Development of a Safe and Scalable Process for the Preparation of

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Development of a safe and scalable process for the preparation of allyl glyoxalate Michele T Buetti-Weekly, Pamela Clifford, Brian P Jones, and Jade D. Nelson Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00345 • Publication Date (Web): 06 Dec 2017 Downloaded from http://pubs.acs.org on December 6, 2017

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Organic Process Research & Development

Development of a safe and scalable process for the preparation of allyl glyoxalate Michele T. Buetti-Weekly*, Pamela Clifford, Brian P. Jones, and Jade D. Nelson Chemical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States Corresponding author: Michele T. Buetti-Weekly

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Table of Contents Graphic


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ABSTRACT

While conversion of dialkyl tartrate esters to the corresponding glyoxalic acid esters has been welldocumented, large scale application of some common laboratory protocols presents a myriad of challenges. The low cost, high availability and predictable reactivity of sodium periodate make it an attractive choice for synthetic chemistry applications; the resulting solid byproducts, however, have a high thermal potential and therefore must be handled with care during clean-up and disposal – especially on large scale. Successful demonstration of the synthesis of glyoxaldehydes by oxidative cleavage of tartrate esters with sodium periodate is discussed herein. Furthermore, this account describes the process safety/engineering investigation carried out to ensure a robust and safe process for the scale manufacture of allyl glyoxalate via sodium periodate-mediated cleavage of diallyl tartrate.

KEYWORDS: allyl glyoxalate, sodium periodate, diallyl tartrate, oxidative cleavage

Introduction The utility of glyoxylic acid esters in target oriented synthesis has been widely reported.1-4 During the course of development of a clinical drug candidate, kilogram quantities of a glyoxalic acid ester were required. The ideal glyoxalate would need to be accessible on large scale, isolated and stored for extended periods with minimal loss of purity, and stable to the fairly strenuous processing conditions required in the downstream synthetic sequence. Additionally, the ester function was to serve as a direct precursor to the free carboxylic acid, so mild conditions for conversion of acid to ester were essential since the API was sensitive to both strong acid and base.


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A series of glyoxaldehydes 2a-d were synthesized via oxidative cleavage of the appropriate tartrate precursor 1 with periodic acid,

5-13

or preferably, with sodium periodate

14-18

as depicted in Scheme 1.

None of the resulting compounds (2) were crystalline solids at room temperature. It was also observed that these glyoxaldehydes tend to hydrate easily (3a-d).19 Thus, these glyoxaldehydes were utilized as crude oils or concentrated solutions in the laboratory during the evaluation period.

Scheme 1. Preparation of Glyoxaldehydes O

O

OH OR

RO OH O

NaIO4

O H

RO

20-40 °C

1a: R = allyl 1b: R = cinnamyl 1c: R = Bn 1d: R = PNB

O 2a-d

H2O

RO

OH OH 3a-d

Several of these glyoxaldehydes were viable options for use in the downstream processing, allyl glyoxalate hydrate 3a was the least expensive to prepare and was effective in the downstream chemistry. Therefore, 3a was selected for further development.

During development, numerous batches of 3a were produced at laboratory scale to support the downstream chemistry. As the program progressed, the demand for the glyoxylic acid ester increased and, therefore, 2a was prepared at 400 L scale via periodate oxidation. At this scale, the reaction performed as expected and the heterogeneous mixture of product dissolved in methyl tert-butyl ether and solid periodate/iodate was filtered. The filter cake was primarily comprised of insoluble periodate and iodate salts. This waste cake was packed out of the filter and placed in a plastic container to be disposed of at a later time. Within hours following the pack-out, an exothermic event was observed that led to vigorous iodine formation. This event was exothermic enough to melt part of the plastic container holding the solids. Since this behavior was not seen at laboratory scale, further investigation around the thermal potential and processing methodology was needed. The following is an account of the ACS Paragon Plus Environment

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laboratory investigation into root cause, and the preventative measures that were implemented to prevent a repeat incident.

Results and Discussion

Initial laboratory procedure of allyl glyoxalate (2a). With the decision to use allyl glyoxalate (2a) as an intermediate for the synthesis of an API, numerous laboratory scale experiments were performed to understand the chemistry. Scheme 2 details the oxidative cleavage of diallyl tartrate with sodium periodate in a methyl t-butyl ether (MtBE)/water solvent matrix. Diallyl tartrate 1a is an oil at room temperature, produced from tartaric acid, and was proven to be quite stable. For this synthesis, 1a was oxidized with sodium periodate to form two equivalents of 2a and water. The reaction proceeded to completion, with essentially no detectable 1a remaining. Resulting 2a product exists primarily in its hydrated form, 3a, and subsequent hydrolysis can occur upon extended storage and/or elevated temperatures to afford glyoxylic acid (4) and allyl alcohol (5).

