An Improved and Efficient Process for the Preparation of Tofacitinib

Article pubs.acs.org/OPRD

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate Yogesh S. Patil, Nilesh L. Bonde, Ankush S. Kekan, Dhananjay G. Sathe,* and Arijit Das* Unichem Laboratories Limited, Center of Excellence, Process Research, Pilerne Industrial Estate, Plot No-12 to 16, Pilerne, Bardez, Goa 403511, India S Supporting Information *

ABSTRACT: The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 and its simple and impurity-free conversion to tofacitinib citrate 1. The current invention is aimed at addressing process development issues related to quality and yields. The disclosed process is capable of delivering much higher yield compared to the prior state-of-the-art process and is able to yield very highly pure compound.

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INTRODUCTION Tofacitinib citrate (1), chemically known as 3-{(3R,4R)-4methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile-2-hydroxypropane-1,2,3-tricarboxylate, was approved in November 2012 by the U.S. FDA with the trade name Xeljanz for the treatment of rheumatoid arthritis (RA). As part of our drive to explore and develop a process for the preparation of tofacitinib citrate 1, we recently initiated a systematic investigation to find new synthetic routes or improve the existing chemical schemes to enhance the yield and quality of the drug substance. In this report, we discuss our attempts to develop an efficient process for the preparation of tofacitinib citrate 1. The first reported synthetic route for the preparation of tofacitinib citrate by Blumenkopf and co-workers1 is depicted in Scheme 1.

There are other routes for the synthesis of tofacitinib or its salt available in the literature.2 The most important part for the preparation of tofacitinib is the synthesis of (3R,4R)-(1-benzyl4-methylpiperidin-3-yl)methylamine salt 3, as it is very tedious and also requires very expensive reagent. Intermediate 3 is the major cost-contributing factor for the synthesis of tofacitinib. There are several processes reported in the literature for the synthesis of compound 3. The other building block is relatively much less expensive and readily available. Ruggeri and co-workers3 disclosed a process for the preparation of 11 from compound 7, as depicted in Scheme 2. The reported chiral purity of intermediate 11 is very poor (84% cis isomer, having 68% ee), and also the process is silent about the chirality of the final tofacitinib citrate 1 produced by this intermediate. There are other complex synthetic routes also available in the literature.4,5 When we consider the drawbacks of prior state-ofthe-art and very complex methodologies applied for the preparation of the intermediate 3, there is an urgent and pressing need to communicate a simple lab process for the preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3, which may be easily scaled up and can deliver tofacitinib citrate 1, meeting stringent specifications as required by ICH guidelines.

Scheme 1a

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RESULTS AND DISCUSSION Our focus to develop an efficient process for the preparation of tofacitinib citrate 1 has mainly two aspects: (i) developing a process to manufacture (3R,4R)-(1-benzyl-4-methylpiperidin-3yl)methylamine as tartarate salt (3); (ii) preparation of tofacitinib citrate 1 following the condensation of intermediate 3 with compound 19. (i). Process To Manufacture (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methylamine as Tartarate Salt 3. We have chosen 3-amino-4-methylpyridine (7) as a starting

a

Reagents and conditions: (i) DTTA or (+)-phenylcylophos IPA; (ii) 4-chloropyrrolo[2,3-d]pyrimidine, K2CO3 in H2O, 90 °C; (iii) Pd(OH)2, ethanol, acetic acid; (iv) cyano acetic acid-2,5-dioxopyrrolidine-1-yl ester. © 2014 American Chemical Society

Received: August 28, 2014 Published: November 17, 2014 1714

dx.doi.org/10.1021/op500274j | Org. Process Res. Dev. 2014, 18, 1714−1720

Organic Process Research & Development

Article

Scheme 2a

a

Reagents and conditions: (i) methylchloroformate, base; (ii) benzyl bromide, toluene; (iii) EtOH, NaBH4; (iv) bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine, tetrahydrofuran, H2, THF; (v) LiAlH4, THF.

