Embodiment
Below explain the embodiment of relevant (methyl) of the present invention acrylic acid hydroxy alkyl ester manufacture method.
The manufacture method of (methyl) of the present invention acrylic acid hydroxy alkyl ester, it is characterized in that, the alcohol that will contain vinyl ether by ester-interchange method carries out after (methyl) acroleic acid esterification generates (methyl) acrylate that contains vinyl ether, when in the presence of acid catalyst, taking off the vinylation reaction, make the water coexistence.
In the present invention, at first, the hydroxyl that will contain the alcohol of vinyl ether carries out esterification, obtains containing (methyl) acrylate of vinyl ether.Mainly can enumerate as esterification method, use (methyl) acrylic acid dehydration esterification process, the ester-interchange method that uses rudimentary (methyl) acrylate, the carboxylic acid halides method of use (methyl) acrylate chloride, wherein, for the dehydration esterification process owing to use acid catalyst, take off vinylation thereby produce simultaneously, therefore inapplicable.In addition, the carboxylic acid halides method is owing to slough halogen by reaction, and remains in the system, therefore needs purification process such as washing, absorption or distillation.And on the other hand, ester-interchange method do not need purification process, so the present invention adopts ester-interchange method because impurity is few.
As the alcohol that contains vinyl ether that uses in the present invention, for example can enumerate, 4-hydroxy butyl vinyl ether, 6-hydroxyl hexyl vinyl ether, 9-hydroxyl nonyl vinyl ether, 10-hydroxy decyl vinyl ether, 12-hydroxyl dodecyl vinyl etc. are with the compound of following general formula (I) expression, cyclohexanedimethanol mono vinyl ethers etc. are with the compound of following general formula (II) expression, phenyl dimethanol mono vinyl ether etc.
[changing 3]
(in the general formula (I), n represents 3~11 integer.)
[changing 4]
(in the general formula (II), A represents cyclopentylidene or cyclohexylidene.)
As rudimentary (methyl) acrylate that in ester-interchange method, uses, specifically can enumerate (methyl) methyl acrylate, (methyl) ethyl propenoate, (methyl) propyl acrylate, (methyl) butyl acrylate etc.Promptly, said rudimentary (methyl) acrylate is meant that having carbonatoms is that alkyl below 4 is as the substituent ester of ester among the application.
When transesterification reaction,,, use rudimentary (methyl) acrylate in preferably from equivalent to excessive scope with respect to the alkylol cpd that contains vinyl ether from the viewpoint of reaction times weak point, ester turnover ratio height, reacted aftertreatment.Particularly, with respect to the 1 mole of hydroxyl that alkylol cpd had that contains vinyl ether, preferred usually rudimentary (methyl) acrylate that in 1.0~20 moles scope, uses.With respect to 1 mole of hydroxyl of the alkylol cpd that contains vinyl ether, rudimentary (methyl) if the usage quantity of acrylate less than 1.0 moles, then react deficiently, in addition, if surpass 20 moles, then reacted enrichment process needs long-time, the productivity variation.
As the catalyzer that in ester-interchange method, uses, can enumerate: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkaline carbonates such as Quilonum Retard, yellow soda ash, salt of wormwood; Basic metal alkoxy compounds such as lithium methoxide, sodium methylate, sodium ethylate, potassium tert.-butoxide; Alkali amides such as Lithamide, sodium amide, potassium amide; Titanium metal alkoxides such as metatitanic acid tetramethyl ester, tetraethyl titanate, metatitanic acid orthocarbonate, titanium isopropylate, tetrabutyl titanate; Other as aluminium alkoxide; Alkanol tin etc.Wherein, from can suppress side reaction, finish the viewpoint that catalyzer can easily be removed by adding water in the back, more preferably titanium metal alkoxide or aluminium alkoxide as far as possible in reaction.
