An efficient method for preparing 6-carboxybenzoxazole derivatives

Abstract

The present invention relates to an effective method for preparing benzoxazole derivatives, which comprises the steps of reacting a 4-amino-3-hydroxybenzoic acid compound of formula III with a 3,5-dichlorophenyl orthoester compound of formula II to provide a compound of formula I, wherein R 1 , R 2a , R 2b and R 2c As defined herein.

Description

Technical Field

[0001] The present invention relates to a method for preparing a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a method for preparing a 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid derivative or a pharmaceutically acceptable salt thereof, which is prepared by reacting 4-amino-3-hydroxybenzoic acid or a carboxyl protected derivative thereof with an appropriate 3,5-dichlorophenyl orthoester compound. The method of the present invention is particularly useful for preparing 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, which can be used to stabilize transthyretin, inhibit transthyretin misfolding, proteolysis, and treat amyloid diseases associated therewith. Background of the Invention

[0003] Transthyretin (TTR) is a 55 kDa homotetramer protein present in serum and cerebrospinal fluid that functions as a transporter for L-thyroxine (T4) and holo-retinol binding protein (RBP). TTR has been found to be an amyloidogenic protein that, under certain conditions, can be converted into fibrils and other aggregates that can lead to disease pathology in humans, such as polyneuropathy or cardiomyopathy.

[0004] U.S. Patent Nos. 7,214,695; 7,214,696; 7,560,488; 8,168,683; and 8,653,119 (each of which is incorporated herein by reference) disclose benzoxazole derivatives that act as transthyretin stabilizers and have the formula

[0005]

[0006] or a pharmaceutically acceptable salt thereof; wherein Ar is 3,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl and methods for preparing these compounds. In particular, 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (Tafamidis) of the following formula and its preparation method are disclosed

[0007]

[0008] Tafamid is an orally active transthyretin stabilizer that inhibits tetramer dissociation and proteolysis and has been approved in certain jurisdictions for the treatment of transthyretin polyneuropathy (TTR-PN) and for the treatment of transthyretin cardiomyopathy (TTR-CM). U.S. Patent No. 9,249,112 and U.S. Patent Application Publication No. US 2019 / 0119226 (also incorporated herein by reference) disclose polymorphic forms of the meglumine salt of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidi meglumine). U.S. Patent No. 9,770,441 (also incorporated herein by reference) discloses polymorphic forms of the free acid of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidi). There is a continuing need to provide efficient synthetic methods for preparing 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid derivatives, pharmaceutically acceptable salts thereof, and polymorphic forms of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid derivatives and pharmaceutically acceptable salts thereof. SUMMARY OF THE INVENTION

[0010] The present invention relates to a method for preparing a 6-carboxyl-2-(3,5-dichlorophenyl)benzoxazole compound of formula I

[0011]

[0012] The method comprises the steps of reacting a 4-amino-3-hydroxybenzoic acid compound of formula III with a 3,5-dichlorophenyl orthoester compound of formula II to provide a compound of formula I

[0013]

[0014] Where R 1 is hydrogen or a carboxyl protecting group; and R 2a , R 2b and R 2c Each independently is a C1-C6 alkyl group, or R 2a , R 2b and R 2c Any two of the groups together are C1-C6 alkanediyl, or R 2a , R 2b and R 2c Together for C3-C 10The method of preparing the compound of formula I of the present invention can be carried out in a suitable solvent, or in some cases where the compound of formula II is an oil, no additional solvent may be required. The method of the present invention can be carried out in the presence of an acid catalyst, a base catalyst or no catalyst, and the method can be carried out at a temperature from 0°C to the reflux temperature of the solvent used, and the method is carried out for a period of 15 minutes to several days. The method of the present invention also includes other steps, such as isolating the compound of formula I or Ia and preparing polymorphic forms of the compound of formula I or Ia. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 : PXRD spectrum of crystalline 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane. DETAILED DESCRIPTION OF THE INVENTION

[0017] A first embodiment of the present invention (designated E1) is a process for preparing a 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole compound of formula I,

[0018]

[0019] The method comprises reacting a 4-amino-3-hydroxybenzoic acid compound of formula III with a 3,5-dichlorophenyl orthoester compound of formula II to provide a compound of formula I

[0020]

[0021] Where R 1 is hydrogen or a carboxyl protecting group; and R 2a , R 2b and R 2c Each independently is a C1-C6 alkyl group, or R 2a , R 2b and R 2c Any two of the groups together are C1-C6 alkanediyl, or R 2a , R 2b and R 2c Together for C3-C 10 Alkanetriyl.

[0022] Additional embodiments of the present invention are described below as embodiments 2 to 46, which are designated E2 to E46, respectively.

[0023] E2 is the process of E1, wherein the reaction of the compound of formula III with the compound of formula II to provide the compound of formula I is carried out in a solvent.

[0024] E3 is the method of E2, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, anisole, ethyl acetate, chloroform, chlorobenzene, heptane, cyclohexane, toluene, acetonitrile and 1,2-dimethoxyethane.

[0025] E4 is the method of E3, wherein the solvent is selected from the group consisting of methanol, isopropanol, acetonitrile, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether, and 1,4-dioxane.

[0026] E5 is the method of any one of E1 to E4, wherein the reaction of the compound of formula III and the compound of formula II to provide the compound of formula I is carried out in the presence of an acid catalyst.

[0027] E6 is the method of E5, wherein the acid catalyst is selected from the group consisting of trifluoroacetic acid, acetic acid, hydrochloric acid and methanesulfonic acid.

[0028] E7 is the method of any one of E1 to E4, wherein the reaction of the compound of formula III with the compound of formula II to provide the compound of formula I is carried out in the presence of a base catalyst.

[0029] E8 is the method of E7, wherein the base catalyst is triethylamine.

[0030] E9 is the method of any one of E1 to E8, wherein the reaction of the compound of formula III and the compound of formula II to provide the compound of formula I is carried out at a temperature of about room temperature to about 100 °C.

[0031] E10 is the method of E9, wherein the temperature is from about room temperature to about 65°C.

[0032] E11 is the method of any one of E1 to E10, wherein the reaction of the compound of formula III and the compound of formula II to provide the compound of formula I is carried out for a time of about 0.25 hours to about 40 hours.

[0033] E12 is the method of any one of E1 to E11, wherein R 1 For hydrogen.

[0034] E13 is the method of any one of E1 to E12, wherein R 2a , R 2b and R 2c Each is independently a C1-C6 alkyl group.

[0035] E14 is the method of E13, wherein R 2a , R 2b and R 2c Each is a methyl group.

[0036] E15 is the method of any one of E1 to E12, wherein R 2a , R 2b and R 2c Together for C3-C 10 Alkanetriyl.

[0037] E16 is the method of E15, wherein the compound of formula II is

[0038]

[0039] E17 is the method of any one of E1 to E16, further comprising the step of isolating the compound of formula I.

[0040] E18 is the method of E17, wherein the compound of formula I is isolated by filtration.

[0041] E19 is a method for preparing 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia,

[0042]

[0043] The method comprises reacting a 4-amino-3-hydroxybenzoic acid of formula IIIa with a 3,5-dichlorophenyl orthoester compound of formula II to provide a 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia,

[0044]

[0045] Where R 2a , R 2b and R 2c Each independently is a C1-C6 alkyl group, or R 2a , R 2b and R 2c Any two of the groups together are C1-C6 alkanediyl, or R 2a , R 2b and R 2c Together for C3-C 10 Alkanetriyl.

[0046] E20 is the method of E19, wherein the reaction of the compound of formula IIIa with the compound of formula II to provide the compound of formula Ia is carried out in a solvent.

[0047] E21 is the method of E20, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, anisole, ethyl acetate, chloroform, chlorobenzene, heptane, cyclohexane, toluene, acetonitrile and 1,2-dimethoxyethane.

[0048] E22 is the method of E21, wherein the solvent is selected from the group consisting of methanol, isopropanol, acetonitrile, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether, and 1,4-dioxane.

[0049] E23 is the method of any one of E19 to E22, wherein the reaction of the compound of formula IIIa with the compound of formula II to provide the compound of formula Ia is carried out in the presence of an acid catalyst.

[0050] E24 is the method of E23, wherein the acid catalyst is selected from the group consisting of: trifluoroacetic acid, acetic acid, hydrochloric acid, and methanesulfonic acid.

[0051] E25 is the method of E24, wherein the acid catalyst is trifluoroacetic acid.

[0052] E26 is the method of any one of E19 to E22, wherein the reaction of the compound of formula IIIa with the compound of formula II to provide the compound of formula Ia is carried out in the presence of a base catalyst.