Scheme 3a

Reagents and conditions: (i) acetyl chloride, acetone, room temperature, 8 h; 95% yield; (ii) benzyl chloride, toluene, 110 °C, 5 h; 95% yield; (iii) sodium borohydride, methanol, water, 0 to 25 °C, 2 h; 91% yield; (iv) HCl, 80−85 °C, 3 h; 95% yield; (v) titanium(IV) tetraisopropoxide, methanolic methylamine, NaBH4, MeOH, 0 to 25 °C, 3 h; 96% yield; (vi) di-p-toluoyl-L-tartaric acid, MeOH−water (1:1), 1 h; 40% yield.

a

material as it is very cheap and commercially available. In our approach, as disclosed in Scheme 3, intermediate 17 is produced by in situ transformation from 3-amino-4-methylpyridine 7. The chemistry involved N-acylation of 3-amino-4methylpyridine 7 to produce intermediate 15. Quarternization of the pyridine ring of intermediate 15 by using benzyl chloride or benzyl bromide in toluene produced compound 16. Partial reduction of compound 16 using sodium borohydride in a mixture of methanol and water produces intermediate 17. Since compound 16 was very hygroscopic and hence very difficult to handle on bulk scale, we considered not isolating it. With the view to minimize drying and testing operations, it was later decided not to isolate even compound 15. Hence, the final

optimized process does not require isolation of compounds 15 and 16. The scheme further discloses the synthesis of intermediate 3 from the in situ transformation from intermediate 17. The optimization for conversion of compound 17 to compound 18 was initiated in the presence of acidic media. In presence of acetic acid, the reaction did not proceed, maybe due to the weak acidic nature of acetic acid. Further optimization with respect to mineral acids and reaction temperature has been carried out. The final acid selected was two volumes of hydrochloric acid (36%), and the reaction temperature was selected to be 65 °C. Reductive amination of intermediate 18 in the presence of titanium(IV) tetraisopropoxide in methanolic methylamine 1715



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unfavorable. The same has been observed from the experimental outcome, as illustrated in Table 1. The analytical GC method as disclosed in prior research3 has been adopted for the diastereomeric assignments of compound 14 and compound 3. Compound 14 shows two major cis isomers such as (R,R) and (S,S) having 50.2 and 43.90% purity, respectively, along with two low yielding trans isomers. Compound 3 shows 98.6% of the required (R,R) isomer along with minor unwanted isomers as indicated in Table 1. The fate of the diastereomeric impurities was studied, and it has been found that the process can tolerate the (S,S) isomer up to 10.0% and the trans isomer up to 1.4% to get ICH-quality final API. (ii). Preparation of Tofacitinib Citrate 1 from Condensation of Intermediate 3. Condensation of Intermediate 3 with Compound 19. The condensation process for the intermediate 3 and compound 19 is very crucial and a key step to form the main skeleton of tofacitinib citrate 1, as disclosed in Scheme 5, and remains the scope of invention to identify the optimum process conditions. Keeping this as an objective, we evaluated coupling reaction conditions by carrying out experimentation with varying potassium carbonate quantity from 6 to 12 equiv. The other approaches tried are also disclosed in Table 2. Entries 1−4 in Table 2 show that, as the equivalence of potassium carbonate increases from 6 to 12, yield increases from 68 to 89% and purity increases from 58.7 to 97.34%, which is shown in Figure 1. Use of 6−9 equiv of potassium carbonate is unable to take the reaction between intermediate 3 and intermediate 19 to completion. To consume compounds 3 and 19 in the reaction, an excess amount of K2CO3 is required in order to increase the yield and purity of the product. In this coupling reaction, no other impurity formation is observed. When the reaction was carried out with compound 12 in entry 5, the yield and purity is inferior; this may be due to the lower stability of free amine 12 at high temperature. In situ generation of 12 from 3 proved to be a better approach, avoiding the isolation of free base 12. Further, an in situ purification was also carried out to avoid isolation of crude compound 20, as indicated in entry 6, which is a similar result to that in entry 4. Entry 7 showed that the use of potassium iodide does not have any significant impact in the reaction. From the above discussions, the condensation process for the intermediate 3 and compound 19 is carried out in the presence of 12 equiv of potassium carbonate in water at 90−100 °C, followed by acetone purification to obtain intermediate 20. Detosylation of Compound 20 To Obtain 4. Initially, the detosylation reaction was envisaged in water using sodium hydroxide as a base.3 However, using water as a media for this

