Method for preparing 1,3-benzodioxole heterocyclic compounds

Abstract

The present invention relates to a method for preparing 1,3-benzodioxole heterocyclic compounds. Specifically, the present invention relates to a novel method for preparing 1,3-benzodioxole heterocyclic compounds and an intermediate for the method. The compound can be used as a PDE4 inhibitor.

Description

[0001] This application is a divisional application of PCT application PCT / EP2016 / 081368, whose invention name is “Method for preparing 1,3-benzodioxole heterocyclic compounds” and was filed on December 16, 2016. The date on which the PCT application entered the Chinese national phase is June 14, 2018, and the application number is 201680073306.7. Technical Field

[0002] The present invention relates to a novel process for preparing 1,3-benzodioxole heterocyclic compounds and intermediates used in the process. The compounds can be used as PDE4 inhibitors. Background Art

[0003] WO 2011 / 160632 discloses benzodioxole and benzodioxepene heterocyclic compounds useful as PDE4 inhibitors and suitable methods for preparing them.

[0004] WO 2008 / 104175 discloses benzodioxole and benzoheptacyclic heterocyclic compounds useful as PDE4 inhibitors and suitable processes for their preparation.

[0005] WO 2008 / 077404 discloses substituted acetophenones useful as PDE4 inhibitors and suitable methods for their preparation.

[0006] PCT / EP2015 / 063942, with an earliest priority date of June 23, 2014, discloses a process for preparing 1,3-benzodioxole heterocyclic compounds.

[0007] Zafrani et al. Tetrahedron 65, 2009, pp. 5278-5283 describe a process for the difluoromethylation of phenols and thiophenols.

[0008] Sperry et al. Org. Process Res. Dev. 15, 2011, pp. 721-725 also describe the difluoromethylation of phenols.

[0009] Frey et al. Tetrahedron 2003, 59, pp. 6363-6373 also describe the demethylation and difluoromethylation of phenols.

[0010] Zhang et al. J. Org. Chem. 2006, 71, 9845-9848 also describe the difluoromethylation of phenols.

[0011] Zheng et al. Chem. Commun. 2007, 5149-5151 also describe the difluoromethylation of phenols.

[0012] In the development of new drug candidates, alternative methods for preparing drug candidates are highly desirable because some effective small-scale syntheses may prove difficult to scale up to production-scale quantities. Furthermore, small-scale syntheses may involve reagents and solvents that are not suitable at the production-scale level.

[0013] It is therefore an object of the present invention to provide alternative processes for the preparation of 1,3-benzodioxole heterocyclic compounds of the type disclosed in WO 2011 / 160632 and PCT / EP2015 / 063942, in which case the alternative processes are able to offer advantages with respect to one or more characteristics, such as number of reaction steps, purity, yield, ease of purification, process economy, availability of starting materials and reagents, safety, predictability, etc.

[0014] Surprisingly, in step (2a) of the present invention, the yield is ≥ 80%, which is much higher than the 32% yield obtained in the deprotection of the phenolic group in the method described in WO 2011 / 160632. In addition, the method described in WO 2011 / 160632 relies on chromatography for purification of the product, while the method of the present invention allows the product to be purified by simple unit operations that are easily scalable in a production plant.

[0015] Furthermore, surprisingly, in step (3) of the present invention, the difluoromethyl group can now be introduced with a yield of ≥76% with or without isolating the intermediate salt. This exceeds the 52% yield obtained by the method described in WO 2011 / 160632. Furthermore, the method described in WO 2011 / 160632 relies on chromatography for purifying the product, while the method of the present invention allows the product to be purified by a very simple unit operation that is easily scalable in a production plant.

[0016] The improved yield and the ease of scale-up of the process of the present invention compared to the process as described in WO 2011 / 160632 are quite surprising. Summary of the invention

[0017] The inventors have discovered that the alternative processes disclosed herein offer advantages over known processes by reducing the number of reaction steps, increasing overall chemical and volumetric yields, and concomitantly reducing production costs.

[0018] Thus, the present invention provides a process for preparing 1,3-benzodioxole compounds, such as compounds of formula (I).

[0019] The intermediates used in the above-mentioned processes for preparing the compounds of formula (I) are also within the scope of the present invention. DETAILED DESCRIPTION

[0020] In a first aspect, the present invention relates to a process for preparing a compound of formula (I)

[0021]

[0022] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine.

[0023] In the compound of formula (I), R 1 Usually CHF 2 Q is typically selected from chlorine, bromine and fluorine, preferably chlorine, wherein Q is preferably the same. In one embodiment, both Q are chlorine.

[0024] definition

[0025] The term "C 1-6 "-alkyl" is intended to mean a saturated straight or branched hydrocarbon chain having 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and isohexyl. In some embodiments, "C 1-6 -alkyl" is C 1-4 -alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. 1-3 "-alkyl" includes methyl, ethyl, propyl and isopropyl.

[0026] The term "halogen" is intended to mean one of fluorine, chlorine, bromine and iodine. In one embodiment, the term "halogen" refers to fluorine or chlorine. In another embodiment, the term "halogen" refers to chlorine.

[0027] The term "aryl" is intended to mean a carbocyclic aromatic ring system derived from an aromatic hydrocarbon by removal of a hydrogen atom. In addition, aryl includes bicyclic, tricyclic and polycyclic ring systems. Examples of preferred aryl moieties include phenyl, naphthyl, indenyl, dihydroindenyl, fluorenyl and biphenyl. Unless otherwise specified, preferred "aryl" is phenyl, naphthyl or dihydroindenyl, particularly phenyl.

[0028] The term "arylalkyl" is intended to mean an aryl group as defined above covalently linked to an alkyl group, for example benzyl.

[0029] Preparation method

[0030] It is apparent that the process provides advantages over known processes by reliance on inexpensive starting materials, facilitation of the production process and increased reaction yields.

[0031] Step (1)

[0032] The process for preparing a compound of formula (I) comprises the formation of a compound of formula (IV) obtained by:

[0033] The compound of formula (II)

[0034]

[0035] Where R 2 Selected from hydrogen, C 1-6 -alkyl and arylalkyl, R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl; and a compound of formula (III)

[0036]

[0037] in represents a single bond, a double bond, or two single bonds, and when When it represents a double bond or two single bonds, is a single bond, and when When a single key is indicated, is a double bond; when When it represents a double bond, R 3 represents oxygen, and when When it represents a single bond or two single bonds, R 3 Indicates OC 1-6 -alkyl; react in the presence of an acid catalyst to form a compound of formula (IV)

[0038]

[0039] Where R 2 and R 21 As defined above.

[0040] The acid catalyst is generally in the form of a silicate mineral. The silicate mineral is generally selected from montmorillonite K10, montmorillonite K30, montmorillonite KSF, zeolite HSZ-341NHA, zeolite HSZ-331NHA, zeolite HSZ-350HUA and zeolite HSZ-360HUA. In one embodiment, the silicate mineral is selected from montmorillonite K10 and zeolite HSZ-360HUA. In another embodiment, the silicate mineral is montmorillonite K10.

