Communication pubs.acs.org/OPRD
Improved Process for Preparation of (3R,4R)‑3-(3,4-Dimethyl-4piperidinyl)phenol, A Key Intermediate for the Synthesis of Alvimopan Beeravalli Ramalinga Reddy,† Kikkuru Srirami Reddy,† Manoj Kumar Dubey,† Y. Bharati Kumari,‡ and Rakeshwar Bandichhor†,* †
Research and Development, Integrated Product Development, Innovative Plaza, Dr Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, R.R. Dist 500072, Andhra Pradesh, India ‡ Center for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India S Supporting Information *
26 to 56% for intermediate 7. This advancement was integrated to the overall process for preparation of 1 with an increased yield from 15 to 30%. The modified synthetic scheme is shown in Scheme 2. Several methods are reported in the literature for the preparation of Alvimopan.4−6 The reported process for Alvimopan in the product patent is outlined in the Scheme 3. Intermediate 1 is subjected to Michael addition in the presence of methyl acrylate to afford compound 12 in 98% yield. Thereafter, intermediate 12 was alkylated to obtain 13 in 33% yield after crystallization in MeOH/HCl. Amino ester coupling with 14 followed by deprotection on 15 afforded Alvimopan (2) in 85% yield. The overall yield of the reported synthesis of Alvimopan (Scheme 3) was found to be 26.74%.
ABSTRACT: This report discloses an industrially feasible and cost efficient process for the preparation of the compound [(3R, 4R)-3-(3,4-dimethyl-4-piperidinyl)phenol] (1), which is used as the key intermediate for preparation of the opioid drug Alvimopan. The overall yield in this process is increased from 15 to 30%, mainly due to the improvement in yield from 26 to 53% for intermediate 7.
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INTRODUCTION Alvimopan ([[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate) (2) is an opioid drug used for the treatment of upper and lower gastrointestinal recovery following partial or large and small bowel resection surgery with primary anastomosis.1 This drug also has an activity toward the treatment of postoperative ilieus and chronic idiopathic constipation.2 Werner et al.3 reported the synthesis of (3R,4R)-3-(3, 4dimethyl-4-piperidinyl)phenol (1), a key intermediate in the synthesis of 2 (Scheme 1). This route involves the reaction of N-methyl-4-piperidinone (4) and aromatic bromo compound 3 to afford the condensed product 5. Subsequently, product 5 was allowed to condense with ethyl chloroformate to give the product 6. Subsequently, compound 6 was resolved to obtain S isomer 7 by employing (+)-di-p-toluoyl-D-tartaric acid as a resolving agent. Thereafter, compound 7 was treated to the pyrolytic elimination conditions to obtain the alkene product 8, which was further treated with BuLi/DMS and reduced with NaBH4 to afford the saturated compound 10. Finally, the deprotection of the N-methyl group was achieved through quaternization with phenyl chloroformate and acidic hydrolysis to obtain the product 1. This strategy has some disadvantages, e.g. low yield and nonrecyclability of the unwanted isomer, which was obtained during resolution of the compound 6. In view of these disadvantages associated with the reported scheme, we intended to devise an improved synthetic scheme for the synthesis of compound 1. Herein we report such a strategy, which is simple and efficient in comparison to the route shown in Scheme 2, with an improved overall yield from © XXXX American Chemical Society
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RESULTS AND DISCUSSION From a process standpoint, resolution of an advanced intermediate may not be considered as an efficient strategy due to the fact that the loss of a significant component of the API could be attributed to the higher cost and poor atom economy, which depends on the efficiency of recycling of unwanted isomer. The reported route involves resolution of the advanced intermediate, leading to an inefficient process. Considering the existing literature, there is no process reported for the racemization of the unwanted isomer (ent-4a), as shown in Scheme 1. In our endeavor, a different strategy was adopted to recycle the unwanted isomer (ent-4a) in the early stage of the synthesis. In particular, this raw material 1,3-dimethyl-4piperidinone (4) is basic in nature and was resolved to the Sisomer and R-isomer (ent-4a); this undesired isomer racemized back to 4 quite efficiently in the presence of base. The racemized isomer again was resolved to obtain the required Sisomer. The overall yield of the resolution was improved to 75−80% (based on the available enantiomer) with 90−93% ee after two cycles of racemization of the unwanted isomer (Scheme 4). The S-isomer prepared by this process is isolable at room temperature, but it is perfectly stable at 0−5 °C. Such an innovative approach led us to develop an improved process for the preparation of advanced intermediate 1. Received: June 2, 2013
