TWI310380B - Process for the preparation of mesylates of piperazine derivatives - Google Patents

Description

1310380 A7 B7 V. INSTRUCTION DESCRIPTION (i) Technical Field The present invention relates to a process for preparing a carbamate salt of a hexahydroquinone derivative. BACKGROUND OF THE INVENTION Japanese Patent Να 3, 〇 44, 383 describes that a hexahydropyridinium derivative can be obtained by reacting a first amine with a reactive ester of a substituted bis(hydroxyethyl)amine. The reactive ester derivative is a sulfonate tooth having the substituted bis(hydroxyethyl)amine compound and a compound of the formula R]SOrHal (wherein Ri represents an alkyl group or an aryl group, and hydrazine is a halogen atom) The reaction was obtained. Using this method, the desired hydrochloric acid or hydrobromic acid addition salt of the hexahydropyridyl derivative is obtained. To obtain the corresponding mesylate salt, the salt obtained must be converted to a free base from which the desired oxime sulfonate can be prepared by using the mesylate salt. It has been found that the mesylate salt of such a hexahydropyridinium derivative can be obtained directly in a high yield and high purity in an economical manner according to the process of the present invention. DETAILED DESCRIPTION The present invention relates to a method for preparing a formula (1)

A novel method of the compound of (1), which is an amine of formula (2) and formula (3)

(2) ~ 4 - (3) 1310380 V. Description of the invention (A7 B7 is a compound and a reductive liver reaction) where X represents a group

Wherein -& is hydrogen or fluoro-r2 is hydrogen, alkyl (Mc), alkoxy (1_4 (:) or an oxo group, -A represents a heterocyclic group of a 5-7 atom ring which has a hydrazine _3 heteroatoms from the group Ο, N and S are present, -Y is a methyl group, an ethyl group, an ethyl group substituted with one or more fluorine atoms, a cycloalkane 7 C) methyl group selective to one or more Substituted by a fluorine atom, or a group having the formula (5) R3 (9) Z wherein Z is hydrogen 'phenyl'phenyl group with 1-3 substituents from the group via the base group, alkyl group (1-4 C) 'Nanoyl (1-4 C) or cyano substituted, and r3 is hydrogen or hydrazine - 3 substituents from the group of halo 'hydroxy' alkyl (1-4 C) or alkoxy (i_4 C). The present invention is preferably concerned with the preparation of a mesylate salt of the compound of the formula (1) wherein X is a group having the formula (6)

This paper scale applies to the Chinese Mushroom Standard (CNS) A4 specification (210 x 297 mm)

Binding

Line 1310380 A7 B7 V. Description of invention (3) and γ have the above meanings. More particularly, the present invention relates to the preparation of a mesylate salt of a compound of formula (1) wherein X is a group of formula (6), and Y represents m-phenylindenyl, benzyl or methyl. The synthesis of the hexahydropyrrole ring and the formation of the mesylate salt in accordance with the process of the present invention are significant advantages in a single step. The formation of a reactive ester of a compound of formula (3) is carried out by reacting it with methanesulfonic acid in the presence of a magnetic, such as triethylamine. The reaction can be carried out in an organic solvent at a temperature of from 0 to 150 ° C, preferably at reflux temperature. Suitable solvents are, for example, monochlorobenzene and methyl ethyl ketone. The starting compounds of formula (2) and (3) are known compounds or may be prepared in the same manner as known compounds which are structurally related. The carboxamide salt of the compound of formula (1) is a novel compound. Some of the free bases, hydrochloric acid addition salts and trans-butenedioates of such compounds are known. The invention also relates to novel mesylate salts of the compounds of formula (1). The invention particularly relates to a mesylate salt of a compound of formula (1) wherein X is a group of formula (6)

