KR20070015936A - Method for preparing hydroxystyrene and its acetylated derivatives - Google Patents

Abstract

The present invention provides a process for the high temperature decarboxylation of phenolic substrates in the presence of a nonamine base catalyst to produce vinyl monomers. The product of the decarboxylation reaction may further be acetylated in the presence of an acetylating agent in the same reactor.

Hydroxystyrene, decarboxylated, acetylated, phenol

Description

A METHOD FOR PREPARING HYDROXYSTYRENES AND ACETYLATED DERIVATIVES THEREOF

The present invention relates to the field of organic synthesis. More specifically, the present invention relates to a process for the preparation of hydroxystyrene by high temperature decarboxylation of phenolic substrates under a base catalyst and by a single reactor of the resulting product, subsequent acetylation in a two step process.

Hydroxystyrenes (eg 4-hydroxystyrene (pHS)) and their acetylated derivatives (eg 4-acetoxystyrene (pAS)) are aromatic compounds with potential utility in a wide range of industrial applications. For example, these compounds are applied to electronic materials as well as monomers for the production of resins, elastomers, adhesives, coatings, automotive finishes and inks. They can also be used as additives for elastomers and resin formulations.

Many methods are known for the chemical synthesis of hydroxystyrenes and their acetylated derivatives. However, these methods require expensive reagents, harsh conditions, and provide relatively low yields (typically 30-63%). See, eg, Sovish, J. Org. Chem. 24: 1345-1347 (1959) describe the preparation of 4-hydroxystyrene (also known as p-vinylphenol) from p-hydroxycinnamic acid (pHCA). pHCA is decarboxylated in copper powdery quinoline at a temperature of about 225 ° C. The yield of 4-hydroxystyrene was about 41%.

US Pat. No. 4,316,995 to Pittet et al. Describes a process for preparing p-vinylphenol. In this method, first, p-hydroxybenzaldehyde is reacted with malonic acid using ethylenediamine as a catalyst to obtain pHCA, which is decarboxylated in situ at 115 to 120 ° C. to form p-vinylphenol mixed with impurities. . P-vinylphenol is isolated from the reaction mixture and reacted with acetic anhydride in the presence of a base (e.g. sodium or potassium hydroxide) to form 4-acetoxystyrene, which is separated from the reaction mixture and hydrolyzed in the presence of a strong base. Obtained purified p-vinylphenol. The yield of 4-vinylphenol was about 31%.

US Pat. No. 5,274,060 to Schadeli describes a process for preparing 4-hydroxystyrene starting with pHCA. In this process, the pHCA is decarboxylated in dimethyl sulfoxide in the presence of an amine catalyst (i.e., 1,8-diazabicyclo [5,4-0] undec-7-ene) and hydroquinone at 135 ° C. Obtain 4-hydroxystyrene. The yield of this method was 63%.

Australian Patent Application No. 7247129 to Lala et al. Discloses a process for the high temperature decarboxylation of ortho- or para-hydroxyarylcarboxylic acids using an amine catalyst in an aprotic solvent to form vinyl derivatives. It is. Also described is a method for producing a vinyl hydroxyaryl compound by forming hydroxyarylcarboxylic acid in situ and then hot decarboxylating. Hydroxyarylcarboxylic acids are formed by reacting aliphatic dicarboxylic acids or aliphatic anhydrides with hydroxyarylaldehyde in the base medium. The yield of these methods was 15-60%.

Steinmann, US Pat. No. 5,324,804, describes the synthesis of 3,4-dihydroxystyrene by high temperature decarboxylation of caffeic acid in dimethyl formamide at 150 ° C. in the absence of a catalyst. The yield obtained by this method is not shown.

Munteanu et al ., J. Thermal Anal. 37: 411-426 (1991) are described by the thermal decomposition of trans-3,5-di-tert-butyl-4-hydroxycinnamic acid in the presence or absence of a non-amine base catalyst in an aprotic bipolar solvent. The preparation of, 5-di-tert-butyl-4-hydroxystyrene is described. The reported yield was 95%. High temperature decarboxylation of other cinnamic acid derivatives is not described in this specification.

High temperature decarboxylation of substituted cinnamic acids has been studied in aqueous media. Pyysalo et al ., Lebensmittel-Wissenschraft u. Technol. 10 (Food Science and Tehchnology): 145-147 (1977) describes high temperature decarboxylation of substituted cinnamic acid derivatives at 100 ° C., pH 1-6 in aqueous buffer. Cohen et al ., J. Amer. Chem. Soc. 82: 1907-1911 (1960) describes high temperature decarboxylation of p-hydroxycinnamic acid in an aqueous buffer at pH 1-12. Isolation of decarboxylated products is not reported in this specification.

Thus, there is a need for a process for producing hydroxystyrene and its acetylated derivatives, which is obtained in high yield using relatively inexpensive reagents, relatively mild conditions.

Applicants have solved the above problems by finding a method for preparing hydroxystyrene and its acetylated derivatives in yields up to 100% using relatively inexpensive reagents under relatively mild conditions. Hydroxystyrene is prepared by high temperature decarboxylation of phenolic substrates in the presence of a nonamine base catalyst. Acetylated derivatives are formed by reaction in the same reactor of the resulting hydroxystyrene and the acetylating agent.

Summary of the Invention

The invention also relates to a process for high temperature decarboxylation of phenolic substrates in the presence of a nonamine base catalyst. The product of the decarboxylation reaction may be further acetylated in the presence of an acetylating agent in the same reactor. Optionally, a polymerization inhibitor or a polymerization retardant can be added to the reaction mixture. The yield of decarboxylation or acetylation product is typically above 63%. therefore,

a) providing a phenolic substrate of formula (I);

b) i) a nonamine base catalyst; And ii) at least one polar organic solvent or a mixture of polar organic solvents; And

c) contacting the phenolic substrate with the reaction mixture of step b) for at least about 100 ° C. for a time sufficient to decarboxylate the phenolic substrate of step a) to the decarboxylation product. It is within the scope of the present invention to provide a method for decarboxylating a substrate to produce vinyl monomers. Optionally, the decarboxylation product can be recovered by means well known in the art.

<Formula I>

Wherein R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ; R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl; R ₆ and R ₇ are H, Halo or cyano, provided that at least one of R ₁ , R ₃ or R ₅ is OH, and both R ₂ and R ₄ are not t-butyl at the same time)

In another embodiment, the present invention

a) providing a phenolic substrate of formula (I);

b) i) a nonamine base catalyst; And ii) at least one polar, aprotic organic solvent or a mixture of polar, aprotic organic solvents;

c) contacting the phenolic substrate with the reaction mixture of step b) for at least about 100 ° C. for a time sufficient to decarboxylate the phenolic substrate of step a) to form a decarboxylation product; And

d) contacting the decarboxylation product of step c) with an acetylating agent to produce an acetylation product of formula (II), which provides a method of synthesizing an acetylation product from a phenolic substrate.

<Formula I>

Wherein R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ; R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl; R ₆ and R ₇ are H, Halo or cyano, provided that at least one of R ₁ , R _3, or R ₅ is OH;

<Formula II>

Wherein R ₈ , R ₁₀ and R ₁₂ are H, O (C═O) CH ₃ or OCH ₃ ; R ₉ and R ₁₁ are H, OH, OCH ₃ , or linear or branched alkyl; R ₁₃ and R ₁₄ are H, halo or cyano; provided that at least one of R ₈ , R ₁₀ or R ₁₂ is O (C═O) CH ₃ ;

The present invention provides a process for preparing hydroxystyrene by high temperature decarboxylation of a phenol substrate under a nonamine base catalyst. The resulting hydroxystyrene can be acetylated by the addition of an acetylating agent in the same reactor. This method is useful because hydroxystyrene and its acetylated derivatives have use as resins, elastomers, adhesives, coatings, automotive finishes, monomers for the manufacture of inks and electronic materials, and as additives in elastomers and resin blends.

