KR101868438B1 - Method for preparing amide derivatives - Google Patents
Method for preparing amide derivatives Download PDFInfo
- Publication number
- KR101868438B1 KR101868438B1 KR1020170048068A KR20170048068A KR101868438B1 KR 101868438 B1 KR101868438 B1 KR 101868438B1 KR 1020170048068 A KR1020170048068 A KR 1020170048068A KR 20170048068 A KR20170048068 A KR 20170048068A KR 101868438 B1 KR101868438 B1 KR 101868438B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- lower alkyl
- group
- compound
- protecting group
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides a process for producing an amide derivative represented by the following general formula (1)
[Chemical Formula 1]
Reacting Formula (2) and Formula (3); And reacting the compound of formula (4) with a compound prepared by the reaction:
(2)
(3)
[Chemical Formula 4]
Description
Methods for making certain amide derivatives are disclosed herein. In particular, a process for preparing a specific amide derivative comprising mirabegron is disclosed.
The specific amide derivative to which Mirabegron belongs was first put on the market as a therapeutic agent for diabetes (WO99 / 20607A, JP2000-516949A, KR10-0506568B) and thereafter a new use as an overactive bladder treatment was added (KR10-0967070B, WO2004 / 041276A).
Mirabegron was prepared by the same method as for (R) -2- (2-aminothiazol-4-yl) -4 '- [2- Amino-ethyl] -acetanilide), 2-amino-N- [4- [2- (2-aminothiazol- 2 - [[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] phenyl] -4- thiazoleacetamide hydroxy-2-phenylethyl amino] ethyl] phenyl] -4-thiazoleacetamide or 2- (2-amino-1,3-thiazol- ) - 2-hydroxy-2-phenylethyl] amino} ethyl) phenyl) acetamide (2- 2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide.
According to WO13 / 119910, an overactive bladder disease is defined as a combination of frequent urination and urinary symptoms associated with nocturia, and these symptoms are usually associated with involuntary contractions of the bladder. In the bladder there is a beta 3 receptor with purinergic receptors and sympathetic nerves. The beta 3 receptor binds to norepinephrine to increase the concentration of cyclic adenosine monophosphate (cAMP), which relaxes the bladder smooth muscle, and enlarges the bladder volume and prolongs the urination interval. Mirabegron is a potent and selective beta 3 receptor agonist, which increases cAMP levels in rats and human bladder tissues and shows relaxation of bladder smooth muscle. These results indicate that Mirabegron stimulates the beta 3 receptors in the bladder to enhance urine storage. Mirabegron, developed in Japan's Astellas, was approved by the Food and Drug Administration (FDA) on June 28, 2012 as an over-the-counter bladder treatment that acts as a beta-3 receptor agonist. In Korea, Astellas, .
The development of various technologies of Mirabegron manufacturing in domestic and foreign countries has not yet been completed. As a conventionally known method for producing mirabegron, WO99 / 20607A discloses a method for producing mirabegron represented by the following reaction formula (2).
[Reaction Scheme 2]
As described above, nucleophilic reaction proceeds using (R) -styrene oxide, which is not only low in purity and yield, but also has a disadvantage in that separation of products is difficult.
Another method of Miravegrone is also known as the following reaction formula (3). Similar patents are disclosed in Japanese Patent Publication Nos. WO2004 / 041276A, WO03 / 037881 and IN201401853. Nitrophenylethylamine is reacted with (R) -mandelic acid under a basic atmosphere, and hydrogenation reaction and 2-aminothiazol- 1 acetic acid to obtain mirabegron. However, there is a limit to use a borane-tetrahydrofuran solution which is not only costly but also difficult to use in a production site by using an expensive starting material. In addition, it has the disadvantage that hydrogen reaction is included in the same manner as the above-mentioned production method.
[Reaction Scheme 3]
As a manufacturing technique for avoiding the hydrogen reaction, which is a disadvantage of the above-described technologies, a method such as CN 103193730 and CN 103232352 is known. According to the following Reaction Scheme 4, mirabegron is prepared by using 2- (4-aminophenyl) ethanol as a starting material and a hydrogen-free reaction is used. However, since expensive (R) -2-amino-1-phenylethanol is used, There is a limit.
