Application of Kinetic Modeling and Competitive Solvent Hydrolysis in

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Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly-Selective Hydrolysis of a Nitrile to an Amide Jeffry K. Niemeier, Roger R Rothhaar, John A Werner, and Jeffrey T Vicenzi Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op4003054 • Publication Date (Web): 11 Feb 2014 Downloaded from http://pubs.acs.org on February 13, 2014

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Organic Process Research & Development

Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a HighlySelective Hydrolysis of a Nitrile to an Amide Jeffry K. Niemeier*, Roger R. Rothhaar*, Jeffrey T. Vicenzi, and John A. Werner

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis IN, 46285

ABSTRACT A combination of mechanism-guided experimentation and kinetic modeling was used to develop a mild, selective, and robust hydroxide-promoted process for conversion of a nitrile to an amide using a substoichiometric amount of aqueous sodium hydroxide in a mixed water and N-methyl2-pyrrolidone solvent system. The new process eliminated a major reaction impurity, minimized over-hydrolysis of the product amide by selection of a solvent that would be sacrificially

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hydrolyzed, eliminated genotoxic impurities, and improved the intrinsic safety of the process by eliminating the use of hydrogen peroxide. The process was demonstrated in duplicate on a 90 kg scale, with 89 % isolated yield and greater than 99.8 % purity.

INTRODUCTION The conversion of a nitrile to an amide by hydrolysis can be carried out under a variety of conditions. The most straightforward methods involve simple acid-mediated or base-mediated hydrolysis. However, these methods are often complicated by over-hydrolysis to the corresponding carboxylic acid. Alternative conditions with improved selectivity for amide formation include: metal-mediated hydrolysis,1 use of substituted hydroxylamine additives,2 enzymatic hydrolysis,3,4 and hydrogen peroxide-based chemistry.5 This paper details the development of a highly-selective, aqueous base-catalyzed process for the preparation of amide 2, a transforming growth factor- β (TGF-β) type I receptor antagonist6,7 that is currently in clinical development. Reaction selectivity was achieved by careful control of reaction conditions and use of a solvent with a competitive rate of hydrolysis relative to the amide. Optimization was aided by kinetic modeling to predict the robustness of the process under manufacturing conditions. Early process development efforts indicated a hydrogen peroxide-mediated hydrolysis would be superior to simple acid- or base-catalyzed processes due to better control of undesired overhydrolysis to the acid impurity. The initial process, using K2CO3, 35% H2O2, H2O, DMSO (Scheme 1, condition “a”), afforded amide 2 in 87% yield at 25 kg scale with little of the undesired acid 3 formed.


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Scheme 1. Reaction products observed in the hydrolysis of 1 to 2.

Reaction Conditons: a) K2CO3, 35% H2O2, H2O, DMSO, carbon treatment (87% yield in Campaign 1) or b) NaOH, 35% H2O2, H2O, NMP, DMSO (87% yield in Campaign 2)

This process was further refined for scale up by using a mixed NMP/DMSO8 solvent system to reduce sulfur emissions,9 and substituting NaOH for K2CO3 to enhance base solubility (condition “b” in Scheme 1). This process afforded amide 2 with an average yield of 87% on a scale up to 50 kg. None of the acid hydrolysis product 3 was formed during the reaction. While this process was relatively robust, discovery of mutagenic N-oxide impurities,10 safety concerns involving hydrogen peroxide,11 oxygen generation during the process, and increased concern regarding incineration of sulfur-containing waste streams on commercial scale prompted exploration for an alternative, peroxide-free process. However, hydrolysis of nitrile 1 with an aqueous hydroxide base, such as aqueous NaOH, in a water-miscible organic solvent gave not only the expected product 2 and impurity 3, but also compound 4, which resulted from the anion of amide 2 reacting with nitrile 1. This impurity was particularly problematic as minimal


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rejection occurred during isolation of 2 by crystallization. Therefore our process optimization efforts needed to target conditions which controlled both impurities 3 and 4.

