WO2006030892A1 - Procede de production de composes heterocycliques - Google Patents

Procede de production de composes heterocycliques Download PDF

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Publication number
WO2006030892A1
WO2006030892A1 PCT/JP2005/017137 JP2005017137W WO2006030892A1 WO 2006030892 A1 WO2006030892 A1 WO 2006030892A1 JP 2005017137 W JP2005017137 W JP 2005017137W WO 2006030892 A1 WO2006030892 A1 WO 2006030892A1
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WO
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Prior art keywords
compound
methyl
cis
dioxane
reaction
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English (en)
Japanese (ja)
Inventor
Tetsuji Harabe
Masaru Tanaka
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Nippon Shinyaku Co Ltd
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Nippon Shinyaku Co Ltd
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Publication of WO2006030892A1 publication Critical patent/WO2006030892A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to 2-methyl-c-5- ⁇ 4- [5-methyl-2- (4-methylphenol) -1,3-oxazole-4-yl] butyl ⁇ 1,3 dioxane useful as a medicine —R— 2 It relates to a method for producing rubonic acid (hereinafter NS-220).
  • NS-220 is a blood triglyceride lowering action and low density lipoprotein cholesterol.
  • LDL-C blood glucose-lowering effect
  • HDL-C blood insulin lowering effect
  • arteriosclerosis index a ratio of high-density lipoprotein cholesterol to HDL-C, calculated as (total cholesterol value-HDL-C value) ZHDL-C value.
  • o NS-220 is It is known that it can be produced by the following method (for example, see Patent Document 1). Bre
  • NS-220 is a cis isomer
  • the production intermediate methyl cis-5- (4 chlorobutyl) 2-methyl-1,3 dioxane 2 carboxylate (compound 4) is Compound 4) was produced by resolution by column chromatography.
  • an unnecessary transformer body has to be discarded, and there is a problem in terms of manufacturing efficiency.
  • the use of a purification method based on column chromatography in large-scale synthesis on an industrial scale necessitates the use of a considerable amount of silica gel and solvent, resulting in a rise in production costs and the adverse effect of the used solvent on the environment. Giving and giving. Further, the operation process is complicated and difficult.
  • the raw material compound 13 is chemically unstable, and the compound 13 is not commercially available, and it is necessary to carry out raw material synthesis (3 steps). There is.
  • the above production method C (for example, see Non-Patent Document 4) has a total yield of 18% and is not strong (in the case of Compound 6 ′), and it is difficult to crystallize Compound 6 in the post-reaction treatment. .
  • the above production method D (for example, see Non-Patent Document 5) has a total yield of only 15% (in the case of Compound 6).
  • Non-Patent Documents 6 to 7 uses a metal such as chromium or ruthenium as a reagent, a separate disposal process is required, and the product may contain these metals. is there.
  • Patent Document 1 International Publication No. 01Z90087 Pamphlet
  • Non-patent literature l J. Chem. Soc, 1948, 310-315
  • Non-Patent Document 2 Tetrahedron Lett., 2000, 41, 8969-8972
  • Non-Patent Document 3 J. Am. Chem. Soc, 1991, 113, 2247-2253
  • Non-Patent Document 4 Chem. Lett., 1989, 449-452, 515-518, 569-572
  • Non-Patent Document 5 Chem. Pharm. Bull, 1979, 27, 1181-1185
  • Non-Patent Document 6 TetrahedronLett "1985, 26, 3433-3436
  • Non-Patent Document 7 Syn ⁇ ett., 1999, 10, 1642-1644
  • the main object of the present invention is to provide a novel method for producing NS-220 suitable for mass synthesis on an industrial scale. Means for solving the problem
  • Examples of the present invention include the following methods.
  • Compound 4 which is an important production intermediate of NS-220 can be produced by the following method.
  • compound 4 ′ is hydrolyzed in the presence of a base, so that the trans form is preferentially hydrolyzed (selective hydrolysis). Therefore, by adjusting the amount of the base used, The hydrolysis rate can be controlled, and the compound 4 having a cis Z-trans ratio of 9 Zl to 50 Zl can be easily produced.
