WO2001066549A1

WO2001066549A1 - Intermediate compounds

Info

Publication number: WO2001066549A1
Application number: PCT/JP2001/001671
Authority: WO
Inventors: Michiro Ohnoda; Junichiro Uda; Yasumasa Iwai; Takahiro Tanase
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 2000-03-07
Filing date: 2001-03-05
Publication date: 2001-09-13
Also published as: AU2001236079A1

Abstract

In the production of N-benzyldioxothiazolidinylmethyl-benzamide derivatives useful in the treatment of diabetes and hyperlipidemia, it is necessary to develop novel intermediates for the production on an industrial scale of 5-formyl-2-methoxybenzoate esters, which are used as starting materials in producing the derivatives, and processes for production of the esters with the intermediates. It has been found that 4-methoxy-3-alkoxycarbonylphenyl-methylhexamethylenetetraminium chlorides represented by the general formula (1) (wherein R is lower alkyl) are useful as intermediates in the production of 5-formyl-2-methoxybenzoate esters on an industrial scale.

Description

Satsuki Itoda β Manufacturing Intermediate Technical Field

The present invention relates to a novel 4-methoxy-3-alkoxycarbonylphenylmethyl which is a production intermediate for producing a ベンジル -benzyldioxothiazolidinylmethylbenzamide derivative useful for the treatment of diabetes and hyperlipidemia. The present invention relates to a derivative hexamethylenetetraminium chloride, a method for producing the same, and uses thereof. Background art

A ベンジル -benzyldioxothiazolidinylmethylbenzamide derivative is known as a compound having an excellent hypoglycemic and hypolipidemic action (JP-A-9-48771). Among these, (±) — 5— [(2,4 dioxothiazolidine-1-yl) methyl] — 2-methoxy Ν— [[4- (trifluoromethyl) phenyl] methyl] benzamide ( KR Ρ-297) has been developed as a promising drug (Μ. Nomura, et al., Bioorg. Med. Chem. Lett. 1999, 53.3). .

In the production of a series of N-benzyldioxothiazolidinylmethylbenzamide derivatives including KPR-297, methyl 5-formyl-12-methoxybenzoate is used as a starting material. I have. 5-Formyl-12-methoxybenzoic acid esters are known compounds, but no industrially advantageous production method capable of supplying them inexpensively and in large quantities has not been known. It is known that 5-formyl-2-methyl benzoate can be obtained, for example, by the following method.

1) A method in which commercially available salicylic acid is formylated by a Reimer-Tiemann reaction, followed by esterification and hydroxyl methylation (E. J. Wayne et al., J. Chem. S. oc., 1 9 2 2_, 1 0 2 2.) o

In this method, 3-formyl isomer is by-produced during formylation, and thus it is necessary to separate it from 5-formyl. For this reason, the operation becomes complicated, and it is difficult to improve the yield.

2) A method of sequentially or simultaneously subjecting commercially available 5-formylsalicylic acid to acid esterification and hydroxyl methylation (R. Filler et al., J. Fluorine Chem. 1995, 74, 69, Μ. L Wh itel aw et al., J. Agric. Chem. 1991, 39, 663.) o

Although this method is simple, the disadvantage is that the raw material, 5-formylsalicylic acid, is quite expensive.

3) A method of reacting commercially available methyl 0-anisate with hexamethylenetetramine in TFA, followed by hydrolysis to form C-formylate (application of Duff reaction, Patent No. 2852659).

Although this is a fairly simple method, it is considered unsuitable for mass production because it uses expensive and extremely strong organic acids such as TFA.

In order to produce 5-formyl-2-methoxybenzoate on an industrial scale, the above-mentioned known method cannot be used as it is.

On the other hand, according to JP-A-48-19539, salicylic acid or its ester is halomethylated and then reacted with hexamethylenetetramin to obtain a hexamethylenetetraminium chloride derivative, which is hydrolyzed. By way of understanding, a method for producing 5-formylsalicylic acid or an ester thereof is disclosed. In order to obtain 5-formyl-12-methoxybenzoate using this method, it is necessary to further methylate the 2-position hydroxyl group. However, methylation while retaining oxidation-sensitive aldehyde groups may reduce yield and purity, and therefore needs to be improved for industrial production.

Against this background, there has been no known industrial process for producing 5-formyl-2-methoxybenzoate, which is useful as a raw material for the production of pharmaceuticals.

In producing an N-benzyldioxothiazolidinylmethylbenzamide derivative useful for the treatment of diabetes and hyperlipidemia, the starting material, 5-formyl-12-methoxybenzoate, was used. The development of new production intermediates is required for production on an industrial scale. Disclosure of the invention

In producing 5-formyl-2-methoxybenzoic acid ester on an industrial scale, the present inventors have proposed an intermediate for the production.

General formula (1)

(R represents a lower alkyl group). Hexamethylenetetraminium chloride of a 4-methoxy-3-alkoxycarbonylphenylmethyl derivative represented by the formula:

That is, the present invention provides a compound represented by the general formula (2):

(R represents a lower alkyl group) by reacting the compound represented by the formula

General formula (1)

(R represents a lower alkyl group) by preparing a hexamethylenetetramine chloride of a 4-methoxy-3-alkoxycarbonyldimethylmethyl derivative represented by the formula:

General formula (3)

(Wherein R represents a lower alkyl group), which industrially advantageously produces 5-formyl-2-methoxybenzoate.

The production process of the present invention adapts the so-called Somme 1 et reaction. However, the compound of the general formula (1) is novel, has not been used for the production of 5-formyl-12-methoxybenzoate, and its industrial utility has not been known. . According to the present invention, 5-formyl-l-2 is obtained by using hexamethylenetetramine chloride of a 4-methoxy-13-alkoxycarbonylphenylmethyl derivative represented by the general formula (1) as a production intermediate. N-benzyldioxothiazo, which is industrially advantageous for producing methoxybenzoic acid esters and is therefore promising for the treatment of diabetes and hyperlipidemia. A lysinylmethylbenzamide derivative can be produced industrially advantageously.

The lower alkyl group in the present invention is a methyl group, an ethyl group or a propyl group, and is preferably a methyl group.

The compound of the general formula (1) is obtained as follows. That is, the public knowledge (R. Quellet et al., Bull. Soc. Chem. Fr. _

969 (5), 1698.) or the compound of the general formula (2) which is easily synthesized by a known method, is dissolved in an organic solvent, and commercially available hexamethylenetetramamine is added thereto with stirring. After cooling with heating and stirring, it can be taken out as crystals. Here, as the organic solvent, 1 to 2 times the amount of ethyl acetate or toluene is used, and in this case, about 1/2 times the amount of alkanols such as isopropanol is added to form a mixed solvent. It is preferable to use them. The amount of hexanemethylentramine used in the reaction is preferably from 1 to 1.2 equivalents of the compound of the general formula (2). Further, the heating and stirring are performed at a temperature of from the boiling point of the solvent to 100 ° C. for 2 to 5 hours. After cooling, the precipitated crystals are collected by filtration, washed with an organic solvent, and dried, whereby the compound of the general formula (1) can be obtained with high yield and high purity.

The thus-obtained compound of the general formula (1) can be easily converted to 5-formyl-2-methoxybenzoate of the general formula (3) by acid hydrolysis. That is, the compound of the general formula (1) is suspended in a 50% aqueous solution of 50% acetic acid, and the mixture is heated and stirred at 90 ° C to 110 ° C. The hydrolysis reaction is completed in 2-3 hours. Then, the mixture is cooled to room temperature or lower, and the crystals are collected by filtration, washed with water, and dried to obtain 5-formyl-2-methoxybenzoate. The 5-formyl-12-methoxybenzoate obtained by this method contains almost no impurities, so there is no need to recrystallize, etc. Can be used accordingly. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

(Reference example)

5-chloromethyl-1-methyl benzoate

<1 process>

6.60 g of paraformaldehyde was added to 72 mL of concentrated hydrochloric acid and dissolved. 20.0 g of commercially available 2-methoxybenzoic acid was charged, and the mixture was stirred at 30 to 35 ° C for 6 hours while introducing hydrogen chloride gas. To the reaction solution, 12 O mL of water under ice was added over 5 minutes, and after stirring for 30 minutes, the precipitated crystals were collected by filtration, washed with 24 mL of water, and washed with white crystals 27. 6 g were obtained. The crystals were dissolved in methyl acetate (8 mL) and washed with saturated saline (2 mL). 10.0 g of anhydrous magnesium sulfate was added and stirred overnight. The anhydrous magnesium sulfate was filtered and washed with 4 mL of methyl acetate. Methyl acetate was concentrated under reduced pressure to obtain 21.8 g (83.0%) of 5-chloromethyl-2-methoxybenzoic acid.

<2 steps>

20.3 g of 5-chloromethyl-2-methoxybenzoic acid was dissolved in 56 mL of methanol. The mixture was cooled to ire, and 19.2 g of acetyl chloride was added with stirring for 18 minutes (the temperature was raised to 24 ° C during this time). Then, after stirring at room temperature (22 to 28 ° C) for 2 hours, the solvent was concentrated under reduced pressure at a bath temperature of 40 ° C. As a concentrated residue, 21.3 g (98.2%) of methyl 5-chloromethyl-2-methoxybenzoate was obtained.

NMR (400 MHz, CDC13): (53.90 (3H, s), 3.92 (3H, s), 4.57 (2H, s), 6.97 (lH, d, J = 8.8 Hz), 7.50 (lH, dd, J = 2.4, 8.8 Hz), 7.83 (1H, d, J = 2 • 4 Hz).

MS (EI): m / e 216 [M + + 2], 214 [M ⁺ ]. (Example 1)

1-[(4-Methoxy-13-methoxycarbonyl) phenylmethyl] hexamethylene tetraminide

21.2 g of methyl 5-chloromethyl-2-methoxybenzoate obtained in Reference Example was dissolved in 74 mL of ethyl acetate. This ethyl acetate layer was washed with 44.5 mL of water and 44.5 mL of a saturated aqueous solution of sodium hydrogen carbonate. Next, 37 mL of isopropanol was added to this organic layer, 17.0 g of hexamethylenetetramamine was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to 7 ° C, and the precipitated crystals were collected by filtration. The residue was washed with 37 mL of ethyl acetate, air-dried at 40 ° C for 15 hours, and dried with 1-[(4-methoxy-3-methoxycarbonyl) phenylmethyl] hexamethylentetraminium 34.7 g (9 8.8%).

Melting point: 200-204 ° C.

_{IR (KBr):. 2924 J} 1732 (cm- 1) ^ NMR (400MHz, d 6 -DMS0): (53.82 (3Η, s), 3.88 (3H, s), 4.08 (2H, s), 4.42 (3H , d), 4.5 † (3H, d), 5.06 (6H, s) 7.29 (lH, d, J = 8.8Hz), '7.66 (lH, dd, J = 2.4,8.8Hz), 7.78 (lH, d MS (FAB): m / e 319 [M ⁺ -C1] ⁺ .

HPLC purity: 99.8% (Inertsil ODS-2, Solv. Acetonitrile-0.1% phosphoric acid (1: 1), UV240nm)

(Example 2)

5-formyl-1-methyl benzoate

1-[(4-Methoxy-3-Methoxycarbonyl) phenyl chloride [Methyl] hexamethylenetetramin 33.0 g, 50% acetic acid (66 mL) was added, and the mixture was stirred at 99 to 101 ° C (gently refluxing state) for 2 hours. The reaction solution was air-cooled, and 132 mL of water was added at 40 ° C. After stirring at 15 to 25 ° C for 4 hours, the precipitated crystals were collected by filtration. After washing with 43 mL of water, air-drying was performed at 40 ° C for 15 hours, followed by drying of 5-formyl-2-methyl benzoate 12.7 g (70.3%) (2-methoxybenzoic acid) 56.7%).

Melting point 86-87 ° (: (Example 3)

1-[(4-Methoxy-13-methoxycarbonyl) phenylmethyl] hexamethylenetetramethyl chloride

<1 process>

5-chloromethyl-2-methoxybenzoic acid

After dissolving 13.2 g (90%, 0.396 mol) of paraformaldehyde in 144 mL of concentrated hydrochloric acid, 40.0 g (0263 m01) of 2-methoxybenzoic acid was added. In addition, the mixture was stirred at 30 to 35 ° C for 6 hours while introducing hydrogen chloride gas.

24 O mL of water was added dropwise to the reaction solution, and the mixture was stirred at 20 to 30 ° C for 30 minutes, and the crystals were collected by filtration and washed with 48 mL of water. The obtained crystals were dissolved in 120 mL of dichloromethane, and the released water was separated. The organic layer was dried over anhydrous sodium sulfate (13.5 g), filtered off anhydrous sodium sulfate, and washed with dichloromethane (13 mL). The dichloromethane solution was distilled off under reduced pressure to obtain 58.9 g of wet crystals of 5-chloromethyl-2-methoxybenzoic acid as a residue. This was used in the next step as it was.

C 2 steps>

1-[(4-Methoxy-3-methoxycarbonyl) phenyl chloride Methyl] hexamethylenetetra minimum

To 12 mL of methanol was added 57.9 g of 5-chloromethyl-12-methoxybenzoic acid wet product and stirred at 10 to 30 ° C at 40 to 30 ° C for 41.3 g of acetyl chloride (0.52 6 mol) was added dropwise, and the mixture was stirred at 20 to 30 ° C for 2 hours.

The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 16 O mL of toluene.

Washing was performed sequentially with 6 mL and 96 mL of a saturated aqueous sodium hydrogen carbonate solution. The toluene layer was dried over anhydrous sodium sulfate and washed with 4 OmL of toluene. The filtrate and the washing solution were combined, and to this, 36.9 g (0.263 mol) of hexamethylenetetrathamine was added, and the mixture was stirred at 98 to: LO O ° C for 5 hours. After cooling to 20 ° C. or lower, the precipitated crystals were collected by filtration and washed with 8 O mL of ethyl acetate. Blow dry at 40 ° C for 16 hours to give the title compound 79.

7 g (84.3% yield from 2-methoxybenzoic acid) were obtained.

(Example 4)

5-formyl-1-methyl benzoate

1-[(4-Methoxy-3-3-methoxycarbonyl) phenylmethyl] hexamethylenetetramine 79.0 g (0.22 m 0 1) was suspended in 50% acetic acid (158 mL), and The mixture was stirred at 00 ° C for 2 hours. After cooling to 40 ° C, the reaction solution was added to 316 mL of water, and stirred at 15 to 25 ° C for 10 hours. The precipitated crystals were collected and washed with 105 mL of water. This was air-dried at 40 ° C. for 17 hours to obtain 31.5 g (74%) of methyl 5-formyl-2-methoxybenzoate.

86-87 ° C. Industrial applicability

N-benzyldioxothiazo useful for the treatment of diabetes and hyperlipidemia In the production of lysinylmethyl penzamide derivatives, a new 4-methoxy intermediate was used as a new production intermediate in order to produce the starting material 5-formyl-12-methoxybenzoate on an industrial scale. Hexamethylenetetramethyl chloride of a 3-alkoxycarbonylphenylmethyl derivative was found. By further hydrolyzing this, 5-formyl-12-methoxybenzoate could be industrially advantageously produced.

As a result, N-benzyldioxothiazolidinylmethylbenzamide derivative, which is promising for the treatment of diabetes and hyperlipidemia, is manufactured on an industrial scale using 5-formyl-2-methoxybenzoate as a raw material. It became possible to do.

Claims

Range of mouth blue

(R represents a lower alkyl group). Hexamethylenetetramine chloride of a 4-methoxy-3-alkoxycarbonylphenylmethyl derivative represented by the formula:

2. A hexamethylenetetraminium chloride of a 4-methoxy-3-methoxycarbonylphenylmethyl derivative in the general formula (1) according to claim 1, wherein R is a methyl group.

3. Equation (2)

(I also represents a lower alkyl group), characterized by reacting hexamethylene pentetramine with a compound represented by the formula:

General formula (1)

(Wherein R represents a lower alkyl group). A method for producing hexamethylenetetramine chloride of a 4-methoxy-3-alkoxycarbonylphenylmethyl derivative represented by the following formula:

4 General formula (1)

(Wherein R represents a lower alkyl group), characterized by acid hydrolysis of hexamethylenetetramethylene chloride of a 4-methoxy-13-alkoxycarbonylphenylmethyl derivative represented by the formula:

General formula (3)

(R represents a lower alkyl group). A method for producing 5-formyl-12-methoxybenzoate.

5. It is a hexamethylenetetraminium chloride of a 4-methoxy-3-alkoxycarboerphenylmethyl derivative represented by the general formula (1) according to claim 1 and is characterized by having diabetes and hyperlipidemia. Intermediate for the production of N-benzyldioxothiazolidinylmethylbenzamide derivatives useful for therapy.