KR20110028199A - An improved preparation method of optically active piperidine compound - Google Patents
An improved preparation method of optically active piperidine compound Download PDFInfo
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- KR20110028199A KR20110028199A KR1020100002579A KR20100002579A KR20110028199A KR 20110028199 A KR20110028199 A KR 20110028199A KR 1020100002579 A KR1020100002579 A KR 1020100002579A KR 20100002579 A KR20100002579 A KR 20100002579A KR 20110028199 A KR20110028199 A KR 20110028199A
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
The present invention reacts (-)-4-chlorophenyl-2-pyridyl-methanol with 4-halogeno-piperidyl) -butanoic acid derivative to give (S) -4- [4- [4] -Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid derivative was prepared, if necessary, by removing the carboxyl protecting group (S) -4- [4- [4-chlorophenyl) (2- The present invention provides a method for preparing pyridyl) methoxy] piperidino] butanoic acid and acid addition salts thereof, and the method of the present invention provides a simple and economical method of maintaining (S) -4- [4- [ 4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid and acid addition salts thereof can be prepared, providing the intermediate material and acid addition salts thereof.
Description
The present invention provides (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid having excellent antihistamine activity and antiallergic activity (common name: bepotastine). It relates to an improved manufacturing method of.
The present invention also provides (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid having excellent antihistamine activity and antiallergic activity (common name: bepotastine). To provide an intermediate material for the production of) and a method for producing the same).
The present invention also provides (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid having excellent antihistamine activity and antiallergic activity (common name: bepotastine). To provide a stable new acid addition salt.
Japanese Patent Application Laid-Open No. 2-25465 discloses that piperidine compound (II) represented by the following formula (II) or a salt thereof minimizes the secondary effect of stimulation or repression on the central nerve, which is often found in the case of conventional antihistamines. It is expected to be used as an allergic skin disease such as rash, eczema and dermatitis, sneezing caused by airway inflammation such as allergic rhinitis and cold, treatment of runny nose, cough and bronchial asthma, and treatment.
Formula II
In formula, A represents a lower hydroxyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a phenyl group, or a lower alkyl substituted phenyl group.
However, this document does not describe the cleavage of the optically active compound.
International Publication No. WO 1998/29409 discloses that the piperidine compound (II) of the following structure is more preferred as a medicament as benzenesulfonate and benzoate of S-enantiomers have better efficacy. In addition, the novel intermediate compound represented by the following structural formula (IV) and the compound represented by the following structural formula (V) are reacted with the intermediate compound (IV) to form bepotastine of the formula (I) and the benzoic acid salt and benzyl sulfide of the bepotastine. It describes about a phosphate salt.
Optical cleavage of the S-enantiomer of compound (III) is optically split into compound (III) with a conventional optical dividing agent, for example, N-methyl-D-glucagon or the like, or efficiently prepared with a preferred optical active agent. In order to do so, the intermediate is optically divided, and the benzenesulfonate salt of S-enantiomer represented by the formula (I) prepared as a raw material is disclosed.
Formula I
In the formula, * represents an asymmetric carbon.
For the preparation of beposatin, bepotastine and acid addition salts of formula (I ') are prepared by reacting an optically active intermediate compound (IV) with a compound of formula (V).
In order to prepare the optically active material of Formula IV, the following compound of Formula III was prepared by optical division using an optical splitting agent. However, when optical splitting is carried out by such an optical splitting method, there is a problem in that the amount of 1/2 of the expensive 4-hydroxypiperidine has to be discarded, and thus the manufacturing cost is increased.
According to the above document, hydrochloride, hydrobromide, sulfate, and the like of the S-enantiomer of the structural formula I are poor in hygroscopicity, and thus are not suitable for use in medicine because of poor hygroscopicity. And that benzoic acid is a crystal and not hygroscopic and can be used for medicament and claims the acid addition salts of benzenesulfonic acid and benzoic acid of the S-enantiomer of Compound I. However, these salts also had problems with stability.
Thus, 100% of the simple, expensive piperidine compound of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid, 100 There has been a need for new ways to leverage%. In addition, development of acid addition salts which are not hygroscopic and stable have been required.
The present invention optically divides the compound represented by the following structural formula (a) to produce an optically active compound represented by the structural formula (b), and reacts the compound represented by the following structural formula (c) with the following optically active compound A bepotastine derivative represented by formula (I ') was prepared, and the bepotastine derivative of formula (I') was hydrolyzed to prepare bepotastine of formula (I) and a stable acid addition salt in a simple and inexpensive manner. It was successful to manufacture.