A
dx.doi.org/10.1021/op400144z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Scheme 1. Reported Synthesis of 1
Scheme 2. Modified Synthesis of 1
Scheme 3. Reported Synthesis of Alvimopan
In essence, the compound 4 (1,3-dimethyl-4-piperidinone) amine functionality as a resolving handle facilitates the resolution by forming a diastereomeric salt with chiral acids, e.g. (L-(+)-tartaric acid, D-(−)-mandelic acid, L-(+)-mandelic acid, L-(−)-camphor sulphonic acid, (+)-di-p-toluoyl-D-tartaric acid, and (−)-di-p-toluoyl-D-tartaric acid) along with different solvents. The solvents used for the resolution were methanol, ethanol, and acetone. Eventually, the optimized resolution conditions were realized with (−)-di-p-toluoyl-D-tartaric acid monohydrate in methanol. The optimal quantity of the (−)-dip-toluoyl-D-tartaric acid and methanol was found to be 1.25 mol and 6.0 volumes, respectively, as shown in Table 1. To our delight, almost every cycle of racemization yielded near quantitative racemized product. The recycling process involves distillation of the filtrate completely, dilution with water/toluene, and pH adjustment of the solution to 10.0−10.5 with sodium hydroxide. We found that the toluene layer contains the total residual quantity of product (desired and undesired isomers). The enantiopurity of the organic layer compound varied from 80 to 95% of the undesired isomer and B
dx.doi.org/10.1021/op400144z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Overall yield is improved due to the recycling of ent-4a. As a result, we considered S-1,4-dimethyl piperidone as an input material in the reaction to offer intermediate 7 with consistent yield in three different batches as shown in Table 3.
Scheme 4. Improved Formal Synthesis of 1
Table 3. Compilation of Consistent Yield Data for Intermediate 7
Table 1. Resolution of 4 with (−)-Di-p-toluoyl-D-tartaric Acid Monohydrate salt (HPLC) S. no.
batch size (kg)
salt yield (%)
1 2 3
0.003 0.005 15
52 57 58.5
Sisomer 95.5 95.1 92.8
S. No.
S-1,4-dimethyl piperidinone quantity
isopropoxy bromobenzene quantity
output
% yield of 7
1. 2. 3.
120 g 120 g 4.5 kg
227 g 227 g 8.5 kg
215 g 217 g 7.87 kg
67.5 68.5 66.3
Isolated material from every batch was analyzed and found to be >88% chirally pure by HPLC, as shown in Table 4.
base (HPLC)
Risomer
base yield (%)
Sisomer (4a)
R-isomer (ent-4a)
4.5 4.9 7.2
80 84 98.7
94.6 94.2 95
5.4 5.8 5
Table 4. Compilation of Consistent Purity Data for Intermediate 7
5−20% of the desired isomer. By treating this organic phase with aqueous sodium hydroxide solution at 25−35 °C for 5−6 h, both the isomers are equilibrated. The recycling procedure was repeated for a second and a third time, and the overall yield obtained was around 80%. The experimental conditions for the racemization and the enantiopurity details are featured in Table 2. Unless the strategy for resolving agent is in place, the resolution procedure cannot be considered efficient. In addition to this, it is also equally important to recycle the resolving agent. The consumption of the resolving agent was found to be 2.5 mol equivalence with respect to the (S)-1,3-dimethyl-4piperidinone. Without recovery of the resolving agent, the process may not be cost-effective. The experimental process for the recovery of the resolving agent was developed. To recover the resolving agent, the aqueous layers obtained during the isolation of (S)-1,3-dimethyl-4-piperidine and during the racemization were combined together. The aqueous layer was washed with toluene (200 mL). Later the pH of the aqueous layer was adjusted to 1.0−2.0 with aqueous HCl (10 N). Thereafter, the compound was filtered and washed with water (200 mL). The (−)-di-p-toluoyl-D-tartaric acid that was recycled was found to be qualitatively as good as the fresh material. The waste generated during the process is only water. Other components, such as toluene, 1,3-dimethyl-4-piperidinone, and (−)-di-p-toluoyl-D-tartaric acid, were recycled completely. During the course of the development, THF (which was used in the known approach) was replaced with 2methyltetrahydrofuran. The recovery of this solvent was achieved by simple layer separation followed by distillation.