RESULTS AND DISCUSSION - Development of the HydroxideMediated Hydrolysis Process Solvent Selection Polar aprotic solvent screening for the hydroxide-promoted hydrolysis was focused on solvents other than DMSO to reduce SOx emissions during waste solvent incineration. Water miscible solvents were given priority in screening partly because water could be added for direct crystallization of the product from the reaction mixture. Alcoholic solvents gave either incomplete conversion or unacceptably high levels of acid 3 depending upon reaction conditions. N,N-Dimethylacetamide (DMAC) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) proved to be quite reactive with NaOH under the reaction conditions, and gave either low conversion of starting materials, or required large amounts of base to give full conversion. Both N-methyl-2-pyrrolidone (NMP) and 1,3-dimethyl-2-imidazolidinone (DMI) gave full conversion under the conditions screened (0.5 equiv. NaOH, 100 ºC, 1:4 water to organic solvent at 5 mL/g of 1), with similar impurity profiles. NMP was chosen over DMI due to availability and lower cost.

Controlling Acid Impurity 3 – Use of k Ratio Analysis Minimizing formation of acid 3 was one of the primary goals of our process optimization work. Some authors have described selective conversion of nitriles to amides as difficult due to


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relatively fast hydrolysis of the amide,12 while others have shown it can be accomplished with high yield.13,14 Under proper conditions selectivity is very good. Solvent choice is one of the key factors.15,16 The acid impurity is formed by what is known as “series-parallel” or “consecutivecompetitive” reactions (Scheme 2).

Scheme 2. General Scheme for Consecutive-Competitive Reactions

A+ B P + B

k1 k2

P I

ki = rate constant for reaction i In our case, the product formation reaction did not consume reactant B (hydroxide), as shown in Scheme 3.

Scheme 3. Conversion of Nitrile to Amide and Acid by Consecutive-Competitve Reactions17

For a reaction scheme of this type, the level of impurity formed will be a strong function of the percent conversion of the starting material and the ratio of the reaction rate constants k1 and k2 (k ratio; defined as k1/k2 for purposes of this paper).

A general mathematical solution for


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consecutive-competitive reactions with various k ratios is shown in Figure 118,19. This relationship between the k ratio and the amount of product and impurity can be shown to also hold for this case in which the first reaction is catalytic in reactant B (hydroxide), and there is an additional reaction consuming some of reactant B; for example, by hydrolysis of the solvent NMP, as discussed below. Figure 1 illustrates that one can’t determine preferred reaction conditions by simply comparing the amount of impurity I formed in two experiments, unless they are at the same percent conversion. Instead, it is necessary to utilize the solution shown in Figure 1 (or the equation on which it is based) to determine the k ratio under different reaction conditions. The shaded region in Figure 1 shows the acceptable range of in situ concentrations of the nitrile 1 (< 0.3%) and acid 3 (< 3%), which were established by measurement of the rejection efficiencies of both compounds in the crystallization process. This allowed us to establish a target k ratio of greater than 200 for the process. A process with this level of selectivity allows for the simultaneous control of both 1 and 3 to acceptable levels at the end of the reaction. At k ratio of 150 or less at least one of the two components would be outside the acceptable range.


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4.0%

3.5%

Desired post-reaction concentrations

wt% acid impurity (3) formed

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3.0%

2.5%

k 1/k 2 = 150

2.0%

k 1/k 2 = 200 1.5%

k 1/k 2 = 300 1.0%

k 1/k 2 = 500 0.5%

k 1/k 2 = 1000 0.0% 0.0%

0.5%

1.0%

1.5%

2.0%

wt% unreacted starting material (1) remaining

Figure 1. Effect of k ratio and % conversion on acid impurity formation for a consecutivecompetitive reaction.