followed by reduction with sodium borohydride produces compound 14. The optimized complexation temperature of titanium(IV) propoxide is derived as 0 to 15 °C. Resolution of compound 14 in the presence of a resolving agent such as dibenzoyl-L-tartaric acid or ditoluoyl-L-tartaric acid in the mixture of methanol and/or water produced intermediate 3. The process was initially investigated by isolating compounds 18 and 14. Telescopic approach was applied to check the impact on quality and yield of intermediate 3. It has been observed that with or without isolation of the intermediates 18 and 14 had no major impact on yield and quality of intermediate 3. Moreover, intermediate 18 was quite unstable at room temperature and required storage under refrigerated conditions. So the in situ transformation provides a better process control. Thus, the above synthetic route in Scheme 3 is a two-step process without the need to use any expensive reagent such as platinum oxide, iridium or rhodium catalyst, lithium aluminum hydride etc. or need to isolate compounds 14, 15, 16, and 18. The final synthesis of compound 3 is an overall two-step process with 26% overall yield from compound 7, as compared to a reported process4 with an overall yield of 15%. The chirality of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 produced in this process is more than 97% ee (Table 1) as compared to 68% ee of Table 1. Chiral GC Purity of 14 and 3 chiral GC purity cis isomer compound name

(R,R) isomer

(S,S) isomer

compound 14 compound 3

50.22% 98.64%

43.90% 0.16%

diastereomeric trans isomer 2.46% and 3.40% 1.06% and 0.13%

intermediate 11 reported in the literature.3 The new process generates a very interesting intermediate 18 which can be isolated. Although we report here that it is simple textbook chemical conversion to intermediate 3, it presents an opportunity for enzymatic or organocatalytic conversion to intermediate 3. Intermediate 18 when treated with monomethylamine followed by reduction with sodium borohydride provides four isomers 14a, 14b, 14c, and 14d (Scheme 4). The cis isomers (14a and 14b) looks to be stable because it has only one 1,3diaxial interaction as compared to the trans isomer (14c and 14d). Isomer 14c has two 1,3-diaxial interactions, and isomer 14d has steric hindrance between the methyl and amino methyl groups, which makes their generation in the reaction Scheme 4

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Scheme 5a

Reagents and conditions: (i) K2CO3, H2O, 90−95 °C, 12 h, 85% yield; (ii) KOH, MeOH, 3 h, 80% yield; (iii) Pd−C, H2O, acetic acid, 3 h, 78% yield; (iv) ethylcyano acetate, n-BuOH, DBU,12 h; (v) citric acid, H2O, n-BuOH, 1 h, 85% yield from compound 5.

a

alcohol, but unfortunately, the reaction did not go to completion. Therefore, the attention was focused on various isolation procedures of compound 4 in order to minimize the formation of the N-oxide impurity, and the results are summarized in Table 3. Thus, after detosylation using methanol as a solvent, the reaction mass was cooled and filtered directly (entry 4) without distillation to obtain intermediate 4 with very good purity (96.3%). Debenzylation of Compound 4 To Obain Compound 5. Debenzylation of intermediate 4 to intermediate 5 was designed in such a way to get the highest purity with minimum impurity formation. Entry 1 discloses the use of palladium hydroxide for the debenzylation as reported in a prior literature procedure.1 When isopropyl alcohol and acetic acid were used as a solvent for the debenzylation step using Pd/C (10% loading), the purity of intermediate 5 was 84.8% (entry 2), which increased to 98.3% (entry 3) in the presence of water with isopropyl alcohol and acetic acid. The impurities have been characterized by LCMS, and the masses are 148.9 and 335.7. Mass of a 148.9 molecular weight compound may be 4-N-methylpyrrolo[2,3-d]pyrimidine, which can be generated due to dealkylation of a N-benzyl piperidine derivative. Mass of 335.7 molecular weight compound has the same mass as compound 4, which may be due to a different diastereomer present in the reaction mixture. Entries 2 and 3 confirm that water has a major role in the completion of the reaction with better isolated yield with good purity. Considering this, we carried out another reaction in water, and the purity of intermediate 5 was 99.27% with optimum yield (entry 4); the results are summarized in Table 4.

