AU619238B2 - Stereoselective preparation of 3-substituted-4-(phenyl anilo) piperidine compounds and derivatives - Google Patents

Description

B OPI DATE 01/06/89 APPLN. ID 28023 89 6 9 W o AOJP DATE 06/07/89 PCT NUMBER PCT/US88/03699 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 04300 C07D 211/58 Al (43) International Public nDate: 18 May 1989 (18.05.89) (21) International Application Number: PCT/US88/03699 (74) Agent: MELLER, Michael, P.O. Box 2198, Grand Central Station, New York, NY 10163 (US).

(22) International Filing Date: 21 October 1988 (21.10.88) (81) Designated States: AT (European patent), AU, BE (Eu- (31) Priority Application Number: 115,276 ropean patent), CH (European patent), DE (European patent), DK, FI, FR (European patent), GB (32) Priority Date: 2 November 1987 (02.11.87) (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), NO, SE (33) Priority Country: US (European patent).

(71) Applicant: BOC, INC. [US/US]; 85 Chestnut Ridge Published Road, Montvale, NJ 07645 With international search report.

Before the expiration of the time limit for amending the (72) Inventors: KUDZMA, Linas, Vladas 7435 Boulevard claims and to be republished in the event of the receipt East, North, North Bergen, NJ 07047 SPEN- of amendments.

CER, Homer, Kenneth 35 Hilltop Terrace, Chatham, NJ 07928 SEVERNAK, Sherry, Ann 131 East Ninth Street, Plainfield, NJ 07060 (US).

'(54)Title: STEREOSELECTIVE PREPARATION OF 3-SUBSTITUTED-4-(PHENYL ANILO) PIPERIDINE COM- POUNDS AND DERIVATIVES Abstract The present invention is directed to an improved stereoselective tandem substitution and reduction of an imine precursor to the cis form of 3-substituted-4-(phenyl anilo) piperidine compounds or their substituted derivatives.

,A 1 11:-1- 1 I II I~ t ii '1 PfW 89/03699 1 JIPLMW 19 JAIN1 -1- STEREOSELECTIVE PREPARATION OF 3-SUBSTITUTED-4- ANILINO-PIPERIDINE COMPOUNDS AND DERIVATIVES BACKGROUND OF THE INVENTION The present invention relates to a stereoselective tandem substitution and reduction reaction of 4-anilino-piperidine derivatives. The resulting 3,4-cis compounds are useful intermediates leading to intravenous analgesics.

U.S. Patent No. 4,584,303 discloses a method of preparing compounds of the following formula:

R

1 2 wherein R 1 is hydrogen or methyl; R 2 is phenyl or substituted phenyl; and

R

3 may be a variety of groups including phenyl alkyl. Hith respect to the R and NHR 2 substituents, it is desirable to obtain the more pharmacologically active cis isomer.

The method taught in U.S. Patent No. 4,584,303 for preparing compounds of the above formula requires a multi-step synthetic route involving the preparation of cis isomers at an advanced stage of the synthetic route.

Furthermore, a cis:trans ratio of not greater than 70:30 can be achieved.

o-1) two

Q-A

PCTM 89/03699 IPEA 19 JAIg19 90 J. Burke, Jr. et al., J. Med. Chem., Vol. 29, No. 6, pp 1087-1093 (1986), discloses a method to prepare piperidine derivatives, which method suffers the same disadvantages of the above-mentioned prior art method. Furthermore, the multi-step method of Burke et al. requires expensive starting materials and protection of the piperidine nitrogen.

The deprotonation of aliphatic imines followed by alkylation is generally known as, for example, shown by Collum et al., J. Am. Chem. Soc., Vol. 106, pp 4865-69 (1984). The reduction of an imine is in itself also conventional.

SUMMARY OF THE INVENTION The invention is directed to a method of preparing a compound of the following formula: 1

R

3 N NHR 2 wherein R is lower alkyl, lower cyclic alkyl, lower cyclic alkyl lower alkyl, lower alkenyl, or phenyl lower alkyl; R 2 is a phenyl or aromatic heterocycle ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations thereof; and R 3 can be a wide variety of groups, for example, selected from phenyl lower alkyl, thnill lo:, k.y, hI a t-tr o1 1 yl) lo.er alkyil, whirh can b- -ubsituted i; th- 1 p- lwerfP-a4cy-, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof.

