JP2003073419A - Method for producing implant polymer, method for separating material and method for detoxifying material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an implant polymer excellent in selective adsorption character to a material to be removed which can easily detoxify the material, a method for separating the material and a method for detoxifying a toxic substance. SOLUTION: A method for producing the implant polymer is characterized by copolymerizing a monomer represented by the formula 1 (X-S-S-Y) [wherein, X is an aromatic ring or triazine ring and Y is a group having a vinyl group] with a vinyl compound, reducing and separating a compound represented by the formula 2 (X-SH) [wherein, X has the above mentioned definition] from a copolymer. The method for separating the material is also provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an imprinted polymer, a method for separating a substance, and a method for detoxifying a substance. More specifically, it removes trace amounts of environmental hormones and toxic pesticides released into the environment. An object is to provide an imprint polymer that can be detoxified.

[0002]

BACKGROUND OF THE INVENTION Over the past many years, harmful chemicals,
For example, nonylphenol and bisphenol, which are suspected to be endocrine disrupters (exogenous endocrine disrupting chemicals), their derivatives and similar structural compounds, and many types of pesticides, are found in the environment such as the atmosphere, soil, lakes, river water, and groundwater. Released to the public, the removal of these substances has become a major social problem.

The influences of the above chemical substances on the human body and the ecosystem are unknown at this stage, but there is concern about chronic toxicity due to the food chain, and a method for removing these substances is required. As the removal method, there is an adsorption removal method using activated carbon which is often used in the process of sewage treatment and industrial wastewater treatment.

[0004] However, although activated carbon is easily available, since it does not adsorb only the above-mentioned target harmful substances, the removal efficiency of the harmful substances is very low,
Also, although it is possible to regenerate activated carbon for repeated use, desorption of the adsorbed material from activated carbon is difficult because activated carbon adsorbs organic compounds of relatively high molecular weight and multi-components when treated with water. Will be higher. Therefore, the activated carbon once used for the adsorption treatment is often discarded, but the treatment of a large amount of activated carbon is expensive and is not preferable in view of recent industrial waste. Therefore, in order to efficiently remove harmful chemical substances, it is desired to develop an adsorbent that selectively adsorbs target harmful substances and can be regenerated and repeatedly used.

On the other hand, the above-mentioned harmful substances are often present in the environment only at extremely low concentrations, and pretreatment is required for their analysis, concentration and removal. The solid-phase extraction method, which is often used as a pretreatment method, has no selectivity and has a drawback in that it takes time to examine optimum conditions suitable for concentrating and removing a substance to be removed. Even in this pretreatment, if the target substance to be removed has specificity, the time spent for the condition examination and the time required for the actual pretreatment can be shortened, and the pretreatment can be performed more easily. Efficiency can be improved.
Therefore, a template polymerization method (molecular imprinting method) for artificially synthesizing a polymer that specifically binds to a substance to be removed has been widely studied.

According to the template polymerization method, a polymer that specifically binds to a substance intended for concentration and removal can be freely synthesized, and is applied to artificial antibodies, catalysts, adsorbents, enzyme synthesis and the like. By utilizing the specific adsorption ability of the polymer for the target substance to be removed, it can be applied to removal of impurities from products, removal of harmful substances from environmental samples, concentration / separation as a pretreatment for analysis, etc. is there.

[0007]

However, the imprinted polymer obtained by the conventional template polymerization method has some drawbacks. For example, covalent bond or non-covalent bond interaction with the template molecule is used to identify the template molecule. Therefore, even if a compound having no functional group or a plurality of functional groups are present, if the configurations are too close, it is difficult to impart specificity to the template molecule (removal target substance). In particular, it has been generally difficult for an imprint polymer for a low molecular weight removal target substance to obtain high selectivity for the removal target substance.

Therefore, an object of the present invention is to provide an imprint polymer which is excellent in selective adsorption property for a target substance to be removed and which can easily render the target substance to be removed, a method for separating the substance and a method for detoxifying the harmful substance. It is to be.