[Reaction Scheme 4]
In one aspect, the invention is directed to the preparation of a particular group of amide derivatives comprising mirabegron.
In one aspect, the present invention aims to economically and efficiently produce a specific group of amide derivatives including mirabegron.
In one aspect, the present invention is directed to the preparation of a specific group of amide derivatives comprising mirabegron without difficult hydrogen reactions in situ.
In one aspect, the present invention provides a process for preparing an amide derivative of the general formula (1)
[Chemical Formula 1]
(Wherein,
B ring is a substituted or unsubstituted heteroaryl group, said substitution being a heteroaryl group substituted with a substituent selected from the group consisting of the following groups, or condensed with a benzene ring,
X is a bond, a hydroxy, a lower alkylene, a lower alkenylene, a carbonyl, a group represented by -NH-, wherein said lower alkylene or lower alkenylene is a substituted or unsubstituted group, And when X is a lower alkylene group, the hydrogen atom bonded to the carbon atom constituting the B ring and the lower alkyl group may be integrated to form a lower alkylene group to form a ring,
A is a group represented by lower alkylene or -lower alkylene-O-,
R1a and R1b are each independently the same or different and are a hydrogen atom or lower alkyl,
R2 is a hydrogen atom or a halogen atom,
Z is a group represented by a nitrogen atom or = CH-,
Wherein said substituent group is selected from the group consisting of halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl- Lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO-, di- N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di- Alkylene-O-, and the substituent thereof is an aryl group, a heteroaryl group, a halogen atom, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl -O-CO-, carboxy, sulfonyl, sulfinyl, lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl- -, di-lower alkyl-N-CO-, nitro, cyano, amino, guanidino, Alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl-N- and substituents of these aryl and heteroaryl groups may also be substituted with halogen atoms , ≪ / RTI >
Wherein R is a hydrogen atom, a halogen atom, a lower alkyl group, an amino group, an aryl lower alkyl group or a haloaryl lower alkyl group,
a) reacting an aromatic amine derivative represented by the following formula (2) with a heteroaryl derivative represented by the following formula (3) to prepare a compound represented by the formula (5); And
(2)
(Wherein, C is a protecting group, R1a, R1b, and A are defined as in Formula 1.)
(3)
(Wherein D is a protecting group and R, B, and X are defined as in Formula 1.)
[Chemical Formula 5]
(Wherein C and D are protecting groups, and R, B, X, A, R 1a and R 1b are as defined in the above formula (1)).
b) deprotecting the protecting group derived from the formula 2 from the compound of the formula 5 obtained in the step a) to obtain the compound of the formula 6, reacting the compound of the formula 6 with the compound of the formula 4 to obtain the compound of the formula 7 And deprotecting the compound of formula (7) to obtain the compound of formula (1): < EMI ID =
[Chemical Formula 4]
(Wherein R2 and Z are defined as in Formula 1).
[Chemical Formula 6]
Wherein R, B, X, A, R1a, and R1b are defined as in Formula 1 and D is a protecting group.
(7)
Wherein R, B, X, A, R1a, R1b, z and R2 are defined as in Formula 1 and D is a protecting group.
Using the process disclosed herein, it is possible to produce a high quality amide derivative, mirabegron, with high purity and yield, which eliminates the hydrogen reaction that is subject to constraints such as high manufacturing costs and low production efficiency in field production . Specifically, the present method can eliminate difficult hydrogen reactions in the field by using the compound of the general formula (2) substituted with a protecting group, and by using the compound of the general formula (3) substituted with a weak basic protecting group, a high quality Mirabegron can be produced.
In the definition used in the formulas herein, the term " lower " means straight or branched chain hydrocarbon of 1 to 6 carbon atoms, unless otherwise specified.
Examples of a "lower alkyl group" are methyl, ethyl and straight or branched chain propyl, butyl, pentyl, or hexyl, preferably an alkyl group of 1 to 4 carbon atoms, particularly preferably methyl, ethyl, propyl or isopropyl.
