阅读说明：本技术 酪氨酸衍生的二酚单体的合成 (Synthesis of tyrosine-derived diphenol monomers ) 是由 S·普拉普拉 F·布维奇 陈祥纪 S·刘 于 2018-05-08 设计创作，主要内容包括：一种用于制备二酚化合物的方法,其包括加入羟苯基羧酸、酪氨酸乙酯、羟基苯并三唑水合物和溶剂,并搅拌以生成第一溶液,将EDCl HCl加入到所述第一溶液中,以生成第一混合物。将乙酸乙酯添加到所述第一混合物中,以生成第二混合物。将所述第二混合物添加到氯化钠中,以生成具有层分离的第三混合物。从所述第三混合物中去除水层。在从所述第三混合物中除去所述水层后,用试剂提取所述第三混合物以生成第四混合物。将硫酸镁添加到所述第四混合物中,以生成第五混合物。过滤所述第五混合物以生成滤液。浓缩所述滤液。诱导浓缩的滤液结晶。将二氯甲烷加入到所述结晶的滤液中,以生成固体产物。(A method for preparing a diphenol compound comprising adding a hydroxyphenylcarboxylic acid, an ethyl tyrosine ester, a hydroxybenzotriazole hydrate and a solvent with stirring to form a first solution, adding EDCl HCl to the first solution to form a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. Adding the second mixture to sodium chloride to produce a third mixture having a layer separation. Removing the aqueous layer from the third mixture. After removing the aqueous layer from the third mixture, extracting the third mixture with a reagent to produce a fourth mixture. Magnesium sulfate is added to the fourth mixture to produce a fifth mixture. Filtering the fifth mixture to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Dichloromethane was added to the crystallized filtrate to produce a solid product.)

1. A process for preparing a diphenol compound having the formula:

the method comprises the following steps:

reacting a hydroxyphenyl carboxylic acid having the formula:

a tyrosine alkyl ester having the formula:

adding hydroxybenzotriazole hydrate and a solvent to a flask and stirring the contents of the flask to produce a first solution;

adding 3-ethyliminomethyleneamino-N, N-dimethylpropan-1-amine (EDCl) HCl to the first solution to produce a first mixture;

adding ethyl acetate to the first mixture to produce a second mixture;

adding the second mixture to sodium chloride to generate a third mixture having a layer separation;

removing the aqueous layer from the third mixture;

after removing the aqueous layer from the third mixture, extracting the third mixture with a reagent to produce a fourth mixture;

adding magnesium sulfate to the fourth mixture to produce a fifth mixture;

filtering the fifth mixture to produce a filtrate;

concentrating the filtrate;

inducing crystallization of the concentrated filtrate; and

methylene chloride was added to the crystallized filtrate to produce a solid product,

wherein R is selected from an alkyl group having 1 to 10 carbon atoms, an alkyl group having 10 to 20 carbon atoms, or an alkyl group having more than 20 carbon atoms.

2. The method of claim 1, wherein R is ethyl.

3. The process of claim 1, wherein the solvent is selected from the group consisting of N-methylpyrrolidone (NMP), Tetrahydrofuran (THF), and dichloromethane.

4. The method of claim 1, wherein the ethyl acetate is added as a co-solvent.

5. The method of claim 1, wherein the first solution comprises at least about a 2% excess of tyrosine ethyl ester relative to hydroxyphenyl carboxylic acid.

6. The process of claim 1, wherein said tyrosine ethyl ester is added to said flask and said hydroxyphenyl carboxylic acid is metered into said flask after said tyrosine ethyl ester is added to said flask.

7. The method of claim 1, wherein the first solution, the mixture, the filtrate, and the solid product are maintained at about 5 ℃ to about 10 ℃.

8. The process of claim 1, wherein the concentrated filtrate is crystallized by the addition of a 10:3 mixture of dichloromethane and toluene.

9. The method of claim 1, wherein the method is completed after about 1 hour to about 2 hours.

10. The method of claim 1, wherein the method is completed in less than 2 hours.

11. A process for preparing a diphenol compound having the formula:

the method comprises the following steps:

reacting a hydroxyphenyl carboxylic acid having the formula:

a tyrosine alkyl ester having the formula:

adding hydroxybenzotriazole hydrate and a solvent to a flask and stirring the contents of the flask to produce a first solution;

adding 3-ethyliminomethyleneamino-N, N-dimethylpropan-1-amine (EDCl) HCl to the first solution to produce a first mixture;

adding ethyl acetate to the first mixture to produce a second mixture;

adding the second mixture to sodium chloride to generate a third mixture having a layer separation;

removing the aqueous layer from the third mixture;

after removing the aqueous layer from the third mixture, extracting the third mixture with a reagent to produce a fourth mixture;

adding magnesium sulfate to the fourth mixture to produce a fifth mixture;

filtering the fifth mixture to produce a filtrate;

concentrating the filtrate; and

methylene chloride was added to the concentrated filtrate to produce a solid product,

wherein R is selected from an alkyl group having 1 to 10 carbon atoms, an alkyl group having 10 to 20 carbon atoms, or an alkyl group having more than 20 carbon atoms.

