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DEVELOPMENT &ENGINEERING0 CENTERC T

ERDEC-TR-073

NOVEL APPROACHES TO THE SYNTHESIS OF CARFENTANIL

Bertrand 0. Fraser-ReidKalula Taba

DUKE UNIVERSITY

Durham, NC 27706

Harold D. Banks

RESEARCH AND TECHNOLOGY DIRECTORATE

D"TXC May 1993

S~~AIND BIOLOGICAL A

Al'-' P•roving Ground. Minryand 21010-5423

93- 16154 4~~A A~~' .

i T• I I ti,•, lii

Disclaimer

The findings in this report ?re not to be construed as anofficial Deparr-menc of the Army position unless so designaced byother authorizing documents.

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F .1993 May Final, 91 May - 92 May4. TITLE AND SUBTITLE 5. FUNDING NUMBERSNovel Approaches to the Synthesis of Carfentanil PR-1L161102A71A

6. AUTHOR(S)

Fraser-Reid, Bertrand 0.; ¶raba, Kalula(Duke University); and Banks, Hiarold D. (ERDEC)

7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATIONREPORT NUMBER

Duke Universityr Department of Chemistry, ERDEC-7'R-073Durham, NC 27706

DIR, ERDEC,* ATTN: SCBRD-RTC, APG, MD 21010-5423

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1.SUPPLIEMENTARY NOTES*At the time this Work waLs completed, ERWEC was known as the U.S. Arm~y Chemical

Resear50.1ch, Dievelopment, andu ExyIezm exutez., mild LIUe EtsE 4LuLiju Wata cue~utidi tuthe ReEiearch Directorate.

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Approved for public release; distribution is unlimited.

13. ABSTRACT (Maximum 200 words)

m.--.-.....-.1 apro1 "h -,,a-s.~ of carcfarn-1 4.r -- ancq .At ~tl.e.-t did

not involve the hydrolysis of the corresponding a-aminonitrile. Starting withcommnercially available l-beruzyl-4-piperidone, regioselective cleavage of an jexoxrysulfone, an aza 13.3] sigmatropic rearrangement and axninolysis of a 1L-bromo-1,2-diene were studied. Of these, -..he most promising was the sigmat~ropicrearrangement.

14. -SUBJECT TERMS IS. NUMBER OF PAGESCarfentanil 20Aza siginatropic rearrangement 1 6. PRICE CODEPiperidine

17. 5ECURITY CLASSIFICATION 18. SECURITY ClASSIFICATION 1,q. SCURITY CLASSIFICATION 20. LIMI tATlION OF ABSTRACTOF REPORT OF THIS PAGF OF ABSTRACI

UN4CLASSIFIED UNCLSli11 1CLASSIFIED DjL

?'JSN 75110 01 281)5500 Startdtid Form 296 tRev 2-89)Prescr, ad by Af4f Std 139 1S29P10

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2

PREFACE

The work described in this report was authorized underProje~ct No. IL161102A71A, Research in CWj/CB Defense. This workwas started in May 1991 and completed in May 1992.

The use of trade names or manufacturers' names in thisreport does not constitute an officia1 endorsement of anycommercial products. This report may not be cited for purposesof advertisement.

Reproduction of this document in whole or in part isprohibited except with permission of the Director, U.S. ArmyEdgewood Research, Development and Engineering Center (ERDEC),*ATTN: SCBRD-RT, Aberdeen Proving Ground, MD 21010-5423.However, the Defense Technical Information Center and theNational Technical Information Service are authorized toreproduce the document for U.S. Government purposes.

This report has been approved for release to thepublic.

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* At the time this work was completed, ERDEC was known as theU.S. Army Chemical Research, Development and EngineeringCenter, and che ERDEC author was assigned to the ResearchDirectorate.