Examples of the "lower alkylene group" include a divalent group obtained by removing one hydrogen atom from the "lower alkyl group", preferably an alkylene group having 1 to 4 carbon atoms, particularly preferably methylene, ethylene, propylene Or butylene.
Examples of " heteroaryl groups " are monocyclic heteroaryl groups such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, Thiazolyl, thiadiazolyl, triazolyl, and tetrazolyl), and bicyclic heteroaryl groups (e.g., naphthyridinyl and pyridopyrimidinyl).
Examples of the "halogen atom" are a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and examples of the "haloaryl lower alkyl group" include the above-mentioned aryl lower alkyl group in which the hydrogen atom (s) ).
When X is a bond, it means that the carbon atom of the group -CO- is bonded directly to ring B,
Since the compound of formula (1), which is an amide derivative of the present invention, has one or more asymmetric carbon atoms, there are optical isomers such as (R) -compound and (S) -conjugate, racemate, diastereomer and the like. The compounds of formula (1) herein include both isolated isomers and mixtures thereof. In addition, the amide derivative compounds of the present invention include hydrates, solvates (for example, solvates with ethanol) and polymorphs of the compound of formula (1).
The compound of formula (I) of the present invention can form a salt with an acid. Examples of the salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, , Tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid).
The starting materials used in the process for preparing the compound of formula (1) according to the present invention can be easily prepared by a method known in the art or can be obtained commercially.
In one embodiment, the amide derivative compound according to the present specification may have R of formula (1) as an amino group.
In one embodiment, the amide derivative compound according to the present disclosure may be a thiazolyl of formula (I).
In one embodiment, the amide derivative compound according to the present invention may be methylene, which is a divalent group obtained by removing one hydrogen atom from the methyl group of X in formula (1).
In one embodiment, the amide derivative compound according to the present invention may be methylene, which is a divalent group obtained by removing one hydrogen atom from the methyl group of A in formula (1).
In one embodiment, an amide derivative compound according to the present disclosure may be represented by R1a and R1b in the formula (1) may be hydrogen.
In one embodiment, an amide derivative compound according to the present disclosure may be a hydrogen of formula (1).
In one embodiment, the amide derivative compound according to the present disclosure may have z in formula (1) = CH-.
In one embodiment, the amide derivative compound according to the present disclosure can be a hydrogen of formula (1).
In one embodiment, the amide derivative compound of Formula 1 may be a compound of Formula 1-1:
[Formula 1-1]
In one embodiment, the compound of Formula 2 may be [2- (4-aminophenyl) ethyl] carbamic acid butyl ester of Formula 2-1.
[Formula 2-1]
In one embodiment, the compound of Formula 3 may be 2- (1,3-dioxo-2H-isoindol-2-yl) -4-thiazole acetic acid of Formula 3-1:
[Formula 3-1]
In one embodiment, the compound of Formula 4 may be (R) -2-chloro-1-phenylethanol of Formula 4-1:
[Formula 4-1]
The preparation method of the present invention will be described by taking the compound of the formula 1-1 as an example.
[Reaction Scheme 1]
A) reacting an aromatic amine derivative of Formula 2 (e.g., Formula 2-1) wherein the alkylamine is substituted with a carboxyl protecting group with a phthalimide of Formula 3 (e.g., Formula 3-1) Reacting a thiazole derivative to prepare a compound of formula 5 (e. G., Formula 5-1); And b) the intermediate obtained in step a) is subjected to a decarboxylation protecting group reaction to obtain a compound of formula 6 (e.g., formula 6-1) and then reacting it with a compound of formula 4 (e. G. -1), and then the compound of formula 1 (for example, formula 1-1), which is the final compound, can be prepared through a dephthalimide protecting group reaction. Such a new synthesis method can produce mirabegron as an economical and reasonable manufacturing method as compared with the conventional manufacturing method including a hydrogen reaction.
[Chemical Formula 5]
(Wherein C and D are protecting groups, and R, B, X, A, R 1a and R 1b are as defined in the above formula (1)).
The C protecting group and the D protecting group may be different from each other.