[0041] The compound of formula (III) is usually selected from

[0042]

[0043] Where R 31 Represents C 1-6In one embodiment, the compound of formula (III) is selected from the compounds of formula (IIIa) and formula (IIIb), wherein R 31 In another embodiment, the compound of formula (III) is tetrahydrothiopyran-4-one.

[0044] The ratio between silicate mineral and compound of formula (II) may have an influence on conversion rate and filtration time. Therefore, it is generally preferred to have an amount of 25%-w / w to 500%-w / w of mineral relative to compound of formula (II). Specifically, the amount of mineral should be 25%-w / w to 75%-w / w, preferably in the range of 45%-w / w to 55%-w / w.

[0045] The reaction is typically carried out in toluene, benzene, 2-methyl-THF (2-methyl-tetrahydrofuran), EtOAc (ethyl acetate), xylene, heptane, octane, chlorobenzene and dichlorobenzene. In one embodiment, the solvent is toluene.

[0046] The reaction is usually carried out at a temperature above 80°C to promote the reaction. Therefore, it is usually preferred that the temperature is in the range of 80°C-200°C, for example in the range of 100°C-160°C, especially at 105°C-115°C. In one embodiment, the reaction is carried out under reflux of the reaction mixture. The reaction is usually carried out for 4-96 hours, such as 24-84 hours, especially 48-84 hours.

[0047] The resulting compound of formula (IV) may be recovered by conventional methods known to those skilled in the art, for example by aqueous work-up, followed by extraction and finally precipitation and filtration.

[0048] In one embodiment of the present invention, the compound of formula (II) is wherein R 2 is selected from hydrogen or methyl and R 21 Selected from hydrogen, COCH 3 or COOH. In another embodiment, the compound of formula (II) is 1-(2,3-dihydroxy-4-methoxyphenyl)ethanone.

[0049] In one embodiment of the present invention, the compound of formula (III) is tetrahydrothiopyran-4-one.

[0050] In one embodiment of the present invention, the compound of formula (IV) is wherein R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl or benzyl, and R 21 Selected from hydrogen, COCH 3 In another embodiment, the compound of formula (IV) is wherein R 2 is methyl and R 21It's COCH 3 .

[0051] Step (2a)

[0052] The compound of formula (IV) is prepared by deprotecting the phenolic moiety.

[0053]

[0054] Where R 2 and R 21 As defined above, converted to a compound of formula (VI)

[0055]

[0056] Where R 21 As defined above.

[0057] This can be accomplished by reacting a compound of formula (IV) with an aromatic or aliphatic thiol in combination with a base.

[0058] The aromatic thiol can be, for example, but not limited to, benzenethiol, 4-methylbenzenethiol, 3,5-dimethylbenzenethiol, 2,5-dimethylbenzenethiol, 4-isopropylbenzenethiol or 5-tert-butyl-2-methyl-benzenethiol. In one embodiment, the aromatic thiol is 5-tert-butyl-2-methyl-benzenethiol.

[0059] The aliphatic thiol can be, for example, but not limited to, 1-dodecyl mercaptan, 1-tetradecyl mercaptan, 1-hexadecanethiol, or tert-dodecyl mercaptan. In one embodiment, the aliphatic thiol is 1-dodecyl mercaptan.

[0060] The deprotection of the phenol group in step (2a) can be carried out using various solvents, such as DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), methanol or ethanol and mixtures thereof. In one embodiment, the solvent is DMF. In another embodiment, the solvent is a mixture of DMF and methanol.

[0061] The deprotection of the phenol group is carried out in the presence of a base, such as K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , CsCO 3 , TEA (triethylamine), potassium tert-butoxide, tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide, and DIPEA (N,N-diisopropylethylamine). In one embodiment, the base is K 2 CO 3In another embodiment, the base is sodium methoxide.

[0062] The reaction is typically carried out at a temperature in the range of 50°C-120°C, such as in the range of 70°C-100°C. The reaction is typically allowed to proceed for 2-36 hours, such as 3-24 hours. The reaction is typically allowed to proceed to a conversion of ≥98%.

[0063] The resulting compound of formula (VI) may be recovered by conventional methods known to those skilled in the art, for example by aqueous work-up, followed by extraction and finally precipitation and filtration.

[0064] In one embodiment of the present invention, the compound of formula (VI) is wherein R 21 C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl. In another embodiment, the compound of formula (VI) is 1-(7-hydroxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0065] Step (2b)

[0066] In step (2b), the compound of formula (VI) is reacted with aqueous N(Bu) 4 + OH - Reaction to form a compound of formula (VII)

[0067]

[0068] Where R 21 As defined above.

[0069] Typically the mixture is heated to a temperature in the range 20°C-80°C, such as 55°C-65°C, until everything has dissolved.

[0070] The resulting solution is typically washed with an aqueous sodium chloride solution by stirring for ≥20 min at a temperature in the range of 20° C.-80° C., such as 55° C.-65° C. A mixture of water and sodium chloride is then added and the mixture is then cooled from ≥35° C. to 0° C.-20° C., e.g. 5° C. over a period of 1-24 hours, such as 1-4 hours, resulting in precipitation of TBA (tetrabutylammonium) salt. The TBA salt is separated, for example, by filtration and dried.

[0071] Step (3)

[0072] Compound of formula (IX)

[0073]

[0074] Where R1 and R 21 As defined above, the obtained compound of formula (VII) can be obtained by alkylation

[0075]

[0076] Where R 21 As defined above, the alkylation is carried out by reaction with a hydrochlorofluorocarbon reagent,

[0077] R 1 -Cl (VIII)

[0078] Where R 1 As defined above.

[0079] The alkylation can be carried out using various possible reagents such as various hydrochlorofluorocarbon gases. In one embodiment, the alkylation reaction is carried out using chlorodifluoromethane in an aprotic polar solvent, such as DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile) and THF (tetrahydrofuran) and mixtures thereof. In a preferred embodiment, the aprotic solvent is selected from DMF and NMP. In a specific embodiment, the reaction is carried out using chlorodifluoromethane in DMF.

[0080] The reaction is typically carried out at a temperature in the range of 40° C. to 120° C., such as in the range of 50° C. to 70° C. The reaction is typically carried out until ≤ 4% phenol remains in the reaction mixture.

[0081] The resulting compound of formula (IX) may be recovered by conventional methods known to those skilled in the art, for example by aqueous work-up followed by precipitation and subsequent filtration.

[0082] In one embodiment of the present invention, the compound of formula (IX) is 1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0083] Alternative Steps (2b+3)

[0084] Alternatively, the compound of formula (IX)

[0085]

[0086] Where R 1 and R 21 As defined above, it can be obtained from a compound of formula (VI) by using a difluorocarbene source in the presence of a base in a polar solvent,

[0087]

[0088] Where R 21 As defined above, no intermediate salt of formula (VII) is formed.