12. The method of claim 11, wherein R is ethyl and the concentrated filtrate is not crystallized.

13. A process for preparing a diphenol compound having the formula:

the method comprises the following steps:

reacting a hydroxyphenyl carboxylic acid having the formula:

tyrosine benzyl esters having the formula:

adding hydroxybenzotriazole hydrate and a solvent to a flask and stirring the contents of the flask to produce a first mixture;

adding triethylamine to the first mixture to produce a second mixture;

adding EDCI HCl to the second mixture to generate a third mixture;

adding ethyl acetate to the third mixture to produce a fourth mixture;

adding the fourth mixture to distilled water to produce a fifth mixture having a layer separation;

removing the aqueous layer from the fifth mixture;

after removing the aqueous layer from the fifth mixture, extracting the fifth mixture with a reagent to produce a sixth mixture;

adding magnesium sulfate to the sixth mixture to produce a seventh mixture;

filtering the seventh mixture to produce a filtrate;

concentrating the filtrate;

inducing crystallization of the concentrated filtrate; and

hexane was added to the crystallized filtrate to produce a solid product.

14. The method of claim 13, wherein the solvent is Tetrahydrofuran (THF).

15. The method of claim 13, wherein the solvent is a chlorinated solvent.

16. The process of claim 13, wherein the mixture, the filtrate, and the solid product are maintained at about 5 ℃ to about 10 ℃ throughout the process.

17. The method of claim 13, further comprising stirring the first mixture for about 15 minutes to about 30 minutes.

18. The method of claim 17, wherein the mixture, the filtrate, and the solid product are maintained at about 5 ℃ to about 10 ℃.

19. The method of claim 13, wherein the method is completed after about 1 hour to about 2 hours.

20. The method of claim 13, wherein the method is completed in less than 2 hours.

Technical Field

The present disclosure generally relates to methods of synthesizing tyrosine-derived diphenol monomers in significantly improved yields and purities.

Technical Field

Conventional methods for synthesizing tyrosine-derived diphenol monomers are often very time consuming and often result in low yields and/or low purity. The present disclosure describes improvements over these prior art techniques.

Disclosure of Invention

In one embodiment, in accordance with the principles of the present invention, there is provided a process for preparing tyrosine ethyl esters having the formula:

the method comprises dissolving tyrosine ethyl ester hydrochloride having the formula:

the solution is mixed with dichloromethane to form a first mixture. Potassium carbonate is added to the first mixture to form a second mixture comprising a separation layer. One of the separate layers is drawn from the second mixture. Magnesium sulfate was added to the separated layer which was withdrawn to form a third mixture. Removing the dichloromethane from the third mixture to form a slurry. Hexane was added to the slurry to form a solid. The solid was washed and dried.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

tyrosine ethyl esters having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask and the contents of the flask were stirred to produce a first solution. 3- (ethyliminomethyleneamino) -N, N-dimethylpropan-1-amine (EDCl) HCl is added to the first solution to produce a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. Adding the second mixture to sodium chloride to produce a third mixture having a layer separation. Removing the aqueous layer from the third mixture. After removing the aqueous layer from the third mixture, extracting the third mixture with a reagent to produce a fourth mixture. Magnesium sulfate is added to the fourth mixture to produce a fifth mixture. Filtering the fifth mixture to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Dichloromethane was added to the filtrate after crystallization to produce a solid product.

In some embodiments, the solvent is Tetrahydrofuran (THF). In some embodiments, the solvent is a chlorinated solvent. In some embodiments, the first solution comprises at least about a 2% excess of tyrosine ethyl ester relative to the hydroxyphenyl carboxylic acid. In some embodiments, the tyrosine ethyl ester is added to the flask and the hydroxyphenyl carboxylic acid is metered into the flask after the tyrosine ethyl ester is added to the flask. In some embodiments, the first solution, the mixture, the filtrate, and the solid product are maintained at about 5 ℃ to about 10 ℃.

In some embodiments, the method further comprises cooling the flask using an ice water bath and stirring the first solution in the cooled flask for about 20 minutes prior to adding EDCl HCl to the first solution. In some embodiments, the first solution, the mixture, the filtrate, and the solid product are maintained at about 5 ℃ to about 10 ℃. In some embodiments, the method is completed after about 1 hour to about 2 hours. In some embodiments, the method is completed in less than 2 hours.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

tyrosine ethyl esters having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask and the contents of the flask were stirred to produce a first solution. EDCl HCl was added to the first solution to generate a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. Adding the second mixture to sodium chloride to produce a third mixture having a layer separation. Removing the aqueous layer from the third mixture. After removing the aqueous layer from the third mixture, extracting the third mixture with a reagent to produce a fourth mixture. Magnesium sulfate is added to the fourth mixture to produce a fifth mixture. Filtering the fifth mixture to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Dichloromethane was added to the concentrated filtrate to yield a solid product. In some embodiments, the concentrated filtrate is not crystallized.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

p-toluenesulfonate salt of benzyl tyrosine having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask, and the contents of the flask were stirred to produce a first mixture. Triethylamine was added to the first mixture to produce a second mixture. EDCl HCl was added to the second mixture to produce a third mixture. Ethyl acetate was added to the third mixture to produce a fourth mixture. The fourth mixture is added to distilled water to produce a fifth mixture having a layer separation. The aqueous layer was removed from the fifth mixture. After the aqueous layer has been removed from the fifth mixture, the fifth mixture is extracted with a reagent to produce a sixth mixture. Magnesium sulfate is added to the sixth mixture to produce a seventh mixture. The seventh mixture is filtered to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Hexane was added to the crystallized filtrate to yield a solid product.

In some embodiments, the solvent is THF. In some embodiments, the solvent is a chlorinated solvent. In some embodiments, the solvent is removed by vacuum distillation. In some embodiments, the slurry, mixture, filtrate, and solid product are maintained at about 5 ℃ to about 10 ℃ throughout the process. In some embodiments, the method further comprises stirring the first mixture for about 15 minutes to about 30 minutes. In some embodiments, the slurry, mixture, filtrate, and solid product are maintained at about 5 ℃ to about 10 ℃. It has been found that maintaining these components at about 5 ℃ to about 10 ℃ allows the amidation reaction to occur more rapidly and limits the amount of trimer formed than maintaining these components at higher temperatures (e.g., room temperature).