[Formula 5-1]
[Chemical Formula 6]
(Wherein D is a protecting group and R, B, X, A, R 1 a and R 1 b are as defined in Formula 1).
[Formula 6-1]
(7)
R, B, X, A, R 1 a, R 1 b, z and R 2 are as defined in the above formula (1).
[Formula 7-1]
In one embodiment, step a) may comprise dissolving the heteroaryl derivative of formula (3) in an inert solvent and adding an alkylamine derivative of formula (2).
Examples of the inert solvent include dimethylformamide (DMF), dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, Xylene, acetonitrile, dimethylsulfoxide, and mixed solvents thereof, but may be selected according to various reaction conditions. For example, the inert solvent may be dichloromethane.
The step a) may include dissolving the heteroaryl derivative of formula 3 in an inert solvent together with the hydroxybenzotriazole hydrate. N, N-dicyclohexylcarbodiimide in an inert solvent and the solution of the above formula (3) can be mixed. Adding a compound of formula (2) to a solution obtained by dissolving a heteroaryl derivative of formula (3) and a hydroxybenzotriazole hydrate in an inert solvent. The compound of formula (2) may be added together with triethylamine.
In one embodiment, the C protecting group of the compound of formula (2) can be used as long as it can proceed under acidic conditions in the deprotecting group of the protecting group for protecting the amine. In one embodiment, these protecting groups include tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilyl ethoxycarbonyl, Acetamide, vinyloxycarbamate, 2,2,2-trichloroethoxycarbonyl, sulfonyl, bis (methylthio) methyleneamine, and the like. ) And diphenylmethyleneamine (diphenylmethyleneamine).
In one embodiment, the D protecting group of the compound of formula (3) can be used as long as it can be carried out under basic conditions in the deprotecting group of the protecting group for protecting the amine. In one embodiment, the protecting group may be a phthalimide protecting group. The C protective group of formula (2) is first subjected to a deprotection reaction under acidic conditions, and then the reaction is carried out with the formula (4). To prevent side reactions during the reaction, the D protective group of formula (3) Lt; / RTI > The amine protecting groups which can be carried out under basic conditions in the deprotecting reaction include phthalimide, trifluoroacetamide, trichloroacetamide, nosylate, and 9-fluorenylmethyl 9-fluorenylmethylcarbamate. ≪ / RTI >
In one aspect, the present invention may further comprise a step of deprotecting the compound of formula (5-1) obtained in step (a). Deprotection of the protecting group can be carried out using any of the methods known in the art. For example, the BOC protecting group may be deprotected by strong acid such as trifluoroacetic acid or dichloromethane, or HCl in methanol. For example, the BOC protecting group can be deprotected by treatment with trifluoroacetic acid.
In one aspect, the invention can include reacting a compound of formula (IV-1) with a deprotected compound of formula (6-1). The compound of formula (6-1) may be dissolved in ethanol and triethylamine may be added. The compound of formula (4-1) can be reacted with the compound of formula (4-1) to obtain the compound of formula (7-1).
In one aspect, the present invention may comprise deprotecting formula (7-1). The deprotection method may be any of those known in the art in which a basic condition is formed. For example, hydrazine can be used. Specifically, hydrazine monohydrate can be used.
Example
Example 1 ; [4- {2- (2- (1,3- Dioxoindole Yl) thiazol-4-yl) Acetamido } Phenylethyl ] Preparation of carbamic acid tert-butyl ester (5-1)
(CAS No. 954268-27-0) (20.0 g, 0.069 mole) and a mixture of hydro- carbons (hydroxymethyl) Roxybenzotriazole hydrate (11.9 g, 0.077 mole) was dissolved in dichloromethane (160 ml) and then cooled to 0-5 ° C. N, N-dicyclohexylcarbodiimide (14.3 g, 0.069 mole) was dissolved in dichloromethane (40 ml) and slowly added dropwise to the cooled mixture, followed by stirring at 0 to 5 ° C for 30 minutes. To the suspended reaction solution, 16.4 g (0.069 mole) of [2- (4-aminophenyl) ethyl] carbamic acid butyl ester (CAS No. 94838-59-2) g, 0.069 mole), and the mixture was stirred at room temperature (20 to 25 ° C) for 24 hours. After completion of the reaction, the reaction solution is cooled to 0 to 5 ° C, stirred for 12 hours, and filtered. After filtration, the filtrate was washed with dichloromethane (20 ml), and the filtrate was extracted with a brine solution (200 ml). The extraction was carried out three times. An organic layer was obtained and concentrated under reduced pressure at 35 to 40 ° C. The obtained solid was vacuum-dried at 35 to 40 ° C for 15 hours to obtain the compound of Formula 5-1 (30.5 g, yield 87%).
