Enantioselective Synthesis of SNAP-7941

Abstract

An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist, was achieved using two organocatalytic methods. The first method utilized to synthesize the enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of β-keto esters to acyl imines and the second was chiral phosphoric acid-catalyzed Biginelli reaction. Completion of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone with the 3-(4-phenylpiperidin-1-yl)propyl amine side chain fragment. The synthesis of SNAP-7921 highlights the utility of asymmetric organocatalytic methods in the construction of an important class of chiral heterocycles.

Introduction

Dihydropyrimidones (DHPMs) are a class of heterocyclic compounds¹ that possess wide ranging biological activity² such as calcium channel modulators,³ antihypertensive agents,⁴ mitotic kinesin Eg5 inhibitors,⁵ and melanin concentrating hormone receptor (MCH1-R) antagonists (Figure 1).⁶ In most cases only one enantiomeric form of the heterocycle is often determined to be biologically active.⁷ While racemic DHPMs are easily constructed via the Biginelli reaction, a 3-component condensation reaction of ureas, β-keto esters, and aldehydes,⁸ a limited number of asymmetric methods exist to access the chiral heterocycle in high enantiomeric purity. Early approaches include chemical resolution,⁹ enzymatic synthesis,¹⁰ and chiral Yb-¹¹ or Ce/In-complex ¹² catalyzed Biginelli reactions. More recently, asymmetric organocatalytic approaches have emerged as effective methods to construct enantioenriched DHPMs. We developed the asymmetric Mannich reaction¹³ of β-ketoesters to acyl imines catalyzed by the Cinchona alkaloids as a way to construct chiral DHPM heterocycles.¹⁴ Subsequent to our initial communication, Gong and coworkers reported the first asymmetric organocatalytic Biginelli reaction catalyzed by a BINOL-derived chiral phosphoric acid catalyst, yielding chiral DHPMs in high enantiomeric ratios.¹⁵ These methods could be readily applied to asymmetric synthesis due to the accessibility of the reagents and catalysts, as well as the useful levels of enantioselectivity.

Figure 1.

Biologically Active DHPMs.

SNAP-7941 is a chiral DHPM identified as a small molecule inhibitor of MCH1-R in a G protein-coupled receptor (GPCR) biased library screening. Inhibition of MCH1-R promotes weight loss in obese rats, and decreases anxiety and depression in both guinea pigs and rats, as shown in social interaction studies.⁶ SNAP-7941 exhibits a K_d of 0.18 nM with specific binding of 98% in COS-7 cells expressing human MCH1-R. However, synthesis of SNAP-7941 in enantioenriched form relies on a chiral separation of the racemic dihydropyrimidone synthon.¹⁶ In an effort to synthesize chiral DHPMs and apply these methods towards the synthesis of a relevant target, SNAP-7941, we investigated using both the Cinchona alkaloid catalyzed asymmetric Mannich reaction and the chiral phosphoric acid-catalyzed Biginelli reaction as the key enantioselective step in the synthesis. Our goal was to illustrate the utility of both the asymmetric Mannich reaction and the asymmetric Biginelli reaction in the synthesis of SNAP-7941.

SNAP-7941 consists of two main structural components, a chiral DHPM and 3-(4-phenylpiperidin-1-yl)propyl amine side chain linked as a urea. The two approaches to the chiral DHPM require different building blocks to construct the amine stereocenter. The Cinchona alkaloid-catalyzed asymmetric Mannich addition of methoxy-methylacetoacetate to N-alloc-3,4-difluorophenyl aldimine results in the amine precursor that is ultimately converted to the heterocycle using microwave irradiation.¹⁷ The chiral phosphoric acid-catalyzed multicomponent Biginelli reaction results in direct formation of the chiral DHPM. Both methods proved to be equally effective in accessing the desired heterocycle for the synthesis of enantioenriched SNAP-7941.

