-dihydro- 5-isoxazolyl]acetic acid are easily prepared from the corresponding oxoester by the reaction with trimethylsilylated mercaptan and aluminum chloride. The selection of mercaptans expands the previous scope of this synthetic method.

The large-scale preparation of the orally active non-peptide platelet GPIIb/IIIa

antagonist roxifiban was recently reported.' The key step of the synthesis was the

production of (R)-isoxazoline 2 via an enzymatic resolution of the racemic

isobutyl ester 1 in 36% yield (Scheme 1). The unreacted @)-ester was

subsequently recovered, racemized by catalytic potassium t-butoxide in toluene

and resubmitted to enzymatic hydrolysis. The need for multiple recycles of the

(5')-ester through racemization to attain high overall yields was inconvenient. A

simpler route was desired a for commcrcial process.

* To whom correspondence should be addressed

381 1

Copyright @ZJ 1999 by Marcel Dekker, Inc www.dekker.com

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

3812

Scheme 1

PESTI, YM, AND CHUNG

t t-BuOWtoluene

A superior version of the preceding reaction would couple racemization with

resolution, also known as dynamic kinetic resolution.’ The benefits are twofold:

the need to remove or recycle the undesired isomer is eliminated, and the

product’s enantiomeric excess becomes independent of the degree of the

conversion and does not degrade toward the end of the r e ~ o l u t i o n . ~ * ~ We’ve

discovered that several n-alkyl thiolesters of 2 permit dynamic enzymatic

resolution in the presence of certain lipases.5 While an additional step was needed

to prepare the thiolester 3, the following enzymatic hydrolysis step was simple,

high yielding, and the overall sequence was shorter. Thiolesters for our initial

process research were derived by the hydrolysis of 1 to form racemic 2, followed

by chlorination with thionyl chloride and reaction with copper (I) mercaptides.6

While the procedures were simple and the yields high (>90% overall yields), the

procedure was too lengthy to be useful.

Thiolesters are generally prepared from their carboxylic analogs.’ Much rarer

are direct conversions to thiolesters from non-activated oxoesters, usually through

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

THIOL CARBOXYLIC ESTERS 3813

the reaction with bis(dimethylaluminum) thiolates.*

reported the preparation of thiolesters by the reaction of the trimethylsilylated

ethanethiol or thiophenol with either ethyl or methyl carboxylic esters in the

presence of aluminum ~ h l o r i d e . ~ This seemingly general reaction has since rarely

been used.'O We wondered if this methodology could be extended to convert 1

into 3. This is in fact true and we've found the preparation of 3b, our pivotal

intermediate to roxifiban, may be rapidly prepared in excellent yield in multi-kilo

lots. In this communication, we report the expansion of the scope of the oxoester

to thiolester transformation along with a general process for the overall reaction.

Mukaiyama et ul. have

Scheme 2

1) R'Li

2) TMSCI N-0 0 RSH - RSSi(Me), + 1

3a-e R = Ethyl, n-Propyl, i-Propyl, n-Butyl or t-Butyl

compd R

3a 3b 3c 3d 3e

Ethyl n-Prop yl i-Prop yl n-Butyl t-Butyl

We initially considered the conversion of the easily-prepared isobutyl oxoester

1 to the n-propyl thiolester 3b.1' It was not obvious that these conditions would

be successful due to the limited nature of the published examples (only methyl

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

3814 PESTI, YIN, AND CHUNG

and ethyl esters were substrates and only ethyl and phenyl sulfides were

appended).9 In addition, if the proposed cyclic transition state was correct, the use

of the branched ester 1 could fail due to steric interactions. Since the few

commercially available silylated mercaptans are very expensive, we developed an

iri situ preparation of the silylsulfide by treatment of the mercaptan with one

equivalent of alkyllithium followed by excess chlorotrimethylsilane. Sulfides may

be silylated by :L variety of reagents,'* however we found the use of alkyllithiums

to be convenient, high-yielding, clean and free of additional manipulations beyond

lithium chloride filtration. Removal of lithium chloride was necessary as it

complexed the aluminum chloride to be charged later, leading to incomplete

reactions unless additional aluminum chloride was charged. The filtrate typically

contained excess chlorotrimethylsilane (this had been overcharged to function as a

convenient sink for any unreacted alkyllithium that could subsequently react with

the esters) but this did not interfere in the subsequent reaction.