1 H NMR (400 MHZ, CDCl 3) δ 1.42 (s, 9H), 2.62 (t, 2H), 3.03 (t, 2H), 3.88 (s, 2H), 7.00 (s, 1H), 7.17 (d, 2H), 7.45 (d, 2H), 7.92 (d, 2H), 7.93 (d, 2H); 13 C NMR (100 MHz, CDCl 3) δ 28.4, 35.0, 36.2, 39.9, 79.5, 104.3, 121.5, 123.7, 127.9, 132.0, 132.2, 135.0, 135.7, 150.8, 155.9, 167.1, 169.9, 171.9.
Example 2 ; N- (4-2- Aminoethyl ) Phenyl ) -2- (2- (1,3- Dioxoindole Yl) thiazol-4-yl) acetamide (6-1)
5-1 (30.0 g, 0.059 mole) obtained in Example 1 was dissolved in dichloromethane (150 ml) and cooled at 0-5 ° C. TFA (67.7 ml, 0.88 mole) was added to the cooled reaction solution and stirred at room temperature (20 to 25 ° C) for 4 hours. After completion of the reaction, the reaction solution was cooled to 5 to 10 ° C, and a 9% aqueous solution of sodium hydrogencarbonate (250 ml) was added thereto, followed by stirring for 30 minutes. The extraction was carried out three times. Purified water (200 ml) was added to the extracted organic layer, followed by stirring and extraction for 15 minutes. Sodium sulfate (10 g) was added to the extracted organic layer, stirred for 20 minutes, and filtered. The filtrate was concentrated under reduced pressure at 35 to 40 ° C and vacuum dried at 30 to 35 ° C for 15 hours to obtain a compound of formula (6-1) (21.6 g, yield 90%).
1 H NMR (400 MHZ, CDCl 3) δ 2.71 (t, 2H), 2.98 (t, 2H), 3.88 (s, 2H), 7.00 (s, 1H), 7.17 (d, 2H), 7.45 (d, 2H), 7.92 (d, 2H), 7.93 (d, 2H); 13 C NMR (100 MHz, CDCl 3) δ 36.2, 39.0, 41.9, 104.3, 121.5, 123.7, 127.9, 132.0, 132.2, 135.0, 135.7, 150.8, 167.1, 169.9, 171.9.
Example 3 ; (R) -2- (2- (1,3- Dioxoindole Yl) thiazol-4-yl) -N- (4- (2 - ((2- Hydroxy -2-phenylethyl) amino) ethyl) phenyl) acetamide (Formula 7-1)
(20.0 g, 0.049 mole) was dissolved in ethanol (200 ml), triethylamine (10.4 g, 0.1 mole) was added thereto, and the mixture was stirred at room temperature (20 to 25 ° C) for 20 minutes. (R) -2-chloro-1-phenylethanol (CAS No.) (7.8 g, 0.05 mole) of the formula (4-1) was added to the reaction solution and refluxed for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 45 to 50 ° C, purified water (100 ml) and dichloromethane (200 ml) were added thereto, and the mixture was stirred for 15 minutes. Dichloromethane (100 ml) was added to the water layer, and the mixture was stirred and extracted for 15 minutes to obtain an organic layer. The organic layer was extracted with the first extraction and concentrated under reduced pressure at 35 to 40 ° C. A 5: 1 mixture of ethyl acetate and heptane ), The silica was shortly packed (diameter 10 cm x height 2.5 cm), and the mixture was mixed with a mixture of ethyl acetate and heptane 1: 2 (400 ml). The filtrate obtained by filtration was concentrated under reduced pressure at 40 to 45 ° C and then vacuum dried at 40 to 45 ° C for 12 hours to obtain a compound of formula 7-1 (20.2 g, yield 78%).