[0053] E27 is the method of E26, wherein the base catalyst is triethylamine.

[0054] E28 is the method of any one of E19 to E27, wherein the reaction of the compound of formula III and the compound of formula II to provide the compound of formula I is carried out at a temperature of about room temperature to about 100 °C.

[0055] E29 is the method of E28, wherein the temperature is from about room temperature to about 65°C.

[0056] E30 is the method of any one of E19 to E29, wherein the reaction of the compound of formula III and the compound of formula II to provide a compound of formula I is carried out for a time of about 0.25 hours to about 40 hours.

[0057] E31 is the method of any one of E19 to E30, wherein R 2a , R 2b and R 2c Each is independently a C1-C6 alkyl group.

[0058] E32 is the method of E31, wherein R 2a , R 2b and R 2c Each is a methyl group.

[0059] E33 is the method of any one of E19 to E30, wherein R 2a , R 2b and R 2c Together for C3-C 10 Alkanetriyl.

[0060] E34 is the method of E33, wherein the compound of formula II is

[0061]

[0062] E35 is the method of any one of E19 to E34, further comprising the step of isolating the compound of formula Ia.

[0063] E36 is the method of E35, wherein the compound of formula Ia is isolated by filtration.

[0064] E37 is the method of any one of E19 to E36, further comprising the step of reacting 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of Formula Ia with a pharmaceutically acceptable base to provide a pharmaceutically acceptable salt of 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole.

[0065] E38 is the method of E37, wherein 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole is reacted with meglumine in a suitable solvent to provide 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole meglumine salt.

[0066] E39 is the method of E38, wherein 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole is reacted with meglumine at room temperature in a solvent selected from methyl isobutyl ketone, MTBE and EtOAc, and the resulting solid is isolated and dried to provide the Form E polymorph of 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole meglumine salt.

[0067] E40 is the method of E38, wherein 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole is reacted with meglumine in a mixture of IPA and water, and the resulting solid is isolated and dried to provide the Form M polymorph of 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole meglumine salt.

[0068] E41 is the method of E35, further comprising the step of stirring the compound of Formula Ia in a mixture of water and IPA, followed by isolating and drying the resulting solid to provide the Form 1 polymorph of 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole.

[0069] E42 is a method for preparing 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia,

[0070]

[0071] The method comprises reacting about one molar equivalent of 4-amino-3-hydroxybenzoic acid of formula IIIa with about one molar equivalent of 3,5-dichlorophenyl orthoester compound of formula IIa in a suitable solvent to provide 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia.

[0072]

[0073] E43 is the method of E42, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, anisole, ethyl acetate, chloroform, chlorobenzene, heptane, cyclohexane, toluene, acetonitrile and 1,2-dimethoxyethane.

[0074] E44 is the method of E43, wherein the solvent is selected from the group consisting of: methanol, isopropanol, acetonitrile, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether and 1,4-dioxane.

[0075] E45 is the process of E44, wherein the process is carried out using an acid catalyst selected from the group consisting of trifluoroacetic acid, acetic acid, hydrochloric acid and methanesulfonic acid.

[0076] E46 is the method of E44, wherein the acid catalyst is trifluoroacetic acid and the solvent is isopropanol.

[0077] E47 is a method for preparing a 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole compound of formula I,

[0078]

[0079] The method comprises reacting a 4-amino-3-hydroxybenzoic acid compound of formula III with a 3,5-dichlorophenyl orthoester compound of formula II to provide a compound of formula I

[0080]

[0081] Where R 1 is hydrogen or a carboxyl protecting group; and R 2a , R 2b and R 2c Each independently is a C1-C6 alkyl group, or R 2a , R 2b and R 2c Any two of the groups together are C1-C8 alkanediyl, or R 2a , R 2b and R 2c Together for C3-C 12 Alkanetriyl, wherein the C1-C8 alkanediyl and C3-C 12 Each alkanetriyl group is optionally substituted with a phenyl group which is optionally substituted with one to two groups independently selected from halo, C1-C3 alkyl and C1-C3 alkoxy.

[0082] E48 is the method of E47, wherein the compound of formula III is 4-amino-3-hydroxybenzoic acid, and the compound of formula II is selected from: 1,3-dichloro-5-(trimethoxymethyl)benzene; 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2] octane; 2-(3,5-dichlorophenyl)-2-methoxy-1,3-dioxolane; 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane; 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane; 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane; and 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane.

[0083] E49 is the method of E48, wherein the reaction of the compound of formula II with the compound of formula III is carried out in IPA as solvent in the presence of MSA as acid catalyst.

[0084] E50 is a compound selected from the group consisting of: 1,3-dichloro-5-(trimethoxymethyl)benzene; 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane; 2-(3,5-dichlorophenyl)- )-2-methoxy-1,3-dioxolane; 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane; 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane; 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane; and 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane.

[0085] E51 is the compound of E50 which is 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane. E52 is the compound of E51 which is a crystalline form of 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane. E53 is the compound of E52 characterized by PXRD peaks at 21.2 and 19.7 2-θ, each ±0.2 2-θ. E54 is the compound of E53 characterized by PXRD peaks at 21.2, 19.7, and 14.4 2-θ, each ±0.2 2-θ. E55 is the compound of E54 characterized by PXRD peaks at 21.2, 19.7, 14.4, and 23.7 2-θ, each ±0.2 2-θ. E56 is the compound of E55 characterized by PXRD peaks at 21.2, 19.7, 14.4, 23.7, and 24.2 2-theta, each ± ​​0.2 2-theta. E57 is the compound of E56 characterized by PXRD peaks at 21.2, 19.7, 14.4, 23.7, 24.2, and 30.6 2-theta, each ± ​​0.2 2-theta.

[0086] E58 is a method for preparing a compound of formula IIa-2,

[0087]

[0088] Where R 3 is selected from the group consisting of isopropyl, tert-butyl and neopentyl, which comprises reacting a compound of formula IV with 3,5-dichlorobenzoic acid in a suitable solvent in the presence of a suitable acid catalyst.

[0089]

[0090] E59 is the method of E58, wherein R 3 is isopropyl or tert-butyl. E60 is the method of E59, wherein the solvent is toluene and the acid catalyst is methanesulfonic acid.

[0091] In the above-mentioned method of the present invention, the compound of formula III is 4-amino-3-hydroxybenzoic acid (when R 1 H) or the carboxyl group is protected (when R 1 Numerous carboxyl protecting groups are known in the art and can be used in which R 1Compounds of formula III having a carboxyl protecting group. Chapter 5 of Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter GM Wuts, Copyright 1999, John Wiley & Sons, Inc. describes various types of carboxyl protecting groups. Tan J, Akakura M, Yamamoto H. "The supersilyl group as a carboxylic acid protecting group: application to highlystereoselective aldol and Mannich reactions" Angew Chem Int Ed Engl. 2013; 52(28): 7198-7202. doi: 10.1002 / anie.201300102 describes the use of supersilyl (EtSi) 3- as a universal carboxyl protecting group. In addition to the supersilyl group, common carboxyl protecting groups that can be used in the compound of formula III include, but are not limited to, ester protecting groups such as methyl, ethyl, tert-butyl, 2-cyanoethyl, 2,2,2-trichloroethyl, allyl, (2,2-dimethylallyl, phenyl, benzyl, p-methoxybenzyl, and trimethylsilyl. Other equivalent carboxyl protecting groups may also be used, such as using thioesters (i.e., C(O)OR 1 Part of it can be replaced by C(O)S(C1-C6 alkyl), or the entire C(O)OR 1 The carboxyl protecting group may be deprotected by methods known in the art, such as by treatment with an acid, base or hydrogenation appropriate to the particular carboxyl protecting group being used, to provide a 1 A compound of H.

[0092] The orthoester and cyclic orthoester compounds (such as Formula II) used in the present method can be prepared according to methods similar to those described by EJ Corey and N. Raju in Tetrahedron Letters, 1983, 24 (50), 5571-5574; P. Wipfet. al. Pure Appl. Chem. 1999, 71 (3), 415-421; S. Tange et. al. Synthesis, 2008, 3219-3222; M. Noe et. al. Green Chem. 2013, 15, 2252; European Patent Application No. 0279698 and Japanese Patent 5419545 (which was published by Japanese Patent Application No. 2010-270091).