Wherein W is a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonyloxy, P-toluenesulfonyl group, and R is hydrogen or a carboxyl protecting group such as methyl, ethyl, propyl, t-butyl.
In addition, the compound of formula (I) first converts the compound of formula (b) to an alkoxide of the following formula (b ') by reacting the compound of formula (b) with an alkali metal, and then converts the compound of formula (b') The compound of formula I may also be prepared by reacting with a compound of formula I) and then hydrolyzing the compound of formula (I ′) obtained.
Wherein W is a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonyloxy, P-toluenesulfonyl group, R is hydrogen or a carboxyl protecting group such as methyl, ethyl, propyl, t-butyl, M is an alkali metal.
Compounds of formula (a) are known materials and are described, for example, in US Pat. No. 4,929,618 and also in Bull. Chem. Soc. Jpn., 60, 2651-2655 (1987), and the optically active material of formula (b) is also Bull. Chem. Soc. Jpn., 60, 2651-2655 (1987).
The compound of formula (c) is prepared by reacting 4-halo-piperidine of formula (d) with 4-halo-butanoic acid or ester thereof of formula (e). The 4-halo-piperidine of (d) is a known substance and the 4-halo-butanoic acid of the formula (e) is also a known substance, for example described in WO.
(d) (e) (c)
Wherein W and R are as defined above.
The present invention is optical division of the compound represented by the structural formula (a) is Bull. Chem. Soc. Optical separation is carried out by the method described in Jpn., 60, 2651-2655 (1987) to obtain an optically active compound represented by formula (b).
The reaction of the optically active substance of formula (b) with the substance of formula (c) is carried out by a base such as trimethylamine, triethylamine, dimethylaniline and an acid such as inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, calcium hydroxide and magnesium hydroxide. React in the presence of a remover. The reaction is prepared by reacting in an organic solvent. The organic solvent used at this time is lower alkanols such as methanol, ethanol, propanol, butanol, esters such as ethyl acetate, methyl acetate, nitriles such as acetoniyl, ketones such as acetone, ethers such as dimethyl ether and diethyl ether. Reaction is carried out in the same or a mixed solvent thereof. After the reaction, a salt or addition salt with hydrogen halide of the produced base by filtration is prepared and concentrated to prepare. When the carboxyl group of the prepared compound of formula I is protected, the protecting group can be removed by reaction with an acid or a base.
The reaction of the compound of formula (d) with the compound of formula (e) is an acid scavenger such as bases such as trimethylamine, triethylamine, dimethylaniline and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, calcium hydroxide, magnesium hydroxide React in the presence of The reaction is prepared by reacting in an organic solvent. The organic solvent used at this time is lower alkanols such as methanol, ethanol, propanol, butanol, esters such as ethyl acetate, methyl acetate, nitriles such as acetoniyl, ketones such as acetone, ethers such as dimethyl ether and diethyl ether. Reaction is carried out in the same or a mixed solvent thereof. After the reaction, a salt or addition salt with hydrogen halide of the produced base by filtration is prepared and concentrated to prepare.
The obtained compound of formula I can be reacted with toluic acid, naphthalenesulfonic acid, toluene sulfonic acid to prepare its nonhygroscopic salt. In the present invention, naphthalene sulfonate is 1-naphthalene sulfonate, 2-naphthalene sulfonate, 1,2-dinaphthalene sulfonate, 1,3-dinaphthalene sulfonate, 1,4-dinaphthalene sulfonate, 1,5- Naphthalenesulfonate selected from dinaphthalenesulfonate, 1,6-dynaphthalenesulfonate, 1,7-dinaphthalenesulfonate, 1,8-dinaphthalenesulfonate.
The present invention is simple by optically dividing the compound represented by the following structural formula (a) to prepare an optically active compound represented by the structural formula (b), and reacting the compound represented by the following structural formula (c) with the optically active compound. Bepotastine of formula I and its acid addition salts can be prepared in an inexpensive manner, and the salts of bepotastene produced by the invention of the present invention are not hygroscopic and are very stable.
Example 1
Partitioning of (S)-[(4-chlorophenyl) -2-pyridyl] methanol
The method for optically dividing the compound of formula (a) to prepare the optically active substance of formula (b) is carried out using (-)-O, O'-dibenzoyltartaric acid.