The original synthesis of 2a involved dissolving 1a in an MtBE/water mixture (19:1 v/v), followed by the addition of sodium periodate at 35 °C under vigorous agitation. The reaction requires an excess of sodium periodate (e.g. 50-100% molar excess) to perform acceptably due to tendency for dense periodate solids to aggregate in the bottom of the reactor. The addition of excess sodium periodate ensured sufficient oxidative surface is available for reaction and consistently affords complete conversion. Sodium periodate was reduced to sodium iodate during the process creating a mixed periodate/iodate waste cake at the end of the reaction. These mixed solids tend to adhere to the reaction vessel walls during processing. Upon reaction complete, the inorganic solids were removed via filtration and the 2a product remained in the filtrate. The organic filtrate was washed with brine and then dried with sodium sulfate. The resulting solution of 2a was concentrated to an oil via partial vacuum distillation to remove MtBE. ACS Paragon Plus Environment

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Scheme 2. Synthesis of allyl glyoxalate (2a) from diallyl tartrate (1a)

OH O O

O O

O

NaIO4

OH

MtBE, H2O 25 °C

1a

O H

O

H2O

OH

O

NaIO3 OH

O

3a

2a H2O

O H

HO

OH O 4

5

Scale up of the allyl glyoxalate synthesis. The laboratory synthesis was evaluated for scale, which included a process safety risk assessment. During these studies, it was noted that the sodium periodate/iodate solids had a high thermal potential, but based on the laboratory procedure, where the filtered solids were rinsed with MtBE and then dried with a stream of nitrogen to remove residual organic solvent, no significant chemical reaction hazards were noted. Several processing aspects, including the suspension of the periodate solids and the final isolation of the product oil, were considered sub-optimal. The final isolation required a precise balance of solvent removal and exposure to heat. The product 2a thermally degrades, reducing yield and quality of the material. With scale-up, extended distillation times are expected to ensure the product is concentrated sufficiently for use in the subsequent chemistry.

While the process to 2a was far from ideal, a larger scale manufacture was deemed necessary due to support the program. When the iodine release incident occurred at 400 L scale, additional engineering and process safety evaluations were performed to determine the root cause of the exothermic event. An assessment of processing parameters such as agitation rate, solvent, and dosing was carried out to identify the process for scale-up and safe processing. ACS Paragon Plus Environment

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Understanding the oxidative cleavage of diallyl tartrate. A thorough investigation was conducted focusing on the exothermicity of the reaction, the thermal potential of the waste solids post-reaction, and the handling of those waste solids after filtration. Inherent in these safety-oriented factors are the processing aspects such as solvent selection, mixing conditions, reaction temperature, and addition mode of reagents. Metrics to determine what constituted the best conditions included yield and purity (i.e., levels of known decomposition products like 4 and 5) of a given set of synthetic conditions, and operability of the process. These studies were done concurrently to expedite recommendations for processing conditions on scale.

The reaction solvent was a key aspect of many of the questions surrounding the process. The solvent matrix provides a heat sink for the reaction, affects the mixing profile within the tank, and influences the final isolation of the oil (i.e., is a solvent exchange required to carry into the next step?). MtBE was the original solvent for the reaction, but several factors suggested that choice be reconsidered. With MtBE, as with most ether solvents, there is always concern for peroxide formation. Since the given reaction employs an oxidizing agent (sodium periodate), these concerns were exacerbated. Furthermore, the allyl glyoxalate product required the removal of MtBE prior to the subsequent chemistry, which is run in isopropyl acetate (i-PrOAc). In response to the exothermic iodine release incident, other solvent choices were evaluated.

Reaction solvent options. Two other solvents, i-PrOAc and dichloromethane (DCM), were considered as potential reaction solvents based on successful cleavage of 1a in their presence. i-PrOAc was a logical choice when considering the downstream chemistry, as the next synthetic step was performed in i-PrOAc. Therefore, by using i-PrOAc for the synthesis of 2a, the final product would not have to be distilled to an oil; it could be stored as an i-PrOAc solution. The second choice for reaction solvent, DCM, was considered based on relative flammability. Both MtBE and i-PrOAc are highly flammable ACS Paragon Plus Environment

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(NFPA 704 flammability 3) and, with the potentially exothermic and reactive waste cake, the use of a highly flammable reaction solvent could increase the safety concerns. DCM has a much lower flammability (NFPA 704 flammability 1) and has the added benefits of a relatively low boiling point and a high density. The boiling point of DCM (bp 39-40 °C vs. MtBE bp 55-56 °C and i-PrOAc bp 8990 °C) allows for easy solvent removal with minimal thermal exposure of 2a prior to the subsequent chemistry, which reduces the risk of degradation to 4 and 5. DCM has a higher density (1.33 g/ml) than either MtBE (0.740 g/ml) or i-PrOAc (0.87 g/ml), and this characteristic could enhance the suspension characteristics of the heterogeneous mixture (discussed later in this paper). The use of a chlorinated solvent is not encouraged from an environmental perspective, but the safety and processing benefits imagined by the use of DCM kept it as a viable option. These two solvents were compared to MtBE as they pertained to both thermal potential of the resulting waste solids and overall suspension characteristics in the reaction environment.