In addition, the usage quantity of catalyzer is preferably the scope of 0.01~5.0 quality % usually with respect to rudimentary (methyl) acrylate and the total amount that contains the alkylol cpd of vinyl ether.Even what influence catalytic amount for more than needing, does not have to speed of response yet, on the contrary, only can when removing, catalyzer need a large amount of water etc. to become uneconomical.
In the transesterification reaction in the present invention, can add, also use known stopper.For example can enumerate as stopper: quinhydrones, hydroquinone monomethyl ether phenols such as (being also referred to as " p methoxy phenol "); Sulphur compound such as thiodiphenylamine, ethylene thiourea; Mantoquitas such as copper dibutyldithiocarbamate; Manganese salt such as manganese acetate; Nitro-compound, nitroso compound, 4-hydroxyl-2,2,6, compound oxygen radical of nitrogen such as 6-tetramethyl piperidine oxyradical etc.The addition of stopper is preferably below the 0.1 quality % with respect to generating ester.If surpass 0.1 quality %, then have because of additive painted situation takes place.
When transesterification reaction, preferably be blown into and be used for preventing the reaction solution polymeric small amount of molecular oxygen of reacting.Preferably under the state of dilution, use as molecular oxygen, use air to suit.In addition, being blown into preferably to evaporate as steam of molecular oxygen exists, and perhaps also can be blown in the polymerization of condensing (methyl) esters of acrylic acid such as the still wall on top in order to prevent.
Molecular oxygen is meant the triplet oxygen molecule (O of the ground state of making by 2 Sauerstoffatoms
2), can participate in reaction directly with the primary state in when reaction, also can be by the interaction of catalyzer or reaction reagent, be transformed into states such as singlet oxygen molecule or Sauerstoffatom, super-oxide, superoxide after, participate in the oxygen molecule of reaction.
As the import volume of molecular oxygen, by the shape of reaction machine or stir power and exert an influence, but, can be blown into the speed of 5~500ml/ branch (as air 25~2500ml/ branch) with respect to as 1 mole of the alcohol that contains vinyl ether of raw material.If the import volume of molecular oxygen is less than the 5ml/ timesharing, resistance polymeric effect is insufficient, if surpass the 500ml/ branch, then rudimentary (methyl) acrylate is extruded the outer effect grow of system, causes the loss as rudimentary (methyl) acrylate of raw material.
Transesterification reaction of the present invention is preferably under normal pressure or decompression, carry out under 60~120 ℃.If temperature is less than 60 ℃, then speed of response reacts slack-off terrifically, if surpass 120 ℃, then is easy to generate the polymerization of (methyl) acrylate that contains vinyl ether that obtains in transesterification reaction, also causes painted easily.
As the form of transesterification reaction, can carry out with the method known to those skilled in the art of general manufactured (methyl) acrylate.When transesterification reaction, need to carry out component distillation and remove with the lower alcohol that rudimentary (methyl) acrylate and/or solvent are given birth to pair.Therefore, for example use the intermittent reaction groove of subsidiary rectifying tower as reaction unit.
Transesterification reaction makes catalyst deactivation by water after finishing, and removes excessive low boiling point component with the concentrating unit distillation.Low boiling point component is removed by concentrating unit distillation, preferred on one side under normal pressure or decompression, the liquid temperature remains on below 90 ℃, Yi Bian carry out, more preferably in 50~70 ℃ the scope.If the liquid temperature surpasses 90 ℃, the painted or polymeric possibility that then produces (methyl) acrylate that contains vinyl ether uprises.
Finish (methyl) acrylate that contains vinyl ether that the distillation of low boiling point component removes and to remove remaining insoluble compositions such as decaying catalyst by filtering.In order to remove insoluble composition effectively, preferably use filtration adjuvants such as diatomite during filtration.
Next, to (methyl) acrylate of containing vinyl ether take off the vinylation reaction, the method that obtains (methyl) acrylic acid hydroxy alkyl ester is illustrated.
Among the present invention, in the presence of acid catalyst, take off the vinylation reaction, as operable acid catalyst, can enumerate usually: sulfuric acid, sodium pyrosulfate, tosic acid, Phenylsulfonic acid, methylsulfonic acid, solid acid (zeolite, An Bailaite, Amberlyst, Nafion etc.).In addition, the catalytic amount of use is preferably 0.01 quality %~10 quality % with respect to (methyl) acrylate that contains vinyl ether that reacts, more preferably 0.1 quality %~5 quality %.If the catalytic amount that uses during less than 0.01 quality %, then have reduce significantly reactive, take off the situation that the vinylation reaction becomes slow terrifically.In addition, if when surpassing 10 quality %,, but then, might produce impurity to almost not influence of speed of response.
The vinylation reaction of taking off that the present invention relates to is characterised in that, makes the water coexistence and carries out.By the water coexistence is reacted, can easily remove secondary aldehyde of giving birth to when taking off the vinylation reaction.Usage quantity as water, so long as be that benchmark serves as to wait more than the mole with (methyl) acrylate that contains vinyl ether, just restriction especially preferably more than the mole, makes with being swift in response and carries out as 2 times of benchmark by using with (methyl) acrylate of containing vinyl ether.If with than etc. the ratio lacked of mole when making water, be reflected at Halfway Stopping.
The vinylation reaction of taking off that the present invention relates to is thermopositive reaction.At this moment,, preferably be controlled at 0 ℃~40 ℃, can obtain highly purified (methyl) acrylic acid hydroxy alkyl ester by temperature of reaction being controlled at below 60 ℃.As the method for control reaction temperature, can enumerate cooling reactor, perhaps in aqueous catalyst solution, add the method for (methyl) acrylate that contains vinyl ether at leisure.In addition, secondary during reaction have acetaldehyde, but by reducing pressure in the system, can promptly remove acetaldehyde, promotes reaction.
After taking off vinylation reaction end, from reaction residue, separate and remove water layer.At this moment, in order to improve separating power, can be used singly or two or more kinds in combination as toluene or dimethylbenzene equal solvent.The water that separates the water layer of removing and obtaining can utilize as the water that is coexisted in taking off the vinylation reaction in later manufacturing next time again.
Isolating organic layer is owing to contain catalyzer, therefore neutralizes with alkali and separates and remove.As alkali, for example can enumerate: the oxyhydroxide or the salt of basic metal such as potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, alkaline-earth metal.Preferably they are used with the form of the aqueous solution, separate the method for removing and using after the neutralization.
After the neutralization, water or neutral brine solution clean excessive alkali and after removing, by concentrate will be excessive the water distillation remove, or when using solvent distillation except that desolvating.Concentrate preferred on one side under normal pressure or decompression, to keep the liquid temperature be below 90 ℃, Yi Bian carry out, in more preferably 50 ℃~80 ℃ the scope.If the liquid temperature surpasses 90 ℃, the painted or polymeric possibility that then produces (methyl) acrylic acid hydroxy alkyl ester becomes big.
After concentrating, can remove remaining insoluble compositions such as neutralized salt by filtering.In order to remove insoluble composition effectively, preferably use filtration adjuvants such as diatomite during filtration.
The manufacture method of (methyl) of the present invention acrylic acid hydroxy alkyl ester owing to make water when taking off the vinylation reaction, can obtain highly purified (methyl) acrylic acid hydroxy alkyl ester, does not therefore need purification procedures such as distillation.
Embodiment
Below, enumerate embodiment and further specifically describe the present invention, but the present invention is not limited among these embodiment.
Embodiment 1
Synthesizing of methacrylic acid vinyloxy group butyl ester
In the detachable flask of four-hole round bottom of 4L, put into 4-hydroxy butyl vinyl ether (ball is apt to petroleum chemistry system HBVE) 1000g, methyl methacrylate 3000g, p methoxy phenol 0.65g, rectifying tower (15 layers), stirrer, air leading-in conduit and thermometer are set.Under agitation, on one side import dry air with 100ml part, begin heating on one side, regulating pressure is about 40kPa, and making the liquid temperature in the flask when refluxing is 75 ℃, removes the interior moisture of system.Moisture in the affirmation system be 300ppm following after, put into tetraisopropoxy titanium 8.6g as catalyzer, be that 95 ± 5 ℃ mode is controlled to be the flask internal pressure about 60kPa with temperature of reaction.If monitor the temperature (tower top temperature) of rectifier when reflux, because near the methyl alcohol that generates and the azeotropic temperature of methyl methacrylate, therefore regulating reflux ratio, to make tower top temperature be about 60 ℃, on one side methyl alcohol is removed as distilling with the azeotrope of methyl methacrylate, Yi Bian react.
Because during through 4 hours, tower top temperature begins to raise, and therefore increases reflux ratio at leisure from reaction, and sustained reaction.React the 5th hour reaction solution with gc analysis, consequently the ester turnover ratio is 99.2%, so termination reaction.The cooling reaction solution when liquid temperature is 75 ℃, adds the salt solution 250g of 17 quality %, hydrolyst.After leaving standstill 15 minutes, by decant organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive methyl methacrylate is removed in distillation, by suction filtration the liquid in the eggplant type flask is filtered, obtain methacrylic acid vinyloxy group butyl ester 1522g as purpose.
Synthesizing of methacrylic acid 4-hydroxyl butyl ester
Pack in the detachable flask of the four-hole of 1L tosic acid 16g, pure water 200g are provided with the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip.In flask, slowly add above-mentioned synthetic methacrylic acid vinyloxy group butyl ester 500g.The system internal pressure is made as 20kPa, removes the acetaldehyde of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask cools off with frozen water on one side, on one side temperature of reaction is remained on 15~30 ℃.React after 3 hours, utilize vapor-phase chromatography analysis, reaction conversion rate is almost 100%, therefore finishes reaction.In the liquid that reaction finishes, add the salt solution 50g of toluene 100g, 17 quality %, carry out oily water separation, only take out organic layer (water layer uses) in embodiment 4.After using the sodium bicarbonate aqueous solution 70g cleaning organic layer of separating funnel, clean with the salt solution 70g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain methacrylic acid 4-hydroxyl butyl ester 395g (yield 92.2%, purity 99.1%) as purpose by suction filtration.
Embodiment 2
Synthesizing of vinylformic acid vinyloxy group butyl ester
In the detachable flask of four-hole round bottom of 4L, put into 4-hydroxy butyl vinyl ether (ball is apt to petroleum chemistry system HBVE) 1000g, ethyl propenoate 3000g, p methoxy phenol 0.65g, rectifying tower (15 layers), stirrer, air leading-in conduit and thermometer are set.Divide with 100ml/ under agitation, on one side to import dry air, Yi Bian begin heating, regulating pressure is about 40kPa, and making the liquid temperature in the flask when refluxing is 75 ℃, removes the moisture in the system.Moisture in the affirmation system be 300ppm following after, put into tetraisopropoxy titanium 8.6g as catalyzer, be that 95 ± 5 ℃ mode is controlled to be the flask internal pressure about 60kPa with temperature of reaction.If monitor the temperature (tower top temperature) of rectifier when reflux, because near the ethanol that generates and the azeotropic temperature of ethyl propenoate, therefore regulating reflux ratio, to make tower top temperature be about 70 ℃, on one side methyl alcohol is removed as distilling with the azeotrope of methyl methacrylate, Yi Bian react.
Because during through 4 hours, tower top temperature begins to raise, and therefore increases reflux ratio at leisure from reaction, and sustained reaction.React the 5th hour reaction solution with gc analysis, consequently the ester turnover ratio is 99.0%, so reaction terminating.The cooling reaction solution when liquid temperature is 75 ℃, adds the salt solution 250g of 17 quality %, hydrolyst.After leaving standstill 15 minutes, by decant organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive ethyl propenoate is removed in distillation, by suction filtration the liquid in the eggplant type flask is filtered, obtain vinylformic acid vinyloxy group butyl ester 1376g as purpose.
Synthesizing of vinylformic acid 4-hydroxyl butyl ester
Pack in the detachable flask of the four-hole of 1L tosic acid 16g, pure water 200g are provided with the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip.In flask, slowly add above-mentioned synthetic vinylformic acid vinyloxy group butyl ester 500g.The system internal pressure is made as 20kPa, removes the acetaldehyde of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask cools off with frozen water on one side, on one side temperature of reaction is remained on 15~30 ℃.React after 3 hours, analyze by vapor-phase chromatography, reaction conversion rate is 99.9%, therefore finishes reaction.In the liquid that reaction finishes, add the salt solution 50g of toluene 200g, 17 quality %, carry out oily water separation, only take out organic layer.After using the sodium bicarbonate aqueous solution 70g cleaning organic layer of separating funnel, clean with the salt solution 70g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain vinylformic acid 4-hydroxyl butyl ester 389g (yield 92.0%, purity 99.0%) as purpose by suction filtration.
Embodiment 3
Synthesizing of cyclohexanedimethanol vinyl ether methacrylic ester
In the four-hole round-bottomed flask of 1L, put into cyclohexanedimethanol mono vinyl ether (ball is apt to petroleum chemistry system CHMVE) 300g, methyl methacrylate 600g, p methoxy phenol 0.20g, rectifying tower (15 layers), stirrer, air leading-in conduit and thermometer are set.Divide with 100ml/ under agitation, on one side to import dry air, Yi Bian begin heating, regulating pressure is about 40kPa, and making the liquid temperature in the flask when refluxing is 75 ℃, removes the moisture in the system.Moisture in the affirmation system be 300ppm following after, put into tetraisopropoxy titanium 2.6g as catalyzer, be that 95 ± 5 ℃ mode is controlled to be the flask internal pressure about 60kPa with temperature of reaction.If monitor the temperature (tower top temperature) of rectifier when reflux, because near the methyl alcohol that generates and the azeotropic temperature of methyl methacrylate, therefore regulating reflux ratio, to make tower top temperature be about 60 ℃, on one side methyl alcohol is removed as distilling with the azeotrope of methyl methacrylate, Yi Bian react.
Because during through 2 hours, tower top temperature begins to raise, and therefore increases reflux ratio at leisure from reaction, and sustained reaction.React the 3rd hour reaction solution with gc analysis, consequently the ester turnover ratio is 99.4%, so reaction terminating.The cooling reaction solution when liquid temperature is 75 ℃, adds the salt solution 100g of 17 quality %, hydrolyst.After leaving standstill 15 minutes, by decant organic layer is fetched in the eggplant type flask, use Rotary Evaporators, after under reduced pressure excessive methyl methacrylate is removed in distillation, by suction filtration the liquid in the eggplant type flask is filtered, obtain cyclohexanedimethanol vinyl ether methacrylic ester 385g as purpose.
Synthesizing of cyclohexanedimethanol monomethacrylates
Pack in the detachable flask of the four-hole of 500mL tosic acid 6.4g, pure water 80g are provided with the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip.In flask, slowly add above-mentioned synthetic cyclohexanedimethanol vinyl ether methacrylic ester 200g.The system internal pressure is made as 20kPa, removes the acetaldehyde of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask cools off with frozen water on one side, on one side temperature of reaction is remained on 15~30 ℃.React after 2 hours, analyze by vapor-phase chromatography, reaction conversion rate is 99.9%, therefore finishes reaction.In the liquid that reaction finishes, add the salt solution 30g of toluene 80g, 17 quality %, carry out oily water separation, only take out organic layer.After using the sodium bicarbonate aqueous solution 20g cleaning organic layer of separating funnel, clean with the salt solution 30g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain cyclohexanedimethanol monomethacrylates 163g (yield 91.5%, purity 99.4%) as purpose by suction filtration.
Embodiment 4
The manufacture method of the methacrylic acid 4-hydroxyl butyl ester that utilizes again based on water
In the detachable flask of the four-hole of 1L, be enclosed among the embodiment 1 and carry out isolating water layer (all wts) after the reaction, the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip is set.In flask, slowly add synthetic methacrylic acid vinyloxy group butyl ester 500g among the embodiment 1.The system internal pressure is made as 20kPa, removes the acetaldehyde of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask cools off with frozen water on one side, on one side temperature of reaction is remained on 15~30 ℃.React after 3 hours, analyze by vapor-phase chromatography, reaction conversion rate is 99.9%, therefore finishes reaction.In the liquid that reaction finishes, add toluene 100g, carry out oily water separation, only take out organic layer.After using the sodium bicarbonate aqueous solution 70g cleaning organic layer of separating funnel, clean with the salt solution 70g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain methacrylic acid 4-hydroxyl butyl ester 398g (yield 92.8%, purity 99.2%) as purpose by suction filtration.
Embodiment 5
Temperature of reaction is the manufacture method of the methacrylic acid 4-hydroxyl butyl ester more than 60 ℃ the time
Pack in the detachable flask of the four-hole of 1L tosic acid 16g, pure water 200g are provided with the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip.In flask, add synthetic methacrylic acid vinyloxy group butyl ester 500g among the embodiment 1 quickly, rapidly the system internal pressure is made as 20kPa, remove the acetaldehyde of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask does not cool off and when placing, temperature of reaction rises to 65 ℃.React after 3 hours, analyze by vapor-phase chromatography, reaction conversion rate is almost 100%, therefore finishes reaction.In the liquid that reaction finishes, add the salt solution 50g of toluene 100g, 17 quality %, carry out oily water separation, only take out organic layer.After using the sodium bicarbonate aqueous solution 70g cleaning organic layer of separating funnel, clean with the salt solution 70g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain methacrylic acid 4-hydroxyl butyl ester 385g (yield 89.9%, purity 97.0%) as purpose by suction filtration.
When temperature of reaction surpasses 60 ℃ like this as can be known, compare with embodiment 1, yield reduces a little.
Comparative example 1
The manufacture method of the methacrylic acid 4-hydroxyl butyl ester under the glycol coexistence
Pack in the detachable flask of the four-hole of 1L tosic acid 16g, ethylene glycol 200g are provided with the vacuum pump of stirrer, thermometer, air leading-in conduit and band cooling clip.In flask, slowly add synthetic methacrylic acid vinyloxy group butyl ester 500g in the synthesis example 1.The system internal pressure is made as 20kPa, removes the acetal of generation under agitation, on one side in the system, advance reaction on one side.At this moment, flask cools off with frozen water on one side, on one side temperature of reaction is remained on 15~30 ℃.React after 3 hours, analyze by vapor-phase chromatography, reaction conversion rate is 78%.In addition, owing to, therefore be heated to 50 ℃, continue reaction by analyzing also remaining acetal compound in reaction system.In the back 1 hour reaction conversion rate of heating beginning is 98.4%, therefore finishes reaction.In the liquid that reaction finishes, add the salt solution 150g of toluene 200g, 5 quality %, carry out oily water separation, only take out organic layer.After using the sodium bicarbonate aqueous solution 70g cleaning organic layer of separating funnel, clean with the salt solution 70g of 17 quality % with 5 quality %.Organic layer is fetched in the eggplant type flask, uses Rotary Evaporators, after under reduced pressure excessive toluene is removed in distillation, filter, obtain methacrylic acid 4-hydroxyl butyl ester 395g (yield 87.6%, purity 92.3%) as purpose by suction filtration.
From above result as can be known, in order to obtain (methyl) acrylic acid hydroxy alkyl ester, when taking off the vinylation reaction,, can obtain highly purified (methyl) acrylic acid hydroxy alkyl ester with high yield by making the water coexistence.In addition, by embodiment 4 as can be known, the water layer that takes off separated recovery behind the vinylation can taking off in the vinylation reaction in later manufacturing next time utilize again.