[0009]

The above object can be achieved by the present invention described below. That is, the present invention, as the first invention, is a monomer represented by the general formula 1 (X-S-S-Y) (X represents an aromatic ring or a triazine ring, and Y represents a group having a vinyl group). And a vinyl compound are copolymerized and then reduced to give a compound of the general formula 2 (X-S
H) (wherein X has the same meaning as described above) is separated, and a method for producing an imprinted polymer, and general formula 2 (X-SH) (where X has the same meaning as described above) Separation of a substance characterized by adsorbing the compound represented by the general formula 2 or a compound having a similar structure to a liquid containing a compound represented by the formula or a compound having a similar structure, and adsorbing the compound represented by the general formula 2 or a compound having a similar structure. Provide a way.

As a second invention, the present invention provides a method for producing an imprint polymer in which the mercapto group in the imprint polymer is replaced with a sulfonic acid group, and a triazine-based compound having at least one halogen atom. A method for detoxifying a halogenated triazine-based compound, which comprises contacting a liquid containing the imprinted polymer having a sulfonic acid group and substituting a halogen atom of the triazine-based compound with a hydroxyl group or an alkoxy group. .

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following preferred embodiments. The imprint polymer of the first invention of the present invention has the general formula 1 (X-S-S-Y).
A monomer represented by the formula (X represents an aromatic ring or a triazine ring and Y represents a group having a vinyl group) and a vinyl compound are copolymerized and then reduced. -SH) (X has the same meaning as above). The method for producing the first imprint polymer can be illustrated as follows when X is a phenyl group, Y is an allyl group, and the vinyl compound is divinylbenzene.

[0012]

In the above figure, the imprint polymer is
Upon contact with a liquid containing phenol or a compound having a similar structure, these compounds are selectively adsorbed and retained in the space A from which thiophenol is desorbed, and the compounds can be concentrated and separated. According to such a principle, in the general formula 1, when X is, for example, a nonylphenyl group, nonylphenol or the like is selectively adsorbed, concentrated and separated. Further, when X is a group obtained by removing at least one hydroxyl group from bisphenols, the bisphenols are selectively adsorbed, concentrated and separated.

Therefore, in the present invention, the above general formula 1
X is a residue of a compound that is diluted and widely distributed in the environment such as an endocrine disruptor or an agricultural chemical, for example, a phenyl group which may have a substituent, a bisphenyl group which may have a substituent, Having a group obtained by removing at least one hydroxyl group from a bisphenol that may have a substituent, a naphthyl group that may have a substituent, an anthracene group that may have a substituent, or a substituent It is preferably a triazine group which may be present.

The imprint polymer of the second invention of the present invention is obtained by oxidizing the mercapto group in the imprint polymer of the first invention with a suitable oxidizing agent under a suitable catalyst. The imprinted polymer is shown schematically as follows. The above imprinted polymer having a sulfonic acid group is useful as a catalyst for adsorptive separation and detoxification of a triazine-based pesticide having a halogen atom, particularly a chlorine atom, when X in the general formula 1 is a triazine group having a substituent. .

The synthesis and catalysis of the above-mentioned imprinted polymer having a sulfonic acid group is illustrated as follows. However, the case where methacrylic acid and divinylbenzene are used as the monomers and a 3,5-substituted diamino-1-triazinyl group is used as X in the general formula 1 is shown.

[0017]

The imprinted polymer B having a sulfonic acid group obtained in the same manner as the above-mentioned first imprinted polymer selectively adsorbs the triazine-based compound as shown in C, and at the same time, the halogen in the triazine-based compound is adsorbed. Atoms can be replaced with hydroxyl groups (in water systems) or alkoxy groups (in alcohol systems) to render triazine compounds harmless.

In the above method, the general formula 1 (X-S-S
In the compound of -Y), the group X is as described above, and a functional group such as a hydroxyl group, a halogen atom, a thiol group, a carbonyl group, a carboxyl group, an amino group, a nitro group, or It represents a group excluding a functional group such as a cyano group. In the present invention, these functional groups are first substituted with thiol groups (except when the functional group is a thiol group).