The following definitions are used herein and should be mentioned for interpretation of the claims and the specification.

"p" means para.

"pAS" is an abbreviation used for para-acetoxystyrene, also referred to as p-acetoxystyrene or 4-acetoxystyrene.

"pHS" is an abbreviation used for para-hydroxystyrene, also referred to as p-hydroxystyrene or 4-hydroxystyrene.

"CA" stands for Sinamsan.

As used herein, the term "yield" refers to the amount of product produced in a chemical reaction. Yields are typically expressed as a percentage of theoretical yield of the reaction. The term "theoretical yield" refers to the expected amount of product expected based on the amount of substrate initially present and the stoichiometry of the reaction.

The term "polar" as applied to a solvent of the present invention refers to a solvent characterized by a molecule having a permanent dipole moment of considerable size.

The term "aprotic" as applied to a solvent of the present invention refers to a solvent that cannot act as an unstable proton donor or acceptor.

The term "protic" as applied to the solvent of the present invention refers to a solvent that can act as an unstable proton donor or acceptor.

The term "polar organic solvent mixture" refers to a mixture of organic solvents comprising at least one polar solvent.

The term "aprotic, polar organic solvent mixture" refers to a mixture of organic solvents comprising at least one aprotic polar solvent.

"TAL" is an abbreviation used for tyrosine ammonia lyase.

"PAL" is an abbreviation used for phenylalanine ammonia lyase.

"PAH" is an abbreviation used for phenylalanine hydroxylase.

The term "TAL activity" refers to the ability of a protein to promote the direct conversion of tyrosine to pHCA.

The term "PAL activity" refers to the ability of a protein to promote the conversion of phenylalanine to cinnamic acid.

" pal " represents a gene encoding an enzyme having PAL activity.

" tal " represents a gene encoding an enzyme having TAL activity.

The term "PAL / TAL activity" or "PAL / TAL enzyme" relates to a protein containing both PAL and TAL activity. These proteins have slightly more specificity for tyrosine and phenylalanine as enzyme substrates.

The term "P-450 / P-450 reductase system" refers to a protein system responsible for the catalytic conversion of cinnamic acid to pHCA. The P-450 / P-450 reductase system is one of several enzymes or enzyme systems known in the art that perform cinnamate 4-hydroxylase functions. As used herein, the term "cinnamate 4-hydroxylase" refers to the general enzyme activity that causes the conversion of cinnamic acid to pHCA, whereas the term "P-450 / P-450 reductase system" Will refer to a specific binary protein with cinnamate 4-hydroxylase activity.

All ranges given herein include the end of the range and also include all midrange points.

The present invention includes a process for the preparation of vinyl monomers, in particular hydroxystyrenes, having the formula:

Where

R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ;

R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl;

R ₆ and R ₇ are H, halo or cyano;

Provided that at least one of R ₁ , R ₃ or R ₅ is OH, wherein it is preferred that both R ₂ and R ₄ are not t-butyl at the same time.

Non-limiting examples of hydroxystyrenes that can be produced by the process of the invention include 4-hydroxystyrene, 3-methoxy-4-hydroxystyrene, 3,5-dimethoxy-4-hydroxystyrene, 3 , 4-dihydroxystyrene, 2-hydroxystyrene and α-cyano-4-hydroxystyrene.

In addition, the resulting hydroxystyrene can be acetylated by adding an acetylating agent to the reactor to obtain an acetylated product having the formula:

Where

R ₈ , R ₁₀ and R ₁₂ are H, O (C═O) CH ₃ or OCH ₃ ;

R ₉ and R ₁₁ are H, OH, OCH ₃ or linear or branched alkyl;

R ₁₃ and R ₁₄ are H, halo or cyano;

Provided that at least one of R ₈ , R ₁₀ or R ₁₂ is O (C═O) CH ₃ .

Non-limiting examples of acetylation products include 4-acetoxystyrene, 3-methoxy-4-acetoxystyrene, 3,5-dimethoxy-4-acetoxystyrene, 3,4-diacetoxystyrene, 2- Acetoxystyrene and α-cyano-4-acetoxystyrene.

Phenolic Substrate

Phenolic substrates for use in the present invention have the formula:

Where

R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ;

R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl;

R ₆ and R ₇ are H, halo or cyano;

Provided that at least one of R ₁ , R ₃ or R ₅ is OH.

Non-limiting examples of suitable phenolic substrates are 4-hydroxycinnamic acid, ferulic acid cinnamic acid, caffeic acid, 2-hydroxycinnamic acid, and α-cyano-4-hydroxycinnamic acid. It has been found that high yields of decarboxylation products have been obtained even with nonstereoscopic phenol substrates that are more prone to degradation than sterically hindered phenols. Hindered phenols are defined herein as phenols having large, bulky groups such as t-butyl in two positions, R ₂ and R ₄ . Nonstereoscopic phenols are phenols that do not have large, bulky groups in both R ₂ and R ₄ positions. Non-limiting examples of nonstereoscopic phenol substrates are phenols wherein at least one of R ₂ or R ₄ is H, OH, OCH ₃ , methyl, ethyl or propyl. It has also been found that high yields of decarboxylation products have been obtained even with ortho unsubstituted phenol substrates, which are also susceptible to degradation. Ortho unsubstituted phenol is defined herein as phenol wherein at least one of R ₂ or R ₄ is H.

These phenolic substrates can be obtained in a number of ways. For example, 4-hydroxycinnamic acid (pHCA), primarily in trans form, is commercially available from companies such as Aldrich (Milwaukee, WI) and TCI America (Portland, Oregon, USA). Available as In addition, pHCA can be prepared by chemical synthesis using any method known in the art. For example, pHCA can be obtained by reacting malonic acid with para-hydroxybenzaldehyde as described in US Pat. No. 4,316,995 to Pitet et al. Or US Pat. No. 5,990,336 to Alexandratos. Alternatively, pHCA can also be isolated from plants (R. Benrief et al., Phytochemistry 47: 825-832 (1998) and US Patent Application Publication No. 20020187207). In one embodiment, the source of pHCA is bioproduction using a production host. In other embodiments, the production host is a recombinant host cell, which may be prepared using standard DNA techniques. These recombinant DNA techniques are described by Sanbrook, J., Frisch, EF, and Manatis, T., Molecular Cloning: A Laboratory Manual, Second Edition, which is incorporated herein by reference. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989).

In one embodiment, the pHCA is generated as described in US Patent Application Publication No. 20030079255 to Qi et al., Incorporated herein by reference. According to this specification, pHCA can be generated using recombinant microorganisms engineered to express one or more genes that encode phenylalanine hydroxylase (PAH) activity and one or more genes that encode tyrosine ammonia lyase (TAL) activity. . Such transformed microorganisms metabolize fermentable carbon sources (eg glucose) into phenylalanine, which is converted to tyrosine by PAH. The resulting tyrosine is converted to pHCA by the TAL enzyme. Any suitable enzyme with TAL activity can be used. For example, enzymes having both PAL and TAL activity (PAL / TAL) can be used. As described in US Pat. No. 6,368,837 to Gatenby et al., TAL enzymes generated through mutations of wild-type yeast PAL enzymes that have enhanced TAL activity can also be used. Alternatively, the inducible TAL enzyme from the yeast Trichosporon cutaneum , or Kyndt et al., As described in US Patent Application Publication No. 200400233457 to Breinig et al. FEBS Lett. 512: 240-244 (2002) or US Pat. Appl. Pub. No. 20040059103 to Huang et al., Bacterial TAL enzymes can be used.

In other embodiments, the pHCA is produced by any one of the methods disclosed by Gatenbai et al., Cited herein by reference. For example, pHCA can be generated using recombinant microorganisms engineered to express genes encoding yeast PAL activity and genes encoding plant P-450 / P-450 reductase system. Such transformed microorganisms metabolize fermentable carbon sources (eg glucose) into phenylalanine, which is converted to cinnamic acid (CA) by the PAL enzyme. The CA is then converted to pHCA by the action of the P-450 / P-450 reductase system. Alternatively, pHCA can be produced using recombinant microorganisms that express genes encoding TAL activity. TAL enzymes directly convert tyrosine to pHCA. Any suitable TAL enzyme can be used as described above.