And Y has the above meaning. More particularly, the invention relates to a mesylate salt of a compound of formula (1) wherein X is a group of formula (6) and Y represents m-phenylbenzyl, benzyl or methyl. The invention relates in particular to the mesylate salt of the compound of formula (1) wherein X is of the paper size applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310380 V. Invention description (4) The group of 6) and Y represent m-phenylbenzyl. Hydrochloric acid addition salts of the compounds of formula (1), together with their attractive pharmacological properties, are known from WO 97/36893. A disadvantage of this known HCl-salt is its poor solubility in water. The solubility at 2 ° C 8 and after 24 hours at 25 ° C was between 0.18 and 0.2 〇 11 ^ / 1111. It has been found that the mesylate salt of this compound has a solubility in water of about 8-10 times that of the hydrochloride, i.e., 1·7 mg/ml at 25 °C. This higher solubility is of great importance as it results in better bioavailability of the active compound. EXAMPLES The invention is illustrated by the following examples. A solution of 27.14 g (100 mmol) of bis(hydroxyethyl) m-phenylbenzylamine in 150 ml of methyl ethyl ketone (MEK) was sent to a thermometer, reflux condenser and machinery under nitrogen. In a 1000 ml round bottom flask with a stirrer. 42.50 g (240 mmol) of hydrazine sulfonic anhydride was dissolved in the solution at room temperature with stirring. The reaction mixture was cooled to 0-5 ° C, and 44.77 g (440 mmol) of triethylamine was added dropwise in 50 ml of MEK during 30-45 minutes, keeping the temperature below 10 °C. Add another 40 ml of MEK while stirring for 15 minutes at 0-5. (:. Add 23.08 g (240 mmol) of sulfonic acid in 30 ml of MEK while maintaining the temperature below i〇 °C during 10-25 minutes. Rinse with 30 ml of MEK while stirring for 15 minutes. The cooling was stopped, and 15.01 g (100 mmol) of the compound of formula (2) wherein X is a group of formula (6) was added. The mixture was rinsed with 130 ml of MEK and warmed at 20-251 for 1 hour. The clear solution is washed into another bottle and washed with 60 ml of MEK. The mixture is heated until reflux and about 60 ml. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 public) 1310380 A7 B7 V. Invention Description (5) MEK distillate. Continue to reflux for 8-24 hours and add 140 ml of MEK. Then distill 150 ml of water/MEK and cool the mixture to 〇-5 °C and mix at this temperature. 2 hours. The product was filtered to give the desired mesylate salt, washed twice with 75 ml cold MEK (0-5 ° C) and dried at 50 ° C (100 mbar) under nitrogen. g; melting range 263-275 ° C. A compound of formula (1) is prepared in a similar manner wherein 1) X is a group of formula (6) and Y is a fluorenyl group 2) X is formula (6) The group and Y are methyl methanesulfonate. -8- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

13103^0391102440 ------i- " Chinese patent application scope 隼 change boat production ^ page change VI, application patent model 1 1. A method for preparing hexahydropyrrolidine derivatives, characterized by a compound of the formula (ι) Sulfonate An amine of formula (2A) Compound with formula (3) And the subsequent anhydride reaction is prepared, wherein Y is a mercapto group, an ethyl group, an ethyl group substituted by one or more fluorine atoms, and the selectivity of the paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 public) 1310380 A8 B8 a ring-burning (3_7 C) group substituted with one or more fluorine atoms, or a group of formula (3) Wherein Z 疋 hydrogen 'phenyl' is a phenyl group substituted with 3 substituents selected from the group consisting of a transalkyl group, a halogenated group, a) an alkoxy group (1_4 C) or a cyano group, and a gas or 13 selected from the group consisting of a substituent of a halogen, a secret, a base c) or an alkoxy group (Bu 4 c). The above reaction is carried out in the presence of an organic solvent t and at a temperature between 〇 ° C and 150 ° C in the presence of the test. 2. The method according to claim 1 of the Patent Application No. 1 Xi Shi Targeting, characterized by the alkali triethylamine. 3. According to the method of claim 1 of the patent scope, or A and B. The organic solvent is monochlorobenzene. 4. According to the method of the patent application, the temperature is the reflux temperature. 5. The method according to the scope of the patent application, characterized in that a formazin is prepared in which a compound of the formula (A) wherein γ represents phenyl-phenyl, aryl or methyl. 6. According to the scope of the patent application! The method of the present invention is characterized in that a methyl orthoformate of the compound of the formula (A) wherein γ is a m-carbyl fluorenyl group is prepared. 7. A method according to the invention of claim i, characterized in that a methionate of the compound of the formula (1A) of the gamma benzyl group is prepared. Characterized by the preparation of a methyl sulphate of the compound of the formula (1A) wherein Y is a method according to the first aspect of the invention. 8. A BCD 1310380 VI. Scope of Application 9. A sulfonate of the compound of formula (1A), Where such symbols have the meaning as defined in item 1 of the scope of the patent application. 10. The mesylate salt according to item 9 of the scope of the patent application, wherein the symbols have the meanings as defined in item 2 of the scope of the patent application. 11. The oxime sulfonate of the compound of formula (1A) according to claim 10, wherein Y is m-phenylbenzyl. 12. The oxime sulfonate of the compound of formula (1A) according to claim 10, wherein Y is a fluorenyl group. 13. The oxime sulfonate of the compound of formula (1A) according to claim 10, wherein Y is a fluorenyl group. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm)