KR20040020457A - A preparation process for 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl) piperidino]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one - Google Patents

Abstract

PURPOSE: A process for preparing 3-{2-£4-(6-fluorobenzo£d|isoxazol-3-yl) piperidino|ethyl}-2-methyl-6,7,8,9- tetrahydro-4H-pyrido £1,2-a|pyrimidin-4-one is provided, thereby increasing the preparation yield, preparing no by-product and carrying out the process under mild condition. CONSTITUTION: A process for preparing 3-{2-£4-(6-fluorobenzo£d|isoxazol-3-yl) piperidino|ethyl}-2-methyl-6,7,8,9- tetrahydro-4H-pyrido £1,2-a|pyrimidin-4-one represented by the formula(1) comprises reacting a compound of the formula(10) with a compound of the formula(7) under the condition of reduction reaction, wherein the reduction reaction is carried out by reacting the compound of the formula(7) with the compound of the formula(10) in a solvent in the presence of a reducing agent; the solvent is water, C1-6 alkanol, ether, halogenated carbohydrate, aromatic carbohydrate, a dipolar nonprotonic solvent or a mixed solvent thereof; the reducing agent is selected from zinc, H/Pd(or Pt, Ni), seleno-phenol, NaBH4, NaCNBH3, NaBH(OAc)3, LiAlH4, hydrosilan/Lewis acid, BH3/amine, pentacarbonyliron/alcoholic potassium hydroxide or formic acid; and the reduction temperature is 0 to 25 deg. C.

Description

3- ｛2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl｝ -2-methyl-6,7,8,9-tetrahydro-4H-pyrido A preparation process for 3-X2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl｝ -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one}

The present invention is a 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6, 7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or a pharmaceutically acceptable acid addition salt thereof.

3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro- of Formula 1 4H-pyrido [1,2-a] pyrimidin-4-one has antipsychotic properties and is widely used as an antipsychotic agent in foreign countries as well as in Korea, and various manufacturing methods have been known so far.

Korean Patent No. 221108 discloses a technique for preparing a compound of Formula 1 through a cyclization reaction, as shown in Scheme 1, using a compound of Formula 2 and a compound of Formula 3.

In Formula 3, Y and Z are the same as or different from each other, and are a protecting group including a halogen, alkylsulfonyloxy or arylsulfonyloxy group.

In Scheme 1, Y and Z are as defined in Chemical Formula 3.

In addition, Korean Patent No. 109642 discloses a technique of preparing a compound of Formula 1 by cyclization reaction using the compound of Formula 4 as shown in Scheme 2 below, and Korean Patent No. 109643 discloses a compound of Formula 5 By using the cyclization reaction as shown in Scheme 3 below to disclose a technique for producing a compound of formula (1).

In Formula 4, L is an acid residue, in particular (C _1-6 alkyl or aryl) carbonyl, (C _1-6 alkyl or aryl) oxycarbonyl, (C _1-6 alkyl or aryl) sulfonyl or N-acyl Aminocarbonyl.

In Scheme 2, L is as defined in Formula 4.

In Formula 5, Y is a reactive leaving group such as halo or nitro.

In Scheme 3, Y is as defined in Formula 5.

However, the method for preparing the compound of Formula 1 disclosed in the above-described Korean Patent No. 221108, Korean Patent No. 109642, and Korean Patent No. 109643 has a disadvantage in that the yield is low because it is a cyclization reaction. The production of starting materials presented by the company is somewhat complicated and the yield is low, making it difficult to use industrially.

Unlike the cyclization reaction of the aforementioned patent document, EP 0196132 and International Patent PCT / IN00 / 00053 prepare a compound of Chemical Formula 1 by reacting a compound of Chemical Formula 6 with a compound of Chemical Formula 7 as shown in Scheme 4. Disclosed is a technique.

In Formula 6, W is halo such as chloro, bromo or iodo; Or a reactive ester residue such as a sulfonyloxy group such as mesylsulfonyloxy and (4-methylphenyl) sulfonyloxy.

In Scheme 4, W is as defined in Chemical Formula 6.