In some embodiments, the method is completed after about 1 hour to about 2 hours. In some embodiments, the method is completed in less than 2 hours.

Additional features and advantages of various embodiments will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of various embodiments. The objectives and other advantages of the various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.

Detailed Description

For the purposes of this specification and the appended claims, all numbers expressing quantities of ingredients, percentages or proportions of materials, and other numerical values used in the specification and claims are to be understood as being modified in all instances by the term "about", unless otherwise indicated. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range of "1 to 10" includes any and all subranges between (including fractional) the minimum value of 1 and the maximum value of 10, that is, any and all subranges having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with these embodiments discussed herein, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the invention, as defined by the appended claims.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing tyrosine ethyl esters having the formula:

the method comprises dissolving tyrosine ethyl ester hydrochloride having the formula:

the solution is mixed with dichloromethane to form a first mixture. Potassium carbonate is added to the first mixture to form a second mixture comprising a separation layer. Withdrawing one of the separate layers from the second mixture. Magnesium sulfate was added to the separated layer which was withdrawn to form a third mixture. Removing the dichloromethane from the third mixture to form a slurry. Hexane was added to the slurry to form a solid. The solid was washed and dried.

In some embodiments, dissolving the tyrosine ethyl ester hydrochloride in distilled water comprises dissolving about 700g to about 800g tyrosine ethyl ester hydrochloride in about 2500ml to about 3500ml distilled water. In some embodiments, dissolving tyrosine ethyl ester hydrochloride in distilled water comprises dissolving about 745g tyrosine ethyl ester hydrochloride in about 3034ml distilled water. In some embodiments, dissolving tyrosine ethyl ester hydrochloride in distilled water comprises dissolving about 2.5 moles to about 3.5 moles of tyrosine ethyl ester hydrochloride in about 2500ml to about 3500ml of distilled water. In some embodiments, dissolving tyrosine ethyl ester hydrochloride in distilled water comprises dissolving about 3.03 moles of tyrosine ethyl ester hydrochloride in about 3034ml of distilled water. In some embodiments, the distilled water is pre-cooled at about 2 ℃ to about 5 ℃. In some embodiments, mixing the solution with dichloromethane comprises mixing from about 4800ml to about 5800ml of dichloromethane with the solution. In some embodiments, mixing the solution with dichloromethane comprises mixing about 5342ml of dichloromethane with the solution. In some embodiments, mixing the solution with dichloromethane comprises adding dichloromethane to a separatory funnel; and the solution was added to the separatory funnel. In some embodiments, the separatory funnel is equipped with an overhead mixer. In some embodiments, mixing the solution and dichloromethane comprises mixing the solution and dichloromethane at a rate to provide homogeneity. The reaction can be scaled up to allow for the preparation of batches of different sizes. For example, batches having less than about 5kg of ethyl tyrosine, batches having from about 5kg of ethyl tyrosine to about 20kg of ethyl tyrosine, and batches having greater than 20kg of ethyl tyrosine can be prepared.

In some embodiments, the potassium carbonate comprises a 5M potassium carbonate solution. In some embodiments, adding potassium carbonate to the first mixture comprises adding about 1100ml to about 1300ml of a 5M potassium carbonate solution to the first mixture. In some embodiments, adding potassium carbonate to the first mixture comprises adding about 1214ml of a 5M potassium carbonate solution to the first mixture. In some embodiments, adding potassium carbonate to the first mixture comprises adding from about 5.5 moles to about 6.5 moles of potassium carbonate to the first mixture. In some embodiments, adding potassium carbonate to the first mixture comprises adding about 6.07 moles of potassium carbonate to the first mixture. In some embodiments, the potassium carbonate is added to the first mixture over a period of about 10 minutes. In some embodiments, withdrawing one of the separate layers comprises withdrawing a lower product layer of the separate layer.

In some embodiments, adding magnesium sulfate to the one of the separated layers that is withdrawn comprises adding from about 25 grams to about 35 grams of anhydrous magnesium sulfate to the second mixture; mixing magnesium sulfate and the second mixture for about 10 minutes; adding about 25 grams to about 35 grams of additional anhydrous magnesium sulfate to the combined magnesium sulfate and the second mixture to form a third mixture. In some embodiments, adding magnesium sulfate to the one of the separated layers that is withdrawn comprises adding about 30 grams of anhydrous magnesium sulfate to the second mixture; mixing magnesium sulfate and the second mixture for about 10 minutes; and about 30 grams of additional anhydrous magnesium sulfate was added to the combined magnesium sulfate and second mixture to form a third mixture. In some embodiments, the method further comprises mixing the third mixture for about 1 hour; the mixed third mixture was allowed to stand for about 1 hour. In some embodiments, the method further comprises filtering the third mixture. In some embodiments, dichloromethane is removed from the third mixture by vacuum distillation. In some embodiments, dichloromethane is removed from the third mixture by vacuum distillation at a temperature of less than or equal to about 40 ℃.

In some embodiments, the method further comprises cooling the slurry to room temperature prior to adding hexane to the slurry. In some embodiments, adding hexane to the slurry comprises adding about 4 liters to about 6 liters of hexane to the slurry and stirring for about 1 hour to about 3 hours. In some embodiments, adding hexane to the slurry comprises adding about 5 liters of hexane to the slurry and stirring for about 1 hour to about 3 hours. In some embodiments, the method further comprises isolating the solid by vacuum filtration. In some embodiments, the method further comprises washing the precipitate with hexane. In some embodiments, the precipitate is washed with 2 × hexane to fix the overflow portion. In some embodiments, the method further comprises drying the solid. In some embodiments, the method further comprises drying the solid at room temperature at less than about 1mm Hg.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

tyrosine ethyl esters having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask, and the contents of the flask were stirred to produce a first solution. EDCl HCl was added to the first solution to produce a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. Adding the second mixture to sodium chloride to produce a third mixture having a layer separation. The aqueous layer was removed from the third mixture. After removing the aqueous layer from the third mixture, the third mixture is extracted with a reagent to produce a fourth mixture. Magnesium sulfate is added to the fourth mixture to produce a fifth mixture. The fifth mixture was filtered to produce a filtrate. The filtrate was concentrated. Crystallization of the concentrated filtrate was induced. Dichloromethane was added to the crystallized filtrate to yield a solid product. In some embodiments, the diphenol compound has a chemical formulaFormula C₂₀H₂₃NO₅And has a molecular weight of 357.4.

In some embodiments, the solvent is N-methylpyrrolidone. In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is THF. In some embodiments, the solvent is a chlorinated solvent. In some embodiments, the first solution is a clear solution. In some embodiments, the contents of the flask are stirred for about 15 minutes to about 30 minutes. In some embodiments, the flask is a 5-liter, three-neck flask.

In some embodiments, the first solution comprises at least about a 2% excess of tyrosine ethyl ester relative to the hydroxyphenyl carboxylic acid. In some embodiments, the first solution comprises an increased molar amount of tyrosine ethyl esters relative to the hydroxyphenyl carboxylic acid. In some embodiments, the first solution comprises equimolar amounts of tyrosine ethyl ester and hydroxyphenyl carboxylic acid. It has been found that increasing the molar amount of tyrosine ethyl ester allows the reaction to be preferentially driven toward amidation rather than esterification. It has been found that as little as about a 2% excess of ethyl tyrosine is sufficient to reduce the by-products to less than about 0.5%, whereas if equimolar amounts are used, the by-products are about 3% to about 5%. In fact, when the molar ratio of ethyl tyrosine to hydroxyphenyl carboxylic acid is 1: 0.9, the trimer ratio is 2.4%; when the molar ratio of tyrosine ethyl ester and hydroxyphenyl carboxylic acid is 1: 1.03, the trimer ratio is 0.32%; when the molar ratio of tyrosine ethyl ester and hydroxyphenyl carboxylic acid is 1.2: 1, the trimer ratio is 15.07. If an excess of hydroxyphenyl carboxylic acid is used, higher amounts of esterification product are formed and should therefore be avoided.

In some embodiments, about 380g to about 480g of tyrosine ethyl ester, about 300g to about 400g of hydroxyphenyl carboxylic acid, about 20g to about 40g of hydroxybenzotriazole hydrate, and about 1200ml to 1300ml of solvent are added to the flask to form the first solution. In some embodiments, about 431g of tyrosine ethyl ester, about 339g of hydroxyphenyl carboxylic acid, about 28.8g of hydroxybenzotriazole hydrate, and about 1200ml to about 1300ml of solvent are added to the flask to form the first solution. In some embodiments, about 1.5 moles to about 2.5 moles of ethyl tyrosine, about 1.5 moles to about 2.5 moles of hydroxyphenyl carboxylic acid, about 0.15 moles to about 2.5 moles of hydroxybenzotriazole hydrate, and about 1200ml to about 1300ml of solvent are added to the flask to form the first solution. In some embodiments, about 2.06 moles of ethyl tyrosine, about 2.04 moles of hydroxyphenyl carboxylic acid, about 0.19 moles of hydroxybenzotriazole hydrate, and about 1200ml to about 1300ml of solvent are added to the flask to form the first solution. In some embodiments, tyrosine ethyl ester is added to the flask and the hydroxyphenyl carboxylic acid is metered into the flask after tyrosine ethyl ester is added to the flask. In practice, to carry out the esterification reaction, the free carboxylic acid must always be present so that more carboxylic acid can react with the amine groups. In some embodiments, esterification is limited by changing the order of addition. In particular, instead of adding the hydroxyphenyl carboxylic acid and the tyrosine ester before the addition of the coupling agent (e.g. EDCI HCl), the process is modified in such a way that only ethyl tyrosine is present at the beginning and the hydroxyphenyl carboxylic acid is metered in during the reaction. This ensures that there is always an excess of amine groups, which favours amidation. In some embodiments, the reaction time for this metering is about 2 hours.

In some embodiments, an excess (e.g., a slight excess) of EDC1 HCl is used. In some embodiments, the amount of EDCl HCl used is reduced to a molar equivalent or reduced by about 10%. It has been found that reducing the amount of EDCl HCl used will ensure a cleaner reaction, as the amine will consume all of the EDCl HCl and limit esterification. In some embodiments, equimolar amounts of EDC1 HCl and hydroxyphenyl carboxylic acid are prepared in the reaction medium. The EDCl HCl and the hydroxyphenyl carboxylic acid are added dropwise to a flask, wherein the flask comprises tyrosine ethyl ester, hydroxybenzotriazole hydrate and/or a solvent. It has been found that this results in an immediate consumption of the hydroxyphenyl carboxylic acid by tyrosine ethyl ester. Thus, even if an excess of hydroxyphenyl carboxylic acid is present, there is no coupling agent available to cause the esterification reaction.

In some embodiments, the method further comprises cooling the flask using an ice water bath and stirring the first solution in the cooled flask for about 20 minutes prior to adding EDCl to the first solution. In some embodiments, EDCl is added to a portion of the stirred first solution.