3.30 g of 4-chlorophenyl-2-pyridyl-methanol is dissolved in 25 ml of isopropyl alcohol, and then 5.37 g of (-)-O.O'-dibenzoyltartaric acid is added to dissolve by heating. Allow to stand and slowly cool to room temperature for 24 hours to afford 3.14 g of (-)-4-chlorophenyl-2-pyridyl-methanol. (-)-O.O'-dibenzoyltartaric acid salt. This salt is collected by filtration and recrystallized twice with 6 ml of isopropyl alcohol to obtain 1.80 g of crystalline salt.
Melting point 145-148 ° C .; [α] D 17 -80.1 ° (c = 0,6, MeOH)
1.8 g of this salt was added to 18 ml of purified water, dissolved, neutralized with saturated aqueous sodium bicarbonate, and extracted with 40 ml of chloroform. The layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. 0.6 g of chlorophenyl-2-pyridyl-methanol are obtained.
Melting point 95-97 ° C., [α] D 17 -123.2 ° (C = 0.6, CHCl 3 )
1 H NMR (CDCl 3 ): δ 3. 5 (1 H), 5.45 (1 H), 7.0-7.2 (2H), 7.2-7.6 (4H),
7.6- 7.8 (1 H), 8.5 (1 H),
Example 2
Synthesis of (S)-[4- (4-chlorophenyl) -2-pyridyl] methanol sodium salt
21.95 g (0.1 mol) of (S)-(-)-4-chlorophenyl-2-pyridyl-methanol is added to 200 ml of anhydrous xylene, and 4 g (0.11 mol) of sodium amide are added thereto. Stir until ammonia gas generation stops to obtain the target compound.
1 H NMR (CDCl 3: δ 5.45 (1H), 7.0-7.2 (2H), 7.2-7.6 (4H),
7.6- 7.8 (1 H), 8.5 (1 H),
This material is used for the next reaction without the aftertreatment process.
Example 3
Synthesis of (S) -4-[[4- (4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid ethyl ester
24.15 g (0.1 mol) of (S)-(-)-4-chlorophenyl-2-pyridyl-methanol sodium salt and 21.95 g (0.1 mol) of ethyl 4- (4-chloropiperidinyl) -butanoate It is dissolved in 200 ml of acetone, and 10.12 g (0.1 mol) of triethylamine is added thereto and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure and purified to give 36.2 g of ethyl (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl butanoate as an oil. (Yield 90%, optical purity 99.3%, e.e.).
1 H NMR (CDCl 3 ): δ 1.0-1.3 (3H), 1.8-2.2 (6 H), 2.3-2.6 (4 H), 2.4 _ 2.8
(4H), 3.5 (1H), 4.0 (2H), 5.45 (1H), 7.0-7.2 (2H),
7.2-7.6 (4H), 7.6- 7.8 (1 H), 8.5 (1 H),
Due Diligence 4
Synthesis of (S) -4- [[4- (4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid
(S) -4- [4- [4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl butyrate obtained in Example 2
After dissolving 36.2 g (0.1 mol) of ester in 220 ml of ethanol, 34.7 ml of 5N sodium hydroxide solution was left overnight, and then neutralized by adding an equivalent amount of 5N hydrochloric acid. The precipitated sodium chloride was filtered off and the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 170 ml of dichloromethane, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to give amber syrup (33.6 g).
α D25 + 3.4 ° (c = 5, MeOH).
1 H NMR (CDCl 3 ): δ 1.8-2.2 (6 H), 2.3-2.6 (4 H), 2.4-2.8 (4 H),
3. 5 (1 H), 5.45 (1 H), 7.0-7.2 (2H),
7.2-7.6 (4H), 7.6- 7.8 (1 H), 8.5 (1 H),
Example 5
Synthesis of (S)-[4- (4-chlorophenyl) -2-pyridyl] methanol sodium salt
21.95 g (0.1 mol) of (-)-4-chlorophenyl-2-pyridyl-methanol is dissolved in 200 ml of anhydrous acetonitrile, and 2.53 g (0.11 mol) of sodium are added thereto. Block moisture and let react for 2 hours under reflux. After the generation of hydrogen was completed, the mixture was filtered, and 21.95 g (0.1 mol) of ethyl 4- (4-chloro-piperidinyl) -butanoate was added to the filtrate to dissolve and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure to obtain 39.0 g of ethyl (S) -4- [4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid as an oil. (Yield 97%, optical purity 99.3%, e.e.).
1 H NMR (CDCl 3 ) data is as in Example 2.
Example 6
Ethyl 4-hydroxypiperidinyl Butyrate Synthesis
18 g of 4-hydroxypiperidine, 450 ml of methyl isobutyl ketone, 30 ml of ethyl 4-bromo butyrate, 49 g of potassium carbonate, and a catalytic amount of potassium iodine are added and heated. After refluxing for 24 hours, cooled to room temperature and 100 ml of cold water are added. Extracted with 100 ml of ethyl acetate, separated the layers, dried over forget-me-not and the solvent was removed under reduced pressure to obtain 28.5 g (74.5%) of the target compound as an oil.