Controlling Acid Impurity 3 – Use of Competitive Solvent Hydrolysis It is well known that basic hydrolysis of a nitrile is a catalytic process, wherein hydroxide is not consumed. This creates an extra challenge in the control of the reaction end-point, since given sufficient time, all the hydroxide would be consumed by hydrolysis of the amide product, leading to increased impurity and decreasing the yield of the reaction. This issue was addressed by selection of NMP as a cosolvent, which hydrolyzes at a rate comparable to the product amide 2, thereby protecting it. This strategy would allow use of relatively high concentrations of


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hydroxide to give rapid product 2 formation, but prevent excessive over-hydrolysis, because the hydroxide is largely consumed by hydrolysis of the solvent rather than of our desired product. We found that NMP hydrolyzed at an appropriate rate to serve this purpose while also providing the necessary solubility for our substrate in the presence of aqueous base (Scheme 4).

Scheme 4. Hydroxide-catalyzed hydrolysis of 1 in the presence of NMP

k1

k2

k3 (1)

(2)

(3) NMP

4-( N-methyl-amino)-butyric acid (5)

Reaction Temperature The effect of temperature on the reaction rate and selectivity is shown in Table 1. Table 1. Hydrolysis Reaction Temperature Screening (6 hr time point) 3 (%)b

4 (%)b

k1/k2 ratioc

7.7

0.0

0.0

--d

22.2

77.0

0.3

0.3

270

75

0.1

97.7

2.2

0.0

420

100

0.0

97.0

3.0

0.0

--d

Entrya

Temp (ºC)

1 (%)b

1

25

92.2

2

50

3 4

2 (%)b


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a) Reaction Conditions: NaOH (0.4 equiv), 22 wt% H2O in NMP (4-6 vol), 4 h b) HPLC area% c) these k ratios were determined using data points near the end of the reaction and the equation shown in endnote 19 d) it was not possible to estimate a k ratio for these experiment due to low measured concentrations of either 1 or 3

A temperature of 75 °C was chosen as it gave an acceptable reaction rate, non-detectable levels of 4, and good selectivity.

Base Stoichiometry Studies With the knowledge that the hydrolysis of NMP as a side reaction would consume base as the desired catalytic process proceeded, a screen of NaOH stoichiometry was carried out from 0.250.60 equivalents, relative to 1. Reasonable reaction times (3-4 hours) and low levels of both impurities 3 and 4 were obtained with 0.25 equivalents.

Optimization of NMP/Water Ratio With preliminary reaction conditions well understood (NMP as solvent, approximately 20 wt % water,20 0.25 equiv. NaOH, 75 °C), the final key parameter, the NMP/water solvent ratio, was optimized. The NMP amount was held at about 4 volumes relative to starting material throughout the development effort, as this was sufficient to give full solubility of both starting material and product under the reaction conditions. The data in Table 2 clearly demonstrates that as the water content of the reaction was increased, the final area % of 4 decreased. At the extreme ends of the screening, the reaction rate for the desired reaction slowed. With regard to k ratio (and hence minimization of acid impurity 3 formation), the optimal amount of water is about 22 wt %. Studies showed impurity 4 is both


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formed and degraded during the reaction, but is degraded to a greater extent under the reaction conditions when higher amounts of water are present. Ultimately, a water content of approximately 24 wt % was chosen to balance acid impurity 3 formation and coupled impurity 4 degradation rate. This gave an acceptable reaction time (3-4 h) and good yield. Table 2. NMP/Water Ratio Screening Results (6 hr time point) Entrya

Water (wt %)

1 (%)b

2 (%)b

3 (%)b

4 (%)b

k1/k2 ratioc

1

1.1

37.8

53.0

0.5

7.5

60

2

5.3

11.8

79.4

0.4

7.0

320

3

12

1.8

96.3

0.8

1.2

390

4

22

0.1

98.3

1.4

0.1

400

5

25

0.0

98.2

1.8

0

350

6

27

0.0

98.1

1.9

0

310

7

41

0.2

97.4

2.4

0

210

8 49 3.3 94.9 1.7 0 a) Reaction Conditions: NaOH (0.4 equiv), X wt% H2O in NMP (4-6 vol), 6 h at 75 oC

140

b) HPLC in situ area%. c) These k ratio values are averages calculated using several data points near the end of reaction and the equation shown in endnote 19.