S. no.
purity by HPLC
SOR (c = 1.01) MeOH
1. 2. 3.
92.6% 92.8% 88.6%
−10.22 −10.20 −9.80
Moreover, yield improvement due to racemization and recycling is also reflected in the raw material cost (RMC) calculation for intermediate 7. Considering the current USD exchange rate with Indian rupees (INR), the RMC for the literature reported route is found to be 1841 USD, whereas the improved process offered RMC 622 USD only as shown in Table 5. Table 5. RMC Comparison for Intermediate 7 RMC as per literature3
RMC as per impropved process
1841 USD
622 USD
We also mapped our improved process considering green chemistry metrics. This exercise indicated that our process is relatively greener, as the atom efficiency and E factor are improved with a margin of 8.08 and 84.37, respectively, as shown in Table 6 as compared with the precedented route.3 Table 6. GC Metrics Calculations for Intermediate 7 green chemistry (GC) metrics
as per literature3
as per improved process
atom efficiency E-factor
8.20 112.46
16.28 28.09
We identified a few obvious potential impurities. These impurities (ent-1, 12, and 13) as shown in Figure 1 are
Table 2. Experimental Results for the Racemization of the DMPP Unwanted Isomer, ent-4a (major) along with 4a (minor) isomer distribution before racemization (HPLC)
isomer distribution after racemization (HPLC)
S. no.
batch size (kg)
filtrate quantity (L)
base used for racemization
base (kg)
S-isomer (4a)%
R-isomer (ent4a)%
S-isomer (4a)%
R-isomer (ent4a)%
1 2 3
0.003 0.005 15
0.2 0.335 85
NaOH NaOH NaOH
0.0075 0.00125 3.75
5.5 5.2 7.7
94.5 94.8 92.3
50 49.6 49.4
50 50.4 50.6
C
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and dichloromethane (240 L) in the reactor at 0−5 °C. Aqueous ammonia was employed to slowly adjust the pH to 10.0−10.5. The phases were separated, and the aqueous phase was extracted with dichloromethane (60 L) at 0−5 °C. The combined organic layers were dried over sodium sulphate. Removal of the solvent by evaporation below 40 °C under reduced pressure affords 7.41 kg (98.7% yield) of the product as a light yellow organic liquid. [α]29.6D −6.86° (c 1.00 MeOH); 1 H NMR (CDCl3) δ 1.0 (d, J = 6.7 Hz, 3H), 2.05 (t, J = 11.3 Hz, 1H), 2.36 (s, 3H), 2.31−2.38 (m, 2H), 2.6−2.7 (m, 2H), 3.03−3.08 (m, 2H); 13C NMR (CDCl3) δ 11.8, 40.8, 44.1, 45.3, 56.2, 63.2, 210.4; IR (cm−1) 2969, 2939, 2790, 1718, 1257. HPLC: 97.8%; Optical purity: 95.2%. Racemization of the Mixture of Isomers [4a(minor)/ ent-4a(major)] to 1,3-Dimethyl-4-piperidinone (4). The filtrate from the preparation of 4a was distilled completely at below 65 °C in a 100 L glass reactor. The distilled product was cooled to 0−5 °C, and 10% NaOH solution was added (21 L). Thereafter, the solution was stirred at 25−35 °C for 4 h. The product was extracted with DCM (1 × 75 L and 1 × 45 L). The organic phase was dried over sodium sulphate. Subsequently, the organic phase was completely distilled under reduced pressure at below 45 °C. The product is distilled below 80 °C under high vacuum (less than 10 mbar) to afford 5.25 kg (70% yields) of 4. [α]29.6D 0.0° (c 1.00 MeOH); 1H NMR (CDCl3) δ 1.0 (d, J = 6.7 Hz, 3H), 2.06 (t, J = 11.2 Hz, 1H), 2.36 (s, 3H), 2.31−2.38 (m, 2H), 2.6−2.7 (m, 2H), 3.04−3.09 (m, 2H); 13C NMR (CDCl3) δ 11.7, 40.7, 44.1, 45.2, 56.2, 63.2, 