Thermal potential of periodate/iodate waste. Since all three solvents can be successfully used in the chemistry, it was necessary to understand how solvent and/or residual reaction components affected the thermal potential of the waste solids. This is different from the initial risk assessment of the process – in that case, the filtered waste solids were blown dry on the filter. This is not representative of what occurred on scale. Therefore, for the follow-up studies, no blow through was performed on the solids tested to get a sense of thermal potential of the solids with residual reaction mixture and/or solvent present.

Thermal potential in this case refers to the onset of thermal decomposition of the solids post-reaction and is rated as it relates to the process temperature. Figure 1 shows the differential scanning calorimetry (DSC) measurements for several sets of post-reaction solids and Table 1 provides the thermal onsets and potentials for the reaction components as well as the waste solids. The first set of solids provided as a base case are seen in Figure 1a – these solids have been filtered from an MtBE reaction by vacuum and ACS Paragon Plus Environment

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left untreated (no rinse with solvent) and wet. Note that these solids have an onset temperature of 113 °C, which is within 100 °C of the reaction temperature of 35 °C. With this low onset, there is a concern that thermal decomposition could occur if there was a temperature excursion and that this decomposition would lead to a heat release. In comparison, three different cake rinses were performed on the waste solids to compare thermal onset versus the un-rinsed solids. The thinking is that the rinse would displace the organic reaction components and reduce the thermal potential of the waste solid cake. For the solids rinsed post-reaction with MtBE (Figure 1b), there is not much improvement over the untreated case - the initial onset of thermal decomposition is still within 100 °C of the reaction temperature.

Figure 1c shows that an i-PrOAc rinse of the solids post-reaction provides an

improvement in terms of onset temperature - these solids had a higher initial onset temperature of 198 °C compared to the untreated and MtBE-rinsed cases, but the heat output during the thermal event in the i-PrOAc case was higher overall. For that reason, the i-PrOAc-rinsed solids are still considered to have a high thermal potential. The final rinse solvent tested was DCM (Figure 1d). The DSC results for DCM-rinsed solids indicate that the onset temperature increased to 258 °C, which is well above the 100 °C threshold with respect to reaction temperature.

Figure 1. DSC measurements (mW heat vs. temperature in °C) for the NaIO4/NaIO3 waste solids postreaction with the following treatments: (a) No rinse, (b) Rinsed with MtBE, (c) Rinsed with iPrOAc, and (d) Rinsed with DCM


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(a)

(b)

(c)

(d)

When comparing the four conditions, it is evident that low onset temperature for these solids is a function of flammable/oxidizable organic material remaining on the periodate/iodate filter cake after the reaction mixture has been filtered off. The magnitude of the thermal event for un-rinsed/undried periodate/iodate solids is 1.21 kJ/g, which combined with the low onset temperature of 113 °C is considered a very high thermal potential and outside of the margin of safety for the operation. Essentially, the residual organic material is easily oxidized by the large excess of oxidant present and, therefore, fuel and oxygen, two parts of the fire triangle, are present within the cake. Oxidation of the residual organic material will produce heat and, therefore, the potential for an incident, such as seen at scale with the melting of the plastic container holding the waste solids, is very real. While the MtBErinse lowered the heat released, MtBE is oxidizable; therefore, trace amounts of MtBE could still be an issue. DCM, however, is not readily oxidized and provides a better rinse option for these waste solids, rinsing away any flammable organic reaction material left on the filter cake. In addition, the magnitude of the heat output during thermal decomposition has been greatly reduced overall (1.2kJ/g for no rinse


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to 0.2 kJ/g with a DCM rinse), which indicates that waste solids rinsed with DCM are of medium thermal potential. Table 1 shows the onset temperatures of decomposition and thermal potential for the reactants, product, solvents, and waste solids in different scenarios for comparison. It was determined based on this study, therefore, that a safe procedure for handling the waste solids was to remove the periodate/iodate waste solids by filtration and rinse them with DCM. This DCM rinse removes any reaction components from the waste cake and reduces thermal potential of solid waste. As an added precaution, DCM-rinsed solids would then be packed out in water to ensure safe storage prior to disposal.