The reaction itself was straightforward. Refluxing a mixture of the silylated

sulfide filtrate, oxoester and aluminum chloride led to smooth conversion to the

thiolester for all silylsulfides except t-butyl. This reacted sluggishly to produce

only a 82%) solution yield of 3e over one day, the slow rate perhaps due to steric

hindrance from the bulky alkyl group within the hypothesized transition state.9

Subsequent water quench of the reaction followed by recrystallization produced

excellent yields of a11 n-alkyl thiolesters and fair yields for the branched

thiolesters (all reactions except 3b are unoptimized). This process has been

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

THIOL CARBOXYLIC ESTERS 3815

conducted in our pilot plant to smoothly produce 45 kg of 3b in 91% yield and is

currently in consideration for commercial scale synthesis. All thiolesters are

crystalline and were used in our discovery process research program for roxifiban.

EXPERIMENTAL

I 13 General. H NMR spectra were determined at 300 MHz and C NMR at

75.4 MHz, all in CDCI,. High Resolution Mass spectra (HRMS) were obtained

by ammonia chemical ionization and possess an uncertainty of +I- 0.1 mDa.

Elemental analyses were performed at Quantitative Technologies Inc.,

Whitehouse, NJ. IR spectra were recorded in KE3r matrix and are reported in cm .

Melting points are uncorrected. Solvent mixtures are defined by volume (v/v).

All solvents and reagents except for tetrahydrofuran (anhydrous) were reagent

grade and were not further purified. All reactions were carried out under a

positive pressure of nitrogen. CAUTION: the thiols produce a powerful stench.

Use of a basic bleach trap for exiting gases prevents odor from escaping the

reaction. HPLC was used to follow the extent of the reaction, and determine

solution yields and product purity versus analytical standards: Zorbax 4.6 mm x

15 cm RX C18 column at 1.00 mUmin at 40 "C and 215 nm. Solvent A: 15%: 1

L watedl.0 mL triethylamine/0.75 mL phosphoric acid; Solvent B: 85%: CH3CN.

3 mL injection volume.

1

Preparation of thiolesters (3a-e). The following procedure for the a-propyl

analog 3b is representative.

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

3816 PESTI, YIN, AND CHUNG

S-Propyl 3-(4-cyanophenyl)-4,5-dihydro-5-isoxazoleethanethioate, (3b):

A solution of 2.6 M n-hexyllithium in cyclohexane (500 mL, 1.30 mol) was added

at 4-15 "C over 1 hour to a solution of 1-propanethiol (98.0 g, 1.29 mol) in THF

(8.50 mL). The slurry was aged for 40 minutes and chlorotrimethylsilane (175

mL, 1.38 mol) was charged at 4-15 "C over 30 minutes. The slurry was warmed

to 25 "C over 3 hours and filtered. The solids were washed with a solution of

heptanes:THF ( I : I , 100 mL) and the filtrate was cooled to 10 "C. Aluminum

chloride (120 g, 0.90 mol) was added in portions at 10-20 "C over 15 minutes

followed by I (200.0 g, 0.70 mol) in one portion. The slurry was heated to reflux

over 20 minutes and monitored by HPLC until complete 70 minutes later. The

solution was cooled to 15 "C and quenched with water (850 mL) at <30 "C over

15 minutes. Toluene (525 mL) was charged, the mixture shaken and the organic

phase removed. The aqueous layer was re-extracted with toluene (100 mL) and

the combined organic layers washed with water (3 x 400 mL). The solution was

clarified by filtration and the volume reduced to 500 mL by vacuum distillation at

100 mmHg. Heptane (1.3 L) was charged at 40 "C over 2 hours to crystallize the

product. The slurry was cooled to 5 "C over 2 hours, aged 1 hour and the solids

collected by filtration. After a heptane (100 mL) wash, the solids were dried at

0.1 mmHg vacuum overnight to yield a pale yellow granular solid (189.5 g, 94%,

>99.5 % purity). An analytical standard was prepared by recrystallization of 6.2 g

from S O mL of - 1 : 1 ethyl acetatelheptane, mp 67.1-68.2 "C; HNMR 6 7.77 (dd, J

= 6.9, 1.8 Hz, ?€I) , 7.70 (dd, J = 6.9, 2.1 Hz, 2H), 5.30-5.10 (m, lH), 3.60-3.40