[0093] Preferred compounds prepared by the process of the present invention are compounds of formula I (more particularly compounds of formula Ia) or pharmaceutically acceptable salts thereof. The compound of formula Ia (6-carboxy-1-(3,5-dichlorophenyl)benzoxazole or 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid), also known by its USAN name tafamidis, has a carboxylic acid moiety at the 6-position of its benzoxazole ring. The carboxylic acid moiety can be readily salted with an appropriate base (such as meglumine) to provide a pharmaceutically acceptable salt of the compound of formula Ia.

[0094] The methods of the present invention include the preparation of compounds of Formula I or Ia in the form of individual salts derived from inorganic or organic bases. Specific salts of compounds of Formula I or Ia may be advantageous due to the physical properties of one or more salts, such as enhanced drug stability at different temperatures and humidities, or desired solubility in water or oil. In some cases, salts of compounds may also be used as adjuvants for the separation, purification and / or resolution of compounds in the methods of the present invention.

[0095] When the salt is intended to be administered to a patient (e.g., as opposed to use in an in vitro setting), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by mixing a compound of Formula I or Ia with a base whose cation is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because they have greater water solubility relative to the parent compound. For use in medicine, the salts of the compounds prepared by the methods of the present invention are non-toxic "pharmaceutically acceptable salts." Salts included in the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free acids of the compounds of Formula I and Ia with a suitable organic or inorganic base.

[0096] Since the compounds prepared by the method of the present invention may have an acidic part (i.e., Formula I, wherein R 1H), its suitable pharmaceutically acceptable salts may include lighter alkali metal salts, i.e. sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, the base salts are formed from bases that form non-toxic salts, including aluminum salts, arginine salts, benzathine salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, meglumine salts, olamine salts, tromethamine salts, and zinc salts.

[0097] Organic salts can be prepared from secondary amines, tertiary amines or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups can be quaternized with substances such as: halogenated lower alkyl (C1-C6) (e.g., chlorinated, brominated and iodinated methyl, ethyl, propyl and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl, dibutyl and diamyl), long chain halides (e.g., chlorinated, brominated and iodinated decyl, lauryl, myristyl and stearyl), halogenated aralkyl (e.g., benzyl bromide and phenethyl), etc. The preferred salt prepared by the method of the present invention is the meglumine salt of tafamidis.

[0098] Hemi-salts of the acids (ie, compounds of Formula I and Ia), such as the hemisulfate and hemicalcium salts of tafamidis, may also be formed by the process of the invention.

[0099] Those skilled in the art will appreciate that such salts include those in which the counterion is optically active, for example, chiral amine bases such as meglumine, which is also known as (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol or N-methyl-D-glucamine.

[0100] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: PropeRTies, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0101] Pharmaceutically acceptable salts of compounds of Formula I and Ia may be prepared by one or more of the following three methods:

[0102] (i) by reacting a compound of formula I or Ia with a desired base;

[0103] (ii) by removing base-labile protecting groups from appropriate precursors of compounds of formula I and Ia using the required base; or

[0104] (iii) converting one salt of the compound of formula I and Ia into another salt by reaction with a suitable base or using a suitable ion exchange column.

[0105] All three reactions are usually carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can range from fully ionized to almost non-ionized. A preferred salt of tafamidis that can be prepared is tafamidis meglumine.

[0106] The compound of formula I or its pharmaceutically acceptable salt prepared by the method of the present invention can exist in unsolvated form and solvated form. The term "solvate" is used herein to describe a molecular complex comprising a compound of formula I or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates according to the present invention include those solvates in which the crystallization solvent can be isotopically substituted (e.g., D2O, d6-acetone and d6-DMSO).

[0107] The currently accepted classification system for organic hydrates is one that defines isolated site hydrates, channel hydrates, or metal-ion coordinated hydrates - see KR Morris, Polymorphism in Pharmaceutical Solids (Ed. HG Brittain, Marcel Dekker, 1995), which is incorporated herein by reference. Isolated site hydrates are those in which the water molecules are separated from each other by intervening organic molecules. In channel hydrates, the water molecules are located in lattice channels where they are adjacent to other water molecules. In metal-ion coordinated hydrates, the water molecules are bound to the metal ion.

[0108] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, as in pipeline solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0109] The scope of the present invention also includes a method for preparing a multi-component complex (other than a salt and a solvate) of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the drug (i.e., a compound of formula I or Ia (tafamidis)) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. Co-crystals are generally defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but may also be complexes of neutral molecules with salts. Co-crystals containing a compound of formula I may be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together - see O. Almarsson and MJ Zaworotko (2004), Chem Commun, 17, 1889-1896, which is incorporated herein by reference. For a general review of multi-component complexes, see Haleblian (August 1975), J Pharm Sci, 64(8), 1269-1288, which is incorporated herein by reference.

[0110] The compounds prepared by the methods of the present invention may exist in a solid state continuum ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid depending on the temperature. Typically such materials do not produce a unique X-ray diffraction pattern and, although exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change in properties from the solid to the liquid state occurs, which is characterized by a change in state, typically second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with well-defined peaks. Such materials also exhibit liquid properties when heated sufficiently, but the change from the solid to the liquid state is characterized by a phase change, typically first order ("melting point"). Preferred forms of the compound of Formula Ia (tafamidib (free acid)) prepared by the methods of the present invention include polymorphic forms as described in U.S. Pat. No. 9,770,441, particularly the Form 1 polymorph of the tafamidib free acid described therein. Preferred forms of the compound of Formula Ia (tafamidis meglumine (meglumine salt of tafamidis)) prepared by the method of the present invention include polymorphic forms of tafamidis meglumine as described in U.S. Patent No. 9,249,112 and U.S. Patent Application Publication No. US 2019 / 0119226. A particularly preferred form of tafamidis meglumine prepared by the method of the present invention is the M-type polymorph as described in U.S. Patent No. 9,249,112. Another form of tafamidis meglumine that can be prepared using the method of the present invention is the E-type polymorph of tafamidis meglumine as described in U.S. Patent Application Publication No. US 2019 / 0119226.

[0111] When subjected to appropriate conditions, the compounds of formula I or Ia prepared by the process of the present invention may also exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state is an intermediate state between the true crystalline state and the true liquid state (melt or solution). Mesomorphism due to changes in temperature is described as "thermotropic" and mesomorphism due to the addition of a second component (such as water or another solvent) is described as "lyotropic". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and, as in the case of thaumadiol, are composed of ionic (such as -COO-Na + 、-COO-K + , or -COO-methylglucamine + For more information, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th Edition (Edward Arnold, 1970), which is incorporated herein by reference.

[0112] abbreviation

[0113] The following abbreviations are used:

[0114] AcOH = acetic acid

[0115] AHBA = 4-amino-3-hydroxybenzoic acid

[0116] BF3.Et2O = boron trifluoride etherate

[0117] 13C = Carbon 13

[0118] ℃ = degrees Celsius

[0119] CDCl3 = Tritiated chloroform

[0120] cm -1 = Reciprocal centimeters

[0121] d = doublet

[0122] dd = doublet

[0123] DCM = dichloromethane

[0124] 1,2-DME = 1,2-dimethoxyethane

[0125] DMSO-d6 = tritiated dimethyl sulfoxide

[0126] EtOAc = Ethyl acetate

[0127] EtOH = Ethanol

[0128] eq. = equivalent

[0129] g = grams

[0130] h = hours

[0131] H = Hydrogen atom

[0132] HCl = Hydrochloric acid

[0133] HPLC = High Pressure Liquid Chromatography

[0134] Hz = Hertz

[0135] IPA = Isopropyl Alcohol

[0136] iPrOAC = isopropyl acetate

[0137] J = coupling constant

[0138] KOH = Potassium Hydroxide

[0139] L = Liters

[0140] m = multiplet

[0141] mm = millimeters

[0142] M = mole

[0143] mbar = millibar

[0144] MEK = Methyl Ethyl Ketone

[0145] MeOH = Methanol

[0146] mg = milligram

[0147] MHz = Megahertz

[0148] μL = microliter

[0149] mL = milliliters

[0150] mmol = millimole

[0151] mol = mole

[0152] MSA or MSOH = Methanesulfonic acid

[0153] MTBE = Methyl tert-butyl ether

[0154] NaOMe = Sodium methoxide

[0155] n-BuOH = n-Butanol

[0156] NMR = Nuclear Magnetic Resonance

[0157] PTSA = p-Toluenesulfonic acid

[0158] RT = Room temperature

[0159] s = unimodal

[0160] t = triplet

[0161] TEA = Triethylamine

[0162] THF = Tetrahydrofuran

[0163] TFA = trifluoroacetic acid

[0164] preparation

[0165] Preparation 1: 1,3-Dichloro-5-(trimethoxymethyl)benzene

[0166] 1,3-Dichloro-5-(trimethoxymethyl)benzene was prepared according to the method described in Scheme P1 and as follows.