Table 2. Synthesis of Compound 20 unreacted starting materials in the isolated compound 20 entry

yield (%)

purity (%)

compound 3

compound 19

1 2 3 4 5

68 68 81 89 67

58.78 60 70.12 97.34 78.75

14.40 10 7.15 ND ND

21.15 19.34 14.1 1.45 18

6

87

96.18

ND

1.53

7

77

94.20

1.16

1.12

reaction conditions 6.0 equiv of K2CO3 7.0 equiv of K2CO3 9.0 equiv of K2CO3 12 equiv of K2CO3 12 equiv of K2CO3, condensation using compound 12 12 equiv of K2CO3, in situ purification by charging acetone in reaction mass 12 equiv of K2CO3, catalyzed by 1% KI

reaction, an unwanted or undesired racemization was observed, which limited the use of water as a solvent for this reaction. Hence, water was replaced with alcohol such as methanol as a solvent. Various developmental experiments were carried out by replacing water with methanol and are tabulated in Table 3. After the detosylation reaction, when methanol was removed by distillation followed by addition of water and filtration (entry 1), the HPLC purity of the isolated material was only 84.21%, having one major impurity that carried to the final tofacitinib citrate and proved to be very difficult to remove. The impurity has been characterized by LCMS, and its mass is 351.7, which suggests that the impurity is N-oxide of intermediate 4. To avoid the formation of this N-oxide impurity, we have tried different alcohol solvents, such as ethanol and isopropyl 1717



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Figure 1. Effect of molar equivalent of K2CO3 on percentage of purity and yield.

Table 3. Detosylation of Compound 20 To Obtain Compound 4 impurity at RRT entry

yield (%)

HPLC purity (%)

1 2 3

97 65 77

84.21 93.36 93.68

4

76

96.30

0.66 4.26 1.25 2.59 ND

1.22

isolation procedures

7.40 3.28 2.73

reaction in methanol and isolated in water reaction in methanol and isolation in water, followed by purification using IPA reaction in methanol, distilled out methanol followed by extraction into MDC and purification using ethyl acetate/hexanes (1:1) reaction in methanol and filtration at 0−5 °C followed by water leaching

3.20

Table 4. Debenzylation of Compound 4 To Obtain Compound 5 impurity at RRT entry

yield (%)

purity (%)

0.92

0.68

2.04

2.28 or compound 4

1

54

91.57

0.58

0.62

0.90

5.16

2 3 4

68 71 71

84.80 98.32 99.27

7.00 ND ND

7.89 0.36 0.11

ND 0.22 0.33

ND 0.66 0.17

remark reaction carried out in IPA/water (1:1), acetic acid, and 20% loading of 10% palladium hydroxide reaction carried out in IPA and acetic acid, 20% loading of 10% Pd/C reaction carried out in IPA/water (1:1) and acetic acid, 20% loading of 10% Pd/C reaction carried out in water and acetic acid, 10% loading of 10% Pd/C

Table 5. Screening Experiments for Tofacitinib Citrate Formationa reaction conditions

impurity at RRT

entry

reagent

base

solvent

yield (%)

purity (%)

SM

0.84

1.1

1.2

1.25

1 2 3 4 5 6

CAAb (2 equiv) ECA (3 equiv) ECA (3 equiv) ECA (3 equiv) ECA (3 equiv) ECA (3 equiv)

TEA (3 equiv) TEA (3 equiv) DBU (1 equiv) DBU (1 equiv) DBU (1 equiv) DBU (0.75 equiv)

MDC toluene IPA methanol n-BuOH n-BuOH

50 50 55 58 75 75

41.58 65.25 65.28 73.58 99.8 99.9

25.5 25 20 15 0.08 ND

16 10 06 03 0.05 0.04

2.56 2.7 1.8 1.5 ND ND

1.2 0.75 0.15 0.18 ND ND

3.5 3.8 2.8 2.5 ND ND

a ECA, ethylcyano acetate; CAA, cyano acetic acid; n-BuOH, n-butyl alcohol; TEA, triethylamine; DBU, 1,8-diazabicyclodec-7-ene; SM, starting material; NI, not isolated; IPA, isopropyl alcohol; ND, not detected. bCyano acetic acid was converted to cyano acetyl chloride.

Formation of Tofacitinib Citrate 1 from Compound 5. Preparation of tofacitinib base 6 is achieved by the condensation of intermediate 5 with either cyano acetyl chloride or ethylcyano acetate. The organic bases were chosen based on literature2c and are either triethylamine (TEA) or 1,8diazabicyclo[5.4.0]undec-7-ene (DBU). A number of solvents with varying reaction conditions were attempted as indicated in Table 5 to obtain the most suitable conditions for the reaction. Non-nucleophilic amidine bases such as DBU along with nbutanol (entries 5 and 6) as a solvent were chosen for this reaction to obtain the maximum yield with maximum purity of

tofacitinib free base, which can be converted to tofacitinib citrate 1 by the reaction with aqueous citric acid.

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CONCLUSION

We have provided a simple, improved, cost-effective process for the synthesis of tofacitinib citrate 1. The tofacitinib citrate produced is free from impurities and meets regulatory requirements with 2-fold overall yield in comparison with the reported procedure.4 1718



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EXPERIMENTAL SECTION All reagents, solvents, and acids are commercially available and are used without further purification. 1H NMR spectra were recorded in CDCl3, MeOD, and DMSO using a JEOL 300 MHz FT NMR spectrometer; the chemical shifts are reported in δ ppm relative to TMS. Reverse phase HPLC carried out using an Alliance Waters 2695 separation module system with UV detector and column used is Inertsil ODS-3 (250 mm × 4.6 mm, 5 μ), using phosphate buffer and acetonitrile (90:10 v/v) as a diluent. Chiral HPLC was carried out using a Shimadzu LC-2010 system with UV detector, and the column used is a Chiralpak IE-3 (250 mm, 4.6 mm, 5 μ), using n-hexane/ ethanol/diethylamine (50:50:0.1 v/v) as a diluent. Chiral GC method: column, Cyclosil B 30 m × 0.32 mm, 0.25 μm, with oven program; isothermal 130 °C 60 min hold and FID detector. Mass spectrometry was carried out using an Agilent LC/MSD Trap 1100 series. Preparation of 1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylacetylamine (17) from 3-Amino-4-methylpyridine (7). A mixture of 3-amino-4-methylpyridine (7) (200 g, 1.85 mol), acetyl chloride (400 mL, 5.60 mol), and acetone (2 L) was stirred for 8 h at room temperature. After the completion of the reaction as monitored by TLC (mobile phase: chloroform/methanol = 8:2), the pH of the reaction mixture was adjusted to 9−11 by aqueous ammonia and then distilled out with acetone to obtain compound 15. Toluene (1 L) and benzyl chloride (202 g, 1.60 mol) were added to the reaction mixture containing compound 15 and stirred for 15 min at room temperature. The temperature of the reaction mass was then increased to 75−85 °C and stirred for 8−10 h as required to complete the reaction (monitored by TLC, mobile phase: chloroform/methanol = 8:2). The reaction mass was then cooled to room temperature. Water (1 L) was then added to the reaction mixture and separated out the aqueous layer. The aqueous layer was then cooled to 0−10 °C. Sodium borohydride solution (140 g, 3.70 mol, in 0.1 N sodium hydroxide) was then added to the aqueous layer dropwise at 0− 10 °C and stirred for 10−12 h as required to complete the reaction (monitored by TLC, mobile phase: chloroform/ methanol = 8:2). After the completion of the reaction, the precipitated solid was filtered by Buckner funnel to obtain compound 17: Yield = 360 g (82%); purity by reverse phase HPLC 95%; MS m/z 245 (M+ + 1); mp 112.8−114 °C; 1H NMR (CDCl3) δ 8.57 (s, 1H), δ 7.25−7.31 (m, 5H), δ 3.51 (s, 2H), δ 2.84 (s, 2H), δ 2.48 (t, 2H), δ 2.06 (t, 2H), δ 1.83 (s, 3H), δ 1.50 (s, 3H). Preparation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3yl)methylamine (3) from 1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylacetylamine (17). Concentrated HCl 35% (600 mL, 2 volume) and 1-benzyl-4-methyl-1,2,5,6tetrahydropyridin-3-ylacetylamine (17) (300 g, 1.23 mol) were charged in a 3 L four-neck round-bottom flask with an overhead stirrer and stirred for 10 min at room temperature. Temperature of the reaction mixture was then increased slowly to 65−70 °C and stirred for 3−4 h to complete the reaction (monitored by TLC, mobile phase: chloroform/methanol = 9:1). The reaction mixture was then cooled to 25−30 °C, and the pH of the mixture was adjusted to 8−12 by using 30% sodium hydroxide. The reaction mass was extracted with hexane (900 mL). The hexane layer was concentrated, and the resulting oily mass was dissolved in methanol (900 mL). The methanolic solution was cooled to 0−15 °C, and titanium(IV)

tetraisopropoxide (385 mL, 1.30 mol) was added to the solution. Methanolic monomethylamine solution (33%, 200 mL, 2.12 mol) was added to the resulting complex, and the mixture was stirred at 5−15 °C for an hour. Sodium borohydride (46.5 g, 1.23 mol) was added to the reaction mixture in a small portion at 5−15 °C and stirred for an hour as monitored by TLC (mobile phase: chloroform/methanol = 8:2). The reaction mass was filtered off followed by distillation to obtain racemic crude amine. The crude amine was resolved by using L-ditoluoyl tartaric acid (240 g, 0.621 mol) in 1:1 mixture of methanol−water (2 L). The reaction mixture was stirred for an hour at 40−45 °C, and the precipitated product was filtered off to get compound 3: Yield = 168 g (37%); purity by chiral GC 98.6%; MS m/z 219 (M+ + 1); mp 202.2−203.6 °C; 1H NMR (MeOD) δ 8.04 (d, 2H, J = 8.0 Hz), δ 7.29 (m, 7H), δ 5.85 (s, 1H), δ 4.91 (s, 3H), δ 3.63 (d, 1H, J = 12.8 Hz), δ 3.42 (d, 1H, J = 12.8 Hz), δ 3.09 (s, 1H), δ 2.90 (m, 1H), δ 2.49 (s, 3H), δ 2.22 (m, 2H), δ 1.91 (m, 1H), δ 1.48−1.64 (m, 2H), δ 1.02 (d, 3H, J = 7.1 Hz). Preparation of 4-Chloro-7-tosylpyrrolo[2,3-d]pyrimidine (19) from 4-Chloro-7H-pyrrolopyrimidine. Sodium hydroxide solution (31 g, 0.75 mol, NaOH in 300 mL water) was added into a stirred mixture of 4-chloro-7Hpyrrolopyrimidine (100 g, 0.65 mol) and paratoluene sulfonyl chloride (137 g, 0.72 mol) in acetone (500 mL). The resulting solution was stirred about 6−8 h at room temperature as progress of the reaction was monitored by TLC (mobile phase: chloroform/methanol = 9:1). After that, the precipitated solid was filtered out and washed with acetone/water 1:1 (100 mL) to obtain the title compound 19: Yield = 196 g (98%); purity by reverse phase HPLC 98%; MS m/z 308, 310 (M+) (M+ + 2); mp 141−146 °C; 1H NMR (CDCl3) δ 8.75 (s, 1H), δ 8.05 (d, 2H, J = 8.3 Hz), δ 7.75 (d, 1H, J = 3.9 Hz), δ 7.29 (d, 2H, J = 8.0 Hz), δ 6.68 (d, 1H, J = 3.9 Hz), δ 2.38 (s, 3H). Preparation of N-((3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7-tosylpyrrolo[2,3-d]pyrimidin-4-yl))amine (20) from the Condensation between Compound 19 and Intermediate 3. A mixture of 4-chlropyrrolo-7-tosyl[2,3-d]pyrimidine (19) (180 g, 0.58 mol) and bis-N-((3R,4R)(1-benzyl-4-methylpiperidin-3-yl))methylamine ditolouyl tartarate (3) (200 g, 0.24 mol) was stirred in 1500 mL of water in the presence of potassium carbonate (400 g, 2.89 mol) at 90 °C. After completion of the reaction as monitored by TLC (mobile phase: chloroform/methanol = 9:1), the reaction mass was cooled and filtered off to obtain compound 20: Yield = 185 g (85%); purity by reverse phase HPLC 98%; MS m/z 490 (M+ + 1); mp 182−184 °C; 1H NMR (CDCl3) δ 8.30 (s, 1H), δ 8.03 (d, 2H, J = 8.3 Hz), δ 7.40 (d, 1H, J = 3.9 Hz), δ 7.19− 7.27 (m, 7H), δ 6.63 (d, 1H, J = 3.9 Hz), δ 5.11 (m, 1H), δ 3.40−3.53 (m, 5H), δ 2.70−2.79 (m, 2H), δ 2.52 (d, 1H), δ 2.31 (m, 4H), δ 2.08 (m, 1H), δ 1.66 (m, 2H), δ 0.86 (d, 3H, J = 6.6 Hz). Preparation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine (4) from ((3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl(7-tosylpyrrolo[2,3-d]pyrimidin-4-yl))amine (20). A mixture of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7tosylpyrrolo[2,3-d]pyrimidin-4-yl)amine (20) (200 g, 0.41 mol) in 600 mL of methanol and potassium hydroxide (46 g, 0.82 mol) was stirred for 0.5 h at room temperature. The temperature of the reaction mixture was increased to 45 °C and stirred for 3 h as required to complete the reaction (monitored by TLC, mobile phase: chloroform/methanol = 8:2). After 1719



