HK1235769A - Process for the preparation of 1-benzyl-3-hydroxymethyl- 1h- indazole and its derivatives and required magnesium intermediates - Google Patents

Description

1-benzyl-3-hydroxymethyl-1H-indazole and derivatives thereof and process for the preparation of the desired magnesium intermediate

The application is a divisional application of Chinese patent application with the application date of 28/7/2010, the application number of 201080034409.5(PCT/EP2010/060941), the invention name of 1-benzyl-3-hydroxymethyl-1H-indazole and derivatives thereof and a preparation method of a required magnesium intermediate.

Technical Field

The invention relates to a preparation method of 1-benzyl-3-hydroxymethyl-1H-indazole.

In particular, the present invention relates to a process for converting 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (II) below into 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (I) below.

Background

European patent EP-B-0382276 describes certain 1-benzyl-3-hydroxymethyl-1H-indazole derivatives of formula (A) having analgesic activity

Wherein

R and R' may be the same or different and are H or C_1-5Alkyl, and

r' is H or C_1-4An alkyl group, a carboxyl group,

when R "is H, it may form its salt form with a pharmaceutically acceptable organic or inorganic base.

In addition, European patent EP-B-0510748 describes, on the other hand, the use of the above derivatives for the preparation of pharmaceutical compositions effective in the treatment of autoimmune diseases.

In addition thereto, the document EP-B1-0858337 describes a composition comprising R ═ R' ═ CH₃And R ═ H of a compound of formula (a) and an immunosuppressive agent.

European patent EP-B-1005332 describes the use of said derivatives for the preparation of pharmaceutical compositions effective in the treatment of disorders deriving from the production of MCP-1.

Finally, international patent application WO 2008/061671 describes the use of compounds of formula (a) for lowering blood levels of triglycerides, cholesterol and glucose.

Various processes for the preparation of the compounds of formula (A) are described in the above-mentioned patent EP-B-0382276.

The process described in patent EP-B-0382276, which regards as a key point the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole, makes it possible to obtain the compound of formula (a) from this compound via three different reaction routes.

The first reaction scheme converts 1-benzyl-3-hydroxymethyl-1H-indazole to the corresponding ethanolate, which is then reacted with X-CRR '-COOR' wherein X is selected from halogen, arylene-SO₂-O-or alkylene-SO₂-O-, to give a compound of formula (A).

The second reaction route converts 1-benzyl-3-hydroxymethyl-1H-indazole to the corresponding 3-halomethyl derivative, which is then reacted with an ethanolate of the formula MeO-CRR' -COOR ", where Me is an alkali metal, to give the compound of formula (a).

A third reaction scheme reacts 1-benzyl-3-hydroxymethyl-1H-indazole with chloroform and a ketone of formula O ═ CRR', in the presence of a basic substrate such as sodium hydroxide, to give a compound of formula (a) wherein R "is hydrogen.

By using a suitable reducing agent, e.g. lithium aluminium hydride (LiAlH)₄) The corresponding 3-carboxylic acid is reduced and the preparation of the key intermediate 1-benzyl-3-hydroxymethyl-1H-indazole is carried out according to the method described in patent EP-B-0382276.

Disclosure of Invention

The applicant has found that the synthetic methods known in the art and described in the above-mentioned patent EP-B-0382276 have a number of drawbacks.

First, 1-benzyl-1 (H) -indazole-3-carboxylic acid is not a readily commercially available product, but rather is extremely expensive. In particular, few suppliers exist, and the synthetic routes described in the literature provide benzylation of the corresponding 1(H) -indazole-3-carboxylic acids, which are also very expensive and not readily available. Secondly, reduction of 1-benzyl-1 (H) -indazole-3-carboxylic acid to obtain 1-benzyl-3-hydroxymethyl-1H-indazole is performed with a high dilution factor.

In addition, the second reaction route uses thionyl chloride to convert 1-benzyl-3-hydroxymethyl-1H-indazole to the corresponding 3-chloromethyl derivative. Thionyl chloride is a highly toxic substance and its use in industrial processes causes considerable safety and regulatory problems.

Finally, the third reaction route (the Bargellini reaction) shows the following industrial drawbacks: low yields (less than 50%), the production of toxic combustible gases, carbon monoxide, and the generation of significant exothermic events that are difficult to control industrially (Davis et al, Synthesis, 12, (2004), 1959-. In addition, the Bargellini reaction has a better application in the synthesis of ethers from phenols rather than aliphatic alcohols (US 3,262,850; Cvetovich et al, J. org. chem., (2005), 70, 8560-.