The optimized process afforded amide 2 with a yield of 89% and at least 99.8% purity in each of two 90 kg batches. The acid hydrolysis product 3 was successfully controlled to 0.12-0.14 % in the isolated product. Compound 4 was observed at below 0.05 % by the end of processing and was undetectable in the isolated product.

DEVELOPMENT AND UTILIZATION OF A KINETIC MODEL Although the kinetic model previously discussed was useful for calculating k1/k2 ratios from experimental results, a more rigorous kinetic model appropriate for the stage of development was developed to provide a deeper understanding of the process, and guide additional development and optimization.


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Development of the Kinetic Model Table 3 shows the reactions that were included in the model. Although there are often many steps involved in a reaction mechanism, generally the best approach is to only include reactions that are rate limiting steps or are important to obtain an accurate mass balance. This is the approach we used to develop a model. Reactions for formation and degradation of the coupled impurity 4 were not included in the model because under all conditions near those of the final selected conditions, the coupled impurity concentrations were < 1% during the reactions, and less than 0.05 area % at the end of the reaction. Although qualitative analytical data showed that NMP hydrolysis was occurring, it proved challenging to develop a reproducible quantitative method. Therefore, the rate of NMP hydrolysis was determined indirectly by an overall best fit of the reaction data. For collection of kinetic data, four reactions were run at small scale (2-40 g) under the selected reaction conditions (NMP-water co-solvent system with 24 wt % water), with concentrations determined by HPLC analysis.21 These reactions differed only in scale and temperature. The data were fit using the Dynochem® program,22 and the resulting parameters are shown in Table 3. The activation energies were fit using data sets from separate reactions run at 65 ºC and 85 ºC. The 95% confidence intervals for the fitted parameters were less than 15%, indicating a good fit. Figure 2 provides a comparison of the experimental data and the prediction from the kinetic model. Notice the hydroxide concentration is expected to decrease significantly over the course of the reaction due to consumption by NMP hydrolysis.


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Table 3. Modeled Reactions and Fitted Kinetic Parameters for NMP-Water Co-solvent with 24 wt % Water23

Reaction

k at 75 ºC

k units

Ea (kJ/mol)

Hydrolysis step 1

1 + OH- RC(OH)=N-

9.27 E-3a

l/(mole*s)

87.1 a

Hydrolysis step 2

RC(OH)=N- + H2O 2 + OH-

1.00 E3b

l/(mole*s)

100 b

Acid impurity formation

2 + OH- RCO2- + NH3

3.63 E-5 a

l/(mole*s)

74.5 a

NMP hydrolysis

NMP + OH- MeNH(CH2)3CO2-

1.91 E-5 a

l/(mole*s)

77.0 a

a) fit using DynoChem software22 b) assigned value for non-rate limiting step

0.5 Nitrile (1), experimental

0.45

Amide (2), experimental

0.4

Acid Impurity (3), experimental Nitrile (1), predicted

0.35

Amide (2), predicted

0.3 Acid Impurity (3), predicted

0.25

Hydroxide, predicted

0.2

0.05

0.15 0.1 0.05 0 0

100

200

300

Time (minutes)

400

500

Concentration (mol/L)

Concentration (mol/L)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0 0

100

200

300

400

500

Time (minutes)

Figure 2. Example of model fit for 24 wt % water at 75 ºC for 40-g run.


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For consecutive-competitive reactions it is advantageous to add the reagent (in this case hydroxide) to the substrate rather than the converse in order to minimize impurity formation.24 If substrate is added to reagent there is an increased tendency to have a high concentration of product in contact with excess reagent, and this leads to a higher rate of impurity formation. For this system the mixing time is fast relative to the reaction time, and our practice has been to add the hydroxide quickly.