In some embodiments, the method further comprises, after adding the EDCl to the portion of the stirred first solution, washing the first solution with about 100ml to about 200ml of N-methylpyrrolidone. In some embodiments, the method further comprises capping the flask and stirring the first mixture for about 4 hours; the temperature of the first mixture was allowed to reach room temperature. In some embodiments, the first mixture is brought to room temperature without supplementing the ice bath with ice. In some embodiments, the method further comprises stirring the first mixture overnight after the first mixture reaches room temperature. In some embodiments, the first solution, mixture, filtrate, and solid product are maintained at about 5 ℃ to about 10 ℃. It has been found that higher temperatures result in higher trimer contents. For example, when the reaction temperature is about 30 ℃, the trimer proportion is 0.48%. However, when the reaction temperature was about 5 ℃, the trimer proportion was 0.16%. Thus, maintaining these components at about 5 ℃ to about 10 ℃ allows the amidation reaction to occur more rapidly and limits the amount of trimer formed, as compared to maintaining these components at higher temperatures (e.g., room temperature).

In some embodiments, adding ethyl acetate to the first mixture comprises adding about 2000ml to about 3000ml of ethyl acetate to the first mixture. In some embodiments, adding ethyl acetate to the first mixture comprises adding about 2600ml of ethyl acetate to the first mixture. In some embodiments, adding ethyl acetate to the first mixture comprises adding about 2000ml to about 3000ml of ethyl acetate to the first mixture and stirring the second mixture for about 15 minutes. In some embodiments, adding ethyl acetate to the first mixture comprises adding about 2600ml of ethyl acetate to the first mixture and stirring the second mixture for about 15 minutes. In some embodiments, adding sodium chloride to the second mixture comprises transferring the second mixture to a separatory funnel comprising sodium chloride. In some embodiments, the separatory funnel is a 12 liter separatory funnel that already contains from about 2000ml to about 3000ml of 20% sodium chloride. In some embodiments, the method further comprises stirring the third mixture with an overhead mixer to provide homogeneity. In some embodiments, the separatory funnel is a 12 liter separatory funnel that already contains about 2600ml of 20% sodium chloride. In some embodiments, the method further comprises stirring the third mixture with an overhead mixer to provide homogeneity.

In some embodiments, the reagents for extracting the third mixture comprise: a first reagent comprising sodium bicarbonate and sodium chloride; a second reagent comprising sodium bicarbonate and sodium chloride; a third reagent comprising HCl and sodium chloride; a fourth reagent comprising sodium chloride; a fifth agent comprising sodium bicarbonate and sodium chloride; a sixth reagent comprising sodium chloride. In some embodiments, the first reagent comprises 1 × about 2000ml to about 3000ml of 3% sodium bicarbonate and about 14% sodium chloride; the second reagent comprises 1 x about 800ml to about 1500ml of 3% sodium bicarbonate and about 14% sodium chloride; the third reagent comprises 3 x about 800ml to about 1600ml of 0.4M HCl and about 20% sodium chloride; the fourth reagent contained 1X 1200ml of about 20% sodium chloride; the fifth reagent comprises from 1 x about 800ml to about 1600ml of about 3% sodium bicarbonate and about 14% sodium chloride; and the sixth reagent comprises from 1 x about 800ml to about 1600ml of about 20% sodium chloride.

In some embodiments, the reagents for extracting the third mixture comprise: a first reagent comprising sodium bicarbonate and sodium chloride; a second reagent comprising sodium bicarbonate and sodium chloride; a third reagent comprising HCl and sodium chloride; a fourth reagent comprising sodium chloride; a fifth agent comprising sodium bicarbonate and sodium chloride; and a sixth reagent comprising sodium chloride. In some embodiments, the first reagent comprises 1 x 2600ml of 3% sodium bicarbonate and about 14% sodium chloride; the second reagent contained 1 x 1200ml of 3% sodium bicarbonate and about 14% sodium chloride; the third reagent contained 3X 1200ml of 0.4M HCl and about 20% sodium chloride; the fourth reagent contained 1X 1200ml of about 20% sodium chloride; the fifth reagent contained 1X 1200ml of about 3% sodium bicarbonate and about 14% sodium chloride; and the sixth reagent comprises 1X 1200ml of about 20% sodium chloride. In some embodiments, the method further comprises withdrawing the upper ethyl acetate layer of the fourth mixture prior to adding the magnesium sulfate to the fourth mixture. In some embodiments, the method further comprises stirring the fifth mixture for about 5 minutes; allowing the fifth mixture to stand in the capped flask for at least one hour; and filtering the fifth mixture. In some embodiments, the method further comprises concentrating the filtrate prior to inducing crystallization of the filtrate. In some embodiments, the filtrate is concentrated by rotary evaporation. In some embodiments, the filtrate is maintained at a temperature of less than about 45 ℃ while concentrating the filtrate.

In some embodiments, inducing crystallization of the filtrate comprises pouring the concentrated filtrate into a kettle and inoculating (feeding) the concentrated filtrate with a diphenolic compound. In some embodiments, adding dichloromethane to the post-crystallization filtrate comprises adding from about 3 liters to about 4 liters of dichloromethane to the post-crystallization filtrate and stirring in a closed kettle until a smooth fine suspension is obtained. In some embodiments, adding methylene chloride to the post-crystallization filtrate comprises adding about 3.5 liters of methylene chloride to the post-crystallization filtrate and stirring in a closed kettle until a smooth fine suspension is obtained. In some embodiments, the filtrate after crystallization and dichloromethane are stirred for about 6 hours to about 24 hours. In some embodiments, the method further comprises: filtering the solid product; washing the filtered solid product with 2 × fixing the overflow of dichloromethane; and drying the washed solid product. In some embodiments, the solid product is dried at about 50 ℃ and less than 1mm Hg.

