WO2015166557A1 - 3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物およびその製造方法 - Google Patents
3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物およびその製造方法 Download PDFInfo
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- WO2015166557A1 WO2015166557A1 PCT/JP2014/061994 JP2014061994W WO2015166557A1 WO 2015166557 A1 WO2015166557 A1 WO 2015166557A1 JP 2014061994 W JP2014061994 W JP 2014061994W WO 2015166557 A1 WO2015166557 A1 WO 2015166557A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
Definitions
- the present invention relates to a 3-chloro-4-methoxybenzylamine hydrochloride-containing composition that can be used as an intermediate for pharmaceuticals and the like, and a method for producing the same.
- CMBA-HCl 3-chloro-4-methoxybenzylamine
- CMBA-HCl-containing composition 4-methoxy Using benzaldehyde (also referred to as “MB” in this specification) as a reactant and chlorination using sulfuryl chloride, 3-chloro-4-methoxybenzaldehyde (also referred to as “CMB” in this specification) is obtained.
- Non-Patent Document 1 N-(2-chloro-4-methoxybenzyl) formamide (also referred to herein as “CMBF”).
- CMBF N-(2-chloro-4-methoxybenzyl) formamide
- hydrochloric acid in the presence of ethanol or the like, 3-chloro-4-methoxybenzyl is reacted.
- Compositions containing amine hydrochloride i.e. a method of obtaining a CMBA-HCl containing compositions are disclosed in Non-Patent Document 1.
- Patent Document 1 discloses a composition containing CMBA-HCl by a method of injecting chlorine gas or a method of reacting with sulfuryl chloride using 4-methoxybenzylamine (also referred to as “MBA” in this specification) as a starting material. A method of obtaining an object is disclosed.
- the method for producing a CMBA-HCl-containing composition obtained by the method described in Non-Patent Document 1 has a problem that the number of steps is large and the yield is low. That is, the yield of the production method for obtaining a crude composition containing CMBA-HCl through MBB and CMBF using MB as a reactant is 44 based on the laboratory-level production results described in Non-Patent Document 1. %. As a result of the inventors confirming this production method on an industrial production scale, the yield of the above-mentioned crude composition remained at about 33%. Further, the purity of CMBA-HCl in the above-mentioned crude composition obtained from the content calculated based on the peak area ratio obtained by GC measurement is about 90%.
- the present invention provides a method for producing a CMBA-HCl-containing composition having a high CMBA-HCl content represented by the following formula (1) in a high yield, and is produced by such a production method.
- An object of the present invention is to provide a CMBA-HCl-containing composition having a high CMBA-HCl purity.
- the reactant was changed from MB to 4-methoxybenzylamine hydrochloride (also referred to as “MBA-HCl” in the present specification), which is easy to obtain a high-purity product, and MBA-HCl was changed to hydrogen peroxide and hydrochloric acid.
- MBA-HCl 4-methoxybenzylamine hydrochloride
- a CMBA-HCl-containing composition with a particularly reduced impurity concentration can be obtained by recrystallizing the CMBA-HCl-containing composition produced by the above method in the presence of a tertiary amine.
- the present invention completed by such knowledge is as follows. (1) It is characterized by comprising a chlorination step including a chlorination reaction for producing 3-chloro-4-methoxybenzylamine hydrochloride from 4-methoxybenzylamine hydrochloride using hydrogen peroxide and hydrochloric acid. A method for producing a 3-chloro-4-methoxybenzylamine hydrochloride-containing composition.
- a 3-chloro-4-methoxybenzylamine hydrochloride-containing composition comprising a purification step of recrystallizing a 3-chloro-4-methoxybenzylamine hydrochloride-containing composition using a solvent containing a tertiary amine Manufacturing method.
- a chlorination step including a chlorination reaction for producing 3-chloro-4-methoxybenzylamine hydrochloride from 4-methoxybenzylamine hydrochloride using hydrogen peroxide and hydrochloric acid, and the chlorination step.
- a method for producing a 3-chloro-4-methoxybenzylamine hydrochloride-containing composition comprising a purification step of recrystallizing the obtained product using a solvent containing a tertiary amine.
- the 4-methoxybenzylamine hydrochloride-containing composition that is the starting material for the chlorination reaction is such that the content of 4-methoxybenzylamine hydrochloride is based on the peak area ratio obtained by HPLC measurement.
- the manufacturing method as described in said (1) or (3) which is 99.5% or more.
- the purification step reduces the content of one or more selected from the group consisting of 3,5-dichloro-4-methoxybenzylamine and derivatives thereof.
- CMBA-HCl-containing composition having a high CMBA-HCl purity in a high yield. Moreover, the CMBA-HCl containing composition with high purity of CMBA-HCl manufactured by such a manufacturing method is provided.
- the method for producing a CMBA-HCl-containing composition comprises a chlorination step and a recrystallization step, which will be described next.
- MBA-HCl is used as a reactant, so that MBA-HCl is first described, and then the above two steps and other steps are described.
- MBA-HCl (4-methoxybenzylamine hydrochloride) is used as a reactant in the chlorination reaction performed in the chlorination step provided in the method for producing a CMBA-HCl-containing composition according to this embodiment.
- An MBA-HCl-containing composition (which may be referred to as “4-methoxybenzylamine hydrochloride-containing composition” in the present specification), which is a composition containing MBA-HCl, is commercially available and can be easily obtained from the market. And since it is stably available, it may be used as a starting material for the chlorination reaction performed in the chlorination step.
- the MBA-HCl purity in the MBA-HCl-containing composition used as a starting material for the chlorination reaction is not particularly limited, but the purity can be increased in the process of obtaining MBA-HCl from MBA, and the purity is 99.5%.
- the MBA-HCl-containing composition as described above can be easily and inexpensively obtained.