(m, lH), 3.25-3.10 (m. 2H), 3.00-2.80 (m, 3H), 1.62 (sextet, J = 7.2 Hz, 2H), 0.98

1

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

THIOL CARBOXYLIC ESTERS 3817

(t , J = 7.4 Hz, 3H). 13CNMR 6 195.81, 155.26, 133.54, 132.44, 127.09, 118.23,

113.45, 78.09, 48.42, 39.30, 30.97, 22.73, 13.25. IR: 2230, 1686. HRMS:

289.101399 (calcd 289.101075 for C15H1702N~S M+H). Anal. calcd. for

CI5HI6O2NzS (288.36): C 62.48, H 5.59, N 9.71, S 11.12%. Found: C 62.38, H

5.58, N 9.67, S 11.03%.

S-Ethyl 3-(4-cyanophenyl)-4,5-dihydro-5-isoxazoleethanethioate (3a):

yield 92%, >99.5 % purity, (96% LC solution yield), mp 92.0-93.2 "C; 'HNMR 6

7.77 ( d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 5.3-5.1 (m, IH), 3.53 (dd, J =

17.0, 10.4 Hz, lH), 3.3-3.05 (m, 2H), 3.00-2.80 (m, 3H), 1.27 (t, J = 7.5 Hz, 3H).

CNMR 6 195.65, 155.24, 133.54, 132.38, 127.05, 118.14, 113.41, 78.03, 48.35,

39.27, 23.49, 14.44. R: 2228, 1684. HRMS: 275.085274 (calcd 275.085425 for

C I ~ H I ~ O ~ N ~ S M+H). Anal. calcd. for C I ~ H ~ ~ O Z N ~ S (274.34): C 61.29, H 5.14, N

10.21,s 11.68%.Found:C61.45,H5.23,N10.15,S 11.96%.

13

S-( 1-Methylethyl) 3-(4-cyanophenyl)-4,5-dihydro-5-

isoxazoleethanethioate (3c): yield 67% (98% HPLC solution yield), mp 97.0-

98.0 "C; IHNMR 6 7.77 (d J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 5.30-5.10

(m, lH), 3.69 (septet, J = 6.8 Hz, lH), 3.51 (dd, J = 16.9, 10.4 Hz, IH), 3.25-3.05

(m, 2H), 2.90-2.75 (m, lH), 1.31 (dd, J = 6.9, 2.4 Hz, 6H). 13CNMR 6 195.79,

155.27, 133.57, 132.44, 127.10, 118.24, 113.46,78.08,48.43, 39.31, 35.10,22.80,

22.77. HRMS: 289.099075 (calcd 289.101075 for C H H I ~ O ~ N ~ S M+H). Anal.

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

3818 PESTI, YIN, AND CHUNG

calcd. for C15IiI,,02N2S (288.36): C 62.48, H 5.59, N 9.71, S 11.12%. Found: C

62.51, H 5.62, h 0.63, S 11.03%.

S-Butyl 3-~4-cyanophenyl)-4,5-dihydro-5-isoxazoleethanethioate (3d):

yield 87%, rnp 71 0-72.0 "C; 'HNMR 6 7.75 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4

Hz, 2H), 5.25-5 1 0 (m, lH), 3.50 (dd, J = 16.8, 10.8 Hz, lH), 3.25-3.05 (m, 2H),

2.95-2.80 (m, 311). 1.65-1.45 (m, 2H), 1.45-1.30 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

CNMR 6 195.80, 155.25, 133.54, 132.42, 127.08, 118.21, 113.43, 78.07, 48.40,

39.29, 31.33, 28.79, 21.85, 13.48. IR: 2228, 1682. HRMS: 303.116758 (calcd

303.1 16725 for C ' I ~ H ~ ~ O ~ N ~ S M+H). Anal. calcd. for C ~ ~ H I X O ~ N ~ S (302.39): C

63.59, H 6.00, h 0.26, S 10.58%. Found: C 63.69, H 5.99, N 9.14, S 10.34%.

I 3

S-( l,l-Dimethylethyl)-3-(4-cyanophenyl)-4,5-dihydro-5-

isoxazoleethanethioate (3e): yield 63%, 94% purity, (LC solution yield 82%),

mp 129.0-129.8 ('; 'HNMR 6 7.75 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H),

5.20-5.05 (m, 111). 3.49 (dd, J = 17.1, 10.5 Hz, IH), 3.15 (dd, J = 17.1,7.3 Hz,

lH), 3.02 (dd, J = 15.3, 5.2 Hz, lH), 2.76 (dd, J = 15.3, 7.5 Hz, lH), 1.45 (s, 9H).

