JPH09100278A - Production of indole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and efficiently produce a high-purity indole derivative useful as a therapeutic agent for osteoporosis according to a specific method. SOLUTION: A compound of formula I (R<1> is H, a lower alkenyl, etc.; R<2> and R<3> are each a lower alkyl, a substituted aralkyl, etc.) is reacted with a compound of formula II (R<6> is H, a lower alkyl, etc.; R<7> and R<8> are each H, an unsubstituted aryl, etc.) in the presence of an acid (e.g. hydrochloric acid or toluenesulfonic acid) to afford the objective compound of formula III. The reaction is preferably carried out at -5 to +10 deg.C by using 1-1.5 equiv. compound of formula I and 1-1.5 equiv. acid. The reaction is usually completed within 0.5-72hr. Furthermore, e.g. 4,4-bis(tetrahydropyranyloxy)benzhydrol is cited as the compound of formula I. For example, 1-(2-chlorophenyl)-4-[1-(2- dimethylaminoethyl)indol-2-ylcarbonyl]piperazine is cited as the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a salt of an indole derivative useful as a therapeutic drug for osteoporosis.

[0002]

It is known that the indole derivative of the present invention is useful as a therapeutic drug for osteoporosis (WO95 /
19343 publication).

However, in the method described in the publication, three steps are required for producing the target compound from the starting compound used in the present production method, and since each step involves isolation operation, the yield is high. Inevitably lowers.
In addition, the intermediate may be an oily substance, which is complicated in operation such as isolation, and in some cases, it is necessary to use a highly dangerous water-prohibiting reagent when performing large-scale synthesis. Further, depending on the raw material, a by-product that is highly reactive and difficult to remove by purification may be generated, and a more efficient production method has been demanded.

[0004]

An object of the present invention is to provide a method for producing a salt of an indole derivative useful as a therapeutic drug for osteoporosis simply and efficiently.

[0005]

According to the present invention, there is provided a compound represented by the general formula (I):

Embedded image [In the formula, R ¹ represents hydrogen, lower alkyl or lower alkenyl, R ² and R ³ are the same or different, and are lower alkyl, lower alkenyl, substituted or unsubstituted aralkyl or the formula:

Embedded image (In the formula, R ⁴ and R ⁵ are the same or different and are hydrogen,
Represents a lower alkyl or a substituted or unsubstituted aralkyl, or represents a substituted or unsubstituted alicyclic heterocyclic group formed by R ⁵ and R ⁵ together with an adjacent oxygen atom, and n is 0 Represents an integer of 6 to 6) and a compound represented by the general formula (II):

Embedded image [In the formula, R ⁶ is hydrogen, lower alkyl or the formula:

Embedded image (In the formula, R ⁹ and R ¹⁰ are the same or different and each represents hydrogen or lower alkyl, or R ⁹ and R ¹⁰ are taken together to form a substituted or unsubstituted alicyclic ring formed together with an adjacent nitrogen atom. Represents a formula heterocyclic group, m represents an integer of 2 to 6), R ⁷ and R ⁸ are the same or different, and are hydrogen, lower alkyl, alicyclic alkyl, substituted or unsubstituted Of aryl or a substituted or unsubstituted heterocyclic group, or R ⁷ and R ⁸ are taken together,
Representing a substituted or unsubstituted alicyclic heterocyclic group formed with an adjacent nitrogen atom] in the presence of an acid, a general formula (III):

Embedded image The present invention provides a method for producing a salt of an indole derivative represented by the formula (wherein R ⁶ , R ⁷ and R ⁸ are as defined above).

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound represented by the general formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

In the definition of each group of the compounds (I) to (III), the lower alkyl is, for example, linear or branched one having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te
Examples thereof include rt-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Examples of alicyclic alkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Can be mentioned. Examples of aryl include phenyl and naphthyl, and examples of lower alkenyl include linear or branched C 2-8 carbons such as vinyl, propenyl, isopropenyl, butenyl,
Examples include isobutenyl and the like. Aralkyl has 7 to 20 carbon atoms, for example, benzyl, benzhydryl,
Examples include trityl, phenethyl, 1,2-diphenylethyl, naphthylmethyl and the like. Examples of the alicyclic heterocyclic group formed with an adjacent oxygen atom include, for example, tetrahydropyranyl, tetrahydrofuranyl, and the like, and the alicyclic heterocyclic group formed with an adjacent nitrogen atom includes, for example, pyrrolidinyl. , Imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino and the like. As the heterocyclic group, in addition to the alicyclic heterocyclic group, pyridyl,
Pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl,
Aromatic heterocyclic groups such as isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl and purinyl.

The substituted alicyclic heterocyclic group formed with an adjacent oxygen atom, the substituted alicyclic heterocyclic group formed with an adjacent nitrogen atom, the substituted heterocyclic group, the substituted aryl and the substituent in the substituted aralkyl are: The same or different and having 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, lower alkylthio, aralkyl, carboxy, lower alkoxycarbonyl, lower alkanoyl, aroyl, nitro, halogen, amino, mono- or di-lower alkyl Amino, trifluoromethyl,
Substituted or unsubstituted phenyl, pyridyl, pyrimidinyl and the like can be mentioned.

In the definition of the substituent, the lower alkyl moiety in lower alkyl and lower alkoxy, lower alkylthio, lower alkoxycarbonyl, mono- or di-lower alkylamino has the same meaning as the above lower alkyl. Aralkyl has the same meaning as the above aralkyl, and the aryl moiety in aroyl has the same meaning as the above aryl. The lower alkanoyl includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like having 1 to 7 carbon atoms. Halogen means each atom of fluorine, chlorine, bromine and iodine. The substituents on the substituted phenyl may be the same or different and have a substitution number of 1
~ 3, for example, lower alkyl, hydroxy, lower alkoxy, lower alkylthio, aralkyl, carboxy,
Lower alkoxycarbonyl, lower alkanoyl, aroyl, nitro, halogen, amino, mono- or di-lower alkylamino, trifluoromethyl and the like, lower alkyl, lower alkoxy, lower alkylthio, aralkyl, lower alkoxycarbonyl, lower alkanoyl,
Aroyl, halogen, and mono- or di-lower alkylamino have the same meanings as described above.

Examples of the acid include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, glyoxylic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid,
Examples thereof include organic acids such as benzenesulfonic acid and toluenesulfonic acid. Examples of the salt include salts of the above various acids.

Hereinafter, the present invention will be described in detail. Among the starting compounds, compound (I) can be obtained by the method described in Tetrahedron Letters 28 , 5651 (1987), or a method analogous thereto. In addition, compound (II) is used in the Journal of the American Chemical Society (J. Am. Chem. So
c.) 67 , 423 (1945) or Journal of Medicinal Chemistry (J. Med. Chem.) 32 , 1681 (19
89) or a method similar thereto.

The salt of compound (III) includes compound (II) and compound (II) in an amount of 1 to 1.5 equivalents, and compound (II) in an amount of 1.1 to 10 equivalents. By reacting in a solvent in the presence of an acid such as 1.1 to 5 equivalents of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. Obtainable. Compound (I)
With respect to R ² and R ^{3 in} , preferable examples of the aralkyl include benzhydryl and trityl. Also,
formula:

Embedded image In the group represented by, preferably n is 0 or 1, and for example, tetrahydropyranyl, methoxymethyl,
Examples include ethoxyethyl and benzyloxymethyl.

As the reaction solvent, an aprotic solvent (eg ethyl acetate, ether, tetrahydrofuran, etc.),
Protic solvents (eg, methanol, ethanol, isopropanol, etc.) are used alone or in combination.

The reaction is carried out at -20 ° C to the boiling point of the solvent, preferably -5 to 10 ° C, and is completed in 0.5 to 72 hours. Since the target compound precipitates as crystals as the reaction progresses, the target compound can be easily isolated by filtration after the reaction is completed.

The target compound in the above-mentioned production method is
It can be purified by subjecting it to a purification method commonly used in synthetic organic chemistry, for example, recrystallization.

Now, according to the present invention, a coupling reaction,
It was found that the deprotection reaction and crystallization by salt formation were carried out in one step, and a method for efficiently producing the target compound was established. Further, the target compound is precipitated as crystals along with the progress of the reaction, which hinders the progress of the side reaction, so that the target compound can be obtained in high purity, so that the present reaction is further useful.

Examples and reference examples of the present invention will be shown below.