Utilization of the Model

Effect of solvent hydrolysis The hydrolysis of NMP provides a built-in control on the maximum amount of acid impurity formed regardless of the reaction time, thereby giving a more robust process. The modelpredicted concentrations of nitrile 1 and acid 3 for the process, both with and without NMP hydrolysis, are shown in Figure 3. The desired reaction endpoint is less than 3% acid impurity with less than 0.3% remaining starting material (1). If another solvent was found that provided the same kinetics for the nitrile and amide hydrolysis reactions, but wasn’t prone to hydrolysis itself, there would be a relatively narrow window of about 30 minutes in which to stop the reaction (e.g., by cooling or neutralization). The process with NMP hydrolysis is much more forgiving, and only requires the reaction time be sufficient (about 3 hours) to reduce the amount of nitrile 1 to an acceptable concentration. Due to the competitive hydrolysis of NMP, the level of acid 3 is always lower than the acceptable level of 3%, even at extended reaction times.


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5.0

4.5

4.0

Acid impurity (3), assuming no NMP hydrolysis Nitrile (1), assuming no NMP hydrolysis

3.5

3.0

Percent

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2.5

Acid impurity (3), assuming NMP hydrolysis

2.0

1.5

Nitrile (1), assuming NMP hydrolysis

1.0

0.5

0.0 0

50

100

150

200

250

300

350

400

450

500

Time (min)

Figure 3. Comparison of process with and without NMP hydrolysis for 75 ºC reaction temperature, 0.25 equivalents NaOH. If NMP hydrolysis did not occur, acceptable times would be between the orange lines. With NMP hydrolysis, time is only constrained on the low end, with all times greater than 180 min being acceptable, as shown by the green lines.

Simulation of process robustness The kinetic model was used to study process robustness for deviations that could occur in manufacturing. The following single-failure scenarios were among those evaluated. •

Temperature control events (desired reaction T ± 12 ºC25)

•

Various NaOH charging events

•

Nitrile 1 charging events (± 6% relative to target)


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•

Reaction time events (± 1 hour stir time)

Only the -12 ºC temperature control event (reaction carried out at 63 ºC instead of 75 ºC ) gave results that were out of process specifications, due to excess remaining starting material. However, a simulation indicated this event could be rectified by re-heating the mixture to 75 ºC (instead of 63 ºC) for one hour, or stirring at 63 ºC for a total of 8 hours. Note that none of the scenarios resulted in predicted acid impurity 3 above the target in-situ level of 3%.

CONCLUSIONS Development of a simple aqueous-base reaction system to carry out the conversion of 1 to 2, while utilizing NMP as a sacrificial solvent to minimize product loss due to hydrolysis, has provided a robust, scalable process. A number of safety and process concerns associated with use of hydrogen peroxide have been eliminated, including the risk of thermal decomposition, inprocess oxygen generation, handling of an oxidizer, and potential formation of genotoxic Noxides in the penultimate step. The process also avoids use of DMSO, thereby eliminating SOx formation during incineration of process waste streams. Careful control of solvent/water composition and reaction temperature controlled the final concentration of impurity 4, which is not rejected during product isolation. The development of this process was enabled by a cross-functional approach leveraging both mechanistic organic chemistry and kinetic modeling. Analysis of the ratio of the kinetic rate constants (k ratio) for the formation of amide 2 and acid 3 provided a quantitative means for rapidly identifying reaction conditions that simultaneously controlled both compounds to acceptable levels. Finally, a kinetic model allowed exploration of process robustness over


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various process operating ranges and failure modes without the need for extensive experimentation. The optimized process was successfully run twice at 90 kg scale. In each case, amide 2 was obtained in 89% yield and greater than 99.8% purity. Impurities 3 and 4 were controlled to 0.120.14% and < 0.01% respectively, demonstrating the robustness of the process.

EXPERIMENTAL SECTION General. All reactions were run under a nitrogen atmosphere, unless otherwise specified. Reagents were used as received from commercial vendors unless otherwise noted. Proton NMR spectra were obtained at 400 MHz and carbon NMR spectra were obtained at 100.6 MHz. NMR chemical shifts are reported in δ units referenced to residual proton signals in the deuterated solvent. Yields are corrected for chemical purity of both the limiting reagent and the product (i.e., yield = (weight of product X purity/MW of product)/(weight of limiting reagent X purity/MW of limiting reagent) X 100). If the purity of the product is not specified, it is greater than 99%. Analytical methods used for reaction monitoring and purity determination as well as other analytical tests are described in the Supporting Information. 4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-6carboxamide monohydrate (2). 4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl)quinoline-6-carbonitrile (1) (90.0 kg, 256 mol) was dissolved in Nmethylpyrrolidinone (NMP), (368.9 kg, 359 L) in a 500-gal glass-lined reactor and was heated to 73-77 ºC with stirring. To this mixture was added 1 N aqueous sodium hydroxide solution (64 L, 64.0 mol). The resultant solution was stirred at 73-77 ºC and was monitored for reaction


