Article pubs.acs.org/OPRD
A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald−Hartwig Amination and Bruylants Reactions Yugang Liu,* Mahavir Prashad, and Wen-Chung Shieh* Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States ABSTRACT: A practical, chromatography-free synthesis for a chemokine receptor antagonist NIBR-1282 (1) is described. Highlights of this scalable synthesis include (1) Buchwald−Hartwig amination reaction using (t-Bu)3P as the ligand and 5−12 mol % of water as an additive affording 6 with yield increase of more than 2-fold; (2) a variant of the Bruylants reaction for the synthesis of α-methyl amine 10 via aminotriazole 15a, instead of classical amino nitrile 8; and (3) development of a crystallization-induced, atropisomer transformation leading to predominantly one atropisomer 1. The new approach was employed for the manufacturing of kilogram quantities of the target active pharmaceutical ingredient.
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INTRODUCTION Chemokine receptor CCR5 has a key role in the pathogenesis of autoimmune and inflammatory disorder.1 It also functions as a coreceptor for a macrophage-infecting strain of HIV. Recently, Novartis developed a selective and competitive CCR5 antagonist, NIBR-1282 (1, Figure 1), with good oral
not feasible for the pilot plant. Herein, we disclosed a robust, scalable and chromatography-free synthesis of 1.
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RESULTS AND DISCUSSION Reductive Amination. The original synthesis began with amination of ketone 2 and aniline 3 with sodium triacetoxyborohydride3 and acetic acid leading to 4 in the environmentally unacceptable solvent dichloroethane. Replacing it with toluene, we were able to complete the reaction in 3 h without the need of acetic acid. Since this reaction was exothermic, sodium triacetoxyborohydride was added in portions while maintaining the reaction temperature between 25 and 36 °C. The reaction was quenched with water to destroy unreacted sodium triacetoxyborohydride, which produced hydrogen gas. Since only 0.2 equiv of excess sodium triacetoxyborohydride was present, the amounts of hydrogen gas could easily be diluted with nitrogen and vented to the atmosphere without any safety concern. Addition of heptane to the concentrated toluene solution induced crystallization of 4, which was collected by filtration. This process was successfully scaled up on kilogram scale in the pilot plant affording 4 in 88% yield with 99% assay. Buchwald−Hartwig Amination. Synthesis of tertiary amine 6 from aniline 4 and bromide 5 using the Buchwald− Hartwig amination4 methodology turned out to be problematic. Initially medicinal chemistry employed typical conditions: 3 mol % of palladium acetate, 4.5 mol % of xantphos, 4 equiv of sodium tert-butoxide in toluene at 110 °C for 16 h. Under these conditions, 6 was synthesized in 41% yield after purification by chromatography. To improve the coupling efficiency involving a sterically hindered 4, we investigated alternative palladium− ligand combinations hoping an optimal pair can be identified. It has been reported that t-Bu3P is a more robust ligand for amination reactions and able to promote cross-coupling
Figure 1. NIBR-1282.
bioavailability and safety profile in several animal species.2 To probe its therapeutic potentials in man, we needed to develop a facile and practical synthesis of 1 to make kilogram quantities of this active pharmaceutical ingredient (API) supporting clinical trials. The initial research synthesis of 1 was a linear, seven-step synthesis utilizing Buchwald−Hartwig amination and Bruylants reactions, and contributed to an overall yield of 16.7% (Scheme 1).2 In order to employ this route on kilogram scale, we had to address several drawbacks. The most challenging one was the Buchwald−Hartwig amination reaction (step 4 to 6), which was low yield (41%) leading to significant loss of materials and decrease in overall synthetic efficiency. A number of unsafe or undesirable reagents such as diethylaluminum cyanide for the Strecker reaction (step 7 to 8) and trifluoroacetic acid for Bocdeprotection reaction (steps 6 to 7 and 10 to 11) should be replaced with safer ones. Hazardous or environmentally unacceptable solvents such as diethyl ether, dichloromethane and dichloroethane must be eliminated. Six chromatographic purifications were used and would ideally have to be totally avoided. The API 1 was purified by silica gel chromatography and isolated as an amorphous powder by scratching the materials out of a round-bottomed flask. This isolation approach is a typical technique for research-scale, however, © XXXX American Chemical Society
Special Issue: Transition Metal-Mediated Carbon-Heteroatom Coupling Reactions Received: September 11, 2013
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Scheme 1. Initial research synthesisa of 1
a
Reagents and conditions: (a) Na(OAc)3BH, AcOH, CH2Cl2, 88%; (b) Pd(OAc)2 (3 mol %), xantphos (4.5 mol %), NaOt-Bu (4 equiv), toluene, 41%; (c) TFA, CH2Cl2, water, 94%; (d) Ti(OiPr)4, CH2Cl2, then Et2AlCN (2 equiv), 77%; (e) ether, THF, 84%; (f) TFA, CH2Cl2, water, quantitative; (g) HBTU, EtN(i-Pr)2, DMF, 76%.