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CONTEINTS

Page

1. INTRODUCTION ................ ................. 7

2. RESULTS AND DISCUSSION .............. ......... 9

3. EXPERIMENTAL METHODS ................ 12

4. CONCLUSIONS ................. .................. 15

LITERATURE CITED ....... .............. .. 17

5[

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U

NOVEL APPROACHES TO THESYNTHESIS OF CARFENTANIL

1. INTRODUCTION

Drug action is mediated by means of macromolecular siteswhich bind to the drug. This idea was suggested in 1905 byLangley, and extensively elaborated by Ehrlich. 1 Thisbinding is often chemo-, regio-, diastereo- andenantiospecific. Binding is not, however, an all-or-nothingphenomenon, and various substances have differing affinityconstants for a given receptor. The nature of bindingappears to be considerably more complex than the originallock and key paradigm of Emil Fischer, requiring not onlycomplementary geometric features, but also favorableelectrostatic forces, hydrogen bonding, hydrophobicinteractions, etc. 2 A glove and hand model appears to becloser to the actual binding mechanism, with each participantmodifiying its shape to better accommodate the other from theinitial interaction to the final binding.

Since the discovery of morphine by Sertarner in 1806,man'c knowledge of the mediation of response to intense painthrough the administration of opiates (drugs that alleviateintense pain by means of CNS activity)) has grown. Severalreceptors, p, 8, and x, have been identified based on thesignal nature of the response to a particular drug as well asantagonism by a specific moiety. The morphine family ofanalgesics bind to the g-receptor. Evidence has recently beenpresented that strongly suggests that there are actually twosites, gl (less selective and R2 (morphine-selective.) 2 b(see p.112 for respiratory depression) It has been suggestedthat X agonists possessing activity can block therespiratory depressant effects of morphine. 3

Due to the complexity of response to opiates it wasdeemed desirable to keep the concentration of the drug low atthe receptor. Under these conditions, only the high affinitysites would be affected by the drug. If the analgesic sitesare high affinity, then the discovery of extremely potentopiates would be highly desirable. Some success hasbeen realized in the isolation of analgesics from naturalproducts; for example, codeine was extracted by Robiquet in

7

1832 from morphine's source, the opium poppy (Papaversomniferum). The most significant discoveries, however, weremade by synthetic chemists, punctuated by the serendipitousdiscovery of the analgesic properties of meperidine, 4 areadily synthesized compound possessing one-eighth thepotency of morphine in rp'an, 5 and the spectacular fi:nding inthe 1960's that fentanyl 1 has a potency of almost 300 tii,,esthat of morphine, . The discovery of fentanyl triggered aflurry of synthetic activity over the next 30 years, usingfentanyl as a lead compound. Of the myriad compounds tested,several had very interesting pharmacological profiles. 6 [vanDaele, et a!.] This report is concerned with a novelsynthetic approach to one of these compounds, "carfentanil,"N-[1-(2-phenylethyl)-4-methoxycarbonyl-4-piperidinyl]-N-phenylpropanamide 2.6,7

Ph Ph PhI I I

6 NCOEt H3 COOC "4OEt 6 'Jb ON

CH2 CH2 Ph CH2 CH 2 Ph CH 2 CH2 Ph

1 23

Synthetic approaches to 2 invariabl-- begin with a-aminonitrile 3, which is readily avail ... 2 from commerciallyavailable l-(2-phenylethyl)--4-piperid(., by means of aStrecker synthesis using aniline and potassium cyanide inacetic acid under optimum conditions. 8 Transformation oft-hs:4 A-cyAnn fimrtin ci-(~rd in-~ ri t -4yntil fuc.o nfraught with difficulties arising from reversion of 3 to thestarting ketone, and the resistance of the intermediate amideto transformation into the ester function by means of theintermediat a-amino acid. Thus, the original Janssenprocedure resulted in an overall yield of only 1%.6Significant improvements in yield have been achieved indirect transformation of the cyano function into themethoxycarbonyl by Taber. 9 Conversion of the carboxamideinto the methoxycarbonyl group in a slightly different systemhas been successfully effected. 1 0 Feldman and BrackeeniIdeveloped a syrith-sis that depended on the transformation of3 to an hydantoin, an intermediate in a classical route to a-amino acidc.12

8

We sought to develop novel synthetic routes for 2 thatwould not proceed through 3. The starting material in thisinvestigation was commercially available l-benzyl-4-piperidone. The protecting benzyl function can be readilycleaved by means of catalytic hydrogenation, and theresulting piperidine alkylated with l-chloro-2-phenyiethaneto provide 2.

2. RESULTS AND DISCUSSION

Our first approach to 2 is outlined in Scheme 1.