210.4; IR (cm−1) 2969, 2939, 2790, 1718, 1257. HPLC: 98.6%; Optical purity: 50.1%. Preparation of (3S)-1,3-Dimethyl-4-[3-(1methoxyethoxy)phenyl]-4-piperidinyl Ester (7). A 200 L glass reactor was arranged and charged with 3-bromoisopropoxy benzene (3; 8.5 kg, 39.53 mol) and 2-methyl-THF (27 L). The solution was cooled to −60 to −70 °C. 15% n-BuLi in hexane (29.75 Lit, 44.62 mol) solution was added slowly at the same temperature for 1 h. The reaction mixture was stirred for 1 h at −60 to −70 °C. Thereafter, (S)-1,3-dimethyl-4piperidinone (4a) (4.5 kg, 35.4 mol) was added at the same temperature for the span of 2 h and maintained for 1 h. The reaction mass was slowly quenched with hydrochloric acid (30 L, 6 N) below 0 °C. The hexane layer was separated at 25−35 °C, and the aqueous phase was washed with hexane (2 × 12 L). Toluene (27.0 L) was charged to the aqueous phase, and the mass was cooled to 15−20 °C. The pH of the mass was adjusted to 10.0−10.5 by using 20% NaOH solution. The phases were separated, and the aqueous phase was extracted
Figure 1. Structure of potential impurities.
synthesized/isolated and well characterized. Impurity ent-1 is an enantiomer of 1 whereas impurities 12 and 13 were the desmethyl derivative of 10 and the dehydro derivative of 1, respectively, which have been formed during chemical manipulations in the downstream process. During manufacturing events, water is considered as a less hazardous effluent, which is due to a matter of fact that we ensured the contaminated water out of the process stream is not discharged before sending it to the effluent treatment plant. In order to account for mass balance, we calculated the molar quantities of starting material, resolving agent output, and unaccounted material as shown in Figure 2. We employed 1.55 mol of (−)-DPTTA monohydrate to resolve 0.79 mol of 4. Considering recycling of ent-4a, we were able to obtain 0.63 mol of 4a whereas 0.16 mol of the mixture 4/4a/ent-4a accounted for handling loss. In addition to this, we are able to recover 1.24 mol of (−)-DPTTA monohydrate (as indicated by KF), and due to its solubility in water, 0.31 mol for the same is lost along with water stream.
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EXPERIMENTAL SECTION The 1H NMR spectra were recorded in CDCl3 and DMSO-d6 on a Varian Gemini-2000 FT NMR spectrometer at 400 and 500 MHz; the chemical shifts are reported in ppm relative to TMS. The solvents and reagents were used without further purification. Preparation of (S)-1,3-Dimethyl-4-piperidinone (4a). A 200 L glass reactor was charged with 1,3-dimethyl-4piperidinone (15 kg, 118.1 mol) and methanol (105 L) and (−)-di-p-toluoyl- D -tartaric acid monohydrate [(−)DPTTA.H2O] (60 kg, 148.5 mol) and stirred for 45 min at 25−35 °C. Methanol was completely distilled under reduced pressure below 75 °C. Subsequently, methanol (90 L) was added and the mixture was cooled to 25−35 °C. The reaction mixture was stirred at the same temperature for 2 h. Thereafter, the product was filtered and washed with chilled methanol (15 L). The filtered product was charged along with water (240 L)
Figure 2. Material balance for 4a. D
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(6) Farrar, J. J.; Schied, P. J.; Schmidt, W. K.; Carpenter, R. L. US6469030B2.