Table 1. Thermal decomposition data for post-reaction periodate/iodate waste solids treated with various solvents and reaction components; if more than one value is listed, there are multiple decomposition events.

Component

Onset (°C)

∆H (kJ/g)

Relative Thermal Potential

Diallyl tartrate (Starting material)

132.9 180.3

-0.013 -0.16

Medium

NaIO4 solids

100.3

-1380.1

Very high

Allyl glyoxalate (Product)

120.8 160.8 107.6 158.5 258.8

-0.011 -0.57 -0.019 -0.18 -0.15

157.8

-0.28

174.0 233.0 144.0 288.3 113 385 130 181 198 359 258.0 333.2

-0.049 -0.27 -0.010 -0.088 -1.21 -0.035 -0.53 -0.91 -1.65 -0.092 -0.20 -0.036

71.1

-0.21

Medium

247.0

-0.32

Medium

Allyl alcohol Glyoxylic acid, monohydrate i-PrOAc MtBE NaIO4/NaIO3 solids post-reaction Control – no treatment NaIO4/NaIO3 solids post-reaction Rinsed with MTBE NaIO4/NaIO3 solids post-reaction Rinsed with i-PrOAc NaIO4/NaIO3 solids post-reaction Rinsed with DCM NaIO4/NaIO3 solids post-reaction Rinsed with MTBE with 1 volume water spike NaIO4/NaIO3 solids post-reaction Rinsed with MeOH

High Medium Medium Medium Low Very high High High Medium


11


NaIO4/NaIO3 solids post-reaction Combined with diallyl tartrate NaIO4/NaIO3 solids post-reaction Combined with allyl alcohol NaIO4/NaIO3solids post-reaction Combined with glyoxylic acid

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99.5

-1.33

Very high

130.8

-2.55

Very high

64.5 329.6

-1.48 -0.29

Very high

Mixing characteristics. While determining the proper handling of the waste solids post-reaction, the same solvents were being tested in the reaction for processing feasibility. As noted previously, all three solvents can be used in the reaction to produce ally glyoxalate from diallyl tartrate. One of the factors that warranted study was whether the solvent would facilitate suspension of the sodium periodate. Good suspension of the periodate solids ensures the oxidant surface is available for the reaction. If the periodate is suspended, the overall amount of oxidant for the reaction could potentially be reduced as it would be used more efficiently (i.e., not piled on the bottom of the reactor). Excess sodium periodate was charged to the reaction to compensate for the settling and caking that occurs in the original process solvent, MtBE. Reducing the oxidant used in the reaction is not only a cost savings, but it will also help with safety concerns as less waste oxidant will need to be disposed following the reaction. Therefore, the mixing characteristics for the system in three solvents (MtBE, iPrOAc, and DCM) were studied at laboratory scale and then modeled for large scale vessels using DynoChem®.

Figure 2 shows the reaction mixture in the three solvents and the physical differences in the suspension characteristics when run in 250 ml dish-bottomed glass vessels. Figure 2a shows the original process with MtBE as solvent - the sodium periodate caking is evident. This settling and caking behavior forms an immovable mass of the solids along the bottom and outside of the vessel. Liquid in this system is clear, showing no evidence of slurried solids. Figure 2b shows the improvement of suspension in a reaction mixture with i-PrOAc. There is still significant accumulation of solids at the bottom of the vessel, but some suspension is achieved as noted by the white-colored liquid. Finally, a DCM reaction is shown in Figure 2c. Some settling is seen, but full suspension can be achieved with the ACS Paragon Plus Environment

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top stirring speeds in these 250 ml reactors. Overall, DCM provides the best observable suspension characteristics for this reaction.

Figure 2. Photographs of the sodium-periodate mediated oxidative cleavage of diallyl tartrate in (a) MtBE at 35 °C, (b) i-PrOAc at 35 °C, and (c) DCM at 30 °C

As part of the physical observations of the reaction mixtures, it was noted that the impeller configuration is also important to proper suspension. Impellers that provide a downward pumping motion push the solids downward toward the wall of the vessel, not allowing for effective mixing of dense solids and encouraging settling and caking along the walls (Figure 3a). This would aid in the settling and caking behavior of the periodate solids observed. Impellers providing an upward pumping mixing motion encourage the dispersion of the dense particles, turning them over and pushing them away from the walls of the vessel. This reaction system would benefit from agitation that provided an upward pumping motion to improve the suspension characteristics.