  • the solvent that can be used for this selective hydrolysis reaction is not particularly limited as long as it can dissolve the substrate compound 4 ′, but acetonitrile, ⁇ , ⁇ dimethylformamide, toluene, tetrahydrofuran, ⁇ -methyl-2-pyrrolidone. 1,3 dimethyl-2-imidazolidinone, acetone, and methanol are suitable, and acetonitrile, ⁇ , dimethylformamide, and tetrahydrofuran are preferred.
  • the amount of the solvent used in this selective hydrolysis reaction is not particularly limited as long as it dissolves compound 4 ′ as a substrate, but 0.5 to L0 amount (volume) with respect to compound 4 ′ as a substrate. (mL) Z weight (g)) is suitable, and 1 to 5 times the amount is more preferable.
  • the base that can be used for this selective hydrolysis reaction is not particularly limited as long as it is a base used for a usual ester hydrolysis reaction, but sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide salt, and the like. Cesium is suitable, and sodium hydroxide and potassium hydroxide are preferred.
  • the hydrolysis rate of compound 4 ′ as a substrate can be controlled. When the hydrolysis rate is low, many unreacted trans isomers remain, and when the hydrolysis rate is high, the yield of compound 4 decreases.
  • the amount of base used varies depending on the cis-Z trans ratio of compound 4 ′, the substrate used, and the type and amount of solvent used. Appropriate, 0.2 to 0.4 times the amount of mono-layered S girls, 0.25 to 0.35 mono-layered amounts of girls! / ⁇ .
  • the reaction temperature of this hydrolysis reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 0 to 60 ° C is preferable, and the range of 10 to 40 ° C is more preferable. A range of 30 ° C is more preferred.
  • the reaction time of this hydrolysis reaction depends on the concentration of the substrate in the reaction solution, but the range of 30 minutes to 10 hours is preferred, and the range of 1 to 5 hours is more preferred.
  • This ketal exchange reaction is a general reaction and can be carried out by a known method. For example, it can be carried out by adding methyl pyruvate in the presence of boron trifluoride jetyl ether complex.
  • the solvent that can be used in this ketal exchange reaction is not particularly limited as long as it can dissolve compound 21 as a substrate, but toluene and acetonitrile are suitable, and toluene is preferable.
  • Amount of solvent used in this ketal exchange reaction Is not particularly limited as long as it is an amount capable of dissolving compound 21 as a substrate, but 1 to L0 volume (volume (mL) Z weight (g)) is appropriate for compound 21 as substrate. 3 to 5 times the amount is preferable.
  • reaction temperature of this ketal exchange reaction is not particularly limited as long as it is lower than the boiling point of the solvent to be used, but in general, the range of 0 to 60 ° C is preferred, and the range of 20 to 40 ° C is more preferred 2 5 A range of ⁇ 35 ° C. is more preferable.
  • reaction time of this ketal exchange reaction depends on the concentration of the substrate in the reaction solution.
  • concentration of the substrate in the reaction solution The range of 1S 30 minutes to 10 hours is preferred.
  • range of 1 to 5 hours is more preferred.
  • compound 4 can be produced by hydrolysis suitable for mass synthesis on an industrial scale, not by column chromatography. Furthermore, since unnecessary transformer bodies can be reused, the production efficiency can be improved.
  • Compound 5 which is an important production intermediate of NS 220 can be produced by the following method in the same manner as the production method of compound 4 described above.
  • compound 5 ′ is hydrolyzed in the presence of a base, whereby the trans form is preferentially hydrolyzed (selective hydrolysis). Therefore, by adjusting the amount of the base used, The hydrolysis rate can be controlled, and the compound 4 having a cis Z-trans ratio of 9 Zl to 50 Zl can be easily produced.
  • trans-form produced by this selective hydrolysis is high in the proportion of 5- (4-iodobutyl) -2-methyl-1,3 dioxane-2-strong rubonic acid (Compound 22) should be ketal-exchanged.
  • the compound 5 can be obtained again by the similar selective hydrolysis of the regenerated compound 5 ′.
  • NS-220 can be synthesized efficiently.
  • the solvent, amount of solvent, base, amount of base, reaction temperature and reaction time that can be used for this selective hydrolysis reaction, and the amount of solvent, solvent, reaction temperature and reaction time that can be used for this ketal exchange reaction are as follows. This is the same as the production method of Compound 4.
  • compound 5 can be produced in large quantities on an industrial scale regardless of column chromatography. It can be produced by hydrolysis suitable for synthesis. Furthermore, since unnecessary transformer bodies can be reused, the production efficiency can be improved.
  • the condensation reaction of compound 5 'and compound 6 can be carried out in the presence of a base, but as a by-product when an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide is used as the base. Since water is generated, hydrolysis reaction of the produced compound 7 ′ can be performed simultaneously by adding an excess base and carrying out this reaction.
  • a base such as sodium hydroxide or potassium hydroxide
  • compound 7 ′ is also hydrolyzed in the presence of a base to preferentially hydrolyze the trans isomer (selective hydrolysis). Therefore, by adjusting the amount of base used, The hydrolysis rate can be controlled, and compound 7 having a cis Z-trans ratio of 9Zl to 50Z1 can be produced.
  • the solvent that can be used in this reaction is not particularly limited as long as it can dissolve the compounds 5 ′ and 6 as substrates, but N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl- 2-Imidazolidinone is suitable, and N, N-dimethylformamide is preferred.
  • the amount of the solvent used in this reaction is not particularly limited as long as it dissolves the compound 5 ′ and the compound 6 as the substrate, but is 0.5 to L0 times the compound 5 ′ as the substrate.
  • the amount (capacity (mL) Z weight (g)) is appropriate, and 1 to 5 times the amount is preferable.
  • the base that can be used in this reaction is not particularly limited as long as it is a base used for ordinary condensation reactions and ester hydrolysis reactions, but sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide salt, and the like. Cesium and sodium hydride are suitable, sodium hydroxide, potassium hydroxide Um is preferred.
  • the hydrolysis rate of compound 7 ′ can be controlled.
  • an equimolar amount of base is required for the condensation reaction of Compound 5 ′ and Compound 6. Therefore, the amount of base used in this reaction varies depending on the cis-Z trans ratio of compound 7 ′, which is the substrate used, and the type and amount of solvent used. 1.
  • a 6-fold molar amount is appropriate, and 1.1 to 1.4-fold molar amount is preferred.
  • the reaction temperature of this reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 0 to 60 ° C is suitable, and the range of 10 to 30 ° C is preferable.
  • reaction time of this reaction depends on the concentration of the substrate in the reaction solution, the range of 30 minutes to 10 hours is appropriate, and the range of 1 to 5 hours is preferable.
  • compound 7 can also be produced by hydrolysis suitable for mass synthesis on an industrial scale.
  • this reaction can be carried out simultaneously with the condensation reaction of compound 5 ′ and compound 6, the production process of NS-220 can be reduced by one step, and the production efficiency can be improved. .
  • Compound 6 which is an important production raw material for NS-220, can be produced by the following method.
  • Process 2 6 Acidify 4-methyl N- (2-hydroxypropyl) benzamide (compound 20) by using 2, 2, 6, 6-tetramethyl-1-piveridi-ruoxy radical (hereinafter referred to as TEMPO) and sodium hypochlorite Can be manufactured.
  • TEMPO 2, 2, 6, 6-tetramethyl-1-piveridi-ruoxy radical
  • Step 1 is an amide formation reaction between an acid chloride and an amine and can be produced by a conventional method.
  • the solvent that can be used in the amide formation reaction is not particularly limited as long as it can dissolve the compound 18 as a substrate, but toluene, acetonitrile, N, N dimethylformamide, N-methyl-2-pyrrolidone, 1, 3 Dimethyl-2-imidazolidinone is suitable, and toluene and acetonitrile are preferred.
  • the amount of the solvent used in this amide formation reaction is not particularly limited as long as compound 18 as a substrate is dissolved, but it is 1 to 10 times the amount of compound 18 as a substrate (volume (mL) Z weight ( g)) is suitable, and 3 to 6 times the amount is preferred.
  • the reaction time of the present amide formation reaction depends on the concentration of the substrate in the reaction solution, but is suitably in the range of 30 minutes to 8 hours, preferably in the range of 1 to 4 hours.
  • the reaction temperature of the present amide formation reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 20 to 60 ° C is appropriate, and the range of 0 to 40 ° C is preferable.
