WO2007142187A1

WO2007142187A1 - Novel production process for macrolide compound

Info

Publication number: WO2007142187A1
Application number: PCT/JP2007/061286
Authority: WO
Inventors: Ariyoshi Kubota; Kazuo Okawa; Masaru Watanabe; Kazuo Ike
Original assignee: Astellas Pharma Inc.
Priority date: 2006-06-05
Filing date: 2007-06-04
Publication date: 2007-12-13
Also published as: JP2009203162A

Abstract

The invention has been achieved as a result of intensive studies of a production process such that a macrolide compound (II) useful as a pharmaceutical can be produced efficiently at a high yield and a low cost and can be stably supplied. The inventors found that the above object is achieved by using a macrolide compound (I) (for example, tacrolimus) as a raw material, and performing Wacker oxidation with the use of a dialkyl sulfoxide, an alkyl aryl sulfoxide or a diaryl sulfoxide as a solvent, or with the use of a palladium complex containing a dialkyl sulfoxide, an alkyl aryl sulfoxide or a diaryl sulfoxide as a ligand. According to theproduction process of this application, it becomes possible to stably supply the macrolide compound (II) from the expensive raw material (I) such as tacrolimus efficiently at a high yield. Thus, it is an industrially very useful process and can provide the macrolide compound (II) which is very useful as a pharmaceutical.

Description

Specification

New production method of macrolide compounds

Technical field

[0001] The present invention relates to an industrial production method of a macrolide compound.

Background art

In the present specification, the compound represented by the formula (II) includes a neuroprotective agent (Patent Document 1), a neurotrophic agent (Patent Document 2), a chondrocyte differentiation promoter (Patent Document 3), and an erectile dysfunction treatment. It is a compound useful as an agent (Patent Document 4). Compound (Ila) is known to be obtained by Wacker oxidation of Tacrolimus (compound (la)), which is useful as an immunosuppressant (Patent Document 5). Since tacrolimus is an expensive fermentation product, the yield has a significant impact on manufacturing costs. However, the method described in the examples of Patent Document 5 is an industrial production method from the viewpoint of cost and work, such as that the yield is about 60% and column chromatography is used for purification. It cannot be adopted.

[0003] On the other hand, Wacker oxidation is a reaction used for the oxidation of olefins, and the oxidation of terminal olefins is known as a reaction in which a ketone is selectively obtained over an aldehyde (Non-patent Document 1). As the solvent, dimethylformamide (DMF) acetonitrile, acetic acid, alcohol, ether, etc. are widely used as a mixed solvent with water. Among them, DMF is a commonly used solvent, and compound (Ila) is also obtained using DMF as a solvent (Patent Document 5). In some cases, when DMF is used, ketone is obtained at a high yield of 90% or more by a selective oxidation reaction (Non-patent Documents 2 and 3). However, only one example of selective ketone synthesis using dimethyl sulfoxide (DMSO) is known (Non-Patent Document 4), and it is particularly superior to DMF. Nor.

[0004] Patent Document 1: International Publication No. WO01Z05385 Pamphlet

Patent Document 2: International Publication No. WO02 / 053159 Pamphlet

Patent Document 3: International Publication No. WO2004 / 078167 Pamphlet

Patent Document 4: International Publication No. WO2005 / 067928 Pamphlet

Patent Document 5: International Publication No. WO89 / 05304 Pamphlet Non-patent document 1: “Synthesis” 1984, p369—384

Non-Patent Document 2: "Tetrahedron Letters" 1994, 35 卷,

35, p6499-6502

Non-Patent Document 3: "Angewante Chemie" 1994, 106 卷, 21, p2296-2298

Non-Patent Document 4: “Journal of Organic Chemistry”, 1991, 56 卷, p6447— 6458

Disclosure of the invention

Problems to be solved by the invention

[0005] An object of the present invention is to provide a novel and excellent industrial production method for macrolide compounds.

Means for solving the problem

[0006] The present invention was made as a result of diligent investigations on a production method capable of reducing the cost and stably supplying the compound (II) useful as a pharmaceutical in a more efficient and high yield. is there. When the reaction described in Patent Document 5 is examined in detail, two impurities (impurities A and B) are generated in the reaction stage, and therefore, separation and purification methods that can be carried out on an industrial scale were examined. It was clear that impurity A can be removed by alumina and impurity B can be removed by synthetic adsorbent. However, two purification steps are required, and the new impurity C, which is thought to be derived from compound (II) in the purification by alumina. As a result, there was a problem that the yield was further reduced. Furthermore, in this reaction, purification with alumina or the like was necessary to remove heavy metal palladium used as a catalyst. When conducting Wacker oxidation using Compound (I) as a raw material, 1) the ability to use dialkyl sulfoxides, alkylaryl sulfoxides or dialyl sulfoxides as a solvent, and Z or 2) By using a palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands as the palladium catalyst, efficient, high yield, cost reduction and stable It was found that an industrially useful production method capable of supplying compound (II) was achieved, and the present invention was completed.

That is, the present invention is as follows. (1) Formula (I)

[Chemical 1]

A compound represented by formula (II), a solvate thereof, or a pharmaceutically acceptable salt thereof,

[Chemical 2]

And the use of dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as a solvent in a method for producing a compound represented by formula (I), a solvate thereof, or a pharmaceutically acceptable salt thereof, and Z or a compound (II) characterized by using a palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands as a palladium catalyst, and its solvate Or a method for producing a pharmaceutically acceptable salt thereof. (2) The production method according to (1), wherein the oxidation reaction is Wacker oxidation.

(3) The production method according to (2), wherein dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used as the solvent.

(4) Dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides and a mixed solvent of water and one or more kinds of compounds (I) and (II) that do not adversely affect the reaction The production method according to (3), wherein a mixed solvent to which a suitable solvent is added is used.

[0008] (5) The production method according to any one of (3) to (4), wherein dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used in an amount of 2 moles or more based on the palladium catalyst.

(6) Palladium catalyst is Pd (CH 2 CO 3), Pd (CF 2 CO 3), PdCl (CH 3 CN), PdCl,

The production method according to (3) to (5), which is PdCl (PhCN), PdCl (Ph P), Pd (BF) (CH CN), palladium (II) / carbon or palladium (II) montmorillonite.

(7) One or more solvents that do not adversely affect the reaction and are suitable for compound (I) and compound (II) are DMF, dimethylacetamide, acetic acid, methanol, ethanol, tetrahydrofuran, N— (4) The production method according to (6), which is a solvent selected from methylpyrrolidone and hexamethylphosphoric triamide.

[0009] (8) The production method according to (2), wherein the palladium catalyst is a palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands.

(9) The production method according to (8), which is palladium catalytic power PdCl′2DMSO containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands.

(10) As a solvent, use one or more mixed solvents of water and a solvent suitable for compound (I) and compound (II) that do not adversely affect the reaction (8) or (9) The manufacturing method described in 1.

(11) One or more solvents suitable for compound (I) and compound (II) that do not adversely affect the reaction are DMF, dimethylacetamide, acetic acid, methanol, ethanol, tetrahydro The production method according to (10), which is a solvent selected from drofuran, N-methylpyrrolidone and hexamethylphosphoric triamide.

The invention's effect

[0010] In the method for producing compound (II) by Wacker oxidation, the present inventors have used a dialkyl sulfoxide, an alkylaryl sulfoxide, or a diaryl sulfoxide as a solvent. , Or by using a palladium complex containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands as a palladium catalyst, the reaction selectivity is improved and the formation of compound (II) is achieved. We found that the rate also improved. As a result, impurities were reduced and residual palladium could be removed by washing with water, eliminating the need for an alumina purification step, resulting in an industrial process with excellent cost and work.

[0011] Further, when dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used as a single solvent, or when a mixed solvent of these solvents and water is used, there is a demerit that the reaction rate becomes slow. The present inventors have used solvents such as N-methylpyrrolidone, Pd (CH 2 CO 3), Pd (CF 2 CO 3), PdCl used in the Wacker reaction.

Dialkyl over palladium catalysts such as (CH CN), PdCl, PdCl (PhCN), PdCl (Ph P), Pd (BF) (CH CN), palladium (II) / carbon or palladium (II) montmorillonite It has also been found that the reaction time can be shortened by adding sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides without affecting the production rate.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] Preferred embodiments of the present invention are shown below.

As a preferred embodiment of compound (I), as an embodiment, compound (la)

[Chemical 3]

Can be mentioned.

Preferred embodiments of compound (II) include, as an embodiment, compound (Ila)

[Chemical 4]

Can be mentioned.

[0013] Hereinafter, the definition of each group in the present invention will be described.

[0014] "Wacker oxidation" usually means an oxidation reaction of ethylene to acetaldehyde with a palladium and copper catalyst using oxygen as an oxidizing agent, and a terminal alkene to an aldehyde or ketone. An oxidation reaction. Usually, internal alkenes can selectively oxidize terminal alkenes that are poorly reactive. As the reaction mechanism, the catalytic cycle functions by oxidation of alkene by palladium, palladium oxidation by copper, and copper oxidation by oxygen molecules. Hypochlorous acid can be used in place of oxygen molecules as an oxidizer, and benzoquinone, hydrogen peroxide, etc. can be used in place of copper as a reoxidizer. If it is an oxidizing agent, it will not be limited to these. The types of palladium and copper are not particularly limited, and may be monovalent or divalent. The reaction solvent is usually an aqueous solution, but is not particularly limited. The reaction conditions, oxidant, reoxidant, solvent and the like described in Non-Patent Document 1 can be used as appropriate.

The “alkyl group” of “dialkyl sulfoxides” and “alkylaryl sulfoxides” may be linear or branched. Preferable specific examples include an alkenyl group having 1 to 6 carbon atoms, such as methylol, ethyl, 1_propyl, isopropyl, 1_butyl, isobutyl, tert butyl, sec butyl, 1 pentyl, isopentyl, sec pentyl , Tert pentyl, methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2 , 2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl and the like. Of these, methylol and ethyl are preferable, and methyl is more preferable.

The “aryl” in the “diaryl sulfoxides” and the “alkylaryl sulfoxides” preferably includes aryl having 6 to 10 carbon atoms, such as phenyl, naphthyl, pentaenyl, etc. Of these, phenyl is particularly preferred.

“Dialkyl sulfoxides” means sulfoxides substituted with two identical or different alkyl groups. Preferred examples include DMSO, jetyl sulfoxide, methyl ethyl sulfoxide and dibutyl sulfoxide, and more preferred is the ability to list DMSO.

The term “alkylaryl sulfoxides” means a sulfoxide substituted with an alkyl group and an aryl group, and preferably includes methylphenyl sulfoxide and ethylphenyl sulfoxide. May include methyl phenyl sulfoxide. The

“Diaryl sulfoxides” means sulfoxide substituted with two aryl groups, and preferred examples include “diphenyl sulfoxide”.

[0018] The "palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as a ligand" includes, for example, PdCl'2DMSO.

“Palladium (II)” in palladium (II) Z carbon or palladium (又は) montmorillonite means divalent palladium. For example, palladium (II) carbon has Pd (OH)

/ Contains carbon.

[0020] The compounds of the present invention of the formulas (I) and (II) may have one or more asymmetric centers, in which case they may exist as enantiomers or diastereomers. The present invention includes both these mixtures and separate individual isomers.

[0021] The compounds of the present invention of the formulas (I) and (II) may exist as geometric isomers, and the present invention includes both a mixture thereof and individual geometric isomers separated from each other.

[0022] The compounds of the present invention of the formulas (I) and (II) can be converted into salts by a conventional method. Suitable salts of the compound (II) are pharmaceutically acceptable salts, such as alkali metal salts (for example, sodium salts and strength sodium salts) and alkaline earth metal salts (for example, calcium salts and magnesium salts). Such metal salts, ammonium salts, organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), organic acid salt (acetate, malonate, tartrate, methane) Sulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc., inorganic acid salt (hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acid salt (alginate) , Aspartate, gnoretamine, etc.). Therefore, the present invention includes all of the compound represented by the formula (I) or a salt thereof, and the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof.

[0023] The compounds of the formulas (I) and (II) can also form hydrates and various pharmaceutically acceptable solvates. These hydrates and solvates are also included in the present invention.

[0024] The present invention also includes radiolabeled derivatives of the compounds of formulas (I) and (II) useful for biological research. Next, the production method of the present invention will be described.

[Chemical 5]

In this production method, compound (II) having a ketone is produced by Wacker oxidation of terminal olefins of the macrolide compound (I). The detailed reaction conditions and selection of the reactants may be appropriately selected with reference to known techniques such as Non-Patent Document 1.

[0026] Examples of the solvent used in this reaction include dialkyl sulfoxides, alkylaryl sulfoxides and diaryl sulfoxides. Dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are preferably used in an amount of 1 mol or more relative to the amount of palladium catalyst, and more preferably in an amount of 2 mol or more. It is more preferable to use an amount of 4 moles or more. A mixed solvent obtained by adding water to these is preferred. DMSO, diphenyl sulfoxide, dibutyl sulfoxide, and a mixed solvent of methylphenyl sulfoxide and water are more preferred. A mixed solvent of DMSO and water is more preferred. . Furthermore, for the purpose of improving the reaction rate, the reaction is carried out in a mixed solvent of dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides and water, and one or more kinds of reaction. A mixed solvent containing a solvent suitable for compound (I) and compound (II) can be used without adverse effects. Here, “one or more kinds of solvents suitable for compound (I) and compound (II) that do not adversely affect the reaction” include DMF, dimethylenoacetamide, acetic acid, methanol, ethanol. Preferred is a solvent selected from alcohols such as tetrahydrofuran, ethers such as tetrahydrofuran, N-methylpyrrolidone or hexamethylphosphoric triamide DMF and N— As a mixed solvent in which a solvent selected from methylpyrrolidone is more preferable, a mixed solvent of DMF, DMSO and water, or a mixed solvent of N-methylpyrrolidone, DMSO and water is most preferable. Masle.

[0027] The mixing ratio is not particularly limited, but, for example, in the case of three kinds of mixed solvents, sulfoxides such as dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides with respect to water 1 as a volume. It is preferable to use 0.02 to 10 times the amount of “Solvent suitable for compound (I) and compound (II) without adversely affecting the reaction” in an amount of 3 to 50 times.

[0028] When a palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as a ligand is used as a palladium catalyst, it is a solvent that does not adversely affect the reaction, and the compound (I) And a suitable solvent for compound (II) are selected, for example, amides such as DMF and dimethylacetamide; acetic acid; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; N-methylpyrrolidone, Xamethylphosphoric triamide, DMSO and the like. These solvents may be used as a mixed solvent with water or as a mixed solvent with another solvent. Furthermore, when the purpose is to improve the reaction rate, it is preferable to use a solvent other than DMSO among the solvents exemplified above.

[0029] The mixing ratio is not particularly limited. For example, it is preferable to use 3 to 50 times the amount of N-methylpyrrolidone with respect to water 1.

[0030] The amount of the solvent is not particularly limited, but the total amount is preferably 3 to 10 ml with respect to the compound (I) lg.

[0031] The palladium catalyst used in this reaction is not particularly limited when dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used as a solvent. For example, Pd (CH 2 CO 3) , Pd (CF CO), PdCI (CH C

N), PdCI, PdCI-2DMSO, PdCI (PhCN), PdCI (Ph P), Pd (BF) (CH C

N), palladium (II) Z carbon, palladium (Π) montmorillonite and the like. The amount of the palladium catalyst is usually from 0.01 to 1.00 monolayers, preferably from 0.20 to 0.30 monolayers per mol of the starting compound. There is no.

[0032] Examples of the palladium complex containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands include PdCl'2DMSO.

2

It is. The amount of the palladium complex containing these sulfoxides as a ligand is usually 0.01 to 1.00 monole, preferably 0.20 to 0.30 mol, with respect to 1 mol of the starting compound. Power is not limited to these.

[0033] When water is used as the solvent, the whole amount may be added at once, or may be added in multiple portions.

[0034] The oxidizing agent is not particularly limited as long as it can be used for Wacker oxidation. Examples thereof include air, oxygen gas, hypochlorous acid, and the like. Air and oxygen gas are preferred. ,. Air or oxygen gas is usually supplied by blowing directly into the reaction solution or stirring in the presence of these gases.

[0035] The reoxidant is not particularly limited as long as it can be used for Wacker oxidation. For example, copper, benzoquinone, hydrogen peroxide, or the like can be used. Monovalent or divalent copper or 1,4-benzoquinone is preferred, CuCl, CuCl, Cu (CH COO), CuBr force S

2 3 2 Further preferred. The amount of the reoxidizing agent is a force that is normally 0.01 to 3.0 mol, preferably 0.20 to 0.30 mol, with respect to 1 mol of the starting compound. is not.

[0036] The reaction temperature is usually 0 to 50 ° C, preferably 20 to 40 ° C, but is not limited thereto.

The pressure is usually performed under normal pressure, but can be performed under pressure.

[0037] After completion of the reaction, if necessary, it can be purified by a known purification means, that is, a means such as activated carbon treatment, recrystallization, column chromatography, thin layer chromatography, high performance liquid chromatography or the like. . In addition, the compound can be identified by NMR spectrum analysis, mass spectrum analysis, IR spectrum analysis, elemental analysis, melting point measurement, and the like.

Example

Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to these examples. It is not specified.

In the following examples, the purity conversion yield means the yield calculated using the amount of the net compound calculated by multiplying the amount of the raw material and the product by the purity.

[0039] Example 1 (Ex. 1)

(1R, 9S, 12S, 13R, 14S, 17R, 18E, 21S, 23S, 24R, 25S, 27R) -1,14-dihydroxy-12- {(E) -2-[(1R, 3R, 4R) _4 -Hydroxy _3-Methoxycyclohexyl] _1-Methylvinyl} _23,25-Dimethoxy-13,19,21,27_Tetramethyl_17_ (2_oxopropyl) _11,28_Dioxa_4_azatricic [ 22.3.1.0 ⁴ ' ⁹ ] Synthesis of Octacosa-18-Yen-2,3,10,16-Tetraone (Ila)

[Chemical 6]

[0040] Compound (la) hydrate (70 g) in N-methylpyrrolidone (350 ml) is dissolved at room temperature, and DMS 0 (35 ml), PdCl (3.8 g), CuCl (2. lg) was added at the same temperature. Water (63 ml) was added to the reaction mixture in portions at 28 to 31 ° C., and the mixture was stirred for 9 hours. The reaction mixture was then diluted with ethyl acetate (630 ml) and washed with dilute hydrochloric acid aqueous solution, sodium bicarbonate water and brine. The resulting solution was concentrated in vacuo to give an oil. This oily substance was purified by a column packed with 420 ml of a synthetic adsorbent (Diaion (registered trademark) HP20SS) (elution acetone: water = 1: 1). The solution of the desired fraction was concentrated in vacuo until acetone was not distilled off, and 700 ml of ethyl acetate was added to the concentrate to separate the solution. The upper layer was separated in vacuo, then added to water 21001111 at 34 and stirred at the same temperature for 1 hour to precipitate the title compound (Ila). The solution was filtered, washed with 210 ml of water, and dried under reduced pressure to obtain 58.2 g of the title compound (Ila).

[0041] Example 2 (Ex. 2) The reaction was performed in the same manner as in Example 1 except that DMSO was used instead of N-methylpyrrolidone. No treatment after the reaction was performed.

[0042] Example 3 (Ex. 3)

The reaction was performed in the same manner as in Example 1 except that 1) DMSO was not added and 2) PdCl (DMSO) was used instead of PdCl. No treatment after the reaction was performed.

[0043] Example 4 (Ex. 4)

Compound (la) hydrate (2. Og) is dissolved in N_methylpyrrolidone (10 ml) at room temperature, and this solution is dissolved at night (this DMS ○ (0.095 g), PdCl (0. 108 g) and 1,4_benzoquinone (0.199 g) were added at the same temperature, with stirring at room temperature in the presence of air, water (2 ml) was added in several portions and allowed to react for 22 hours. No further processing was performed.

[0044] Example 5 (Ex. 5)

Dissolve compound (la) hydrate (70 g) in N_methylpyrrolidone at room temperature and add DMSO (6 · Oml), PdCl (3.8 g), CuCl (2. lg) to this solution. Was added at the same temperature. Three

Water (49 ml) was added to the reaction mixture in portions at 0 to 33 ° C, and the mixture was stirred for 7 hours. The reaction mixture was then diluted with ethyl acetate (630 ml), washed with dilute hydrochloric acid aqueous solution, sodium bicarbonate water and brine, and concentrated to dryness in vacuo to obtain 71.7 g of powder. This powder 15 · Og was dissolved in an aqueous methanol solution and purified by a column packed with 90 ml of a synthetic adsorbent (Diaion (registered trademark) HP20SS) (elution acetone: water = 1: 1). The desired fraction solution was concentrated in vacuo until acetone was no longer distilled off, and 150 ml of ethyl acetate was added to the concentrated solution for separation. The upper layer of the liquid separation was concentrated to dryness in vacuo to obtain 14. lg of powder. After dissolving 10.0 g of the obtained powder in an aqueous methanol solution, it was added to 320 ml of 34 ° C. water and stirred at the same temperature for 1 hour to precipitate the title compound (Ila). The solution was filtered, washed with 32 ml of water, and dried under reduced pressure to obtain 9.02 g of the title compound (Ila).

[0045] Comparative Example 1 (Re. 1)

In N_methylpyrrolidone (150 U, compound (la) hydrate (30. OKg) is dissolved at room temperature, and PdCl (1.6 kg), CuCl (0.9 kg) and water (1.3 U The mixture was stirred for 22 hours at 20 to 29 ° C., and an air stream was gradually passed through the reaction mixture.The reaction mixture was then diluted with ethyl acetate (270 U, diluted hydrochloric acid aqueous solution, sodium bicarbonate Water and salt water And concentrated to 180 L in vacuo. This concentrated solution was purified with a column packed with 300 L of alumina resin (elution: ethyl acetate). The fraction solution was concentrated in vacuo to 30 L to give an oil. This oily substance was purified with a column packed with 210 L of a synthetic adsorbent (Diaion (registered trademark) HP 20SS) (elution: aqueous methanol solution). The fraction solution was concentrated in vacuo until methanol was not distilled off, and 300 L of ethyl acetate was added to the concentrate to separate the solution. The upper layer of the separated liquid was concentrated to an oil in a vacuum, added to 900 L of water at 30 ° C., and stirred at the same temperature for 1.5 hours. The solution was filtered, washed with 90 L of water, and dried under reduced pressure to obtain 15.08 kg of the title compound (Ila).

[0046] Comparative Example 2 (Re. 2)

The reaction was performed in the same manner as in Comparative Example 1 except that DMF was used instead of N_methylpyrrolidone. No treatment after the reaction was performed.

[0047] The results are shown in Table 1 below.

[table 1]

RA AP HP

Y A B Y A B Y A B

EX.1 92.0 1.1 0.4 79.2 1.0 0.2

EX.2 89.0 0.5 N.D.X X X

EX.3 94.8 1 .8 1.4 X X X

Ex.4 96.8 3.0 1, 0 X X X

Ex.5 94.6 2.5 0.8 X X X 77.2 2.2 0.4

Re.1 83.5 8.9 N.D. 61.3 1.4 N.D. 47.9 1 .5 N.D.

Re.2 65.8 4.8 9.8 ― ― 1. Since Example 5 was purified using a portion of the crude product, the calculated yield in terms of purity was listed.

RA: At the end of reaction AP: At the end of purification of alumina HP: At the end of purification of HP20SS

Y: Purity conversion yield (%)

A, B: HPLC area percentage value of impurities A and B measured when calculating purity conversion yield (%)

1: Not measured

X: No alumina purification required

N. D .: Not detected

[0048] In Examples 1 and 5, the production rate of compound (Ila) shows a high value of 90% or more, and impurities A The production of alumina was so small that the alumina purification step could be omitted, and the compound (Ila) could be obtained in a high yield of about 80% even after purification with synthetic adsorption resin. In Examples 2 to 4, the compound (Ila) is not isolated, but since the production of impurities A and B is small, the alumina purification step can be omitted as in Example 1 or 5. On the other hand, in Comparative Example 1, the production rate of the compound (Ila) at the time of the reaction is about 10% of that of the Example, but since the production of impurities A is large, an alumina purification step is required. The typical compound (Ila) yield was less than 50%.

[0049] HPLC measurement conditions

Packing column: XTerra RP18 (registered trademark) (Waters)

Particle diameter δ μ -m, inner diameter 4.6 mm, length 150 mm

Mobile phase: Phosphate buffer (pH 8.0) (55%) / acetonitrile (45%)

A phosphate buffer solution (PH 8.0) was prepared by dissolving 17.42 g of dipotassium hydrogen phosphate in 1 L of water and then adding 10% phosphoric acid to adjust the pH to 8.0.

Flow rate: 0.9 mL / min

Detection wavelength: 220nm

Column temperature: 58 ° C

Injection volume: 10 i L

[0050] Retention time

Compound (Ila): about 12.5 minutes

Compound (la): about 26 minutes

Impurity A: about 11 minutes

Impurity B: about 28 minutes

Industrial applicability

[0051] The compound represented by the formula (II) is a compound useful as a neuroprotective agent, a neurotrophic agent, a chondrocyte differentiation promoter, and an erectile dysfunction therapeutic agent. Compound (Ila) is known to be obtained by Wacker oxidation of tacrolimus (compound (la)), which is useful as an immunosuppressant. Since tacrolimus is an expensive fermentation product, the yield has a large impact on manufacturing costs. The present inventors produce Compound (II) from Compound (I) by Wacker oxidation In this method, dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used as a solvent, or dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used as a catalyst. It has been found that by using a palladium complex contained as a ligand, the reaction selectivity is improved and the production rate of compound (II) is also improved. As a result, the present invention provides an industrial production method of Compound (II) that is excellent in terms of cost and work.

Claims

Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[Chemical 2]

In the method for producing a compound represented by the formula: solvate or pharmaceutically acceptable salt thereof, the power of using dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as a solvent, and / or Alternatively, as the palladium catalyst, a compound (II) characterized by using a palladium catalyst containing a dialkyl sulfoxide, alkylaryl sulfoxide, or diaryl sulfoxide as a ligand, and its solution A method for producing a solvate or a pharmaceutically acceptable salt thereof.

[2] The production method according to claim 1, wherein the oxidation reaction is Wacker oxidation.

[3] The production method according to claim 2, wherein dialkyl sulfoxides, alkylaryl sulfoxides or diallyl sulfoxides are used as the solvent.

[4] Dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides and a mixed solvent of water and one or more kinds of compounds (I) and ( 4. The production method according to claim 3, wherein a mixed solvent containing a solvent suitable for II) is used.

[5] The dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides are used in a molar amount of 2 times or more with respect to the rhodium catalyst.

4. The production method according to 4.

[6] Palladium catalytic power Pd (CH 2 CO 3), Pd (CF 2 CO 3), PdCl (CH 3 CN), PdCl, Pd

6. The production method according to claim 3, which is CI (PhCN), PdCl (Ph P), Pd (BF 4) (CH 3 CN), palladium (II) / carbon or palladium (II) montmorillonite.

[7] One or more solvents that do not adversely affect the reaction and are suitable for compound (I) and compound (II) are DMF, dimethylacetamide, acetic acid, methanol, ethanol, tetrahydrofuran, N— 7. The production method according to claim 4, wherein the solvent is selected from methylpyrrolidone and hexamethylphosphoric triamide.

8. The production method according to claim 2, wherein the palladium catalyst is a palladium catalyst containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as ligands.

[9] The production method according to claim 8, which is palladium catalytic power PdCl′2DMSO containing dialkyl sulfoxides, alkylaryl sulfoxides or diaryl sulfoxides as a ligand.

[10] The solvent according to claim 8 or 9, wherein one or two or more kinds of solvents that do not adversely affect the reaction and are suitable for the compound (I) and the compound (II) and water are used. Manufacturing method

[11] Suitable for one or more compounds (I) and (II) without adversely affecting the reaction 11. The production method according to claim 10, wherein the solvent is a solvent selected from DMF, dimethylacetamide, acetic acid, methanol, ethanol, tetrahydrofuran, N-methylpyrrolidone and hexamethylphosphoric triamide.