When the functional group is a hydroxyl group, the hydroxyl group can be substituted with a thiol group by acting diphosphorus pentasulfide, and when the functional group is a sulfochloride group, a disulfide group or a sulfamido group, reduction is achieved. Can be substituted with a thiol group, and when the functional group is an amino group, it can be substituted with a thiol group by reacting a diazonium salt with a xanthate, and when it is another group, it can be substituted with a thiol group by a known method. It can be substituted with

Then, the compound represented by X-SH is reacted with, for example, N-bromsuccinimide under a suitable catalyst, and the reaction product is reacted with a compound having a mercapto group and a vinyl group. General formula 1 (X-S-S
-Y) compound is synthesized. When X-SH is thiophenol and the compound having a mercapto group and a vinyl group is allyl mercaptan, the synthetic reaction is represented by the following reaction formula. Of course, the following reaction formula is for explanation,
It does not limit the invention.

[0022]

As Y-SH in the above general formula 1,
The above-exemplified allyl mercaptan is preferable, but 2-mercaptoethyl (meth) acrylate, 2-
Examples thereof include mercaptopropyl (meth) acrylate. Further, a compound having another functional group in addition to the vinyl group, in which the other functional group is substituted with a mercapto group can also be used.

The vinyl monomer reacted with the template molecule monomer represented by the general formula 1 preferably contains a polyfunctional monomer having at least two vinyl groups.
As the polyfunctional monomer, any conventionally known polyfunctional monomer can be used, but in consideration of reactivity, easiness of handling and cost, divinylbenzene or its derivative, poly (meth) acrylic acid ester of polyhydric alcohol are used. Can be mentioned. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, tetramethylene glycol, glycerin and the like. These polyfunctional monomers may be used alone or other monofunctional monomers such as (meth) acrylic acid, (meth) acrylic acid ester, (meth) acrylic acid amide, vinyl acetate, vinyl chloride, styrene. Other general-purpose monofunctional monomers can also be used.

In the above copolymerization, the template molecule monomer represented by the general formula 1 and the polyfunctional monomer alone or a mixture of the polyfunctional monomer and the monofunctional monomer are mixed and, if necessary, in a suitable organic solvent. Then, a copolymer is obtained by heat polymerization or photopolymerization using a conventional polymerization initiator such as azobisisobutyronitrile. At this time, the mixing ratio of the template molecule monomer (A) represented by the general formula 1 and the monomer (B) is A: B = 0.5 to 20: 1.
It is preferable to carry out at a weight ratio of 10 to 10. If the amount of the monomer A is too small, the selective adsorption property to the template molecule or structural analogue of the finally obtained imprinted polymer will be poor. On the other hand, if the amount of the monomer A is too large, the copolymerization itself will proceed smoothly. However, the physical strength of the finally obtained imprinted polymer and the selective adsorption to template molecules or structural analogues are not uniform.

The first imprinted polymer obtained as described above contains phenols or their derivatives, bisphenols, benzidine or its derivatives, naphthylamine or its derivatives, such as environmental hormones and carcinogens. Effective for separation and removal. In addition, the second imprint polymer is effective as a catalyst for adsorption and detoxification of triazine-based pesticides such as atrazine, simazine, propazine, norazine, triethazine, ipazine, chlorazine, cebutyrazine, terbutyrazine, cyanazine, and mesoprazine. The adsorption and detoxification of harmful substances as described above can be selectively and effectively performed even when the harmful substances are extremely dilute. Further, the imprinted polymer of the present invention can be packed in an HPLC column and used for analysis of a template molecule or its structurally similar compound, and is also useful for selective concentration of a target substance in pretreatment for analysis. It can also be used as a sensor for simple detection of target substances.

[0027]

EXAMPLES Next, the present invention will be described more specifically with reference to Examples and Comparative Examples. <Example 1> [Method for producing imprint polymer specifically recognizing phenol] N- (phenylthio) succinimide (2.
0 mM) and allyl mercaptan (2.0 mM) are dissolved in benzene (10 mL) and refluxed at 60 ° C. overnight. After filtration with a filter, the filtrate was subjected to silica gel chromatography (Wakogel C-200, benzene / hexane =
2/1) to obtain a colorless oily monomer. This monomer was used as a template monomer.

The above template monomer (5.20 mM), divinylbenzene (95 mM) as a cross-linking agent, and azobisisobutyronitrile (2.2 as a polymerization initiator).
(mM) was dissolved in chloroform (10 mL), the gas phase was replaced with nitrogen, and then ultraviolet irradiation was performed at 5 ° C. for 24 hours.
Then, it heated at 80 degreeC for 3 hours, and obtained the polymer. The polymer was crushed to an appropriate size and sieved to a particle size of 26 to 32 μm.