Scheme 1

I I I IC0 2 Ph CH2 Ph CH2 Ph CH2 Ch

Incentive for pursuing this route was supplied by the findingthat a-azido aldehydes can be obtained by azide ion

exploited in the synthesis of a-amino acids and branchedsugars. 1 3 Opening of a,p-epoxysulfone 4 with aniline is thekey reaction in this sequence. This reaction should occurregioselectively, yielding in principle a-anilinoaldehyde 5which, after oxidation, would a-amino acid 6. Darzenreaction of l-benzyl-4-piperidone withchloromethylphenylsulf one. 1 4 led to isolation of 5 in 97%yield. Aminolysis of oxiranes has been found to occur readilyin the presence of Lewis acids 1 5, 17 or metal ions. 18

Accordingly,4 was treated with aJ.umxna, a 1, wis acid, usingPosner's method. 1 9 Under these conditions, the startingmaterial decomposed. Similar results were obtained withcobalt (II) chloride2 0 , titanium isopropoxidel 6 and lithium

9

perchlorate. 1 8 Even the Grignard reagent, anilinomagnesiumbromide, failed to give the desired product.

The second approach to 2 was based on an aza [3.3]sigmatropic rearrangement of unsaturated urethane 7. Thjeral

Scheme 2

OOEt CH 2OH

Nail DIdAL

(EtO) 2 POCH 2 QOOEt -780

CH2 Ph C 2 Ph

P h N C O P d Ui )

I N H P h

N 3N

I ICH 2 Ph CH 2 Ph

9~ 30

8-

I 3C liH3

CA2 och N, -K-Nh

Pd(II) 03

I ~IPhNCCChH 3 2 Ph Ci 21'h

11 12 13

and metal-catalyzed rear-ngements of allyl imidates have

10

provided a convenient means of formation of allylic carbon-nitrogen bonds. 2 1 , 2 2 The required carbamate S was preparedfrom 4 by means of a Horner-Emmons modification of the Wittigreacti,,n. The ethoxycarbonyl function of 7 could becarefully reduced with diisobutylaluminum hydride (DIBAL) at-780. Treatnment of 8 with phenylisocydnte in triethylaminegave 9 in an overall yield of 65%.

Attempted [3.3]sigmatropic rearrangement of 9 with acatalytic amount of Pd(PhCN) 2 Cl 2 in refluxing toluene orxylene led to recovery of starting material.

Failure to achieve [3.3] sigmatropic rearrangement withcarbamate 9 prompted consideration of iiiiidate 11 which haspreexisting C=C and C=N bonds. Accordingly, 8 was treatedwith n-BuLi, followed by phenylacetamrtide. The crude productwas treated directly with Pd(PhCN) 2 CI 2 and refluxed in toluenefor 15 h. Flash chromatography of the crude product produced1• in. 20% yield. A preliminary study of the ozonolysis of 10did not result in formation of desired aniilidoaldehyde 13,but rather polar material that proved difficult to isolateand characterize. It is possible that ozonolysis wasnonchemoselective, occuring not oniy at-. the desired position,but also at the ring nitrogen as well.

A third approach was suggested by the work of Caporussoand ccworkers 2 5 who found that proparcylamines were obtainedin higi: yield by aminolysis of 1-bromo-1,2-dienes 2 4 in thepresence of copper(T) bromide. For example, under theseconditions, cyclohexylallene gave l-ethynyl-l-aminocyclohexane. Thus, a preparation of bromoallene 15 wassought. The route for conversion to desired amino acid 17 ispresented in Scneme 3. Bromoallenes have been prepared froma-ethynyl alcohols. 2 5 ,2 6 When 4 was treated with sodiumacetylide, an 80% yield -)f alcohol 14 was isolated. When 14was subjected to the reported procedures 2 7 , 28 no 15 wasobtained. It is likely that LiCuBr 2 formed a complex withfthcn -.- nrfl nr tr- v gr~ o -r~t-ligý, 1-i An "n-rf- 4 r-ýY-N~- rirT n mtocly1 =t-ý

displacement.