In other embodiments, the pHCA is generated using two stage fermentation, as described in co-pending and generally assigned US Patent Application No. 60/563633, incorporated herein by reference. The first step includes providing a microbial production host (overproduct) with enhanced ability to produce aromatic amino acid tyrosine. These cells grow at physiological pH until tyrosine accumulates in the growth medium. During the second stage of fermentation, the cells are contacted with a TAL source with a pH of about 8.0 to about 11.0. During this stage tyrosine is converted to pHCA at a relatively high rate and yield. Alternatively, these two steps can be done as two separate steps, where tyrosine is isolated from the fermentation medium of the first step and then contacted with the TAL source.

In the biogeneration of pHCA, the microorganisms used are cultured in a suitable growth medium in the fermentor. Any suitable fermenter can be used, including stirred tank fermenters, air pumping fermentors, bubble fermenters, or any mixed form thereof. Materials and methods for the maintenance and growth of microbial cultures are well known to those in microbiology or fermentation science (see, eg, Bailey et al., Biochemical Engineering Fundamentals , second edition, McGraw Hill, New York, 1986). Reference). Biogenerated pHCA can be isolated from the fermentation medium used in the present invention using methods known in the art. For example, the solid can be removed from the fermentation medium by centrifugation. The medium can then be acidified to precipitate pHCA and recovered by centrifugation. If desired, the pHCA can be further purified, for example using organic solvent extraction.

Similarly, ferulic acid, cinafinic acid and caffeic acid are commercially available from companies such as Aldrich (Milwaukee, WI) and TCI America (Portland, Oregon, USA). Alternatively, since these substrates are all natural plant products that include elements of the lignin biosynthetic pathway, they can be easily isolated from plant tissues (eg, Jang et al., Archives of Pharmacal Research (2003). ), 26 (8), 585-590; Matsufuji et al., Journal of Agricultural and Food Chemistry (2003), 51 (10), 3157-3161; WO 2003046163; Couteau; Et al., Bioresource Technology (1998), 64 (1), 17-25; and Bartolome et al., Journal of the Science of Food and Agriculture (1999), 79 (3), 435-439. Reference). In addition, methods of chemical synthesis for many more common phenolic substrates are known (see, for example, WO2002083625 ("Preparation of Ferulic Acid Dimer and its Pharmaceutically Acceptable Salts, and Their Treatment for Treating Dementia). (Preparation of ferulic acid dimers and their pharmaceutically acceptable salts, and use according to treating dementia), JP 2002155017 ("Preparation of caffeic acid from ferulic acids"; and Taniguchi ( Taniguchi, et al., Anticancer Research (1999), 19 (5A), 3757-3761) The preparation of alkylated pHCA derivatives is described in Australian patent application 7247129 to Lala et al.

Non-amine base catalyst

The process of the present invention uses a nonamine base catalyst. The nonamine base catalyst is any basic compound capable of catalyzing the reaction of the present invention that does not contain an amine. Comparative examples of amine containing catalysts are pyridine and ethylenediamine. Practically any non-amine base catalyst suitable for the reaction conditions of the present invention can be used, with metal salts, in particular potassium salts or acetate salts being preferred. Non-limiting examples of particularly suitable catalysts for the present invention are potassium acetate, potassium carbonate, potassium hydroxide, sodium acetate, sodium carbonate, sodium hydroxide and magnesium oxide.

All non-amine catalysts of the present invention are commercially available, for example, from EM Science (Gibstown, NJ) or Aldrich (Milwaukee, WI).

The optimal concentration of the nonamine base catalyst will vary depending on the concentration of the substrate, the nature of the solvent used and the reaction conditions. Typically, a concentration of about 1 mol% to about 30 mol% with respect to the substrate in the reaction mixture is preferred.

Organic solvent

For the decarboxylation reaction alone, a wide range of organic solvents can be used including aprotic, polar organic solvents and protic, polar organic solvents. One protic, polar solvent or one aprotic, polar solvent can be used. In addition, aprotic, mixtures of polar solvents, protic, mixtures of polar solvents, aprotic and protic, mixtures of polar solvents, and mixtures of aprotic or protic and nonpolar solvents can be used, where Preferred are aprotic, polar solvents or mixtures thereof. Non-limiting examples of suitable aprotic, polar solvents include N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide and hexa Methylphosphorus triamide. Non-limiting examples of suitable protic, polar solvents include di (propylene glycol) methyl ether (Dowanol ™ DPM), di (ethylene glycol) methyl ether, 2-butoxyethanol, ethylene glycol, 2-meth Methoxyethanol, propylene glycol methyl ether, n-hexanol and n-butanol.

For a two stage decarboxylation-acetylation process, the organic solvent should have the final character of being aprotic and polar. One aprotic, polar solvent can be used, or a mixture of aprotic, polar solvents can be used. Alternatively, aprotic, polar solvents may be used with the nonpolar solvents, but protic solvents are not preferred because of their reactivity and tend to consume acetylating agents. Non-limiting examples of particularly suitable solvents for the two-step process of the present invention include N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphor Amide and hexamethylphosphorus triamide.

Polymerization inhibitor

Polymerization inhibitors are useful but not necessary in the process of the present invention. As described herein, any suitable polymerization inhibitor that can withstand the temperatures required for the decarboxylation reaction can be used. Non-limiting examples of suitable polymerization inhibitors are hydroquinone, hydroquinone monomethyl ether, 4-tert-butyl catechol, phenothiazine, N-oxyl (nitroxide) inhibitors, examples of which are Prostab® 5415 (bis (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, CAS # 2516-92-9, Ciba Specialty Chemicals, Terrytown, NY Available from Specialty Chemicals), 4-hydroxy-TEMPO (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yloxy, CAS # 2226-96-2, from TCI America) Available) and Uvinul® 4040 P (1,6-hexamethylene-bis (N-formyl-N- (1-oxyl-2,2,6,6-tetramethylpiperidine-) 4-yl) amine, available from BASF Corp. of Worcester, Mass., USA.

Polymerization retardant

In some cases, it may be advantageous to use a polymerization retardant in combination with a polymerization inhibitor in the reaction of the present invention. Polymerization retardants are well known in the art and are compounds which slow down the rate of the polymerization reaction but cannot completely inhibit the reaction. Common retardants are aromatic nitro compounds such as dinitro-ortho-cresol (DNOC) and dinitrobutylphenol (DNBP). Methods of making polymerization retardants are common and well known in the art (see, eg, US Pat. No. 6,339,177; Park et al., Polymer (Korea) (1988), 12 (8), 710-19). Their use in the inhibition of styrene polymerization is well documented.

Reaction conditions

Phenolic substrates, non-amine base catalysts, and organic solvents are added to the reactor to form a reaction mixture. Any suitable reactor can be used.

The reaction temperature can vary depending on the concentration of the substrate, the stability of the product formed, the catalyst selected and the desired yield. Typically, a temperature of at least about 100 ° C. is suitable, wherein a temperature of at least about 100 ° C. to about 200 ° C. is suitable for effective production of the product. For reactions using 4-hydroxycinnamic acid as a substrate, the preferred temperature range is from about 120 ° C to about 150 ° C. For substrates that provide less stable products (eg, caffeic acid), a lower temperature range of about 100 ° C. to about 120 ° C. is used. For substrates that provide more stable products, such as 3,5-dimethyl-4-hydroxycinnamic acid, a higher temperature range of about 150 ° C. to about 200 ° C. can be used.

