RU2814175C2 - Methods of preparing 1,3-benzodioxol heterocyclic compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a method of producing a compound of formula (I), where R₁ represents CHF₂ and Q represents chlorine, comprising the following steps: (1) introduction into the reaction of a compound of formula (II) wherein R₂ is selected from hydrogen, C_1-6 alkyl and arylalkyl, and R₂₁ is COCH₃; with a compound of formula (III) in the presence of an acid catalyst in the form of clay or zeolite, to form a compound of formula (IV); (2a) introduction into the reaction of a compound of formula (IV) with an aliphatic or aromatic thiol in the presence of a metal hydroxide in a suitable solvent to obtain a compound of formula (VI); (3') introduction into the reaction of the compound of formula (VI) by adding a solution of the compound of formula (VI) and sodium chlorodifluoroacetate in DMF to a preheated mixture of DMF, water and potassium carbonate over an extended period of time to obtain the compound of formula (IX); (4) introduction into the reaction of a compound of formula (IX) with a pyridine compound of formula (X), wherein Q_X is selected from chlorine, bromine, fluorine and iodine, to form a compound of formula (XI); and (5) oxidizing the resulting compound of formula (XI) to obtain a compound of formula (I).

EFFECT: development of a new method of obtaining a compound of formula (I) with high yield and purity, which finds its use in medicine as PDE4 inhibitors.

16 cl, 1 dwg, 10 ex

Description

Field of technology

The present invention relates to new methods for the preparation of 1,3-benzodioxole heterocyclic compounds. These compounds are useful as PDE4 inhibitors.

BACKGROUND OF THE INVENTION WO 2011/160632 discloses benzodioxole and benzodioxepene heterocyclic compounds useful as PDE4 inhibitors, as well as suitable methods for their preparation.

WO 2008/104175 discloses benzodioxole and benzodioxepene heterocyclic compounds useful as PDE4 inhibitors, as well as suitable methods for their preparation.

WO 2008/077404 discloses substituted acetophenones useful as PDE4 inhibitors, as well as suitable methods for their preparation.

WO 2015/197534 discloses methods for the preparation of 1,3-benzodioxole heterocyclic compounds.

WO 2017/103058 discloses additional methods for the preparation of 1,3-benzodioxole heterocyclic compounds.

In Zafrani et al. Tetrahedron 65 , 2009, pp 5278-5283 describes a method for the difluoromethylation of phenols and thiophenols.

In Sperry et al Org. Process Res. Dev. 15, 2011, pp 721-725 also describes the difluoromethylation of phenols.

Frey et al. In Tetrahedron 2003, 59 , pp. 6363-6373 also describes the demethylation and difluoromethylation of phenols.

In Zhang et al. J. Org. Chem. 2006, 71 , 9845-9848 also describes the difluoromethylation of phenols.

In Zheng et al. Chem. Commun. 2007, 5149-5151 also describes the difluoromethylation of phenols.

When developing new drug candidates, it is highly desirable to have access to alternative routes for preparing drug candidates, as some efficient small-scale syntheses may be difficult to scale up to industrial-scale quantities. In addition, small-scale syntheses may involve reagents and solvents that cannot be used at the industrial scale level.

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, WO 2015/197534 and WO 2017/103058, since such alternative methods provide advantages with respect to one or more features, such such as number of reaction steps, purity, yield, ease of purification, process economy, availability of starting materials and reagents, safety, predictability, etc.

Compared to step (2a) in WO 2017/103058, step (2a) of the present invention used cheaper reagents and more environmentally friendly solvents, and the solution was refluxed and stirred until ≥98% conversion.

In step (3), when carrying out the reaction as described in Example 3 in WO 2017/103058 (Example 5 of the present invention), carbon dioxide is released in amounts equimolar to the amount of sodium chlorodifluoroacetate added to the reaction. With increased gas production and possible increased pressure in the equipment being used, the procedure may become a potential safety issue. Therefore, an alternative procedure was developed to control the release of carbon dioxide over time.

The identification of a by-product at this stage (3) led to new reaction conditions, since the by-product is not removed during normal workup and isolation of the compound. Using TFA (trifluoroacetic acid) or MSA (methanesulfonic acid) in a polar solvent at elevated temperature and then removing them by treatment with an aqueous base such as NaOH or KOH during crystallization results in a purity of this compound >94%.

The identification of impurities at this stage (4) led to new reaction conditions. The use of DMF/tBuOH solvent and tert-BuOK base suppressed the formation of impurities to a minimum, which made it possible to obtain a practical yield of 70-73%. This is superior to the 57% yield obtained by the method described in WO 2017/103058.

Improved yield, elimination of potential safety concerns, use of different reaction conditions and use of cheaper reagents optimize the process economics of the process of the present invention compared to the process described in WO 2017/103058, WO 2011/160632 and WO 2015/197534 are quite unexpected.

The essence of the invention

The present inventors have found that the alternative steps and use of alternative reagents disclosed herein provide advantages over prior art methods through improved overall chemical and volumetric yield, avoidance of potential safety issues, and reduced production costs.

Therefore, the present invention provides a method for the preparation of 1,3-benzodioxole compounds, for example the compounds of formula (I).

Also included within the scope of the invention are the intermediates used in the above-mentioned process for preparing the compounds of formula (I).

Detailed Description of the Invention

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

(I),

where R ₁ is selected from CHF ₂ and CF ₃ , and Q is selected from chlorine, bromine and fluorine.

In the compound of formula (I), R ₁ is typically CHF ₂ . Q is usually selected from chlorine, bromine and fluorine, preferably chlorine, where Q is preferably the same. In one embodiment of the invention, both Q are chlorine.

Definitions

The term "C ₁ - ₆ -alkyl" means a saturated, straight or branched hydrocarbon chain having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl , tertiary pentyl, hexyl and isohexyl. In some embodiments, "C ₁ - ₆ -alkyl" is a C ₁ - ₄ -alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl. Accordingly, "C ₁ - ₃ -alkyl" includes methyl, ethyl, propyl, isopropyl.

The term "halogen" is intended to refer to one of fluorine, chlorine, bromine, and iodine. In one embodiment of the invention, the term “halogen” means fluorine or chlorine. In another embodiment of the invention, the term “halogen” means chlorine.

The term "aryl" is intended to denote a carbocyclic aromatic ring system derived from an aromatic hydrocarbon by the removal of a hydrogen atom. Aryl further includes bi-, tri- and polycyclic ring systems. Examples of preferred aryl groups include phenyl, naphthyl, indenyl, indanyl, fluorenyl and biphenyl. Preferred "aryl" is phenyl, naphthyl or indanyl, particularly phenyl, unless otherwise specified.

The term "arylalkyl" is intended to mean an aryl radical, as defined above, covalently attached to an alkyl group, such as benzyl.

Methods of obtaining

It is obvious that this method provides advantages over known methods based on cheap starting materials, simplicity of the production method and increased yield in reactions.