Figure 3: Behavior of the periodate/iodate solids in the reaction mixture; the dense solids settle at the bottom of the vessel and then when agitation is increased the pile will decrease (blue arrows). The two types of motion based on impeller blade pitch and shape cause this to happen: (a) solids are spread out ACS Paragon Plus Environment

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along the sides of the vessel in an immovable mass by a downward pumping impeller or solids are dispersed, settle and get dispersed again by a upward pumping impeller.

The physical mixing characteristics each solvent demonstrated were then used in a DynoChem® mixing template to model the reaction system at larger scale. The template requires detailed dimensional information on the experimental vessels (250 ml dish-bottomed glass) as well as the planned scale reactors. Understanding the minimum impeller speed needed to suspend the sodium periodate and the sodium iodate for a given vessel geometry would provide insight into whether the stir motors could provide enough power for suspension and if stir rates would be practical at scale. It would also indicate whether an excess of oxidant was needed to ensure reaction completion due to the tendency of the solids to settle in a given vessel geometry. In this case, the goal was to determine whether the standard reactor vessels at 400 L and 4000 L would be able to suspend the sodium periodate reagent in the three different solvents.

Both solids were studied independently at the most extreme cases - the start of reaction (or solids = 100% sodium periodate) and if all sodium periodate oxidized (or solids = 100% sodium iodate). These ACS Paragon Plus Environment

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scenarios were chosen due to the difference in density of the two solids and the fact that the solids are changing over the reaction time to some mixture of sodium periodate and sodium iodate. The 250 ml lab scale vessel was used to obtain the physical data that were in turn compared to the model output for verification. With the laboratory scale model and the scale vessel geometry, mixing characteristics were modeled in the larger scale vessels. The DynoChem ® template determines the “Just suspended” stirring speed by the formula from Zwietering 20, which includes terms for the density as well as the viscosity of the liquid:

NJS = S ν

0.1

(g ∆ρ/ρL)

0.45

X

0.13

dp

0.2

D

–0.85

Equation (1)

where S = geometrical constant dependent on impeller type, diameter and clearance (-) ν

= liquid kinematic viscosity (m2/s)

g = gravitational acceleration (m/s2) ρL

= liquid density (kg/m3)

∆ρ = density difference between

solid and liquid (-)

X = mass ratio of solid to liquid = weight of solids/weight of liquid x 100 (-) dp = diameter of spherical particles (m) D = impeller diameter (m)

Once the “Just suspended” stirring speed (NJS) was determined, the value for a given vessel could be used to calculate the power that would be required from the motor in that vessel to achieve suspension (Equation (2)) as well as the more commonly used expression for characterizing mixing at a given stir speed, power/unit mass.

3

P = Po ρL NJS D

5

Equation (2)

where P = power input (W) ACS Paragon Plus Environment

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Po = power number dependent on impeller type (-) ρL = liquid

density (kg/m3)

N = impeller speed (s-1) D = impeller diameter (m)

The DynoChem® vessel mixing assessment for suspension is shown for the sodium periodate solids case in Table 2 and for the sodium iodate solids case in Table 3 for the laboratory and 4000 L vessel geometries. The assessment includes “Just Suspended” values for impeller speed, tip speed, and power for the different vessels in all three solvents. Basic geometries for DeDietrich 400 L and 4000 L glasslined vessels (OPX AE400 and OPX BE4000) were used for reaction system model at scale. In all cases, suspension of either type of solid in the reaction mixture (at the predicted loading of 1.8 equivalents) was achieved at lower power/unit mass (εJS) in DCM than in either of the other two solvents. Suspension in MtBE or i-PrOAc for this reaction would require up to 15x the power for a given reactor volume in the scale vessels. Suspending these solids fully in either scale vessel using iPrOAc or MtBE as reaction solvent will be a physical challenge as the motor might not be rated to run at such high power output; suspension in DCM should be easily attainable with the modeled equipment. The difference between the suspension requirements has to do with density differences between the solvents. DCM has a higher density than the other solvents, which affects the “Just Suspended” speed and power input calculations. Higher liquid density means that the overall density contribution to NJS is lower, which in turn affects the power calculation since the variable NJS is cubed. Overall, the density of DCM provides an observed and calculated improvement in physical suspension of the periodate solids.

Table 2. DynoChem modeling results for the suspension of sodium periodate in i-PrOAc, MtBE, and DCM for lab and commercial scale reactor geometries.