11

Scheme 3

(I3r

NaC r=CH n-Buli

THF N )1 cLiCiBr2

CH2 Ph CH2 Ph

24 15

ILNHPh HOWC NNPh

CH2 Ph CH2 Ph

16

3. EXPERIMENTAL METHODS

1 H and 1 3 C NMR spectra were recorded with a Varian XL-

300 spectrometer operating at 300.0 arid 75 MHz respectively.Chemical shifts are reported in 6 values usingtetramethylsilane &s in internal standard. Chemicalionization mass spectrometry was done with 10% NH3 in methanewith a source temperature of 1500. Tetrahydrofuran (VHF) wasdistilled from benzophenone ketyl under an argon atmosphere.

3.1 2'-Phenylsulfonyl-5-benzyl-l-oxa-5-auzaepiror2.5]octane(5). To a solution of chloromethylphenyl sultone (5.03 g,26.4 mmol) and l-benzyl-4-piperidone (5.00 g, 26.4 mmol) in100 nL of dry THF maintained at -100 was added a solution ofpotassium tert-butoxide (2.96 g, 26.4 mmol) in tert-butanol.The reaction mixture was then allowed to come to roomtemperature and was stirred for 8 h. It was then poured into500 mL of water and extracted with ether. The ether extracts

12

were conbined, dried (Na2SO4) and concenwrated, providing aviscous brown material. The crude product after purificationby flash chromatography on silica gel using 1:1 ethylacetate/petroleum ether (v:v) provided 8.8.g (97.01) of 5, rMAp

= 80 - 820 C. 1 H NMR 1.45 - 1.55 (m, IH); 1.85 - 1.95 (m,1H); 2.35 - 2.85 (m, 6H); 3.55 (d, 2H, CH2 Ph); 3.80 (s, IH);7.20 - 7.40 (m, 5H, aromatic protons); 7.55 - 7.70 (m, 3R,aromatic protons); 7.95 (d, 2H, aromatic protons). 13C NMR:32, 48, 49, 56, 62, 114, 114.5, 117, 120, 125, 126, 128,128.7, 128.9, 129, 138, 145, 170. Anal. Calcd forCI9H21NS03: C, 66.5; H, 6.1; N, 4.1. Found: C, 66.5; H,6.1; N, 4.1.

3.2 1-Benzyl-4- [ (ethoxylcarbonyl)methyleneJ piperidine (7).Sodium hydride (2.21 g of a 60% suspension in mineral oil,53.2 mmol) was washed twice with 50 mL of pentane under anitrogen atmosphere and then 50 Ml of dry THF was added.Triethylphosphonoacetate (12.35 g , 55.10 mmol) was addeddropwise 30 min before the addition of 4 (10.43 g , 55.50mmol). The mixture became yellow and sticky. After 20 minthe reaction mixture was agitated with 500 mL, of water andextracted with Et20. The ethe.s layers were dried (Na2SO4) andconcentrated to yield a quantitative yield of the ester,I H NMR: 1.25 (t, 3H, CHG3 ); 2.3 - 3.0 (m, 6H); 3.5 (s, 2H,CH2 Ph); 4.12 (q, 2H, CH2 ); 5.62 (s, 1H, CH); 7.35 (s, 5H,aromatic).

3.3 1-Benzyl-4- [ (l-hydroxymethyl)metbylene) ]piperidine (8).Diisobutylaluminium hydride (100 mL, 1.0 M in THF, 100 nmmol)was added dropwise to a solution of 7 (14.5 g, 55.9 mmol) inCH2C12 at -780 C. The reaction mixture was stirred for anadditional 2 h, brought to 00 C, and quenched with saturatedaqueous NH4CI, followed by addition of 40 mL of 1N NaOH. Themixture was filtered through a Celite pad. The organic layerwas separated, and the aqueous layer extracted with ether.The combined organic layers were dried (Na2SO) andconcentrated. Purification by silica gel chromatography,eluting with 2:1 ethyl acetate/petroleum ether (v:v),provided 10.7 g (87.0%) of product, 1 H NMR: 2.20 - 2.50 (i,8H); 3.5 (s, 2H, CH2 Ph); 4.15 (d, 2H, CH2OH); 5.40 (t, 1H,CH); 7.20 - 7.25 (m, 5H, aromatic).