According to the method of the present invention, an aryl imine precursor is capable of being stereoselectively substituted in a single reactor without requiring intermediate separations or purifications. Readily available starting materials are utilized and no special pr6tection of the piperidine ^S ujI ~SSTYw1i WB 91 lMtf Iiii nitrogen is necessary. Very high selectivity of the cis isomer (typically 96%) can be achieved, resulting in an easier purification at an early stage of the overall synthetic route leading to the final product. Production of the non-recyclable trans isomer is minimized.

According to a first embodiment of this invention, there is provided a method of 3 1 preparing the cis isomer of a 1-R -3-R 1 -4-anilinopiperidine, wherein the phenyl portion of the anilino group may be substituted or unsubstituted and wherein: R is lower alkyl, lower cyclic alkyl lower cyclic alkyl lower alkyl, phenyl lower 3 c.orsiss 'f alkyl, or lower alkenyl; R I omprises phenyl lower alkyl, rMlI l i ywh'icbh c-an -ubtitut.Cd--in t^ 4p..tin it n QLo ay gu 41-p ith a l-or al.kyl or substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof, said method comprising: deprotonating a 4-(N-phenyl) iminopiperidine with a non-nucleophilic base to form a deprotonated anion at the three position of the piperidine ring; (ii) reacting said anion with a substituting agent to introduce an R 1 group in S•said three position; and (iii) reducing the compound of step (ii) with a sterically hindered reducing Sagent, to produce the cis isomer thereof whereby a cis:trans selectivity of greater than about 90 percent is obtainable.

According to a second embodiment of this invention, there is provided a method 3 1 of preparing a cis isomer of a 1-R -3-R -4-anilinopiperidine of the formula: 1 wherein R is a lower alkyl, lower cyclic alkyl, lower cyclic alkyl lower alkyl, lower alkyl, lower alkenyl, or phenyl lower alkyl; R 2 is a phenyl group which may be substituted with one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, halogen or combinations thereof and R 3 comprises phenyl lower alkyl, or substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof; said method comprising: 5309459/309 26/08/91 3A 2 reacting 1 2 N-R with a compound of the following formula: 2 to form an imine compound of the formula (ii) deprotonating the imine compound with a non-nucleophilic base to form a deprotonated anion at the three position of the piperidine ring; (iii) reacting said anion with a substituting agent to introduce an R 1 group in said three position; and ge se reducing the compound of step (iii) with a sterically hindered selectivity of greater than about 90 percent is obtainable.

i 26/08/91 3B DETAILED DESCRIPTION OF THE INVENTION Applicants have found an improved method for the efficient and economical preparation of compounds according to the formula below: R1

R

3 N N 2 1 wherein R 1 is lower alkyl, lower cyclic alkyl, lower cyclic alkyl lower alkyl, 2 lower alkenyl, or phenyl lower alkyl; R is a phenyl or aromatic heterocyclic ring either of which may be substituted with one or more groups selected from the group consisting of lower alkoxy, lower alkyl, halogen, or combinations S 3 "-r-kcV-o p S: thereof; and R is selected g-r-m w k a-id ae-it with a 840llo alhYl group, (4,5 H i va R-i~u'lli *lulryl.

t, t Ly ,zvcr zl ky i ~ttr.LJ X. U r.u if) te ,I-itn Wy4, and substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof.

S By the term lower alkyl, lower alkoxy, lower cyclic alkyl, or lower alkenyl are meant branched or unbranched chain groups with seven or less carbon atoms and preferably 5 or less carbons. By aromatic heterocyclic ring is meant a fully unsaturated ring having 5 or 6 members including 0-3 nitrogen atoms and 0-2 oxygen or sulfur atoms. The term halogen is meant to include fluoro, chloro, bromo, or iodo substituents.

Examples of suitable R groups include methyl, ethyl, cyclopropyl, cyclopropylmethyl, allyl and benzyl.

/309 26/08/91 0459/309- 26/08/91 PCT/IS 8/03699 IPEA S 19 JA 1990 2 Examples of suitable R groups include phenyl, 2-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, pyrazolyl, or thienyl.

Examples of suitable R 3 groups include phenyl ethyl, benzyl, 2-(4-ethyl- 4-4,5-dihydro-5-oxo-lH-tetrazol-1-yl)ethyl, and 2-(4-methyl-thiazoyl)ethy1.

The route to compounds of the above formula proceeds as follows: R HNR

N-R

2 1 1 1 wherein R 1 R and R are as defined above and R 1 X is a reagent capable of adding the R I group to the 3 position of the piperidine ring, for example, a lower alkyl iodide alkylating agent.