Results and Discussion

Synthesis of SNAP-7941 DHPM core via the Mannich reaction

Synthesis of the SNAP-7941 DHPM using the asymmetric Mannich reaction required the addition of a β-ketoester to an acyl imine, followed by urea formation and subsequent ring closure (Scheme 2). Based on our previous work, cinchonine would be the preferred catalyst for the asymmetric Mannich reaction; however, additional catalysts were evaluated in the reaction including other Cinchona alkaloids and thiourea Cinchona alkaloid derived catalyst 7.¹⁸ A catalyst screen was conducted in order to identify the optimal catalyst for the reaction.

Scheme 2.

Synthesis of DHPMs via asymmetric Mannich reaction.

Low yield and selectivity was observed for the asymmetric Mannich addition of methoxy-methylacetoacetate 8a to N-alloc-3,4-difluorophenyl imine 9 catalyzed by cinchonine 5 (Table 1, entry 1). We suspected that the C4 methoxy substituent was problematic as better reaction rates and selectivities were observed in the absence of a C4 substituent on the β-ketoester (Table 1, entry 2). Mannich addition of methylacetoacetate 8b catalyzed by cinchonine proceeded in moderate yield and good enantiomeric ratio (Table 1, entry 2). The addition with methylacetoacetate 8b was further optimized by increasing catalyst loading to 20 mol% while reducing the reaction temperature, to afford the desired chiral amine 10b in high yield with an enantiomeric ratio of 93.5:6.5 (Table 1, entry 5). While the additions of methylacetoacetate 8b to acyl imine 9 provided enantioenriched Mannich products, we investigated a method utilizing α,α-allylcarbamate-3,4-difluorophenyl sulfone and generating the corresponding acyl imine in situ. The α-amido sulfones are bench stable and easily synthesized,¹⁹ and we have previously illustrated the utility of the α-amido sulfones in the asymmetric Mannich reaction.^14b

Table 1.

Asymmetric Mannich Reactions with N-alloc-3,4-difluorophenyl imine ^a

Entry	Catalyst	β-ketoester	% Yieldb	erc
1	5	8a	72	71 : 29
2	5	8b	68	91 : 9
3	7	8b	77	85 : 15
4	5d	8b	88	93 : 7
5	5e	8b	89	93.5 : 6.5

^aReactions were run with imine 9 (1.00 mmol), β-ketoester 8a, 8b (3.00 mmol), and catalyst (0.10 mmol) in CH₂Cl₂ (10 mL) at -35 °C for 24 h, followed by flash chromatography on silica gel.

^bYield of isolated product.

^cDetermined by chiral HPLC analysis.

^dReaction run at -50 °C with 0.20 mmol catalyst in CH₂Cl₂ (5 mL).

^eReaction run at -50 °C with 0.20 mmol catalyst in CH₂Cl₂ (10 mL).

Addition of C4 methoxy substituted β-ketoester 8a to α-amido sulfone 11 again provided the Mannich adduct 10a in low yields and moderate enantioselectivities (Table 1, entries 1 and 2). We hypothesized that the C4 substituent plays a crucial role. The observed decrease in reactivity may be attributed to a disruption of hydrogen bonding nature between the catalyst and the β-ketoester, as additions with methoxy-methylacetoacetate 8a generally provided lower yields and selectivities when compared to the unsubstituted methylacetoacetate 8b. To determine whether the change in reactivity and selectivity was a steric or electronic effect, the Mannich reaction with C4 methyl substituted β-ketoester 8c was examined. Mannich addition of 8c to α-amido sulfone 11 catalyzed by cinchonine did not significantly decrease selectivity or yield (Table 2, entry 5). We reasoned that an intramolecular hydrogen bond of the tautomer alcohol and the C4 methoxy substituent of 8a interrupts the catalytic pre-transition state. To overcome the low selectivity, we sought to synthesize the DHPM core with β-ketoester 8b and install the methoxy- substituent at a later stage. Best results were obtained for the Mannich reaction of β-ketoester 8b and α,α-allylcarbamate-3,4-difluorophenyl sulfone 11 catalyzed by cinchonine, providing chiral amine 10b in high yield and high enantiomeric ratio (Table 2, entry 3).

Table 2.