1 H NMR (CDCl 3 ): δ 1.2 (3H), 1.8-2.2 (4 H), 2.3-2.6 (6 H),
2.4 _ 2.8 (4 H), 3. 4 (1 H), 4.0 (2 H)
Example 7
Ethyl 4-bromo piperidinyl butyrate synthesis
10 g of ethyl 4-hydroxypiperidinyl butyrate, 5.3 ml of phosphorus tribromide, and 4 ml of benzene are added at room temperature and heated. After refluxing for 12 hours, it is cooled to room temperature. 40 ml of cold water is added and the pH is adjusted to 10 with 25% ammonia water while maintaining the temperature below 5 ° C. The layers are separated and the organic layer is taken and dried over anhydrous magnesium sulfate. Filtration removes the organic layer under reduced pressure to obtain 10.3 g (80%) of the target compound.
1 H NMR (CDCl 3 ): δ 1.2 (3H), 2.0-2.4 (4 H), 2.5-2.6 (6 H),
2.4 _ 2.8 (4 H), 3. 8 (1 H), 4.2 (2 H)
Example 8
Preparation of (S) -Bepotastine Benzene Sulfonate
5.0 g of (S) -bepotastine is added to 260 ml of ethyl acetate and dissolved, and then 2 g of benzenesulfonic acid dihydrate is added to make a homogeneous solution. The solvent was removed under reduced pressure, and 260 ml of ethyl acetate was added to the residue, followed by stirring overnight. The solvent is removed by re-abrasion, 100 ml of acetonitrile are added to the residue, and stirred at room temperature for 3 days to obtain 3.g of the target compound.
Melting Point: 159-163 ℃
1 H NMR (CDCl 3 ): δ 1.8-2.2 (6 H), 2.3-2.6 (4 H), 2.4 _ 2.8 (4 H),
3. 5 (1 H), 5.45 (1 H), 7.0-7.2 (2H),
7.2-7.6 (9H), 7.6- 7.8 (1 H), 8.5 (1 H),
Example 9.
Preparation of (S) -bepotastine naphthalene sulfonate
5.0 g of (S) -bepotastine is added to 260 ml of ethyl acetate and dissolved. 3.7 g of α-naphthalenesulfonic acid monohydrate is added to make a homogeneous solution. The solvent was removed under reduced pressure, and 260 ml of ethyl acetate was added to the residue, followed by stirring overnight. The solvent was removed again by depressurization and 100 ml of acetonitrile were added to the residue and stirred at room temperature for 3 days to obtain 4.7 g of the target compound as an anhydride.
Melting Point: 238-242 ℃
1 H NMR (CDCl 3 ): δ 1.8-2.2 (6 H), 2.3-2.6 (4 H), 2.4 _ 2.8 (4 H),
3. 5 (1 H), 5.45 (1 H), 7.0-7.2 (6H),
7.2-7.6 (7H), 7.6- 7.8 (1 H), 8.5 (1 H),
Example 10
Preparation of (S) -bepotastine naphthalene-1.5-disulfonate
5.0 g of (S) -bepotastine is added to 260 ml of ethyl acetate and dissolved. 3.7 g of naphthalene 1.5-disulfonic acid is added to make a homogeneous solution. The solvent was removed under reduced pressure, and 260 ml of ethyl acetate was added to the residue, followed by stirring overnight. The solvent is removed by depressurization again, 100 ml of acetonitrile are added to the residue, and the mixture is stirred at room temperature for 3 days to obtain 5.0 g of the target compound as an anhydride.
Melting Point: 150-155 ℃
1 H NMR (CDCl 3 ): δ 1.8-2.2 (6 H), 2.3-2.6 (4 H), 2.4 _ 2.8
(4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (6H),
7.2-7.6 (6H), 7.6- 7.8 (1 H), 8.5 (1 H),
Test Example 1
Commercially available bepotastine benzenesulfonate, bepotastine naphthalene-1-sulfonate and bepotastine naphthalene-1,5-disulfonate of the present invention were allowed to stand for 28 days under conditions of 40 ° C and 75% relative humidity. The moisture content was measured on the 3rd, 7th, 15th, 21st and 28th days, and the hygroscopicity was measured by the Karl Fischer method. The results are shown in Table 1 below.