1 H NMR (400 MHZ, CDCl 3) δ 2.59 (t, 2H), 2.88 (t, 2H), 2.90 (t, 1H) 3.15 (t, 1H), 3.88 (s, 2H), 4.87 (t, 1H 2H), 7.42 (d, 2H), 7.92 (d, 2H), 7.00 (d, 2H) 7.93 (d, 2H); 13 C NMR (100 MHz, CDCl 3) δ 35.6, 36.2, 48.8, 53.7, 69.4, 104.3, 121.5, 123.7, 127.1, 127.6, 127.9, 128.9, 132.0, 132.2, 135.0, 135.7, 137.7, 150.8, 167.1, 169.9 , 171.9.
Example 4 ; 2- (2-amino-1,3-thiazol-4-yl) -N- [4- (2- Hydroxy -2- Phenylethyl ] Amino} ethyl) phenyl] acetamide
The compound of Formula 7-1 (20.0 g, 0.037 mole) was dissolved in ethanol (500 ml), and hydrazine monohydrate (2.9 g, 0.045 mole) was slowly added dropwise. When the addition was complete, reflux was carried out for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature (20 to 25 ° C), concentrated under reduced pressure at 40 to 45 ° C, and dichloromethane (200 ml) was added thereto to remove the precipitate by filtration. To the filtrate obtained by filtration, purified water (200 ml) is added to extract. The extraction was carried out twice. Sodium sulfate (10 g) was added to the organic layer washed with water, stirred and filtered, and then concentrated under reduced pressure at 40 to 45 ° C. The solid obtained by concentration was vacuum-dried at 45 to 50 ° C for 12 hours to obtain the compound of Formula 1-1 (12.6 g, yield 84%).
1 H NMR (400 MHZ, DMSO -d6) δ 2.88-2.93 (m, 2H), 3.13-3.32 (m, 3H), 3.45 (s, 2H) 4.87 (m, 1H), 6.15 (brs, 1H), 2H), 7.17 (d, 2H), 7.30-7.34 (m, 1H), 7.38-7. 41 (m, 4H), 7.56 ), 10.05 (br s, 1H); 13 C NMR (100 MHz, DMSO-D6)? 31.2, 40.5, 48.4, 53.8, 68.6, 104.1, 119.6, 126.3, 128.2, 128.8, 129.3, 132.4, 138.2, 142.2, 167.5, 169.3.
Claims (8)
[Chemical Formula 1]
(Wherein,
B ring is a substituted or unsubstituted heteroaryl group, said substitution being a heteroaryl group substituted with a substituent selected from the group consisting of the following groups, or condensed with a benzene ring,
X is a bond, a hydroxy, a lower alkylene, a lower alkenylene, a carbonyl or a group represented by -NH-, wherein said lower alkylene or lower alkenylene is a substituted or unsubstituted group, And when X is a lower alkylene group, the hydrogen atom bonded to the carbon atom constituting the B ring and the lower alkyl group may be integrated to form a lower alkylene group to form a ring,
A is a group represented by lower alkylene or -lower alkylene-O-,
R1a and R1b are each independently the same or different and are a hydrogen atom or lower alkyl,
R2 is a hydrogen atom or a halogen atom,
Z is a group represented by a nitrogen atom or = CH-,
Wherein said substituent group is selected from the group consisting of halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl- Lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO-, di- N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di- Alkylene-O-, and the substituent thereof is an aryl group, a heteroaryl group, a halogen atom, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl -O-CO-, carboxy, sulfonyl, sulfinyl, lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl- -, di-lower alkyl-N-CO-, nitro, cyano, amino, guanidino, Alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl-N- and substituents of these aryl and heteroaryl groups may also be substituted with halogen atoms , ≪ / RTI >
Wherein R is a hydrogen atom, a halogen atom, a lower alkyl group, an amino group, an aryl lower alkyl group or a haloaryl lower alkyl group,
a) reacting an aromatic amine derivative represented by the following formula (2) with a heteroaryl derivative represented by the following formula (3) to prepare a compound represented by the formula (5); And
(2)
(Wherein, C is a protecting group, and R1a, R1b, and A are defined as in Formula 1).