[0167] Reaction route P1

[0168]

[0169] Step 1: Preparation of (E)-[(3,5-dichlorophenyl)-methoxy-methylene]-methyl-phenylammonium; trifluoromethanesulfonate

[0170] TEA (141.7 g, 1400 mmol) was added to a stirred solution of N-methylaniline (150 g, 1399.9 mmol) in DCM (1200 mL, 1590 g) and the resulting solution was cooled to 0°C over a period of 30 minutes. A solution of 3,5-dichlorobenzoyl chloride (308 g, 1470.4 mmol, 1.05 eq.) in DCM (300 mL, 398 g) was added to this solution over 60 minutes while maintaining the temperature at <5°C. The reaction mixture was stirred at 0°C for 30 minutes and then filtered to remove triethylamine hydrochloride. The resulting filtrate was cooled to 0°C and methyl trifluoromethanesulfonate (288.3 g, 1687 mmol, 1.205 eq.) was added over 60 minutes. The reaction mixture was heated to 52°C and stirred for 12 h and then concentrated to a volume of 900 mL by distillation. The mixture was cooled to 20°C within 20 minutes and MTBE (1500 mL, 1113 g) was added thereto within 60 minutes. The mixture was cooled to 0°C within 30 minutes and stirred at 0°C for 30 minutes. The reaction mixture was filtered and the filter cake was washed with MTBE (300 mL, 223 g). The resulting solid was dried under vacuum overnight to provide 450 g of (E)-[(3,5-dichlorophenyl)-methoxy-methylene]-methyl-phenylammonium; trifluoromethanesulfonate (72% yield).

[0171] Step 2: Preparation of 1,3-dichloro-5-(trimethoxymethyl)benzene

[0172] A solution of (E)-[(3,5-dichlorophenyl)-methoxy-methylene]-methyl-phenyl-ammonium; trifluoromethanesulfonate (450 g, 1013 mmol) in MeOH (3000 mL) was added to a solution of sodium methoxide in methanol (25 wt %, 364.9 g, 386.1 mL, 1520 mmol, 1.5 eq.) at 0°C over 60 min while maintaining the temperature at <5°C. The reaction mixture was stirred for 30 min before AcOH (206.4 mL, 216.3 g, 3.2 eq.) was added over 30 min while maintaining the temperature at <5°C. This reaction mixture was then added to a reactor containing 4M aqueous potassium hydroxide solution (1317 g, 1126 mL, 4 eq.) over 60 min while maintaining the temperature at 20°C. The reaction mixture was then heated and concentrated by distillation to a volume of 1500 mL. The reaction mixture was adjusted to 20 ° C and added to water (1250 mL) and DCM (1250 mL). The mixture was stopped to stir, and the layers were separated, and the lower organic layer was then collected. DCM (1250 mL) was added to the remaining aqueous layer, and the mixture was stirred for 10 minutes, the stirring was stopped, the layers were separated, and the lower organic layer was collected. The combined organic layer was then distilled, and the fraction boiling up to 100 ° C at atmospheric pressure was first discarded, followed by vacuum distillation at 5-10 mbar, while the reactor temperature was raised from 95 ° C to 160 ° C in 2 h. The desired orthoester, 1,3-dichloro-5-(trimethoxymethyl)benzene (201.9 g, 803.4 mmol, 79.3% yield) was collected as a light yellow oil. 1H NMR (500MHz, CDCl3) δ7.48 (d, J=1.9Hz, 2H), 7.36 (t, J=1.9Hz, 1H), 3.15 (s, 9H). 13C NMR (126MHz, CDCl3) δ 140.4, 134.9, 129.0, 126.2, 113.7, 49.9. FTIR(neat): 1568.2,1418.8,1256.3,1094.5,987.2,862.7,796.0,656.6,517.3cm -1 .

[0173] Preparation 2: 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane

[0174] 1-(3,5-Dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared according to the method described in Scheme P2 and as follows.

[0175] Reaction route P2

[0176]

[0177] Step 1: Synthesis of (3-methyloxetane-3-yl)methyl 3,5-dichlorobenzoate

[0178] A solution of 3,5-dichlorobenzoyl chloride (111.4 g, 0.53 mol) in DCM (100 mL) was added to a solution of 3-methyl-3-oxetanesmethanol (54.3 g, 0.53 mol) in DCM (400 mL) at ~0 ° C in 45 minutes. The mixture was stirred at ~0 ° C for 1.5 h, then washed with water (3x200 mL). The organic layer was then concentrated to remove DCM. This produced 143.7 g (98.6% crude yield) of colorless viscous oil, which crystallized when standing. Half of this material was carried out to the next step, while the other half was recrystallized from IPA (250 mL) to provide 55.0 g of (3-methyloxetanes-3-yl) methyl 3,5-dichlorobenzoate as a colorless crystalline solid. 1H NMR (44MHz, CDCl3)d 7.85 (d, 2H), 7.55 (t, 1H), 4.75-4.28 (m, 6H), 1.45 (s, 3H).

[0179] Step 2: Synthesis of 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane

[0180] A solution of (3-methyloxetan-3-yl)methyl 3,5-dichlorobenzoate (71.85 g, 0.261 mol) in DCM (435 mL) was cooled to -5 °C in an acetone / ice bath. Boron trifluoride etherate (BF3.Et2O, 9.4 g, 66.25 mmol) was added to this solution and the solution was stirred overnight while warming to RT to provide a yellow solution. TEA (25.0 g, 0.247 mol) was added to this solution and the mixture was stirred at RT for 1 h, then MTBE (520 mL) was added thereto. As no precipitate formed, the mixture was concentrated to remove the solvent, which gave an orange-yellow solid (crude weight -85 g), which was recrystallized in IPA (250 mL) to provide 41.6 g (57% yield) of the desired product. Two additional crops were obtained by concentrating the mother liquor and seeding with material from the first crop to provide additional 5.0 g and 3.46 g of the desired product, 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane, respectively. The total yield obtained was 50.06 g (68%).

[0181] HPLC retention time: 5.062 min; 1H NMR (44 MHz, CDCl 3 ) δ 7.83-7.13 (m, 3H), 4.15 (s, 6H), 0.97 (s, 3H).

[0182] Crystalline 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane was evaluated using PXRD. Figure 1 Peak detected spectra are provided. 2-theta values ​​are provided in PXRD Table 1 below and are ± 0.2 2-theta. The crystalline form of 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane is characterized by PXRD peaks at 21.2 and 19.7 2-θ, each ±0.2 2-θ; PXRD peaks at 21.2, 19.7, and 14.4 2-θ, each ±0.2 2-θ; PXRD peaks at 21.2, 19.7, 14.4, and 23.7 2-θ, each ±0.2 2-θ; PXRD peaks at 21.2, 19.7, 14.4, 23.7, and 24.2 2-θ, each ±0.2 2-θ; PXRD peaks at 21.2, 19.7, 14.4, 23.7, 24.2, and 30.6 2-θ, each ±0.2 2-θ.

[0183] PXRD Table 1

[0184]

[0185]

[0186] Preparation 3: 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane

[0187]

[0188] 2-Ethyl-2-(hydroxymethyl)-1,3-propanediol (5.375 g, 40.0 mmol) followed by TFA (0.3 mL, 3.9 mmol) was added to a solution of 1,3-dichloro-5-(trimethoxymethyl)benzene (10.04 g, 40.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 65 h. Anhydrous K2CO3 (2.2 g) was added, the mixture was stirred for 3 h, then filtered. The filtrate was concentrated using a rotary evaporator and the residue was dissolved in hot toluene (70 mL), cooled to rt and filtered through a PTFE membrane, then concentrated in vacuo to provide a solidified residue (12.40 g). The residue was crystallized from heptane: heptane (50 mL) was added, the solid was dissolved under reflux, and the solution was then kept at -5 °C for 3 h. The solid precipitate was filtered off, rinsed with cooled heptane and air-dried; this provided the first batch of crude product (6.12 g). The combined filtrates were evaporated to half the original volume and then left overnight at -5°C; a second crop of material (1.45 g) was collected by filtration. Both fractions contained the desired 2,6,7-trioxabicyclo[2.2.2]octane mixed with the byproduct 2,2-bis(hydroxymethyl)butyl 3,5-dichlorobenzoate. The molar ratio of desired product:byproduct for the first batch was 1:0.25, and the molar ratio of desired product:byproduct for the second batch was 1:0.37.

[0189] The two crude fractions obtained were combined with another batch (7.58 g, 1:0.18 ratio of desired product:byproduct) prepared in a similar manner.