<Comparative Example 1> [Method for producing Comparative Polymer 1] A polymer was prepared in the same manner as in Example 1 without adding a template monomer, and Comparative Polymer 1 was prepared.
Got [Evaluation of Polymer] About 2 imprinted polymers obtained
g was suspended in methanol (50 mL), an appropriate amount of sodium borohydride was added, and reduction was performed for 12 hours. After repeating this operation twice, the polymer was slurry-filled in a stainless steel column (inner diameter 4.6 mm × length 150 mm). The comparative polymer 1 was also packed in a stainless steel column in the same manner, and the retention performance for phenol, aniline, thiophenol and pyridine was examined by high performance liquid chromatography. Hexane is used as an eluent, the flow rate is 1.0 mL / min, and the detection wavelength is 263 using a UV detector
Under a condition of nm, 20 μL of each sample having a concentration of 10 mM was injected and the retention time of each sample was measured. The retention capacity k ′ was determined using toluene as a void marker.

The retention capacity k'is obtained by the following equation, where T _{R is} the retention time of the injected sample and T ₀ is the retention time of toluene. The calculation results are shown in Table 1. k '= (T
_R- T ₀ ) / T ₀

From Table 1, it can be seen that the imprinted polymer of the present invention, while being a covalent polymer of thiophenol, retained little thiophenol, but strongly retained phenol. Calculating the hydrogen bonding capacity between the methyl mercaptan at the thiol group binding site in the polymer and the sample, the results show that phenol is higher than thiophenol, which is, as expected, for imprinted polymers. It was possible to impart a strong phenol selectivity. On the other hand, Comparative Polymer 1 having no thiol group retained only a small amount of phenol.

<Example 2> [Production of imprinted polymer specifically recognizing nonylphenol] N- (phenylthio) in Example 1
An imprinted polymer was obtained in the same manner as in Example 1 except that equimolar N- (nonylphenylthio) succinimide was used instead of succinimide. [Evaluation of Adsorption Performance of Imprint Polymer on Nonylphenol] As a sample, 10 nonylphenol each
A solution (chloroform) containing mM was prepared, 20 mg of each of the imprint polymer and the comparative polymer 1 was added to 10 mL of the sample solution, and the mixture was stirred at room temperature for 24 hours. After the reaction, 1 mL of the supernatant was collected and dried in an empty vial bottle, and then 1 mL of acetonitrile: water = 7: 3.
It was dissolved in a (V / V) solution and the concentration of nonylphenol was measured by high performance liquid chromatography. In addition, for high performance liquid chromatography analysis, a column (Shodex
RSPak DE-413), using acetonitrile: water = 7: 3 (V / V) as an eluent, and a flow rate of 1.0 per minute.
The measurement was carried out with a sample amount of 20 μL under conditions of a detection wavelength of 220 nm using a UV detector at a column temperature of 40 ° C. in mL. The adsorption rate was determined from the concentration of nonylphenol after adsorption with respect to the initial concentration of nonylphenol and is shown in Table 2.

[0033] From the results in Table 2, it was confirmed that the imprint polymer of the present invention strongly adsorbed nonylphenol and was useful as an adsorbent for nonylphenol. On the other hand, Comparative Polymer 1 adsorbs a small amount of nonylphenol, but this is considered to be due to nonspecific adsorption. Therefore, strong adsorption of nonylphenol was proved to be the effect of the imprint polymer of the present invention.

Example 3 The imprint polymer of the present invention to which nonylphenol was adsorbed in Example 2 was suspended in 10 mL of methanol and stirred at room temperature for 24 hours. After stirring, the mixture was left to stand and 1 mL of the supernatant was collected and dried in an empty vial bottle, and then 1 mL of acetonitrile: water = 7: 3.
It was dissolved in a (V / V) solution and the concentration of nonylphenol was measured by high performance liquid chromatography. In addition, for high performance liquid chromatography analysis, a column (Shodex
RSPak DE-413), using acetonitrile: water = 7: 3 (V / V) as an eluent, and a flow rate of 1.0 per minute.
The measurement was carried out with a sample amount of 20 μL under conditions of a detection wavelength of 220 nm using a UV detector at a column temperature of 40 ° C. in mL. Calculate the recovery rate of nonylphenol from this measurement,
The results are shown in Table 3.

[0035] From the results shown in Table 3, 98% of nonylphenol adsorbed on the imprint polymer of the present invention could be recovered. This result shows that the imprint polymer of the present invention is useful for concentrating the target substance in the sample. Further, the imprint polymer after recovering the nonylphenol can be reused, and the regeneration is easier than the conventional adsorbent.

<Example 4> [Production of imprinted polymer specifically recognizing bisphenol A] In place of N- (phenylthio) succinimide in Example 1, 1.0 mM of a compound represented by the following formula was used. An imprint polymer was obtained in the same manner as in Example 1 except for above.

[Evaluation of Adsorption Performance of Imprinted Polymer on Bisphenol A] As a sample, a solution containing 1 mM of bisphenol A (chloroform) was prepared, and imprinted polymer and Comparative Polymer 1 of 20 were prepared.
Add each mg to 10 mL of sample solution and
Stir for 4 hours. After the reaction, 1 mL of the supernatant was collected and dried in an empty vial bottle, and then 1 mL of acetonitrile:
It was dissolved in a water = 5: 5 (V / V) solution and the concentration of bisphenol A was measured by high performance liquid chromatography. A column (Shodex RSPak DE-413) was used for high performance liquid chromatography analysis, and acetonitrile: water = 5: 5 (V / V) was used as an eluent.
Sample volume 20 μL under conditions of detection wavelength 217 nm using UV detector at flow rate 1.0 mL / min, column temperature 40 ° C.
Was measured. From this measurement, the adsorption rate was determined from the concentration of bisphenol A after adsorption with respect to the initial concentration of bisphenol A, and the results are shown in Table 4.

<Example 5> [Production of imprinted polymer having selective catalytic activity for decomposition of atrazine] Instead of N- (phenylthio) succinimide in Example 1, equimolar amounts of N- (3
-Isopropylamino-5-ethylamino-1-thiotriazine) succinimide (the following formula) was used, and 45 mM of methacrylic acid and 50 mM of divinylbenzene were used as monomers, and the polymerization was performed in the same manner as in Example 1 except for the above.

About 2 g of the obtained polymer was added to methanol (1
(00 mL), an appropriate amount of sodium borohydride was added, and the mixture was reduced for 12 hours. This operation was repeated twice.
Further, the polymer was suspended in acetic acid (100 mL), hydrogen peroxide (30%, 100 mL) was added, and the polymer was oxidized for 12 hours. This operation was repeated twice. The obtained polymer was slurry-filled in a stainless steel column (inner diameter 4.6 mm × length 150 mm). Similarly, the following comparative polymer 2 was packed in a stainless steel column, and the retention performance for atrazine was examined by high performance liquid chromatography. Acetonitrile was used as the eluent and the flow rate was 1.
Under a condition of a detection wavelength of 274 nm using a 5 mL UV detector, 20 μL of a 10 mM sample was injected into each sample, and the retention time of each sample was measured. The retention capacity k ′ was determined according to the method of Example 1 using acetone as a void marker.

Comparative Example 2 [Method for producing comparative polymer 2] Known method (Takeuchi, T
Et al .: Chem. Lett., 6,530-531 (2001)), and comparative polymer 2 was synthesized. Like the imprint polymer of Example 4, the powder was crushed to an appropriate size and sieved to a particle size of 26 to 32 μm. From Table 5, the retention capacity of the imprint polymer of the present invention is higher than that of Comparative Polymer 2, and the imprint polymer obtained by the reduction of the thiol group followed by the oxidation of the sulfonic acid group is better than the imprint polymer obtained by the conventional method. It was shown to be excellent.