Stage (1)

A method for preparing a compound of formula (I) involves forming a compound of formula (IV), which is obtained by

introducing into the reaction a compound of formula (II)

(II),

where R ₂ is selected from hydrogen, C ₁ - ₆ -alkyl and arylalkyl, R ₂₁ is selected from hydrogen and C(O)R ₂₂ , and R ₂₂ is selected from hydrogen and C ₁ - ₆ -alkyl; with a compound of formula (III)

(III),

in the presence of an acid catalyst to form a compound of formula (IV)

(IV),

where R ₂ and R ₂₁ correspond to the definitions above.

The acid catalyst is usually in the form of clay or zeolite. The zeolite is usually selected from CBV 720, CBV 760, CBV 780, HSZ-390HUA. The clay typically selected is Montmorillonite K10, Taiko Classic, Taiko Omega, Actol-10, Actol-20, Actol-20X, Tonsil Supreme 116 FF or Tonsil Supreme 115 FF. In one embodiment of the invention, the clay is selected from Montmorillonite K10, Tonsil Supreme 116 FF or Tonsil Supreme 115 FF. In another embodiment of the invention, the clay is montmorillonite K10.

The ratio between the zeolite or clay and the compound of formula (II) can influence the conversion and filtration time. Therefore, it is generally preferable to have an amount of zeolite or clay of 10% w/w. up to 500% w/w in relation to the compound of formula (II). In particular, the amount of mineral substance should be between 25% w/w. to 75% w/w, preferably in the range of 45% w/w. up to 55% w/w

This reaction is usually carried out in toluene, benzene, 2-methyl-THF (2-methyl-tetrahydrofuran), EtOAc (ethyl acetate), xylenes, heptane, octane, chlorobenzene and dichlorobenzene. In one embodiment of the invention, the solvent is toluene or xylenes. In another embodiment of the invention, the solvent is toluene.

The reaction is usually carried out at a temperature above 80°C in order to promote the reaction. Therefore, it is generally preferred that the temperature be in the range of 80-200°C, for example in the range of 100-160°C, especially 105-115°C or 135-145°C. In one embodiment of the invention, the reaction is carried out by refluxing the reaction mixture. The reactions are usually allowed to proceed for 4-96 hours, such as 24-84 hours, especially 48-84 hours.

The resulting compound of formula (IV) can be isolated by conventional methods known to those skilled in the art, for example by aqueous treatment followed by extraction and finally precipitation and filtration.

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

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

In one embodiment of the invention, the compound of formula (IV) is one wherein R ₂ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, tertiary butyl or benzyl, and R ₂₁ is selected from hydrogen, COCH ₃ or COOH . In another embodiment of the invention, the compound of formula (IV) is wherein R ₂ is methyl and R ₂₁ is COCH ₃ .

Stage (2a)

Compound of formula (IV)

(IV),

where R ₂ and R ₂₁ are as defined above, convert to the compound of formula (VI)

(VI),

where R ₂₁ corresponds to the definitions above, by deprotecting the phenolic moiety.

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

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

The aliphatic thiol may be, for example, but not limited to, 1-dodecanethiol, 1-tetradecanethiol, 1-hexadecanethiol or tert-dodecanethiol. In one embodiment of the invention, the aliphatic thiol is 1-dodecanethiol.

Deprotection of the phenolic group in step (2a) can be carried out using various solvents, for example selected from DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), methanol, ethanol, 1-propanol, 2-propanol and mixtures thereof. In one embodiment of the invention, the solvent is DMF. In another embodiment of the invention, the solvent is a mixture of DMF and methanol. In another embodiment of the invention, the solvent is ethanol. In yet another embodiment of the invention, the solvent is 1-propanol.

Deprotection of the phenolic group is carried out in the presence of a base, for example selected from K ₂ CO ₃ , Na ₂ CO ₃ , KHCO ₃ , NaHCO ₃ , CsCO ₃ , TEA (triethylamine), metal hydroxide, for example selected from NaOH, KOH and LiOH ; and potassium tert-butoxide, tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide and DIPEA (N,N-diisopropylethylamine). In one embodiment of the invention, the base is K ₂ CO ₃ . In another embodiment of the invention, the base is sodium methoxide. In another embodiment, the base is a metal hydroxide; in another embodiment, the base is NaOH.

The reaction is usually carried out at a temperature in the range of 50-120 °C, for example in the range of 70-100 °C. The reaction is usually allowed to proceed for 2-36 hours, for example 3-24 hours. Reactions are typically allowed to proceed until conversion is ≥98%.

In a specific embodiment of the present invention, a mixture of a compound of formula (IV), a metal hydroxide, 1-dodecanethiol and an alcohol is heated to reflux and stirred. In another specific embodiment of the present invention, the metal hydroxide is NaOH and the alcohol is EtOH. In another specific embodiment of the present invention, the metal hydroxide is NaOH and the alcohol is 1-propanol.

The resulting compound of formula (VI) can be recovered by conventional methods known to those skilled in the art, for example aqueous treatment followed by extraction and finally precipitation and filtration.

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

Stage (2b)

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

N(Bu ⁾ ₄₊

(VII),

where R ₂₁ corresponds to the definitions above.

The mixture is usually heated to a temperature in the range of 20-80°C, for example 55-65°C, until everything is dissolved.

The resulting solution is usually washed with a solution of sodium chloride in water with stirring at a temperature in the range of 20-80 °C, for example 55-65 °C, for > 20 minutes. Subsequent addition of a mixture of water and sodium chloride followed by cooling the mixture from ≥35°C to 0-20°C, e.g. 5°C, over a period of 1-24 hours, e.g. 1-4 hours, causes the TBA (tetrabutylammonium) salt to precipitate ). The TBA salt is isolated, for example by filtration and drying.

Stage (3)

Compound of formula (IX)

(IX),

where R ₁ and R ₂₁ are as defined above, can be prepared by alkylation of the resulting compound of formula (VII)

N(Bu ⁾ ₄₊

(VII),

where R ₂₁ corresponds to the definitions above, by reacting with a hydrochlorofluorocarbon reagent,

R ₁ -Cl (VIII),

where R ₁ corresponds to the definitions above.

Alkylation can be carried out using one of various possible reagents, such as various hydrochlorofluorocarbon gases. In one embodiment of the invention, the alkylation reaction is carried out using chlorodifluoromethane in an aprotic polar solvent, for example selected from 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 one preferred embodiment of the invention, the aprotic solvent is selected from DMF and NMP. In a specific embodiment of the invention, the reaction is carried out using chlorodifluoromethane in DMF.

The reaction is usually carried out at a temperature in the range of 40-120 °C, for example in the range of 50-70 °C. The reaction is typically allowed to proceed until ≤4% phenol remains in the reaction mixture.

The resulting compound of formula (IX) can be isolated by conventional methods known to those skilled in the art, for example, aqueous treatment followed by precipitation and subsequent filtration.