The reaction may be carried out at atmospheric pressure to pressures of about 1000 psig (6895 kPa) in addition to about 500 psig (3447 kPa). The pressure can be adjusted using an inert gas such as nitrogen. For reactions at elevated pressures, any conventional pressure reactor can be used, non-limiting examples of which are shaker vessels, rocker vessels, and stirred autoclaves.

There is no limit to the reaction time, but most reactions will be carried out in less than 4 hours, with reaction times of about 45 minutes to about 180 minutes being typical.

Acetylation of Hydroxystyrene

In one embodiment, the decarboxylated phenolic product is converted to an acetylated derivative by adding an acetylating agent directly to the reaction mixture after the decarboxylation reaction is completed. Typically the acetylating agent is added in excess when a concentration of at least 1 molar equivalent relative to the substrate is desired. Non-limiting examples of suitable acetylating agents include acetic anhydride, acetyl chloride and acetic acid. In one embodiment, the acetylating agent is acetic anhydride.

The acetylation reaction may be carried out at high yield in a temperature range of about 25 ° C. to about 150 ° C., in addition to the range of about 100 ° C. to about 140 ° C. at atmospheric pressure to about 1000 psig (6895 kPa). Those skilled in the art will appreciate that temperatures must be used in which both the substrate and the catalyst are soluble. The simplest method is to add the acetylating agent immediately after the end of the decarboxylation step and to carry out acetylation at the same temperature as the decarboxylation reaction.

Isolation and Purification of Decarboxylation and Acetylation Products

After the reaction is finished, the decarboxylation product or acetylation product can be isolated using any suitable method known in the art. For example, the reaction mixture can be poured onto ice water and extracted into an organic solvent such as ethyl acetate or diethyl ether. The product can then be recovered by removing the solvent using evaporation at reduced pressure. In one embodiment, the product yield of the hydroxystyrene product is at least 63% of the theoretical yield. In other embodiments, the yield of acetylation product is at least 63% of theoretical yield.

The decarboxylation product or acetylated derivatives thereof can be further purified using recrystallization, vacuum distillation, flash distillation, or chromatography techniques well known in the art.

The resulting hydroxystyrenes or acetylated derivatives thereof can then be used as resins, elastomers, adhesives, coatings, automotive finishes, monomers for the preparation of inks, and additives of elastomers and resin blends.

The invention is further defined in the following examples. It should be understood that these examples illustrate preferred embodiments of the invention but are provided for illustration only. From the foregoing discussion and these examples, those skilled in the art can make various changes and modifications to identify essential features of the present invention and to adapt the present invention to various uses and conditions without departing from the spirit and scope of the present invention.

The abbreviations used are as follows: "min" means minutes, "h" means hours, "sec" means seconds, "ml" means milliliters, "ℓ" means Liter means "μl" means microliter, "μm" means micrometer, "mol" means mole, "mmol" means millimolar and "g" means gram "Mg" stands for milligrams, "ppm" stands for parts per million, "M" stands for molar concentration, " m " stands for molar concentration, "eq" stands for equivalent , "v / v" stands for volume ratio, "㎩" stands for Pascal, "MPa" stands for millipascal, "psig" stands for pounds / inch ² gauge, "MHz" is megahertz "TLC" stands for thin layer chromatography, "HPLC" stands for high performance liquid chromatography, "LC-MS" stands for liquid chromatography-mass spectrometer, and "NMR" stands for nuclear magnetic resonance. Means spectrometer, "DMF" means N, N-dimethylfo Amide, "DMAc" means N, N-dimethylacetamide, "NMP" means 1-methyl-2-pyrrolidinone, "nd" means not determined, ", "Kilopascal", "rpm" means revolutions per minute, "UV" means ultraviolet light.

General way:

reagent:

Para-hydroxycinnamic acid was obtained from Aldrich (Milwaukee, WI) or TCI America (Portland, Oregon, USA) unless otherwise indicated; 3,4-dihydroxycinnamic acid was obtained from Aldrich. All solvents were reagent grade and obtained from Aldrich. Base catalysts used were obtained from Aldrich or EM Sciences, Gibbstown, NJ. Polymerization inhibitor ProStop 5415 was obtained from Ciba Specialty Chemicals, Terrytown, NY.

Analysis method:

TLC method:

TLC was performed using silica gel 60F ₂₅₄ (EM Science) as a solid support. A 1: 1 mixture of ethyl acetate and hexane was used as the mobile phase for the analysis of pHCA, and a 1: 4 mixture of ethyl acetate and hexane was used as the mobile phase for the analysis of pHS. Samples were compared to real samples of pHCA and pHS. The TLC plate was observed using ultraviolet rays at 254 nm or the like.

HPLC Method:

Method 1 : Agilent 1100 HPLC system (Agilent Technologies, Wilmington, Delaware) was run on a reversed-phase Zorbax SB-C8 column (4.6 mm x 150 mm, 3.5 μm, Mac-Mod Analytical Inc., Wepford, Pa., USA. HPLC separation was achieved using a gradient mixing two solvents: solvent A, 0.1% trifluoroacetic acid in HPLC grade water and solvent B, 0.1% trifluoroacetic acid in acetonitrile. Mobile phase flow rate was 1.0 ml / min. The solvent gradient used is shown in Table 1 below. A temperature of 45 ° C. and 5 μl sample injection volume were used.

Solvent Gradient Used in HPCL Method 1 Minutes Solvent A Solvent B 0 95% 5% 8 20% 80% 10 20% 80% 11 95% 5%

After each run, the column was re-equilibrated for 5 minutes with a solvent mixture of A 95% and B 5%.

A standard calibration curve was made using a standard pHS solution. PHS for standards were prepared from acetoxystyrene using a method similar to that described by Leuteritz et al., Polymer Preprints 43 (2): 283-284 (2002). A calibration curve was used to determine the weight percent of pHCA and pHS of each sample from the HPLC peak area. With this information and the total weight of the reaction mixture at the sampling time, the conversion of pHCA and yield of pHS were calculated.

Method 2: An Agilent 1100 HPLC system was used with a reversed phase Zorbax SB-C18 column (4.6 mm x 150 mm, 3.5 μm, supplied by Agilent Technologies). HPLC separation was achieved using a gradient mixing two solvents: solvent A, 0.1% trifluoroacetic acid in HPLC grade water and solvent B, 0.1% trifluoroacetic acid in acetonitrile. Mobile phase flow rate was 1.25 ml / min. The solvent gradient used is shown in Table 2 below. A temperature of 40 ° C. and 1 μl sample injection volume was used.

Solvent Gradient Used for HPCL Method 2 Minutes Solvent A Solvent B 0 90% 10% 35 35% 65% 35.1 90% 10% 45 90% 10%

A suitable calibration curve was made and used to determine the weight percent of pHCA and pHS of each sample from the HPLC peak area as described above. With this information and the total weight of the reaction mixture at each time (including correction for the loss of CO ₂ upon decarboxylation), the weight and moles of pHCA and pHS over time were calculated.

Method 3: The Agilent 1100 HPLC system was used with a reversed phase Zorbax SB-C18 column (2.1 mm x 50 mm, supplied by Agilent Technologies). HPLC separation was achieved using a gradient of two solvents: solvent A, HPLC grade water + 0.05% trifluoroacetic acid, and solvent B, HPLC grade acetonitrile + 0.05% trifluoroacetic acid. The gradient was A 95% to A 0% over 4.5 minutes, stopped for 0.5 minutes, and returned to the initial conditions. Mobile phase flow rate was 0.8 ml / min. A temperature of 60 ° C. and 1 μl sample injection volume was used.

Method 4: An Agilent 1100 HPLC system was used with a reversed phase Zorbax SB-C18 column (4.6 mm x 150 mm, 3.5 μm, supplied by Agilent Technologies). HPLC separation was achieved using a gradient mixing two solvents: solvent A, 0.1% trifluoroacetic acid in HPLC grade water and solvent B, 0.1% trifluoroacetic acid in acetonitrile. Mobile phase flow rate was 1.0 ml / min. The solvent gradient used is shown in Table 3 below. A temperature of 40 ° C. and 1 μl sample injection volume was used.