The condition of Scheme 4 disclosed in EP 0196132 is low in yield as it proceeds under an inert organic solvent, while the condition of Scheme 4 disclosed in International PCT / IN00 / 00053 is in an aqueous solution in the presence of an inorganic salt. It has the advantage that the yield is relatively high compared to the reaction of EP 0196132.

The preparation method by the substitution reaction disclosed in EP 0196132 and International Patent PCT / IN00 / 00053 can be seen simply as the reaction of the compound of Formula 8 and the compound of Formula 9, as shown in Scheme 5 below. It is well known that the elimination reaction as in Scheme 6 occurs competitively in the form of substitution reaction, and as the temperature of the reaction increases, the elimination reaction prevails over the substitution reaction, thereby increasing the by-product generation rate (A Guidebook to Mechanism in Organic Chemistry, 6th ed, 1991, Peter Sykes, pp. 246-269).

In addition, the reaction of the compound of Formula 8 with the compound of Formula 9 may produce quaternary ammonium salts through Scheme 7 and Scheme 8 when W is a halogen or other reactive leaving group (Advanced Organic Chemistry, 4th ed, Jerry March, 1992, p. 422; Comprehensive Organic Functional Group Transformations, vol 2, Alan R. Katritzky et al., 1995, p. 760).

Therefore, the preparation method by the substitution reaction disclosed in EP 0196132 and International Patent PCT / IN00 / 00053 is carried out at a high temperature of 85 ~ 90 ℃ can produce alkene compounds and quaternary ammonium salts as by-products. As a result, the yield is low (46 to 72%), high reaction temperature (85 to 90 ℃) and the reaction time is long.

Thus, the present inventors completed the present invention after studying a method of obtaining the compound of Formula 1 in a high yield without generating by-products as well as being able to be carried out under mild reaction conditions to improve the above disadvantages.

Accordingly, the present invention provides 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino in high yield without the formation of by-product alkene compounds and quaternary ammonium salts under mild reaction conditions. It is an object of the present invention to provide a method for preparing] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one.

The present invention to achieve the above object

A method of preparing a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof by reacting a compound of formula 10 or an acid adduct thereof with a compound of formula 7 or an acid adduct thereof under reducing reaction conditions to provide.

<Formula 1>

<Formula 7>

Hereinafter, the present invention will be described in more detail.

In the present invention, 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8, having a structure of Formula 1, 9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or a pharmaceutically acceptable acid addition salt thereof as a method for preparing 2- (2-methyl- 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde compound or acid adduct thereof and 6-fluoro- Provided is a method of reacting a 3- (4-piperidyl) benzo [d] isoxazole compound or an acid adduct thereof under reducing reaction conditions.

Since the pharmaceutically acceptable acid addition salt for the compound of Formula 1 can be obtained by the same method as the method for preparing the compound of Formula 1 using the acid addition of the compound of Formula 10 or the compound of Formula 7, In the following description, focusing on the method for preparing the compound of Formula 1, it is obvious that the method for preparing a pharmaceutically acceptable acid addition salt of the compound of Formula 1 is also included in the scope of the present invention.

According to the present invention, the compound of Formula 7 and the compound of Formula 10 are reacted under reducing reaction conditions. More specifically, the aldehyde compound of Formula 10 and the amine compound of Formula 7 are reacted in the presence of a reducing agent to form a bond between nitrogen and carbon. Entails reductive alkylation of the amine. This is a reduction alkylation reaction of an amine which induces a bond between nitrogen and carbon by reacting a carbonyl compound with an amine compound in the presence of a reducing agent.

However, since a compound containing an isoxazole ring tends to be easily reduced and decomposed to a nitrogen-oxygen bond under a hydrogen reduction condition by a heavy metal catalyst, a compound of Formula 7 and a compound of Formula 10 through conventional reduction reactions are well known. Reaction causes the reduction and decomposition of the isoxazole ring of formula (7), so that the target compound, that is, the compound of formula (1) cannot be obtained.

Therefore, in the present invention, the reaction was performed by mixing and stirring the amine compound represented by Chemical Formula 7, the compound represented by Chemical Formula 10, and a reducing agent so as not to cause reduction and decomposition of the isoxazole ring.

Solvents that can be used include water; C _1-6 alkanols (eg methanol, ethanol, 2-propanol, etc.); Ethers such as 1,4-dioxane, tetrahydrofuran, 2-methoxyethanol and the like; Halogenated hydrocarbons such as trichloromethane and the like; Aromatic hydrocarbons (eg benzene, toluene, etc.); bipolar aprotic solvents (eg N, N-dimethylformamide); Or mixed solvents thereof.

Reducing agents include zinc, hydrogen / Pd (or Pt, Ni), selenophenol, NaBH ₄ , NaCNBH ₃ , NaBH (OAc) ₃ , LiAlH ₄ , hydrosilane / lewisic acid, BH ₃ / amine, pentacarbonyl iron / One selected from alcoholic potassium hydroxide or formic acid can be used.

As described above, a suitable acid (eg, 4-methylbenzenesulfonic acid, methanesulfonic acid, acetic acid, etc.) is added to the solvent to prepare the compound of Chemical Formula 1 by mixing and stirring the compound of Chemical Formula 7, the compound of Chemical Formula 10, and the reducing agent. Reaction can be induced.

In this case, the reaction proceeds at 0 to 25 ° C. In the present invention, even when the reaction proceeds under such mild conditions, the compound of Formula 1 can be obtained with a high yield of 80% or more.

In particular, in the production method disclosed in the prior art EP 0196132 and the international patent PCT / IN00 / 00053 can be produced by-product alkene compound and quaternary ammonium salt, in the present invention by-products by using the aldehyde compound as a starting material There is no possibility of formation of phosphorus alkenes or quaternary ammonium salts. It is already known that there is no possibility of the formation of by-product alkenes or quaternary ammonium salts during reductive alkylation of the aldehyde and amine compounds (Reductions in Organic Chemistry, 2nd ed, Milos Hudlicky, 1995, pp. 187-190).

Therefore, the present invention not only can produce the target compound of Chemical Formula 1 by performing a reduction reaction without the above side reactions under mild conditions, and also improves the yield compared to conventional known methods, and it is easy to apply industrial production due to less byproducts. Has the advantage.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only presented to aid the understanding of the present invention, but the present invention is not limited thereto.

<Example 1>

Preparation of 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde

After filling 40 ml of dichloromethane and 1.4 g (0.011 mol) of oxalyl chloride and cooling the reactor to -60 ° C, 1.73 g (0.022 mol) of dimethyl sulfoxide was slowly added to 5 ml of dichloromethane. Stir at the same temperature for 10 minutes, 3- (2-hydroxyethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one 2.1 g (0.010 mol) is dissolved in 8 ml of dichloromethane and added slowly. After stirring at −60 ° C. for 15 min, 7 ml (0.05 mol) of triethylamine are added slowly. Stir for another 5 minutes, remove the chiller and add 30 ml of water at room temperature. The organic layer was separated, the aqueous layer was extracted with 20 ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. 1.95 g of 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde by removing the solvent at reduced pressure (94%) was obtained.

¹ H NMR data of the obtained compound are as follows.

1 H NMR (CDCl ₃ ), (ppm): 9.58 (s, 1H), 3.81 (t, 2H), 3.53 (s, 2H), 2.78 (t, 2H), 2.10 (s, 3H), 1.87-1.77 ( m, 4H).

<Example 2>

3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido Preparation of [1,2-a] pyrimidin-4-one

2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) in a reactor cooled to 0 ° C. under a nitrogen stream. 950 mg (4.6 mmol) of acetaldehyde and 1015 mg (4.6 mmol) of 6-fluoro-3- (4-piperidyl) benzo [d] isoxazole were dissolved in 25 ml of methanol and stirred with 92.5 mg (1.44 mmol) of NaCNBH ₃ . After addition, it is stirred for 4 hours at room temperature. A small amount of ice is added and the solvent is evaporated at reduced pressure. Extracted with dichloromethane 20ml, dried over anhydrous sodium sulfate, the solvent was evaporated to dryness under reduced pressure and recrystallized in ethanol to give a white solid 1516mg (80.2%).

¹ H NMR data of the obtained compound are as follows.