Vessel Solvent

iPrOAc

250 ml lab vessel MtBE DCM

iPrOAc

4000 L vessel MtBE

DCM


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Vessel flow regime Just suspended speed, NJS (rpm) Tip speed, Vtip_JS (m/s) Total power input, PJS (W) Power input per unit mass, εJS (W/kg)

Turbulent

Turbulent

Turbulent

Turbulent

Turbulent

Turbulent

1766

1897

1211

161

173

82

3.66

3.94

2.51

6.32

6.79

3.22

3.2

3.6

1.4

11018

12302

1188

22.26

28.52

6.61

4.801

6.16

0.34

882

768

1336

882

768

1336

0.52

0.35

0.42

0.52

0.35

0.42

1068

961

1494

1068

961

1494

Impeller type

3-bladed pitched blade turbine



Hydrofoil

Hydrofoil

Hydrofoil

2nd impeller type

None

None

None

4-bladed flat blade turbine



Liquid density, ρL (kg/m3) Liquid dynamic viscosity, µ (cP) Average density of slurry (kg/m3)

Table 3. DynoChem modeling results for the suspension of sodium iodate in i-PrOAc, MtBE, and DCM for lab and commercial scale reactor geometries.

Vessel Solvent Vessel flow regime Just suspended speed, NJS (rpm) Tip speed, Vtip_JS (m/s) Total power input, PJS (W) Power input per unit mass, εJS (W/kg) Liquid density, ρL (kg/m3)

iPrOAc

250 ml lab vessel MtBE DCM

iPrOAc

4000 L vessel MtBE

DCM

Turbulent

Turbulent

Turbulent

Turbulent

Turbulent

Turbulent

1874

1973

1298

171

180

88

3.89

4.09

2.69

6.72

7.07

3.46

3.8

4.1

1.8

8560

9143

1469

26.76

32.10

8.19

3.73

4.47

0.42

882

786

1336

882

786

1336


17


Liquid dynamic viscosity, µ(cP) Average density of slurry (kg/m3)

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0.52

0.35

0.42

0.52

0.35

0.42

1075

984

1503

1075

984

1503

Impeller type




Hydrofoil

Hydrofoil

Hydrofoil

2nd impeller type

None

None

None




Heat of reaction and dosing studies. With the potential of a solvent change for the reaction, the final two parameters to understand are heat of reaction and mode of dosing. These two parameters are interrelated as the method of dosing can help to mitigate the heat flow of a reaction.

The original procedure places all the reagents in the reactor initially and then heats the whole system to 35 °C. This mode of operation has all the potential heat energy in the pot, with observed temperature rises in the laboratory of 15 °C above the desired reaction temperature. To understand the heat flow, calorimetry studies were performed using a 500 ml RC-1 reactor in three modes: (1) charging the reactants at 35 °C and holding temperature constant for reaction (original procedure), (2) charging the reagents at 15 °C and using a controlled temperature ramp to 25 °C, and (3) charging the reagents at 15 °C and using a controlled temperature ramp to 40 °C. These studies were carried out in parallel to the solvent studies and the calorimetry experiments were performed in MtBE and i-PrOAc initially. The results for the initial studies are shown in Table 4. The reaction completion times are vastly different between the constant temperature and the temperature-ramped procedures. The addition of heat energy to the system appears to help the reaction progress. The heat of reaction for these systems is on the order of 165-185 kJ/mol diallyl tartrate. A further benefit of the temperature ramp procedure is that less allyl alcohol is formed in the process. This appears to be related to final reaction temperature, since no allyl alcohol was detected when the MtBE system was held for 21 hours at 25 °C after the temperature ramp. ACS Paragon Plus Environment

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To further understand the heat flow of the system, reaction trends for the MtBE system in both isothermal and temperature-ramp modes are shown in Figure 4.

The reaction held at constant

temperature is considerably less energetic at any one time because the total heat is distributed over 22 hours, whereas a reaction that is complete in 3 hours with the temperature ramp releases the same amount of heat in a shorter time. The heat for the temperature ramp reaction procedure is evident in the Tr-Tj trend (Figure 4b) - a sudden increase in the trend that is sustained for approximately 3 hours. The Tr-Tj curve for the reaction at constant temperature shows a gradual change over 22 hours (Figure 4a). Periodate solids caking was seen immediately when the system was held at 35 °C. During the heating ramp procedure, caking was seen at the point that the reaction temperature reached ~22 °C, which corresponds to an endotherm seen in the reaction trends (Figure 4b). A similar endotherm was not observed in the heat flow data for the constant temperature case, however, where caking was immediate. The heat ramp appears to give the system time to react prior to the solid oxidant caking; more of the oxidant surface is available and this allows the reaction to progress faster than when there is enough heat to cause the solids to cake initially as in the isothermal system.