reactions at room temperature in high yields.4,5 Recently, we discovered that palladium-catalyzed amination reactions involving sterically hindered anilines can be efficiently performed employing t-Bu3P as the ligand.6 To probe whether this ligand could provide any benefits to the current synthesis, we allowed a mixture of 4, 5 (1.1 equiv), Pd(dba)2 (0.5 mol %), t-Bu3P (1.5 mol %) and NaOtBu (1.5 equiv) in xylene to be heated to 120 °C. Under these conditions, the reaction stalled after 5 h. Product 6 was isolated in 78% yield, a slight increase over the research one. Utilizing a cheaper catalyst Pd(OAc)2 (1 mol %) and toluene (xylene was difficult to remove by distillation), the amination reaction achieved a clean and total conversion to 6 in 5 h at 110 °C. The reaction was quenched by addition of water at room temperature. A problem of muddy solids was overcome by treating the brown reaction mixture with charcoal followed by filtration, which improved phase separation. The charcoal treatment also served as a purpose for removing residual palladium metal. In a typical protocol, charcoal (PICA P1400) was added to the reaction mixture and stirred at 80−85 °C for 4 h. After filtration and phase separation, toluene was removed from the organic layer by distillation, heptane was added to the residual mixture to induce crystallization, and product 6 was isolated by filtration. The palladium content of 6 after charcoal treatment was determined to be less than 50 ppm (vs 300−500 ppm without charcoal treatment), which was acceptable for ICH guidelines. It was known that the Buchwald−Hartwig amination reaction was sensitive to even small amount of poisons. This proved to be the case when a lower quality (95%) of 3-bromopyridine (5) was utilized, which led to 50% conversion under the same reaction conditions. It is obvious that the partial conversion problem can be solved by using distilled 3-bromopyridine. However distillation of a high boiling-point liquid in the pilot plant is not a practical approach. Interestingly, we found that by adding 5−12 mol % of water to the reaction mixture involving less-pure (95%) 5,
the coupling reaction can be accelerated. Under optimal conditions by employing 10 mol % of water, we observed a total conversion to 6 in 4−5 h. Product 6 was isolated as an offwhite solid in 85% yield with 99.1% purity. During the course of the study, we realized that the amination reaction would be inhibited by a stainless-steel reactor. This was demonstrated by running the same coupling reaction in the presence of a stainless-steel coupon in a glass flask, which resulted in no product but starting materials. Therefore, it was very important that a glass-lined reactor be used in the pilot plant. The new conditions not only eliminated silica gel chromatography but also enhanced the yield of 6 by 2.1-fold. Boc-Deprotection. In the research synthesis, removal of the Boc-protecting group from 6 was carried out with trifluoroacetic acid (TFA) and dichloroethane, and purified by silica gel chromatography. Since neither TFA nor dichloroethane are good process reagent or solvent, we decided to look for alternatives. By heating a solution of 6 with aqueous sulfuric acid in toluene at 45−45 °C for 3 h followed by neutralization with sodium hydroxide, we were able to produce 7 as a toluene solution in quantitative yield. This solution can be used directly for the next step without any further purification, which eliminated chromatographic purification of 7. The optimized deprotection process was used successfully in the plant, affording 7 with 98% assay. Strecker and Bruylants Reactions. A reported two-step approach7- a Strecker reaction of ketone 2, amine 7, and diethylaluminum cyanide; and a Bruylants reaction of the resulting aminonitrile with Grignard reagent 9 - was originally utilized in the medicinal chemistry for the synthesis of α-methyl amine 10 (Scheme 1). There are two safety issues if this synthetic strategy is adopted in the plant for large-scale operations. First, diethylaluminum cyanide is poisonous and hazardous to plant personnel. Second, quaternary aminonitrile 8 could generate B