- the “purity” of MBA-HCl and CMBA-HCl is the purity obtained from the content based on the peak area ratio obtained by performing HPLC measurement with the measurement method shown in the Examples described later. Means.
- the starting material in the method described in Non-Patent Document 1 is a material containing MB
- this starting material may contain a dimerization substance of MB as an impurity.
- subsequent processes including a process including a reaction for generating CMB from MB, a process including a reaction for generating CMBF from CMB, a process including a reaction for generating CMBA-HCl from CMBF
- a method for producing a CMBA-HCl-containing composition according to this embodiment uses an MBA-HCl-containing composition as a starting material, and hydrogen peroxide and hydrochloric acid from MBA-HCl contained in the starting material.
- the method for producing a CMBA-HCl-containing composition according to this embodiment is a starting method.
- a CMBA-HCl containing composition can be obtained with only one step including chemical reaction from the material.
- the method for producing a CMBA-HCl-containing composition according to the present embodiment is superior to the method for producing a CMBA-HCl-containing composition according to the prior art only in that the number of steps including a chemical reaction is small. It can be said that it is a method.
- the chlorination reaction is carried out as follows. First, an MBA-HCl containing composition is dissolved in a polar solvent such as water to obtain an MBA containing solution.
- a polar solvent such as alcohol
- the mass ratio of solvent to MBA-HCl (solvent / MBA-HCl) in the MBA-HCl-containing solution is not particularly limited. If this mass ratio is too low, it is difficult to carry out the chlorination reaction uniformly, and if this mass ratio is too high, there may be a disadvantage that the amount of waste liquid increases or the time required for the reaction increases.
- the above-described mass ratio may be set as appropriate in consideration of the increase in performance. Usually, this mass ratio is appropriately set in the range of about 1.5 to 10 times, preferably 2 to 8 times, more preferably 2.5 to 6 times.
- the MBA-containing solution is a solution containing hydrochloric acid (also referred to as “hydrochloric acid solution” in the present specification) in a stirred MBA-containing solution within a range of 5 ° C. to 70 ° C., preferably 10 ° C. to 60 ° C. .) Is added dropwise.
- the solvent of the hydrochloric acid solution is usually water, but is not limited to water as in the MBA-containing solution.
- the dropping amount of the hydrochloric acid solution should be about 1.5 or more and about 4 or less in terms of the number of moles of hydrochloric acid dropped to the number of moles of MBA-HCl contained in the MBA-containing solution (hydrochloric acid / MBA-HCl).
- the hydrochloric acid concentration of the hydrochloric acid solution is not particularly limited. If the hydrochloric acid concentration is excessively low, the amount of hydrochloric acid solution to be added increases, which increases the time required for the reaction or decreases the reactivity. If the hydrochloric acid concentration is excessively high, The hydrochloric acid concentration may be set as appropriate in consideration of the possibility that the uniformity is reduced. Usually, the hydrochloric acid concentration in the hydrochloric acid solution is preferably 10% by mass or more and 60% by mass or less, and more preferably 20% by mass or more and 50% by mass or less.
- the dropping time of the hydrochloric acid solution may be appropriately set in consideration of the hydrochloric acid concentration in the hydrochloric acid solution. An example of the dropping time is about 0.5 to 1 hour.
- hydrogen peroxide is added to the stirred MBA-containing solution while maintaining the temperature of the MBA-containing solution to which the hydrochloric acid solution has been dropped in the range of 60 ° C to 70 ° C, preferably 62 ° C to 68 ° C.
- a solution also referred to as “hydrogen peroxide solution” in this specification
- the solvent of the hydrogen peroxide solution is usually water, but it is not limited to water as in the MBA-containing solution. Since the temperature of the MBA-containing solution is increased by the dropwise addition of the hydrogen peroxide solution, the liquid temperature is controlled in the range of 60 ° C. to 70 ° C., preferably in the range of 62 ° C. to 68 ° C.
- the amount of hydrogen peroxide solution dropped is about 0.8 or more in terms of the ratio of moles of hydrogen peroxide dropped to the number of moles of MBA-HCl contained in the MBA-containing solution (hydrogen peroxide / MBA-HCl). It is preferably about 2.5 or less, and more preferably 1 or more and 2 or less.
- the relationship between the dropping amount of the hydrochloric acid solution and the dropping amount of the hydrogen peroxide solution is such that the number of moles of hydrogen peroxide dropped is about 0.2 as the ratio (hydrogen peroxide / hydrochloric acid) to the number of moles of hydrochloric acid dropped. It is preferably about 1 or less and more preferably 0.35 or more and 0.7 or less.
- the hydrogen peroxide concentration of the hydrogen peroxide solution is not particularly limited. If the hydrogen peroxide concentration is too low, the amount of hydrogen peroxide solution to be dropped increases, so the time required for the reaction may increase and the reactivity may decrease, and the hydrogen peroxide concentration is excessively high. In such a case, the hydrogen peroxide concentration may be set as appropriate in consideration of the possibility that the uniformity of the reaction decreases. Usually, the hydrogen peroxide concentration in the hydrogen peroxide solution is preferably 20% by mass to 60% by mass, and more preferably 25% by mass to 50% by mass.
- the dropping time of the hydrogen peroxide solution may be appropriately set in consideration of the concentration of hydrogen peroxide in the hydrogen peroxide solution. An example of the dropping time is about 1 to 2 hours.
- stirring is continued for a predetermined time while maintaining the temperature of the MBA-containing solution in the above temperature range, thereby completing the reaction.
- a measure for determining the stirring time when the MBA-containing solution after stirring (also referred to as “reaction liquid” in this specification) is sampled and subjected to HPLC measurement under the measurement conditions shown in the examples described later, And the time until the ratio of the peak area of the obtained MBA-based material is 0.5% or less with respect to the peak area of the MBA-based material obtained by sampling the MBA-containing solution before dropping the hydrochloric acid solution.
- the stirring time is set within a few hours to a few dozen hours.
- the ratio of the peak area of the MBA material is also referred to as “MBA remaining amount”.
- the hydrogen peroxide solution may be further dropped and stirred.
- the amount of hydrogen peroxide related to the additional dripping is not particularly limited, and an example is about 10% or less of the amount of hydrogen peroxide dripped.
- the stirring time after the additional addition of hydrogen peroxide is not particularly limited, and examples thereof include the same time as the stirring time after the first hydrogen peroxide solution is dropped. Additional dropping of hydrogen peroxide and subsequent stirring may be performed multiple times.
- chlorination is performed only in the liquid phase using hydrochloric acid and a hydrogen peroxide solution.
- chlorination reaction is performed by introducing chlorine gas into the MBA-containing solution.
- the equipment load required for the reaction is low, and the work safety is excellent.
- hydrogen peroxide used in the production method according to the present embodiment is decomposed, only water remains in the liquid phase, and thus impurities hardly remain in the CMBA-HCl-containing composition.
- the chlorination step included in the production method according to the present embodiment uses MBA or a substance based on this, particularly MBA-HCl as a reaction substance, while reducing the possibility of impurity contamination and simply, a composition containing CMBA-HCl.
- MBA and substances based thereon may be collectively referred to as “MBA substances” or “4-methoxybenzylamine substances”.
- MAA substance refers to a substance in which a peak obtained by HPLC measurement under the conditions described in the examples described later is indistinguishable from MBA because it overlaps with an MBA peak. Means.
- the chlorination step in the production method according to the present embodiment can reduce the amount of unreacted MBA contained in the MBA-containing solution.
- a considerable amount of unreacted MBA remains in the reaction solution after completion of the chlorination reaction.
- unreacted MBA remains about 2% in the case of using chlorine gas and about 1% in the case of using sulfuryl chloride. Since such unreacted MBA has similar chemical properties to the intended CMBA, MBA-HCl tends to remain in the CMBA-HCl-containing composition (in other words, MBA-HCl is difficult to remove even by purification means). ) Contributes to a decrease in the purity of the CMBA-HCl-containing composition.
- CMBA-HCl-containing composition with a small impurity content is easily obtained.
- the content of MBA-based substances such as MBA-HCl or components based thereon may be severely limited. Reducing the concentration of the MBA-based substance contained in the composition by the production method according to this embodiment is directly related to increasing the product value of the CMBA-HCl-containing composition.
- the above-described chlorination reaction is performed by dripping hydrogen peroxide into the MBA-containing solution into which the hydrochloric acid solution has been dropped, and subsequent stirring and repeating those operations (dropping and stirring) performed on the reaction solution as necessary. Then, the reaction solution is cooled until crystals are precipitated.
- the cooling temperature is not particularly limited. Crystal precipitation begins when the liquid temperature is approximately 50 ° C. or lower.
- the subsequent cooling rate is not particularly limited. It is sufficient to stop heating and let it cool (1-2 ° C./min). When the precipitation starts, it is preferable to stop the cooling and prevent the impurities from being mixed into the crystal. Specifically, it is preferable to control the liquid temperature to within ⁇ 5 ° C., preferably within ⁇ 2 ° C.
- the time for continuing this temperature control is not particularly limited, but is exemplified within several hours. Thereafter, the liquid temperature is further cooled to 10 ° C. or less, preferably 5 ° C. or less, and by continuing this state for a predetermined time (for example, within several hours), crystals may be precipitated. Good.
- CMBA-HCl-containing composition when crystals are precipitated in the reaction solution, they are collected by filtration, and the filtered product is washed with an appropriate washing solvent (for example, isopropyl alcohol cooled to about 10 ° C.), whereby a composition containing CMBA-HCl is obtained. Is obtained as a wet cake.
- an appropriate washing solvent for example, isopropyl alcohol cooled to about 10 ° C.
- Recrystallization step By recrystallizing the first CMBA-HCl-containing composition obtained by the chlorination step, the purity of CMBA-HCl contained in the composition can be increased. it can. Purity can also be increased by increasing the number of recrystallizations. However, increasing the number of recrystallizations results in a decrease in productivity due to an increase in work, and also a decrease in yield and an increase in the amount of waste liquid. Therefore, it is preferable that the purity of CMBA-HCl can be sufficiently increased even if the first CMBA-HCl-containing composition is recrystallized once.
- a basic aqueous solvent containing a tertiary amine such as triethylamine or trimethylamine is preferable.
- a basic aqueous solvent containing a tertiary amine such as triethylamine or trimethylamine is preferable.
- the dissociation of hydrochloric acid from benzylamine hydrochloride takes precedence over the dissociation of hydrochloric acid from CMBA-HCl.
- the type of tertiary amine contained in the basic aqueous solvent is not particularly limited. Triethylamine is preferred from the standpoint of handleability.
- the concentration of the tertiary amine in the solvent is not limited, and is appropriately determined in consideration of the type of tertiary amine, the amount of CMBA-HCl contained in the first CMBA-HCl-containing composition, the concentration of other components of the solvent, and the like. You only have to set it.
- the amount of triethylamine used may be in the range of 2% or more and 20% or less as a molar ratio with respect to the amount of CMBA-HCl in the first CMBA-HCl-containing composition. Preferably, the range is 5% or more and 15% or less.
- Components other than the tertiary amine contained in the basic aqueous solvent are not particularly limited. It may be water alone or may contain a polar organic compound such as alcohol. When such a component is contained, the content thereof is preferably in the range of about 5% to 20% by volume with respect to water.
- the method for producing a CMBA-HCl-containing composition according to this embodiment may include only one of the chlorination step and the recrystallization step, or both. Moreover, you may provide processes other than said chlorination process and a recrystallization process. Examples of such a process include activated carbon treatment.
- CMBA-HCl-containing composition The CMBA-HCl-containing composition produced by the production method according to the present embodiment has a high CMBA-HCl purity. Specifically, the CMBA-HCl content (purity) is high. It is 99.9% or more.
- the CMBA-HCl-containing composition manufactured by the above-described manufacturing method according to the present embodiment contains an MBA-based material as compared with the CMBA-HCl-containing composition manufactured by the manufacturing method disclosed in Patent Document 1. There is little quantity and these content can be 200 ppm or less in conversion of MBA.
- CMBA-HCl-containing composition manufactured by the above-described manufacturing method according to the present embodiment is present in a considerable amount in the CMBA-HCl-containing composition manufactured by the manufacturing method disclosed in Non-Patent Document 1.
- a substance based on a CMBF dimerization substance (in this specification, such a substance has a peak obtained by HPLC measurement under the conditions shown in the examples described later, and the peak obtained by CMBF dimerization substance overlaps with that of CMBF. It means a substance indistinguishable from a dimerized substance), and is less than the lower limit of detection (100 ppm) under the analysis conditions described below.
- the content of the MBA-based material and the content of the material based on the CMBF dimerization material were also obtained by HPLC measurement under the conditions shown in the examples described later, in the same manner as the content (purity) of CMBA-HCl. It means a value calculated based on the peak area ratio.
- Mobile phase B methanol for HPLC (manufactured by Kanto Chemical) (Mobile phase composition)
- Mobile phase A / mobile phase B 10% by volume / 90% by volume (50 minutes from the start of analysis) (Mobile phase flow rate) 1.0 mL / min (Measurement wavelength) 210nm (Column temperature) 40 ° C (Injection volume) 10 ⁇ L (Sample preparation method) 30 mg is weighed into a 50 mL volumetric flask and diluted with mobile phase A.
- Example 1 Synthesis of MBA-HCl-containing composition
- a 1000 mL four-necked flask equipped with a thermometer, a Dimroth condenser, and a stirrer was charged with 110 g of MBA having a purity of 96.0% (mass equivalent to pure matter: 105.7 g (. 77 mol)) and 440 g of toluene were added and stirred.
- 91.9 g of 35% hydrochloric acid (theoretical molar ratio to MBA: 1.1) was added dropwise over 30 minutes while maintaining the temperature.
- the reaction solution was heated to carry out azeotropic dehydration.
- Example 2 Synthesis of First CMBA-HCl Containing Composition
- a 200 mL four-necked flask equipped with a thermometer, Dimroth condenser and stirrer was charged with 99.7% pure MBA-HCl obtained in Example 1.
- 35 g of wet crystals of the containing composition (mass in terms of dry product: 30.8 g (0.177 mol)) were added, 153.3 g of water was added and stirred, and 46.1 g (MBA) of 33.7% hydrochloric acid at room temperature.
- the theoretical molar ratio to HCl—2.4) was added dropwise over 30 minutes.
- the internal temperature was raised to 63 ° C., and 35.6% hydrogen peroxide solution 25.6 g (theoretical molar ratio with respect to MBA-HCl 1.43) was added over 30 minutes while maintaining the temperature. It was dripped. The reaction was carried out at 63 ° C. for 10 hours, and it was confirmed by HPLC analysis that the remaining amount of the MBA material was 0.5% or less, and the heating was terminated. The reaction solution was gradually cooled (about 5 to 15 ° C./hour) for crystallization. Since precipitation of crystals was confirmed at 48 ° C., the liquid temperature was maintained at 48 ° C. for 1 hour.
- the retained reaction liquid was filtered, and the obtained wet cake was washed with 22.4 g of isopropyl alcohol cooled to 5 ° C. to obtain 17.2 g of wet crystals of a composition containing CMBA-HCl.
- the obtained wet crystals were dried with a vacuum dryer, and a dried product consisting of 12.5 g of pale yellow crystals was obtained as a CMBA-HCl-containing composition.
- the yield was 71.8 mol%, and the HPLC purity was 98.2%.
- 0.13% of the MBA substance remained and 1.57% of dichloro form was by-produced.
- Example 3 Synthesis of CMBA-HCl-containing composition (recrystallization step) In a 200 mL four-necked flask equipped with a thermometer, a Dimroth cooler, and a stirrer, 25.0 g of wet crystals of the first CMBA-HCl-containing composition (purity: 99.1%, dry product equivalent mass: 21.1 g ( 0.10 mol)), 92.5 g of isopropyl alcohol, 13.3 g of water and 1.54 g of triethylamine (theoretical molar ratio with respect to CMBA-HCl: 0.15) were added and stirred, and the temperature was raised until refluxing was achieved. It was.
- the wet crystals were dried with a vacuum dryer to obtain a dried product composed of 16.9 g of white crystals as a composition containing CMBA-HCl.
- the recovery rate was 80.5%, and the HPLC purity was 99.9%.
- the content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.01%, and the content of the MBA substance was 0.02%.
- Example 4 Synthesis of CMBA-HCl-containing composition (recrystallization step) In a 100 mL four-necked flask equipped with a thermometer, a Dimroth condenser and a stirrer, 5.0 g of a CMBA-HCl-containing composition containing 0.08% MBA material and 1.17% dichloro compound (purity: 99. 1%, mass in terms of pure content: 4.96 g (0.024 mol)), 23.4 g of isopropyl alcohol, 2.6 g of water and 0.24 g of triethylamine (theoretical molar ratio to CMBA-HCl: 0.1) The mixture was stirred and heated up to a reflux state.
- the reaction solution was gradually cooled (5 to 15 ° C./hour) for crystallization. Since precipitation of crystals was confirmed at 72 ° C., the liquid temperature was maintained at 72 ° C. for 1 hour. Subsequently, cooling was performed at a cooling rate of 5 to 15 ° C./hour to 5 ° C., and the liquid temperature was maintained at 5 ° C. for 1 hour.