3.4 N- [ (1-Benzyl-4-piperidilenyl)m~thoxycarbonylJ aniline(9). To a solution of allyic alcohol 8 (1.5g, 6.9 mmol) in 40ML of dry CH2C12 was added 1.9 mL (13.6 mmol) oftriethylamine, followed by addition of 1.2 mL (10 mmol) ofphenylisosyanate. The reaction mixture was stirred overnightat room temperature. Saturated aqueous NH4Cl (30 mL) wasadded, and after the organic layer was separated, the aqueous

13

layer was extracted with CH2C12 After drying Na2SO4), thecombined organic layers were concentrated and passed througha silica gel column, eluting with 1:1 ethyl acetate/petroleumether (v:v), to yield 2.14 g (92.1%) of carbamate 8. mp = 80- 820 C. I H NMR: 2.2 - 2.5 (m, 8H); 3.5 (s, 2H, CH2 Ph); 4.6(c, 21, CH2 OCONHPh) ; 5.4 (t, 1H, CH) ; 6.65 (br. s, 1H, NH);7.0 - 7.5 (m, 10H, aromatic). Mass spec: 337 (M+), 293,200. Anal. Calcd for C21H24N202: C, 74.9; H,7.0; N, 8.3.Found: C, 74.3; H, 7.1; N,8.3.

3.5 1-Dený.i-44-ethylnyl-4-piperidino1 (14). Sodiumacetyli6,- (15 niL, 18% suspension in xylene) was added to asolution of 5.00 g (26.4) of 4 in 40 mL of THF. The reactionrtru.-,ure was stirred at 40 - 500 C for 6 h. After cooling thereaction mixture was mixed with an equal volume of water, andthe aqueous ph.se dried over MgSO 4 . Concentration gave ayellow solid that was collected by filtration, and washedseveral tinte., with n-pentane to provide 4.5 g (80%) of 14,ip = 152 - 1530 C. 1 H NMR: 1.9 - 2.8 (in, 10 ): 3.5 (s, 2H,

KII 2 Ph); 7.2 - 7.4 (m, 5H, aromatic). Mass spec: 215 (M+),1b9.

.6 N- (l-Benzyl-4-vinyl-4 -piperidinyl) -N-phenyletaaAmide(12). A inixture of PC1 5 (7.25 g, 35.0 mrtol) and N-,.':enylacetamide '4.72, 35.0 rmmol) in benzene (25 mL) wasrefluxed for 1 'i. After removal of the solvent and POC13 invacuo, the zej":ion vessel was filled with Ar, and 10 mL ofdry THF wa• added. This solution was added dropwise to thelithium alkoxide solution prepared by the dropwise additionof 2M n-BuLi (18.9 mL, 38,8 inmol) to 8.44 g (38.8 rmeol) of;tllylic alcohol 8 at 00 C, followed by stirring for 30 rain.The resulting mixture waq stirred at room temperature for15 h. The solvent was removed and the residue dissolved inUH2Ci2. Atter washing with saturated aqueous NH4 CI, theorganic layer was dried (Na2SO4) and concentrated to give thecrude imidate 11. 1 H NMR: 1.4 (t, 3H, Ck-4); 2.2 - 2.4 (m,8H); 3.75 (s, 2H, CH2 Ph); 4.8 (d, 2H, CH2); 5.5 (s, IH, CH);7.0 - 7.8 (m, 10H, aromatic).

The crude imidate was dissolved in dry toluene andPd(C6H5CN)2C12 (300 mg) was added. The reaction mixture wasrefluxed overnight, and after cooling and removal of solvent,the product was isolated by chronmotography on silica gel,eluting with 1:1 ethyl acetate/petroleum ether (v:v) in 20%yield (2.04 g). 1 H NMR: 14 - 2.7 (m, 8H); 3.5 (,, 21f,CH2 Ph); 5.2 (q, 2H, CHJ2 ); 6.0 (ni, 1H, CH); 6.7 (s, 1I1, NH);6.6 - 7.2 (m, 1011, aromatic). Mass spec: 292 (M÷), 200.