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

Alternate stage (2b+3)

Alternatively, a compound of formula (IX),

(IX),

where R ₁ and R ₂₁ are as defined above, can be obtained from a compound of formula (VI),

(VI),

where R ₂₁ is as defined above, without forming the intermediate salt of formula (VII), using a difluoromethylate reagent in a polar solvent in the presence of a base.

The difluoromethylating reagent is selected from, for example, but not limited to, sodium chlorodifluoroacetate, sodium bromodifluoroacetate, diethyl bromodifluoromethylphosphonate, chlorodifluoromethylphenylsulfone, and 2-chloro-2,2-difluoroacetophenone. One skilled in the art may readily select another suitable analogue of said difluoromethylating reagent. In one embodiment of the invention, the difluoromethylating reagent is sodium chlorodifluoroacetate. In another embodiment of the invention, the difluoromethylating reagent is diethyl bromodifluoromethylphosphonate.

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

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

The reaction is usually carried out at a temperature in the range of 0-120 °C, for example 6-115 °C. In one embodiment of the invention, the reaction is carried out at 6-20 °C using diethyl bromodifluoromethylphosphonate as the difluoromethylating reagent. In another embodiment of the invention, the reaction is carried out at an ambient temperature of 111 °C using sodium chlorodifluoroacetate as the difluoromethylating reagent.

When the above reaction is performed as described in the present Example 5, carbon dioxide is released in equimolar amounts to the amount of sodium chlorodifluoroacetate added to the reaction. With increased gas production and possible increased pressure in the equipment used, this method may become a potential safety issue.

Therefore, an alternative method was developed to be able to control the release of carbon dioxide long after the start of the reaction.

Alternative stage (2b+3’)

Alternatively, a compound of formula (IX),

(IX),

where R ₁ and R ₂₁ are as defined above, can be obtained from a compound of formula (VI),

(VI),

wherein R ₂₁ is as defined above by adding a solution of the compound of formula (VI) and sodium chlorodifluoroacetate in DMF to a preheated mixture of DMF, water and potassium carbonate over an extended period of time; as described in this Example 8.

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

The resulting compound of formula (IX), wherein R ₁ and R ₂₁ are as defined above, can be prepared by conventional methods known to those skilled in the art, for example aqueous treatment followed by precipitation and subsequent filtration.

During the reaction to form the compound of formula (IX), the by-product of formula (IXb) is formed in significant quantities.

(IXb)

The by-product is hydrolyzed to the corresponding phenol, which compound is then removed from the product by treatment with TFA or MSA in a polar solvent such as DMF at elevated temperature and subsequent removal by treatment with an aqueous base such as NaOH or KOH to crystallize the compound of formula (IX).

Stage (4)

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

(X),

where Q is as defined above and Q _X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI)

(XI),

where R ₁ and Q correspond to the definitions above.

The pyridine cross-coupling in step (4) is usually carried out in a polar solvent, for example selected from DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO ( dimethyl sulfoxide), MeCN (acetonitrile), THF (tetrahydrofuran), tBuOH (tert-butyl alcohol), and mixtures thereof, in the presence of a base, for example selected from t-BuOK (potassium t-butoxide), t-BuOLi (lithium t-butoxide ), tert-BuONa (sodium tert-butoxide), sodium or potassium methoxide, sodium 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 of the invention, the solvent is DMF and the base is tert-BuOK.

Typically two or more equivalents of base are used relative to the compound of formula (IX), for example where the molar ratio (base)/(formula IX) is from 5:1 to 2:1, for example from 3:1 to 2:1, especially from 2 .4:1 to 2.7:1.

The reaction in step (4) is usually carried out at a temperature of 0-40 °C, for example 5-25 °C.

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

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

During the reaction, an impurity of formula (XII) is formed in a significant amount.

(XII)

The product is purified from this impurity by crystallizing the product from a solvent selected, for example, from 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.

During a detailed study of the reaction, an impurity of formula (XIIb) was isolated in a significant amount.

(XIIb)

The identification of impurity (XIIb) led to new reaction conditions as described below.

In step (4), the solvent used was a mixture of DMF/tBuOH 30/70 v/v. and the base was tert-BuOK. Under these conditions, the formation of impurity (XIIb) was suppressed to a minimum, while the reaction time was usually 3-24 hours. The temperature range was 20-30 °C. The new method achieved a practical yield of 70-73%, exceeding the 57% yield obtained by the method described in WO 2017/103058.

Stage (5)

Oxidation of the resulting compound of formula (XI) is carried out to form a compound of formula (I)

(I),

where R ₁ and Q are as defined above by reacting said compound of formula (XI) with an oxidizing reagent.

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

The reaction is usually carried out at a temperature in the range of 30-70 °C, for example 40-60 °C, especially 48-55 °C, and stirred for 3-48 hours, for example 16-24 hours.

Purification of a compound of formula (I)

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

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

In another embodiment of the invention, the first crystallization from water is passed and the compound of formula (I) is crystallized (Form E) directly from the concentrated reaction mixture.

Crystalline form E 2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxo-spiro[1,3- benzodioxol-2,4'-thian]-4-yl]ethanone has a powder X-ray diffraction pattern as shown in FIG. 1.

EXPERIMENTAL PART

Methods and reagents

All chemicals and reagents used were available from commercial sources.

¹ H nuclear magnetic resonance (NMR) spectra were recorded at the indicated magnetic field, and chemical shift values (δ, ppm) are given in the indicated solvent relative to tetramethylsilane (δ=0.00).

HPLC: Column: Aeris Peptide 3.6 µm XB-C18, 100 x 4.6 mm, eluent gradient 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 gradients were used:

Stage 2a, 2b, 3 and 5 gradients

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

Stage 4 gradient

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

EXAMPLE 1

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

1-(2,3-dihydroxy-4-methoxy-phenyl)ethanone (60.0 kg, 329 mol), tetrahydrothiopyran-4-one (37.2 kg, 320 mol), montmorillonite K 10 (30, 0 kg) and toluene (720.0 l). The mixture was stirred at reflux using a jacket temperature of 140-150°C for 84 hours. The mixture was cooled to 86-90°C and filtered through a layer of filter media. The reactor was washed with hot (86-90 °C) toluene (120 L), and the hot toluene was then used to wash the filter media bed. Rinsing the reactor and subsequent washing of the filter media layer was repeated twice with hot toluene (120 L) and once with hot (70 °C) ethyl acetate (60 L). All toluene and ethyl acetate filtrates were combined and cooled to 2-6 °C over approximately 6 hours. The mixture was stirred at 2-6°C for about half an hour.

The unconverted starting material was collected by filtration and dried in vacuum at 43-47 °C. Yield 32.0 kg.