Solvent Gradient Used in HPCL Method 4 Minutes Solvent A Solvent B 0 95% 5% 10 100% 0% 12 100% 0% 12.5 95% 5%

Suitable calibration curves were made as described above and used to determine the weight percent of pHCA and pHS of each sample from the HPLC peak area. With this information and the total weight of the reaction mixture at each time (including correction for the loss of CO ₂ upon decarboxylation), the weight and moles of pHCA and pHS over time were calculated.

^One H NMR:

Proton NMR data was obtained using a Bruker DRX (Bruker NMR, Billerica, Mass.) At 500 MHz.

LS-MS method:

Hewlett Packard LC / MSD Series 1100 instrument (Agilent Technologies, Wilmington, Delaware) was used for LC-MS analysis. Zorbax Eclipse XDB-C18 column (2.1 mm x 50 mm, Mac-mode Analytical Incorporated), two solvents: Solvent A, 0.05% trifluoroacetic acid and solvent B in water, aceto A solvent gradient consisting of 0.05% trifluoroacetic acid in nitrile was used for LC separation. The gradient returned from solvent A 95% to solvent A 0% over 4.5 minutes, solvent A 0% over 2.5 minutes, followed by solvent A 95%, and the flow rate was 0.8 / min. LC separation was performed by detecting at 220 nm at a temperature of 60 ° C.

Examples 1 to 13

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid

The purpose of these examples was to prepare 4-hydroxystyrene by high temperature decarboxylation of para-hydroxycinnamic acid under base catalyst using various mixtures of base catalyst and solvent in the presence of a polymerization inhibitor.

In these examples, para-hydroxycinnamic acid was used as the phenolic substrate at a concentration of 1 M in 1 ml of solvent. Base catalysts and solvents used in these examples are shown in Table 4 below. Base catalyst was used at a concentration of 3 mol% relative to the phenolic substrate. Polymerization inhibitor ProStop 5415 was used at a concentration of 1000 ppm in all reactions. These reactions were performed in a mini-block pressure reactor customized at 150 ° C. under 500 psig of nitrogen. The mini-block pressure reactor is a stainless steel reactor designed to receive eight 1 to 2 ml glass vials each containing a separate reaction mixture. The maximum rating of the reactor is 260 ° C at 1250 psig. After adding the glass vial containing the reaction mixture to the reactor, it was sealed, pressurized with nitrogen and heated in a block heater.

After 1 hour of reaction time, the reactor was depressurized and samples of the reaction mixture were analyzed by HPLC using Method 1 as described above. The amount of phenolic substrate and the yield of 4-hydroxystyrene consumed in the reaction (pHCA conversion) for each example are summarized in Table 4 below.

Base catalyst and solvent mixtures used in Examples 1-13 Example menstruum Base catalyst pHCA conversion,% Product yield,% One DMF Potassium acetate 99.8 88.8 2 DMAc Sodium methoxide 90.7 81.5 3 2-heptanone Potassium carbonate 64.2 68.2 4 Toluene / DMF (80/20, v / v) Magnesium oxide 98.9 55.0 5 γ-butyrolactone Potassium hydroxide 99.9 78.7 6 DMF Potassium hydroxide 99.7 95.2 7 Diglyme Potassium acetate 7.2 30.8 8 2-heptanone Sodium methoxide -7.7 9.6 9 Toluene / DMF Potassium carbonate 67.1 49.0 10 γ-butyrolactone Magnesium oxide 3.7 20.4 11 DMF Potassium carbonate 99.8 84.9 12 DMF Potassium acetate 99.0 106.9 13 NMP Potassium acetate 99.7 107.2

As can be seen from the results in Table 4, the best product yields were obtained for DMF, DMAc and NMP using potassium acetate, sodium methoxide, potassium hydroxide and potassium carbonate as base catalysts.

Example 14

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid using potassium acetate as base catalyst in DMF

The purpose of this example was to provide 4-by-high temperature decarboxylation of para-hydroxycinnamic acid under base catalyst using potassium acetate (10 mol%) as base catalyst in DMF in the presence of a polymerization inhibitor (Prostop 5415 1000 ppm). It was to prepare hydroxystyrene. In a three-neck round bottom flask, pHCA (5 g, 30.458 mmol, 1 eq), 30 mL DMF (to make 1 M pHCA solution), 1000 ppm prostop 5415 (5 mg), and potassium acetate (0.3 g, 10 mol%) were added. Added. The reaction was carried out under nitrogen using a reflux condenser while stirring. The reaction was heated to 150 ° C. using an oil bath and temperature controller (with overheat protection). Potassium acetate is insoluble at room temperature, but when heat is applied, it dissolves into a pale yellow solution. As described above, the reaction was monitored by TLC. After 1.5 hours at 150 ° C., the reaction was complete as determined by TLC. The heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then poured onto 100 mL of ice water saturated with sodium chloride and extracted twice with ethyl acetate (75 mL volume). The combined organic layers from the two extracts were washed with 100 ml of 2% NaHCO ₃ solution followed by 100 ml of water. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated by evaporation on a rotary evaporator. The residue was stored at -20 ° C overnight. The residue was then further dried under reduced pressure (10 cc) to give 3.44 g of a pale yellow / tan brown solid (94% of theoretical yield). The product was analyzed using ¹ H NMR.

¹ H NMR (500 M㎐, MeOD): δ (ppm) 7.998 (0.04 H, s), 7.275 (2H, ABq, J = 9.0 Hz), 6.758 (2H, ABq, J = 9.1 Hz), 6.65 (1H, dd, J = 17.6 and 11.0 Hz), 5.575 (1H, dd, J = 17.6 and 1.1 Hz), 5.048 (1H, dd, J = 11.0 and 1.4 Hz).

Example 15

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid using potassium acetate as base catalyst in DMF

The purpose of this example was to find the result of 4- by high temperature decarboxylation of para-hydroxycinnamic acid under base catalyst using potassium acetate (3 mol%) as base catalyst in DMF in the presence of a polymerization inhibitor (Prostop 5415 100 ppm). It was to prepare hydroxystyrene.

The reaction was carried out as described in Example 14 except using 100 ppm prostop 5415 (0.5 mg, added as 250 μl of a 2 mg / ml solution in DMF) and 3 mol% potassium acetate (90 mg). The product was isolated as described in Example 14 to give 3.82 g of a golden yellow semisolid (104.6% of theoretical yield). The product was analyzed using ¹ H NMR.

¹ H NMR (500 M㎐, MeOD): δ (ppm) 7.993 (0.22 H, s), 7.275 (2H, ABq, J = 8.6 Hz), 6.76 (2H, ABq, J = 8.6 Hz), 6.65 (1H, dd, J = 17.6 and 10.9 Hz), 5.577 (1H, dd, J = 17.6 and 1.4 Hz), 5.048 (1H, dd, J = 11.0 and 0.7 Hz).

Example 16

Preparation of 4-acetoxystyrene by acetylation after decarboxylation of para-hydroxycinnamic acid in a single reactor

The purpose of this example is to prepare 4-acetoxystyrene by high temperature decarboxylation of para-hydroxycinnamic acid under a base catalyst in a two-step, single reactor, followed by acetylation of the resulting 4-hydroxystyrene with acetic anhydride. It was. As a polymerization inhibitor, 100 ppm of prostop 5415 was used.