The applicant therefore considered the problem of developing a new process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole to obtain the compound of formula (a), which is able to overcome the above drawbacks. In particular, the applicant extended the problem to a process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole having formula (II) below.

So as to obtain a compound of formula (I)

Wherein the substituent R₁To R₁₂Have the meanings indicated in the following detailed description and claims.

The applicant has found a new process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole of formula (II) capable of obtaining the compound of formula (I), which, on the one hand, significantly improves the industrial applicability, yield and cost compared to the processes known hitherto, and, on the other hand, improves the quality of the compounds obtained using it.

The applicant has surprisingly found that 1-benzyl-3-hydroxymethyl-1H-indazole of formula (II) or derivatives thereof can be readily obtained by reaction of a grignard reagent having formula (IV) as described below with a suitable electrophilic compound such as, for example, an aldehyde, ketone or amide, followed by reduction of the intermediate carbonyl compound if necessary.

In particular, the applicant has surprisingly found that the grignard reagent of formula (IV) can be easily obtained from 1-benzyl-3-halo-1H-indazole of formula (III) or derivatives thereof as described below, via a halogen/magnesium exchange reaction with a grignard reagent of the alkylmagnesium halide type at low temperatures.

The applicant also believes that grignard reagents of formula (IV) are not known in the art.

In fact, the only indazole organometallic derivatives known in the art having a metal in the 3-position are those having metals such as zinc (Knochel et al, Synlett 2005, 267) or copper (Knochel et al, Synthesis 2006, 15, 2618 and Knochel et al, Synlett 2004, 13, 2303-2306), although indazole ring-degrading reactions are known which attempt to prepare the corresponding 3-organolithium compounds (Welch et al, Synthesis, 1992, 937) and 3-organosodium derivatives (Tertov et al, Zhurnal Organic heskoi Khimii 1970, 6; 2140).

The 1-benzyl-3-halo-1H-indazole derivatives of formula (III), which are generally known in the literature, can be readily obtained by halogenation of the 1H-indazole at the 3-position followed by benzylation at the 1-position (Collot et al, Tetrahedron, 1999, 55, 6917; Coller et al, Aust.J.Chem.1974, 27, 2343).

The applicant has also surprisingly found that 1-benzyl-3-hydroxymethyl-1H-indazole of formula (II) or derivatives thereof can be easily converted into the corresponding 3-halomethyl derivatives by simple treatment with a hydrohalic acid and then converted into the compound of formula (I) by etherification with the appropriate hydroxycarboxylic acid or ester of formula (VI).

Alternatively, the applicants have also surprisingly found that 1-benzyl-3-hydroxymethyl-1H-indazole of formula (II) or derivatives thereof can be readily converted to compounds of formula (I) by etherification with a suitable α -halocarboxylic acid or ester of formula (VII) as described below.

Accordingly, the present invention relates to a process for the preparation of a 1-benzyl-3-hydroxymethyl-1H-indazole derivative represented by the following formula (I):

wherein the substituent R₁To R₁₂Have the meanings indicated in the following detailed description and claims.

Wherein the content of the first and second substances,

a) 1-benzyl-3-hydroxymethyl-1H-indazole or derivative thereof represented by the following formula (II)

With a hydrohalic acid of the formula HX 'wherein X' is a halogen atom selected from the group consisting of chlorine, bromine and iodine, preferably chlorine, to form a 1-benzyl-3-halomethyl-1H-indazole represented by the following formula (V) or a derivative thereof

b) Reacting 1-benzyl-3-halomethyl-1H-indazole represented by the above formula (V) or a derivative thereof with a compound represented by the following formula (VI) in the presence of a strong base:

to form the 1-benzyl-3-hydroxymethyl-1H-indazole derivative represented by the formula (I).

Detailed Description

Advantageously, a process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole and derivatives thereof represented by the following formula (II):

wherein

R₁And R₂Which may be identical or different, are hydrogen or alkyl having 1 to 6 carbon atoms,

R₃、R₄and R₈Which may be the same or different, may be hydrogen, alkyl groups having 1 to 5 carbon atoms, alkoxy groups having 1 to 3 carbon atoms and halogen atoms,

R₅can be hydrogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 3 carbon atoms, halogen, or with R₆And R₇One of which may form a ring having 5 or 6 carbon atoms, and

R₆and R₇May be the same or different and may be hydrogen, alkyl having 1 to 5 carbon atoms, or R₆And R₇One of and R₅A ring having 5 or 6 carbon atoms may be formed,

provided that

a) 1-benzyl-3-halo-1H-indazole of formula (III)

Wherein X is a halogen atom selected from iodine and bromine, preferably iodine, R₃-R₈Has the meaning of the above-mentioned formula,

with alkylmagnesium halides of the formula RMgX ', where R is an alkyl radical having from 1 to 6 carbon atoms and X' is a halogen atom selected from bromine and chlorine, preferably chlorine, to form the intermediate compounds (IV)

b) The intermediate compound (IV) and the formula R₁-CO-R₂In which R is₁And R₂Having the above-mentioned meanings, to form compounds of the formula (II), or, as an alternative to b), are

b ') the intermediate compound (IV) with the formula R' N-CO-R₁Wherein R 'and R' may be the same or different and are an alkyl group having 1 to 3 carbon atoms, R₁Having the above meaning, to form an intermediate compound (VIII)

Which reacts with a carbonyl reducing agent to form a compound of formula (II).

Advantageously, step a) is carried out in the presence of a suitable solvent such as tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, dioxane, tert-butyl-methyl ether, dibutyl ether, xylene, toluene, dichloromethane, chloroform, n-hexane, n-heptane, mixtures thereof and the like, preferably 2-methyl-tetrahydrofuran, toluene, xylene and mixtures thereof, even more preferably 2-methyl-tetrahydrofuran.

The alkylmagnesium halide of formula RMgX' used in step a) may be methyl MgCl, ethyl MgCl, n-propyl MgCl, isopropyl MgCl, n-butyl MgCl, isobutyl MgCl, sec-butyl MgCl, tert-butyl MgCl, n-pentyl MgCl, n-hexyl MgCl, allyl MgCl, cyclohexyl MgCl, methyl MgBr, ethyl MgBr, n-propyl MgBr, isopropyl MgBr, n-butyl MgBr, isobutyl MgBr, sec-butyl MgBr, tert-butyl MgBr, n-pentyl MgBr, n-hexyl MgBr, allyl MgBr, cyclohexyl MgBr, preferably isopropyl MgCl. These reagents may be commercially available or prepared according to methods widely described in the literature (Silverman et al, Handbook of Grignard reagents, Chapter 2, CRC Press).

Advantageously, the exchange reaction in step a) may be catalyzed by the addition of lithium salts, for example LiCl, as described in the literature (Knochel et al, chem.

Advantageously, step a) is carried out at a temperature of from-30 ℃ to +30 ℃, preferably from-20 ℃ to-10 ℃.

Advantageously, step a) is carried out using a molar ratio of alkylmagnesium halide of formula RMgX' to 1 to 4, preferably 1.5 to 4, of 1-benzyl-3-halo-1H-indazole of formula (III).

Advantageously, step b) is carried out in the presence of a suitable solvent such as tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, dioxane, tert-butyl-methyl ether, dibutyl ether, xylene, toluene, dichloromethane, chloroform, n-hexane, n-heptane and mixtures thereof and the like, preferably 2-methyl-tetrahydrofuran, toluene, xylene and mixtures thereof, even preferably 2-methyl-tetrahydrofuran.

Advantageously, step b) is carried out using carbonyl compounds selected from aldehydes, such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, caproaldehyde and the like, and ketones, such as acetone, ethyl methyl ketone, isobutyl methyl ketone and the like. Preferably formaldehyde is used, in particular polymers such as paraformaldehyde or trioxane, which are suitable for depolymerization, are used as formaldehyde source.

Advantageously, step b) is carried out using a 1-benzyl-3-halo-1H-indazole of formula (III) and R in a molar ratio of 1 to 6₁-CO-R₂The carbonyl compound of (1).

Advantageously, step b) is carried out at a temperature of from-30 ℃ to +30 ℃, preferably from-10 ℃ to 0 ℃.

Advantageously, step b') is carried out using an alkylamide selected from N, N-dimethylformamide, N-diethylformamide, N-di-N-propylformamide, N-dimethylacetamide, N-diethylacetamide, N-di-N-propylacetamide, N-dimethylpropionamide, N-diethylpropionamide, N-di-N-propylpropionamide, preferably N, N-dimethylformamide.

Advantageously, step b') is carried out at a temperature of from-30 ℃ to +30 ℃, preferably from-10 ℃ to 0 ℃.

In particular, step b ') is carried out using a 1-benzyl-3-halo-1H-indazole of formula (III) and a compound of formula R' N-CO-R in a molar ratio ranging from 1 to 4₁Is carried out by the amide of (1).

Advantageously, the carbonyl reducing agent used in step b') is chosen from hydrides, such as NaBH₄、KBH₄、LiBH₄、Zn(BH₄)₂、Ca(BH₄)₂、NaAlH₄、LiAlH₄、Et₃SiH、Bu₃SnH、i-Bu₂AlH, 70% NaAlH in toluene₂(OCH₂CH₂OCH₃)₂And derivatives thereof. The carbonyl reducing agent is preferably 70% NaAlH in toluene₂(OCH₂CH₂OCH₃)₂. Carbonyl reductants are widely reported in the literature (e.g., as described in Smith, March, March's Advanced organic chemistry, 5 th edition, pp. 1197-&Sons, inc. and Carey, Sundberg, advanced organic Chemistry, 4 th edition, page 262-290).

Advantageously, the reduction in step b') is carried out in the presence of a suitable solvent, such as tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, dioxane, tert-butyl-methyl ether, dibutyl ether, xylene, toluene, dichloromethane, chloroform, n-hexane, n-heptane, methanol, ethanol, n-propanol, isopropanol, diglyme (bis- (2-methoxyethyl) ether), pyridine, dimethyl sulfoxide (DMSO), acetic acid, mixtures thereof and the like, preferably toluene, xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran and mixtures thereof.

Advantageously, the reduction in step b') is carried out at a temperature of from 10 ℃ to 100 ℃, preferably from 20 ℃ to 60 ℃.

In particular, the reduction of the carbonyl group in step b') is carried out using 1 to 3, preferably 2 equivalents of hydride.

Advantageously, R in formulae (II), (III), (IV) and (VIII) as described above₁-R₈The radicals may have the following meanings.

Preferably, R₁And R₂Which may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms.

Preferably, R₃、R₄And R₈Which may be the same or different, may be a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a chlorine atom and a fluorine atom.

Advantageously, R₅Can be hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine atom and fluorine atom, or with R₆And R₇One together may form a ring having 6 carbon atoms.

Preferably, R₆And R₇May be the same or different and may be hydrogen, methyl, ethyl, or R₆And R₇One and R₅Together may form a ring having 6 carbon atoms.

The present invention relates to a method for producing a 1-benzyl-3-hydroxymethyl-1H-indazole derivative represented by the following formula (I):

wherein

R₁-R₈Having the meaning given above for formula (II),

R₁₀and R₁₁Which may be the same or different, is hydrogen or an alkyl group having 1 to 5 carbon atoms, and

R₁₂is hydrogen or an alkyl group having 1 to 4 carbon atoms.

The process for preparing the 1-benzyl-3-hydroxymethyl-1H-indazole derivative shown in the above formula (I) according to the present invention provides

a) 1-benzyl-3-hydroxymethyl-1H-indazole represented by the following formula (II) or a derivative thereof

Wherein R is₁-R₈Has the meaning of the above-mentioned formula,

with a hydrohalic acid of the formula HX 'wherein X' is a halogen atom selected from the group consisting of chlorine, bromine and iodine, preferably chlorine, to form a 1-benzyl-3-halomethyl-1H-indazole represented by the following formula (V) or a derivative thereof

Wherein R is₁-R₈And X' has the above-mentioned meaning,

b) reacting 1-benzyl-3-halomethyl-1H-indazole represented by the above formula (V) or a derivative thereof with a compound represented by the following formula (VI) in the presence of a strong base:

wherein R is₁₀、R₁₁May be the same or different, and R₁₂All have the above meanings to form the 1-benzyl-3-hydroxymethyl-1H-indazole derivative represented by the above formula (I).

Preferably, the 1-benzyl-3-hydroxymethyl-1H-indazole derivative represented by formula (I) can be prepared by a method comprising forming a compound represented by the formula-COOR by treating with a pharmaceutically acceptable organic or inorganic base₁₂A salt of a carboxyl group represented by the formula. When R is₁₂When hydrogen, the treatment may be carried out directly on the corresponding acid, or when R is₁₂In the case of an alkyl group of 1 to 4 carbon atoms, the reaction for hydrolyzing the ester is followed.

Advantageously, step a) is carried out in aqueous solution or in an organic solvent. The hydrohalic acid of formula HX "used is concentrated or dilute hydrochloric, hydrobromic or hydroiodic acid, preferably hydrochloric acid in a concentration such that the molar ratio between the acid and the compound of formula (II) is from 1 to 20, preferably from 1 to 5, even more preferably about 3.

Advantageously, step a) is carried out at a temperature of from 25 ℃ to 100 ℃, preferably from 60 ℃ to 90 ℃.

The organic solvent preferably used in step a) is selected from toluene, xylene, acetic acid, dioxane, dibutyl ether, 2-methyl-tetrahydrofuran.

Advantageously, step b) is carried out in an aprotic solvent, such as tetrahydrofuran, dioxane, N-dimethylformamide, toluene, N-methylpyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, acetone, isobutyl methyl ketone, methyl ethyl ketone or mixtures thereof, preferably toluene or N, N-dimethylformamide and mixtures thereof.

The strong base used in step b) is preferably selected from the group consisting of sodium hydride, sodium metal, potassium metal, butyllithium, lithium diisopropylamide, sodium amide, potassium hydride, preferably sodium hydride.

Advantageously, step b) is carried out using an α -alkyd selected from glycolic acid, lactic acid, α -hydroxyisobutyric acid, α -hydroxybutyric acid, 2-ethyl-2-hydroxybutyric acid, 2-hydroxyisovaleric acid, 2-hydroxy-3, 3-dimethylbutyric acid, 2-hydroxyisocaproic acid, preferably α -hydroxyisobutyric acid.

Advantageously, step b) is carried out using an alpha-hydroxy ester selected from methyl glycolate, ethyl glycolate, butyl glycolate, methyl lactate, ethyl lactate, butyl lactate, tert-butyl lactate, propyl lactate, isobutyl lactate, methyl-2-hydroxyisobutyrate, ethyl-2-hydroxyvalerate, tert-butyl-2-hydroxybutyrate, preferably ethyl-2-hydroxyisobutyrate.

Preferably, the molar ratio between the 1-benzyl-3-halomethyl-1H-indazole of formula (V) and the α -alkyd acid or ester of formula (VI) is from 1 to 2, preferably about 1.2.

In particular, the molar ratio between the α -alkyd acid of formula (VI) and the strong base is between 1 and 3, preferably about 2. Similarly, the molar ratio between the α -hydroxy ester of formula (VI) and the strong base is from 1 to 1.5, preferably about 1.

Advantageously, the group R in the formulae (I), (II), (V), (VI) and (VII) as described above₁-R₁₂May have the following meanings.

Preferably, R₁And R₂Which may be the same or different, represent a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms.

Preferably, R₃、R₄And R₈Which may be the same or different, may be a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a chlorine atom and a fluorine atom.

Advantageously, R₅Can be hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine atom and fluorine atom, or with R₆And R₇One together may form a ring having 6 carbon atoms.

Preferably, R₆And R₇May be the same or different and may be hydrogen, methyl, ethyl or R₆And R₇One and R₅Together may form a ring having 6 carbon atoms.

Preferably, R₁₀And R₁₁Which may be identical or different, are hydrogen or alkyl having 1 to 3 carbon atoms, R₁₂Is hydrogen or an alkyl group having 1 to 3 carbon atoms.

The following examples are intended to illustrate the invention without limiting it in any way.

Detailed Description

The compounds 3-iodo-1H-indazole and 1-benzyl-3-iodo-1H-indazole were prepared according to the method reported by Collot et al (Tetrahedron, 55, 6917, 1999). The compound 3-bromo-1H-indazole was prepared using the method reported by Coller et al (aust.j.chem.1974, 27, 2343).

Example 1

Preparation of 1-benzyl-3-bromoindazole

3-bromo-1H-indazole (90.4g, 0.459mol, 1.0eq.) and toluene (450mL) were placed in a 1-liter flask equipped with a mechanical stirrer under a nitrogen atmosphere. Then, potassium tert-butoxide (t-BuOK, 54.2g, 0.483mol, 1.05eq.) was added over about half an hour at room temperature, and benzyl bromide (86.3g, 0.505mol, 1.1eq.) was added over about 1.5 hours. At the same temperature, the mixture was stirred until the reaction was complete (checked by TLC, about 3 hours). Then, 0.1M HCl (45mL) and water (90mL) were added and the resulting phases were separated. The organic phase was washed with water and the solvent was evaporated under reduced pressure to give a red oily residue. The product was then precipitated by addition of n-heptane, filtered off and dried in vacuo at room temperature. Yield 65.9g of a light brown solid (50% yield).

¹H NMR(300MHz,DMSO-d₆)(ppm)5.67(s,2H),7.29(m,6H),7.50(ddd,1H,J＝8.6Hz,6.9Hz,1.0Hz),7.60(dd,1H,J＝8.2Hz,0.7Hz),7.80(dd,1H,J＝8.6Hz,0.7Hz)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)52.2,110.4,119.5,121.7,122.9,127.4,127.4,127.6,127.7,128.6,128.6,129.6,136.9,140.5。

Example 2

Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

A solution of isopropylmagnesium chloride (i-PrMgCl) in 2-methyltetrahydrofuran (Me-THF) was prepared from a solution of magnesium metal (Mg, 10.91g, 0.4489mol, 1.5eq.) activated with iodine crystals and isopropylchloride (i-PrCl, 41.0mL, 0.4489mol, 1.5eq.) in anhydrous Me-THF (185mL) in a suitably well-dried flask, kept under a nitrogen atmosphere. After cooling to about-10 ℃, a solution of 1-benzyl-3-iodo-1H-indazole (100g, 0.2993mol, 1.0eq.) in anhydrous Me-THF (120mL) was added over 1 hour while keeping the temperature constant. The reaction mixture was stirred for an additional 1 hour to complete the halogen/magnesium exchange to give a yellow suspension. Gaseous formaldehyde (generated by heating a suspension of 54g of paraformaldehyde in 150mL of xylene at about 115 ℃) was passed through it for about two hours at a temperature below 0 ℃. When the reaction is complete, dilute H is added₃PO₄And the excess of the repolymerized paraformaldehyde is removed by filtration. Phase separation, then with NaHCO₃The organic phase is washed with a dilute solution and then concentrated. The product precipitated by addition of n-hexane was collected by filtration and dried. Yield: 56.8g of a white solid (79.6%).

mp：85-86℃

¹H NMR(300MHz,DMSO-d₆)(ppm)4.79(d,2H,J＝5.8Hz),5.27(t,1H,J＝5.8Hz),5.6(s,2H),7.12(t,1H,J＝7.5Hz),7.28(m,5H),7.36(t,1H,J＝7.2Hz),7.64(d,1H,J＝8.5Hz),7.86(d,1H,J＝8.2Hz)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)51.6,56.6,109.6,120.0,120.9,122.2,126.2,127.3,127.3,127.4,128.5,128.5,137.7,140.3,145.2。

Example 3

Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

A solution of 2M i-PrMgCl in THF (69mL, 138mmol, 4.0eq.) is added to a suitably well dried flask maintained under a nitrogen atmosphere. The solution was cooled to about-10 ℃. Over about 1 hour, a solution of 1-benzyl-3-bromo-1H-indazole (10g, 34.8mmol, 1.0eq.) in anhydrous THF (40mL) was added while keeping the temperature constant. The reaction mixture was kept under stirring for at least 6 hours, giving a yellow suspension. Gaseous formaldehyde (generated by heating a suspension of 16.7g of paraformaldehyde in 60mL of xylene at about 115 ℃) was passed through it for about two hours at a temperature below 0 ℃. When the reaction is complete, dilute H is added₃PO₄And the excess of the repolymerized paraformaldehyde is removed by filtration. To this mixture was added Me-THF (60) and the phases were separated. The organic phase is treated with NaHCO₃And (5) washing with a dilute solution. After concentration of the organic phase, an oily residue containing the product was obtained. Next, the crude product was purified by silica gel chromatography to obtain 2.8g of a white solid (yield: 34%).

mp：85-86℃

¹H NMR(300MHz,DMSO-d₆)(ppm)4.79(d,2H,J＝5.8Hz),5.27(t,1H,J＝5.8Hz),5.6(s,2H),7.12(t,1H,J＝7.5Hz),7.28(m,5H),7.36(t,1H,J＝7.2Hz),7.64(d,1H,J＝8.5Hz),7.86(d,1H,J＝8.2Hz)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)51.6,56.6,109.6,120.0,120.9,122.2,126.2,127.3,127.3,127.4,128.5,128.5,137.7,140.3,145.2。

Example 4

Preparation of 1-benzyl-3-chloromethyl-1H-indazole

1-benzyl-3-hydroxymethyl-1H-indazole (400g, 1.7mol, 1eq.), toluene (1.6L) and concentrated HCl (422mL, 5.1mol, 3.0eq.) were added to a three-necked flask equipped with a mechanical stirrer and a reflux condenser.