The filtrate, after isolating the unconverted starting material, was cooled to 10-16°C with stirring, and a mixture of sodium hydroxide (26.40 kg) and water (162.0 L) was added at 10-16°C. The reaction mixture was then stirred for approximately half an hour at 10-16 °C, then stirring was stopped and the phases were allowed to separate. The lower aqueous phase was discarded and then a mixture of sodium hydroxide (26.40 kg) and water (162 L) was added with stirring at 10-16 °C. The mixture was stirred for approximately one hour, then stirring was stopped and the phases were allowed to separate. The lower aqueous phase was discarded and the organic phase was transferred to a container. The reactor was rinsed with toluene and then the organic phase was transferred back to the reactor through a cartridge filter.

The solution was concentrated as much as possible in vacuo using a temperature of ≤70 °C. Ethanol (90.0 L) was added and the mixture was heated to 47-53°C and stirred at this temperature for 10-15 minutes. The mixture was then concentrated as much as possible in vacuum at a temperature of ≤55 °C. Ethanol (120.0 L) was added to the reactor, the mixture was heated to reflux with stirring, and water (90.0 L) was added while heating, maintaining the mixture at reflux. The mixture was cooled to 2-8°C over about 10 hours and stirred at this temperature for about half an hour.

The product was isolated by filtration, washed with a mixture of ethanol (30.0 L) and water (22.8 L) and dried in vacuum at 43-47 °C. Yield 21.80 kg (24%, but 51% adjusted for isolated starting material). ¹ H NMR (600 MHz, DMSO-d6) δ 7.30 (d, J=9.0 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 3.88 (s, 3H), 2.91-2.84 (m, 2H), 2.84-2.77 (m, 2H), 2.49 (s, 3H), 2.30-2.22 (m, 2H) , 2.22-2.12 (m, 2H).

If necessary, step (1) was repeated to obtain the required amount of 1-(7-methoxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone.

Other catalysts have been used in this process; The table below summarizes the reaction yield and the amount of starting material recovered when the above method was carried out with a series of clays and zeolites.

Catalyst Provider Input source material Exit
% Dedicated IM
% HSZ-390HUA Tosoh Corp. 20 g 15 63 CBV 720 Zeolyst Int. 20 g 17 56 CBV 760 Zeolyst Int. 150 g 18 57 CBV 780 Zeolyst Int. 50 g 16 48 Taiko Classic Taiko Clay Group 10 g 9 61 Taiko Omega Taiko Clay Group 10 g 18 63 Actol-10 Ashapura Perfoclay ltd 20 20 55 Actol-20 Ashapura Perfoclay ltd 20 g 20 56 Actol-20X Ashapura Perfoclay ltd 150 g 20 57 Tonsil Supreme 116 FF Clariant Produkte GmbH 150 g 41 33 Tonsil Supreme 115 FF Clariant Produkte GmbH 100 g 31 41

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

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 with stirring to 85-92°C until ≥98% conversion was achieved by HPLC. The mixture was then cooled to 25°C, water (104 L) and sodium hydroxide (28% in water, 21.4 kg) were added and stirred for ≥10 minutes. If the pH of the mixture was below 12, more sodium hydroxide (28% in water) was added. Toluene (65 L) was then added and stirring was continued for ≥15 minutes. Stirring was stopped and the phases were allowed to separate. The phases were separated and the organic phase was discarded. The two lower aqueous phases were mixed with toluene (65 L) and the mixture was stirred for ≥15 minutes. Stirring was stopped to allow the phases to separate. The phases were separated and the organic phase was discarded. The two aqueous phases were returned to the reactor and hydrochloric acid (18% in water, 67.6 kg) was slowly added while stirring to control gas evolution. The resulting mixture was stirred for ≥10 minutes. More hydrochloric acid (18% in water, 10.2 kg) was added to achieve pH ≤6.

The temperature of the mixture was brought to 35-45 °C and maintained at this level during the following extractions. Ethyl acetate (156 L) was added and the mixture was stirred for ≥30 minutes. Stirring was stopped and the phases were allowed to separate. 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 separate. The aqueous phases were 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 allowed to separate. The aqueous phase was discarded.

The organic phases were concentrated to the maximum possible extent at a jacket temperature of 50–60 °C and vacuum was 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 in vacuum at 40-50 °C. Yield 19.75 kg (80%). ¹ H NMR (600 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.18 (d, J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 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).

Step (2b): 7 - acetylspiro[1,3 - benzodioxole - 2,4' - tetrahydrothiopyran] - 4 - tetrabutylammonium olate

1-(7-Hydroxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (19.75 kg, 74.16 mol) was charged to a suitable reactor, followed by the addition of tetrabutylammonium hydroxide (40% solution in water, 53.0 kg, 81.7 mol). The jacket temperature was set to 60°C and the mixture was stirred until everything was dissolved. A saturated solution of sodium chloride in water (59.2 kg) was added and stirring was continued at a jacket temperature of 60°C for ≥20 minutes. Stirring was stopped to allow the phases to separate. The lower aqueous phase was discarded. The mixture in the reactor was again stirred with a jacket temperature of 60 °C. A saturated solution of sodium chloride in water (29.6 kg) was added, followed by water (25 L) again. The mixture was stirred for ≥15 minutes at a mixture temperature of ≥35°C. The mixture was cooled to 0-5°C at a rate of approximately 20°C/h, the mixture was seeded at 40°C and again at 35°C. The mixture was stirred at 0-5°C for ≥2 hours, and then the title compound was isolated by filtration and dried in vacuum at 40-50°C. Yield 32.9 kg (87%). ¹ H NMR (600 MHz, DMSO-d6) δ 6.94 (d, J=9.1 Hz, 1H), 5.74 (d, J=9.1 Hz, 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 (g, J=7.4 Hz, 8H), 0.93 (t, J=7.4 Hz, 12H).

Step (3): 1 - [7 - (difluoromethoxy)spiro[1,3 - benzodioxole - 2,4' - tetrahydrothiopyran] - 4 - yl]ethanone

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 completely dissolved. Chlorodifluoromethane (39.5 kg, 457 mol) was added to the solution through a submerged tube in the reactor. The reaction mixture was heated to 50-55°C and stirred until ≤4% of the starting material remained, as measured by HPLC. The reaction mixture was cooled to 20-25°C and transferred into a container through a filter. The reactor and filter solid were washed with dimethylformamide (10 L), which was also added to the container.

Water (198 L) and sodium hydroxide (28% in water, 11.0 kg) were loaded into the reactor and heated to 45-55 °C. The reaction mixture in the container was slowly added to the reactor with stirring, maintaining the temperature at 45-55 °C. The mixture was then cooled to 5-10 °C and stirred at this temperature for ≥2 hours. The product was isolated by filtration, washed with water (82 l) and dried in vacuum at 45-55 °C with nitrogen removal. Yield 19.08 kg (94%). ¹ H NMR (600 MHz, DMSO-d6) δ 7.34 (t, J=73.1 Hz, 1H), 7.32 (d, J=9.1 Hz, 1H), 6.86 (d, J=9.1 Hz, 1H), 2.92-2.80 (m, 4H), 2.54 (s, 3H), 2.34-2.27 (m, 2H), 2.27-2 .19 (m, 2H).