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completion by HPLC analysis (typically 4 samples were taken in the first 3 hours to obtain kinetic data, with an additional sample taken at 4 h reaction time). When the reaction was confirmed complete by HPLC (< 0.4 area % 1 and < 0.1 area % 4), it was cooled to 50-55 ºC. Water (44.1 L) was added to the solution and the resultant mixture was seeded with 2 (90 g, 0.1 wt %). The seed slurry was stirred at 50-55 ºC for 40 min, then water (180 L) was added at 5055 ºC over 1 h. The resultant product slurry was cooled to 20-25 ºC over 1 h and was stirred at that temperature for 12 h. The slurry was filtered over a single-plate filter. The wet cake was washed at room temperature with a mixture of NMP/water (46.3 kg NMP/135 L water) followed by water (540 L). The solids were dried in vacuo at 45 ºC-55 ºC and 28 – 30 mm Hg to give 2 as the desired monohydrate crystal form (88.0 kg, 89%) as an off-white solid, mp 137 oC, and an HPLC purity of 99.8% (HPLC method found in Supporting Information). Anal. Calcd for C22H19N5O·H2O: C, 68.20; H, 5.46; N, 18.08. Found: C, 68.18; H, 5.34; N, 17.90. 1H NMR (DMSO-d6: δ) 1.74 (s, 3H), 2.63 (m, 2H), 2.82 (br s, 2H), 4.30 (t, J = 7.2 Hz, 2H), 6.93 (m, 1H), 7.37 (s, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.56 (m, 1H), 7.58 (m, 1H), 8.04, (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 8.12 (dd, J = 8.8, 1.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H).

13

C

NMR (DMSO-d6: δ 22.56, 23.24, 25.58, 48.01, 109.36, 117.74, 121.26, 122.95, 126.73, 127.16 (2C), 129.01, 131.10, 136.68, 142.98, 147.20, 148.99, 151.08, 151.58, 152.13, 156.37, 167.47. IR (KBr): 3349, 3162, 3067, 2988, 2851, 1679, 1323, 864, 825 cm-1. HRMS (m/z M+1): Calcd for C22H19N5O: 370.1653. Found: 370.1662.

ASSOCIATED CONTENT The Supporting Information section includes: • •

effect of solvent ratio, temperature, and equivalents of NaOH on mixture homogeneity studies on alternative bases


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•

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analytical methods

This material is available free of charge via the Internet at http://pubs.acs.org.

TOC Graphic

AUTHOR INFORMATION

Corresponding Author * To whom correspondence should be addressed. Jeffry K. Niemeier: Telephone: (317) 2762066. E-mail: [email protected]. Roger R. Rothhaar: Telephone: (317) 433-3769. Email: [email protected].

ABBREVIATIONS

DMAC, N,N-dimethylacetamide; DMPU, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone; NMP, N-methyl-2-pyrrolidone; DMI, 1,3-dimethyl-2-imidazolidinone; HPLC, high performance liquid chromatography;


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REFERENCES 1

Pombeiro, A. J. L.; Kukushkin, V. Y. Inorg. Chim. Acta 2005, 358, 1-21.

2

Ma, X.; Lu, M. J. Chem. Res. 2011, 35 (8), 480-483.

3

Hopmann, K. H.; Guo, J.; Himo, F. Inorg. Chem. 2007, 46 (12), 4850-4856.

4

Feng, Y. S.; Lee, C.; Chen, L. Int. Biodeterioration Biodegradation 2007, 59 (3), 211-215.