The reaction mixture was heated to about 90 ℃ and kept stirring until the reaction was complete (checked by TLC for about two hours). After cooling to room temperature, NaCl (about 10g) was added, the phases were separated and the aqueous phase was discarded. With NaHCO₃The organic phase was washed with a saturated solution (about 100mL) and then concentrated. The product precipitated by the addition of n-hexane (about 500mL) was filtered and dried. Yield: 398.2g of a white solid (91%).

mp：89-91℃

¹H NMR(300MHz,DMSO-d₆)(ppm)5.14(s,2H),5.65(s,2H),7.27(m,6H),7.43(m,1H),7.12(d,1H,J＝8.5Hz),7.88(d,1H,J＝8.2Hz)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)38.2,51.8,110.2,120.1,120.9,121.7,126.7,127.3,127.3,127.5,128.5,128.5,137.2,140.4,140.6。

Example 5

Preparation of 2- [ (1-benzyl-1H-indazol-3-yl) methoxy ] -2-methylpropanoic acid

Ethyl-2-hydroxyisobutyrate (18.5g, 140mmol, 1.2eq.), toluene (100mL), and DMF (20mL) were placed in a three-necked flask equipped with a mechanical stirrer and reflux condenser under an inert atmosphere. Over about 1.5 hours, a dispersion of 60% NaH (5.6g, 140mmol, 1.2eq.) was added to the mixture in portions. Then, a solution of 1-benzyl-3-chloromethyl-1H-indazole (30g, 117mmol, 1eq.) in toluene (90mL) and DMF (60mL) was added dropwise. The reaction mixture was heated to about 90 ℃ and held at that temperature until the reaction was complete (checked by TLC, about 10 hours). After cooling to room temperature, the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the resulting oily residue was treated with 10M NaOH (36mL) at reflux temperature for at least 3 hours. The product precipitated by addition of concentrated HCl was filtered and dried. Yield: 32.3g of a white solid (85%).

mp：133-134℃。

Elemental analysis

Calculated values: c (70.35), H (6.21), N (8.64),

measured value: c (70.15), H (6.17), N (8.63).

¹H NMR(300MHz,DMSO-d₆)(ppm)1.44(s,6H),4.76(s,2H),5.60(s,2H),7.14(t,1H,J＝7.6Hz),7.20-7.34(m,5H),7.37(ddd,1H,J＝8.3Hz,7.0Hz,1.1Hz),7.66(d,1H,J＝8.4Hz),7.94(d,1H,J＝8.1Hz),12.77(s,1H)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)24.48,24.48,51.63,59.65,76.93,109.69,120.22,121.06,122.62,126.28,127.36,127.36,127.44,128.46,128.46,137.49,140.31,141.97,175.46。

Example 6

Preparation of 1-benzyl-1H-indazole-3-carbaldehyde

In a suitably well-dried flask kept under nitrogen atmosphere, a solution of i-PrMgCl in THF is prepared from a solution of metallic magnesium (Mg, 164Mg, 6.75mmol, 1.5eq.) activated with iodine crystals and i-PrCl (0.62mL, 6.75mmol, 1.5eq.) in anhydrous THF (2.8 mL).

After cooling to about-10 ℃, a solution of 1-benzyl-3-iodo-1H-indazole (1.5g, 4.5mmol, 1.0eq.) in anhydrous THF (5mL) was added to the reaction mixture over 1 hour while keeping the temperature constant. The reaction mixture was stirred for an additional 1 hour to complete the halogen/magnesium exchange to give a yellow suspension. Dimethylformamide (DMF) (1.4mL, 18mmol, 4eq.) was added to the suspension over 1 hour at a temperature below 0 ℃ with stirring and the reaction mixture was continued to be stirred at the same temperature until the reaction was complete (checked by TLC).

Diluting with H₃PO₄And toluene were added to the reaction mixture and the phases were separated. With dilute NaHCO₃The solution washes the organic phase. After the concentration of the organic phase, the organic phase is,the product precipitated by addition of n-hexane was filtered off and dried. Yield: 1.0g of a pale yellow solid (94%).