In a three-neck round bottom flask, pHCA (5 g, 30.458 mmol, 1 eq), 30 mL DMF (to make 1 M in pHCA solution), 100 ppm prostop 5415 (0.5 mg, added as 250 μL of 2 mg / mL solution in DMF) And potassium acetate (30 mg, 1 mol%) were added. The reaction was carried out under nitrogen using a reflux condenser while stirring. The reaction was heated to 150 ° C. using an oil bath and temperature controller (with overheat protection). Potassium acetate is insoluble at room temperature, but when heat is applied, it dissolves into a pale yellow solution. As described above, the reaction was monitored by TLC. After 2 hours at 150 ° C., the reaction appeared to be complete as determined by TLC. The reaction temperature was then dropped to 140 ° C. and acetic anhydride (4.32 mL, 45.687 mmol, 1.5 eq) was added dropwise to the reaction mixture, which was kept at 140 ° C. The color of the reaction mixture became bright. The reaction was complete after 0.75 h as determined using TLC. The heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was stored at -20 ° C overnight.

4-acetoxystyrene was isolated using the procedure described for isolation of 4-hydroxystyrene in Example 14 to give 5.39 g of a pale yellow semisolid (109% of theoretical yield). The product was analyzed using ¹ H NMR. It can be seen that the product contains some impurities from the point at which the yield is obtained higher than the theoretical yield and the characteristics of the product (ie, light yellow semisolid).

¹ H NMR (500 M㎐, CDCl ₃ ): δ (ppm) 7.40 (2H, ABq, J = 8.6 Hz), 7.045 (2H, ABq, J = 8.5 Hz), 6.693 (1H, dd, J = 17.5 and 11.0 Iii), 5.693 (1H, dd, J = 17.6 and 0.7 Hz), 5.234 (1H, dd, J = 10.9 and 0.8 Hz), 2.29 (2.64H, s).

Example 17

Preparation of 4-acetoxystyrene by acetylation after decarboxylation of para-hydroxycinnamic acid in a single reactor

The purpose of this example is to prepare 4-acetoxystyrene by high temperature decarboxylation of para-hydroxycinnamic acid under a base catalyst in a two-step, single reactor, followed by acetylation of the resulting 4-hydroxystyrene with acetic anhydride. It was. As a polymerization inhibitor, ProStop 5415 at a concentration of 1000 ppm was used.

Decarboxylation and acetylation reactions were carried out as described in Example 16 except using 1000 ppm of Prostop 5415 (5 mg) as polymerization inhibitor. The 4-acetoxystyrene product was isolated as described in Example 16 to yield 4.82 g of yellow oil (97.5% of theoretical yield). The product was analyzed using ¹ H NMR.

¹ H NMR (500 MPa, CDCl ₃ ): δ (ppm) 7.40 (2H, ABq, J = 8.4 Hz), 7.04 (2H, ABq, J = 8.5 Hz), 6.695 (1H, dd, J = 17.6 and 11.0 Iii), 5.695 (1H, d, J = 17.6 Hz), 5.235 (1H, d, J = 10.9 Hz), 2.29 (3H, s).

Example 18

Preparation of 3,4-diacetoxystyrene by acetylation after decarboxylation of 3,4-dihydroxycinnamic acid in a single reactor

The purpose of this example was to perform a high temperature decarboxylation of 3,4-dihydroxycinnamic acid under a base catalyst in a two-step, single reactor, and then to acetylate the resulting 3,4-hydroxystyrene with acetic anhydride, 4-diacetoxystyrene was prepared. As a polymerization inhibitor, ProStop 5415 at a concentration of 1000 ppm was used.

To a 1 L three-necked round bottom flask under mechanical mixing, 0.5 g of prostop 5415, 2.725 g of potassium acetate and 50.0 g of 3,4-dihydroxycinnamic acid were added. Then DMF (280 mL) was added to give a dark brown solution. The reaction mixture was heated to 100 ° C. using a water condenser. Samples were taken and analyzed using LC-MS to periodically check the progress of the reaction. After 4.5 hours, it was determined that 96.6% of the theoretical yield of 3,4-dihydroxystyrene intermediate was formed. The reaction was further heated for 45 minutes. Then, 132.7 ml of acetic anhydride was added over 15 minutes to the reaction mixture. The reaction was allowed to proceed for an additional 15 minutes, after which the reaction mixture was cooled to room temperature over 45 minutes.

The reaction mixture was poured into a beaker containing about 400 mL of water and then extracted three times with diethyl ether. The combined organic layers from these extracts were extracted three times with 2% NaHCO ₃ solution and then extracted once with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated by evaporation at 40 ° C. on a rotary evaporator for 1 hour to give 95.2 g of a dark brown oil. The oil was stored overnight at -20 ° C. The oil was then distilled using vacuum distillation at a pressure of 1.3 MPa at 105-107 ° C. to give 45.11 g of a colorless viscous liquid (79.1% of theoretical yield). The 3,4-diacetoxystyrene product was analyzed by ¹ H NMR and LC-MS and found to be 99.7% pure.

¹ H NMR (500 M㎐, CDCl ₃ ): δ (ppm) 7.26 (1H, dd, J = 8 and 2 Hz), 7.22 (1H, J = 2 Hz), 7.13 (1H, d, J = 9 Hz) , 6.65 (1H, dd, J = 18 and 11 Hz), 5.68 (1H, dd, J = 18 and 1 Hz), 5.26 (1H, d, J = 11 Hz), 2.27 (3H, s), 2.26 ( 3H, s).

Example 19

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid in the absence of polymerization inhibitor

The purpose of this example was to provide high temperature decarboxylation of concentrated para-hydroxycinnamic acid (4 m or 2.54 M) under a base catalyst using potassium acetate (1 mol%) as base catalyst in DMAc in the absence of a polymerization inhibitor. To produce 4-hydroxystyrene.

To three neck round bottom flasks, pHCA (20.035 g, 122.05 mmol) and 30.034 g DMAc (to make a 2.54 M pHCA solution) were added. The reaction flask was immersed in a preheated oil bath at 150 ° C. and the solution reached temperature after about 15 minutes. Potassium acetate (0.124 g, 1 mol%) was added all at once. The reaction was carried out under nitrogen for 8 hours using a reflux condenser with stirring. Samples were taken immediately before addition of potassium acetate (time 0) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours and were subjected to pHCA and pHS using Method 2 as described above. Analyze by HPLC. The results provided in Table 5 below show that the conversion of pHCA was essentially complete after 4 hours, at which time the yield of pHS was 87.1%.

HPLC determination of pHCA and pHS at various time zones Reaction time (minutes) pHCA (mmol) pHS (mmol) 0 116.9 4.8 15 97.0 23.4 30 83.0 42.5 60 50.6 66.1 120 17.0 96.0 240 0.6 106.3 360 0 103.4 480 0 96.6

Examples 20-22

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid using different levels of potassium acetate as base catalyst in DMAc

The purpose of these examples was to prepare 4-hydroxystyrene by high temperature decarboxylation of concentrated para-hydroxycinnamic acid (2.5M) in DMAc under base catalyst using different levels of potassium acetate as base catalyst. .

In these examples, the same procedure as described in Example 19 was used except for the amount of potassium acetate added to the reaction solution. To three round bottom flasks, pHCA (19.11 g, 116.4 mmol) and 30.0 g DMAc (to make a 2.5 M pHCA solution) were added. The reaction flask was immersed in a preheated oil bath at 135 ° C. and the solution reached temperature after about 15 minutes. Potassium acetate (the amount given in Table 6 below) was added all at once. The reaction was carried out under nitrogen for 4-6 hours using a reflux condenser with stirring. Samples were taken immediately before addition of potassium acetate (time 0) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours and were subjected to HPLC for pHCA and pHS using Method 2 as described above. Analyzed by. For Comparative Example 22 without potassium acetate, time 0 was considered to be the time when the temperature of the reaction solution was equilibrated to 135 ° C.