[0190] The combined crude product (15.15 g) was recrystallized from i-PrOAc (35 mL). The solid was dissolved under heating below reflux temperature and then the solution was placed at room temperature for 2 h. The precipitated solid was filtered out, rinsed with cold i-PrOAc and air-dried; thus, a material (0.77 g) with a product / by-product ratio of 1:5.2 was obtained.

[0191] The filtrate was left overnight at -5 °C, the precipitated solid was separated and the filtrate was gradually evaporated / cooled. These operations produced four batches of insufficient purity. They were combined into one batch (11.02 g, product / by-product ratio 1:0.11) and the crystallization was repeated: the batch was dissolved in i-PrOAc (25 mL) kept at RT for 1 h, followed by cooling to -5 °C and brief ultrasonic treatment. This resulted in spontaneous crystallization. Vacuum drying followed by immediate filtration provided 2.46 g of the crystalline product, batch 1, analysis 97.4% (qNMR).

[0192] The filtrate provided a number of crystallization batches of insufficient quality; these were subsequently recombined.

[0193] Recrystallization of the collected material from isopropanol (8.50 g): The sample was dissolved in 45 mL of i-PrOH by heating, an additional 45 mL volume of i-PrOH was added, the solution was cooled to rt and kept at this temperature for 1 h, then placed in a refrigerator at -5°C for 10 minutes. The first batch of crystals appeared at this time. The solution was further kept at 0°C for 1 h, then the crystalline material was collected by filtration, rinsed with cooled i-PrOH and dried under vacuum. The title compound was obtained in an amount of 6.67 g, batch 2, analysis 95.4% (qNMR).

[0194] The filtrate was evaporated to half its original volume and left overnight at 0°C. The next crop of crystals was collected by filtration, rinsed with cooled i-PrOH and dried under vacuum. The target material was obtained in an amount of 1.81 g, batch 3, assay 97.2% (qNMR).

[0195] Regarding batches 1-3: Each batch had mp 76°C; Each batch had the following 1 H NMR and 13 C NMR:

[0196] 1 H NMR (400MHz, CDCl3), δ, ppm: 7.52 (d J = 2.0Hz, 2H), 7.33 (t J = 2.0Hz, 1H), 4.09 (s, 6H), 1.32 (q J = 7.7Hz, 2H), 0.88 (t J = 7.7Hz).

[0197] 13 C NMR (101MHz, CDCl3), δ, ppm: 140.7, 134.8, 129.3, 124.9, 106.7, 72.0, 33.7, 22.5, 7.7.

[0198] HRMS: ES+m / z, (%): C 13 H 15 Cl2O3[M+1] + Theoretical value 289.0398; Batch 1 Found 289.0410; Batch 2 Found 289.0407; and Batch 3 Found 289.0404.

[0199] Preparation 4: 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane

[0200]

[0201] Step 1: Preparation of 1,1,1-tris(hydroxymethyl)phenylmethane

[0202] Phenylacetaldehyde (12.4 mL, 0.11 mol) and Ca(OH)2 (31.5 g, 0.43 mol) were added to a suspension of paraformaldehyde (12.8 g, 0.43 mol) in anhydrous THF (160 mL). The reaction mixture was stirred at 60-65°C (bath temperature) for 4 days.

[0203] After cooling to room temperature, the reaction mixture was filtered through Celite and the filter column was rinsed with DCM. The combined filtrate was concentrated using a rotary evaporator. The residual oil was treated with ethyl acetate, seeded (with the solid separated by chromatography in a previous experiment) and left in a refrigerator overnight.

[0204] The crystalline solid formed was collected by filtration and washed with cold EtOAc, and dried to afford the desired triol compound (9.8 g, 49% yield).

[0205] Step 2: Preparation of 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane

[0206] 0.19 mL (0.0025 mol) of TFA was added to 1,3-dichloro-5-(trimethoxymethyl)benzene (6.3 g, 0.025 mol) and 1,1,1-tris(hydroxymethyl)phenylmethane (4.6 g, 0.025 mol) suspended in anhydrous DCM (40 mL). The suspension became a clear solution and was left at room temperature for 48 h, then K2CO3 was added and the mixture was stirred for 3 h. The mixture was filtered and the solvent evaporated. An attempt was made to dissolve the residue (~9 g) in boiling toluene (25 mL), resulting in incomplete dissolution. After cooling to ambient temperature, the solution was decanted and cooled. The solid formed was collected by filtration and crystallized from n-heptane to obtain a white soft substance (5.2 g).

[0207] Another experiment performed on the same scale produced 5.0 g of product.

[0208] The combined batches were crystallized from isopropyl acetate to provide 5.78 g of 2,6,7-trioxabicyclo[2.2.2]octane; batch 1, assay 99.6% (qNMR);

[0209] The filtrate from batch 1 was cooled and stored at 0°C overnight. An additional 1.85 g of 2,6,7-trioxabicyclo[2.2.2]octane was then collected by filtration. Batch 2, assay 98.0% (qNMR). The total yield of the recrystallized product was 45%.

[0210] Batch 1 had an mp of 139°C; Batch 2 had an mp of 138°C.

[0211] Batch 1 and Batch 2 each have

[0212] 1 H NMR (400MHz, CDCl3), δ, ppm: 7.59 (d J = 2.0Hz, 2H), 7.39-7.45 (m, 2H), 7.33, 7.39 (m, 2H), 7.17-7.23 (m, 2H), 4.15 (s, 6H).

[0213] 13 C NMR spectrum (101MHz, CDCl3), δ, ppm: 140.4, 135.6, 134.9, 129.5, 129.4, 128.4, 125.4, 125.0, 107.2, 72.4, 37.1.

[0214] HRMS ES+m / z,(%): C 17 H 15 Cl2O3[M+1] + Theoretical value: 337.0398; measured value: 337.0406.

[0215] Preparation 5: 2-(3,5-dichlorophenyl)-2-methoxy-1,3-dioxolane

[0216]

[0217] Ethylene glycol (2.7 mL, 48.3 mmol, 1.2 eq) followed by TFA (0.3 mL, 3.9 mmol) was added to a solution of 1,3-dichloro-5-(trimethoxymethyl)benzene (10.04 g, 40.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 72 h. Anhydrous K2CO3 (1.5 g) was added and the mixture was stirred for 2 h and then filtered. The filtrate was evaporated to dryness to produce a yellow oil (10.76 g). The resulting oil was vacuum distilled and the fraction boiling at 160-185 ° C / 16 mbar was collected. The collected fractions (turbid green oil) were further purified by repeated distillation, and the distillate was collected at 180-183 ° C / 16 mbar. Distillation provided the desired product (5.63 g) as a yellow oil, analyzing 96.2% (qNMR).

[0218] 1 H NMR spectrum (400MHz, CDCl3), δ, ppm: 7.47 (d J = 1.9Hz, 2H), 7.34 (t, J = 1.9Hz, 1H), 4.19-4.30 (m, 2H), 4.03-4.13 (m, 2H), 3.28 (s, 3H).

[0219] 13C NMR spectrum (101MHz, CDCl3), δ, ppm: 141.4, 135.0, 129.1, 125.0, 120.1, 65.6, 50.4.

[0220] GCMS m / z,(%):217(100)[M-OMe] + ,173(71)[C7H3Cl2O] + ,145(30)[C6H3Cl2] +

[0221] Preparation 6: 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane

[0222]

[0223] 1,2,4-Butanetriol (3.57 mL, 40.0 mmol) was added to a solution of 1,3-dichloro-5-(trimethoxymethyl)benzene (10.04 g, 40.0 mmol) in anhydrous DCM (50 mL), followed by the addition of TFA (0.3 mL, 3.9 mmol), and the mixture was stirred at room temperature for 18 h. Anhydrous K2CO3 (1.5 g) was added, the mixture was stirred for 2 h, and then filtered. The filtrate was evaporated to dryness to produce a yellow oil (10.6 g) which slowly solidified.

[0224] The crude material is dissolved in toluene (30mL), filtered through a PTFE membrane, and then evaporated under reduced pressure. Heptane (80mL) is added to the residue, refluxed, then cooled, and the upper layer (hexane solution) is decanted. The bottom layer (oil) is repeatedly treated with hot heptane. The combined heptane solutions are reduced to approximately 25mL and kept for 3h at 4°C. Filter out the white precipitate, rinse with cold heptane and air-dry overnight.

[0225] The isolated 2,7,8-trioxabicyclo[3.2.1]octane (4.27 g) contained about 11 mol-% of an open-chain byproduct (dihydroxybutyl 3,5-dichlorobenzoate). This product was combined with another sample obtained in a similar manner (4.03 g, contaminated with about 7 mol-% of an open-chain benzoate) for further purification.