Table 4. Results of MtBE and i-PrOAc reaction studies, including heat output (ND = none detected)

Solvent

MtBE

Temperature profile

35 °C

Time to completion (hr)

Allyl alcohol (wt%)

Qr (kJ/mol diallyl tartrate)

∆Τad (K)

22.2

35.5

183.9

45.3

21.3*

ND

174.3

44.9

3.0

ND

178.6

40.2

(Figure 4a)

MtBE

Ramp from 15-25 °C at 0.5° C/min; hold @ 25 °C Ramp from 15-40 °C at

MtBE

0.25 °C/min; hold @ 40 °C (Figure 4b)


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i-PrOAc

Ramp from 15-40 °C at

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3.8

ND

166.4

38.5

4.3

ND

174.4

40.5

0.25 °C/min; hold @ 40 °C i-PrOAc

Ramp from 15-40 °C at 0.25 °C/min; hold @ 40 °C

* still 24.9% diallyl tartrate remaining after this time – caking of periodate stalled reaction as no reactive surface available for oxidation

Figure 4. Process trends, including heat flow (qr_hf) and Tr-Tj, for the allyl glyoxalate synthesis run in MtBE: (a) Periodate charged at 35 °C with a hold at 35 °C – 22 hours to reaction completion and (b) Periodate charged at 15 °C with a slow ramp to 40 °C – 3 hours to reaction completion


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To mitigate the 165-185 kJ/mol heat released during this reaction, dosing modes for the reaction were considered. Two possible dosing scenarios existed: (1) dose the diallyl tartrate starting material into the periodate slurry in solvent or (2) dose the solid sodium periodate into the reactor with the starting material dissolved in the solvent. The second scenario was not a preferred mode of operation due to increased solids handling required on scale.

The dosing of diallyl tartrate was investigated first through a comparative study using all three solvents. Figure 5 compares the Tr-Tj results for the three reactions where diallyl tartrate is dosed into the reactor; in each case, diallyl tartrate is dissolved in the reaction solvent to aid in pumping the material into the


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reactor. The proportionality constant between heat of reaction and Tr-Tj is combination of the overall heat transfer coefficient (U) multiplied by the heat transfer surface area (A) (Equation 3). The same 250 ml glass reactor equipment was used for each reaction, which renders the UA term irrelevant as it is constant in the comparison. Diallyl tartrate was added to the reactor over 30 minutes in each case and time zero in Figure 5 represents the start of the dose. The results indicate that the reaction in MtBE saw a much higher exotherm (on the order of 7 °C) versus the reactions run in i-PrOAc or DCM. The exotherm for the DCM reaction was fairly mild at any one time with a broad overall heat profile for the duration of the reaction. Both i-PrOAc and MtBE presented a larger exotherm over a short time, reaffirming the superiority of DCM as solvent for this reaction chemistry.

Qr α UA∆T = UA(Tr-Tj)

Equation (3)


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Figure 5. Tr-Tj curves for the diallyl tartrate dosing experiments in iPrOAc, MtBE, and DCM; dosing time for all cases was 30 minutes.

Results of the reaction completion times for the diallyl tartrate dosing studies are shown in Table 5. This table also includes the dosing studies focused on dosing of the sodium periodate to the reactor. Based on the calorimetry results using MtBE vs. i-PrOAc, the solid dosing studies focused on i-PrOAc and DCM as preferred solvents in this reaction at 1.8 equivalents sodium periodate. For comparison, the DCM solvent system was trialed with only 1.2 equivalents of sodium periodate to determine feasibility of a lower amount of oxidant for the reaction with better suspension. The experiments with solids dosing proved to be successful in terms of shorter reaction completion times. The best results were seen repeatedly with DCM, purportedly due to the increased suspension achieved in comparison with the other solvents. The reduced equivalents of sodium periodate in DCM did allow the reaction to complete, but there was a significant increase in the time to reaction completion. ACS Paragon Plus Environment

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Table 5. Dosing study results incorporating two possible dose modes – (1) dosing diallyl tartrate and (2) dosing sodium periodate solids – and reduction of sodium periodate equivalents. (ND = none detected)

Solvent

diallyl tartrate dosed (in solvent)

Temperature (°C)

Equiv NaIO4

Time to completion (hrs)

MtBE

35

1.8

11

i-PrOAc

35

1.8

11

DCM

30

1.8

6.5

i-PrOAc

40

1.8

6.5

DCM

30

1.8

4.5

DCM

30

1.2

23

DCM

30

1.8

5.0

Solids dosed

Solids dosed

Vessel 250 ml glass with 3-bladed pitch blade turbine 250 ml glass with 3-bladed pitch blade turbine 250 ml glass with 3-bladed pitch blade turbine 250 ml glass with 3-bladed pitch blade turbine 250 ml glass with 3-bladed pitch blade turbine 500 ml glass with flat blade turbine 500 ml glass with flat blade turbine

% diallyl tartrate remaining ND

ND

2.2

1.8

ND

ND

ND

Conclusion


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The overarching objective of this work was to ensure that the optimum processing conditions for the synthesis of allyl glyoxalate were determined to support future scale-up manufacturing. The iodine release incident indicated that there were some gaps in process understanding that needed to be closed with respect to the treatment of the oxidant waste cake. This work focused on the process operability, potential safety hazards and the thermal potential of the components. The entire process was reviewed and the following concerned were highlighted:

•

the mixing/suspension requirements to allow the reaction to proceed cleanly and in a relatively short time,

•

stoichiometry of sodium periodate used

•

the sodium periodate waste solids handling/disposal

•

the overall heat of reaction.