HPLC determination of pHCA and pHS at various times of the reaction with different levels of potassium acetate Example 20 Example 21 Example 22 Potassium acetate 1.146 g (10 mol%) 2.860g ^* (25mol%) 0 (0 mol%) Response time (minutes) pHCA (mmol) pHS (mmol) pHCA (mmol) pHS (mmol) pHCA (mmol) pHS (mmol) 0 113.3 0 114.3 0 114.2 0 15 87.0 26.7 67.6 46.4 114.7 1.5 30 63.4 50.0 35.8 79.2 112.1 3.7 60 28.5 84.7 8.3 105.2 105.0 8.8 120 4.7 107.9 0.5 102.1 95.9 18.3 240 0 102.1 0 88.7 76.9 34.1 360 0 89.5 0 71.9 nd nd ^* Solid identified as potassium acetate in Example 21 precipitated between 60 and 120 minutes

As can be seen from the results provided in Table 6, Example 20 had a yield of 92.7% of pHS after 2 hours, and Example 21 had a yield of 90.4% of pHS after 1 hour. Both examples show complete conversion of pHCA within 4 hours. In contrast, Comparative Example 22, run at the same conditions except for the absence of a base catalyst, had a yield of pHS of only 29.3% and a pHCA conversion of only 33.9% even after 4 hours.

Example 23

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid using potassium acetate as base catalyst in di (propylene glycol) methyl ether

The purpose of this example was to use potassium acetate (10 mol%) as the base catalyst in the protic solvent di (propylene glycol) methyl ether (Dauanol DPM; Dow Chemical Co., Midland, Mich.). 4-hydroxystyrene was prepared by high temperature decarboxylation of para-hydroxycinnamic acid (2.5 m ) under a base catalyst using.

To a three neck round bottom flask was added pHCA (12.318 g, 75.04 mmol) and 30.052 g di (propylene glycol) methyl ether (to make a 2.5 m pHCA solution). The reaction flask was immersed in a preheated oil bath at 135 ° C. and the solution reached temperature after about 15 minutes. pHCA dissolved completely when the solution was heated. Potassium acetate (0.739 g, 10 mol%) was added all at once. The reaction was carried out under nitrogen for 8 hours using a reflux condenser with stirring. The addition of base formed a solid, increased up to about 3 hours and then completely dissolved again for about 5 hours. Samples were taken immediately before addition of potassium acetate (time 0) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours and were subjected to pHCA and pHS using Method 2 as described above. Analyze by HPLC. The results (see Table 7 below) showed that after 2h the yield of pHS was 67.3%. Additional reaction time reduced yield. This result demonstrates that protic solvents can be used for high temperature decarboxylation reactions.

TABLE 7

HPLC determination of pHCA and pHS at various time points of the reaction using di (propylene glycol) methyl ether as solvent

Reaction time (minutes) pHCA (mmol) pHS (mmol) 0 73.5 0 15 60.6 12.0 30 46.2 21.9 60 31.6 38.0 120 12.3 50.5 240 2.2 45.9 360 0 17.7 480 0 7.2

Example 24

Preparation of 4-hydroxystyrene by decarboxylation of para-hydroxycinnamic acid using potassium acetate as base catalyst in DMF using microwave heating

The purpose of this example was to prepare 4-hydroxystyrene by high temperature decarboxylation of para-hydroxycinnamic acid under base catalyst using potassium acetate as base catalyst in DMF in the presence of a polymerization inhibitor (Prostop 5415 1000 ppm). It was. This example uses microwave heating, resulting in higher temperatures and shorter reaction times.

In a 5 ml Biotage test tube vial with a stir bar (Biotage AB, Charlottesville, VA), pHCA (1.002 g, 6.104 (mol)), 3 mL DMF (pHCA approx. 1000 ppm prostop 5415 (1 mg) and potassium acetate (63 mg, 10 mol%) were added to make a 2M solution, nitrogen was blown into the test tube, and the test tube was quickly crimp-capping. The prepared vial was placed in a Biotage Initiator 60 microwave reactor (Biotage AB) At a medium power of 150 watts, the sample temperature reached 190 ° C. after a heating time of 70 to 80 seconds. It was held for a minute, but also briefly exceeded about 200 ° C. The pressure of the sample reached 16 bar (1600 kPa) during the run As described above, qualitative HPLC analysis of the exposed sample using Method 3 As a result, the pHCA is completely No pHCA was detected over the UV spectral range of 220 to 312 nm, peaks due to pHS were 73.3 area% at 220 nm and 100 area% at 312 nm, indicating good selectivity of this reaction. .

Example 25

Preparation of 4-acetoxystyrene by acetylation after decarboxylation of para-hydroxycinnamic acid in a single reactor

The purpose of this example was to prepare 4-acetoxystyrene using acetylation of the resulting 4-hydroxystyrene after high temperature decarboxylation of para-hydroxycinnamic acid under a base catalyst in a two step, single reactor. . No inhibitor was used in this example and the starting pHCA was derived from the biotransformation of tyrosine, with a purity of about 85%.

Starting pHCA material was produced using a method similar to that described in US Pat. Appl. No. 60/563633 to Ben Bassat et al., Co-pending and generally assigned. This method involves a two step process for producing pHCA from glucose. In the method used in this example, two steps were performed as two separate steps. In the first step, tyrosine was produced by fermentation from glucose using tyrosine overproducing strains. Tyrosine was isolated from fermentation broth using low speed centrifugation. The resulting precipitate was suspended in water and separated again using low speed centrifugation. The purity of tyrosine was determined to be 90-98% using HPLC. Next, in the second step, tyrosine was converted to pHCA at pH 10.0 using a host cell comprising an enzyme having tyrosine ammonia lyase activity. pHCA accumulated in the fermentation medium. About 7.5 kg of pHCA-containing culture was centrifuged and the solid was discarded. The supernatant was transferred to a 14 L Braun fermenter BioStat C.B. (Braun Biotech International, Melesunden, Germany) operating at 35 ° C. and 600 rpm. The pH of the solution was adjusted to 9.0 using sulfuric acid. Next, 0.254 mL of Alcalase (Novozymes, Bagsvaerd 2880 Krogshoei Bay, Denmark) and Bromelain (Fisher Scientific, Pittsburgh, Pa.) 0.134 g of Acros Organics obtained from Fisher Scientific) was added. After incubation for 1 hour, the solution was titrated to pH 2.2 to precipitate pHCA. The resulting suspension was centrifuged and the pHCA recovered as 600 g of wet cake with about 40% solids. In addition to pHCA, the wet cake also contained protein, cell debris, salt, about 0.21% cinnamic acid and 0.1% tyrosine. The wet cake was dried at 80 ° C. for 12 hours under nitrogen to give a dried cake containing about 85% pHCA.

Biogenerated pHCA was purified by extraction as follows. To a 1 L kettle was added 163.88 g of dried cake containing pHCA. 350 ml of DMAc was added to the kettle and the contents were heated to 60 ° C. for 2 hours with mechanical stirring. The mixture was filtered through Whatmann No. 4 paper and the insolubles were washed with 50 ml of DMAc.

The washings from the filtrate and extraction were combined and added to a 1 L four-necked flask equipped with an overhead stirrer, reflux condenser, addition funnel and temperature probe. The reaction mixture was analyzed by HPLC method 4 described above and found to contain 122.98 g of pHCA. To the mixture was added 8.8 g (10 mol%) of potassium acetate and the mixture was heated to 135 ° C. for 3 hours under nitrogen. 91.77 g of acetic anhydride, 84.97 ml were added over 8 minutes via an addition funnel. The reaction mixture was stirred for an additional 0.5 hour and then cooled to room temperature. The solvent was removed in a rotary evaporator at 2.8 Torr (0.37 kPa) and 65 ° C. The solid was separated from the mixture and filtered using Whatman 4 paper. The solid was washed with 30 mL DMAc. The filtrates were combined and further concentrated in a rotary evaporator at 2.5 Torr (0.33 kPa) and 65 ° C. until no more solvent was distilled off.