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

Dimethylformamide (96 L) was charged into a suitable reactor, followed by the addition of potassium tert -butoxide (17.60 kg, 156.8 mol). Transfer of potassium t -butoxide was achieved by rinsing with dimethylformamide (3 L) and the mixture was stirred until the potassium t -butoxide dissolved. The solution was transferred from the reactor to a container, the reactor was rinsed with dimethylformamide (6 L), which was also transferred to the container.

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 10-15 °C, and then a solution of potassium tert -butoxide in dimethylformamide was slowly added, maintaining the temperature of the reaction mixture at 5-25 °C. Transfer of the potassium tert-butoxide solution was ensured by rinsing with dimethylformamide (6 L). The mixture was heated to 20-25°C and stirred until the conversion reached ≥98% by HPLC.

Water (96 L) was slowly added to the reaction mixture while cooling, maintaining the temperature within 20-30 °C. This was followed by the addition of saturated sodium chloride in water (115.2 kg) and ethyl acetate (134 L). The mixture was stirred for 20-60 minutes and then stirring was stopped to allow the phases to separate. The phases were separated and the aqueous phase was returned to the reactor. Ethyl acetate (96 L) was added and the mixture was stirred for 20-60 minutes. Stirring was stopped to allow the phases to separate. The phases were separated. The organic phases were combined in a reactor and stirred with water (48 L) and saturated sodium chloride in water (57.8 kg) for ≥20 minutes. Mixing was stopped to allow the phases to separate. The lower aqueous phase was discarded and water (48 L) and saturated sodium chloride (57.6 kg) were added. The mixture was stirred for 20-60 minutes, and then stirring was stopped to allow the phases to separate. The lower aqueous phase was discarded and water (84 L) and sodium hydroxide (28% in water, 14.0 kg) were added. The mixture was stirred for 20-60 minutes and then stirring was stopped to allow the phases to separate. The lower aqueous phase was discarded.

The organic phase in the reactor was concentrated using vacuum and heating at a jacket temperature of 50-65 °C to a residual volume of approximately 40 L. 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 for ≥5 hours and stirred at this temperature for ≥3 hours. The product was isolated by filtration and transfer was achieved by rinsing with ethanol (10 L). The product was washed with cold (≤5°) ethanol (48 l) and dried in vacuum at 45-55 °C. Yield 15.57 kg (56%). ¹ H 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%.

Stage (5): 2 - (3,5 - dichloro - 1 - oxido - pyridine - 1 - y - 4 - yl) - 1 - [7 - (difluoromethoxy) - 1',1' - dioxo - spiro [1, 3 - benzodioxol - 2,4' - tian] - 4 - yl]ethanone

2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-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% in acetic acid, 6.52 kg, 32.6 mol) was added slowly while maintaining 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% in acetic acid, 6.51 kg, 32.5 mol) was slowly added, maintaining 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% 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, maintaining the temperature below 35°C.

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, maintaining the temperature above 55°C. The mixture was stirred for 30-60 minutes at 60-65°C, 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 dried under vacuum for approximately two hours.

The solid was returned to the reactor and heated to reflux with ethanol (390 L). Then the mixture was cooled to 68-72°C and the seeds were added. 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 in vacuum at 45-55 °C with nitrogen removal. Yield 14.6 kg (85%). 1H NMR (600 MHz, chloroform-d) δ 8.23 (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%.

EXAMPLE 2

1 - (7 - hydroxyspiro[1,3 - benzodioxol - 2,4' - tetrahydrothiopyran] - 4 - yl)ethanone

Sodium methoxide in methanol (30%, 64.2 ml, 0.34 mol) was added to a solution of 1-(7-methoxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone (50, 0 g, 0.178 mol) in dimethylformamide (250 ml) at 25-30 °C. 1-Dodecanethiol (64.88 ml, 0.271 mol) was then added at 25-30 °C and the mixture was heated to 95-100 °C for three hours. The reaction mixture was cooled to 25-30°C and sodium hydroxide (28% in water, 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 with hydrochloric acid (6 M) to approximately pH 6 and extracted with ethyl acetate (250 ml) four times. The ethyl acetate extracts were combined, washed with sodium chloride solution (250 ml) four times and concentrated to approximately 50 ml using a rotary evaporator. Heptane (300 ml) was added and the mixture was stirred for one hour at ambient temperature. The product was isolated by filtration, washed with heptane (100 ml) and dried. Yield 44.3 g (93%). The NMR corresponds to the NMR of the product from step (2a) in Example 1.

EXAMPLE 3

1 - (7 - hydroxyspiro[1,3 - benzodioxol - 2,4' - tetrahydrothiopyran] - 4 - yl)ethanone

Sodium hydroxide (31 .4 g, 0.785 mol) at 25-30 °C. 1-Dodecanethiol (197 ml, 0.87 mol) was then added at 25-30 °C and the mixture was heated to reflux and stirred for twenty-four hours. 300 ml of solvent was then removed from the reaction mixture in vacuo. Water (500 ml) was then added to the remaining suspension. Then the resulting solution was extracted with toluene (500 ml). The organic phase was then discarded and the remaining aqueous phase was acidified with hydrochloric acid (1 M) to approximately pH 3-5. The product was isolated by filtration, washed with water (2x100 ml) and dried in vacuum at 60 °C. Yield 93.0 g (98%). The NMR corresponds to the NMR of the product from step (2a) in Example 1.

EXAMPLE 4

1 - (7 - hydroxyspiro[1,3 - benzodioxol - 2,4' - tetrahydrothiopyran] - 4 - yl)ethanone

Sodium hydroxide (4 .7 g, 117.7 mmol) at 25-30 °C. 1-Dodecanethiol (29.5 mL, 123.1 mmol) was then added at 25-30 °C and the mixture was refluxed and stirred for six hours. The reaction mixture was cooled to 25 °C. Water (75 ml) was then added to the reaction mixture and then extracted twice with toluene (2×75 ml). The organic phases were then discarded and the remaining aqueous phase was acidified with hydrochloric acid (1 M) to approximately pH 3-5. The product was isolated by filtration, washed with water (2x50 ml) and dried in vacuum at 60 °C. Yield 11.3 g (79%). The NMR corresponds to the NMR of the product from step (2a) in Example 1.

EXAMPLE 5

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

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) were stirred in a 5 liter reaction flask and slowly heated to 106-111 °C, gas evolution was observed at approximately 78 °C . The reaction mixture was stirred at 106-111°C until gas evolution ceased, approximately two hours. The mixture was cooled in an ice bath and water (1.00 L) was added slowly at 30–32 °C. The resulting suspension was further cooled to 6 °C with stirring. The crude product was isolated by filtration and washed with water.

