Method and compound for preparing orexin-2 receptor antagonist, and low-impurity lybologxant

Abstract

The invention relates to a method and a compound for preparing an orexin-2 receptor antagonist, and lebovolisan with less impurities, and particularly relates to a method and a compound for preparing an orexin-2 receptor antagonist. A process for preparing a compound of Formula (XI) and a compound are disclosed. Further, the present application discloses a compound of formula (XI) comprising a small amount of impurities. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202080030535.7 (PCT application number is PCT / JP2020 / 019037), whose application date is May 13, 2020 and whose invention name is "Methods and compounds for preparing orexin-2 receptor antagonists, and leborexant with few impurities". Technical Field

[0002] The present invention relates to compounds and methods for preparing lemborexant, which is useful as an orexin-2 receptor antagonist. Furthermore, the present invention relates to lemborexant containing a small amount of impurities. Background Art

[0003] Orexin receptors are G protein-coupled receptors that are primarily observed in the brain. The endogenous ligands of the orexin receptor, orexin-A and orexin-B, are expressed by neurons localized in the hypothalamus. Orexin-A is a 33 amino acid peptide and orexin-B contains 28 amino acids (Sakurai T. et al., Cell, 1998, Vol. 92, pp. 573-585). Orexin receptors have two subtypes, OX1 and OX2; OX1 preferentially binds to orexin-A, but OX2 binds to both orexin-A and orexin-B. It is suggested that orexin stimulates food consumption in rats, and orexin signaling may play a role in a central feedback mechanism for regulating feeding behavior (Sakurai et al., supra). Orexin has also been observed to control wakefulness-sleep states (Chemelli RM et al., Cell, 1999, Vol. 98, pp. 437-451). Orexins may also play a role in brain changes associated with opioid and nicotine dependence (SL Borgland et al., Neuron, 2006, vol. 49, pp. 598-601; CJ Winrow et al., Neuropharmacology, 2010, vol. 58, pp. 185-194) and alcohol dependence (JR Shoblock et al., Psychopharmacology, 2011, vol. 215, pp. 191-203). Furthermore, orexins have been suggested to play a role in some stress responses (T. Ida et al., Biochem. Biophys. Res. Commun., 2000, vol. 270, pp. 318-323).

[0004] Compounds such as (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropylcarboxamide (Lebrexan) are known to be potent orexin receptor antagonists and are useful in the treatment of sleep disorders such as insomnia and other therapeutic applications.

[0005]

[0006] List of cited references

[0007] Patent Literature

[0008] [Patent Document 1] WO 2012 / 039371

[0009] [Patent Document 2] WO 2013 / 123240

[0010] Non-patent literature

[0011] [Non-patent document 1] Sakurai T. et al., Cell, 1998, Vol. 92, pp. 573-585

[0012] [Non-patent document 2] Chemelli RM et al., Cell, 1999, Vol. 98, pp. 437-451

[0013] [Non-patent document 3] SL Borgland et al., Neuron, 2006, Vol. 49, pp. 598-601

[0014] [Non-patent document 4] CJ Winrow et al., Neuropharmacology, 2010, Vol. 58, pp. 185-194

[0015] [Non-patent document 5] JR Shoblock et al., Psychopharmacology, 2011, Vol. 215, pp. 191-203

[0016] [Non-patent document 6] T. Ida et al., Biochem. Biophys. Res. Commun. [Biochemistry and Biophysics Research Communications], 2000, Vol. 270, pp. 318-323 Summary of the invention

[0017] Technical issues

[0018] As a method for preparing lebrexan, there is known a method described in Patent Document 1. However, in Patent Document 1, lebrexan is synthesized from Compound Prep 14-2 of Preparation Example 14 through Compound Prep 14-3.

[0019]

[0020] This preparation method has a low yield, and thus there remain problems in applying the above preparation method to industrial production.

[0021] As a method for producing lebrexan, the method described in Patent Document 2 is known. However, in Patent Document 2, the compound 5 is synthesized through the compound 6 by acetylation using an enzyme.

[0022]

[0023] In this preparation method, since the enzyme residue must be considered during equipment washing, there are still problems when applying the above preparation method to industrial production.

[0024] Furthermore, the present inventors have found that compounds of Formula VI, Formula IX, Formula X, Formula XII, Formula XIII, Formula XIV and Formula XV are contained as impurities in the preparation of Lebrexan compounds.

[0025]

[0026] Therefore, there is a need for a synthetic method and an intermediate for preparing Lebrexan useful as a medicine. Therefore, the purpose of the present application is to provide such a synthetic method and an intermediate. In addition, there is a need for Lebrexan useful as a medicine and containing a small amount of impurities. Therefore, the purpose of the present application is to provide Lebrexan containing a small amount of impurities.

[0027] Solution to the problem

[0028] The present invention provides a compound and a method for producing lebrexan useful as an orexin-2 receptor antagonist, and further provides lebrexan containing a small amount of impurities.

[0029] The present invention provides a method for preparing a compound of formula III,

[0030]

[0031] It includes:

[0032] a) to a compound comprising formula II

[0033]

[0034] adding a Grignard reagent to a mixture of toluene and tetrahydrofuran; and

[0035] b) adding the above mixture to a mixture comprising acetyl chloride and ethyl acetate.

[0036] In one embodiment, the Grignard reagent is cyclohexylmagnesium chloride.

[0037] The present invention provides a method for preparing a compound of formula XI,

[0038]

[0039] It includes:

[0040] The manufacturing steps for preparing the compound of formula III are as described above.

[0041] The present invention provides a method for preparing a compound of formula XI as described above, which comprises

[0042] i) a compound of formula IX

[0043]

[0044] ii) Compound of formula X

[0045]

[0046] iii) ethyl acetate,

[0047] iv) N,N-diisopropylethylamine, and

[0048] v) The mixture of 1-propanephosphonic acid is stirred at a temperature of 60°C to 80°C.

[0049] The present invention provides a process for preparing a compound of formula IX,

[0050]

[0051] It includes:

[0052] The compound of formula III is prepared as described above.

[0053] The present invention provides a process for preparing a compound of formula IX,

[0054]

[0055] It includes:

[0056] The compound of formula VII

[0057]

[0058] Reacts with oxidants.

[0059] In one embodiment, the step of reacting the compound of formula VII with an oxidizing agent is performed by sequentially adding sodium hypochlorite and sodium chlorite as the oxidizing agent.

[0060] The present invention provides a process for preparing a compound of formula IX,

[0061]

[0062] It includes:

[0063] a) Compound of formula VII

[0064]

[0065] The aldehyde of formula VIII is prepared by oxidation with sodium hypochlorite,

[0066]

[0067] as well as

[0068] b) oxidizing the aldehyde with sodium chlorite.

[0069] In one embodiment, the oxidation in step a) is catalyzed by an effective amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).

[0070] The present invention provides a process for preparing a compound of formula VII,

[0071]

[0072] It includes:

[0073] The manufacturing steps for preparing the compound of formula III as described above, and

[0074] Add sodium hydroxide aqueous solution to the compound of formula V

[0075]

[0076] The two were stirred at a temperature of 30°C-50°C.

[0077] The present invention provides a method for preparing a compound of formula V,

[0078]

[0079] It includes:

[0080] a) To

[0081] i) Compounds of formula VI

[0082]

[0083] ii) N-methylpyrrolidone, and

[0084] iii) adding potassium tert-butoxide to the mixture of acetonitrile and

[0085] Stirring at a temperature of 40°C to 70°C; and

[0086] b) by adding the above mixture

[0087] Add i) a compound of formula IV

[0088]

[0089] The resulting mixture was stirred at a temperature of 40°C-70°C.

[0090] The present invention provides a method for preparing a compound of formula IV,

[0091]

[0092] It includes:

[0093] to a compound of formula III prepared by the process as described above,

[0094]

[0095] To the composition of toluene, triethylamine and 1-methylimidazole is added ii) a mixture of p-toluenesulfonyl chloride, toluene and acetonitrile.

[0096] The present invention provides a method for preparing a compound of formula II,

[0097]

[0098] It includes:

[0099] To a compound comprising formula I

[0100]

[0101] Methanol is added to the composition of toluene, tetrahydrofuran, and sodium borohydride.

[0102] The present invention provides a compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less.

[0103]

[0104] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XII is determined by high performance liquid chromatography (HPLC).

[0105] The present invention provides a compound of formula XI, wherein the content of total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0 mass % or less.

[0106]

[0107] The present invention provides a compound of formula XI as described above, wherein the content of total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0108] The present invention provides a compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less, and the content of the total related substances including the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0 mass % or less.

[0109]

[0110] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XII, and the total related substances including compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0111] The present invention provides a compound of formula XI, wherein the content of the compound of formula VI is 0.05 mass % or less.

[0112]

[0113] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula VI is determined by high performance liquid chromatography (HPLC).

[0114] The present invention provides a compound of formula XI, wherein the content of the compound of formula IX is 0.05 mass % or less.

[0115]

[0116] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula IX is determined by high performance liquid chromatography (HPLC).

[0117] The present invention provides a compound of formula XI, wherein the content of the compound of formula X is 0.05 mass % or less.

[0118]

[0119] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula X is determined by high performance liquid chromatography (HPLC).

[0120] The present invention provides a compound of formula XI, wherein the content of the compound of formula XIII is 0.05 mass % or less.

[0121]

[0122] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XIII is determined by high performance liquid chromatography (HPLC).

[0123] The present invention provides a compound of formula XI, wherein the content of the compound of formula XIV is 0.05 mass % or less.

[0124]

[0125] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XIV is determined by high performance liquid chromatography (HPLC).

[0126] The present invention provides a compound of formula XI, wherein the content of the compound of formula XV is 0.05 mass % or less.

[0127]

[0128] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XV is determined by high performance liquid chromatography (HPLC).

[0129] The present invention provides the compound of formula XI as described above, wherein the content of the compound of formula XI is 97.0 mass % or more.

[0130] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XI is determined by high performance liquid chromatography (HPLC).

[0131] The present invention provides a compound comprising a compound of formula XI and a compound of formula XII, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula XII is 0.10% by mass or less.

[0132]

[0133] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula XII is determined by high performance liquid chromatography (HPLC).

[0134] The present invention provides a compound containing a compound of formula XI, a compound of formula XII and total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV, wherein the content of the compound of formula XI is 97.0% by mass or more, the content of the compound of formula XII is 0.10% by mass or less, and the content of the total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0% by mass or less.

[0135]

[0136] The present invention provides compounds as described above, wherein the content of the compound of formula XI, the compound of formula XII, and the total related substances comprising the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0137] The present invention provides a compound comprising a compound of formula XI and a compound of formula VI, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula VI is 0.05% by mass or less.

[0138]

[0139] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula VI is determined by high performance liquid chromatography (HPLC).

[0140] The present invention provides a compound having a formula comprising a compound of formula XI and a compound of formula IX, wherein the content of the compound of formula XI is 97.0 mass % or more, and the content of the compound of formula IX is 0.05 mass % or less.

[0141]

[0142] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula IX is determined by high performance liquid chromatography (HPLC).

[0143] The present invention provides a compound comprising a compound of formula XI and a compound of formula X, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula X is 0.05% by mass or less.

[0144]

[0145] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula X is determined by high performance liquid chromatography (HPLC).

[0146] The present invention provides a compound comprising a compound of formula XI and a compound of formula XIII, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula XIII is 0.05% by mass or less.

[0147]

[0148] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula XIII is determined by high performance liquid chromatography (HPLC).

[0149] The present invention provides a compound comprising a compound of formula XI and a compound of formula XIV, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula XIV is 0.05% by mass or less.

[0150]

[0151] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula XIV is determined by high performance liquid chromatography (HPLC).

[0152] The present invention provides a compound comprising a compound of formula XI and a compound of formula XV, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula XV is 0.05% by mass or less.

[0153]

[0154] The present invention provides the compound as described above, wherein the content of the compound of formula XI and the compound of formula XV is determined by high performance liquid chromatography (HPLC).

[0155] This application provides the following items:

[0156] Item 1. A method for preparing a compound of formula III,

[0157]

[0158] It includes:

[0159] a) to a compound comprising formula II

[0160]

[0161] adding a Grignard reagent to a mixture of toluene and tetrahydrofuran; and

[0162] b) adding the above mixture to a mixture containing acetyl chloride and ethyl acetate. Item 2. The method of Item 1, wherein the Grignard reagent is cyclohexylmagnesium chloride. Item 3. A method for preparing a compound of formula XI,

[0163]

[0164] It includes:

[0165] The manufacturing steps for preparing the compound of formula III as described in item 1.

[0166] Item 4. The method of Item 3, comprising:

[0167] i) a compound of formula IX

[0168]

[0169] ii) Compound of formula X

[0170]

[0171] iii) ethyl acetate,

[0172] iv) N,N-diisopropylethylamine, and

[0173] v) The mixture of 1-propanephosphonic acid is stirred at a temperature of 60°C to 80°C.

[0174] Item 5. A method for preparing a compound of formula IX,

[0175]

[0176] It includes:

[0177] Prepare the compound of formula III as described in item 1.

[0178] Item 6. A method for preparing a compound of formula IX,

[0179]

[0180] It includes:

[0181] The compound of formula VII

[0182]

[0183] Reacts with oxidants.

[0184] Item 7. The method of Item 6, comprising:

[0185] Sodium hypochlorite and sodium chlorite are added sequentially as oxidants. Item 8. A method for preparing a compound of formula IX,

[0186]

[0187] It includes:

[0188] a) Compound of formula VII

[0189]

[0190] The aldehyde of formula VIII is prepared by oxidation with sodium hypochlorite,

[0191]

[0192] as well as

[0193] b) oxidizing the aldehyde with sodium chlorite.

[0194] Item 9. The method of Item 8, wherein the oxidation in step a) is catalyzed by an effective amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).

[0195] Item 10. A method for preparing a compound of formula VII,

[0196]

[0197] It includes:

[0198] The manufacturing steps for preparing the compound of formula III as described in item 1, and

[0199] Adding aqueous sodium hydroxide to the compound of formula V,

[0200]

[0201] The two were stirred at a temperature of 30°C-50°C.

[0202] Item 11. A method for preparing a compound of formula V,

[0203]

[0204] It includes:

[0205] a) To

[0206] i) Compounds of formula VI

[0207]

[0208] ii) N-methylpyrrolidone, and

[0209] iii) adding potassium tert-butoxide to the mixture of acetonitrile and

[0210] Stirring at a temperature of 40°C to 70°C; and

[0211] b) by adding the above mixture

[0212] Add i) a compound of formula IV

[0213]

[0214] The resulting mixture was stirred at a temperature of 40°C-70°C.

[0215] Item 12. A method for preparing a compound of formula IV,

[0216]

[0217] It includes:

[0218] i) a compound of formula III prepared by the method described in item 1,

[0219]

[0220] To the composition of toluene, triethylamine and 1-methylimidazole is added ii) a mixture of p-toluenesulfonyl chloride, toluene and acetonitrile.

[0221] Item 13. A method for preparing a compound of formula II,

[0222]

[0223] It includes:

[0224] To a compound comprising formula I

[0225]

[0226] Methanol is added to the composition of toluene, tetrahydrofuran, and sodium borohydride.

[0227] Item 14. A compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less,

[0228]

[0229] Item 15. The compound of formula XI as described in Item 14, wherein the content of the compound of formula XII is determined by high performance liquid chromatography (HPLC).

[0230] Item 16. A compound of formula XI, wherein the content of the compound of formula XII is 0.10% by mass or less, and the content of the total related substances comprising the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0% by mass or less

[0231]

[0232] Item 17. A compound of formula XI as described in Item 16, wherein the content of the compound of formula XII, and the total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0233] Item 18. The compound of formula XI according to any one of items 14 to 17, wherein the content of the compound of formula XI is 97.0% by mass or more.

[0234] Item 19. The compound of formula XI as described in Item 18, wherein the content of the compound of formula XI is determined by high performance liquid chromatography (HPLC).

[0235] Item 20. A compound comprising a compound of formula XI and a compound of formula XII, wherein the content of the compound of formula XI is 97.0% by mass or more, and the content of the compound of formula XII is 0.10% by mass or less

[0236]

[0237] Item 21. The compound as described in Item 20, wherein the content of the compound of Formula XI and the compound of Formula XII is determined by high performance liquid chromatography (HPLC).

[0238] Item 22. A compound comprising a compound of formula XI, a compound of formula XII, and total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV, and formula XV, wherein the content of the compound of formula XI is 97.0% by mass or more, the content of the compound of formula XII is 0.10% by mass or less, and the content of the total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV, and formula XV is 1.0% by mass or less,

[0239]

[0240] Item 23. A compound as described in Item 22, wherein the content of the compound of formula XI, the compound of formula XII, and the total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0241] Advantageous Effects of the Invention

[0242] The present invention can provide a synthetic method and intermediates for preparing orexin-2 receptor antagonists. Furthermore, the present invention can provide lebrexan containing a small amount of impurities. DETAILED DESCRIPTION

[0243] Hereinafter, the meanings of symbols, terms, and the like used in this specification will be described, and this specification will be described in detail.

[0244] In this specification, the structural formula of the compound is not limited to the convenient formula, and the compound may also form a salt. Furthermore, there are cases where polymorphism exists, but it is also not limited, and it may be any single crystal form or a mixture thereof, and in addition to anhydrous, it may also be a hydrate or a solvate, all of which are included in the present invention.

[0245] In the present specification, unless otherwise specified, specific examples of the salt include hydrohalide salts (e.g., hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salts (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), and the like.

[0246] In one embodiment, the compound described in this specification can be provided in the form of a salt, such as a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" is a salt that retains the desired biological activity of the parent compound but does not impart undesirable toxicological effects. Specific examples of pharmaceutically acceptable salts include inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.), organic carboxylates (acetates, oxalates, maleates, tartrates, fumarates, citrates, etc.), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, camphorsulfonates, etc.), amino acid salts (aspartate, glutamate, etc.), quaternary ammonium salts, alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (magnesium salts, calcium salts, etc.).

[0247] The present invention also includes isotope-labeled compounds of the compounds described in the specification and methods of preparing the same using the same. Isotope-labeled compounds are identical to the compounds described in the specification except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Isotopes that can be incorporated into the compounds of the present invention are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, phosphorus, sulfur, and iodine, including 2 H. 3 H. 11 C. 14 C. 13 N. 15 O. 18 F. 32 P. 35 S. 123 I, and 125I, etc. The compounds of the present invention and pharmaceutically acceptable derivatives (such as salts) containing these isotopes and / or other isotopes are also included in the scope of the present patent application.

[0248] The isotope-labeled compounds of the present invention, for example, incorporate 3 H and / or 14 Compounds containing radioactive isotopes such as C are useful for measuring the tissue distribution of drugs and / or substrates. 3 H and 14 C is considered useful because it is easy to prepare and detect. 11 C and 18 F is useful in PET (positron emission tomography) and is considered an isotope. 125 I is useful in SPECT (single photon emission computed tomography), and all of these isotopes are useful in brain imaging. 2 Substitution with heavier isotopes such as H may afford some type of therapeutic advantage, such as increased in vivo half-life due to greater metabolic stability or reduced dosage requirements, and therefore may be considered useful in certain situations.

[0249] The structures represented in this specification are intended to also include all enantiomeric forms, diastereomeric forms and geometric (or conformational) forms of the structure; for example, R-type and S-type configurations, (Z)-type and (E)-type double bond isomers and (Z)-type and (E)-type conformational isomers for each asymmetric center. Therefore, single stereochemical isomers, enantiomers, diastereomers and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, the tautomeric forms of the compounds of the present invention are all within the scope of the present invention.

[0250] In this specification, "compound" means a compound containing 90% by mass or more of the compound, and may contain starting materials or by-products that may be produced in its preparation steps as related substances. For example, "compound of formula XI" is a compound containing 90% by mass or more of formula XI, and may contain starting materials or by-products that may be produced in each preparation step of compounds of formula VI, compounds of formula IX, compounds of formula X, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, etc. Therefore, since the "compound" in this specification may contain by-products as impurities, it also has the case of being called a "composition". Here, when expressing the content of impurities such as compounds of formula VI, compounds of formula IX, compounds of formula X, compounds of formula XII, compounds of formula XIII, compounds of formula XIV, compounds of formula XV, the content is calculated based on the total mass of the compound of formula XI.

[0251] In the present specification, "the content of total related substances" refers to the total amount (mass %) of related substances including Formula VI, Formula IX, Formula X, Formula XIII, Formula XIV or Formula XV.

[0252]

[0253] In the present specification, provided are compounds (e.g., intermediate compounds) for preparing (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropylcarboxamide (lebrexan), which is known to be a potent orexin receptor antagonist and is useful in the treatment of sleep disorders such as insomnia and other therapeutic applications, and methods for preparing the same. Furthermore, in the present specification, provided is lebrexan containing a small amount of impurities.

[0254]

[0255] The present invention provides a method for preparing a compound of formula III,

[0256]

[0257] It includes:

[0258] a) Inclusive

[0259] Compound II

[0260]

[0261] adding a Grignard reagent to a mixture of toluene and tetrahydrofuran; and

[0262] b) adding the above mixture to a mixture comprising acetyl chloride and ethyl acetate.

[0263] In the above method, step a) may be performed at 60°C or below, and step b) may be performed at 20°C or below.

[0264] In one embodiment, the Grignard reagent is cyclohexylmagnesium chloride.

[0265] The present invention provides a method for preparing a compound of formula XI,

[0266]

[0267] It includes:

[0268] The compound of formula III is prepared as described above.

[0269] The present invention provides a process for preparing a compound of formula XI as described above,

[0270] Will

[0271] i) a compound of formula IX

[0272]

[0273] ii) Compound of formula X

[0274]

[0275] iii) ethyl acetate,

[0276] iv) N,N-diisopropylethylamine, and

[0277] v) 1-Propanephosphonic acid

[0278] The mixture was stirred at a temperature of 60°C-80°C.

[0279] In the above method, the reaction solvent may be ethyl acetate, and the temperature of the step of stirring the above mixture may be 70°C.

[0280] The present invention provides a process for preparing a compound of formula IX,

[0281]

[0282] It includes:

[0283] The compound of formula III is prepared as described above.

[0284] The present invention provides a process for preparing a compound of formula IX,

[0285]

[0286] It includes:

[0287] The compound of formula VII

[0288]

[0289] Reacts with oxidants.

[0290] In the above method, the reaction solvent may be a mixture of toluene and water, and the reaction temperature may be 35° C. or below.

[0291] In one embodiment, the step of reacting the compound of formula VII with an oxidizing agent is performed by sequentially adding sodium hypochlorite and sodium chlorite as the oxidizing agent.

[0292] The present invention provides a process for preparing a compound of formula IX,

[0293]

[0294] It includes:

[0295] a) Compound of formula VII

[0296]

[0297] The aldehyde of formula VIII is prepared by oxidation with sodium hypochlorite,

[0298]

[0299] as well as

[0300] b) oxidizing the aldehyde with sodium chlorite.

[0301] In the above method, the reaction solvent in step a) and step b) can be a mixture of toluene and water, and the reaction temperature can be 25° C. or below.

[0302] In one embodiment, the oxidation of step a) is catalyzed by an effective amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).

[0303] The present invention provides a process for preparing a compound of formula VII,

[0304]

[0305] It includes:

[0306] The manufacturing steps for preparing the compound of formula III as described above, and

[0307] Add sodium hydroxide aqueous solution to the compound of formula V

[0308]

[0309] The two were stirred at a temperature of 30°C-50°C.

[0310] In the above method, the reaction solvent may be a mixture of toluene, N-methylpyrrolidone, acetonitrile and water, and the reaction temperature may be 40°C.

[0311] The present invention provides a method for preparing a compound of formula V,

[0312]

[0313] It includes:

[0314] a) To

[0315] i) Compounds of formula VI

[0316]

[0317] ii) N-methylpyrrolidone, and

[0318] iii) adding potassium tert-butoxide to the mixture of acetonitrile and

[0319] Stirring the two at a temperature of 40°C-70°C; and

[0320] b) by adding the above mixture

[0321] Add i) a compound of formula IV

[0322]

[0323] The resulting mixture was stirred at a temperature of 40°C-70°C.

[0324] In the above method, the reaction solvent in step a) can be a mixture of N-methylpyrrolidone and acetonitrile, and the reaction temperature can be 50°C. The reaction solvent in step b) can be a mixture of toluene, N-methylpyrrolidone and acetonitrile, and the reaction temperature can be 50°C.

[0325] The present invention provides a method for preparing a compound of formula IV,

[0326]

[0327] It includes:

[0328] to a compound of formula III prepared by the process as described above,

[0329]

[0330] To the composition of toluene, triethylamine and 1-methylimidazole is added ii) a mixture of p-toluenesulfonyl chloride, toluene and acetonitrile.

[0331] In the above method, the reaction solvent can be a mixture of toluene and acetonitrile, and the reaction temperature can be 8°C.

[0332] The present invention provides a method for preparing a compound of formula II,

[0333]

[0334] It includes:

[0335] To a compound comprising formula I

[0336]

[0337] Methanol is added to the composition of toluene, tetrahydrofuran, and sodium borohydride.

[0338] In the above method, the reaction solvent may be a mixture of toluene, tetrahydrofuran and methanol, and the reaction temperature may be 50° C. or below.

[0339] The present invention provides a compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less.

[0340]

[0341] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XII is determined by high performance liquid chromatography (HPLC).

[0342] The present invention provides a compound of formula XI, wherein the content of total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0 mass % or less.

[0343]

[0344] The present invention provides a compound of formula XI as described above, wherein the content of total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0345] The present invention provides a compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less, and the content of the total related substances including the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0 mass % or less.

[0346]

[0347] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XII, and the total related substances including compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

[0348] The present invention provides a compound of formula XI, wherein the content of the compound of formula VI is 0.05 mass % or less.

[0349]

[0350] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula VI is determined by high performance liquid chromatography (HPLC).

[0351] The present invention provides a compound of formula XI, wherein the content of the compound of formula IX is 0.05 mass % or less.

[0352]

[0353] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula IX is determined by high performance liquid chromatography (HPLC).

[0354] The present invention provides a compound of formula XI, wherein the content of the compound of formula X is 0.05 mass % or less.

[0355]

[0356] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula X is determined by high performance liquid chromatography (HPLC).

[0357] The present invention provides a compound of formula XI, wherein the content of the compound of formula XIII is 0.05 mass % or less.

[0358]

[0359] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XIII is determined by high performance liquid chromatography (HPLC).

[0360] The present invention provides a compound of formula XI, wherein the content of the compound of formula XIV is 0.05 mass % or less.

[0361]

[0362] The present invention provides a compound of formula XI as described above, wherein the content of the compound represented by formula XIV is determined by high performance liquid chromatography (HPLC).

[0363] The present invention provides a compound of formula XI, wherein the content of the compound of formula XV is 0.05 mass % or less.

[0364]

[0365] The present invention provides a compound of formula XI as described above, wherein the content of the compound of formula XV is determined by high performance liquid chromatography (HPLC).

[0366] The compounds listed above and used in the methods disclosed in this specification can all be provided in stereochemically pure forms, and it should be understood that these are included in the present invention. In one embodiment, the stereochemically pure compound has about more than 75% by weight of one stereoisomer of the compound and about less than 25% by weight of other stereoisomers of the compound; about more than 80% by weight of one stereoisomer of the compound and about less than 20% by weight of other stereoisomers of the compound; or about more than 85% by weight of one stereoisomer of the compound and about less than 15% by weight of other stereoisomers of the compound; or about more than 90% by weight of one stereoisomer of the compound and about less than 10% by weight of other stereoisomers of the compound; or about more than 95% by weight of one stereoisomer of the compound and about less than 5% by weight of other stereoisomers of the compound; or about more than 97% by weight of one stereoisomer of the compound and about less than 3% by weight of other stereoisomers of the compound; or about more than 98% by weight of one stereoisomer of the compound and about less than 2% by weight of other stereoisomers of the compound. In one embodiment, a stereochemically pure compound has greater than 99% by weight of one stereoisomer of the compound and less than 1% by weight of the other stereoisomer of the compound.

[0367] As mentioned above, in one embodiment, the compounds described herein can be provided in the form of a salt, such as a pharmaceutically acceptable salt.

[0368] A certain embodiment makes it possible to prepare a compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass% or less, the content of each compound of formula VI, formula IX, formula X, formula XIII, formula XIV or formula XV is 0.05% or less, and the content of the total related substances including the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0 mass% or less.

[0369] A certain embodiment makes it possible to prepare a compound of formula XI, wherein the content of the compound of formula XI is 97.0% by mass or more, 98.0% by mass or more, or 98.5% by mass or more, and is 102.0% by mass or less, 100.0% by mass or less, 99.9% by mass or less, 99.0% by mass or less, or 98.9% by mass or less. Here, the content of the compound of formula XI is determined by high performance liquid chromatography (HPLC). More specifically, HPLC is performed under the conditions described in the "Purity Test" section of the following example, and the peak area of ​​the compound of formula XI of the sample is divided by the peak area of ​​the standard of the compound of formula XI on the chromatogram, and the resulting numerical value represents the content of the compound of formula XI.

[0370] Another embodiment of the present invention is a pharmaceutical composition containing a compound of formula XI or a crystal thereof, and a pharmaceutically acceptable additive. The pharmaceutical composition can be prepared by mixing a pharmaceutically acceptable additive with a compound of formula XI or a crystal thereof. The pharmaceutical composition according to the present invention can be prepared, for example, according to known methods such as the method described in the general principles of preparations of the 17th revised edition of the Japanese Pharmacopoeia.

[0371] Examples

[0372] Hereinafter, the present invention will be described in detail according to examples. However, the present invention is not limited to these examples. In addition, the abbreviations used in the following examples are commonly used abbreviations well known to practitioners, and some of the abbreviations are as follows.

[0373] Proton NMR ( 1 Chemical shifts in H-NMR spectra are reported in δ units (ppm) relative to tetramethylsilane, and coupling constants are reported in Hertz (Hz). In the pattern, s, d, br, and m represent singlet, doublet, broad, and multiplet, respectively.

[0374] 1 H-NMR spectrum and 13 The C-NMR spectrum was measured using a Varian 400 or 500 MHz spectrometer or a JNM-AL400 nuclear magnetic resonance apparatus (400 MHz) manufactured by JEOL Ltd.

[0375] In the following examples, "room temperature" generally means about 10° C. to about 35° C. Unless otherwise specified, "%" means weight percentage.

[0376] (A) Preparation of (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (compound of formula I)

[0377]

[0378] (A-1) Synthesis of (1S,2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile (compound of formula Ib) become

[0379]

[0380] A solution of (3-fluorophenyl)acetonitrile (120 kg, 888 mol, 1.0 equiv.) and tetrahydrofuran (9.0 kg) was added dropwise to a solution of sodium tert-butoxide (188 kg, 1954 mol, 2.2 equiv.) and tetrahydrofuran (890 kg) at -10°C to 0°C. After stirring for more than 1 hour, (2R)-2-(chloromethyl)oxirane (94.5 kg, 1021 mol, 1.15 equiv.) was added dropwise at -12°C to 18°C. After confirming the completion of the reaction by high performance liquid chromatography (hereinafter referred to as "HPLC") analysis, water (50 kg) was added and stirred. The solvent was distilled off under reduced pressure to obtain a (1S,2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile solution, which was used directly in the next step.

[0381] HPLC conditions used to confirm the above reaction:

[0382] Reagents and mobile phase:

[0383] Pure water

[0384] Acetonitrile (Kanto Chemical Co., Inc. Catalog No. 01031-2B HPLC or equivalent)

[0385] Perchloric acid (70%) (Wako Pure Chemical Industries, Ltd. Catalog No. 162-00695 Special Grade Chemical or equivalent)

[0386] Mobile phase A: a mixture of water, acetonitrile and perchloric acid (70%) (950:50:1, v / v / v)

[0387] Mobile phase B: a mixture of water, acetonitrile and perchloric acid (70%) (100:900:1, v / v / v)

[0388] Solution: mixture of water and acetonitrile (50:50, v / v)

[0389] HPLC device needle flushing agent: water and acetonitrile mixture (50:50, v / v)

[0390] ·(3-Fluorophenyl)acetonitrile standard sample

[0391] HPLC conditions:

[0392] Detector: Shimadzu SPD-20A UV absorption meter (measurement wavelength: 262nm) or equivalent

[0393] Column: Stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, filled with 2.7 μm octadecylsilane silica gel for liquid chromatography

[0394] Example: Meteoric Core C18 (YMC), (equivalent to USP packaging type L1)

[0395] Column temperature: Constant temperature close to 30°C

[0396] Mobile Phase:

[0397] Solution A: a mixture of water, acetonitrile and perchloric acid (70%) (950:50:1, v / v / v)

[0398] Solution B: a mixture of water, acetonitrile and perchloric acid (70%) (100:900:1, v / v / v)

[0399] Flow rate: 0.9 mL / min

[0400] Gradient conditions:

[0401]

[0402] Injection volume: 10 μL

[0403] Sample holder temperature: Constant temperature close to 5°C

[0404] Area measurement range: 30 minutes

[0405] (A-2) Synthesis of (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (compound of formula I) become

[0406]

[0407] (A-2-1) Preparation of Seed Crystals

[0408] To a solution of (3-fluorophenyl)acetonitrile (20 g, 0.15 mol, 1.00 equiv.) and tetrahydrofuran (150 mL) was added sodium bis(trimethylsilyl)amide (tetrahydrofuran solution) (150 mL, 0.30 mol, 2.00 equiv.) dropwise at 0-7°C. After stirring for 0.5 hours, (2R)-2-(chloromethyl)oxirane (11.8 mL, 0.15 mol, 1.00 equiv.) was added dropwise at 17°C. After stirring at 5°C for 2 hours and at room temperature for 3 days, water (10 mL) was added and stirred. The solvent was distilled off under reduced pressure to obtain (1S,2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile, which was used directly in the next step.

[0409] To the obtained (1S,2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile, ethanol (150 mL) and 2M potassium hydroxide aqueous solution (148 mL, 0.30 mol, 2.00 equiv.) were added, and the mixture was stirred at 80°C for 4 hours, and then water (66 mL) and concentrated hydrochloric acid (47.5 mL, 0.57 mol, 3.80 equiv.) were added. The mixture was stirred at 60°C for 1 hour and further at room temperature for 45 hours. The precipitated solid was filtered, washed with water until the pH was confirmed to be 5, and dried under a nitrogen gas stream to obtain (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (23 g) with a yield of 81% (total yield obtained from (3-fluorophenyl)acetonitrile).

[0410] (A-2-2) (1S, 5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (compound of formula I) synthesis

[0411] (A-2-2-Step 1)

[0412] Ethanol (237 kg), water (237 kg) and 25% aqueous sodium hydroxide solution (220 kg, 1376 mol, 1.55 equiv.) were added to the (1S, 2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile solution, and stirred at an internal temperature of 77°C to 87°C. After the completion of the reaction was confirmed by HPLC analysis, the solvent was distilled off under reduced pressure, and toluene (624 kg) and water (60 kg) were added thereto, stirred, and then allowed to stand. After the organic layer was discharged, toluene (624 kg) was added to the aqueous layer, stirred, and then allowed to stand. The organic layer was discharged and used directly in the next step.

[0413] HPLC conditions used to confirm the above reaction:

[0414] Reagents and mobile phase:

[0415] Purified water, acetonitrile, perchloric acid (70%), mobile phase A, mobile phase B, solvent, and needle flushing solution of the HPLC device were the same as those of (A-1).

[0416] (1S,2R)-1-(3-Fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile standard sample

[0417] HPLC conditions:

[0418] Same as (A-1).

[0419] (A-2-2-Step 2)

[0420] Toluene (409 kg) and 35% hydrochloric acid (287 kg, 2753 mol, 3.10 equiv.) were added to the solution obtained in (A-2-2-Step 1). The mixture was stirred at an internal temperature of 55°C to 65°C, and the reaction was confirmed to be complete by HPLC analysis. After confirming that the internal temperature was below 35°C, the mixture was allowed to stand and the aqueous layer was discharged. Thereafter, toluene (172 kg) and a 7% aqueous sodium bicarbonate solution (482 kg) were added to the organic layer, stirred, and then allowed to stand. After the aqueous layer was discharged, water (480 kg) was added to the organic layer, stirred, and then allowed to stand. The aqueous layer was discharged, and the content of (1S, 5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one in the organic layer was calculated. After the solvent was distilled off under reduced pressure, ethanol (614 kg) was added thereto. After the solvent was distilled off under reduced pressure, ethanol was added thereto so that the total volume became twice the amount of (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one.

[0421] (1S, 5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one was heated and dissolved under stirring at an internal temperature of 60°C-65°C, and water was added thereto in an amount of 0.8 times the content of (1S, 5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one. After cooling, 60 g of seed crystals were added thereto at an internal temperature of 40°C-50°C, and crystal precipitation was confirmed. After the mixture was stirred at an internal temperature of 40°C-50°C for more than 1 hour, it was cooled to -5°C-5°C or less at -10°C / H--20°C / H, the precipitated solid was filtered out, and washed with ethanol. The obtained solid was dried under reduced pressure at an external temperature of 45° C. or below to obtain (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (103 kg) with a yield of 60% (total yield from (3-fluorophenyl)acetonitrile).

[0422] HPLC conditions used to confirm the above reaction:

[0423] Reagents and mobile phase:

[0424] Purified water, acetonitrile, perchloric acid (70%), mobile phase A, mobile phase B, solvent, and needle flushing solution of the HPLC device were the same as those of (A-1).

[0425] (1S,2R)-1-(3-Fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid solution (concentration about 0.5 mg / mL)

[0426] HPLC conditions:

[0427] The detector, column, column temperature, mobile phase, flow rate, injection volume, and sample holder temperature were the same as those in (A-1).

[0428] Gradient conditions:

[0429]

[0430] Area measurement range: 40 minutes

[0431] NMR data

[0432] (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one:

[0433] 1 H NMR (500MHz, DMSO-d6) δ7.43-7.36(m,1H),7.35-7.31(m,1H),7.31-7.28(m,1H),7.14-7.08(m,1H),4.46(dd,J=9.1 ,4.6Hz,1H),4.25(d,J=9.1Hz,1H),2.80(dt,J=8.0,4.6Hz,1H),1.72(dd,J=7.9,4.8Hz,1H),1.37(t,J=4.8Hz,1H);

[0434] 13 C NMR (126MHz, DMSO-d6) δ175.35, 161.98 (d, JCF = 243.1Hz), 137.67 (d, JCF = 8.2Hz), 130.15 (d, JCF = 8.6Hz), 124.1 9(d,JCF=2.8Hz), 115.01(d,JCF=22.4Hz), 113.95(d,JCF=20.9Hz), 67.93, 30.70(d,JCF=2.4Hz), 25.57, 19.99.

[0435] (B) Preparation of 2,4-dimethylpyrimidin-5-ol (compound of formula VI)

[0436]

[0437] (B-1) Preparation of 1-(4-nitrophenoxy)propan-2-one (compound of formula VIa)

[0438]

[0439] A mixture of 4-nitrophenol (305.0 kg, 2192.5 mmol), potassium carbonate (318.2 kg, 2302.1 mmol) and acetonitrile (1678 kg) was stirred at 60°C for 30 minutes. Chloroacetone (net weight 213.0 kg, 2302.1 mmol) was added dropwise to the reaction mixture at 60°C (external temperature) and the obtained mixture was stirred at 60°C (external temperature) for 7 hours. After the reaction mixture was cooled in an ice bath, toluene (1847 kg) and water (1830 kg) were added to the reaction mixture at the same temperature. After the obtained reaction mixture was stirred at room temperature, the organic layer was separated and washed with brine (1525 kg of water and 170.8 kg of salt). The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in toluene (1319 kg) at 55°C (internal temperature), cooled to an internal temperature of 5°C, and the precipitated solid was filtered out. The obtained solid was washed with an appropriate amount of toluene to obtain a wet solid of the title compound (equivalent to a dry yield of 343.9 kg, a yield of 80%).

[0440] 1 H-NMR (CD3Cl) δ (ppm): 2.31 (3H, s), 4.67 (2H, s), 6.95 (2H, d, J = 9.3 Hz), 8.22 (2H, d, J = 9.3 Hz).

[0441] (B-2) Preparation of (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (compound of formula VIb) Preparation

[0442]

[0443] Toluene (1785 kg) was added to 1-(4-nitrophenoxy)propane-2-one (equivalent to 343.9 kg on dry basis, 1762.1 mmol) and a portion was concentrated. Then, N,N-dimethylformamide dimethyl acetal (231.0 kg, 1938.3 mmol) was added and stirred at 78°C (internal temperature) for 20 hours. Toluene (595 kg) was added to the reaction mixture at the same temperature, and methanol (163 kg) was added thereto at an internal temperature of 55°C and aged for 30 minutes, and then cooled to 5°C. The precipitated solid was filtered out. After washing the obtained solid with an appropriate amount of toluene, a wet body of the title compound (equivalent to 159.0 kg on dry basis, yield 36%) was obtained.

[0444] 1 H-NMR (CD3Cl) δ (ppm): 2.00 (3H, brs), 3.01 (6H, s), 6.90-7.16 (2H, brm), 7.16-7.46 (1H, brs), 8.22 (2H, d, J = 8.8Hz).

[0445] In addition, the compound of formula VIb can also be prepared by the method described below.

[0446] (B-2-a) (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (compound of formula VIb) preparation

[0447]

[0448] Acetonitrile (15 mL) was added to 1-(4-nitrophenoxy)propan-2-one (15.0 g, 76.9 mmol) and 4-nitrophenol (802 mg, 5.76 mmol), and N,N-dimethylformamide dimethyl acetal (15.4 mL, 115 mmol) was added thereto, and stirred at 78°C (external temperature) for 19 hours. Toluene (300 mL) was added to the reaction mixture at 50°C (external temperature), cooled to 5°C (external temperature), and the precipitated solid was filtered out. The obtained solid was washed with an appropriate amount of toluene, and then dried at 50°C under reduced pressure to obtain the title compound (12.4 g, yield 64%).

[0449] (B-2-b) (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (compound of formula VIb) preparation

[0450]

[0451] A mixture of 4-nitrophenol (50.0 g, 359 mmol), potassium carbonate (52.2 g, 377 mmol) and acetonitrile (350 mL) was stirred at 60°C (external temperature) for 1 hour. Chloroacetone (31.5 mL, 377 mmol) was added dropwise to the reaction mixture at the same temperature, and the obtained mixture was stirred at the same temperature for 25 hours. The reaction mixture was stirred under ice-cold water, and toluene (350 mL) and water (300 mL) were added to the reaction mixture at 13°C (internal temperature). After the obtained reaction mixture was stirred at room temperature, the organic layer was separated and washed with brine (250 mL of water and 27.8 g of salt). The solvent was distilled off from the organic layer (168.5 g) under reduced pressure, and acetonitrile (60 mL) was added to the obtained residue (1-(4-nitrophenoxy)propane-2-one (compound of formula VIa); net weight 16.7 g, 85.6 mmol), and the solvent was distilled off under reduced pressure. To the obtained residue was added acetonitrile (60 mL), and after the solvent was distilled off under reduced pressure, acetonitrile (16.7 mL) was added and dissolved, and then N,N-dimethylformamide dimethyl acetal (17.2 mL, 128 mmol) was added thereto, and stirred at 78°C (external temperature) for 19.5 hours. Toluene (200 mL) was added to the reaction mixture at the same temperature, cooled to 6°C (external temperature), and the precipitated solid was filtered out. The obtained solid was washed with an appropriate amount of toluene, and then dried at 50°C under reduced pressure to obtain the title compound (12.3 g, yield 58%).

[0452] (B-2-c) (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (compound of formula VIb) preparation

[0453]

[0454] Triethylamine (5.3 mL, 38.2 mmol) and chloroacetone (3.0 mL, 36.4 mmol) were added to a mixture of 4-nitrophenol (5.57 g, 40.1 mmol) and acetonitrile (17 mL) at 18°C ​​(internal temperature), and the mixture was stirred at 55°C (external temperature) for 69 hours. N,N-dimethylformamide dimethyl acetal (7.3 mL, 54.6 mmol) was added to the reaction mixture at 30°C (external temperature), and the mixture was stirred at 80°C (external temperature) for 43 hours. N,N-dimethylformamide dimethyl acetal (7.3 mL, 54.6 mmol) was added to the reaction mixture at 36°C (internal temperature), and the mixture was stirred at 80°C (external temperature) for 18.5 hours. After the internal temperature was cooled to 45°C or less, toluene (40 mL) was added, and the solvent was distilled off under reduced pressure. Toluene (111 mL) and acetonitrile (5.6 mL) were added to the obtained residue and stirred at 80° C. (external temperature), methanol (4.4 mL) was added thereto, and the mixture was cooled to 6° C. (external temperature), and the precipitated solid was filtered out. The obtained solid was washed with an appropriate amount of toluene and dried at 50° C. under reduced pressure to obtain the title compound (3.97 g, yield 44%).

[0455] (B-2-d) (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (compound of formula VIb) preparation

[0456]

[0457] A mixture of 4-nitrophenol (50.0 g, 359 mmol), potassium carbonate (49.6 g, 359 mmol) and acetonitrile (350 mL) was stirred at room temperature for 25 minutes. Chloroacetone (33.3 g, 359 mmol) was added dropwise to the mixture at the same temperature, and the mixture was stirred at 60° C. (external temperature) for 14 hours. Toluene (350 mL) and water (300 mL) were added to the obtained reaction mixture (a mixture of 1-(4-nitrophenoxy)propane-2-one (a compound of Formula VIa) and 4-nitrophenol (97:3)) at room temperature and stirred. The organic layer was separated and washed with water (250 mL). The solvent of the organic layer was distilled off under reduced pressure, and toluene (500 mL) was added to the obtained residue (284 g), and the solvent was distilled off under reduced pressure. Toluene (103 g) and N,N-dimethylformamide dimethyl acetal (52.9 mL, 395 mmol) were added to the obtained residue (149 g), and stirred at 80° C. (external temperature) for 15 hours. The obtained reaction mixture was cooled to room temperature and aged for 3 hours, then cooled to 5° C. (external temperature) and aged for 2 hours. The precipitated solid was filtered out and washed with an appropriate amount of toluene. The solid was dried at 50° C. under reduced pressure to obtain the title compound (55.7 g, yield 62%).

[0458] (B-3) Preparation of 2,4-dimethyl-5-(4-nitrophenoxy)pyrimidine (compound of formula VIc)

[0459]

[0460] Sodium ethoxide 20% ethanol solution (518.8 kg, 1524.9 mol), ethanol (213 kg) and acetamidine hydrochloride (net weight 144.2 kg, 1524.9 mmol) were added, and stirred at 25°C (internal temperature) for 94 minutes. (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (equivalent to dry 159.0 kg, 635.4 mmol) was added, and the mixture was stirred at 60°C (internal temperature) for 5 hours. After the reaction mixture was cooled to 5°C (internal temperature), water (2385 kg) was added, and the precipitated solid was filtered out. After the obtained solid was washed with an appropriate amount of water, a wet body of the title compound (equivalent to dry yield 146.1 kg, yield 94%) was obtained.

[0461] 1 H-NMR (CD3Cl) δ (ppm): 2.40 (3H, s), 2.75 (3H, s), 6.96 (2H, d, J = 9.0 Hz), 8.24 (2H, d, J = 9.0 Hz), 8.32 (1H, s).

[0462] (B-4) Preparation of 2,4-dimethylpyrimidin-5-ol (compound of formula VI)

[0463]

[0464] A mixture of 2,4-dimethyl-5-(4-nitrophenoxy)pyrimidine (equivalent to dry 146.1 kg, 595.8 mmol), methanol (579 kg) and sodium hydroxide aqueous solution (sodium hydroxide 71.5 kg, water 77.5 kg, 1787.3 mmol) was stirred at 60°C (internal temperature) for 13 hours. Toluene (1264 kg) and water (584 kg) were added to the reaction mixture and stirred. After standing, the aqueous layer was separated and concentrated under reduced pressure. After the obtained concentrated solution was cooled to 8°C (internal temperature), toluene (316 kg) was added thereto, and concentrated hydrochloric acid (310.3 kg, 2978.8 mmol) was added at an internal temperature of 0°C-15°C. Ethyl acetate (328 kg) was added thereto to separate the liquid. The aqueous layer was separated and washed with toluene-ethyl acetate (316 kg-328 kg). After adding ethyl acetate (1311 kg) to the obtained water layer, cool it to 5°C (internal temperature), add 5 mol / l sodium hydroxide aqueous solution until the pH of the reaction mixture is 6.5. The organic layer is separated and the water layer is extracted again with ethyl acetate (1311 kg). After the obtained organic layers are combined, they are washed with water (44 kg) and the solvent is distilled off under reduced pressure. Toluene (379 kg) is added to the obtained residue to suspend it and stirred at 50°C (internal temperature) for 2 hours. The mixture is cooled to below 10°C (internal temperature), stirred for 2 hours and filtered. After washing the obtained solid with an appropriate amount of toluene, it is dried at 45°C under reduced pressure to obtain the title compound (63.7 kg, 86%).

[0465] 1 H-NMR (CD3Cl) δ (ppm): 2.51 (3H, s), 2.65 (3H, s), 8.02 (1H, s), 10.01 (1H, brs).

[0466] (C) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid Preparation of (Compound of Formula IX)

[0467]

[0468] (C-1) Preparation of [(1S, 2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl] dimethanol (compound of formula II)

[0469]

[0470] Methanol (58.3 kg, 1821 mol, 5.00 equiv.) was added to a mixture of (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one (70 kg, 364 mol, 1.00 equiv.), toluene (350 L), tetrahydrofuran (350 L), and sodium borohydride (13.8 kg, 364 mol, 1.00 equiv.) at 50°C or below, and the mixture was stirred. The reaction was confirmed to be complete by HPLC analysis, and the reaction solution and toluene (140 L) were added to a 20% aqueous citric acid solution (350 kg), stirred, and then allowed to stand. The aqueous layer was drained, and a 5% aqueous sodium bicarbonate solution (140 kg) was added to the organic layer, and the mixture was allowed to stand. The aqueous layer was drained, and a 5% aqueous sodium chloride solution (140 kg) was added to the organic layer, stirred, and then allowed to stand. The aqueous layer was drained, and the solvent was distilled off under reduced pressure to obtain a toluene solution of [(1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl]dimethanol (equivalent to 67.2 kg, yield 94%), which was used directly in the next step.

[0471] HPLC conditions used to confirm the above reaction:

[0472] Reagents and mobile phase:

[0473] Pure water

[0474] Acetonitrile (Kanto Chemical Co., Inc. Catalog No. 01031-2B HPLC or equivalent)

[0475] Trifluoroacetic acid (Wako Pure Chemical Industries, Ltd. Catalog No. 208-02741 Special Grade Chemical or equivalent)

[0476] Mobile phase A: a mixture of water and trifluoroacetic acid (1000 / 1, v / v)

[0477] Mobile phase B: mixture of acetonitrile and trifluoroacetic acid (1000 / 1, v / v)

[0478] Solution: mixture of water, acetonitrile and trifluoroacetic acid (500 / 500 / 1, v / v / v)

[0479] Needle flushing agent for HPLC device: mixture of water and acetonitrile (100 / 900, v / v)

[0480] (1S,5R)-1-(3-Fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one standard sample

[0481] HPLC conditions:

[0482] Detector: Shimadzu SPD-20A UV absorption meter (measurement wavelength: 220nm) or equivalent

[0483] Column: Stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, filled with 3.5 μm octadecylsilane silica gel for liquid chromatography

[0484] Example: SunFire C18 (Waters) (equivalent to USP package L1)

[0485] Column temperature: Constant temperature close to 40°C

[0486] Mobile Phase:

[0487] Solution A: a mixture of water and trifluoroacetic acid (1000 / 1, v / v)

[0488] Solution B: mixture of acetonitrile and trifluoroacetic acid (1000 / 1, v / v)

[0489] Flow rate: fixed flow rate of about 1.0 mL / min

[0490] Gradient conditions:

[0491]

[0492]

[0493] Injection volume: 5μL

[0494] Sample holder temperature: Constant temperature close to 10°C

[0495] Needle flushing solution: mixture of water and acetonitrile (10 / 90, v / v)

[0496] Area measurement range: Up to 34 minutes

[0497] (C-2) [(1R, 2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methyl=acetate (chemical formula III Preparation of compounds

[0498]

[0499] Cyclohexylmagnesium chloride (1 mol / kg tetrahydrofuran solution) (349 kg, 349 mol, 1.02 equiv.) was added to a mixture of a toluene solution of [(1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl]dimethanol (equivalent to 67.2 kg, 342 mol, 1.00 equiv. of [(1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl]dimethanol and tetrahydrofuran (269 L) at 60°C or less, and the mixture was stirred. The obtained solution was added to a mixture of ethyl acetate (336 L) and acetyl chloride (29.6 kg, 377 mol, 1.10 equiv.) at 20°C or less, and the mixture was stirred. After confirming the completion of the reaction by HPLC analysis, water (202 L) was added, the mixture was stirred, and the mixture was allowed to stand. After the aqueous layer was discharged, a 6% sodium bicarbonate aqueous solution (215 kg) was added to the organic layer, the mixture was stirred, and the mixture was allowed to stand. After the water layer was drained, a 4% sodium chloride aqueous solution (175 kg) was added to the organic layer and stirred, and then allowed to stand. The water layer was drained, the solvent was distilled off under reduced pressure, and toluene (134 L) was added thereto. The solvent was distilled off under reduced pressure to obtain a toluene solution of [(1R, 2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methyl=acetate, which was used directly in the next step.

[0500] HPLC conditions used to confirm the reaction:

[0501] Reagents and mobile phase:

[0502] Pure water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing liquid of the HPLC device are the same as (C-1).

[0503] Solution: water / acetonitrile (500 / 500, v / v)

[0504] [(1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl]dimethanol solution (concentration about 0.5 mg / mL)

[0505] HPLC conditions

[0506] The detector, column, column temperature, mobile phase, flow rate, injection volume, and sample holder temperature were the same as those in (C-1).

[0507] Gradient conditions:

[0508]

[0509] Area measurement range: Up to 44 minutes

[0510] (C-3) Preparation of [(1R, 2S)-2-(3-fluorophenyl)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl=acetate (compound of formula IV)

[0511]

[0512] To a mixture of a toluene solution of [(1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methyl acetate (corresponding to 81.6 kg, 342 mol, 1.00 equiv. of [(1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methyl acetate), toluene (294 L) (including the amount of toluene in the toluene solution), triethylamine (69.3 kg, 685 mol, 2.00 equiv.), and 1-methylimidazole (1.41 kg, 17 mol, 0.05 equiv.), a solution of p-toluenesulfonyl chloride (71.8 kg, 377 mol, 1.10 equiv.) in toluene (34 L) and acetonitrile (69 L) was added at 30° C. or less, and the mixture was stirred at an external temperature of 8° C. After the completion of the reaction was confirmed by HPLC analysis, acetonitrile (34 L) was added and stirred. The triethylamine hydrochloride was removed by filtration, and the filter residue was washed and mixed with a mixture of toluene (51 L) and acetonitrile (51 L) to obtain a solution of [(1R,2S)-2-(3-fluorophenyl)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl=acetate, which was used directly in the next step.

[0513] HPLC conditions used to confirm the above reaction:

[0514] Reagents and mobile phase:

[0515] Purified water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing solution of the HPLC device are the same as those of (C-1).

[0516] Solution: Acetonitrile

[0517] ·Toluene solution of [(1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methyl=acetate (final product of the previous step)

[0518] HPLC conditions

[0519] Same as (C-1).

[0520] (C-4) [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl] Preparation of methyl=acetate (compound of formula V)

[0521]

[0522] Potassium tert-butoxide (46.1 kg, 411 mol, 1.20 equiv.) was added to a mixture of 2,4-dimethylpyrimidin-5-ol (51.0 kg, 411 mol, 1.20 equiv.), N-methylpyrrolidone (273 L) and acetonitrile (85 L), and the mixture was stirred at an external temperature of 50°C. A solution of [(1R,2S)-2-(3-fluorophenyl)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl=acetate was added to the obtained solution, and the mixture was stirred at an external temperature of 50°C. After confirming the completion of the reaction by HPLC analysis, water (547 L) was added thereto at 30°C or less, the mixture was stirred, and the mixture was allowed to stand. After separation of the liquid, the organic layer was stored, and toluene (220 L) was added to the aqueous layer, the mixture was stirred, and the mixture was allowed to stand. The aqueous layer was drained and the organic layers were combined to obtain a [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methyl=acetate solution which was used directly in the next step.

[0523] HPLC conditions used to confirm the above reaction:

[0524] Reagents and mobile phase:

[0525] Purified water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing solution of the HPLC device are the same as those of (C-1).

[0526] Solution: Acetonitrile

[0527] · Solution of [(1R,2S)-2-(3-fluorophenyl)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl acetate (concentration about 1 mg / mL)

[0528] HPLC conditions

[0529] Same as (C-1).

[0530] (C-5) [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl] Preparation of methanol (compound of formula VII)

[0531]

[0532] Water (734 L) and 25% aqueous sodium hydroxide solution (107 L, 856 mol, 2.50 equiv.) were added to the [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methyl=acetate solution, and the mixture was stirred at an external temperature of 40°C. After the completion of the reaction was confirmed by HPLC analysis, the mixture was cooled and allowed to stand. After the aqueous layer was discharged, an aqueous sodium dihydrogen phosphate solution (41.1 kg of sodium dihydrogen phosphate and 255 L of water) was added to the organic layer, the mixture was stirred, and the mixture was allowed to stand. After the aqueous layer was discharged, water (204 L) was added to the organic layer, the mixture was stirred, and the mixture was allowed to stand. The aqueous layer was discharged, and toluene (86 L) was added thereto to obtain a toluene solution of [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol, which was used as it was in the next step.

[0533] HPLC conditions used to confirm the above reaction:

[0534] Reagents and mobile phase:

[0535] Purified water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing solution of the HPLC device are the same as those of (C-1).

[0536] Solution: mixture of water and acetonitrile (1 / 1, v / v)

[0537] [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methyl=acetate solution (concentration about 1 mg / mL)

[0538] HPLC conditions

[0539] Except that the detection wavelength of the detector is 283 nm, everything else is the same as (C-1).

[0540] (C-6) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropane Preparation of acid (compound of formula IX)

[0541]

[0542] (1) Preparation of seed crystals

[0543] A mixture of a toluene solution of [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol (corresponding to 46.48 kg, 154 mol, 1.00 equiv. of [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol), 2,2,6,6-tetramethylpiperidin-1-oxyl free base (0.48 kg, 3.1 mol, 0.02 equiv.), toluene (186 L) and an aqueous sodium dihydrogen phosphate solution (sodium dihydrogen phosphate 6.1 kg, 51 mol, 0.33 equiv. and water 56 kg) was cooled to an external temperature of 7° C., and a 12% aqueous sodium hypochlorite solution (9.1 kg, 15.4 mol, 0.10 equiv.) was added, followed by stirring. At 25°C, add a 25% aqueous sodium chlorite solution (61.2 kg, 169 mol, 1.10 equiv.). After confirming the completion of the reaction by HPLC analysis, add an aqueous sodium sulfite solution (9.7 kg of sodium sulfite and 93 L of water) and stir. Add a 25% aqueous sodium hydroxide solution (39 L), stir at an external temperature of 70°C for 1 hour, cool to 50°C or below and let stand. The aqueous layer is stored, water (23 L) is added to the organic layer and stirred, and then allowed to stand. The organic layer is drained, the aqueous layer is mixed, toluene (139 L) and a 5N aqueous hydrochloric acid solution are added to prepare a pH of 2.5-4.0, and the mixture is allowed to stand. After draining the aqueous layer, water (93 L) is added to the organic layer and stirred, and then allowed to stand. The aqueous layer is drained, and the obtained organic layer is distilled under reduced pressure to remove the solvent. The operation of adding acetonitrile (232 L) and distilling off the solvent under reduced pressure is performed more than once. Acetonitrile (232 L) was added to obtain a solution of (1R, 2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid, and then a part of the solvent was distilled off under reduced pressure. Acetonitrile was added to the concentrated residue containing substantially 47.7 kg of (1R, 2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid to a total volume of 232 L. The mixture was dissolved under stirring at an external temperature of 65°C. After cooling, crystal precipitation was confirmed. After heating to an internal temperature of 40°C or more, the mixture was cooled at -20°C / H to an internal temperature of -15°C or less to precipitate a solid, which was filtered out and washed with acetonitrile. The obtained solid was dried under reduced pressure at an external temperature of 50° C. to obtain 43.5 kg of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid.

[0544] (2) Preparation of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula IX)

[0545] A toluene solution of [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol (equivalent to 82.8 kg, 274 mol, 1.00 equiv. of [(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol), 2,2,6,6-tetramethylpiperidin-1- A mixture of alkoxyl radical (0.856 kg, 5.48 mol, 0.02 equiv.), toluene (25 L) and sodium dihydrogen phosphate aqueous solution (sodium dihydrogen phosphate 10.8 kg, 90 mol, 0.33 equiv. and water 82.8 kg) was cooled at an external temperature of 8°C, and a 12% sodium hypochlorite aqueous solution (48.5 kg, 82 mol, 0.30 equiv.) was added at 35°C or below and stirred. After confirming the progress of the reaction by HPLC analysis, the mixture was allowed to stand and the aqueous layer was discharged. A 25% sodium chlorite aqueous solution (119 kg, 329 mol, 1.20 equiv.) was added to a mixture of the organic layer and sodium dihydrogen phosphate aqueous solution (sodium dihydrogen phosphate 16.4 kg, 137 mol, 0.50 equiv. and water 82.8 kg) at 35°C or below. After confirming the completion of the reaction by HPLC analysis, a sodium sulfite aqueous solution (sodium sulfite 17.3 kg and water 166 L) was added and stirred. Add 25% sodium hydroxide aqueous solution (85.9 L), heat at an external temperature of 70°C and stir, cool to 50°C or less and let stand. The aqueous layer is stored, water (41 L) is added to the organic layer, stirred, and then left to stand. The organic layer is discharged, the aqueous layer is mixed, toluene (248 L) and 5N hydrochloric acid aqueous solution are added to adjust the pH to 2.5-4.0 and left to stand. After the aqueous layer is discharged, water (166 L) is added to the organic layer, stirred, and then left to stand. The aqueous layer is discharged, and the solvent is distilled off from the obtained organic layer under reduced pressure. The operation of adding acetonitrile (414 L) and distilling off the solvent under reduced pressure is performed more than once. After adding acetonitrile (414 L) to obtain a (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid solution, a part of the solvent is distilled off under reduced pressure. Acetonitrile was added to the concentrated residue containing substantially 84.9 kg of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid to a total volume of 497 L. The mixture was dissolved under stirring at an external temperature of 65°C. After cooling, 83 g of seed crystals were added thereto, and crystal precipitation was confirmed. After heating to an internal temperature of 40°C or higher, the mixture was cooled to 10°C or lower at -20°C / H to precipitate a solid, which was filtered out and washed with acetonitrile.The obtained solid was dried under reduced pressure at an external temperature of 60°C or below to obtain 62 kg of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid with a yield of 54% (total yield obtained from (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexane-2-one).

[0546] HPLC conditions used to confirm the above reaction:

[0547] Reagents and mobile phase:

[0548] Purified water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing solution of the HPLC device are the same as those of (C-1).

[0549] Solution: mixture of water and acetonitrile (1 / 1, v / v)

[0550] ·[(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol solution (concentration about 1 mg / mL)

[0551] HPLC conditions

[0552] Except that the detection wavelength of the detector is 283 nm, everything else is the same as (C-1).

[0553] NMR data

[0554] (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid:

[0555] 1 H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.17(s,1H),7.39(td,J=8.0,6.4Hz,1H),7.29(d,J=7.9Hz,1H),7.27-7.22(m,1H),7.10(td,J=8. 3,2.1Hz,1H),4.63(d,J=10.2Hz,1H),4.30(d,J=10.2Hz,1H),2.46(s,3H),2.26(s,3H),2.13(dd,J=7.7,6.6Hz,1H),1.63-1.54(m,2H);

[0556] 13C NMR(126MHz,DMSO-d6)δ172.65,162.48(d,JCF=243.6Hz),159.08,156.24,149.45,145.15(d,JCF=7.5Hz),139.60,130.71(d,JCF=8.5H z), 124.79 (d, JCF = 2.6Hz), 115.60 (d, JCF = 21.8Hz), 114.32 (d, JCF = 20.8Hz), 71.15, 33.92 (d, JCF = 2.0Hz), 26.46, 24.96, 19.72, 18.70.

[0557] (D) (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyrimidin-5-yl)oxy)methyl Preparation of 2-pyridin-2-yl)cyclopropylcarboxamide (Lebrexan: compound of formula XI)

[0558]

[0559] A mixture of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid (62.4 kg, 197 mol, 1.00 equiv.), 5-fluoropyridin-2-amine (24.3 kg, 217 mol, 1.10 equiv.), ethyl acetate (499 L), N,N-diisopropylethylamine (53.5 kg, 414 mol, 2.10 equiv.) and 1-propanephosphonic anhydride (50% ethyl acetate solution) (188 kg, 296 mol, 1.50 equiv.) was heated at an external temperature of 70°C, and the reaction was confirmed to be complete by HPLC analysis. After cooling the reaction liquid, 312 L of pure water was added thereto, stirred, and then allowed to stand. After the water layer was discharged, an aqueous sodium carbonate solution (68.9 kg of sodium carbonate and 312 L of water) was added to the organic layer, stirred, and then allowed to stand. After draining the water layer, pure water (187 L) was added to the organic layer and stirred, and then allowed to stand. Drain the water layer, add pure water (187 L) to the organic layer and stir, and then let it stand. Drain the water layer and filter the organic layer. After rinsing the clarifying filter line with ethyl acetate, a portion of the solvent was distilled off under reduced pressure. Ethyl acetate was added to the concentrated residue (containing essentially 75.3 kg of Lebroxan) to prepare a mixture in a manner such that the total volume reached 256 L, and the mixture was heated and dissolved under stirring at an external temperature of 60°C, and then n-heptane (12.8 kg) was added and cooled to 45°C or below. Ethyl acetate (31 L) was added thereto, and n-heptane (670 kg) was added after cooling to 35°C or below. Then, the suspension was cooled to 10°C or below, the solid in the mixture was filtered out, and washed with a mixed solution of ethyl acetate and n-heptane. The obtained solid was dried under reduced pressure at an external temperature below 60°C to obtain Lebroxan (70 kg) with a yield of 87%.

[0560] HPLC conditions used to confirm the above reaction:

[0561] Reagents and mobile phase:

[0562] Purified water, acetonitrile, trifluoroacetic acid, mobile phase A, mobile phase B and the needle flushing solution of the HPLC device are the same as those of (C-1).

[0563] Solution: mixture of water and acetonitrile (1 / 1, v / v)

[0564] ·(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid standard sample

[0565] HPLC conditions

[0566] Except that the detection wavelength of the detector is 283 nm, everything else is the same as (C-1).

[0567] NMR data

[0568] (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropylcarboxamide:

[0569] 1 H NMR(500MHz,DMSO-d6)δ11.19(s,1H),8.31(d,J=3.0Hz,1H),8.12(s,1H),7.94-7.85( m,1H),7.62(tt,J=8.7,3.1Hz,1H),7.44(dd,J=10.6,1.5Hz,1H),7.41-7.40(m,1H),7. 39(s,1H),7.14-7.06(m,1H),4.67(d,J=10.2Hz,1H),4.29(t,J=9.9Hz,1H),2.63(t,J =7.0Hz,1H),2.38(s,3H),2.03(s,3H),1.76-1.64(m,1H),1.49(dd,J=8.0,4.8Hz,1H);

[0570] 13C NMR(125MHz,DMSO-d6)δ168.68,161.98(d,JCF=242.3Hz),158.46,155.15,155.38(d,JCF=247 .9Hz),148.90,148.51,145.00(d,JCF=7.7Hz),139.37,135.15(d,JCF=24.9Hz),130.06(d,JCF =8.4Hz),125.05(d,JCF=19.5Hz),124.70(d,JCF=2.6Hz),115.71(d,JCF=21.7Hz),114.20(d,J CF=4.1Hz), 113.70 (d, JCF=20.9Hz), 70.80, 34.09 (d, JCF=1.9Hz), 26.90, 24.38, 18.37, 17.78.

[0571] Purity test

[0572] A standard of the compound of formula XI prepared by the method of International Publication WO.2013 / 123240 was used as an external control, and the peak areas of the standard and impurities in the sample were compared to calculate the mass % of each compound in the sample. The total amount of impurities detected exceeding 0.05 mass % was taken as the total content of related substances.

[0573] Test method: Liquid chromatography, UV absorption meter, peak area

[0574] Quantitative method for compounds of formula XI

[0575] Compound of formula XI (%) = A T / C T ×C S / A S ×100

[0576] A T : The peak area of ​​the compound of formula XI in the sample solution

[0577] A S : Peak area of ​​the compound of formula XI in the standard solution

[0578] C T : Concentration of the compound of formula XI in the sample solution (mg / mL)

[0579] C S : Concentration of the compound of formula XI in the standard solution (mg / mL)

[0580] Each related substance (%) = A T / C T ×C S / AS

[0581] Total related substances (%) = Total related substances in sample solution

[0582] A T : Peak area of ​​each related substance in the sample solution

[0583] A S : Peak area of ​​the compound of formula XI in 1% standard solution

[0584] C T : Concentration of the compound of formula XI in the sample solution (mg / mL)

[0585] C S : Concentration of the compound of formula XI in the standard solution (mg / mL)

[0586] Analytical methods

[0587] Sample solution: Dissolve the product in diluent (about 0.5 mg / mL)

[0588] Standard solution of the compound of formula XI: Dissolve the standard substance of the compound of formula XI in diluent (about 0.5 mg / mL)

[0589] 1% standard solution: Dilute the standard solution of the compound of formula XI (about 0.5 mg / mL) to 100 times with diluent

[0590] Dilution: Methanol and water mixture (7:3)

[0591] Injection volume: 10 μL

[0592] Area measurement range: 70 minutes after injection of sample solution

[0593] Test conditions

[0594] HPLC conditions:

[0595] Measurement wavelength: 281nm

[0596] Column: Stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, filled with 2.7 μm octadecylsilane silica gel for liquid chromatography

[0597] Example: Meteoric Core C18 (YMC) (or equivalent)

[0598] Column temperature: Constant temperature close to 40°C

[0599] Mobile Phase:

[0600] Solution A: a mixture of water, acetonitrile and ammonium formate (950:50:1 (v / v / w)

[0601] Solution B: mixture of acetonitrile, water and ammonium formate (900:100:1 (v / v / w)

[0602] Flow rate: fixed flow rate of about 1.0 mL / min

[0603] [Table 1]

[0604] Mobile phase feeding

[0605] Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%) 0-10 95-67 5-33 10-40 67 33 40-65 67-0 33-100 65-70 0 100

[0606] The purity of the compound represented by Formula XI obtained in the above example and the compound represented by Formula XI obtained in different Examples 1-5 in which the same experiment as the above example was performed were analyzed by liquid chromatography. The results are shown in Table 2.

[0607] [Table 2]

[0608]

[0609] The retention time of the compound represented by Formula XI is 28±3 minutes. The relative retention times of the impurities relative to the retention time of the compound represented by Formula XI are as follows.

[0610] Compound of formula XV: 0.08

[0611] Compound of formula VI: 0.11

[0612] Compound of formula X: 0.16

[0613] Compound of formula IX: 0.39

[0614] Compound of formula XIV: 0.41

[0615] Compound of formula XII: 0.76

[0616] Compound of formula XIII: 1.36

Claims

1. A compound of formula XI, wherein the content of the compound of formula XII is 0.10 mass % or less, 2. The compound of formula XI as claimed in claim 1, wherein the content of the compound of formula XII is determined by high performance liquid chromatography (HPLC).

3. The compound of formula XI as claimed in claim 1, wherein the content of the compound of formula XII is 0.10% by mass or less, and the content of the total related substances comprising the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0% by mass or less 4. The compound of formula XI as claimed in claim 3, wherein the content of the compound of formula XII, and the total related substances comprising compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is determined by high performance liquid chromatography (HPLC).

5. The compound of formula XI according to any one of claims 1 to 4, wherein the content of the compound of formula XI is 97.0% by mass or more.

6. The compound of formula XI as claimed in claim 5, wherein the content of the compound of formula XI is determined by high performance liquid chromatography (HPLC).

7. A compound of formula XI, wherein the content of the compound of formula XI is 97.0% by mass or more, 8. The compound of formula XI as claimed in claim 7, wherein the content of the compound of formula XI is determined by high performance liquid chromatography (HPLC).

9. The compound of formula XI as claimed in claim 7, wherein the compound contains a compound of formula XI and a compound of formula XII, wherein the content of the compound of formula XII is 0.10% by mass or less, 10. The compound of formula XI as claimed in claim 9, wherein the content of the compound of formula XI and the compound of formula XII is determined by high performance liquid chromatography (HPLC).

11. The compound of formula XI as claimed in claim 7, which contains a compound of formula XI, a compound of formula XII and total related substances including compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV, wherein the content of the compound of formula XII is 0.10% by mass or less, and the content of the total related substances including compounds of formula VI, formula IX, formula X, formula XIII, formula XIV and formula XV is 1.0% by mass or less, 12. The compound of claim 11, wherein the content of the compound of formula XI, the compound of formula XII, and the total related substances comprising the compounds of formula VI, formula IX, formula X, formula XIII, formula XIV, and formula XV is determined by high performance liquid chromatography (HPLC).

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