CNMR 6 196 34. 155.25, 133.63, 132.38, 127.08, 118.18, 113.41,78.14,48.85, I 3

48.76, 39.20, 29.65. IR: 2228, 1672. HRMS: 303.116148 (calcd 303.116725 for

CI6Hl9O2N2S M+H). Anal. calcd. for C16H1802N2S (302.39): C 63.59, H 6.00, N

9.26, S 10.58%. Found: C 63.63, H 6.01, N 9.20, S 10.86%.

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

THIOL CARBOXYLIC ESTERS 3819

Acknowledgements

The authors are grateful to John Blackwell for analytical support, and R.J.

Cvetovich for the review of a preliminary manuscript.

References and Notes

1) a) Zhang, L.-H.; Anzalone, L.; Ma, P.; Kauffman, G.S.; Storace, L.; Ward, R.

Tetrahedron Lert. 1996, 37, 4455. b) Zhang, L.-H.; Chung, J.C.; Costello, T.D.;

Valvis, I.; Ma, P.; Kauffman, G.S.; Ward, R. J. Org. Chem. 1997,62, 2466.

2) Morrison, J.D. “Asymmetric Synthesis,” Academic, New York, 1983, Vol.

11, pp. 3-6.

3) Cgen, C.S.; Fujimoto, Y.; Girdaukas, G.; Sih, C.J. J. Am. Chem. SOC. 1982,

104, 7294.

4) Fulling, G.; Sih, C.J. J. Am. Chem. SOC. 1987,109,2845.

5 ) Pesti, J.A., Yin, J., Zhang, L.-H., and Anzalone, L. Manuscript in preparation.

6) Reissig, H.U.; Scherer, B. Tetrahedron Letters 1980, 21,4259.

7 ) Voss, J. “Comprehensive Organic Synthesis,” eds Trost, B.M. and Fleming, I.,

Pergamon Press, Oxford, 1991, vol. 6, ch.2.5, p. 435-459.

8) a) Corey, E.J.; Beames, D.J. J. Am. Chem. SOC. 1973, 95, 5830; b) Hatch,

R.P.; Weinreb, S.M. J . Org. Chem. 1977, 42 , 3960; c) Cohen, T.; Gapinslu, R.E.

Tetrahedron Letters 1978, 19, 4319; d) Warwel, S.; Ahlfaenger, B. Chem. Ztg.

1977,101, 103.

9) Mukaiyama, T.; Takeda, T.; Atsumi, K. Chemistry Lett. 1974, 187.

10) a) Krause, N. Chemishe Ber. 1990, 123,2173; b) Vigante, V.A.; Ozols, Y.A.;

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4

3820 PESTI, YIN, AND CHUNG

Dubur, G.Y. Khimiya Geterotsiklicheskikh Soedinenii 1991, 7,953.

11)Preparation of the isobutyl ester 1 is the most efficient route to 2 since

isohutyl vinylacetate is available for cycloaddition to form the substituted

isoxazoline ring. The corresponding carhoxylic acid, vinyl acetic acid, is far more

expensive and the cycloaddition does not proceed well. Otherwise, we could have

produced racemic 2 directly and used any of a number of means to form the

thiolester for resolution to (R)-2.

12) a) Abel, E.W. J. Chern. SOC. 1960, 4406; b) Glass, R.S. J. Orgaiionietallic

Chern. 1973, 61, 81; c) Kuwajima, 1.; Abe, T. BulZ. Ckern. SOC. Japaii 1978, 5 1 ,

2183; d) Olah, G.A.; Husain, A.; Gupta, B.G.B.; Salem, G.F.; Narang, S.C. J.

Org. Chern. 1981. 46, 5212; e) Aizpurua, J.M.; Palomo, C.; Palomo, A.L. Can. J.

Chern. 1984, 62, 336; f) Aizpurua, J.M.; Palomo, C. Tetruliedroii Letters 1985,

26,475; g) Takagi, K. Cliernistry Lett. 1986, 1379.

(Received in the USA 06 April 1999)

Dow

nloa

ded

by [

Uni

vers

ity o

f Il

linoi

s C

hica

go]

at 2

0:31

18

Oct

ober

201

4