The wet crude product was stirred with ethyl acetate (1.66 L) and sodium hydroxide (1 M, 560 ml) for approximately 20 minutes and then the phases were separated in a separatory funnel. The lower aqueous phase was discarded and the organic phase was washed twice with water (two times 560 ml). The organic phase was concentrated using a rotary evaporator (vacuum at 60°C in a water bath) to approximately 450 ml. Ethyl acetate (1.56 L) was added and the mixture was again concentrated using a rotary evaporator as described above to approximately 450 ml. Ethyl acetate (1.44 L) was added and the opaque solution was filtered, transferred and washed with fresh ethyl acetate (100 ml). The combined filtrates were filtered through a pad of activated carbon (6.0 g), transferred and washed with ethyl acetate (200 ml). The combined filtrates were concentrated by rotary evaporation as described above to a volume of approximately 450 ml. The resulting hot solution (approximately 60 °C) was stirred at ambient temperature while heptane (2.00 L) was added slowly over approximately half an hour. The suspension was stirred at room temperature for 14 hours.

The mixture was stirred in an ice bath for approximately 2.5 hours, after which the temperature of the mixture was 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 in vacuum at 50 °C with air removed. Yield 201 g (76%). The NMR corresponds to the NMR of the product from step 3 in Example 1.

EXAMPLE 6

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

Sodium hydroxide (6.16 g, 154 mmol) was dissolved in water (40 ml) and the solution was stirred while cooling in an ice 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 was continued with cooling. Diethyl bromodifluoromethylphosphonate (2.67 mL, 15.0 mmol) was added in one portion at 6 °C and stirring was continued with cooling for approximately 20 minutes. The cooling bath was removed and the mixture was stirred for approximately 21 hours at ambient temperature.

The phases were separated using a separatory funnel and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (20 ml) and then sodium chloride solution (20 ml). The organic phase was concentrated to dryness using a rotary evaporator. Ethyl acetate (20 ml) was added to the residue and the mixture was again concentrated to dryness using a rotary evaporator.

The residue was dissolved in ethyl acetate (30 ml) and filtered, transferred and washed 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 yellowish solid. Yield 2.14 g (90%). The NMR corresponds to the NMR of the product from step 3 in Example 1.

EXAMPLE 7

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

Sodium hydroxide (301 g, 7.52 mol) was stirred with water (2.0 L) and the resulting solution was cooled in an ice 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 approximately 40 minutes at a reaction temperature of 15-20 °C. Stirring was continued for approximately two more hours at 15-20 °C. The phases were separated.

Water (920 ml) was slowly added to the organic phase while stirring and the resulting suspension was stirred at ambient temperature for approximately 18 hours. The product was isolated by filtration, washed with a 1:1 mixture of acetonitrile and water (120 ml) and dried in vacuum at 50°C with air removed. Yield 108 g (91%). The NMR corresponds to the NMR of the product from step 3 in Example 1.

EXAMPLE 8

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

A solution of 1-(7-hydroxyspiro[1, 3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (2.0 g, 7.51 mmol) and sodium chlorodifluoroacetate (2.86 g, 18.8 mmol) in DMF (6.2 ml) over a period of 2-4 hours. After addition was complete, the reaction mixture was stirred for an additional 60 minutes. Then the temperature of the reaction mixture was reduced to 70 °C, and an aqueous 0.5 M NaOH solution (10 ml) was added to the reaction mixture.

The resulting reaction suspension was then slowly cooled to 10-20 °C. The product was isolated by filtration, washed with water (40 ml) and dried in vacuum at 60 °C. Yield 1.73 g (73%). The NMR corresponds to the NMR of the product from step (3) in Example 1.

EXAMPLE 9

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

Dimethylformamide (128 ml) and tert -butanol (298 ml) were charged into a suitable reactor followed by the addition of potassium tert-butoxide (81.4 g, 726 mmol). The mixture was stirred until potassium tert -butoxide dissolved.

The second reactor was charged with 1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone (85.0 g, 269 mmol), 3,4,5-trichloropyridine (58.8 g, 322 mmol), dimethylformamide (76.5 ml) and tert -butanol (179 ml). The mixture was stirred at 22-25 °C, slowly adding a solution of potassium tert -butoxide in dimethylformamide and tert-butanol, maintaining the temperature of the reaction mixture <30 °C. The reaction mixture was stirred at 22-25 °C until the conversion reached ≥98% by HPLC.

Water (340 mL) was slowly added to the reaction mixture, maintaining the temperature < 30 °C. The reaction mixture was transferred to a separatory funnel and diluted with ethyl acetate (850 ml). The aqueous lower phase was discarded. The organic phase was washed with aqueous sodium hydroxide (2 M, 500 ml) and the lower aqueous phase was discarded. The organic phase was washed with water (340 ml) and the lower aqueous phase was discarded. The organic phase was transferred to a suitable reactor and concentrated under reduced pressure (100 mbar) at 50 °C (jacket temperature) until the steam temperature reached 39 °C. Ethanol (255 ml) was then added and the suspension was heated to reflux (90 °C) and stirred for one hour. Then the solution was slowly cooled to 5 °C. The product was isolated by filtration and transfer was achieved by rinsing with ethanol (20 ml). The product was washed with cold (≤5°) ethanol (150 ml) and dried in vacuum at 45-55°C. Yield 91.0 g (73.2%). ¹ H 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%.

EXAMPLE 10

Preparation of 1 - (7 - hydroxyspiro[1,3 - benzodioxole - 2,4' - tetrahydrothiopyran] - 4 - yl)ethanone

A suitable reaction vessel was purged with nitrogen. The nitrogen flow was temporarily stopped and 1-(7-methoxyspiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone (1.00 kg, 3.57 mol) was charged into the reaction vessel, followed by the addition of ethanol (2.5 L), sodium hydroxide (314 g, 7.85 mol, 2.2 eq.) and 1-dodecanethiol (1.66 kg, 8.2 mol, 2.3 eq.). The reaction mixture was heated to reflux with stirring, and this temperature was maintained for 22-24 hours.

IPC (ion pair chromatography) was performed in ethanol for HPLC analysis (220 nm). If the starting material was present in less than 2% of the area, the reaction mixture was cooled to 20-25 °C.

Next, water (5 l) was added to the reaction mixture with stirring. Subsequently, toluene (1.5 L) was added and the mixture was stirred for at least 15 minutes.

Stirring was stopped and the phases were allowed to separate.

The aqueous phase was washed twice with toluene (2 x 1.5 L).

Water (1 L) was added followed by aqueous hydrochloric acid (18%, 1.5-1.6 kg, 2.1-2.2 eq.).

The precipitate was filtered and washed twice with water (2 × 2 L) and heptane (2 L). The wet solid was transferred to a reaction vessel and heptane (5 L) was added. The suspension was stirred and heated to reflux, and the water was removed by azeotropic distillation.

The mixture was cooled to 20-25°C and the solid was filtered and dried in vacuo.

Yield: 80-90%. The NMR corresponds to the NMR of the product from step (2a) in Example 1.