¹ H NMR (CDCl ₃ ), (ppm): 7.74 (dd, 1H), 7.25 (dd, 1H), 7.05 (ddd, 1H), 3.92 (t, 2H), 3.15 (m, 3H), 2.86 (t , 3H), 2.80 (m, 2H), 2.59 (m, 2H), 2.32 (s, 3H), 2.13 (m, 4H), 1.92 (m, 6H)

<Example 3>

3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido Preparation of [1,2-a] pyrimidin-4-one

500 mg (2.42 mmol) and 6- 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde 529 mg (2.4 mmol) of fluoro-3- (4-piperidyl) benzo [d] isoxazole was dissolved in 5 ml of ethanol, and 0.3 ml (2.4 mmol) of BH ₃ -pyridine complex was added with stirring, followed by 3 hours at room temperature. Stir about. The solvent is removed at reduced pressure and 100 ml of dichloromethane and 100 ml of water are added. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by short silica gel chromatography to obtain 828 mg (84%) of a white solid.

¹ H NMR data of the obtained compound is the same as the data of Example 2.

<Example 4>

3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido Preparation of [1,2-a] pyrimidin-4-one

500 mg (2.42 mmol) of 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde under nitrogen stream And 529 mg (2.4 mmol) of 6-fluoro-3- (4-piperidyl) benzo [d] isoxazole in 20 ml of 1,2-dichloroethane and stirred while stirring for 763 mg (3.6 mmol) of NaBH (OAc) ₃ . Add 0.14 ml (2.4 mmol) of acetic acid and stir for 2 hours at room temperature. A small amount of ice is added and the solvent is evaporated at reduced pressure. Extracted with 80 ml of dichloromethane, dried over anhydrous sodium sulfate, and purified by short silica gel chromatography to obtain 878 mg (89.1%) of a white solid.

¹ H NMR data of the obtained compound is the same as the data of Example 2.

The compound obtained in Examples 2 to 4 was 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl}-of Chemical Formula 1 from the ¹ H NMR data. It can be seen that 2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, and the yield is greatly improved compared to the conventional method. .

As described above, the present invention provides 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) in high yield without formation of by-product alkenes and quaternary ammonium salts under mild reaction conditions. Useful invention providing a process for preparing piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one to be.

Claims (6)

3- {2- [4- (6), wherein the compound of Formula 10 or an acid adduct thereof is reacted with a compound of Formula 7 or an acid adduct thereof under reducing reaction conditions to produce a compound of Formula 1 -Fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- A method of preparing 4-one or a pharmaceutically acceptable acid addition salt thereof. <Formula 1> <Formula 7> <Formula 10> The method of claim 1, wherein the reducing reaction is performed by mixing and stirring a compound of Formula 7 or an acid adduct thereof and a compound of Formula 10 or an acid adduct thereof together with a reducing agent in a solvent. -(6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] Method for producing pyrimidin-4-one or acid addition salts thereof. The process of claim 2, further comprising water; C _1-6 alkanols; ether; Halogenated hydrocarbons; Aromatic hydrocarbons; Dipolar aprotic solvents; Or 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7, characterized by using a mixed solvent thereof. Method for producing 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or acid addition salts thereof. The method of claim 3, wherein the reducing agent is zinc, hydrogen / Pd (or Pt, Ni), selenophenol, NaBH ₄ , NaCNBH ₃ , NaBH (OAc) ₃ , LiAlH ₄ , hydrosilane / Lewis acid, BH ₃ / amine, penta 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidino] ethyl} -2-characterized by using those selected from carbonyl iron / alcoholic potassium hydroxide or formic acid A method for producing methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or acid addition salts thereof. The 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl according to any one of claims 2 to 4, wherein the temperature of the reaction part in the reduction reaction is 0 to 25 ° C. ) Piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or its acid addition salt. The 3- {2- [4- (6-fluorobenzo [] according to claim 5, wherein an acid selected from 4-methylbenzene sulfonic acid, methanesulfonic acid and acetic acid is further added to the solvent during the reduction reaction. d] isoxazol-3-yl) piperidino] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one or its Method for preparing acid addition salt.