- the retained reaction solution was filtered, and the resulting wet cake was washed with 8.5 g of isopropyl alcohol cooled to 5 ° C.
- the obtained wet crystals were dried with a vacuum dryer to obtain a dried product comprising 3.78 g of white crystals as a composition containing CMBA-HCl.
- the recovery rate was 75.7% and the HPLC purity was 99.9%.
- the content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.06%, and the content of the MBA material was 0.01%.
- Example 5 Synthesis of a composition containing CMBA-HCl (recrystallization step) The treatment was carried out under the same conditions as in Example 4 except that the amount of triethylamine was changed to 0.18 g (theoretical molar ratio with respect to CMBA-HCl: 0.075). As a result, a dried product consisting of 4.05 g of white crystals was obtained as a CMBA-HCl-containing composition. The recovery rate was 81.0%, and the HPLC purity was 99.9%. The content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.08%, and the content of the MBA substance was 0.01%.
- Example 6 Synthesis of CMBA-HCl-containing composition (recrystallization step) The treatment was carried out under the same conditions as in Example 4 except that the amount of triethylamine was changed to 0.12 g (theoretical molar ratio with respect to CMBA-HCl: 0.05). As a result, a dried product consisting of 4.28 g of white crystals was obtained as a CMBA-HCl-containing composition. The recovery rate was 85.6%, and the HPLC purity was 99.9%. The content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.09%, and the content of the MBA substance was 0.02%.
- Example 7 Synthesis of CMBA-HCl-containing composition (recrystallization step) In a 100 mL four-necked flask equipped with a thermometer, a Dimroth condenser, and a stirrer, 5.0 g of a CMBA-HCl-containing composition containing 4.24% of MBA-based material and 2.42% of dichloro compound (purity: 91. 5%, mass in terms of pure content: 4.58 g (0.022 mol)), 22.5 g of isopropyl alcohol, 3.5 g of water and 0.24 g of triethylamine were added and stirred, and the temperature was raised until the reflux state was reached. .
- the reaction solution was gradually cooled (5 to 15 ° C./hour) for crystallization. Since precipitation of crystals was confirmed at 75 ° C., the liquid temperature was kept at 75 ° C. for 1 hour. Subsequently, cooling was performed at a cooling rate of 5 to 15 ° C./hour to 5 ° C., and the liquid temperature was maintained at 5 ° C. for 1 hour.
- the retained reaction solution was filtered, and the resulting wet cake was washed with 8.5 g of isopropyl alcohol cooled to 5 ° C.
- the obtained wet crystals were dried with a vacuum dryer to obtain a dry product consisting of 3.68 g of white crystals as a composition containing CMBA-HCl.
- the recovery rate was 78.2%, and the HPLC purity was 97.4%.
- the content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.25%, and the content of the MBA substance was 2.28%.
- the reaction liquid was gradually cooled (5 to 15 ° C./hour) and finally cooled to 5 ° C., and the liquid temperature was maintained at 5 ° C. for 1 hour.
- the retained reaction liquid was filtered, and the resulting wet cake was washed with 53 g of a toluene-methanol mixed solution cooled to 5 ° C.
- the obtained wet crystals were dried with a vacuum dryer to obtain a dried product comprising 41.2 g of white crystals as a composition containing CMBA-HCl.
- the recovery rate was 76.8%, and the HPLC purity was 99.88%.
- the content of the dichloro compound contained in the CMBA-HCl-containing composition was 0.11%, and the content of the MBA substance was 0.01%.