【Example】

Example 1 1- {3- [bis (4-hydroxyphenyl) methyl] -1
-(2-Dimethylaminoethyl) indol-2-ylcarbonyl} -4- (2-chlorophenyl) piperazine methanesulfonate (Compound 1) 4,4'-bis (tetrahydropyranyloxy) benzhydrol 500 g (1 .30 mol) and 1- (2-chlorophenyl) -4- [1- (2-dimethylaminoethyl) indol-2-ylcarbonyl] piperazine 64
0 g (1.30 mol) was suspended in a mixed solvent of methanol (2.5 L) and isopropanol (2.5 L), and 0
At 25 ° C. 625 g (6.5 mol) of methanesulphonic acid were added. The mixture was stirred at -5-5 ° C for 22 hours. The precipitated crystals were collected by filtration to obtain 940 g of a crude product (content correction value: 798 g). 800 g of the crude product obtained
By recrystallizing (content correction value 679 g) from methanol, the title compound (582 g, 0.877 mmol,
A total yield of 74.6%) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ (pp
m): 2.26 to 2.30 (1H, m), 2.41 (3)
H, s), 2.55 to 2.68 (1H, m), 2.70 to
2.95 (7H, m), 2.95 to 3.20 (2H,
m), 3.30 to 3.50 (3H, m), 3.60 to 3.7
5 (1H, m), 3.80 to 3.95 (1H, m), 4.
33 to 4.40 (1H, m), 4.55 to 4.64 (1
H, m), 5.50 (1H, s), 6.55 to 6.70
(4H, m), 6.80 to 7.10 (8H, m), 7.1
5 to 7.35 (2H, m), 7.37 (1H, dd, J =
1.5, 7.9 Hz), 7.62 (1H, d, J = 8.3
Hz), 9.11 (1H, br.s), 9.19 (1H,
br. s), 9.70 to 9.83 (1H, br.s) IR (KBr tablet): 1612, 1595, 1512, 1
450,1231,1150 cm ^-1 Melting point 197-200 ° C Elemental analysis C ₃₇ H ₄₁ ClN ₄ O ₆ S CHN theoretical value (%); 63.01 5.86 7.94 Found value (%); 62. 89 5.87 7.65

Example 2 1- {3- [bis (4-hydroxyphenyl) methyl] -1
-(2-Dimethylaminoethyl) indol-2-ylcarbonyl} -4- (2-chlorophenyl) piperazine methanesulfonate (Compound 1) 4,4'-bis (methoxymethoxy) benzhydrol 2.02 g (6 .64 mmol) and 1- (2-chlorophenyl) -4- [1- (2-dimertiaminoethyl) indol-2-ylcarbonyl] piperazine 2.27 g
(5.53 mmol) was suspended in a mixed solvent of methanol (10.6 ml) and isopropanol (10.6 ml), and 0
At 66C, 2.66 g (27.7 mmol) of methanesulfonic acid were added. The mixture was stirred at 0-5 ° C for 20 hours. The precipitated crystals were collected by filtration to give the title compound as a crude product 4.22 g (content correction value 3.63 g, 5.04 mmo
l, 91.1%) was obtained. The same data as in Example 1 were obtained for NMR, melting point and elemental analysis.

Example 3 1- {3- [bis (4-hydroxyphenyl) methyl] -1
-(2-Dimethylaminoethyl) indol-2-ylcarbonyl} -4- (2-chlorophenyl) piperazine methanesulfonate (Compound 1) 4,4'-bis (tetrahydropyranyloxy) benzhydrol 4.51 g (11.7 mol) and 1- (2-
Chlorophenyl) -4- [1- (2-dimethylaminoethyl) indol-2-ylcarbonyl] piperazine 4.0 g (9.75 mmol) was suspended in ethanol (44 ml) and methanesulfonic acid 4.68 g was added at 5 ° C. (48.7mmo
l) was added. The mixture was stirred at 0-5 ° C for 18 hours. The precipitated crystals were collected by filtration to give 7.03 g of the title compound as a crude product (content correction value 6.54 g,
9.28 mmol, 95.1%) was obtained. The same data as in Example 1 were obtained for NMR, melting point and elemental analysis.

Reference Example 1 4,4'-bis (tetrahydropyranyloxy) benzophenone 4,4'-dihydroxybenzophenone 20.0 g (9
3.4 mmol) was suspended in methylene chloride (200 ml),
23.6 g (281 mmol) of dihydropyran were added.
1.18 g (4.7 mmol) of pyridinium paratoluene sulfonate was added to this mixture at room temperature, and then the mixture was stirred under reflux conditions for 10 hours. After cooling to room temperature, 5
% Aqueous sodium hydrogen carbonate solution, then water. After evaporating the solvent under reduced pressure, the title compound (30.3 g, 78.8 mm) was crystallized from isopropanol.
ol, 84.4%).