It has been found that longer reaction times lead to higher trimer contents. For example, a reaction time of about 20 hours produces 0.71% of trimer, while a reaction time of about 2 hours produces 0.37% of trimer. As such, in some embodiments, the method is completed after about 1 hour to about 2 hours. In some embodiments, the method is completed in less than 2 hours. It has been found that reducing the reaction time from 24 hours to about 1 hour to about 2 hours reduces the trimer content in the monomer, as amidation is thermodynamically preferred over esterification.

In some embodiments, tyrosine ethyl ester is released (liberate) and used without isolation. To this end, tyrosine ethyl ester hydrochloride having the following formula is suspended or dissolved in the reaction medium:

an equimolar amount of organic base (e.g., N-ethylmorpholine or triethylamine) is added and the reaction mixture is stirred for about 1 hour. The free base is released and dissolved in the reaction medium. Hydroxyphenyl carboxylic acid, hydroxybenzotriazole hydrate and solvent are added to the reaction medium and stirred to produce a first solution. EDCl HCl was added to the first solution to produce a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. The second mixture is added to sodium chloride to produce a third mixture having a layer separation. Removing the aqueous layer from the third mixture. After removing the aqueous layer from the third mixture, the third mixture is extracted with a reagent to produce a fourth mixture. Magnesium sulfate was added to the fourth mixture to produce a fifth mixture. The fifth mixture was filtered to produce a filtrate. The filtrate was concentrated. Crystallization of the concentrated filtrate was induced. Dichloromethane was added to the crystallized filtrate to yield a solid product. This allows the direct synthesis of diphenolic compounds.

In some embodiments, if a solvent such as THF is used, the by-product of the reaction, for example triethylamine HCl having the formula:

in such embodiments, the salt may be filtered off prior to addition of the other reagents. In some embodiments, the tyrosine ethyl ester hydrochloride is in slight excess, for example between about 0.5% to about 2% excess, over the organic amine to ensure that all of the organic base is used up, as such bases can catalyze side reactions and produce impurities. In some embodiments, the reaction medium is analyzed using a suitable analytical method (e.g., high performance liquid chromatography or gas chromatography) to accurately determine the concentration of ethyl tyrosine.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

p-toluenesulfonate salt of tyrosine ethyl ester having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask, and the contents of the flask were stirred to produce a first solution. EDCl HCl was added to the first solution to produce a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. The second mixture is added to sodium chloride to produce a third mixture with layer separation. The aqueous layer was removed from the third mixture. After removing the aqueous layer from the third mixture, the third mixture is extracted with a reagent to produce a fourth mixture. Magnesium sulfate was added to the fourth mixture to produce a fifth mixture. The fifth mixture was filtered to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Dichloromethane was added to the concentrated filtrate to yield a solid product. In some embodiments, the solids are slurried repeatedly with dichloromethane and filtered to reduce the amount of by-products that may be formed. In some embodiments, the concentrated filtrate is not crystallized. In some embodiments, the solid is slurried with dichloromethane and filtered repeatedly. This reduces the amount of by-products that may be formed.

In some embodiments, the concentrated filtrate is crystallized by the addition of a 10:3 mixture of dichloromethane and toluene. In these embodiments, the ethyl acetate is evaporated until the concentration of DTE is about 15%. For every 10 g of 15% strength DTE, 100ml of dichloromethane and 30ml of toluene are added. The mixture of DTE, dichloromethane and toluene was stirred for up to 48 hours until all material crystallized. The solids are separated. The same technique can be used for the isolated DTE, which has a high trimer content.

In one embodiment, in accordance with the principles of the present invention, there is provided a process for preparing a diphenol compound having the formula:

the process comprises reacting a hydroxyphenyl carboxylic acid having the formula:

p-toluenesulfonate salt of benzyl tyrosine having the formula:

hydroxybenzotriazole hydrate and solvent were added to a flask, and the contents of the flask were stirred to produce a first mixture. Triethylamine was added to the first mixture to produce a second mixture. EDCl HCl was added to the second mixture to produce a third mixture. Ethyl acetate was added to the third mixture to produce a fourth mixture. The fourth mixture is added to distilled water to produce a fifth mixture having a layer separation. The aqueous layer was removed from the fifth mixture. After the aqueous layer has been removed from the fifth mixture, the fifth mixture is extracted with a reagent to produce a sixth mixture. Magnesium sulfate is added to the sixth mixture to produce a seventh mixture. The seventh mixture is filtered to produce a filtrate. The filtrate was concentrated. Inducing concentration of the filtrateAnd (4) crystallizing. Hexane was added to the crystallized filtrate to yield a solid product. In some embodiments, the diphenol compound is of formula C₂₅H₂₅NO₅And has a molecular weight of 419.47.

In some embodiments, the first mixture is a smooth slurry. In some embodiments, the contents of the flask are stirred for about 15 minutes to about 30 minutes. In some embodiments, the solvent is N-methylpyrrolidone. In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is THF. In some embodiments, the solvent is a chlorinated solvent. In some embodiments, about 350g to about 450g of benzyl tyrosine, about 35g to about 50g of hydroxyphenyl carboxylic acid, about 5g to about 15g of hydroxybenzotriazole hydrate, and about 150ml to about 350ml of solvent are added to a flask to form a slurry. In some embodiments, about 391.3g of benzyl tyrosyl ester, about 43.4g of hydroxyphenyl carboxylic acid, about 10.96g of hydroxybenzotriazole hydrate, and about 250ml of solvent are added to the flask to form a slurry. In some embodiments, about 0.75 moles to about 0.95 moles of benzyl tyrosine, about 0.75 moles to about 0.95 moles of hydroxyphenyl carboxylic acid, about 0.075 moles to about 0.095 moles of hydroxybenzotriazole hydrate, and about 250ml of solvent are added to the flask to form a slurry. In some embodiments, about 0.8823 moles of benzyl tyrosine, about 0.8632 moles of hydroxyphenyl carboxylic acid, about 0.088 moles of hydroxybenzotriazole hydrate, and about 150ml to about 350ml of solvent are added to the flask to form a slurry. In some embodiments, the method further comprises stirring the first mixture for about 15 minutes to about 30 minutes.