5

Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis, 1989, 12, 949-950.

6

Bueno, Lorea; de Alwis, Dinesh P.; Pitou, Celine; Yingling, Jonathan; Lahn, Michael; Glatt,

Sophie; Troconiz, Inaki F. Eur. J. Cancer, 2008, 44, 142-150. 7

Mundla, Sreenivasa Reddy; Preparation of 2-(6-methylpyridin-2-yl)-3-[6-amidoquinolin-4-

yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate as a transforming growth factor-β (TGF-β) inhibitor. US 20100120854, 2010. 8

The use of NMP may be regulated in the European Union under REACH Registration,

Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation. The status of NMP and other solvents continues to evolve. 9

While sulfur-containing wastes can be incinerated, control of sulfur emissions to regulatory

limits can present a challenge. In addition, DMSO can cause process safety concerns due to the potential for autocatalytic decomposition and decomposition catalyzed by impurities. See Zhe Wang, Z.; Richter, S. M.; Gates, B. D.; Grieme, T. A., Org. Process Res. and Dev., 2012, 16(12), 1994-2000.


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Low levels of two N-oxides were formed, with oxidation at either the pyridine or quinoline

nitrogens. Both compounds gave positive results in the Ames assay. 11

Process safety concerns with hydrogen peroxide include: the potential for runaway reaction

with gas evolution, initiated by heat and/or catalytic impurities such as inappropriate metals; and the potential for oxidation reactions during waste handling in the event of inadequate quenching. 12

Devarajan, T. S.; Pintauro, P. N. Ind. Eng. Chem. Res. 1991, 30, 581-585.

13

Bendale, P. M.; Khadilkar, B. M. Synth. Commun. 2000, 30 (10), 1713-1718.

14

Dotani, M.; Ookawa, T. Jpn. Kokai Tokkyo Koho 1994, JP 06116221 A 19940426. |

15

Hall, J. H.; Gisler, M. J. Org. Chem. 1976, 41 (23), 3769-3770.

16

Kojo, I, K; Awazu, S.; Hanano, M. Chem. Pharm. Bull. 1974, 22 (4), 864-870.

17

The first reaction is expected to occur in two steps as shown in Table 3.

18

For derivation of the solution, see one of these references: (a) Hill, C.G. Introduction to

Chemical Engineering Kinetics and Reactor Design; John Wiley and Sons: New York, 1977; Equation 9.3.9. or (b) Levenspiel, O. Chemical Reaction Engineering, 3rd ed.; John Wiley and Sons: New York, 1999; p 188. 19

The only assumption in the derivation of this solution is that the reactions are irreversible

and first order in the concentration of A, B, and P and that no other side reactions serve to consume significant amounts of these species. The plot also assumes the initial concentrations


20

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of product P and impurity I were zero. The following equation describes the relationship between the product and starting material concentrations, and is the basis of Figure 1.

Cp C A0

1 = k 1− 2 k1

 C  A  C A0 

   

k 2 / k1

−

CA   C A0  

20

Relative to total solvent.

21

Experiments were run in virtually-full sealed Teflon® tubes to minimize loss of water to the

headspace. Teflon was selected over glass to eliminate the potential for reaction of hydroxide with glass at elevated temperature. Several samples were collected for HPLC analysis during the course of the experiments. 22

DynoChem® software website is www.scale-up.com. The program’s fitting routine

minimizes the error between experimental and model values. 23

For purposes of modeling the reactions were presumed to be irreversible, bimolecular, and

not transport limited. The carboxylate forming steps are irreversible because hydroxide is a much stronger base than the carboxylic acids. 24

Levenspiel, O. Chemical Reaction Engineering, 3rd ed.; John Wiley and Sons: New York,

1999; p 188 25

Seibert, K. D.; Sethuraman, S., Mitchell, J. D.; Griffiths, K. L.; McGarvey, B. J Pharm

Innov 2008, 3, 105–112. This paper describes the rationale behind the selection of temperature control events of up to 12 oC.


21

Application of Kinetic Modeling and Competitive Solvent Hydrolysis in

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