[0089] The difluorocarbene source is selected from, for example, but not limited to, sodium chlorodifluoroacetate, diethyl bromodifluoromethylphosphonate, chlorodifluoromethylphenyl sulfone and 2-chloro-2,2-difluoroacetophenone. Those skilled in the art can easily select other suitable analogs of the mentioned difluorocarbene source. In one embodiment, the difluorocarbene source is sodium chlorodifluoroacetate. In another embodiment, the difluorocarbene source is diethyl bromodifluoromethylphosphonate.

[0090] The reaction is carried out in a solvent selected from, for example, NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol, methanol, water, and mixtures thereof. In one embodiment, the solvent is a mixture of water and DMF. In another embodiment, the solvent is a mixture of water and acetonitrile.

[0091] The reaction is carried out in the presence of a base, which is selected from, for example, K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , CsCO 3 , TEA (triethylamine), tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide, DIPEA (N,N-diisopropylethylamine), KOH, NaOH, LiOH. In one embodiment, the base is K 2 CO 3 In another embodiment, the base is NaOH.

[0092] The reaction is typically carried out at a temperature ranging from 0° C. to 120° C., such as 6° C. to 115° C. In one embodiment, the reaction is carried out at 6° C. to 20° C. using diethyl bromodifluoromethylphosphonate as the difluorocarbene source. In another embodiment, the reaction is carried out at ambient temperature to 111° C. using sodium chlorodifluoroacetate as the difluorocarbene source.

[0093] In one embodiment of the present invention, the compound of formula (IX) is 1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0094] The resulting compound of formula (IX), wherein R 1 and R 21 As defined above.

[0095] Step (4)

[0096] In step (4), the compound of formula (IX) is reacted with a pyridine compound of formula (X)

[0097]

[0098] Where Q is as defined above and Q X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI)

[0099]

[0100] Where R 1 and Q are as defined above.

[0101] The pyridine coupling in step (4) is usually carried out in the presence of a base in a polar solvent, such as DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), MeCN (acetonitrile) and THF (tetrahydrofuran) and mixtures thereof, and the base is such as tert-BuOK (potassium tert-butoxide), tert-BuOLi (lithium tert-butoxide), tert-BuONa (sodium tert-butoxide), sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , Et 3 N(triethylamine) and DIPEA (N,N-diisopropylethylamine). In one embodiment, the solvent is DMF and the base is tert-BuOK.

[0102] Typically two equivalents or more of the base are used relative to the compound of formula (IX), such as where the molar ratio (base) / (formula IX) is from 5:1 to 2:1, for example 3:1 to 2:1, especially 2.4:1 to 2.7:1.

[0103] The reaction in step (4) is usually carried out at a temperature of 0°C to 40°C, such as 5°C to 25°C.

[0104] In one embodiment of the present invention, the compound of formula (X) is 3,4,5-trichloropyridine.

[0105] In one embodiment of the invention, the compound of formula (XI) is 2-(3,5-dichloro-4-pyridinyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0106] During the reaction, a considerable amount of the impurity of formula (XII) is formed.

[0107]

[0108] Such impurities are removed from the product by crystallizing the product from a solvent selected from, for example, dimethylformamide (DMF), ethanol, methanol, ethyl acetate, hexane, heptane and mixtures thereof. In one embodiment of the invention, the solvent is a mixture of ethyl acetate and ethanol.

[0109] Step (5)

[0110] The oxidation of the obtained compound of formula (XI) is carried out by reacting the obtained compound of formula (XI) with an oxidizing agent to form a compound of formula (I)

[0111]

[0112] Where R 1 and Q are as defined above.

[0113] The oxidizing agent is usually selected from PAA (peracetic acid) in AcOH (acetic acid) and H in formic acid or acetic acid. 2 O 2 (aq). In a preferred embodiment, the oxidizing agent is PAA in AcOH. In one embodiment, the amount of PAA used relative to (XI) (molar ratio) is typically 3 to 6, such as 3.8 to 4.2. The oxidizing agent is typically added slowly over a period of 1-8 hours, such as 3-5 hours, while maintaining the temperature in the range of 15°C-100°C, such as in the range of 15°C-50°C, especially in the range of 15°C-40°C.

[0114] The reaction is typically carried out at a temperature in the range 30-70°C, such as 40-60°C, especially 48-52°C, and stirred for 3-48 hours, such as 16-24 hours.

[0115] Purification of the compound of formula (I)

[0116] The obtained crude product of formula (I) can advantageously be purified by crystallization, precipitation, chromatography or the like.

[0117] In one embodiment, the resulting crude product of formula (I) is crystallized from a mixture of water and EtOH (ethanol), isolated by filtration and dried.

[0118] Intermediates

[0119] In another aspect, the present invention relates to intermediates useful for preparing compounds of formula (I), wherein R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine.

[0120] In one embodiment, the present invention relates to an intermediate compound of formula (VI)

[0121]

[0122] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl. In another embodiment, the intermediate compound of formula (VI) is 1-(7-hydroxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0123] In another embodiment, the present invention relates to an intermediate compound of formula (VII)

[0124]

[0125] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl. In another embodiment, the intermediate compound of formula (VII) is tetrabutylammonium 7-acetylspiro[1,3-benzodioxole-2,4'-tetrahydro-thiopyran]-4-olate.

[0126] In another embodiment, the present invention relates to an intermediate compound of formula (IX)

[0127]

[0128] Where R 1 Selected from CHF 2 and CF 3 , and R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl.

[0129] In another embodiment, R1 Indicates CHF 2 , and R 21 C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl. In another embodiment, the intermediate compound of formula (IX) is 1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl]ethanone.

[0130] experiment

[0131] Methods and reagents

[0132] All chemicals and reagents used were available from commercial sources.

[0133] 1 H nuclear magnetic resonance (NMR) spectra were recorded at the indicated magnetic fields and chemical shift values ​​(δ, in ppm) are quoted relative to tetramethylsilane (δ=0.00) in the indicated solvents.

[0134] HPLC: Column: Aeris Peptide 3.6 μm XB-C18, 100x4.6 mm, eluent was a gradient of: A: 10% MeCN; 90% H2O; 0.1% TFA and B: 90% MeCN; 10% H2O; 0.1% TFA, column temperature: 35°C, UV detection at 220 nm, flow rate: 1.5 mL / min. The following eluent gradient was used:

[0135] Gradient steps 2a, 2b, 3 and 5

[0136] Time (min) ％A ％B 0 85 15 8 20 80 10 20 80 10 85 15 12.2 85 15

[0137] Gradient step 4

[0138] Time (min) ％A ％B 0 75 25 5 20 80 12.2 20 80 12.2 75 25 13.2 75 25

[0139] Example 1

[0140] Step (1): 1-(7-methoxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone Preparation

[0141] The reactor was charged with 1-(2,3-dihydroxy-4-methoxy-phenyl)ethanone (60.0 kg, 329 mol), tetrahydrothiopyran-4-one (37.2 kg, 320 mol), montmorillonite K10 (30.0 kg) and toluene (720.0 L). The stirred mixture was heated to reflux, with a jacket temperature of 140°C-150°C applied for 84 hours. The mixture was cooled to 86°C-90°C and filtered through a filter aid bed. The reactor was rinsed with hot (86°C-90°C) toluene (120 L), and the filter aid bed was then washed with hot toluene. The reactor was rinsed twice with hot toluene (120 L) and the filter aid bed was subsequently washed, and once with hot (70°C) ethyl acetate (60 L). All toluene and ethyl acetate filtrates were combined and cooled to 2°C-6°C over about 6 hours. The mixture was stirred at 2°C-6°C for about half an hour.

[0142] The unconverted material was collected by filtration and dried in vacuo at 43°C-47°C. Yield: 32.0 kg.

[0143] The filtrate obtained by separating the unconverted raw material is cooled to 10°C-16°C under stirring, and a mixture of sodium hydroxide (26.40 kg) and water (162.0 L) is added at 10°C-16°C. The reaction mixture is then stirred at 10°C-16°C for about half an hour, then agitation is stopped, and the phases are allowed to settle. The lower aqueous phase is discarded, and a mixture of sodium hydroxide (26.40 kg) and water (162 L) is then added under stirring at 10°C-16°C. The mixture is stirred for about one hour, then agitation is stopped, and the phases are allowed to settle. The lower aqueous phase is discarded and the organic phase is transferred to a container. The reactor is rinsed with toluene, and the organic phase is then transferred back to the reactor through a cartridge filter.

[0144] Under the condition of applying ≤70 ℃ temperature, the solution is vacuum concentrated as far as possible. Ethanol (90.0 L) is added, and the mixture is heated to 47 ℃-53 ℃, and stirred at this temperature for 10-15 minutes. The mixture is then vacuum concentrated as far as possible at a temperature of ≤55 ℃. Ethanol (120.0 L) is added to the reactor, the mixture is heated to reflux under stirring, and water (90.0 L) is added under heating while the mixture is kept at reflux. The mixture is cooled to 2 ℃-8 ℃ over about 10 hours, and stirred at this temperature for about half an hour.

[0145] The product was isolated by filtration, washed with a mixture of ethanol (30.0 L) and water (22.8 L), and dried under vacuum at 43-47° C. Yield 21.80 kg (24% but 51% if corrected for recovered starting material). 1H NMR(600MHz,DMSO-d6)δ7.30(d,J=9.0Hz,1H),6.75(d,J=9.0Hz,1H),3.88(s,3H),2.9 1–2.84(m,2H),2.84–2.77(m,2H),2.49(s,3H),2.30–2.22(m,2H),2.22–2.12(m,2H).

[0146] Step (1) was repeated as necessary to produce the desired amount of 1-(7-methoxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0147] Step (2a): 1-(7-Hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone Preparation

[0148] The reactor was charged with 1-(7-methoxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (26.0 kg, 92.7 mol), potassium carbonate (14 kg, 101 mol), dimethylformamide (104 L) and 5-tert-butyl-2-methyl-benzenethiol (26.8 kg, 149 mol). The mixture was heated to 85-92° C. with stirring until a conversion of ≥98% as indicated by HPLC was achieved. The mixture was then cooled to 25° C., water (104 L) and sodium hydroxide (28% aqueous solution, 21.4 kg) were added, and stirred for ≥10 minutes. If the pH of the mixture was below 12, more sodium hydroxide (28% aqueous solution) was added. Toluene (65 L) was then added and stirring continued for ≥15 minutes. Agitation was stopped and the phases were allowed to settle. The phases were separated and the organic phase was discarded. The two lower aqueous phases were stirred with toluene (65 L) and the mixture was stirred for ≥15 minutes. Agitation was stopped to allow each phase to settle. Each phase was separated and the organic phase was discarded. The two aqueous phases were returned to the reactor and hydrochloric acid (18% aqueous solution, 67.6 kg) was slowly added under stirring to control gas evolution. The resulting mixture was stirred for ≥10 minutes. In order to achieve pH ≤ 6, more hydrochloric acid (18% aqueous solution, 10.2 kg) was added.

[0149] The temperature of the mixture was adjusted to 35°C-45°C and maintained in this range during the following extraction process. Ethyl acetate (156 L) was added and the mixture was stirred for ≥30 minutes. Stirring was stopped and the phases were allowed to settle. The phases were separated. The aqueous phase was stirred with ethyl acetate (78 L) for ≥30 minutes. Stirring was stopped and the phases were allowed to settle. The aqueous phase was discarded. The two ethyl acetate phases were combined in a reactor and stirred with water (78 L) for ≥15 minutes. Stirring was stopped and the phases were separated. The aqueous phase was discarded.

[0150] The organic phase was concentrated as much as possible, with a jacket temperature of 50°C-60°C and vacuum applied. Heptane (39 L) was then added and the resulting mixture was cooled to ≤5°C at a rate of ≤10°C / h and maintained at this temperature for ≥3 hours. The title compound was isolated by filtration, washed with a cold (≤5°C) mixture of ethyl acetate (10 L) and heptane (10 L), and dried under vacuum at 40°C-50°C. Yield 19.75 kg (80%). 1 H NMR (600MHz, DMSO-d6) δ10.51(s,1H),7.18(d,J=9.0Hz,1H),6.50(d,J=9.0Hz,1H),2. 93–2.85(m,2H),2.84–2.78(m,2H),2.46(s,3H),2.31–2.23(m,2H),2.20–2.11(m,2H).

[0151] Step (2b): Tetrabutylammonium 7-acetylspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4- Alkoxide

[0152] A suitable reactor was charged with 1-(7-hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (19.75 kg, 74.16 mol) followed by tetrabutylammonium hydroxide (40% aqueous solution, 53.0 kg, 81.7 mol). The jacket temperature was set to 60°C and the mixture was stirred until all had dissolved. Saturated aqueous sodium chloride solution (59.2 kg) was added and stirring was continued at a jacket temperature of 60°C for ≥20 minutes. Agitation was stopped and the phases were allowed to separate. The lower aqueous phase was discarded. The mixture in the reactor was stirred again at a jacket temperature of 60°C. Saturated aqueous sodium chloride solution (29.6 kg) was added followed by water (25 L). The mixture was stirred at a mixture temperature of ≥35°C for ≥15 minutes. The mixture was cooled to 0°C-5°C at a rate of about 20°C / h and seeded at 40°C and again at 35°C. The mixture was stirred at 0-5° C. for ≥ 2 hours, then the title compound was isolated by filtration and dried in vacuo at 40-50° C. Yield 32.9 kg (87%). 1 H NMR(600MHz, DMSO-d6)δ6.94(d,J=9.1Hz,1H),5.74(d,J=9.1Hz,1H),3.23–3.07(m,8H),2.87–2.72(m,4H),2.25 (s,3H),2.16–2.07(m,2H),2.06–1.96(m,2H),1.62–1.51(m,8H),1.30(h,J=7.4Hz,8H),0.93(t,J=7.4Hz,12H).

[0153] Step (3): 1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4- ethyl ketone

[0154] Tetrabutylammonium 7-acetylspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-olate (32.93 kg, 64.85 mol) and dimethylformamide (198 L) were added to the reactor. The mixture was stirred until all dissolved. Chlorodifluoromethane (39.5 kg, 457 mol) was added to the solution through a dip tube on the reactor. The reaction mixture was heated to 50°C-55°C and stirred until the residual raw material was ≤4% as indicated by HPLC. The reaction mixture was cooled to 20°C-25°C and transferred to a container through a filter. The solids in the reactor and filter were washed with dimethylformamide (10 L) which was also added to the container.

[0155] Water (198 L) and sodium hydroxide (28% aqueous solution, 11.0 kg) were charged into the reactor and heated to 45°C-55°C. The reaction mixture in the container was slowly added to the reactor under stirring while maintaining the temperature at 45°C-55°C. The mixture was then cooled to 5°C-10°C and stirred at this temperature for ≥2 hours. The product was isolated by filtration, washed with water (82 L), and vacuum dried at 45°C-55°C under nitrogen flow. Yield 19.08 kg (94%). 1 HNMR(600MHz,DMSO-d6)δ7.34(t,J=73.1Hz,1H),7.32(d,J=9.1Hz,1H),6.86(d,J= 9.1Hz,1H),2.92–2.80(m,4H),2.54(s,3H),2.34–2.27(m,2H),2.27–2.19(m,2H).

[0156] Step (4) 2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxolane [2,4'-tetrahydrothiopyran-4-yl]ethanone

[0157] Dimethylformamide (96 L) is loaded into a suitable reactor and potassium tert-butoxide (17.60 kg, 156.8 mol) is then added. The potassium tert-butoxide is transferred by flushing with dimethylformamide (3 L) to ensure that the potassium tert-butoxide is transferred, and the mixture is stirred until the potassium tert-butoxide has dissolved. The solution is transferred from the reactor to a container and the reactor is rinsed with dimethylformamide (6 L) which is also transferred to the container.

[0158] The reactor was charged with 1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone (19.08 kg, 60.32 mol), 3,4,5-trichloropyridine (14.30 kg, 78.38 mol) and dimethylformamide (96 L). The mixture was stirred and cooled to 10°C-15°C, and then a solution of potassium tert-butoxide in dimethylformamide was slowly added while maintaining the temperature of the reaction mixture at 5°C-25°C. The transfer of the potassium tert-butoxide solution was ensured by flushing with dimethylformamide (6 L). The mixture was heated to 20°C-25°C and stirred until the conversion was ≥98% as indicated by HPLC. The content of impurity of formula (XII) in the reaction mixture: 12%

[0159] Water (96L) was slowly added to the reaction mixture under cooling while maintaining the temperature between 20°C and 30°C. Saturated sodium chloride aqueous solution (115.2kg) and ethyl acetate (134L) were added thereafter. The mixture was stirred for 20-60 minutes, then agitation was stopped to allow each phase to settle. Each phase was separated and the aqueous phase was returned to the reactor. Ethyl acetate (96L) was added and the mixture was stirred for 20-60 minutes. Agitation was stopped to allow each phase to settle. Each phase was separated. The organic phase was combined in the reactor and stirred with water (48L) and saturated sodium chloride aqueous solution (57.8kg) for ≥20 minutes. Agitation was stopped to allow each phase to settle. The lower aqueous phase was discarded, and water (48L) and saturated sodium chloride (57.6kg) were added. The mixture was stirred for 20-60 minutes, then agitation was stopped to allow each phase to settle. The lower aqueous phase was discarded, and water (84L) and sodium hydroxide (28% aqueous solution, 14.0kg) were added. The mixture was stirred for 20-60 minutes, then agitation was stopped and the phases were allowed to settle. The lower aqueous phase was discarded.

[0160] The organic phase in the reactor was concentrated to a residual volume of about 40 L by vacuum and heating with a jacket temperature of 50°C-65°C. Ethanol (57 L) was charged into the reactor and the mixture was heated to reflux until a clear solution was obtained. The mixture was cooled to 5°C over ≥5 hours and stirred at this temperature for ≥3 hours. The product was isolated by filtration and rinsed with ethanol (10 L) to ensure transfer. The product was washed with cold (≤5°) ethanol (48 L) and dried under vacuum at 45°C-55°C. Yield 15.57 kg (56%). 1H NMR (600 MHz, Chloroform-d) δ 8.52 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.73 (t, J = 73.3 Hz, 1H), 4.59 (s, 2H), 3.01-2.85 (m, 4H), 2.47-2.30 (m, 4H). HPLC: Purity: 97.8%, content of impurity of formula (XII): 1.0%.

[0161] Step (5): 2-(3,5-dichloro-1-oxo-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-di Oxy-spiro[1,3-benzodioxole-2,4'-cyclopentylsulfide]-4-yl]ethanone

[0162] The reactor was charged with 2-(3,5-dichloro-4-pyridine)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone (15.6 kg, 33.7 mol) and glacial acetic acid (78.0 kg), and the mixture was cooled to 13-20°C. Peracetic acid (36%-40% solution in acetic acid, 6.52 kg, 32.6 mol) was added slowly while keeping the temperature below 40°C. The mixture was heated to 40-50°C and stirred for 10-25 minutes. The mixture was cooled to 13-20°C and a second portion of peracetic acid (36%-40% solution in acetic acid, 6.51 kg, 32.5 mol) was added slowly while keeping the temperature below 40°C. The mixture was heated to 40-50°C and stirred for 10-25 minutes. The mixture was cooled to 20-30°C and a third portion of peracetic acid (36%-40% solution in acetic acid, 14.3 kg, 71.5 mol) was slowly added. The mixture was heated to 48-55°C and stirred until the conversion was ≥ 98.5%. The mixture was cooled to 20-25°C and a mixture of sodium metabisulfite (7.21 kg, 37.9 mol) and water (46 L) was slowly added while maintaining the temperature below 35°C.

[0163] 2-Propanol (78 L) was added and the mixture was heated to 60-65 ° C and filtered hot. The reactor was cleaned and the filtered reaction mixture was returned to the reactor. The mixture was heated to 60-65 ° C and water (234 L) was slowly added while keeping the temperature above 55 ° C. The mixture was stirred at 60-65 ° C for 30-60 minutes, slowly cooled to 5 ° C over 12 hours, and stirred at 0-10 ° C for ≥ 2 hours. The crude product was isolated by filtration, washed with water (27 L), and vacuum dried for about 2 hours.

[0164] The solid was returned to the reactor and heated to reflux with ethanol (390 L). The mixture was then cooled to 68-72 °C and seeded. The mixture was cooled to 5 °C over 13 hours and stirred at 0-10 °C for ≥ 2 hours. The product was isolated by filtration, washed with a cold (0-10 °C) mixture of water (4 L) and ethanol (39 L), and dried under vacuum at 45-55 °C under nitrogen flow. Yield 14.6 kg (85%). 1H NMR (600MHz, Chloroform-d) δ8.23 (s, 2H), 7.52 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 6.71 (t, J = 72.3 Hz, 1H), 4.49 (s, 2H), 3.47-3.38 (m, 2H), 3.33-3.24 (m, 2H), 2.83-2.75 (m, 2H), 2.75-2.68 (m 2H). HPLC: Purity: 98.6%.

[0165] Example 2

[0166] 1-(7-Hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone

[0167] A solution of sodium methoxide in methanol (30%, 64.2 mL, 0.34 mol) was added to a solution of 1-(7-methoxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (50.0 g, 0.178 mol) in dimethylformamide (250 mL) at 25°C-30°C. 1-Dodecane-thiol (64.88 mL, 0.271 mol) was then added at 25°C-30°C, and the mixture was heated to 95°C-100°C for three hours. The reaction mixture was cooled to 25°C-30°C and sodium hydroxide (28% aqueous solution, 50 mL) and water (250 mL) were added. The resulting mixture was stirred for half an hour, and then the mixture was extracted three times with toluene (250 mL). The aqueous solution was acidified to about pH 6 with hydrochloric acid (6 M) and extracted four times with ethyl acetate (250 mL). The ethyl acetate extracts were combined, washed four times with brine (250 mL), and concentrated to about 50 mL using a rotary evaporator. Heptane (300 mL) was added and the mixture was stirred at ambient temperature for one hour. The product was isolated by filtration, washed with heptane (100 mL) and dried. Yield 44.3 g (93%). NMR was consistent with the NMR of the product from step (2a) in Example 1.

[0168] Example 3

[0169] 1-[7-(Difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone

[0170] A mixture of 1-(7-hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (221.6 g, 0.8322 mol), potassium carbonate (161.3 g, 1.167 mol), sodium chlorodifluoroacetate (292.0 g, 1.915 mol), dimethylformamide (1.50 L) and water (500 mL) was stirred and slowly heated to 106°C-111°C in a 5-liter reaction flask, and gas evolution was observed from about 78°C. The reaction mixture was stirred at 106°C-111°C until gas evolution had stopped for about 2 hours. The mixture was cooled with an ice-water bath, and water (1.00 L) was slowly added at 30°C-32°C. The resulting suspension was further cooled to 6°C under stirring. The crude product was separated by filtration and washed with water.

[0171] The wet crude product was stirred with ethyl acetate (1.66L) and sodium hydroxide (1M, 560mL) for about 20 minutes, and then separated in a separatory funnel. The lower aqueous phase was discarded, and the organic phase was washed with water twice (twice, 560mL). The organic phase was concentrated to about 450mL using a rotary evaporator (vacuum, 60°C in a water bath). Ethyl acetate (1.56L) was added, and the mixture was concentrated to about 450mL again using a rotary evaporator as above. Ethyl acetate (1.44L) was added, and the unclear solution was filtered, while transferring and washing with a new portion of ethyl acetate (100mL). The combined filtrate was filtered through an activated carbon plug (6.0g), while transferring and washing with ethyl acetate (200mL). The combined filtrate was concentrated to about 450mL on a rotary evaporator as above. The hot solution (about 60°C) of the obtained solution was stirred at ambient temperature, while slowly adding heptane (2.00L) through about half an hour. The suspension was stirred at ambient temperature for 14 hours.

[0172] The mixture was stirred in an ice-water bath for about 2.5 hours, and the temperature of the mixture was then 4° C. The product was isolated by filtration, washed with an ice-cold mixture of heptane and ethyl acetate (10:1, 200 mL), and dried under vacuum at 50° C. with air flow. Yield 201 g (76%). NMR was consistent with that of the product from step 3 in Example 1.

[0173] Example 4

[0174] 1-[7-(Difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone

[0175] Sodium hydroxide (6.16 g, 154 mmol) was dissolved in water (40 mL) and the solution was stirred while cooling in an ice-water bath. 1-(7-hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (2.00 g, 7.51 mmol) and acetonitrile (20 mL) were added and stirring continued while cooling. Diethyl bromodifluoromethylphosphonate (2.67 mL, 15.0 mmol) was added in one portion at 6 °C and stirring continued for about 20 minutes while cooling. The cooling bath was removed and the mixture was stirred at ambient temperature for about 21 hours.

[0176] Use separating funnel to separate each phase, and water is extracted with ethyl acetate (20mL).With the organic phase water (20mL) merged and then with salt solution (20mL) washing.As in embodiment 3, use rotary evaporator that organic phase is concentrated to dry.Ethyl acetate (20mL) is joined to resistates, and once more uses rotary evaporator that mixture is concentrated to dry.

[0177] The residue was dissolved in ethyl acetate (30 mL) and filtered, transferring and washing with ethyl acetate (20 mL). The combined filtrates were concentrated to dryness using a rotary evaporator as above to give the title compound as a pale yellow solid. Yield 2.14 g (90%). The NMR was consistent with that of the product from step 3 in Example 1.

[0178] Example 5

[0179] 1-[7-(Difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone

[0180] Sodium hydroxide (301 g, 7.52 mol) was stirred with water (2.0 L) and the resulting solution was cooled with an ice-water bath. 1-(7-Hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (100.1 g, 0.3757 mol) and acetonitrile (1.0 L) were added. Diethyl bromodifluorophosphonate (150.5 g, 0.5637 mol) was added slowly over about 40 minutes at a reaction mixture temperature of 15°C-20°C. Stirring was continued at 15°C-20°C for about two more hours. The phases were separated.

[0181] Water (920 mL) was slowly added to the organic phase under stirring and the resulting suspension was stirred at ambient temperature for about 18 hours. The product was isolated by filtration, washed with a 1:1 mixture of heptane and water (120 mL), and dried under vacuum at 50° C. under air flow. Yield 108 g (91%). NMR was consistent with the NMR of the product from step 3 in Example 1.

[0182] Terms

[0183] In view of the description, the inventors have provided in particular:

[0184] Item 0. A method for preparing a compound of formula (I)

[0185]

[0186] Where R 1 Selected from CHF 2 and CF 3 , Q is selected from chlorine, bromine and fluorine,

[0187] The method comprises one or more of the following steps:

[0188] (1) making the compound of formula (II)

[0189]

[0190] Where R 2 Selected from hydrogen, C 1-6 -alkyl and arylalkyl, R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl; and a compound of formula (III)

[0191]

[0192] in represents a single bond, a double bond, or two single bonds, and when When it represents a double bond or two single bonds, is a single bond, and when When a single key is indicated, is a double bond; when When it represents a double bond, R 3 represents oxygen, and when When it represents a single bond or two single bonds, R 3 Indicates OC 1-6 -alkyl; react in the presence of an acid catalyst to form a compound of formula (IV)

[0193]

[0194] Where R 2 and R 21 As defined above;

[0195] (2a) reacting the obtained compound of formula (IV) with an aromatic or aliphatic thiol to form a compound of formula (VI)

[0196]

[0197] Where R21 As defined above;

[0198] (2b) reacting the compound of formula (VI) with aqueous N(Bu) 4 + OH - Reaction to form a compound of formula (VII)

[0199]

[0200] Where R 21 As defined above;

[0201] (3) alkylating the obtained compound of formula (VII) with the following hydrochlorofluorocarbon reagent:

[0202] R 1 -Cl (VIII)

[0203] Where R 1 As defined above, to form a compound of formula (IX)

[0204]

[0205] Where R 1 and R 21 As defined above;

[0206] (4) reacting the compound of formula (IX) with a pyridine compound of formula (X)

[0207]

[0208] Where Q is as defined above and Q X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI);

[0209]

[0210] Where R 1 and Q are as defined above; and

[0211] (5) oxidizing the obtained compound of formula (XI) to prepare the compound of formula (I)

[0212]

[0213] Where R 1 and Q are as defined above.

[0214] Item 1. A method for preparing a compound of formula (I)

[0215]

[0216] Where R1 Selected from CHF 2 and CF 3 , Q is selected from chlorine, bromine and fluorine,

[0217] The method comprises each of the following steps:

[0218] (1) making the compound of formula (II)

[0219]

[0220] Where R 2 Selected from hydrogen, C 1-6 -alkyl and arylalkyl, R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl; and a compound of formula (III)

[0221]

[0222] in represents a single bond, a double bond, or two single bonds, and when When it represents a double bond or two single bonds, is a single bond, and when When a single key is indicated, is a double bond; when When it represents a double bond, R 3 represents oxygen, and when When it represents a single bond or two single bonds, R 3 Indicates OC 1-6 -alkyl; react in the presence of an acid catalyst to form a compound of formula (IV)

[0223]

[0224] Where R 2 and R 21 As defined above;

[0225] (2a) reacting the obtained compound of formula (IV) with an aromatic or aliphatic thiol to form a compound of formula (VI)

[0226]

[0227] Where R 21 As defined above;

[0228] (2b) reacting the compound of formula (VI) with aqueous N(Bu) 4 + OH - Reaction to form a compound of formula (VII)

[0229]

[0230] Where R 21 As defined above;

[0231] (3) alkylating the obtained compound of formula (VII) with the following hydrochlorofluorocarbon reagent:

[0232] R 1 -Cl(VIII)

[0233] Where R 1 As defined above, to form a compound of formula (IX)

[0234]

[0235] Where R 1 and R 21 As defined above;

[0236] (4) reacting the compound of formula (IX) with a pyridine compound of formula (X)

[0237]

[0238] Where Q is as defined above and Q X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI);

[0239]

[0240] Where R 1 and Q are as defined above; and

[0241] (5) oxidizing the obtained compound of formula (XI) to prepare the compound of formula (I)

[0242]

[0243] Where R 1 and Q are as defined above.

[0244] Item 2. The method according to Item 1, wherein the deprotection in step (2a) is carried out in the presence of a base in a solvent, the solvent is selected from, for example, NMP, DMSO, DMF, methanol, ethanol and mixtures thereof, the base is selected from, for example, K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , CsCO 3 , TEA and DIPEA, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide.

[0245] Clause 3. The method according to clause 2, wherein the solvent is DMF and the base is K 2 CO 3 .

[0246] Clause 4. The process according to clause 2, wherein the solvent is a mixture of DMF and methanol and the base is sodium methoxide.

[0247] Clause 5. A process according to any one of the preceding clauses, wherein the reaction in step (3) is carried out in the presence of a polar solvent using a hydrochlorofluorocarbon R 1 The polar solvent is selected from, for example, DMF, NMP, DMI, DMSO, EtOAc and THF.

[0248] Clause 6. The process according to clause 5, wherein the reaction is carried out in DMF using chlorodifluoromethane.

[0249] Clause 7. A method according to any one of the preceding clauses, wherein in step (4), the coupling is carried out in the presence of a base in a polar solvent, the polar solvent being selected, for example, from NMP, DMF, DMI, DMSO, MeCN and THF and mixtures thereof, the base being selected, for example, from tert-BuOK, tert-BuOLi, tert-BuONa, sodium or potassium methoxide, sodium or potassium ethoxide, K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , Et 3 N and DIPEA.

[0250] Clause 8. The process according to Clause 7, wherein the polar solvent is DMF and the base is tert-BuOK.

[0251] Clause 9. A method according to any one of the preceding clauses, wherein R 1 is CHF 2 .

[0252] Clause 10. A method according to any one of the preceding clauses, wherein Q and Q x It's all chlorine.

[0253] Clause 11. A method according to any one of the preceding clauses, wherein the impurity of formula (XII)

[0254]

[0255] The product obtained in step (4) is cleaned by crystallizing the product from a solvent selected from, for example, dimethylformamide (DMF), ethanol, methanol, ethyl acetate, hexane, heptane and mixtures thereof.

[0256] Clause 12. The process according to clause 11, wherein the solvent is a mixture of ethyl acetate and ethanol.

[0257] Item 13. An intermediate compound of formula (VI)

[0258]

[0259] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl.

[0260] Item 14. The intermediate compound according to Item 13, which is 1-(7-hydroxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

[0261] Item 15. An intermediate compound of formula (VII)

[0262]

[0263] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl.

[0264] Item 16. The intermediate compound according to Item 15, which is tetrabutylammonium 7-acetylspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-olate.

[0265] Item 17. An intermediate compound of formula (IX)

[0266]

[0267] Where R 1 Selected from CHF 2 and CF 3 , and R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl.

[0268] Item 18. The intermediate compound according to Item 17, which is 1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl]ethanone.

[0269] Item 19. A method for preparing a compound of formula (VI)

[0270]

[0271] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl, the method comprising reacting the compound of formula (IV) with an aliphatic or aromatic thiol.

[0272] Clause 20. The method according to Clause 19, wherein the thiol is 1-dodecane-thiol.

[0273] Clause 21. The method according to clause 19, wherein the thiol is 5-tert-butyl-2-methyl-benzenethiol

[0274] Item 22. A method for preparing a compound of formula (VII)

[0275]

[0276] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl, the process comprising steps (1), (2a) and (2b) as defined in clause 1.

[0277] Item 23. A method for preparing a compound of formula (VII)

[0278]

[0279] Where R 21 Selected from hydrogen and C(O)R 22 And R 22 Selected from hydrogen and C 1-6 -alkyl, the process comprising steps (2a) and (2b) as defined in clause 1.

[0280] Item 24. A method for preparing a compound of formula (VII)

[0281]

[0282] Where R 21 Selected from hydrogen and C(O)R22 And R 22 Selected from hydrogen and C 1-6 -alkyl, the process comprising step (2b) as defined in clause 1.

[0283] Item 25. A method for preparing a compound of formula (IX)

[0284]

[0285] Where R 1 Selected from CHF 2 and CF 3 , and R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl, the process comprising steps (2b) and (3) as defined in clause 1.

[0286] Item 26. A method for preparing a compound of formula (IX)

[0287]

[0288] Where R 1 Selected from CHF 2 and CF 3 , and R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl, the method comprising step (3) as defined in clause 1.

[0289] Item 27. A method for preparing a compound of formula (IX)

[0290]

[0291] Where R 1 Selected from CHF 2 and CF 3 , and R 21 Selected from hydrogen and C(O)R 22 , and R 22 Selected from hydrogen and C 1-6 -alkyl, the method comprising reacting the compound of formula (VI) with a difluorocarbene source in the presence of a base in a polar solvent.

[0292] Clause 28. The method according to Clause 27, wherein the difluorocarbene source is sodium chlorodifluoroacetate.

[0293] Clause 29. The method according to Clause 27, wherein the difluorocarbene source is diethyl bromodifluoromethylphosphonate.

[0294] Clause 30. The process according to Clause 28, wherein the polar solvent is a mixture of water and DMF.

[0295] Clause 31. The process according to Clause 29, wherein the polar solvent is a mixture of water and acetonitrile.

[0296] Clause 32. The method according to clause 30, wherein the base is K 2 CO 3 .

[0297] Clause 33. The method according to Clause 31, wherein the base is NaOH.

[0298] Item 34. A method for preparing a compound of formula (I)

[0299]

[0300] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, and the compound is obtained by the method described in Item 1.

[0301] Clause 35. A method for preparing a compound of formula (I)

[0302]

[0303] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the process comprising each of steps (2a), (2b), (3) and (4) as defined in clause 1, and subsequently carrying out oxidation of the resulting compound.

[0304] Clause 36. A method for preparing a compound of formula (I)

[0305]

[0306] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the process comprising each of steps (2b), (3) and (4) as defined in clause 1, and subsequently carrying out oxidation of the resulting compound.

[0307] Clause 37. A method for preparing a compound of formula (I)

[0308]

[0309] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the process comprising each of steps (3) and (4) as defined in clause 1, and subsequently carrying out oxidation of the resulting compound.

[0310] Clause 38. A method for preparing a compound of formula (I)

[0311]

[0312] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the method comprises each of the following steps: (2a), (2b+3) and (4), and then oxidation of the resulting compound is performed.

[0313] Item 39. A compound of formula (I)

[0314]

[0315] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, and the compound is obtained by the method described in Item 1.

[0316] Item 40. A compound of formula (I)

[0317]

[0318] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the compound being prepared by carrying out steps (2a), (2b), (3) and (4) as defined in clause 1, and then oxidizing the resulting compound.

[0319] Item 41. A compound of formula (I)

[0320]

[0321] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the compound is prepared by carrying out steps (2b), (3) and (4) as defined in clause 1, and then oxidizing the resulting compound.

[0322] Item 42. A compound of formula (I)

[0323]

[0324] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, the compound is prepared by carrying out steps (3) and (4) as defined in clause 1, and then oxidizing the resulting compound.

[0325] Item 43. A compound of formula (I)

[0326]

[0327] Where R 1 Selected from CHF 2 and CF 3 , and Q is selected from chlorine, bromine and fluorine, and the compound is prepared by carrying out steps (2a), (2b+3) and (4), and then oxidizing the resulting compound.

Claims

1. A method for preparing a compound of formula (I) Where R 1 is CHF 2 , Q is chlorine, The method comprises each of steps (4) and (5), in: Step (4) comprises: making a compound of formula (IX) reacting with a pyridine compound of formula (X), Where Q and R 1 As defined above, Q X is selected from chlorine, bromine, fluorine and iodine, and R 21 is C(O)CH 3 , to form a compound of formula (XI); Where R 1 and Q is as defined above; wherein the compound of formula (XI) is crystallized from a solvent selected from dimethylformamide (DMF), ethanol, methanol, ethyl acetate, hexane, heptane and mixtures thereof; and Step (5) comprises: oxidizing the obtained compound of formula (XI) to obtain the compound of formula (I).

2. The method according to claim 1, wherein the reaction in step (4) is carried out in a polar solvent in the presence of a base, the polar solvent is selected from DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), MeCN (acetonitrile), THF (tetrahydrofuran), or a mixture thereof, and the base is selected from tert-BuOK (potassium tert-butoxide), tert-BuOLi (lithium tert-butoxide), tert-BuONa (sodium tert-butoxide), sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , Et 3 N(triethylamine) and DIPEA(N,N-diisopropylethylamine).

3. The process according to claim 2, wherein the solvent is DMF and the base is tert-BuOK.

4. The method according to claim 1, wherein the reaction in step (4) is carried out at a temperature of 0°C-40°C.

5. The process according to claim 1, wherein in step (4), the compound of formula (XI) is crystallized from a mixture of ethyl acetate and ethanol.

6. The method according to claim 1, wherein in the reaction of step (5), the oxidizing agent is selected from PAA (peracetic acid) in AcOH (acetic acid), H in formic acid, 2 O 2 aq. and H in acetic acid 2 O 2 aq.

7. The process of claim 6, wherein the oxidizing agent is PAA in AcOH.

8. The method according to any one of claims 1 to 7, further comprising step (2b+3), in: Step (2b+3) comprises obtaining the compound of formula (IX) by the following method: The compound of formula (IX) is obtained from the compound of formula (VI) using a difluorocarbene source in a polar solvent in the presence of a base, Without forming the intermediate salt of formula (VII) Where R 1 is CHF 2 , and R 21 is C(O)CH 3 .

9. The method according to claim 8, wherein the difluorocarbene source is selected from sodium chlorodifluoroacetate, diethyl bromodifluoromethylphosphonate, chlorodifluoromethylphenyl sulfone and 2-chloro-2,2-difluoroacetophenone.

10. The process of claim 9, wherein the difluorocarbene source is sodium chlorodifluoroacetate.

11. The method according to claim 8, wherein the reaction of step (2b+3) is carried out in a solvent selected from NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol, methanol, water and mixtures thereof.

12. The method according to claim 8, wherein the solvent is a mixture of water and DMF.

13. The method according to claim 8, wherein the base is selected from K 2 CO 3 、Na 2 CO 3 , KHCO 3 、NaHCO 3 , CsCO 3 , TEA (triethylamine), tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide, DIPEA (N,N-diisopropylethylamine), KOH, NaOH and LiOH.

14. The method of claim 13, wherein the base is K 2 CO 3 .

15. The method according to claim 8, wherein the reaction of step (2b+3) is carried out at a temperature of 6°C-115°C.

16. The method according to claim 1, wherein Q x It's chlorine.

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