It is noted that the present invention does not involve the N-substituted- 3-substituted-4-piperidone intermediate compound conventionally employed, for example, in the prior art synthetic route of U.S. Patent No. 4,584,303. This latter compound is difficult to make. Instead, Applicants' above described reaction scheme begins with the intermediate compound N-substituted-4-piperidone, which is commercially available from Aldrich Chemical Co. (Milwaukee, Wisconsin) or Chemical Dynamics Corp. (So. Plainfield, or else easily made by a Mannich condensation, as will be readily appreciated by those skilled in the art. The latter piperidone compound is then reacted with a substituted or unsubstituted phenyl amine or aromatic heterocyclic amine to form the imine precursor (II) above. This reaction is suitably carried out in the presence of p-toluene sulfonic acid and refluxed while collecting water.

The imine precursor (II) is then stirred at a low temperature with a nonnucleophilic base such as freshly prepared lithium diisopropyl amine in order S0 ssm$B w

IVE'

PCT/M 88/03699 5 IPEAU 19 JAN1990 to deprotonate the imine. Other suitable non-nucleophilic bases include LDC (lithium dicyclohexylamide), LIC (lithium isopropylcyclohexylamide), LTP (tetramethylpiperamide) and LHS [lithium bis(trimethylsilyl)] amide.

By removal of the alpha (to the schiff base) proton, the following anion is generated: 3- N 2 (IIa) Addition of a substituting agent RIX such as the alkylating agent alkyl iodide results in the anion IIa attacking the electrophile R X to form the following alkylated imine intermediate.

R

J

SNR~ (III) The most preferred substituting agents are iodides, bromides and chlorides. Tosylates and mesylates and other substituting agents known to those skilled In the art are also suitable.

Finally, without the necessity of isolating the alkylated imine compound (III), a very selective reduction to the desired valuable intermediate (IV) above is carried out. This reduction is a steric approach control reaction wherein the least crowded side of the alkylated imine compound (II) is preferably attacked by a relatively highly hindered reducing agent such as the hindered borohydride reducing agents.

sum Mt

S

PC

t M 88/03699 S(PE 19 JAN1990 -6- The most preferred reducing agent is "Super-Hyd ide", i.e. lithium triethylborohydride, because of its superior combination of cis selectivity and speed. Other preferred hindered borohydride reducing agents include L-selectride (lithium tri-sec-butylborohydride, 1.0 molar in THF) and NB-Enantride (lithium hydride, a 9-BBN-nopol- benzyl ether adduct, 0.5 molar in THF). A cis:trans selectivity of greater than 90 percent and typically 96 percent is thereby obtainable. Other suitable reducing agents include Red-Al S(sodium bis(2-methoxy-ethoxy)aluminum hydride, 3.4 molar in toluene, and LiAlH 4 Typically, a selectivity of only about 60-70 percent cis:trans is obtained with the latter reducing agents. All of the above named reducing agents are commercially available from Aldrich Chemical Co. (Milwaukee, WI).

A major advantage of the above described synthetic route is that the reactions occur in a single vessel by the sequential introduction of the necessary reactants. Consequently, successive isolations and purifications are obviated, thereby greatly simplifying the overall route to a variety of therapeutic agents, notably of the fentanyl type, which are used in humans for inducing anesthesia or analgesia, for example cis-l[2-4-ethyl-4-5-dihydro-5oxy-1H-tetrazol-l-yl)ethyl]-3-methyl-4-EN-2(2-fluorophenyl methoxyacetamido] piperidine hydrochloride. The remaining steps in the overall synthesis to such compounds are disclosed in detail in U.S. Patent No. 4,584,303 to Huang et al., which hereby is incorporated by reference. Other compounds which may be prepared by a synthetic route within the scope of the present invention include 8-hydroxyl-3-methylfentanyl and cis-3-methyl fentanyl (known in the chemical and pharmaceutical literature as F-7302 and R 26,800, respectively) which have demonstrated potent analgesic activity.

EXAMPLE 1 This example illustrates the preparation of 1-benzyl-3-(cls-methyl)-4- (2-fluorophenyl)amino piperidine. A solution of l-benzyl-4-piperidone, 15.20 gms (80.31 mmol), 2-fluoroanillne, 9.02 gms (81.17 mmol) and p-toluenesulfonic acid monohydrate, 0.48 gms in 200 ml of toluene was rofluxed overnight under argon collecting water in a Dean- Stark trap. After 18 hours the theoretical amount of water had separated and the trap was drained several times to dis- $f lA/ (J V- ,uj'"ka si t~n rT S i® sPCI/I 88/03699 7- IPEA/U 9 JAM till off 100 mis of toluene. The reaction was cooled under argon and diluted with 40 mls anhydrous THF. The deep orange solution of crude imine was used "as is" for next step.