The crude pAS 157.5 g thus obtained was stabilized by the addition of 200 ppm of methyl hydroquinone, and the surface area was 0.04 m 3 from a thin film evaporator (UIC Inc. Distillation on phosphorus model KDL-4). Distillation was performed at 2.00 mm Hg (0.267 kPa) with a feed rate of 2.0 ml / min and a stirring speed of 300 rpm. The inlet temperature was 71 ° C., the outlet temperature was 70 ° C. and the cold rod was kept at 10 ° C. pAS was overhead with 112.9 g of remaining DMAc and the light fraction (27.6 g) contained pAS and its oligomers formed during the final distillation. DMAc was removed from the overhead fractions by distillation at 0.02 Torr (2.7 kPa) and 45 ° C. to give 86.2 g (71% yield) of pAS.

Claims (39)

a) providing a phenolic substrate of formula (I); b) i) a nonamine base catalyst; And ii) at least one polar organic solvent or a mixture of polar organic solvents; And c) contacting the phenolic substrate with the reaction mixture of step b) for at least about 100 ° C. for a time sufficient to decarboxylate the phenolic substrate of step a) to the decarboxylation product. A method of decarboxylating a phenolic substrate, comprising: producing a vinyl monomer. <Formula I>

Wherein R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ; R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl; R ₆ and R ₇ are H, Halo or cyano, provided that at least one of R ₁ , R ₃ or R ₅ is OH, and both R ₂ and R ₄ are not t-butyl at the same time) The method of claim 1, wherein R ₃ is OH. The phenolic substrate according to claim 1, wherein the phenolic substrate is selected from the group consisting of 4-hydroxycinnamic acid, ferulic acid, cinafinic acid, caffeic acid, 2-hydroxycinnamic acid and α-cyano-4-hydroxycinnamic acid. Way. The process of claim 1 wherein the decarboxylation product is 4-hydroxystyrene, 3-methoxy-4-hydroxystyrene, 3,5-dimethoxy-4-hydroxystyrene, 3,4-dihydroxystyrene , 2-hydroxystyrene and α-cyano-4-hydroxystyrene. The process of claim 1 wherein the nonamine base catalyst comprises potassium. The process of claim 1 wherein the nonamine base catalyst is an acetate salt. The process of claim 1 wherein the nonamine base catalyst is a metal salt. 8. The process of claim 7, wherein the non-amine base catalyst is selected from the group consisting of potassium acetate, potassium carbonate, potassium hydroxide, sodium acetate, sodium carbonate, sodium hydroxide and magnesium oxide. The process of claim 1 wherein the non-amine base catalyst is at a concentration of about 1 mol% to about 30 mol% with respect to the substrate in the reaction mixture. The method of claim 1, wherein the polar organic solvent is aprotic. The process according to claim 10, wherein the aprotic, polar organic solvent is N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, And hexamethylphosphorus triamide. The method of claim 1 wherein the polar organic solvent is protic. 13. The process of claim 12 wherein the protic solvent is di (propylene glycol) methyl ether (Dowanol ™ DPM), di (ethylene glycol) methyl ether, 2-butoxyethanol, ethylene glycol, 2-methoxyethanol , Propylene glycol methyl ether, n-hexanol and n-butanol. The method of claim 1 wherein the reaction mixture optionally comprises a polymerization inhibitor. 15. The polymerization inhibitor according to claim 14, wherein the polymerization inhibitor is hydroquinone, hydroquinone monomethyl ether, 4-tert-butyl catechol, phenothiazine, N-oxyl (nitroxide) inhibitor, 4-hydroxy-TEMPO (4-hydroxy- 2,2,6,6-tetramethylpiperidin-1-yloxy, CAS # 2226-96-2) and Uvinul® 4040 P (1,6-hexamethylene-bis (N- Formyl-N- (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) amine). The process of claim 15, wherein the polymerization inhibitor is Prostab® 5415 (bis (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, CAS # 2516- 92-9). The process of claim 1 wherein the reaction mixture optionally comprises a polymerization retardant. 18. The process of claim 17, wherein the polymerization retardant is selected from the group consisting of dinitro-ortho-cresol (DNOC) and dinitrobutylphenol (DNBP). The process of claim 1 wherein the yield of decarboxylation product is greater than 63%. The method of claim 1 wherein the temperature is from about 100 ° C. to about 200 ° C. 3. a) providing a phenolic substrate of formula (I); b) i) a nonamine base catalyst; And ii) at least one aprotic, polar organic solvent or a mixture of aprotic, polar organic solvents; c) contacting the phenolic substrate with the reaction mixture of step b) for at least about 100 ° C. for a time sufficient to decarboxylate the phenolic substrate of step a) to form a decarboxylation product; And d) contacting the decarboxylation product of step c) with an acetylating agent to produce an acetylation product of Formula II Sequentially comprising a method of synthesizing an acetylated product from a phenolic substrate. <Formula I>

Wherein R ₁ , R ₃ and R ₅ are H, OH or OCH ₃ ; R ₂ and R ₄ are H, OH, OCH ₃ , or linear or branched alkyl; R ₆ and R ₇ are H, Halo or cyano, provided that at least one of R ₁ , R _3, or R ₅ is OH; <Formula II>

Wherein R ₈ , R ₁₀ and R ₁₂ are H, O (C═O) CH ₃ or OCH ₃ ; R ₉ and R ₁₁ are H, OH, OCH ₃ , or linear or branched alkyl; R ₁₃ and R ₁₄ are H, halo or cyano; provided that at least one of R ₈ , R ₁₀ or R ₁₂ is O (C═O) CH ₃ ; The method of claim 21 wherein the acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride and acetic acid. The method of claim 21 wherein the acetylating agent is acetic anhydride. The method of claim 21, wherein the acetylation product is 4-acetoxystyrene, 3-methoxy-4-acetoxystyrene, 3,5-dimethoxy-4-acetoxystyrene, 3,4-diacetoxystyrene, 2 -Acetoxystyrene and α-cyano-4-acetoxystyrene. The method of claim 21, wherein the acetylated product is 4-acetoxystyrene. The method of claim 21, wherein the phenolic substrate is selected from the group consisting of 4-hydroxycinnamic acid, ferulic acid, cinafinic acid, caffeic acid, 2-hydroxycinnamic acid and α-cyano-4-hydroxycinnamic acid Way. The method of claim 21, wherein the nonamine base catalyst comprises potassium. The method of claim 21, wherein the nonamine base catalyst is an acetate salt. The method of claim 21, wherein the nonamine base catalyst is a metal salt. 29. The method of claim 28, wherein the non-amine base catalyst is selected from the group consisting of potassium acetate, potassium carbonate, potassium hydroxide, sodium acetate, sodium carbonate, sodium hydroxide and magnesium oxide. The method of claim 21, wherein the nonamine base catalyst is at a concentration of about 1 mole% to about 30 mole% relative to the substrate in the reaction mixture. The process of claim 21 wherein the aprotic, polar organic solvent is N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide and Hexamethylphosphorus triamide. The method of claim 21, wherein the reaction mixture optionally comprises a polymerization inhibitor. 34. The polymerization inhibitor of claim 33 wherein the polymerization inhibitor is hydroquinone, hydroquinone monomethyl ether, 4-tert-butyl catechol, phenothiazine, N-oxyl (nitroxide) inhibitor, 4-hydroxy-TEMPO (4-hydroxy- 2,2,6,6-tetramethylpiperidin-1-yloxy, CAS # 2226-96-2) and Uvinul® 4040 P (1,6-hexamethylene-bis (N- Formyl-N- (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) amine). The method of claim 34, wherein the polymerization inhibitor is Prostab® 5415 (bis (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, CAS # 2516- 92-9). The method of claim 21, wherein the reaction mixture optionally comprises a polymerization retardant. The method of claim 36, wherein the polymerization retardant is selected from the group consisting of dinitro-ortho-cresol (DNOC) and dinitrobutylphenol (DNBP). The method of claim 21, wherein the yield of acetylated product is greater than 63%. The method of claim 21, wherein the temperature of step c) is from about 100 ° C. to about 200 ° C. and the temperature of step d) is from room temperature to about 150 ° C. 23.