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their respective tert-butyl groups in the mixture). Only enamine 16 and 2 were detected when pyrrole was used (entry 5). When 15 formation was completed according to 1H NMR analysis, its solution was slowly added to a solution of methylmagnesium chloride (9, 4 equiv) in THF affording the desired product 10. The addition sequence and rate was designed to minimize additional enamine 16 formation, which could also be promoted by basic methylmagnesium chloride via a 1,2elimination reaction. Among the heterocycles that we investigated, 1,2,3-triazole contributed to the highest formations of both 15 (88%) and product 10 (73% isolated yield) (Table 1, entry 1). For five-membered heterocycles, their activities in promoting the formation of adducts 15 and αmethyl amine 10 correlated to the acidity (pKa) of their respective nitrogen protons (N−H) (Table 1, entries 1−5). It suggested that less basic heterocycles (lower N−H pKa values) favor the formation of adduct 15 and the desired amine 10. We selected 1,2,3-triazole as the promoter for the Bruylants reaction (Scheme 3) affording the desired product 10 in the plant in 73% yield with 98.7% purity. The palladium contents of 10 were determined to be 0.3 ppm, meeting heavy metal specifications for the active pharmaceutical ingredient. The scale and quality of 10 demonstrated the robustness of the Bruylants protocol that was developed in our lab. Penultimate Compound 11. In research synthesis, removal of Boc protecting group from 10 leading to 11 was accomplished with trifluoroacetic acid in dichloroethane. By employing the same conditions developed for Step 6 to 7 (H2SO4 in toluene), compound 11 was produced cleanly. However, it was important to maintain the temperature of toluene solution greater than 40 °C during the workup to prevent 11 from crystallization during phase separation. After workup, toluene was removed by distillation. Crystallization, filtration and drying furnished 11 in 77% yield with 99.4% purity. Isolation of 11, a regulatory starting material according to ICH guidelines, provided a crystalline solid in high purity without chromatography purification. End-Game Synthesis and Crystallization-Induced Atropisomer Transformation. To synthesize the desired drug substance 1 from piperidine 11 and pyridine-N-oxide carboxylic acid 12, we utilized a popular amidation protocol: N(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and N,N′-diisopropylethylamine in DMF at 50 °C. After aqueous workup that removed one major byproduct, N,N′-diisopropylethylamine hydrochloride, 1 was isolated as an amorphous solid by chromatography purification. Initially, we attempted to prepare organic salts of 1, hoping a crystalline form could be obtained. Unfortunately, several salts preparedhydrochloride, succinate, and p-toluenesulfonateexhibited hygroscopic properties that inhibited isolation of products by filtration. Efforts were then focused on developing a crystallization procedure for the free base of 1. From HPLC, LC−MS and NMR studies, we observed that amorphous solid 1 contained a mixture of two atropisomers9 (M)-1 and (P)-1 in a ratio of 50:50 (Scheme 4). This is presumably caused by a restricted rotation of the Ar−CO bond. Existence of atropisomeric stereoisomers for a compound of similar chemical structure was reported.10 We obtained small amounts of crystalline 1 by allowing a concentrated solution of 1 in DMF to stand at ambient temperature for a few days. The atropisomeric ratio of this crystalline solid was determined to be 93:7 by NMR analysis. The optical rotation was measured to