?F

LDA was prepared under an atmosphere of argon by adding freshly distilled diisopropyl amine, 15 ml (107 mmol) dropwise to a cold (O0C) solution of m1s of 1.6M n-butyllithium (88 mmol) in hexane in 60 mis of anhydrous THF.

After 15 minutes at O"C the LDA solution was cooled to -78°C in an isopropanol-dry ice slush bath. The solution of imine (80.31 mmol) was added dropwise with stirring. The reaction was stirred at -78°C for 1 hour followed by rapid addition of methyl iodide, 12.9 gms (90.88 mmol). The reaction was stirred at -78C for 15 minutes followed by warming to room temperature.

After 10 minutes at -78'C a precipitate formed which redissolved as the reaction warmed up. After stirring at room temperature for 2 hours the reaction was cooled to O'C in an ice bath and 120 mis 1.0 M lithium triethylooroh)dride in THF was added dropwise via syringe. The reaction was stirred overnight (16 hours) warming to room temperature. The reaction was then cooled back down to 0OC and 50 mis of water was added slowly dropwise (exotherm and vigorous gas evolution). The quenched reaction mixture was concentrated to a pasty oil which was dissolved in 200 mls toluene and washed with 100 mls of water. The toluene layer was separated, dried over anhydrous sodium sulfate and concentrated to give a crude mixture of cis and trans diamine. Analytical LC showed the cis/trans diamine ratio to be 92.2:7.8.

This crude oil was flash chromatographed on Silica 60, 230-400 mesh (400 gms) eluting with 1:10 EtOAc/Hex with 0.1% ammonium hydroxide added to give 9.74 gms pure cis diamine shown below and 1.57 gms cis and trans diamine mixture. Total isolated yield of cis and trans diamine was 47.2%.

C I49 fl S3M TgO WIAJ p 1 PCT/ B8/03699 IPEA.JS 19 JAN So 55-560C NMR 7.40(s,SH), 7.20-6.35(m,4H), 3.90(br s,lH), 3.40 (br s,2H), 3.00-l.30(complex,8H), 0.95(d,3H) EXAMPLE 2 In an analogous manner to the synthesi s of Exampl e 1 except usi ng al ly] bromide as the substituting agent, the compound l-benzyl-3-Ccis-ally)-4-(2fluorophenyl)amino piperidine was prepared having the following formula: oil at room temnperature NMR 7.30(m,5H), 6.95(m,2H), 6.60(m,2H), 5.65(m,lH), 4.45(m,2H), 3.95(br 2,JH), 3.60(rn,lH), 3.50 (ABq,2H), 2.60-1.65(complex,9H) EXAMPLES In an analogous manner to the synthesis of Example 1, except using 1-lodopropane, benzyl bromide, and (bromomethyl)-cyclopropane, respectively as the substituting agent, the following compounds were prepared: 1-ezl3Ci-npoy)--2furpey~mn piperidine oil at R.T.

NMR: 7.40(s,5H), 7.40-6.50(m,4H), 3.95(br s,lH), 3.50(ABq,2H), 2. 60-0 .30( complex ,14H)

-F~

i 1

I

PCi/U 6-8./03699 IPE"S 19JAN i

C

l-benzyl-3-(cis-benzyl)-4-(2-fluorophenylamino) piperidine oil at R.T.

NMR: 7.40-6.40(complex,14H), 4.05(r,lH), 3.50(br s,2H) 3.85-1.45(complex,lOH)

F

l-benzyl-3-(cis-(cyclopropyl)methylj-4-(2-fluorophenylamino) piperidine oil at

R.T.

NMR: 7.50-6.50(m,9H), 4.35(m,lH), 3.40(br s,2H) 3.35-O.80(complex,10H), O.60-Q.05(m,5H) It will be understood that the embodiments described herein are merely exemplary and that a person skilled in the art may make variations and modifications without departing from the spirit and scope of the invention.

All such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.

Ni A

ILI

v- :s K~ffU7 ~~at MEMEElb-

Claims (20)

1. A method of preparing the cis isomer of a 1-R -3-R -4-anilinopiperidine, wherein the phenyl portion of the anilino group may be substituted or unsubstituted and wherein: R is lower alkyl, lower cyclic alkyl, lower cyclic 3 ConsSts alkyl lower alkyl, phenyl lower alkyl, or lower alkenyl; R oempRi4es phenyl lower alkyl, or substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, low-r alkoxy, lower alkyl or combinations thereof, said method comprising: deprotonating a 4-(N-phenyl) iminopiperidine with a non-nucleophilic base to form a deprotonated anion at the three position of the piperidine ring; 1 (ii) reacting said anion with a substituting agent to introduce an R group in said three position; and (iii) reducing the compound of step (ii) with a sterically hindered reducing agent, to produce the cis isomer thereof whereby a cis:trans selectivity Sof greater than about 90 percent is obtainable.

2. A method according to claim 1, wherein the cis isomer prepared is •S represented by the formula: R2 R3 N i 2 and wherein R is a phenyl group which may be substituted with one or more substituents selected from the group consisting of lower alkoxy, lower alkyl, halogen or combinations thereof and wherein the iminopiperidine of step i: 3460/309- 21/08/91 R =N-R| 0460/309 21/08/91 _1 ~-iil ~i il~' i -I I i I i -1 L l r 11

3. The meth d of claim 1 or 2, wherein said non-nucleophilic base is a lithium dilower alkyl amide. I or 5. ,.ArcA\r sc\ on- C\eo cse-

4. The method of claim3 h .roi. oi- lithium dlilower l.yl a is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropylcyclohexyl amide, lithium tetramethylpiperamide and lithium bis (trimethylsilyl) amide.

The method of any one of claims 1 to 4 wherein said substituting agent is an alkylating agent.

6. The method of any one of claims 1 to 5 wherein said deprotonating is carried out in a solvent comprising tetrahydrofuran.

7. The method of claim 5, wherein said alkylating agent is an iodide or tosylate.

8. The method of claim 7, wherein said iodide is an alkyl iodide.

9. The method of any one of claims 1 to 8, wherein said reducing agent is sodium bis (2-methoxy-ethoxy) aluminium hydride.

10. The method of any one of claims 1 to 8, wherein said reducing agent is S a hindered borohydride reducing agent.

11. The method of claim 9, wherein said hindered borohydride reducing agent is lithium triethylborohydride, lithium tri-sec-butyl borohydride, or lithium hydride (9- 1 fN-nopolbenzyl-ether adduct).

12. The method of any one of claims 1 to 11, wherein said steps through (iii) are carried out continuously without purification or isolation of intermediates.

13. The method of claim 12, wherein the said steps through (iii) are continuously carried out in the same reactor means. 090460/309 21/08/91 i i _J U 12

14. The method of any one of claims 1 to 13, comprising the further step of purifying said cis isomer from said trans isomer.

A method of preparing a cis isomer of a 1-R 3 -3-R1-4-anilinopiperidine of the formula: 1 R 3 Nc I R2 wherein R 1 is a lower alkyl, lower cyclic alkyl, lower cyclic alkyl lower alkyl, l lower alkyl, lower alkenyl, or phenyl lower alkyl; R is a phenyl group which may be substituted with one or more substituents selected from the group S *3 consisting of lower alkoxy, lower alkyl, halogen or combinations thereof and R comprises phenyl lower alkyl, or substituted phenyl lower alkyl in which the substituents on the phenyl ring are selected from halogen, lower alkoxy, lower alkyl or combinations thereof; said method comprising: reacting H2N-R 2 with a compound of the following formula: to form an imine compound of the formula deprotonating the Imine compound with a non-nucleophilic base to form a deprotonated anion at the three position of the piperidine ring; 26/08/91 i 13 (iii) reacting said anion with a substituting agent to introduce an 1, group in said three position; and (iv) reducing the compound of step (iii) with a sterically hindered reducing agent, to produce the cis compound above whereby a cis:trans selectivity of greater than about 90 percent is obtainable.

16. The method of claim 15, wherein said substituting agent is an alkylating agent.

17. The method of claim 15 or 16, wherein said non-nucleophilic base is a lithium dilower alkyl amide.

18. The method of any one of claims 15 to 17, wherein said reducing agent is a hindered borohydride reducing agent.

19. The method of any one of claims 15 to 18, comprising the further step of purifying said cis isomer from a trans isomer.

20. The productlef the method of any one of claims 1 to 19. 0,0 3090460/309 21/08/91