[0226] The combined batch (8.30 g in total) was dissolved in heptane (30 mL) by heating, and the solution was filtered hot and kept at room temperature for 5 h. The precipitated solid was collected by filtration and air-dried. This provided 6.78 g of crystalline product. The filtrate was partially evaporated (until about half of the original volume) and stored overnight at -5 ° C. This produced an additional amount (second batch) of solids of 1.03 g, and its quality was similar to that of the main batch. The second batch of products contained about 6 mol-% of dihydroxybutyl benzoate. Two batches of samples were combined and recrystallized from i-PrOAc as follows. The combined sample (7.84 g) was dissolved in hot isopropyl acetate (10 mL), the solution was cooled, and then placed overnight at -5 ° C. The formed white crystalline material was collected by filtration, rinsed with cooled i-PrOAc, and dried under vacuum at RT to provide the title compound (5.30 g). Analysis 96.2% (qNMR), mp81-84 ° C.

[0227] 1 H NMR spectrum (400MHz, CDCl3), δ, ppm: 7.53 (d J=2.0Hz, 2H), 7.36 (t J=2.0Hz, 1H), 4,83 (td J=3.4, 1.6Hz, 1H), 4.27 (dt J=11.7, 4.2Hz, 1H), 4.24 (d J=7.2Hz,1H),4.12(ddd J=7.3,4.8,1.6Hz,1H),4.03(ddd J=11.7,6.7,1.0Hz,1H),2.41(dddd J=13.8,12.2,6.7,3.4,1.8Hz,1H),1.51(dddd J=13.8,4.2,2.0,0.5Hz,1H).

[0228] 13 C NMR spectrum (101MHz, CDCl3), δ, ppm: 139.7, 134.9, 129.6, 125.0, 117.2, 73.9, 69.6, 59.5, 28.2.

[0229] HRMS ES+m / z,(%): C 11 H 11 Cl2O3[M+1] + Theoretical value: 261.0085; measured value: 261.0094.

[0230] Preparation 7: 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane

[0231]

[0232] Cis-phloroglucitol (2.92 g, 22.16 mmol) was added to a solution of 1,3-dichloro-5-(trimethoxymethyl)benzene (6.42 g, 25.57 mmol) in anhydrous DCM (50 mL), followed by the addition of BF3.OEt2 (0.28 mL, 2.21 mmol, ~0.1 eq) dropwise to the stirred suspension. The mixture was stirred at room temperature for 34 h, then the residual phloroglucitol (0.14 g) was filtered off and the solution evaporated under reduced pressure. TBME (40 mL) was added to the residue and the mixture was briefly refluxed, no complete dissolution was achieved. The mixture was cooled, maintained at 0 °C for 1 h, then filtered to collect the white precipitate (5.03 g).

[0233] The filtrate was evaporated to one quarter of its original volume to yield another crop of solid (0.50 g).

[0234] A similar experiment starting with 1.61 g (6.41 mmol) of 1,3-dichloro-5-(trimethoxymethyl)-benzene and 0.85 g (6.44 mmol) of cis-m-cyclohexanetriol provided 1.27 g of a crude solid.

[0235] All solids were combined and dissolved in MEK (30 mL) heated to reflux. The solution was filtered hot and stored overnight at room temperature, then the crystalline solid was filtered out, washed with a small amount of cold MEK and dried under vacuum at room temperature. This provided 5.586 g of the title compound (yield 61%*), analysis 99.8% (qNMR), mp 188 ° C.

[0236] The filtrate was evaporated to 1 / 3 volume and stored at -5°C for 4 h, yielding another batch of crystals of the same mass, 0.79 g (yield 9%*), assay 99.8% (qNMR), mp 188°C.

[0237] *The yields of both operations were calculated based on the total amount of the starting orthoester.

[0238] 1 H NMR (400MHz, CDCl3), δ, ppm: 7.57 (d, J=1.9Hz, 2H), 7.33 (t, J=1.9Hz, 1H), 4.56 (m, 3H), 3.11-2.49 (m, 3H), 1.81 (ddt, J=12.9, 2.1, 1.2Hz, 2H)

[0239] 13 C NMR (101MHz, CDCl3), δ, ppm: 142.5, 134.8, 129.3, 124.4, 108.1, 69.3, 33.0.

[0240] HRMS ES+m / z,(%): C 13 H 13 Cl2O3[M+1] + Theoretical value: 287.0242; measured value: 287.0253.

[0241] Preparation 8: 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane

[0242]

[0243] Step 1: Synthesis of 2-isopropyl-2-hydroxymethyl-1,3-propanediol

[0244] Isovaleraldehyde (83 g, 1.0 mol) was added to a solution of sodium hydroxide (60 g, 1.5 mol) in water (1200 mL) containing 37% formaldehyde solution (324 g, 4.0 mol) at RT over 0.5 hours. The solution was then stirred at 50-55 ° C for 3 h and placed overnight at RT. It was filtered out from a small amount (2.7 g) of crystalline solid, and the solution (1725 g) was weighed. 15% (259 g) of it was obtained and extracted 4x with DCM (200 mL). The extract was concentrated to provide 7.0 g of crystalline oil. The resulting solid was shown as an ether dimer by 1H NMR, i.e. (2,2'-(oxybis(methylene))bis(2-isopropylpropane-1,3-diol)).

[0245] The aqueous solution remaining from the previous DCM extraction was treated with solid sodium chloride (40 g) and extracted with isopropyl acetate (4 x 200 mL). The combined isopropyl acetate extracts were concentrated in vacuo to provide 14.5 g (97.8 mmol) of the desired 2-isopropyl-2-hydroxymethyl-1,3-propanediol (pure, but with a small amount of isopropyl acetate by 1H NMR).

[0246] Step 2: Synthesis of 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane

[0247] Toluene (150 mL) was added, followed by 3,5-dichlorobenzoic acid (DCBA, 17.0 g, 89 mmol) and methanesulfonic acid (MSA, 0.8 g). The mixture was refluxed under Dean-Stark for 6 h; 1.9 g of water (theoretical amount is 3.2 g) was collected and left overnight. The mixture was extracted with 10% KOH solution (100 mL and 20 mL) at 60-70°C and then washed with water at the same temperature. The aqueous extract was acidified, and the resulting white solid was filtered and dried to produce 8.8 g (53% of the initial) of DCBA.

[0248] The toluene solution was concentrated to provide 14.5 of an oil which contained about 30% of the desired orthoester by NMR. Upon dissolution in methanol (100 mL) and treatment with solid KOH (5.0 g, 89 mmol), a solution was obtained which deposited crystals upon standing. Filtration and washing (methanol) provided pure 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane (1.6 g, 13% more (ex) reacted DCBA); 1 H NMR: δ7.4m(2H); 4.0(s,6H); 1.4m(1H) and 0.8d(6H).

[0249] Alternatively, when step 2 was performed using p-toluenesulfonic acid (PTSA) as the catalyst instead of MSA, the conversion to the desired orthoester was very poor (yielding 90% recovery of DCBA and 30% of theoretical amount of water).

[0250] Another batch of the desired orthoester was obtained as follows. 388 g of the 1725 g solution (from step 1 above) (22.5% of the total) was taken and worked up in the same manner as above: extracted 4 times with DCM (250 mL) to remove tetraol dimers, then NaCl (60 g) was added and extracted 4 times with isopropyl acetate (200 mL) to provide 17.5 g (118.2 mmol) of pure (2-(hydroxymethyl)-2-isopropylpropane-1,3-diol) as a semisolid. 3,5-Dichlorobenzoic acid (16.5 g, 86.39 mmol) was added to this semisolid, followed by toluene (200 mL) and MSA (1.2 g, 12.5 mmol). The solution was refluxed under Dean-Stark for 6 h and cooled to ambient temperature. There was 2.3 g of water in the trap. Additional MSA (1.2 g) was added and reflux was continued for another 6 h, resulting in an additional 0.5 mL of water. The batch was cooled to ambient temperature, treated with 100 mL of 6% KOH solution at 40-50 ° C, and then washed with 100 mL of water at the same temperature. Toluene was removed to leave 28 g of oil. This oil was dissolved in methanol (150 mL) and water (10 mL) and treated with potassium hydroxide (6 g, 107 mmol) at ambient temperature (which converts the positive ester into a soluble triol and potassium 3,5-dichlorobenzoate). The orthoester then began to crystallize rapidly; the suspension was cooled to 0-10 ° C for 0.5 h, and filtered and washed and dried with methanol to provide 1- (3,5-dichlorophenyl) -4- isopropyl -2,6,7- trioxabicyclo [2.2.2] octane (5.6 g, 21.5%) as a white crystalline powder.