  • the amount of 19 used in this amide formation reaction varies depending on the type and amount of the solvent used, the reaction temperature, and the reaction time, but a 1 to 10-fold molar amount relative to 18 is appropriate. The amount is good.
  • the compound 20 as a substrate may be partially used. Although it does not ask
  • the amount of solvent used in this oxidation reaction is not particularly limited as long as it partially dissolves the compound 20 as a substrate, but it is 1 to 40 times the amount of compound 20 as a substrate (volume (mL) Z Weight (g)) is suitable, 3 to 20 times the amount is preferred.
  • the amount of TEMPO used in this oxidation reaction varies depending on the type and amount of the solvent used, the reaction temperature, and the reaction time, but 0.001 to 2 times the molar amount is preferred with respect to the substrate. It is preferable to mass.
  • reaction temperature of the oxidation reaction in step 2 is suitably in the range of ⁇ 20 to 30 ° C., preferably in the range of ⁇ 10 to 20 ° C., more preferably in the range of 0 to 10 ° C.
  • the reaction time of the oxidation reaction in step 2 is preferably in the range of 30 minutes to 10 hours, more preferably in the range of 1 to 5 hours, although it depends on the concentration of the substrate in the reaction solution.
  • Test Example 1 Methyl cis 5- (4 chlorobutyl) 2 methyl 1.3 dioxane 2 carboxylate Debate
  • Carrier gas Argon gas
  • the cis-to-trans ratio is 9 or more (90% or more of the cis-isomer)
  • the trans-isomer can be removed in the subsequent purification step in each reaction. Therefore, if the hydrolysis rate is controlled to 20% or more, it is possible to produce compound 4 without using conventional column chromatography.
  • compound 5 ′ having a cis / Z trans ratio of 3.6 / 1 synthesized by the method described in Patent Document 1 is dissolved in an equal amount (volume (mL), Z weight (g)) of acetonitrile. Then, sodium hydroxide was added in a molar amount 0.4 times that of Compound 5 'and subjected to hydrolysis at 20 ° C for 2 hours. Thereafter, the hydrolysis rate after the reaction and the cis-Z trans ratio of the unhydrolyzed compound 4 ′ were calculated by gas chromatography (GC). The GC measurement conditions are the same as in Test Example 1. As a result, when the hydrolysis rate was 39.5%, the cis-Z trans ratio of the unreacted compound 4 ′ was 148.9Z1.
  • the production method of Compound 5 using Compound 5 ′ is related to the cis-Z trans ratio by controlling the hydrolysis rate in the same manner as the production method of Compound 4 using Compound 4 ′ of Test Example 1. This manufacturing method can be used.
  • compound 7 ′ synthesized by the method described in Patent Document 1 and having a cis-Z trans ratio of 3.5 / 1 is dissolved in a three-fold amount (volume (mL) Z weight (g)) of solvent. Then, various bases were added in a predetermined molar amount with respect to the compound 4 ′ and subjected to hydrolysis reaction at 10 to 20 ° C. for 2 hours. Thereafter, the hydrolysis rate after the reaction and the cis-Z trans ratio of the unhydrolyzed compound 7 ′ were calculated by HP LC. The results are shown in Table 2.
  • the hydrolysis rate of compound 7 ′ can be controlled by increasing or decreasing the amount of base, as in the case of compound 4 ′ of Test Example 1, by hydrolysis of compound 7 ′. If the hydrolysis rate is controlled, it is possible to produce compound 7 without using conventional column chromatography.
  • TEMPO is a well-known oxidant and has a particularly superior combination of TEMPO and sodium hypochlorite in the oxidation of 4-methyl-N- (2-hydroxypropyl) benzamide.
  • the discovery of a powerful oxidant that could not be conceived has made it possible to easily produce Compound 7 which is an important raw material for producing NS-220, which is useful as a medicine, in high yield.
  • Example 1 Production of NS-220 including the production process of obtaining compound 4 by selective hydrolysis (Step 1) Production of compound 4 by selective hydrolysis
  • the aqueous layer obtained in Step 1 of Example 1 was extracted by adding 128.3 g of concentrated hydrochloric acid and 700 mL of toluene to recover trans-rich compound 21.
  • 15.5 g of methyl pyruvate and 6.9 g of boron trifluoride ether complex were added to 50 mL of the toluene solution of the recovered compound 21 and reacted at 60 ° C for 8 hours. After the reaction, the mixture was washed with 77% 20% aqueous sodium hydroxide solution, 39ml 10% aqueous sodium hydroxide solution and 10ml 10% aqueous sodium chloride solution in this order. The organic layer was concentrated under reduced pressure to obtain 2.4 g of compound 4 ′.
  • Example 3 Production of NS-220 including production process for obtaining compound 7 by selective hydrolysis
  • the compound obtained in Step 1 was mixed with 300.0 g of TEMPO 0.4851 g, sodium odorite 15. 97 g, magnesium sulfate 9.34 g, ethyl acetate 450 ml, water 30 ml, and sodium hypochlorite.
  • Aqueous solution (effective chlorine 5% or more)
  • a solution of 6.52 g of sodium bicarbonate in 222.2 g was dropped at 2 to -10 ° C. After stirring at 0 ° C for 40 minutes, the layers are separated, and the upper layer is a solution in which 2.558 g of rhodium iodide is dissolved in 56.6 g of 1% hydrochloric acid aqueous solution, 10% -Na 2 SO 4 aqueous solution 1
  • the production method according to the present invention is a column chromatograph as compared to the conventional production method. It is useful as a medicine without using a metal compound.
  • NS-220 can be manufactured.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Cette invention concerne un procédé pour la production de NS-220 convenant à la production de masse à échelle industrielle. L'invention comprend (1) un procédé pour la production du cis-5-(4-chlorobutyl)-2-méthyl-1,3-dioxane-2-carboxylate de méthyle, caractérisé par l'hydrolyse d'un mélange isomère cis/trans du 5-(4-chlorobutyl)-2-méthyl-1,3-dioxane-2-carboxylate de méthyle en présence d'une base ; (2) un procédé pour la production de la 4-méthyl-N-(2-oxopropyl)benzamide, caractérisé par l'oxydation de la 4-méthyl-N-(2-hydroxypropyl)benzamide avec des radicaux 2,2,6,6-tétraméthyl-1-pipéridinyloxyle et de l'hypochlorite de sodium; et ainsi de suite.
PCT/JP2005/017137 2004-09-17 2005-09-16 Procede de production de composes heterocycliques Ceased WO2006030892A1 (fr)

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JP2004271349 2004-09-17
JP2004-271349 2004-09-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016056031A1 (fr) 2014-10-08 2016-04-14 Council Of Scientific & Industrial Research Procédé de synthèse de nouveaux composés de diol et son utilisation pour la synthèse formelle d'acide (2r, 3s)-3-hydroxypipécolique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001090087A1 (fr) * 2000-05-26 2001-11-29 Nippon Shinyaku Co., Ltd. Composes heterocycliques
JP2002522557A (ja) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｃ型肝炎インヒビターペプチド
JP2002522554A (ja) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｃ型肝炎インヒビタートリペプチド
JP2004217608A (ja) * 2002-02-13 2004-08-05 Dai Ichi Seiyaku Co Ltd （１ｓ，２ｓ）−２−フルオロシクロプロパンカルボン酸誘導体の製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002522557A (ja) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｃ型肝炎インヒビターペプチド
JP2002522554A (ja) * 1998-08-10 2002-07-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｃ型肝炎インヒビタートリペプチド
WO2001090087A1 (fr) * 2000-05-26 2001-11-29 Nippon Shinyaku Co., Ltd. Composes heterocycliques
JP2004217608A (ja) * 2002-02-13 2004-08-05 Dai Ichi Seiyaku Co Ltd （１ｓ，２ｓ）−２−フルオロシクロプロパンカルボン酸誘導体の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUWABARA K.: "A novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay mice.", J PHARMACOL EXP THER., vol. 309, no. 3, June 2004 (2004-06-01), pages 970 - 977, XP002995210 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016056031A1 (fr) 2014-10-08 2016-04-14 Council Of Scientific & Industrial Research Procédé de synthèse de nouveaux composés de diol et son utilisation pour la synthèse formelle d'acide (2r, 3s)-3-hydroxypipécolique

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