lethal hydrogen cyanide gas via elimination reaction. To circumvent these concerns, we decided to develop alternative and safer Strecker−Bruylants reactions for the synthesis of 10. Recently, our lab discovered that 1,2,3-triazole is a safer and practical replacement of cyanide for the Bruylants reaction, affording several tertiary amines.8 Applying this methodology for the synthesis of a more complicated tertiary amine 10, we prepared a series of heterocyclic analogues (15, Scheme 2) of cyanide 8 (from ketone 2 and amine 7) and probed their impacts on the efficiency of the Bruylants reaction. Scheme 2. Bruylants reaction via heterocyclic adducts 15
Under typical conditions, a mixture of ketone 2, amine 7 (1.1 equiv) and a heterocycle 12 (1.2−1.5 equiv) in toluene was heated to reflux with a Dean−Stark trap to collect water generated during this three-component condensation. The mixture was analyzed by 1H NMR as soon as water formation had been halted. We observed the presence of the desired heterocyclic adduct 15, a byproduct (enamine 16) and unreacted ketone 2. The amounts of 15 and 16 depended on the nature of heterocycles involved. For example, when 1,2,3triazole was used (Table 1, entry 1), adduct 15 was the major product as demonstrated by a ratio of 88:1:11 for 15, 16, and 2, respectively (the ratio was determined by NMR integrations of Table 1. Impacts of heterocycles on formation of adduct 15 and yield of 10 from Bruylants reaction
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Scheme 3. Bruylants reaction via triazole-adduct 15a
properties provided us an opportunity to isolate and develop a single atropisomeric drug11 via a dynamic-kinetic-resolutionlike approach.12 We discovered that crystalline 1 can be generated by adding ethyl acetate (as an antisolvent) to the DMF solution containing 1. In a typical procedure, amidation of piperidine 11 and pyridine-N-oxide carboxylic acid 12 was performed by employing N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), HOBt, and tri-n-butylamine in DMF at 50 °C. After the reaction was determined to be complete by HPLC analysis, crystalline 1 was obtained by adding EtOAc to the DMF solution in a controlled manner. Tri-n-butylamine was selected as the base because its hydrochloride salt (a byproduct) is soluble in this solvent system (DMF/EtOAc) and can easily be separated from the product by filtration. Filtration also removed EDC-urea (a liquid) formed as another byproduct during the amidation reaction. As a result, crystalline
Scheme 4. Atropisomerism of 1
be zero. Attempts to isolate a single and purer (>99:1) atropisomer were unsuccessful. Our studies also revealed that both atropisomers of 1 interconverted rapidly at elevated temperature. For example, when a DMSO-d6 solution of crystalline 1 with 93:7 atropisomeric ratio was heated to 80 °C for a few minutes, 1H NMR analysis indicated a conversion to two isomers in 50:50 ratio (at equilibrium). At 20 °C, complete equilibrium of 1 required 36 h, implying the existence of high barrier to the rotation of the Ar−CO bond and an interconversion half-life of 18 h. These physicochemical Scheme 5. Final scalable synthesis of 1