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completion of the reaction, the mass was cooled to 5−10 °C and filtered out to obtain the title compound 4: Yield = 110 g (80%); purity by reverse phase HPLC 96%; MS; m/z 336 (M+ + 1); mp 137.5−138.5 °C; 1H NMR (CDCl3) δ 11.60 (br s, 1H), δ 8.05 (s, 1H), δ 7.20−7.35 (m, 5H), δ 7.10 (d, 1H, J = 3.9 Hz), δ 6.55 (d, 1H, J = 3.9 Hz), δ 5.10 (m, 1H), δ 3.49 (m, 5H), δ 2.77 (m, 1H), δ 2.57 (m, 2H), δ 2.21 (m, 2H), δ 1.65 (m, 2H), δ 0.89 (d, 3H, J = 6.8 Hz). Preparation of (3R,4R)-(4-Methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine (5) from (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)amine (4). A mixture of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine (4) (40 g, 0.12 mol), 200 mL of water, 14 mL of acetic acid, and 8 g 10% Pd/C was stirred at room temperature. The temperature of the reaction mass was increased to 50 °C, and the resulting reaction mass was stirred for 8 h as required to complete the reaction (monitored by TLC, mobile phase: chloroform/methanol = 8:2). The reaction mass was then basified and extracted with 1-butanol (200 mL). The organic layer was distilled off, and the wet cake was washed with ethyl acetate (50 mL) to obtain 20 g of title product 5: Yield = 23 g (78%); purity by reverse phase HPLC 99%; MS m/z 246 (M+ + 1); mp 158.5−159.5 °C; 1H NMR (CDCl3) δ 11.52 (br s, 1H), δ 8.31 (s, 1H), δ 7.06 (d, 1H, J = 3.4 Hz), δ 6.55 (d, 1H, J = 3.4 Hz), δ 4.90 (m, 1H), δ 3.40 (s, 3H), δ 3.28 (m, 1H), δ 3.04 (m, 1H), δ 3.04 (m, 1H), δ 2.94 (m, 1H), δ 2.84 (m, 1H), δ 2.50 (m, 1H) δ 1.87−1.94 (m, 2H) δ 1.60− 1.64 (m, 1H), δ 1.08 (d, 3H J = 7.1 Hz). Preparation of 3-{(3R,4R)-4-Methyl-3-[methyl(7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile-2-hydroxypropane-1,2,3-tricarboxylate (1) from (3R,4R)-(4-Methylpiperidin-3-yl)methyl-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)amine (5). A mixture of (3R,4R)-(4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine (5) (20 g, 0.08 mol), DBU (12.41 g, 0.08 mol), and ethylcyano acetate (27.68 g, 0.24 mol) was stirred in 100 mL of 1-butanol. The resulting solution was stirred at 45 °C until completion of the reaction as monitored by TLC (mobile phase: chloroform/methanol = 8:2). After the completion of the reaction, 65 mL of 43% (w/v) aqueous citric acid solution was added to the reaction mass. The solid product obtained was filtered off to get chirally pure title product: Yield = 35 g (85%); purity by reverse phase HPLC 99.7%; purity by chiral HPLC 99.9%; MS m/z 313 (M+ + 1); mp 201−202 °C; 1H NMR (CDCl3) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93−4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13−1.18 (m, 3H).