Preparation of 1 - [7 - (difluoromethoxy)spiro[1,3 - benzodioxole - 2,4' - tetrahydrothiopyran] - 4 - yl]ethanone

Potassium carbonate (3.12 kg, 22.6 mol, 1.4 eq.) and DMF (15.8 kg) were added to a suitable reaction vessel (No. 1). The suspension was stirred at 20-25°C, and the vessel and mixture was purged with nitrogen for at least 1 hour at 20-25°C.

1-(7-hydroxyspiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl)ethanone (4.3 kg, 16. 2 mol, 1 eq.), sodium chlorodifluoroacetate (6.16 kg, 40.4 mol, 2.5 eq.) and DMF (12 kg). The suspension was stirred at 20-25°C, and the vessel and mixture was purged with nitrogen for at least 1 hour at 20-25°C.

The suspension in the vessel (No. 1) was heated to 115 °C, and the contents of the vessel (No. 2) were transferred to the vessel (No. 1) for 7-8 hours.

IPC was performed in acetonitrile for HPLC analysis (220 nm), with the criterion for further flow being <5 area % of 1-(7-hydroxyspiro[1,3-benzodioxol-2,4′-tetrahydrothiopyran]4-yl)ethanone.

The reaction mixture was cooled to 20-25°C, and an aqueous solution of KOH (0.75 M, 18.8 kg) was added to the reaction mixture.

The precipitate was filtered and washed with KOH solution (0.75 M, 9 kg) and then with water (86 kg).

The wet material was washed in DMF (16 kg) and heated to 40-45 °C. MSA (methanesulfonic acid) (3.44 kg, 35.8 mol, 2.2 eq) was added, maintaining the temperature between 45-50 °C.

IPC was performed in acetonitrile for HPLC analysis (272 nm), with the criterion for further progress being <4 area % of the chemical by-product of formula (IXb).

The reaction mixture was cooled to 35-40°C, and an aqueous solution of KOH (3.25M, 18.7 kg) was added to the mixture. Once the addition was complete, the mixture was cooled to 20-25 °C. The criterion for further progress was the solution pH value of 10-12.

The solid was filtered and washed with KOH solution (0.75 M, 9 kg) and then with water (86 kg). The solid was dried in vacuum at 60 °C.

Yield: > 85% (purity > 93%). The NMR corresponds to the NMR of the product from step (3) in Example 1.

Alternatively, instead of MSC, TFA can be used for processing. The wet material after the first isolation was washed in DMF (100 ml). TFA (trifluoroacetic acid) (13.4 g, 116.4 mmol, 1.5-3 eq.) was added along with water (21 ml), the reaction was carried out at a temperature of 60-70 °C.

The reaction mixture was cooled to 44-50 °C, and an aqueous NaOH solution (1.25 M, 140 ml) was added to the mixture. After addition was complete, the mixture was stirred for 1 hour.

The solid was isolated by filtration and washed with 0.5 M NaOH and then with water (480 ml). The solid was dried in vacuum at 50 °C. Yield: > 90% (purity > 94%). The NMR corresponds to the NMR of the product from step (3) in Example 1.

Preparation of 3,4,5 - trichloropyridine

Step 1: A stirred solution of 4-pyridinol (1.0 eq.) in acetonitrile (15.0 vol.) and water (0.1 vol.) was heated to 40°C and then N-chloro succinamide (2.2 eq.) at 40-55 °C. The reaction mixture was stirred for 6-8 hours at 45-55 °C, the progress of the reaction was monitored using HPLC. After completion of the reaction, the reaction mixture was cooled and stirred for 3-4 hours. The solid was filtered and washed with acetonitrile (1x2.0 vol.) and water (5.0 vol. + 2.0 vol.). The product was dried in an oven until constant weight was obtained.

Step 2: To a stirred suspension of 3,5-dichloro-4-pyridinol (1.0 eq) in acetonitrile (5.0 vol) was added POCl ₃ (2.0 eq). The reaction mixture was heated to 50-55°C and stirred for 24 hours. The reaction progress was monitored using HPLC. After completion of the reaction, the mixture was cooled. Then the reaction mixture was slowly poured into water (5.0 vol.) at 2-10 °C. The mixture was stirred for 20-30 minutes and the pH was adjusted to 9-10 with 50% NaOH _(aq) . The temperature was raised to 25-30°C and the mixture was extracted with n-heptane (1x18.0 vol., 2x10.0 vol.). The combined organic layers were washed with water (1 x 5.0 vol) and then charcoal (15% w/w) was added and stirred for 1-2 hours. The organic phase was filtered through a pad of hyflo and the filter cake was washed with heptane (2.0 vol). The collected organic phase was concentrated in vacuo at 40 °C or lower until 1.0 vol. The mixture was cooled to 25-30°C and water (2.0 vol.) was added. The mixture was again concentrated in vacuo to remove more heptane. Concentration was stopped when less than 2.0 vol. Water (5.0 vol) was added and the mixture was stirred for 2-3 hours. The solid was isolated by filtration and washed with water (2.0 vol). Dried in a vacuum oven at 40-45°C until constant weight was achieved. 1H NMR (600 MHz, chloroform-d) δ 8.52 (s, 2H)

Preparation of 2 - (3,5 - dichloro - 4 - pyridyl) - 1 - [7 - (difluoromethoxy)spiro[1,3 - benzodioxole - 2,4' - tetrahydrothiopyran] - 4 - yl]ethanone

DMF (5 L) was added to the reaction vessel and subsequently potassium tert-butoxide (0.92 L, 0.8 mol, 2.6 eq.) was added in portions with vigorous stirring. The mixture was stirred at 20-25°C in an inert atmosphere overnight.

1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl]ethanone (1 kg, 3.16 mol, 1 eq.) was added to the reaction vessel (No. 2). and 3,4,5-trichloropyridine (0.73 kg, 4.1 mol, 1.3 eq.) followed by DMF (4.5 L). Stirring was started at a speed that ensured good mixing of the reagents.

A solution of potassium tert-butoxide was added to the vessel (No. 2).

When 1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl]ethanone was <2%, the reaction mixture was cooled and water (1 L) and ethyl acetate (10 L) were added ).

Water (19 L) was added and the mixture was stirred. Mixing was stopped and the phases were allowed to separate. The temperature was maintained at 35-45 °C.

The lower aqueous phase was discarded. Ethyl acetate (5 L) was added, followed by water (20 L). The mixture was stirred and after stirring the phases were allowed to separate.

The lower aqueous phase was discarded. The organic phase was heated to boiling with stirring. While refluxing, ethanol (15 L) was added to the mixture at a rate to maintain reflux conditions. The azeotropic mixture of solvents was distilled until the steam temperature reached 74-76 °C.

The mixture was cooled and the product was filtered and washed twice with cold ethanol (2 x 2.5 L).

The product was dried in vacuum at 40-50°C. Yield: 45-80%. The NMR corresponds to the NMR of the product from step (4) in Example 1.