Asymmetric Mannich Reactions with α,α-allylcarbamate-3,4-difluorophenyl sulfone ^a

Entry	Catalyst	β-ketoester	% Yieldb	erc
1	5	8a	67	78 : 22
2	7	8a	81	82 : 18
3	5	8b	95	94 : 6
4	7	8b	67	85 : 15
5	5	8c	98	89 : 11

^aReactions were run with amido sulfone 11 (1.00 mmol), β-ketoester 8a-8c (3.00 mmol), and catalyst (0.10 mmol) in CH₂Cl₂ (10 mL) and Na₂CO₃ in brine (10 mL) at -15 °C for 24 h, followed by flash chromatography on silica gel.

^bYield of isolated product.

^cDetermined by chiral HPLC analysis.

Conversion of the chiral imine to the desired enantioenriched DHPM proceeded via a two-step process. Exposure of Mannich adduct 10b to a catalytic amount of Pd(PPh₃)₄, an excess of trimethylsilyl isocyanate, and 3,5-dimethylbarbituric acid as an allyl scavenger affords the desired silyl urea (Scheme 3). Formation of the heterocycle proceeds without purification of the silyl urea with subsequent ring closure under acidic conditions. The desired DHPM was achieved in 80% yield with retention of stereochemistry (Scheme 3). The heterocycle was purified by recrystallization to provide DHPM 12 in an enantiomeric ratio of >99:1.

Scheme 3.

DHPM formation from Mannich adduct.

Installation of the C4 methoxy substituent proceeded through bromination and subsequent methanolysis of DHPM 12. Mono-bromination of the C4 methyl of the DHPM was achieved in high yield using a solid supported brominating agent reported by Kappe and co-workers (Scheme 4).²⁰ The mono-brominated DHPM was also synthesized using brominating reagent Ph(CH₃)₃NBr₃, providing DHPM 13 in equally high yield. Installation of the methoxy substituent proceeded through nucleophilic substitution with sodium methoxide. Use of either microwave or thermal conditions provided the heterocyclic core of SNAP-7941 14 in 85% yield with retention of enantioenrichment.

Scheme 4.

Synthesis of the C4 methoxy-substituted DHPM.

Synthesis of the DHPM core via the asymmetric Biginelli reaction

The asymmetric Biginelli reaction catalyzed by BINOL-derived phosphoric acids was also investigated to produce the desired SNAP-7941 DHPM core. Use of methoxy-methylacetoacetate 8a in the multicomponent reaction provided DHPM 14 in low yield and enantioselectivity (Table 3, entry 1). This observation is again attributed to an unfavorable catalytic pre-transition state as the use of methylacetoacetate 8b greatly improved yield and selectivity (Table 3, entries 2 and 3). Optimal reaction conditions were achieved with a limiting amount of urea and an excess of both aldehyde and methylacetoacetate (Table 3, entries 4, 5 and 6). DHPM 12 was synthesized in 96% yield with 94.5:5.5 er, utilizing 3,3′-diphenyl substituted BINOL-derived phosphoric acid catalyst 17b. The Biginelli product was recrystallized and functionalized via the previously described bromination and methanolysis procedures to provide the enantioenriched SNAP-7941 core.

Table 3.

Asymmetric Biginelli reaction catalyzed by chiral binapthol-derived phosphoric acid ^a

Entry	15 : 8 : 16	Catalyst	β-ketoester	% Yieldb	erc
1	1.0 : 5.0 : 2.0	17b	8a	27	64.5 : 35.5
2	1.2 : 5.0 : 1.0	17a	8b	50	63 : 37
3	1.2 : 5.0 : 2.0	17b	8b	42	83 : 17
4	1.0 : 5.0 : 2.0	17b	8b	96	94.5 : 5.5
5	1.0 : 5.0 : 2.0	17c	8b	65	77.5 : 22.5
6 d	1.0 : 5.0 : 2.0	17b	8b	27	64.5 : 35.5

^aReactions were run with urea 15, phosphoric acid catalyst 17a-17c (0.02 mmol), aldehyde 16 in CH₂Cl₂ (3 mL) for 2 hours. β-ketoester 8a, 8b (1.00 mmol) was added, and the mixture reaction was stirred at room temperature for 6 days, and subsequently purified by flash chromatography on silica gel.

^bYield of isolated product.