- CMBA-HCl-containing composition having high CMBA-HCl purity with high productivity.
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Abstract
Description
(1)反応物質をMBから、高純度品を得やすい4-メトキシベンジルアミン塩酸塩(本明細書において「MBA-HCl」ともいう。)に変更し、MBA-HClを、過酸化水素および塩酸を用いてクロロ化することにより、不純物濃度が低いCMBA-HCl含有組成物を高収率かつ簡便に製造することができる。
(2)上記の方法により製造したCMBA-HCl含有組成物を3級アミン存在下で再結晶することにより、特に不純物濃度が低減されたCMBA-HCl含有組成物を得ることができる。
(1)4-メトキシベンジルアミン塩酸塩から、過酸化水素および塩酸を用いて3-クロロ-4-メトキシベンジルアミン塩酸塩を生成するクロロ化反応を含むクロロ化工程を備えることを特徴とする、3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物の製造方法。
1.CMBA-HCl含有組成物の製造方法
本実施形態に係るCMBA-HCl含有組成物の製造方法は、次に説明するクロロ化工程および再結晶工程を備える。クロロ化工程において行われるクロロ化反応では、MBA-HClを反応物質とするため、まずMBA-HClについて説明したのち、上記の2工程およびその他の工程について説明する。
上記のとおり、本実施形態に係るCMBA-HCl含有組成物の製造方法が備えるクロロ化工程において行われるクロロ化反応では、MBA-HCl(4-メトキシベンジルアミン塩酸塩)を反応物質とする。MBA-HClを含有する組成物であるMBA-HCl含有組成物(本明細書において、「4-メトキシベンジルアミン塩酸塩含有組成物」ということもある。)は市販されており、市場から容易にかつ安定的に入手可能であるから、クロロ化工程において行われるクロロ化反応の出発材料とすればよい。クロロ化反応の出発材料とするMBA-HCl含有組成物におけるMBA-HCl純度は特に限定されないが、MBAからMBA-HClを得る工程において純度を高めることが可能であるため、純度が99.5%以上であるMBA-HCl含有組成物を容易にかつ安価に入手することができる。なお、本明細書において、MBA-HClやCMBA-HClの「純度」とは、後述する実施例に示される測定方法でHPLC測定を行って得られたピーク面積比率に基づく含有量から求めた純度を意味する。
本実施形態に係るCMBA-HCl含有組成物の製造方法は、MBA-HCl含有組成物を出発材料とし、当該出発材料に含有されるMBA-HClから、過酸化水素および塩酸を用いてCMBA-HClを生成するクロロ化反応を含むクロロ化工程を備える。すなわち、非特許文献1では出発材料からCMBA-HCl含有組成物を得るために化学反応を含む工程を3つ必要としていたところ、本実施形態に係るCMBA-HCl含有組成物の製造方法は、出発材料から化学反応を含む工程を1つ備えるだけでCMBA-HCl含有組成物を得ることができる。化学反応を含む工程の増加が、製造方法としての煩雑さを増やし、生産性を低下させ、収率や純度を低下させることは言うまでもない。したがって、本実施形態に係るCMBA-HCl含有組成物の製造方法は、従来技術に係るCMBA-HCl含有組成物の製造方法に比べて、化学反応を含む工程数が少ないという点のみでも、優れた方法であるといえる。
まず、MBA-HCl含有組成物を水などの極性溶媒に溶解させ、MBA含有溶液を得る。溶媒の種類は、上記のとおり水が典型例であり、必要に応じ、アルコールなどの極性溶媒を含有させてもよい。MBA-HCl含有溶液におけるMBA-HClに対する溶媒の質量比率(溶媒/MBA-HCl)は特に限定されない。この質量比率が過度に低い場合にはクロロ化反応を均一に行うことが困難となり、この質量比率が過度に高い場合には廃液量が増えたり反応に要する時間が伸びたりする不利益が生じる可能性が高まることを考慮して、上記の質量比率を適宜設定すればよい。通常、この質量比率は、1.5倍程度から10倍程度の範囲で適宜設定され、2倍以上8倍以下とすることが好ましく、2.5倍以上6倍以下とすることがより好ましい。
上記のクロロ化工程により得られた第1のCMBA-HCl含有組成物に対して再結晶を行うことにより、当該組成物に含有されるCMBA-HClの純度を高めることができる。また、再結晶の回数を増やすことによっても純度を高めることができる。しかしながら、再結晶の回数を増やすことは作業増加に起因する生産性の低下をもたらし、さらに、収率の低下および廃液量の増加をももたらす。したがって、第1のCMBA-HCl含有組成物の再結晶が1回であっても十分にCMBA-HClの純度を高めることができることが好ましい。
本実施形態に係るCMBA-HCl含有組成物の製造方法は、上記のクロロ化工程および再結晶工程の一方のみを備えていてもよいし、両方を備えていてもよい。また、上記のクロロ化工程および再結晶工程以外の工程を備えていてもよい。そのような工程として、活性炭処理などが例示される。
本実施形態に係る上記の製造方法により製造されたCMBA-HCl含有組成物は、CMBA-HClの純度が高い、具体的には、CMBA-HClの含有量(純度)が99.9%以上である。また、本実施形態に係る上記の製造方法により製造されたCMBA-HCl含有組成物は、特許文献1に開示される製造方法により製造されたCMBA-HCl含有組成物に比べてMBA系物質の含有量が少なく、これらの含有量をMBA換算で200ppm以下とすることができる。さらに、本実施形態に係る上記の製造方法により製造されたCMBA-HCl含有組成物は、非特許文献1に開示される製造方法により製造されたCMBA-HCl含有組成物においては相当量存在する、CMBFの二量化物質に基づく物質(本明細書において、かかる物質は、後述する実施例に示される条件でのHPLC測定により得られるピークが、CMBFの二量化物質によるピークと重複して、CMBFの二量化物質と区別不能な物質を意味する。)の含有量も少なく、以下記載の分析条件では検出下限(100ppm)以下である。なお、MBA系物質の含有量およびCMBFの二量化物質に基づく物質の含有量も、CMBA-HClの含有量(純度)と同様に、後述する実施例に示される条件でのHPLC測定により得られたピーク面積比率に基づいて算出された値を意味する。
(移動相)
移動相A:HPLC用の水に、HPLC用リン酸(和光純薬社製)を水に対して0.1質量%滴下して調製した。
移動相B:HPLC用メタノール(関東化学製)
(移動相組成)
移動相A/移動相B:10体積%/90体積%(分析開始から50分間)
(移動相流量)1.0mL/min
(測定波長)210nm
(カラム温度)40℃
(注入量)10μL
(サンプル調製法)30mgを50mLメスフラスコに秤量し、移動相Aでメスアップする。
温度計、ジムロート冷却器および攪拌機を備えた1000mL四つ口フラスコに、純度96.0%のMBA110g(純分換算質量:105.7g(0.77モル))およびトルエン440gを加えて撹拌し、60℃に昇温後、温度を保持しながら35%塩酸91.9g(MBAに対する理論モル比:1.1)を30分かけて滴下した。ディーンスターク管を取り付けた後反応液を昇温し共沸脱水を実施した。90℃付近より還流が始まり、トルエンを反応器に戻しながら内温が110℃になるまで共沸脱水を継続した。20℃まで冷却を行い、1時間保持を行った。反応液をろ過し、得られたウェットケーキを165gのトルエンで洗浄し、ウェット結晶139.6gを得た。得られたウェット結晶を四つ口フラスコに戻し、トルエン275gを加えて20℃にて1時間の懸濁洗浄を実施した。洗浄後の反応液をろ過し、得られたウェットケーキを165gのトルエンで洗浄し、ウェット結晶131.8gを得た。真空乾燥機で乾燥し、129.9gの白色結晶からなる乾燥品をMBA-HCl含有組成物として得た。収率は97.0モル%、HPLC純度は99.7%であった。
温度計、ジムロート冷却器および攪拌機を備えた200mL四つ口フラスコに、実施例1により得られた純度99.7%のMBA-HCl含有組成物のウェット結晶35g(乾燥品換算の質量:30.8g(0.177モル))を仕込み、水153.3gを加えて撹拌し、常温下、33.7%塩酸46.1g(MBA-HClに対する理論モル比2.4)を30分かけて滴下した。滴下後、内温を63℃まで昇温した後、その温度を維持した状態で、33.6%過酸化水素水25.6g(MBA-HClに対する理論モル比1.43)を30分かけて滴下した。63℃で10時間反応を行い、HPLC分析にてMBA系物質の残量が0.5%以下であることを確認し加熱を終了した。反応液を徐々に(5~15℃/時間程度)冷却し晶出を実施した。48℃で結晶の析出が確認されたため、液温が48℃の状態を1時間保持した。引き続き冷却速度を5~15℃/時間として5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したイソプロピルアルコール48.7gで洗浄し、第1のCMBA-HCl含有組成物のウェット結晶31.4gを得た。このウェット結晶を真空乾燥機で乾燥し、26.5gの白色結晶からなる乾燥品を第1のCMBA-HCl含有組成物として得た。収率は71.1モル%、HPLC純度は99.1%であった。CMBA-HCl含有組成物中にMBA系物質は0.08%残存し、ジクロロ体が0.84%副生した。
温度計、ジムロート冷却器および攪拌機を備えた200mL四つ口フラスコに、MBA11.7g(0.08モル)を仕込み、水49.0gを加えて撹拌し、60℃に昇温後、温度を保持しながら35%塩酸28.9g(MBAに対する理論モル比:3.4)を30分かけて滴下した。滴下後、内温を63℃に維持した状態で、35%過酸化水素水10.9g(MBAに対する理論モル比:1.39)を30分かけて滴下した。63℃で16時間反応を行い、HPLC分析にてMBA系物質の残量が0.05%以下であることを確認し加熱を終了した。反応液を徐々に(10℃/時間程度)冷却し晶出を実施した。45℃で結晶の析出が確認され、そのまま10℃/時間の速度で5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したイソプロピルアルコール22.4gで洗浄し、CMBA-HCl含有組成物のウェット結晶17.2gを得た。得られたウェット結晶を真空乾燥機で乾燥し、乾燥品として12.5gの淡黄色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。収率は71.8モル%、HPLC純度は98.2%であった。CMBA-HCl含有組成物中にMBA系物質は0.13%残存し、ジクロロ体が1.57%副生した。
温度計、ジムロート冷却器および攪拌機を備えた500mL四つ口フラスコに、MBA20g(0.146モル)を加え、反応液を20℃以下に冷却した状態で、酢酸250gを加え撹拌を開始した。反応液温を25℃以下に維持しながら、塩化スルフリル29.3g(MBAに対する理論モル比:1.5)を1時間かけて滴下した。滴下後、内温を20~25℃に保持した状態で26時間反応を行い、HPLC分析にてMBA系物質の残量が0.5%以下であることを確認し反応を終了した。反応液にトルエン150gを添加し、5℃まで冷却後1時間保持を行った。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したトルエン20gで洗浄を行なった。得られたウェット結晶を真空乾燥機で乾燥し、22.8gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。収率は75.5モル%、HPLC純度は98.9%であった。CMBA-HCl含有組成物中にMBA系物質は0.50%残存し、ジクロロ体が0.23%副生した。
温度計、ジムロート冷却器および攪拌機を備えた200mL四つ口フラスコに、第一のCMBA-HCl含有組成物のウェット結晶25.0g(純度:99.1%、乾燥品換算質量:21.1g(0.10モル))、イソプロピルアルコール92.5g、水13.3gおよびトリエチルアミン1.54g(CMBA-HClに対する理論モル比:0.15)を加えて撹拌し、還流状態になるまで昇温を行った。途中、78.5℃で結晶は完溶した。1時間還流後、反応液を徐々に(5~15℃/時間)冷却し晶出を行った。72℃で結晶の析出が確認されたため、液温が72℃の状態を1時間保持した。引き続き冷却速度を5~15℃/時間として5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の得られた反応液をろ過し、得られたウェットケーキを、5℃に冷却したイソプロピルアルコール42.2gで洗浄を行い、ウェット結晶21.0gを得た。このウェット結晶を真空乾燥機で乾燥し、16.9gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は80.5%、HPLC純度は99.9%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.01%、MBA系物質の含有量は0.02%であった。
温度計、ジムロート冷却器および攪拌機を備えた100mL四つ口フラスコに、MBA系物質を0.08%、ジクロロ体を1.17%含有するCMBA-HCl含有組成物5.0g(純度:99.1%、純分換算質量:4.96g(0.024モル))、イソプロピルアルコール23.4g、水2.6gおよびトリエチルアミン0.24g(CMBA-HClに対する理論モル比:0.1)を加えて撹拌し、還流状態になるまで昇温を行った。1時間還流後、反応液を徐々に(5~15℃/時間)冷却し晶出を行った。72℃で結晶の析出が確認されたため、液温が72℃の状態を1時間保持した。引き続き冷却速度を5~15℃/時間として5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したイソプロピルアルコール8.5gで洗浄を行った。得られたウェット結晶を真空乾燥機で乾燥し、3.78gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は75.7%、HPLC純度は99.9%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.06%、MBA系物質の含有量は0.01%であった。
トリエチルアミン量を0.18g(CMBA-HClに対する理論モル比:0.075)に変更した以外は、実施例4と同様の条件にて処理を実施した。その結果、4.05gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は81.0%、HPLC純度は99.9%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.08%、MBA系物質の含有量は0.01%であった。
トリエチルアミン量を0.12g(CMBA-HClに対する理論モル比:0.05)に変更した以外は、実施例4と同様の条件にて処理を実施した。その結果、4.28gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は85.6%、HPLC純度は99.9%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.09%、MBA系物質の含有量は0.02%であった。
温度計、ジムロート冷却器および攪拌機を備えた100mL四つ口フラスコに、MBA系物質を4.24%、ジクロロ体を2.42%含有するCMBA-HCl含有組成物5.0g(純度:91.5%、純分換算質量:4.58g(0.022モル))、イソプロピルアルコール22.5g、水3.5gおよびトリエチルアミン0.24gを加えて撹拌し、還流状態になるまで昇温を行った。1時間還流後、反応液を徐々に(5~15℃/時間)冷却し晶出を行った。75℃で結晶の析出が確認されたため、そのまま液温が75℃の状態を1時間保持した。引き続き冷却速度を5~15℃/時間として5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したイソプロピルアルコール8.5gで洗浄を行った。得られたウェット結晶を真空乾燥機で乾燥し、3.68gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は78.2%、HPLC純度は97.4%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.25%、MBA系物質の含有量は2.28%であった。
トリエチルアミンを添加しなかった以外は、参考例1と同条件にて処理を実施した。3.68gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は78.2%、HPLC純度は96.6%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.72%、MBA系物質の含有量は2.44%であった。
温度計、ジムロート冷却器および攪拌機を備えた2000mL四つ口フラスコに、MBA系物質を0.03%、ジクロロ体を0.70%含有するCMBA-HCl含有組成物のウェット結晶75.0g(純度:99.2%、純分換算質量:53.6g(0.258モル))、メタノール193gおよびトルエン579gを加えて撹拌し、60℃まで昇温を行った。反応液を徐々に(5~15℃/時間)冷却し最終的に5℃まで冷却を行い、液温が5℃の状態を1時間保持した。保持後の反応液をろ過し、得られたウェットケーキを、5℃に冷却したトルエンーメタノール混合溶液53gで洗浄を行った。得られたウェット結晶を真空乾燥機で乾燥し、41.2gの白色結晶からなる乾燥品をCMBA-HCl含有組成物として得た。回収率は76.8%、HPLC純度は99.88%であった。CMBA-HCl含有組成物中に含有されるジクロロ体の含有量は0.11%、MBA系物質の含有量は0.01%含有であった。
Claims (6)
- 4-メトキシベンジルアミン塩酸塩から、過酸化水素および塩酸を用いて3-クロロ-4-メトキシベンジルアミン塩酸塩を生成するクロロ化反応を含むクロロ化工程を備えることを特徴とする、3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物の製造方法。
- 3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物を、3級アミンを含む溶媒を用いて再結晶する精製工程を備える、3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物の製造方法。
- 4-メトキシベンジルアミン塩酸塩から、過酸化水素および塩酸を用いて3-クロロ-4-メトキシベンジルアミン塩酸塩を生成するクロロ化反応を含むクロロ化工程、および
前記クロロ化工程により得られた生成物を、3級アミンを含む溶媒を用いて再結晶する精製工程を備えること
を特徴とする3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物の製造方法。 - 前記クロロ化反応の出発材料である4-メトキシベンジルアミン塩酸塩含有組成物は、4-メトキシベンジルアミン塩酸塩の含有量が、HPLC測定により得られたピーク面積比率に基づく含有量として99.5%以上である、請求項1または3に記載される製造方法。
- 前記精製工程により、3,5-ジクロロ-4-メトキシベンジルアミンおよびその誘導体からなる群から選ばれる一種または二種以上の含有量が低減される、請求項2または3に記載される製造方法。
- 請求項1から5のいずれか一項に記載される製造方法により製造されたことを特徴とする3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物。
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US15/306,646 US20170044091A1 (en) | 2014-04-30 | 2014-04-30 | Composition containing 3-chloro-4-methoxybenzylamine hydrochloride, and method for producing same |
PCT/JP2014/061994 WO2015166557A1 (ja) | 2014-04-30 | 2014-04-30 | 3-クロロ-4-メトキシベンジルアミン塩酸塩含有組成物およびその製造方法 |
EP14891029.2A EP3138830A4 (en) | 2014-04-30 | 2014-04-30 | Composition containing 3-chloro-4-methoxybenzylamine hydrochloride, and method for producing same |
JP2016515801A JP6389513B2 (ja) | 2014-04-30 | 2014-04-30 | 3−クロロ−4−メトキシベンジルアミン塩酸塩含有組成物およびその製造方法 |
US15/730,317 US10059654B2 (en) | 2014-04-30 | 2017-10-11 | Composition containing 3-chloro-4-methoxybenzylamine hydrochloride, and method for producing same |
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US15/730,317 Division US10059654B2 (en) | 2014-04-30 | 2017-10-11 | Composition containing 3-chloro-4-methoxybenzylamine hydrochloride, and method for producing same |
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EP (1) | EP3138830A4 (ja) |
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SU386891A1 (ru) * | 1971-07-13 | 1973-06-21 | Сумгаитский филиал Ордена Трудового Красного Знамени института нефтехимических процессов Ю. Г. Мамедалиева | Способ получения хлорбензола или алкилхлорбензола |
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-
2014
- 2014-04-30 JP JP2016515801A patent/JP6389513B2/ja not_active Expired - Fee Related
- 2014-04-30 EP EP14891029.2A patent/EP3138830A4/en not_active Withdrawn
- 2014-04-30 US US15/306,646 patent/US20170044091A1/en not_active Abandoned
- 2014-04-30 WO PCT/JP2014/061994 patent/WO2015166557A1/ja active Application Filing
-
2017
- 2017-10-11 US US15/730,317 patent/US10059654B2/en active Active
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Also Published As
Publication number | Publication date |
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JP6389513B2 (ja) | 2018-09-12 |
EP3138830A1 (en) | 2017-03-08 |
US20180029974A1 (en) | 2018-02-01 |
EP3138830A4 (en) | 2018-05-30 |
JPWO2015166557A1 (ja) | 2017-04-20 |
US20170044091A1 (en) | 2017-02-16 |
US10059654B2 (en) | 2018-08-28 |
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