[0251] Preparation 9: 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane

[0252]

[0253] 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane can be prepared in a manner similar to the preparation of the compound of 8 starting from 3,3-dimethylbutanal (1.0 mol) which is added to a solution of sodium hydroxide (60 g, 1.5 mol) in water (1200 mL) containing 37% formaldehyde solution (324 g, 4.0 mol) at RT over 0.5 h. The reaction sequence is then carried out in a manner similar to the preparation of 8 to provide the desired 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane. In step 2 of the synthesis, boron trifluoride etherate can be used in a similar manner as an alternative acid catalyst, in addition to using methanesulfonic acid. Example

[0254] Examples 1-47 were performed to investigate the effect of various parameters as described below on the reaction of 4-amino-3-hydroxybenzoic acid with 1,3-dichloro-5-(trimethoxymethyl)benzene to provide 6-carboxy-1-(3,5-dichlorophenyl)benzoxazole (tafamidil), as described below.

[0255]

[0256] Example 1

[0257] 4-Amino-3-hydroxybenzoic acid (0.500 g, 3.26 mmol, 1.0 eq) was dissolved in 8.00 mL MeOH and 1,3-dichloro-5-(trimethoxymethyl)benzene (0.86 g, 3.4 mmol, 1.05 eq) in 2.00 mL MeOH was added thereto. The reaction mixture was stirred at RT for 6 h, then heated to 60 ° C and stirred overnight. The reaction mixture became a viscous slurry. At 23 h, HPLC analysis of the reaction mixture indicated 77.29 area % of the desired product. The reaction mixture was cooled and filtered. The resulting solid was washed with MeOH (10 mL) and dried under vacuum (65 ° C, ~50 mbar) to provide 0.531 g (52.8% isolated yield) of the desired product tafamidib as a yellow-pink solid.

[0258] Example 2

[0259] 4-Amino-3-hydroxybenzoic acid (0.500 g, 3.26 mmol, 1.0 eq) was dissolved in 8.00 mL MeOH, and TFA (25.0 μL, 0.33 mmol, 0.1 eq) was added followed by 1,3-dichloro-5-(trimethoxymethyl)benzene (0.86 g, 3.4 mmol, 1.05 eq) in 2.00 mL MeOH. The reaction mixture was stirred at RT for 6 h, then heated to 60 ° C and stirred overnight. The reaction mixture became a viscous slurry. At 23 h, HPLC analysis of the reaction mixture indicated 92.19 area % of the desired product. The reaction mixture was cooled and filtered. The resulting solid was washed with MeOH (10 mL) and dried under vacuum (65 ° C, ~50 mbar) to provide 0.834 g (82.9% isolated yield) of the desired product tafamidib as a pink solid.

[0260] Example 3

[0261] 4-Amino-3-hydroxybenzoic acid (0.500 g, 3.26 mmol, 1.0 eq) was dissolved in 8.00 mL MeOH, and TFA (63.0 μL, 0.82 mmol, 0.25 eq) was then added to 1,3-dichloro-5-(trimethoxymethyl)benzene (0.86 g, 3.4 mmol, 1.05 eq) in 2.00 mL MeOH. The reaction mixture was stirred at RT for 6 h, then heated to 60 ° C and stirred overnight. The reaction mixture became a viscous slurry. At 23 h, HPLC analysis of the reaction mixture indicated 91.29 area % of the desired product. The reaction mixture was cooled and filtered. The resulting solid was washed with MeOH (10 mL) and dried under vacuum (65 ° C, ~50 mbar) to provide 0.818 g (81.3% isolated yield) of the desired product tafamidib as a pink solid.

[0262] Example 4

[0263] 4-Amino-3-hydroxybenzoic acid (0.500 g, 3.26 mmol, 1.0 eq) was dissolved in 8.00 mL MeOH, and TFA (63.0 μL, 0.82 mmol, 0.25 eq) was then added to 1,3-dichloro-5-(trimethoxymethyl)benzene (0.86 g, 3.4 mmol, 1.05 eq) in 2.00 mL MeOH. The reaction mixture was seeded by adding tafamidil (50 mg, 0.16 mmol, 0.05 eq). The reaction mixture was stirred at RT for 6 h, then heated to 60 ° C and stirred overnight. The reaction mixture became a slurry that was easier to stir than the slurry obtained in Example 1-3. At 23 h, HPLC analysis of the reaction mixture indicated 92.36 area % of the desired product. The reaction mixture was cooled and filtered. The resulting solid was washed with MeOH (10 mL) and dried under vacuum (65 °C, -50 mbar) to afford 0.831 g (82.7% isolated yield) of the desired product as a pink solid.

[0264] The reaction of Examples 1-3 was monitored using high performance liquid chromatography (HPLC) with UV detection at 1 h, 2 h, 4 h, 7 h and 23 h. 25 mL of the reaction mixture was sampled and diluted with 975 mL of DMSO.

[0265] The HPLC chromatographic conditions used to monitor the reaction (Method A) were as follows:

[0266] Column: Agilent Zorbax SB-C18, 1.8 mm, 3.0 x 50 mm; Column temperature: 50°C; Mobile phase A (MPA): 0.05% TFA in water; Mobile phase B (MPB): acetonitrile;

[0267] Gradient [time (min), (%MPA / %MPB)]: 0 (95.0 / 5.0); 1 (95.0 / 5.0); 9 (0 / 100); 11.5 (0 / 100); 11.6 (95.0 / 5.0); 12.0 (95.0 / 5.0);

[0268] UV detection; injection volume: 1 mL; collection time: 12 min, 2 min after collection.

[0269] The chromatographic results indicated that the reaction catalyzed by TFA proceeded much faster than the uncatalyzed reaction and was essentially complete after 4 h, whereas the uncatalyzed reaction was not complete at 23 h (see Table 1 below). Seeding the catalyzed reaction with tafamidib provided a reaction mixture slurry that was easier to stir than the unseeded reaction mixture.

[0270] Table 1:

[0271]

[0272] The material obtained from this process was analyzed by 1H, 13C NMR and LCMS. The results obtained indicated that the desired product tafamidis was obtained.

[0273] 1H NMR (500MHz, DMSO-d6)δ 1 H NMR (500MHz, DMSO-d6) δ13.20 (s, 1H), 8.18 (dd, J = 1.5, 0.6 Hz, 1H), 8.02 ( d, J = 1.9 Hz, 2H), 7.97 ( dd, J = 8.4, 1.5 Hz, 1H), 7.86-7.81 (m, 2H).

[0274] 13C NMR (126MHz, DMSO-d6) δ167.07,162.35,150.42,145.05,135.58,132.06,129.47,129.16,126.89,126.23,120.36,112.59.

[0275] SQ-LCMS analysis of the product from this method was compared to a standard sample of thafamidis free acid, and the retention time, observed molecular ion (m / z 308.10 (M+H)), and fragments of the product of this method were consistent with thafamidis free acid.

[0276] Example 5-23

[0277] The reaction of 4-amino-3-hydroxybenzoic acid (AHBA) with 1,3-dichloro-5-(trimethoxymethyl)benzene (orthoester = "OE") in the presence of 0.25 eq TFA as a catalyst was evaluated in various solvents according to the following general procedure.

[0278] AHBA (0.100 g, 0.653 mmol, 1.0 eq) was mixed in 1.50 mL of solvent for about 1 h, and TFA (12.6 μL, 0.163 mmol, 0.25 eq) was added thereto, and the mixture was stirred for 10 minutes. OE (0.18 g, 0.718 mmol, 1.1 eq) in 0.50 mL of solvent was then added to the AHBA mixture. The reaction mixture was heated at 60° C. The reaction mixture was sampled at 1 h, 5 h, and 21.5 h, and the area % of the desired product tafamidib was determined using HPLC analysis using the aforementioned HPLC method A (see Table 2 below).

[0279] Table 2:

[0280]

[0281] The reaction was found to proceed rapidly in several solvents. In MeOH, EtOH, IPA, n-BuOH, acetonitrile, acetone, MEK, EtOAc, and 1,2-DME, the reaction appeared to be substantially complete in an hour or less. However, impurities were observed in the reactions carried out in EtOH, IPA, n-BuOH, acetone, and MEK. The impurities in the reactions in which EtOH, IPA, or n-butanol were solvents may be the corresponding ethyl, isopropyl, or n-butyl esters of 3,5-dichlorobenzoic acid, respectively. The reaction was found to proceed more slowly in the ether solvents THF, 1,4-dioxane, or MTBE, but no significant levels of impurities were observed. In the less polar solvents anisole, chloroform, chlorobenzene, heptane, cyclohexane, and toluene, the reaction proceeded very slowly, and significant amounts of impurities with a retention time of 6.1 minutes were observed in each of these reactions. Water is not an ideal solvent because 1,3-dichloro-5-(trimethoxymethyl)benzene is insoluble in water and can be easily hydrolyzed.