^cDetermined by chiral HPLC analysis.

^dThe reaction was run at 0.5 M.

Synthesis of 3-(4-Phenylpiperidin-1-yl)propyl Amine Side Chain

Piperidine 18 and boronic acid 19 were synthesized according to previously reported literature procedures.²¹ Suzuki coupling of 18 and 19 provided the desired piperidinyl amide 20 in 51% yield. Subsequent hydrogenation followed by acid deprotection of 20 afforded the piperidinyl phenyl acetamide hydrochloride salt 22 in 86% overall yield. Nucleophilic substitution of N-Boc propyl bromide 23¹⁹ with piperidinyl hydrochloride salt 22 yielded the Boc protected amide side chain 24. Deprotection of the Boc group using TFA and subsequent pH adjustment afforded the desired amine 25.

Synthesis of SNAP-7941

Synthesis of N-substituted DHPM carbamate 26 via addition of p-nitrophenyl chloroformate was achieved in 70% yield (Scheme 6). The urea moiety of SNAP-7941 was constructed via addition of piperidine side chain 25 to N-substituted DHPM carbamate 26. Optimal yield and reaction time was obtained using Hünig’s base, providing the enantioenriched form of SNAP-7941 in 90% yield.

Scheme 6.

Synthesis of SNAP-7941.

Conclusion

We have developed two organocatalytic enantioselective approaches to SNAP-7941 that focus on the synthesis of the chiral dihydropyrimidone core. The asymmetric Mannich reaction catalyzed by Cinchona alkaloids and the asymmetric Biginelli reaction catalyzed by chiral phosphoric acids were equally effective at producing the desired heterocycle. The additional steps required by the Mannich route are offset by the time required for the enantioselective Biginelli reaction. Despite the progress to date, some challenges still remain. However, these approaches are the first highly enantioselective routes to this important class of biologically and pharmaceutically relevant compounds. The development of effective synthetic approaches will hopefully facilitate future efforts to characterize the activity and biological properties of these chiral heterocycles.

Experimental Section

General procedure for asymmetric Mannich reaction of α-amido sulfones

To an oven dried 50 mL round bottom flask equipped with stir bar, was added α-amido sulfone 11 (0.40 g, 1.00 mmol), (+)-cinchonine (0.029 g, 0.10 mmol) and CH₂Cl₂ (10 mL). The solution was cooled to -15 °C. The dicarbonyl compound (8a-c) (3.00 mmol) and 10 mL of a solution of Na₂CO₃/NaCl were sequentially added dropwise. The reaction was stirred for 24 hours at -15 °C and then diluted with CH₂Cl₂ (20 mL) and H₂O (20 mL). The organic layer was quickly separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel (elution with 30% to 40% ethyl acetate in hexanes) to afford the Mannich reaction products as white solids.

General procedure for conversion from Mannich adduct to dihydropyrimidone

To an oven dried 50 mL round bottom flask equipped with stir bar, was added 10b (0.34 g, 1.00 mmol), 3,5-dimethylbarbituric acid (0.156 g, 1.00 mmol) and THF (10 mL). To another oven dried 50 mL round bottom flask equipped with stir bar, was added Pd(PPh₃)₄ (0.060 g, 0.050 mmol), trimethylsilyl isocyanate (0.346 g, 3.00 mmol) and THF (10 mL). The solution containing the 10b and 3,5-dimethylbarbituic acid was transferred via cannula to the palladium and isocyanate mixture. The reaction mixture was stirred for 4 h. The solution is then concentrated under reduced pressure, and a solution of 75% acetic acid in ethanol (3 mL) is added. The solution was transferred to a 10 mL microwave tube, and irradiated for 3 min at 30 °C. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography over silica gel (elution with 80% to 100% EtOAc in hexanes) to afford the dihydropyrimidone reaction product as a white solid.