With proper solvent choice, these concerns can be mitigated, including concerns around the handling and disposal of the oxidant waste. While dichloromethane is not an ideal solvent for large scale, the advantages of its use in this reaction versus other commonly employed solvents work in its favor to provide a safe and effective reaction process. It has a lower flammability rating than either MtBE or iPrOAc and, in thermal testing, DCM proved to lower the potential for thermal onset of the waste cake significantly. Physically, DCM provides a movable slurry, more easily suspending the oxidant in the reactor. The oxidative system has an exotherm that was determined to be easily mitigated through dosing of the sodium periodate oxidant as well as solvent choice. The dosing regimen reduces the amount of potential energy in the reactor at any given time by limiting the amount of active oxidant. The recommendation from this work incorporates the use of DCM as the reaction solvent and a portion-


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wise addition of sodium periodate to the reaction, while also supporting a DCM rinse of the oxidant waste cake and storage in water prior to disposal.

Experimental Section

Initial procedure for synthesis of 2a. In a capped flask equipped with an overhead stirrer, diallyl tartrate (1.00 equiv [LR]; 43.4 mmoles; 10.0 g) was taken up in methyl t-butyl ether (842 mmoles; 100 mL; 74.2 g). Sodium periodate (130 mmoles; 27.9 g) and sodium bicarbonate (0.869 mmoles; 73.0 mg) are charged to the reaction vessel. Water (555 mmoles; 10.0 mL; 10.0 g) is then added to the reactor and the mixture is slurried at room temperature overnight. After reaction is deemed complete, the mixture is filtered to remove white solid; the product is contained in the filtrate. The filter cake is rinsed with MtBE and the rinses are added to the filtrate. The filtrate is washed with saturated NaHCO3 (10 ml, 1ml/g). The resulting organic phase is dried over magnesium sulfate and concentrated to a clear oil in 70-75% yield.

Improved procedure for synthesis of 2a. Dichloromethane (10.9 moles; 700 mL; 928 g), water (2.78 moles; 50.0 mL; 50.0 g), and diallyl tartrate (1.00 equiv [LR]; 434 mmoles; 100 g) are combined in a suitable reaction vessel equipped with vigorous upward pumping agitation and a nitrogen atmosphere. Sodium periodate (1.8 eq, 782 mmoles; 167 g) is prepared for charging to the reactor in three portions, with each portion charged over 10 minutes and allowed at least 30 minutes of reaction time between charges. (NOTE: Sodium periodate charge can be within the target range of 1.2-1.8 equivalents. Lower amount of sodium periodate has effectively completed the reaction, but extends the reaction time to ~ 10-12 hours on this scale. If 1.8 equivalents sodium periodate is used, the reaction is complete within 45 hours.). The resulting white heterogeneous reaction mixture is stirred vigorously under a nitrogen ACS Paragon Plus Environment

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atmosphere at 25-30 °C until completion. Upon reaction completion, the white solids are removed via filtration. The filter cake is washed with additional dichloromethane (100 mL; 1ml/g) two times. Filtrate contains product and solids are waste (see below for recommended treatment of waste solids). The filtrate is washed with 18% sodium chloride (100 mL; 1 ml/g) and the organic layer is dried over sodium sulfate for at least 30 minutes. The product is then obtained in 65-70% yield via concentration under partial vacuum, maintaining a reactor jacket temperature of ≤ 40 °C. Waste solid treatment – filter cake solids are washed thoroughly with fresh dichloromethane (400 mL; 4 ml/g) and are disposed of as a slurry in at least 4 vol of water.

Acknowledgement

The authors would like to gratefully acknowledge Mark Delude, Mark Olivier, R. Matt Weekly, Jerry Weisenberger, Dave am Ende, Stephane Caron, the Pfizer Chemical Research & Development Management Team, and the extended R&D and Manufacturing Teams at IDT Australia Limited (Melbourne, Australia) for valuable technical contributions to this work and the development program.

Associated Content

Author Information

Corresponding Author *[email protected]


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Development of a Safe and Scalable Process for the Preparation of

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