In some embodiments, the method further comprises: after stirring the first mixture, the flask was cooled using an ice-water bath; the first mixture was stirred in the cooled flask for about 20 minutes. In some embodiments, adding triethylamine to the first mixture comprises adding about 100ml to about 130ml of triethylamine to the first mixture. In some embodiments, adding triethylamine to the first mixture comprises adding about 123.3ml of triethylamine to the first mixture. In some embodiments, adding triethylamine to the first mixture comprises adding about 0.75 moles to about 0.95 moles of triethylamine to the first mixture. In some embodiments, adding triethylamine to the first mixture comprises adding about 0.884 moles of triethylamine to the first mixture. In some embodiments, adding EDCl HCl to the second mixture comprises adding EDCl HCl to a portion of the stirred first mixture in the cooled flask. In some embodiments, an excess (e.g., a slight excess) of EDC1 HCl is used. In some embodiments, the amount of EDCl HCl used is reduced to a molar equivalent or reduced by about 10%. It has been found that reducing the amount of EDCl HCl used will ensure a kinetically faster reaction, as the amine will consume all EDCl HCl and limit esterification. In some embodiments, equimolar amounts of EDCl HCl and hydroxyphenyl carboxylic acid are prepared in the reaction medium (e.g., a flask). EDCl HCl and hydroxyphenyl carboxylic acid were added dropwise to a flask containing benzyl tyrosine, hydroxybenzotriazole hydrate and/or solvent. It has been found that this results in immediate consumption of the hydroxyphenyl carboxylic acid by tyrosine benzyl ester. Thus, even if an excess of hydroxyphenyl carboxylic acid is present, there is no coupling agent for causing the esterification reaction. In some embodiments, the slurry comprises an increased molar amount of benzyl tyrosine ester relative to the hydroxyphenyl carboxylic acid. In some embodiments, the slurry comprises equimolar amounts of tyrosine benzyl ester and hydroxyphenyl carboxylic acid. It has been found that increasing the molar amount of benzyl tyrosine allows the reaction to be preferentially driven toward amidation rather than esterification. It has been found that as little as about a 2% excess of benzyl tyrosine is sufficient to reduce the by-products to less than about 0.5%, while if equimolar amounts are used, the by-products are about 3% to about 5%. If an excess of hydroxyphenyl carboxylic acid is used, higher amounts of esterification products are formed and should therefore be avoided.

In some embodiments, the method further comprises, after adding EDCl HCl to the portion of the stirred first mixture in the cooled flask, washing the third mixture with about 200ml to about 300ml of ethyl acetate. In some embodiments, the method further comprises, after adding EDCl HCl to the portion of the first mixture stirred in the cooling flask, washing the third mixture with about 100ml of ethyl acetate. In some embodiments, the method further comprises: the flask was capped and the third mixture was stirred for about 4 hours; and the temperature of the third mixture was allowed to reach room temperature. In some embodiments, the third mixture is brought to room temperature without supplementing the ice bath with ice. In some embodiments, the method further comprises stirring the third mixture overnight after the first mixture reaches room temperature.

In some embodiments, the slurry, mixture, filtrate, and solid product are maintained at about 5 ℃ to about 10 ℃. It has been found that higher temperatures result in higher levels of trimer. For example, when the reaction temperature is about 30 ℃, the trimer proportion is 0.48%. And when the reaction temperature was about 5 ℃, the trimer proportion was 0.16%. Thus, maintaining these components at about 5 ℃ to about 10 ℃ allows the amidation reaction to occur more rapidly and limits the amount of trimer formed, as compared to maintaining these components at higher temperatures (e.g., room temperature).

In some embodiments, adding ethyl acetate to the third mixture comprises adding about 1500ml to about 2500ml of ethyl acetate to the third mixture, and stirring the fourth mixture for about 1 hour. In some embodiments, adding ethyl acetate to the third mixture comprises adding about 1956ml of ethyl acetate to the third mixture, and stirring the fourth mixture for about 1 hour. In some embodiments, adding the fourth mixture to distilled water comprises adding the fourth mixture to a separatory funnel comprising distilled water. In some embodiments, the separatory funnel is a 22 liter separatory funnel that already contains about 2000ml of distilled water. In some embodiments, the method further comprises stirring the fourth mixture with an overhead mixer to provide homogeneity.

In some embodiments, the reagents for extracting the fifth mixture comprise: a first reagent comprising sodium bicarbonate; a second reagent comprising sodium chloride; a third reagent comprising HCl; a fourth reagent comprising sodium chloride. In some embodiments, the first reagent comprises 3 x about 400ml to about 600ml of 0.5M sodium chloride; the second reagent comprises 1 × about 400ml to about 600ml of 20% sodium chloride; the third reagent comprises 3 x about 400ml to about 600ml of 0.2M HCl; and the fourth reagent comprises from 1 x about 400ml to about 600ml of 20% sodium chloride. In some embodiments, the reagents for extracting the fifth mixture comprise: a first reagent comprising sodium bicarbonate; a second reagent comprising sodium chloride; a third reagent comprising HCl; a fourth reagent comprising sodium chloride. In some embodiments, the first reagent comprises 3 x 500ml of 0.5M sodium chloride; the second reagent contained 1X 500ml of 20% sodium chloride; the third reagent contained 3X 500ml of 0.2M HCl; and the fourth reagent contained 1X 500ml of 20% sodium chloride.