¹ H-NMR (CDCl ₃ ) δ (pp
m): 1.56-2.07 (12H, m), 3.56-
3.93 (4H, m), 5.39 (2H, t, J = 3.1H
z), 7.00 (4H, d, J = 8.7Hz), 7.27 (4
H, d, J = 8.5 Hz) Melting point 106-109 ° C. EI-MS m / z 382 (M ⁺ ), C ₂₃ H ₂₆ O ₅ = 38.
2

Reference Example 2 4,4'-bis (tetrahydropyranyloxy) benzhydrol 4,4'-bis (tetrahydropyranyloxy) benzophenone 800 g (2.09 mol) was added to methanol (4.0%).
L) and dissolved, sodium borohydride 59.4 g
(1.56 mol) and a suspension of 13.3 g of potassium hydroxide in methanol (1.9 L) were added at room temperature. The mixture was stirred at 30 ° C. for 4 hours. After adding acetone (0.8 L), the solvent was distilled off under reduced pressure. After dissolving in methylene chloride, it was washed with water and then with saturated saline, and the methylene chloride solution was dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the title compound (760 g, 1.98 mol, 94.7) was crystallized from isopropanol-water.
%).

¹ H-NMR (CDCl ₃ ) δ (pp
m): 2.14 (1H, d, J = 3.5Hz), 1.56
~ 2.07 (12H, m), 3.56 to 3.93 (4H,
m), 5.39 (2H, t, J = 3.1Hz), 5.76
(1H, d, J = 3.5Hz), 7.00 (4H, d, J =
8.7 Hz), 7.27 (4 H, d, J = 8.5 Hz) Melting point 97-99 ° C. Elemental analysis C ₂₃ H ₂₈ O ₅

[0025]

INDUSTRIAL APPLICABILITY According to the present invention, a salt of an indole derivative useful as a therapeutic drug for osteoporosis can be simply and efficiently produced and provided in high purity.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Yukiyasu Kuge, 30-1-714 Minami Kibogaoka, Kawachinagano City, Osaka Prefecture (72) Inventor, Masatsugu Kasai 3-12 Kugenuma Matsugaoka, Fujisawa City, Kanagawa Prefecture 15 (72) Inventor Shinji Tomioka 690-4 Shimohyogo, Sumida Town, Hashimoto City, Wakayama Prefecture

Claims (4)

[Claims] 1. A compound of the general formula (I): [In the formula, R ¹ represents hydrogen, lower alkyl or lower alkenyl, R ² and R ³ are the same or different, and are lower alkyl, lower alkenyl, substituted or unsubstituted aralkyl or the formula: (In the formula, R ⁴ and R ⁵ are the same or different and are hydrogen,
Represents lower alkyl or substituted or unsubstituted aralkyl, or represents a substituted or unsubstituted alicyclic heterocyclic group in which R ⁴ and R ⁵ together form an adjacent oxygen atom, and n is 0 Represents an integer of 6 to 6) and a compound represented by the general formula (II): [In the formula, R ⁶ is hydrogen, lower alkyl or the formula: (In the formula, R ⁹ and R ¹⁰ are the same or different and each represents hydrogen or lower alkyl, or R ⁹ and R ¹⁰ are taken together to form a substituted or unsubstituted alicyclic ring formed together with an adjacent nitrogen atom. Represents a formula heterocyclic group, m represents an integer of 2 to 6), R ⁷ and R ⁸ are the same or different, and are hydrogen, lower alkyl, alicyclic alkyl, substituted or unsubstituted Of aryl or a substituted or unsubstituted heterocyclic group, or R ⁷ and R ⁸ are taken together,
A compound represented by a substituted or unsubstituted alicyclic heterocyclic group formed together with an adjacent nitrogen atom] in the presence of an acid, represented by the general formula (III): ] (Wherein R ⁶ , R ⁷ and R ⁸ have the same meanings as defined above), and a method for producing a salt of the indole derivative. 2. The acid is used in an amount of 1.1 to 5 equivalents with respect to the compound represented by the general formula (II).
Production method as described. 3. Acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, glyoxylic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, The method according to claim 2, wherein the reaction is carried out using an acid selected from the group consisting of benzenesulfonic acid and toluenesulfonic acid. 4. The method according to claim 3, wherein the reaction is carried out at −5 to 10 ° C.