(3)
(Wherein D is a protecting group and R, B, and X are defined as in Formula 1.)
[Chemical Formula 5]
(Wherein C and D are protecting groups, and R, B, X, A, R 1a and R 1b are as defined in the above formula (1)).
b) deprotecting the protecting group derived from the formula 2 from the compound of the formula 5 obtained in the step a), reacting the deprotected compound with the compound of the formula 4 to obtain the compound of the formula 7, Protecting the compound of formula (I) to obtain a compound of formula (I)
[Chemical Formula 4]
(Wherein R2 and Z are defined as in Formula 1).
(7)
R, B, X, A, R 1a, R 1b, z, and R 2 are defined as in Formula 1).
Wherein the protecting group C of the compound of Formula 2 is a protective group which is deprotected under acidic conditions.
Wherein the protecting group D of the compound of Formula 3 is a protecting group which is deprotected under basic conditions.
The protecting group C of the compound of Formula 2 may be selected from the group consisting of tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilyl ethoxycarbonyl, Acetamide, vinyloxycarbamate, 2,2,2-trichloroethoxycarbonyl, sulfonyl, bis (methylthio) methyleneamine, and the like. ) And diphenylmethyleneamine, wherein the protecting group is selected from the group consisting of:
The protecting group D of the compound of the formula 3 may be prepared by reacting phthalimide, trifluoroacetamide, trichloroacetamide, nosylate, and 9-fluorenylmethyl carbamate (9 -fluorenylmethylcarbamate). < / RTI >
Wherein the amide derivative compound of Formula 1 is a compound of Formula 1-1:
[Formula 1-1]
Wherein the compound of Formula 2 is a [2- (4-aminophenyl) ethyl] carbamic acid tert-butyl ester of the following Formula 2-1:
[Formula 2-1]
Wherein the compound of Formula 3 is 2- (1,3-dioxo-2H-isoindol-2-yl) -4-thiazoleacetic acid of Formula 3-1:
[Formula 3-1]
Wherein the compound of Formula 4 is (R) -2-chloro-1-phenylethanol of Formula 4-1:
[Formula 4-1]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170048068A KR101868438B1 (en) | 2017-04-13 | 2017-04-13 | Method for preparing amide derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170048068A KR101868438B1 (en) | 2017-04-13 | 2017-04-13 | Method for preparing amide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR101868438B1 true KR101868438B1 (en) | 2018-06-20 |
Family
ID=62769843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170048068A KR101868438B1 (en) | 2017-04-13 | 2017-04-13 | Method for preparing amide derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101868438B1 (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020607A1 (en) | 1997-10-17 | 1999-04-29 | Yamanouchi Pharmaceutical Co., Ltd. | Amide derivatives or salts thereof |
| WO2003037881A1 (en) | 2001-10-30 | 2003-05-08 | Yamanouchi Pharmaceutical Co., Ltd. | α-FORM OR ß-FORM CRYSTAL OF ACETANILIDE DERIVATIVE |
| WO2004041276A1 (en) | 2002-11-07 | 2004-05-21 | Yamanouchi Pharmaceutical Co., Ltd. | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient |
| CN103193730A (en) | 2013-04-17 | 2013-07-10 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
| CN103232352A (en) | 2013-05-11 | 2013-08-07 | 苏州永健生物医药有限公司 | (R)-4-(2-(2-hydroxyl-2-phenylethylamino)-ethyl) tert-butyl phenylcarbamate |
| WO2013119910A1 (en) | 2012-02-09 | 2013-08-15 | Altherx, Inc. | Combination of muscarinic receptor antagonists and beta- 3 adrenoceptor agonists for treating overactive bladder |
| CN105198830A (en) * | 2015-09-14 | 2015-12-30 | 河南师范大学 | Mirabegron preparation method |
| CN106083758A (en) * | 2016-06-20 | 2016-11-09 | 河南师范大学 | A kind of high-efficiency synthesis method of Mirabegron |