14

4. CONCLUSIONS

Three novel synthetic approaches to the extremely potentopioid, carfentanil, have been explored. These were cleavageof a phenylsulfonyl epoxide by aniline, an aza (3.3]sigmatropic rearrangement, and aminolysis of a bromoallene.ý,hile tirae did not permit a rigorous exploration of an>o ofthese routes, the chemistry reported here should serve as apoint of departure for additional research on syntheticroutes that are not based on a-aminonitrile hydrolyticroutes.

15

)iiarik

16

LITERATURE CITED

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- ~Pharmacology, Wiley-Intersci~ence, New York, pp 128 - 136,1970.

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142, 1988. (c) Zimmerman, D.M.; Leander, J.D., NSelectiveOpioid Receptor Agonists and Antagonists: Research Tools andPotential Therapeutic Agents," J. Med. Chem., Vol. 33, pp 895- 902 (1990) . (d) Snyder, S.H., "Drug and NeurotransmitterReceptors in the Brain," Science, Vol. 224, pp 22 - 31(1984). (e) Portoghese, P.S., "Sterecisomeric Ligands asOpioid Receptor Proben," Accts. Chem~. Res., Vol. 11, pp 21 -

29 (1978). (f) Casy, A.F., "Analgesics and TheirAntagoni.sts: Recent Developments,* Ellis, G.P.; West,G.D.,EDS., In Pr gQes in Medig.jnal Chemnistr , Butterworths,London, Vol. 7, pp. 229 - 284 , 1970. (g) Thorpe, D.H.,"Opiate Structure and Ac~;vity-A Guide to Understanding theReceptor," Anesth. Analg.., Vol. 63, pp 143 - 151. (1984).(h) Lena, G.Ii.; Evans, S.M.; Walters, D.E.; Hopfinger, A.J.,Opiates, Academic Press, Inc., New York, pp 318 - 376 (1986).(i) Martin, W.R., Pharmacology of Opioids," Pharmacol.Revs., Vol.35, pp 283- 323 (1984). (j) Barnard, E.A.;Demoliou-Mason, C., "Molecular Properties of OpioidReceptors,"' Brit. Med. Bull., Vol. 39, pp 37 - 45 ( 1983).(k) Chang, K-J., "Opioid Receptors: Multiplicity andSequelae of Ligand-Receptor Interactions," Conn, M.P. ED.,Academic Press, Inc., New York, pp I - 81 (1984). (1) Chau-Pharn. T.T., "The Opiate Receptors and the Discovery ofPepti~de-like Peptides," Drug. Met. Revi., Vol. 7, pp 255 -294 (1978).

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7. Compounds having structures similar to carfentanil nvebeen synthesized and evaluated ph~rmacologically:(a) Colapret, J.A.; Diamantidis, G.; Spencer, H.K.;Spaulding, T.C., 'Synthesis and Pharmacological Evalutaion of4,4-Disubstituted Piperidines," J. Med. Chem., Vol. 32, pp968 - 974 (1989). (b) Bagley, J.R.; Thomas, S.A.; Rudo,F.G.; Spencer, H.K.; Doorley, B.M.; Ossipov, M.H.; Jerussi,T.P.; Benvenga, M.J.; Spaulding, T., "New1-(Heterocyclylalkyl)-4-(proionanilido)-4-piperidinyl MethylEster and Methylene Methyl Ether Analgesics," J. Med. Chem.,Vol. 34, pp 827 - 841 (1991).

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18

15. 7amada, J-i.; Yumoto, M.; Yamamoto, Y., "AminoleadCompounds As A New Reagent For Regeoselective Ring Opening ofEpoxides," Tetranedron Lett., Vol. 30, pp 4255 - 4258 (1989).

16. Caaas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Peric~s,M.A.; Riera, A., "Regioslective Ring Opening of ChiralEpoxyalcohols by Primary Amines," Tetrahedron Le t., Vol. 32,pp 6931 - 6934 (1991).

17. Overman, L.E.; Flippin, L.A., "Facile Aminolysis ofEpoxides with Diethylaluminum Amides," Tetrahedron Lett.,Vol. 22, pp 195 - 198 ( 1591).

18. Chini, M; Crotti, P.; Macchia, F., "RegioalternatingSelectivity in the Metal Salt Catalyzed Aminolysis of StyreneOxide," J. Org. Chem., Vol. 56, 5939 - 5942 (1991).

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