Preparation of 2 - (3,5 - dichloro - 1 - oxido - pyridine - 1 - y - 4 - yl) - 1 - [7 - (difluoromethoxy) - 1',1' - dioxo - spiro[1,3 - benzodioxol - 2,4' - tian] - 4 - yl]ethanone

2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxol-2,4'-tetrahydrothiopyran]-4-yl]ethanone (16, 1 kg, 34.8 mol, 1 eq.) and glacial acetic acid (33.8 kg). The suspension was cooled to 15-20 °C. Peracetic acid (36-40%, 20.5 kg, 104.7 mol, 3.01 eq.) was added to the mixture in portions. The mixture was heated to 60°C and stirred for 12-24 hours.

IPC was performed in acetonitrile for HPLC analysis (220 nm). The reaction was completed when the area of 2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxo-spiro[1, 3-benzodioxol-2,4'-thian]-4-yl]ethanone was >98.5%.

Acetic acid (36 kg) and sodium metabisulfite (2.415 kg, 12.7, 0.36 eq.) were added to the reaction mixture. The mixture was heated to 40-45°C for at least 3 hours.

Acetic acid was removed by evaporation in vacuo, and then ethanol (386 L) was added with stirring, followed by water (16 L).

The title compound (141 g, Form E) was added to the mixture and the mixture was then heated to reflux.

The solid was filtered, washed with ethanol (39 L) and dried in vacuum at 50 °C.

Yield: 80-90%). The NMR corresponds to the NMR of the product from step (5) in Example 1. Powder X-ray diffraction pattern.

Claims (79)

1. Method for preparing the compound of formula (I) (I), where R ₁ represents CHF ₂ and Q represents chlorine, including each of the stages: (1) reacting a compound of formula (II) (II), where R ₂ is selected from hydrogen, C _1-6 alkyl and arylalkyl, and R ₂₁ represents COCH ₃ ; with a compound of formula (III) (III) in the presence of an acid catalyst in the form of clay or zeolite, to form a compound of formula (IV) (IV), where R ₂ and R ₂₁ correspond to the definitions above; (2a) reacting a compound of formula (IV) (IV), where R ₂ and R ₂₁ are as defined above, with an aliphatic or aromatic thiol in the presence of a metal hydroxide in a suitable solvent to give a compound of formula (VI) (VI), where R ₂₁ is as defined above; (3’) introducing into the reaction a compound of formula (VI), (VI), where R ₂₁ is as defined above, by adding a solution of a compound of formula (VI) and sodium chlorodifluoroacetate in DMF to a preheated mixture of DMF, water and potassium carbonate over an extended period of time to obtain a compound of formula (IX), (IX), where R ₁ and R ₂₁ correspond to the definitions above (4) reacting a compound of formula (IX) with a pyridine compound of formula (X) (X), where Q is as defined above, and Q _X is selected from chlorine, bromine, fluorine and iodine, to form a compound of formula (XI); (XI), where R ₁ and Q correspond to the definitions above; And (5) oxidizing the resulting compound of formula (XI) to obtain a compound of formula (I) (I), where R ₁ and Q correspond to the definitions above. 2. The method according to claim 1, wherein the metal hydroxide in step (2a) is NaOH. 3. Method according to claim 1 or 2, in which the reaction in step (2a) is carried out using NaOH, 1-dodecanethiol and ethanol. 4. Method according to claim 1 or 2, in which the reaction in step (2a) is carried out using NaOH, 1-dodecanethiol and 1-propanol. 5. The method according to any one of the preceding claims, wherein in step (3') the compound of formula (IX) is treated with TFA or MSA in DMF at elevated temperature, followed by removal by treatment with aqueous NaOH or KOH during crystallization of the compound of formula (IX). 6. The method according to any one of the preceding claims, wherein the reaction in step (4) is carried out in a DMF/tBuOH solvent using tert-BuOK as a base. 7. The method according to claim 6, in which the DMF/tBuOH solvent is a mixture of 30/70 v/v. 8. The method according to any one of the preceding claims, wherein in step (5) the compound of formula (I) is crystallized directly from the concentrated reaction mixture. 9. The method according to any one of the preceding claims, wherein each Q and each Q _X represent chlorine. 10. The method according to any one of the preceding claims, wherein in step (1) the acid catalyst is a silicate material montmorillonite K10. 11. Method for preparing the compound of formula (I) (I), where R ₁ represents CHF ₂ and Q represents chlorine, comprising each of steps (2a), (3') and (4), and subsequent oxidation of the resulting compound, where step (2a) involves introducing into the reaction a compound of formula (IV) (IV), with an aliphatic or aromatic thiol in the presence of a metal hydroxide in a suitable solvent to give a compound of formula (VI) (VI), where R ₂ is selected from hydrogen, C _1-6 alkyl and arylalkyl, and R ₂₁ represents COCH ₃ ; step (3’) involves introducing a compound of formula (VI) into the reaction (VI), where R ₂₁ is as defined above, by adding a solution of the compound of formula (VI) and sodium chlorodifluoroacetate in DMF to a preheated mixture of DMF, water and potassium carbonate over an extended period of time to obtain the compound of formula (IX) (IX), where R ₁ and R ₂₁ correspond to the definitions above; step (4) involves reacting a compound of formula (IX) with a pyridine compound of formula (X) (X), where Q is as defined above and Q _X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI) (XI), where R ₁ and Q correspond to the definitions above. 12. Method for preparing the compound of formula (I) (I), where R ₁ represents CHF ₂ and Q represents chlorine, including steps (3'), (4) and (5): (3’) introducing into the reaction a compound of formula (VI) (VI), where R ₂₁ represents COCH ₃ by adding a solution of the compound of formula (VI) and sodium chlorodifluoroacetate in DMF to a preheated mixture of DMF, water and potassium carbonate over an extended period of time to obtain the compound of formula (IX) (IX), where R ₁ and R ₂₁ correspond to the definitions above; (4) reacting a compound of formula (IX) with a pyridine compound of formula (X) (X), where Q is chlorine and Q _X is selected from chlorine, bromine, fluorine and iodine to form a compound of formula (XI) (XI), where R ₁ and Q correspond to the definitions above; And (5) oxidizing the resulting compound of formula (XI) to obtain a compound of formula (I). 13. Method according to claim 11 or 12, where the reaction in step (4) is carried out in a DMF/tBuOH solvent, using tert-BuOK as a base. 14. The method according to claim 13, in which the DMF/tBuOH solvent is a mixture of 30/70 v/v. 15. The method according to claim 11 or 12, where the compound of formula (IX) in step (3’) is treated with TFA or MSA in DMF at elevated temperature, followed by its removal by treatment with aqueous KOH or NaOH during crystallization of the compound of formula (IX). 16. Method according to any one of paragraphs. 1-15, wherein the method further comprises preparing a compound of formula (X) (X), where each Q and Q _X represents chlorine, including each of the stages: (i) chlorination of 4-pyridinol to form 3,5-dichloro-4-pyridinol; And (ii) chlorinating 3,5-dichloro-4-pyridinol to form a compound of formula (X).