As confirmed in Table 1 above, the bepotastine naphthalene sulfonate of the present invention has a very low hygroscopicity and a stable substance with little change over time, compared to known bepotastine benzenesulfonate. Confirmed.
Formulation Example 1
Bepotastine Custom Manufacturing
Bepotastine naphthalene-1-sulfonate 16.0 mg
(10 mg as bepotastine)
Microcrystalline Cellulose 12.0mg
Lactose 60.0 mg
Polyethylene glycol 10.0 mg
Colloidal Silicon Dioxide 1.0mg
Magnesium Stearate 1.50mg
Opadry Y 1 7000 3.0mg
Gross weight 103.5mg
After mixing the above components, a tablet was prepared by dry or wet tableting according to a conventional tablet manufacturing method.
Formulation Example 2
Bepotastine Custom Manufacturing
Bepotastine naphthalene-1,5-disulfonate 17.44 mg
(10 mg as bepotastine)
Microcrystalline Cellulose 12.0mg
Lactose 60.0 mg
Polyethylene glycol 10.0 mg
Colloidal Silicon Dioxide 1.0mg
Magnesium Stearate 1.50mg
Opadry Y 1 7000 3.0mg
Gross weight 104.94mg
After mixing the above components, a tablet was prepared by dry or wet tableting according to a conventional tablet manufacturing method.
Formulation Example 3
Preparation of Bepotastine Capsules
Bepotastine naphthalene-1-sulfonate 16.0 mg
(10 mg as bepotastine)
Microcrystalline Cellulose 40.0mg
D-mannitol 20.0 mg
Hydroxypropyl Cellulose 25mg
Phthalate Hydroxypropyl Cellulose 15mg
Talc 2.0mg
Magnesium Stearate 1.50mg
Opadry Y 1 7000 3.0mg
Gross weight 122.5mg
After mixing the above components was filled in gelatin capsules according to the conventional capsule production method to prepare a capsule.
Formulation Example 4
Preparation of Bepotastine Capsules
Bepotastine naphthalene-1,5-disulfonate 17.44 mg
(10 mg as bepotastine)
Microcrystalline Cellulose 40.0mg
D-mannitol 20.0 mg
Hydroxypropyl Cellulose 25mg
Phthalate Hydroxypropyl Cellulose 15mg
Talc 2.0mg
Magnesium Stearate 1.50mg
Opadry Y 1 7000 3.0mg
Gross weight 123.94mg
After mixing the above components was filled in gelatin capsules according to the conventional capsule production method to prepare a capsule.
Claims (6)
Wherein W is a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonyloxy, P-toluenesulfonyl group, R is hydrogen or a carboxyl protecting group such as methyl, ethyl, propyl, t-butyl, M is an alkali metal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100049479A KR20110028207A (en) | 2009-09-11 | 2010-05-27 | An improved preparation method of optically active piperidine compound |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20090086090 | 2009-09-11 | ||
| KR1020090086090 | 2009-09-11 | ||
| KR20090094016 | 2009-10-01 | ||
| KR1020090094016 | 2009-10-01 | ||
| KR20090121081 | 2009-12-08 | ||
| KR1020090121081 | 2009-12-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20110028199A true KR20110028199A (en) | 2011-03-17 |
Family
ID=43934684
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020100002579A KR20110028199A (en) | 2009-09-11 | 2010-01-12 | An improved preparation method of optically active piperidine compound |
| KR1020100049479A KR20110028207A (en) | 2009-09-11 | 2010-05-27 | An improved preparation method of optically active piperidine compound |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020100049479A KR20110028207A (en) | 2009-09-11 | 2010-05-27 | An improved preparation method of optically active piperidine compound |
Country Status (1)
| Country | Link |
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| KR (2) | KR20110028199A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101154767B1 (en) * | 2009-12-24 | 2012-06-18 | 주식회사 엠씨켐 | New process for the preparation of optical active piperidine compounds |
| JP2012240982A (en) * | 2011-05-23 | 2012-12-10 | Toray Fine Chemicals Co Ltd | Method for producing benzenesulfonate of optically active piperidine derivative |
| CN113480521B (en) * | 2021-07-12 | 2024-04-16 | 成都丽凯手性技术有限公司 | Full synthesis method of bepotastine besilate |
-
2010
- 2010-01-12 KR KR1020100002579A patent/KR20110028199A/en active Search and Examination
- 2010-05-27 KR KR1020100049479A patent/KR20110028207A/en not_active Application Discontinuation
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| Publication number | Publication date |
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| KR20110028207A (en) | 2011-03-17 |
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