In some embodiments, the method further comprises withdrawing an upper ethyl acetate layer of the sixth mixture prior to adding the magnesium sulfate to the sixth mixture. In some embodiments, the method further comprises: stirring the seventh mixture for about 30 minutes; allowing the seventh mixture to stand in the capped flask for at least one hour; and filtering the seventh mixture. In some embodiments, the method further comprises concentrating the filtrate prior to inducing crystallization of the filtrate. In some embodiments, the filtrate is concentrated by vacuum distillation. In some embodiments, the filtrate is maintained at a temperature of less than about 45 ℃ while concentrating the filtrate. In some embodiments, inducing crystallization of the filtrate comprises pouring the concentrated filtrate into a kettle and inoculating the concentrated filtrate with about 50mg to about 100mg of the diphenolic compound. In some embodiments, adding hexane to the crystallized filtrate comprises adding about 0.8 liters to about 1.2 liters of hexane to the crystallized filtrate and stirring. In some embodiments, adding hexane to the filtrate after crystallization comprises adding about 1 liter of hexane to the filtrate after crystallization and stirring. In some embodiments, the crystallized filtrate and hexane are stirred for about 4 hours. In some embodiments, the method further comprises: filtering the solid product; washing the filtered solid product with 2 × hexane from the overflow fraction; and drying the washed solid product. In some embodiments, the solid product is dried at about 50 ℃ and less than 1mm Hg.

It has been found that longer reaction times lead to higher trimer contents. For example, a reaction time of about 20 hours produces 0.71% of trimer, while a reaction time of about 2 hours produces 0.37% of trimer. Thus, in some embodiments, the method is completed after about 1 hour to about 2 hours. In some embodiments, the method is completed in less than 2 hours. It has been found that reducing the reaction time from 24 hours to about 1 hour to about 2 hours reduces the trimer content in the monomer, as amidation is thermodynamically preferred over esterification.

It has been found that the bifunctionality of diphenols having the following formula may contribute to achieving high molecular weights:

indeed, if the phenol group is not present or protected, it will not be reactive in the next step, thus resulting in a lower yield. If this unreacted compound is not removed in the purification step, it will proceed to the polymerization step where the monomers discussed herein are used to form a polymer. The non-reactive compound has only one reactive phenolic group and therefore it acts as a chain terminator during the polymerization step. If the phenol group is not present or protected, it is coupled to an amine during the synthesis of the monomers discussed herein. However, the resulting compounds act as monofunctional phenols during the synthesis steps, thus limiting polymerization. Thus in some embodiments, one or more of the methods discussed herein comprise purifying a hydroxyphenyl carboxylic acid having the formula:

in some embodiments, to purify the hydroxyphenyl carboxylic acid, it is recrystallized from a mixture of toluene and ethyl acetate. In some embodiments, the mixture is heated and then filtered without immediate recrystallization.

In some embodimentsWherein the reaction is carried out in THF, NMP and/or another water-soluble solvent, and the hydroxyphenyl carboxylic acid is purified by adding the reaction mixture to water and stirring to give a solid. The solid was then repulped in dilute hydrochloric acid until acidic. The re-slurried solid is treated with water and NaHCO₃And (5) diluting until the solution is alkaline. Water was added until it was neutral and the solid was dried.

In one embodiment, in accordance with the principles of the present disclosure, there is provided a process for preparing a diphenol compound having the formula:

in this embodiment, both diphenol compounds are prepared in the same pot.

The process comprises combining tyrosine ethyl ester hydrochloride having the formula with tyrosine benzyl ester having the formula, hydroxyphenyl carboxylic acid having the formula to obtain a mixture of the two aforementioned diphenols DTE and DTBn:

in some embodiments, the ratio of tyrosine ethyl ester hydrochloride to tyrosine benzyl ester is directly proportional to the ratio of DTE to DTBn in the final product. For example, to make 75% DTE and 25% DTBn, the copolymer contains 75% ethyl tyrosine hydrochloride and 25% benzyl tyrosine. In contrast, to prepare 25% DTE and 75% DTBn, the copolymer contained 25% ethyl tyrosine hydrochloride and 75% benzyl tyrosine.

One mole of trimethylamine is added to the mixture of diphenols to produce a mixture. Adding one mole of each of the following (a) to (c) reagents to the mixture to produce a first solution:

(a) hydroxyphenyl carboxylic acids having the formula:

(b) EDCl and

(c) hydroxybenzotriazole.

EDCl HCl was added to the first solution to produce a first mixture. Ethyl acetate was added to the first mixture to produce a second mixture. Adding the second mixture to sodium chloride to produce a third mixture having a layer separation. Removing the aqueous layer from the third mixture. After removing the aqueous layer from the third mixture, the third mixture is extracted with a reagent to produce a fourth mixture. Magnesium sulfate was added to the fourth mixture to produce a fifth mixture. The fifth mixture was filtered to produce a filtrate. The filtrate was concentrated. The concentrated filtrate was induced to crystallize. Dichloromethane was added to the concentrated filtrate to yield a solid product.

It is envisaged that the reactions discussed herein may be carried out on a small or large scale without modification of the present process. In some embodiments, the reaction is carried out on a multi-kilogram scale using a reactor (e.g., a 50 gallon reactor).