-
2017
- 2017-04-13 KR KR1020170048068A patent/KR101868438B1/en active IP Right Grant
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020607A1 (en) | 1997-10-17 | 1999-04-29 | Yamanouchi Pharmaceutical Co., Ltd. | Amide derivatives or salts thereof |
| WO2003037881A1 (en) | 2001-10-30 | 2003-05-08 | Yamanouchi Pharmaceutical Co., Ltd. | α-FORM OR ß-FORM CRYSTAL OF ACETANILIDE DERIVATIVE |
| WO2004041276A1 (en) | 2002-11-07 | 2004-05-21 | Yamanouchi Pharmaceutical Co., Ltd. | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient |
| WO2013119910A1 (en) | 2012-02-09 | 2013-08-15 | Altherx, Inc. | Combination of muscarinic receptor antagonists and beta- 3 adrenoceptor agonists for treating overactive bladder |
| CN103193730A (en) | 2013-04-17 | 2013-07-10 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
| CN103232352A (en) | 2013-05-11 | 2013-08-07 | 苏州永健生物医药有限公司 | (R)-4-(2-(2-hydroxyl-2-phenylethylamino)-ethyl) tert-butyl phenylcarbamate |
| CN105198830A (en) * | 2015-09-14 | 2015-12-30 | 河南师范大学 | Mirabegron preparation method |
| CN106083758A (en) * | 2016-06-20 | 2016-11-09 | 河南师范大学 | A kind of high-efficiency synthesis method of Mirabegron |
Non-Patent Citations (2)
| Title |
|---|
| J. Chem. Pharm. Res., 2015, 7(4):1473-1478 * |
| Tetrahedron: Asymmetry 22 (2011) 722-727 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6392436B2 (en) | Process for the preparation of substituted 5-fluoro-1H-pyrazolopyridines | |
| ES2323288T3 (en) | Phenylacetylene derivatives that have affinity for the MGLURS RECEIVER. | |
| US8420679B2 (en) | Aminothiazole derivatives and their use as CRF receptor ligands | |
| US8518936B2 (en) | Method for preparing acid addition salts of polyacidic basic compounds | |
| JP2008538779A (en) | Acetylene derivatives | |
| JP5463592B2 (en) | Novel compounds as adenosine A1 receptor antagonists | |
| US20200347047A1 (en) | Solid state form of valbenazine | |
| JP5727482B2 (en) | Synthesis of neurostimulatory piperazine | |
| HUE030696T2 (en) | Process for the manufacture of dabigatran etexilate and intermediates thereof | |
| AU2003257300A1 (en) | Amino benzothiazole compounds with nos inhibitory activity | |
| WO2011002103A2 (en) | A cycloalkane derivative | |
| WO2011065420A1 (en) | Method for manufacturing a 6-substituted-1-methyl-1h-benzimidazole derivative, and manufacturing intermediate from said method | |
| KR101868438B1 (en) | Method for preparing amide derivatives | |
| WO2021101854A1 (en) | Compounds and methods of preparing compounds s1p1 modulators | |
| TWI571460B (en) | Process for producing diamine derivative | |
| TW200424184A (en) | Cyclization process for substituted benzothiazole derivatives | |
| JP5923499B2 (en) | Synthesis and use of kinase inhibitors | |
| KR102398639B1 (en) | Salts of amide derivatives and method for preparing the same | |
| US11932631B2 (en) | Process for preparing aficamten | |
| JP2010509250A (en) | Novel 2-amino-pyridine derivatives and their use as potassium channel modulators | |
| AU2021403606A1 (en) | Chemical compounds useful for inhibiting nav1.8 voltage-gated sodium channels and treating nav1.8 mediated diseases | |
| JP2020531585A (en) | Octenidin compounds | |
| SK19496A3 (en) | Substituted dihydropyranopyridines single and for application in the medicine, method and intermediate products for their production, pharmaceutical agents on their base and producing method thereof | |
| JP2005112787A (en) | Method for producing aminopyrrolidine derivative | |
| JPH0348180B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| GRNT | Written decision to grant |