with toluene (25 L). The organic phase was washed with water (18 L). Thereafter, the organic phase was dried over sodium sulphate. After filtration, triethyl amine (6.4 kg, 63.36 mol) was added to the organic phase and cooled to 0−5 °C; subsequently, ethyl chloroformate (5.3 kg, 48.84 mol) was also added to it below 10 °C for 1 h and 30 min. Stirring was continued for 2 h at 25−35 °C. Completion of the reaction was confirmed by TLC. Water was added, and the biphasic solution was stirred for 30 min. The pH of the reaction mass was adjusted to 12 with NaOH solution (20%) at below 30 °C. The organic phase was separated, and the aqueous phase was extracted with toluene (9.0 L). The organic phase was dried over sodium sulphate. The toluene was evaporated completely below 70 °C under reduced pressure to obtain 7.87 kg (66.3% yield) of 7 as an organic liquid. An analytical sample was obtained by enriching the compound with (+)-di-p-toluoyl tartaric acid monohydrate. [α]29.6D 6.43° (c 1.01 MeOH); 1H NMR (CDCl3) δ 0.72 (d, J = 6.8 Hz, 3H), 1.30−1.32 (m, 9H), 1.90−1.93 (m, 1H), 2.16 (td, 1H), 2.22−2.27 (t, J = 10.2 Hz, 1H), 2.33 (s, 3H), 2.33−2.40 (m, 1H), 2.63 (dd, 1H), 2.78 (br d, J = 11.5 Hz, 1H), 2.95 (dt, J = 9.6, 2.5 Hz, 1H), 4.12−4.20 (m, 2H), 4.5 (septet, J = 6.1 Hz), 6.74−6.79 (m, 3H), 7.19− 7.26 (t, 8 Hz, 1H); 13C NMR 12.6, 14.4, 22.0,22.1, 32.8, 42.6, 45.9, 51.0, 58.8, 63.5, 69.9, 76.7, 77.1, 77.4, 84.3, 113.2, 114.3, 117.3, 129.0, 143.4, 153.2, 157.7. IR (cm−1) 2980, 2941, 2805, 1743, 1604, 1583, 1277, 1259, 1235. HPLC: 91.6%. Optical purity: 88.6%.
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CONCLUSION In conclusion we have developed an industrially feasible and cost efficient process for the preparation of compound [(3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol] 1, which is used as the key intermediate for the preparation of the opioid drug Alvimopan. The overall yield in this process is increased from 15 to 30% due to the improvement in yield from 26 to 53% for intermediate 7.
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ASSOCIATED CONTENT
S Supporting Information *
Green metrics calculations and raw material cost calculation. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Telephone: +914044346000. Fax: +91 4044346285. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors wish to thank the management of Dr. Reddy’s Laboratories Ltd. for supporting this work. REFERENCES
(1) (a) Farrar, J. J. WO 2001037785 A2. (b) Zimmerman, D. M.; Charles, H. M. US4891379A. (c) Charless, B. J. US4581456A. (2) Carpenter, L. R.; Dukes, G. E.; Jackson, D.; Schmidt, W. K. US20050148630A1. (3) Werner, J. A.; Cerbone, L. R.; Frank, S. A.; Ward, J. A.; Labib, P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org. Chem. 1996, 61, 587−597. (4) Centrell, B. E.; Zimmerman, D. M. US5250542A. (5) Frank, S. A.; Prather, D. E.; Ward, J. A.; Werner, J. A. US5434171 E
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