¹H NMR(300MHz,DMSO-d₆)(ppm)5.84(s,2H),7.32(m,5H),7.39(ddd,1H,J＝8.1Hz,7.0Hz,1.0Hz),7.53(ddd,1H,J＝8.4Hz,7.0Hz,1.2Hz)7.90(dt,1H,J＝8.5Hz,1.0Hz),8.16(dt,1H,J＝8.1Hz,1.2Hz),10.19(s,1H)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)52.9,111.0,121.0,121.2,124.2,127.5,127.6,127.6,127.9,128.6,128.6,136.2,140.7,142.4,186.8。

Example 7

Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

1-benzyl-1H-indazole-3-carbaldehyde (2.36g, 10mmol, 1eq.) and toluene (12mL) were placed in a well-dried 100mL flask equipped with a magnetic stirrer and inerted with nitrogen. Then, a 70% solution of sodium dihydro-bis (2-methoxyethoxy) aluminate in toluene (2.8mL, 10mmol, 2eq.) was slowly added to the solution at room temperature. Once the reaction was complete (after about 15 minutes), 2M HCl (10mL), H was added₂O (10mL) and toluene (15 mL). The phases were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with water and concentrated. The product was then precipitated by addition of n-hexane, filtered off and dried. Yield: 1.95g of a white solid (82.0%).

mp：85-86℃。

¹H NMR(300MHz,DMSO-d₆)(ppm)4.79(d,2H,J＝5.8Hz),5.27(t,1H,J＝5.8Hz),5.6(s,2H),7.12(t,1H,J＝7.5Hz),7.28(m,5H)7.36(t,1H,J＝7.2Hz),7.64(d,1H,J＝8.5Hz),7.86(d,1H,J＝8.2Hz)。

¹³C NMR(300MHz,DMSO-d₆)(ppm)51.6,56.6,109.6,120.0,120.9,122.2,126.2,127.3,127.3,127.4,128.5,128.5,137.7,140.3,145.2。

Claims (7)

1. A process for preparing 1-benzyl-3-hydroxymethyl-1H-indazole represented by the following formula (I):

wherein

R₁And R₂Which may be identical or different, are hydrogen or alkyl having 1 to 6 carbon atoms,

R₃、R₄and R₈May be the same or different, may be hydrogen, haveAn alkyl group of 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a halogen atom,

R₅can be hydrogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 3 carbon atoms, halogen, or with R₆And R₇One together may form a ring having 5 or 6 carbon atoms,

R₆and R₇May be the same or different and may be hydrogen, alkyl having 1 to 5 carbon atoms, or R₆And R₇One and R₅Together may form a ring having 5 or 6 carbon atoms, R₁₀And R₁₁Which may be the same or different, is hydrogen or an alkyl group having 1 to 5 carbon atoms, and

R₁₂is hydrogen or alkyl having 1 to 4 carbon atoms,

wherein

Step a) reacting 1-benzyl-3-hydroxymethyl-1H-indazole or derivative thereof represented by the following formula (II)

Reacting with hydrochloric acid to form 1-benzyl-3-halomethyl-1H-indazole or derivative thereof represented by the following formula (V)

Step b) reacting 1-benzyl-3-halomethyl-1H-indazole represented by the above formula (V) or a derivative thereof with a compound represented by the following formula (VI) in the presence of a strong base:

forming a 1-benzyl-3-hydroxymethyl-1H-indazole represented by formula (I) above;

wherein step a) is carried out at a temperature of from 60 ℃ to 90 ℃.

2. The production process according to claim 1, wherein X "is a chlorine atom.

3. The preparation method according to claim 1, wherein the 1-benzyl-3-hydroxymethyl-1H-indazole represented by the formula (I) is formed to have a carboxyl group-COOR by treating with a pharmaceutically acceptable organic base or inorganic base₁₂A salt.

4. The process according to claim 1, wherein R is₁And R₂Which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

5. The process according to claim 1, wherein R is₃、R₄And R₈Which may be the same or different, may be a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a chlorine atom and a fluorine atom.

6. The process according to claim 1, wherein R is₅Can be hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine atom and fluorine atom, or with R₆And R₇Together may form a ring having 6 carbon atoms.

7. The process according to claim 1, wherein R is₆And R₇May be the same or different and may be hydrogen, methyl, ethyl, or R₆And R₇One and R₅Together may form a ring having 6 carbon atoms.