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4-Phenylamino-piperidine-1-carboxylic Acid tertButyl Ester (4, Laboratory-Scale Process). To a solution of aniline 3 (147 g; 1.58 mol) in toluene (2 L) was added a solution of tert-butyl 4-oxo-1-piperidinecarboxylate 2 (300 g, 1.51 mol). The mixture was stirred for 1 h. Sodium triacetoxyborohydride (383 g, 1.81 mol) was added in 10 portions over 1 h at 25−36 °C. The solid addition funnel was rinsed with toluene (400 mL). The reaction mixture was stirred for 2.5 h. Water (1 L) was added over 30 min at 25−36 °C. The resulting two-phase mixture was heated to 45 °C. The organic layer was separated, washed with warm water (45 °C, 500 mL), and concentrated under reduced pressure (35−70 °C/160−80 mbar) until ∼2.2 L of solvent was collected. The remaining residue was heated to 80−85 °C, and heptane (2.0 L) was added over 20 min at 80−85 °C. The resulting suspension was cooled to 5 °C over 2 h and stirred for 3 h. The precipitate was filtered, rinsed with cold (5 °C) heptane (1.0 L) containing 7% EtOH and dried under reduced pressure (15−40 mbar) at 65 °C to afford 368 g (88% yield) of 4 as an off-white solid: mp 137−139 °C; 1H NMR (300 MHz, DMSO-d6): 7.08−7.02 (m, 2H), 6.59−6.47 (m, 3H), 5.42 (d, 1H, J = 8.3 Hz), 3.86 (m, 2H), 3.39 (m, 1H), 2.90 (m, 2H), 1.87 (m, 2H), 1.40 (s, 9H), 1.20 (m, 2H); 13C NMR (75 MHz, DMSO-d6) 154.3, 148.0, 129.3, 115.9, 112.8, 78.9, 48.9, 42.7, 31.9, 28.4; MS (ESI) m/z 276.9 (M + H+). Anal. Calcd for C16H24N2O2: C, 69.53; H, 8.75; N, 10.14. Found: C, 69.62; H, 8.87; N, 10.13. HPLC for 3 (tR = 2.37 min); 4 (tR = 8.98 min) purity 99%: Luna 5 μm C-18 150 mm × 4.6 mm, flow rate = 1 mL/min, 25 °C, isocratic A/B = 70:30; A = methanol; B = water; UV λ = 230 nm. 4-(Phenylpyridin-3-ylamino)piperidine-1-carboxylic Acid tert-Butyl Ester (6, Laboratory-Scale Process). To a solution of 4 (250 g, 0.9 mol) in toluene (1 L), sodium tertbutoxide (130 g, 1.36 mol) was added over 10 min at 20−25 °C. Slurry of palladium acetate (2.03 g, 9.05 mmol) in toluene (400 mL) was added, followed by the addition of water (1.63 g, 90.5 mmol). A solution of 3-bromopyridine 5 (186 g, 1.18 mmol) in toluene (1.0 L) was added, followed by the addition of a solution of t-Bu3P (3.65 g, 18.1 mmol) in toluene (33 g). The mixture was heated to 97−103 °C over 40 min and stirred for 1 h. The reaction temperature was raised to 112 °C and stirred for 5 h. The mixture was cooled to 20−25 °C over 1 h, and water (500 mL) was added over 15 min at 20−30 °C. After stirring the mixture for 5 min, charcoal (50 g) was added. The suspension was heated to 80−85 °C and stirred for 2 h. The mixture was cooled to 20−30 °C and filtered over a pad of Celite (50 g). The filter cake was rinsed with toluene (200 mL). The filtrates were combined. The organic layer was separated, washed with water (500 mL), and concentrated at 35−70 °C under reduced pressure (160−80 mbar) until ∼2 L of solvent was collected. The remaining residue was heated to 80−85 °C, and heptane (2 L) was added over 20 min at 70−85 °C. The suspension was cooled to 20−25 °C over 2 h and stirred for 4 h. The solid was filtered, washed with cold (5 °C) heptane (500 mL) containing 7% of ethanol (v/v), and dried under reduced pressure (15−40 mbar) at 65 °C to give 6 (272 g, 85% yield) as an off-white solid: mp 129−131 °C; 1H NMR (300 MHz, DMSO-d6) 8.05−7.95 (m, 2H), 7.40 (m, 2H), 7.21 (m, 2H), 7.07 (m, 1H), 6.96 (m, 2H), 4.15 (m, 1H), 3.97 (m, 2H), 2.89 (m, 2H), 1.90 (m, 2H), 1.32 (s, 9H), 1.07 (m, 2H); 13C NMR (75 MHz, DMSO-d6) 154.0, 143.7, 143.3, 141.0, 140.9, 130.1, 126.5, 125.6, 124.8, 124.1, 79.0, 54.0, 43.0, 30.6, 28.3; MS (ESI) m/z 354.1 (M + H+); ICP-MS