Example 6 Evaluation of Decomposition Catalytic Activity of Imprint Polymer of Example 5 for Atrazine 20 mg of the imprint polymer of Example 5 and Comparative Polymer 2 each having a particle size of 26 to 32 μm sieved , 500 μM atrazine solution (methanol: chloroform = 9: 1 (V / V)) 10
It was added to mL and stirred at room temperature for 24 hours. After stirring, collect 1 mL of the supernatant and dry it in an empty vial,
1 mL of acetonitrile: acetic acid buffer (0.1 M, p
H6.0) = 4: 6 (V / V) solution was dissolved and the atrazine concentration was measured by high performance liquid chromatography. A column (SUPELCO LC-8DB) was used for high performance liquid chromatography analysis, and acetonitrile: acetic acid buffer (0.1 M, pH 6.0) was used as an eluent.
Using 6: 6 (V / V), a flow rate of 1.5 mL / min, a UV detector and a detection wavelength of 274 nm, and a sample amount of 20
The measurement was performed in μL. Evaluation of the decomposition catalytic ability of the polymer is
The comparison was made by comparing the amount of residual atrazine with the amount of decomposition product, atlaton, and the results are shown in Table 6.

[0042] Comparative Example 3 is a polymer polymerized in the same manner as in Example 5 without using the template monomer.

From Table 6, the imprinted polymer of the present invention and Comparative Polymer 2 decomposed atrazine and produced atlaton, but Comparative Polymer 3 did not produce atlasone at all. Further, the decomposition rate of atrazine was higher in the imprint polymer of the present invention than in Comparative Polymer 2, and it was confirmed that the resolution was improved.

[0044]

EFFECTS OF THE INVENTION According to the present invention as described above, an imprint polymer excellent in selective adsorption property for a substance to be removed and capable of easily detoxifying a substance to be removed, a method for separating a substance and detoxifying a harmful substance. A method can be provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C08F 228/02 C08F 228/02 (72) Inventor Takashi Mukawa 2-2 Chorakuji, Asanan-ku, Hiroshima City, Hiroshima −17− 106 (72) Inventor Chiaki Kawamura 1-9-8 Higashikanda, Chiyoda-ku, Tokyo F-term within Environmental Engineering Co., Ltd. (reference) 4G066 AB09A AB15A AC12A AC14A AC14B AC31B AC33B AD02B AD07B AD08A AD08B CA25 CA27 CA52 DA08 EA13 FA03 FA09 FA37 4H039 CA61 CD10 CD20 4J100 AB02R AB16Q AC03R AG04R AJ02R AL02R AL08P AL62Q AL63Q AM15R AP01P BA30P BA50P BA52H BA52P BA56H BA56P BC43P BC75P CA01 CA04 CA05 CA31 HA01 HA03 HA61 JA15

Claims (7)

[Claims] 1. A monomer represented by the general formula 1 (X-S-S-Y) (X represents an aromatic ring or a triazine ring, and Y represents a group having a vinyl group) and a vinyl compound. After being polymerized and then reduced, the compound of the general formula 2
A method for producing an imprint polymer, which comprises separating a compound represented by (X-SH) (X has the same meaning as described above). 2. X is at least one hydroxyl group selected from a phenyl group which may have a substituent, a bisphenyl group which may have a substituent and a bisphenol which may have a substituent. The method for producing an imprint polymer according to claim 1, wherein the group is a removed group, a naphthyl group which may have a substituent, an anthracene group which may have a substituent, or a triazine group which may have a substituent. . 3. The method for producing an imprint polymer according to claim 1, wherein Y is an allyl group. 4. The method for producing an imprint polymer according to claim 1, wherein the imprint polymer according to claim 1 is oxidized to oxidize a mercapto group in the copolymer into a sulfonic acid group. 5. The imprint polymer according to claim 1 is brought into contact with a liquid containing a compound represented by the general formula 2 (X-SH) (where X has the same meaning as described above) or a compound having a similar structure. A method for separating a substance, which comprises adsorbing a compound represented by the general formula 2 or a compound having a similar structure to an imprint polymer. 6. A liquid containing a triazine-based compound having at least one halogen atom is brought into contact with the imprint polymer having a sulfonic acid group according to claim 4,
A method for detoxifying a halogenated triazine-based compound, which comprises substituting a halogen atom of the triazine-based compound with a hydroxyl group or an alkoxy group. 7. The detoxified halogenated triazine compound according to claim 6, wherein the triazine compound is a pesticide such as atrazine, simazine, propazine, norazine, triethazine, ipazine, chlorazine, cebutyrazine, terbutyrazine, cyanazine, and mesoprazine. Method.