General procedure for the chiral phosphoric acid catalyzed asymmetric Biginelli reaction

An oven dried 10 mL round bottom flask equipped with stir bar was charged with urea 15 (0.012 g, 0.20 mmol), phosphoric acid catalyst (17a-c) (0.02 mmol), 3,4-difluoro-benzaldehyde 16 (44 μL, 0.40 mmol) and CH₂Cl₂ (3 mL). The flask was sealed with a teflon cap (caplug®), and the solution was stirred for 2 h at room temperature. The dicarbonyl compound (8a, 8b) (1.0 mmol) was slowly added, and the solution was stirred for 6 days. Silica gel was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting solid was purified by flash chromatography over silica gel (with 80-100% EtOAc in hexanes) to afford the Biginelli reaction products as white solids.

Synthesis of SNAP-7941

A solution of 25 (0.050 g, 0.10 mmol) and 24 (0.083 g, 0.30 mmol), DIPEA (0.078, 0.60 mmol) and anhydrous CH₂Cl₂ (3 mL) is stirred at room temperature under argon atmosphere for 24 hours. The mixture is concentrated and the resulting residue is purified by flash chromatography over silica gel (elution with 1-5% methanol in ethyl acetate) to provide the desired final compound as a yellow oil.

Characterization Data for Selected Compounds

(a) 2-[(R)-Allyloxycarbonylamino-3,4-diflurophenyl-methyl)-3-oxo-4-methoxy-butyric acid methyl ester (10a): Clear viscous oil (0.25 g, 67 % yield). ¹H NMR (CDCl₃, 400 MHz, both diastereomers reported): δ 7.10 (m, 8H), 6.41 (d, J = 9.2 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.86 (m, 2H), 5.53 (m, 1H), 5.43 (m, 1H), 5.30 (s, 1H), 5.27 (s, 1H), 5.23 (s, 1H), 5.20 (s, 1H), 4.50 (d, J = 5.6, 4H), 4.32 (m, 2H), 4.08 (dd, J = 7.2, 6.8, 2H), 3.87 (dd, J = 14.8, 6.0, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.44 (s, 3H), 3.29 (s, 3H). ¹³C NMR (CDCl₃, 75.0 MHz, both diastereomers reported): δ 204.5, 202.2, 171.4, 169.0, 167.4, 156.0, 155.8, 151.7, 149.3 (d, ¹J_CF = 212.0 Hz), 136.9, 132.7, 122.8 (d, ²J_CF = 80.0 Hz), 117.8 (d, ²J_CF = 60.0 Hz), 116.1 (d, ²J_CF = 72.0 Hz), 66.3, 60.1, 59.6, 57.5, 53.4, 53.2, 52.8, 51.9. IR (thin film, cm^-1): 3425, 2956, 1722, 1612, 1519, 1503, 1437, 1345, 1284, 1222, 1118, 1059. High resolution mass spectrum m/z 394.1095 [(M + Na⁺) calcd for C₁₇H₁₉NO₆NaF₂⁺: 394.1078]. [α]²³_D = -28.7° (c = 4.0, CHCl₃). 78:22 er; HPLC analysis, t_r major (of single diastereomer): 9.7 min, t_r minor (of single diastereomer): 11.2 min, [Chiralcel®AD column, Hexanes:IPA 90: 10, 1.0 mL/min]. (b) 2-[(R)-Allyloxycarbonylamino-3,4-diflurophenyl-methyl)-3-oxo-butyric acid methyl ester (10b) White Solid (0.97 g, 97% yield). mp: 97-100 °C. ¹H NMR (CDCl₃, 400 MHz, both diastereomers reported): δ 7.12 (m, 6H), 6.99 (s, 2H), 6.41 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 9.2 Hz, 1H), 5.85 (m, 2H), 5.47 (m, 1H), 