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the management of Unichem Laboratories Limited for the permission to publish this work. We also thank to Process Research Analytics (PRA) team for their support.

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REFERENCES

(1) (a) Blumenkopf, T. A.; Flanagan, M. E.; Munchhof, M. J. U.S. Patent USRE41783E, 2010. (b) Flanagan, M. E.; Munchhof, M. J. U.S. Patent US7301023B2, 2007. (c) Ernest, W. G.; Christian, K.; Ton, V.; Edward, F. M.; Munchhof, M. J. PCT WO 02096909, 2002. (2) (a) Adolfo, M.; Mario, J. S.; Leonardo, S. S. Tetrahedron Lett. 2013, 54, 5096−5098. (b) Stavber, G.; Cluzean, J. PCT WO 2014016338A1, 2014. (c) Kristin, E. P.; Claude, L.-A.; Brett, M. L.; Robert, W. M.; Jason, M.; Kevin, W. H.; Jeol, M. H.; Rajappa, V. Org. Lett. 2009, 11, 2003−2006. (3) Ruggeri, S. G.; Hawkins, J. M.; Makowski, T. M.; Rutherford, J. L.; Urban, F. J. PCT WO 2007012953, 2007. (4) Rao, T. S.; Zhang, C. PCT WO 2010123919, 2010. (5) (a) Iorio, M. A.; Ciuffa, P.; Damia, G. Tetrahedron 1970, 26, 5519−5527. (b) Brown Ripin, D. H.; Abele, S.; Cai, W.; Blumenkopf, T.; Casavant, J. M.; Doty, J. L.; Flanagan, M.; Koecher, C.; Laue, K. W.; McCarthy, K.; Meltz, C.; Munchhoff, M.; Pouwer, K.; Shah, B.; Sun, J.; Teixeira, J.; Vries, T.; Whipple, D. A.; Wilcox, G. Org. Process Res. Dev. 2003, 7, 115−120. (c) Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.; Makowski, T.; Mazur, D. J.; Phillips, J.; Brown Ripin, D. H.; Ruggeri, S. G.; Stearns, J. F.; White, T. D. Org. Process Res. Dev. 2005, 9, 51−56. (d) Brown Ripin, D. H. PCT WO 2004/046112, 2004. (e) Hu, X. E.; Kim, N. K.; Ledoussal, B. Org. Lett. 2002, 4, 4499−4502.

ASSOCIATED CONTENT

S Supporting Information *

1

H NMR for compounds 1, 3, 4, 5, 17, 19, and 20, chiral GC analysis for compounds 14 and 3, and chiral HPLC for compound 1. This material is available free of charge via the Internet at http://pubs.acs.org.

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