5.37 (dd, J = 6.8, 2.0 Hz, 1H), 5.21 (m, 5H), 4.49 (d, J = 1.6, 4H), 4.00 (d, J = 5.6, 1H), 3.94 (d, J = 4.0, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 2.23 (s, 3H), 2.00 (s, 3H). ¹³C NMR (CDCl₃, 75.0 MHz, both diastereomers reported): δ 202.0, 199.6, 170.5, 168.2, 166.6, 155.0, 154.8, 150.6 (d, ¹J_CF = 220.0 Hz), 148.1 (d, ¹J_CF = 220.0 Hz), 131.8, 121.6 (d, ²J_CF = 24.0 Hz), 117.2 (d, ²J_CF = 44.0 Hz), 115.2 (d, ²J_CF = 72.0 Hz), 65.4, 63.0, 59.7, 52.1, 51.7, 30.0, 29.5, 22.0. IR (thin film, cm^-1): 3423, 2996, 1720, 1649, 1612, 1519, 1503, 1437, 1363, 1284, 1219, 1147, 1119, 1061. High resolution mass spectrum m/z 364.0954 [(M + Na⁺) calcd for C₁₆H₁₇NO₅NaF₂⁺: 364.0972]. [α]²³_D = -32.4° (c = 4.0, CHCl₃). 94:6 er; HPLC analysis, t_r major (of single diastereomer): 23.7 min, t_r minor (of single diastereomer): 31.9 min, [Chiralcel®AD-H column, Hexanes:IPA 95: 5, 1.0 mL/min]. (c) (S)-methyl-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12): White Solid (0.254 g, 90 % yield). mp: 204-206 °C. ¹H NMR (DMSO, 400 MHz): δ 9.31 (s, 1H), 7.82 (s, 1H), 7.35 (d and dd_CF, J = 6.4 Hz, ⁴J = 8.4 Hz, ⁴J_CF = 10.8 Hz, 1H), 7.20 (d and dd_CF, J = 6.0 Hz, ⁴J_CF = 8.0 Hz, ⁴J_CF = 10.8 Hz, 1H), 7.07 (m, 1H), 5.15 (d, J = 3.6 Hz, 1H), 3.52 (s, 3H), 2.25 (s, 3H). ¹³C NMR (DMSO, 75.0 MHz): δ 165.9, 152.2, 149.7, 147.9 (d, ¹J_CF = 236.3 Hz), 142.6 (d, ²J_CF = 16.0 Hz), 123.1, 117.8 (d, ²J_CF = 68.3 Hz), 115.5 (d, ²J_CF = 68.0 Hz), 98.5, 53.3, 51.1, 18.3. IR (thin film, cm^-1): 3328, 2922, 2850, 1696, 1645, 1516, 1434, 1279, 1228, 1093. High resolution mass spectrum m/z 283.0912 [(M + H⁺) calcd for C₁₃H₁₃N₂O₃F₂⁺: 283.0894]. [α]²³_D = +10.0°(c = 2.0, CHCl3). >99: 1 er HPLC analysis, t_r minor: 18.2 min, t_r major: 27.0 min, [Chiralcel®OD column, Hexanes:IPA 95: 5, 1.0 mL/min]. (d) SNAP-7941 (1): Yellow Oil. (0.055g, 0.090 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.90 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.50 (d, J = 8.00 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.13 (m, 2H), 7.02 (m, 2H), 6.84 (d, J = 8.00 Hz, 1H), 6.56 (s, 1H), 4.61 (s, 2H), 3.65 (s, 3H), 3.42 (s, 3H), 3.31 (m, 3H), 2.82 (m, 2H), 2.54 (m, 2H), 2.18 (m, 2H), 2.12 (s, 3H), 1.99 (m, 4H), 1.83 (d, J = 16.0 Hz, 2H). ¹³C NMR (CDCl₃, 75.0 MHz): δ 171.5, 169.2, 153.9, 152.6, 149.2, 146.5, 144.6, 139.0, 137.7, 129.5, 123.3, 122.8, 118.0, 117.8 (d, ²J_CF = 68.0 Hz), 116.6 (d, ²J_CF = 72.0 Hz), 101.7, 68.3, 59.5, 55.5, 53.6, 53.5, 52.1, 40.9, 38.6, 30.6, 25.0, 24.9, 21.4. IR (thin film, cm^-1): 3291, 2950, 2501, 1713, 1647, 1409, 1517, 1436, 1394, 1313, 1280, 1219, 1117, 1083, 964, 912. [α]²³_D = + 130°(c = 2.0, CHCl₃).

Scheme 1.

Retrosynthetic Analysis of SNAP-7941.

Scheme 5.

Synthesis of 3-(4-phenylpiperidin-1-yl)propyl amine side chain.