[0282] Examples 24-28

[0283] The effect of varying amounts of the orthoester 1,3-dichloro-5-(trimethoxymethyl)-benzene (1.0, 1.5, 2.0, 5.0 or 10.0 equivalents) on the reaction to form tafamidis was evaluated in Examples 24-28.

[0284] General Operation

[0285] 4-Amino-3-hydroxybenzoic acid AHBA (0.200 g, 1.31 mmol) was added to a solution of TFA (0.0050 mL, 0.065 mmol) in MeOH (4 mL), followed by the addition of 1,3-dichloro-5-(trimethoxymethyl)-benzene (orthoester). The reaction mixture was stirred and heated at 60 ° C. The reaction mixture was sampled at 1 h, 2 h, 5 h and 22 h 40 min and analyzed and determined by HPLC using the aforementioned HPLC method A. The area % of the desired product hefamidide. All reactions proceeded rapidly and precipitated within 15 minutes. The reaction progress was tracked by monitoring the disappearance of the AHBA peak. The more orthoesters used, the faster the reaction was completed. Example 24 (wherein 1.0 eq. of orthoesters was used) was not completely completed, which may be due to the fact that a small amount of orthoesters were hydrolyzed to 3,5-dichlorobenzoic acid methyl esters during the reaction. The reaction mixtures of Examples 27 and 28 (wherein 5.0 and 10.0 eq. of orthoesters were used) turned purple. The desired product tafamidate was isolated by filtration and the filter cake was washed with methanol. The isolated products from Examples 27 and 28 were slightly pink in color.

[0286] Example 24: The amount of 1,3-dichloro-5-(trimethoxymethyl)-benzene used was 0.260 mL, 1.31 mmol, 1.0 eq.

[0287] Example 25: The amount of 1,3-dichloro-5-(trimethoxymethyl)-benzene used was 0.390 mL, 1.96 mmol, 1.5 eq.

[0288] Example 26: The amount of 1,3-dichloro-5-(trimethoxymethyl)-benzene used was 0.521 mL, 2.61 mmol, 2.0 eq.

[0289] Example 27: The amount of 1,3-dichloro-5-(trimethoxymethyl)-benzene used was 1.30 mL, 6.52 mmol, 5.0 eq.

[0290] Example 28: The amount of 1,3-dichloro-5-(trimethoxymethyl)-benzene used was 2.60 mL, 13.1 mmol, 10.0 eq.

[0291] The results of Examples 24-28 are provided in Table 3 below.

[0292] Table 3:

[0293]

[0294] Examples 29-33

[0295] Examples 29-33 were conducted to determine the effect of varying amounts (5, 10, 25, 50 and 100 mol % relative to AHBA) of trifluoroacetic acid (TFA) on the reaction of AHBA with 1,3-dichloro-5-(trimethoxymethyl)-benzene.

[0296] General procedure: Prepare a stock solution of TFA (1.263 mL) in MeOH (50 mL). Add MeOH to 0.200 g of AHBA (1.31 mmol), followed by the stock solution of TFA in MeOH to provide a total volume of 4.0 mL. Add 1,3-dichloro-5-(trimethoxymethyl)benzene (0.286 mL, 1.44 mmol, 1.10 eq.) to this solution. Heat the reaction mixture to 60°C and maintain at this temperature overnight. Sample the reaction mixture at 0.5 h, 1.0 h, 2.0 h, 5.0 h and 21.25 h and analyze and determine the area % of the desired product tafamidib by HPLC method A. (See Table 4 below).

[0297] Table 4:

[0298]

[0299] The reactions of Examples 29-33 proceeded very quickly, forming a precipitate while the reaction mixture heated up, ultimately causing the reaction mixture to become an unstirrable slurry. The reactions of Examples 29 and 30 initially proceeded at a slower rate than Examples 31-33 but were substantially complete, while the reactions of Examples 31-33 initially proceeded at a faster rate than Examples 29-30, but Examples 31-33 all had unreacted AHBA present at 21.25 hours.

[0300] Examples 34-46

[0301] Examples 34-46 were conducted to determine the effect of no acid, 10 mol % or 25 mol % of various acids (relative to AHBA), or 0.75, 1.00 or 1.25 equivalents of triethylamine on the reaction of AHBA with 1,3-dichloro-5-(trimethoxymethyl)-benzene.

[0302] General procedure: 2.50 mL of MeOH was added to 150 mg of AHBA (0.979 mmol, 1.0 eq). No acid, 10 mol% or 25 mol% of acid, or 0.75 eq, 1.0 eq or 1.25 eq of TEA (see Examples below) was added thereto. 1,3-dichloro-5-trimethoxymethylbenzene (0.246 g, 0.980 mmol, 1.00 eq) in 0.50 mL of MeOH was added thereto. The reactions of Examples 34-43 were stirred at RT and the reactions of Examples 44-47 were stirred at RT for 6 h, followed by heating at 60 ° C overnight. The reaction mixture was sampled at 1 h, 6 h and as specified in Table 5, and analyzed and determined by HPLC Method A for the area % of the desired product tafamidib. (See Table 5 below). After 24.25 h the reaction mixtures from Examples 34-39 and 42-43 were filtered and the solids were washed with MeOH (3 mL) and dried under vacuum (65 °C, -50 mbar) to afford tafamidate as a pink solid (yield provided in Table 5).

[0303] Example 34: Acid: TFA, 0.0075 mL, 0.098 mmol, 10 mol%.

[0304] Example 35: Acid: TFA, 0.0188 mL, 0.246 mmol, 25 mol%.

[0305] Example 36: Acid: HCl in water (12.2 M) 0.0080 mL, 0.098 mmol, 10 mol%.

[0306] Example 37: Acid: HCl in water (12.2 M) 0.0201 mL, 0.245 mmol, 25 mol%.

[0307] Example 38: Acid: HCl in MeOH (1.0 M) 0.098 mL, 0.098 mmol, 10 mol%.

[0308] Example 39: Acid: HCl in MeOH (1.0 M) 0.24 mL, 0.24 mmol, 25 mol%.

[0309] Example 40: Acid: AcOH, 0.0056 mL, 0.098 mmol, 10 mol%.

[0310] Example 41: Acid: AcOH, 0.0140 mL, 0.244 mmol, 25 mol%.

[0311] Example 42: Acid: MsOH, 0.0064 mL, 0.098 mmol, 10 mol%.

[0312] Example 43: Acid: MsOH, 0.0161 mL, 0.246 mmol, 25 mol%.

[0313] Example 44: Base: TEA, 0.102 mL, 0.732 mmol, 75 mol%.

[0314] Example 45: Base: TEA, 0.137 mL, 0.983 mmol, 100 mol%.

[0315] Example 46: Base: TEA, 0.171 mL, 1.23 mmol, 125 mol%.

[0316] Example 47: No acid or base was added.

[0317] Table 5:

[0318]

[0319] Examples 48-51

[0320]

[0321] Procedure: Solutions of TFA (316.25 μL) in MeOH (50 mL) and TFA (316.25 μL) in IPA (50 mL) were prepared. In Example 48, 3.20 mL of MeOH was added to AHBA (0.200 g, 1.31 mmol, 1.0 eq.), followed by 0.80 mL of the above prepared TFA solution in MeOH (0.065 mmol, 5 mol%). In Example 49, 4.0 mL of TFA solution in MeOH (0.327 mmol, 25 mol%) was added to AHBA (0.200 g, 1.31 mmol, 1.0 eq.). In Example 50, 3.20 mL of IPA was added to AHBA (0.200 g, 1.31 mmol, 1.0 eq.), followed by 0.80 mL of the above prepared TFA solution in IPA (0.065 mmol, 5 mol%). In Example 51, 4.0 mL of TFA solution in IPA (0.327 mmol, 25 mol%) was added to AHBA (0.200 g, 1.31 mmol, 1.0 eq.). The cyclic orthoester 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (0.395 g, 1.44 mmol, 1.10 eq.) was added to each of the mixtures in Examples 48-51. The reaction mixture was heated at 60°C and samples were taken at 1 h, 2 h, 4 h and 19.75 h and the area % of tafamidate was determined by HPLC (see Table 6 below). In Example 51, the reaction mixture was filtered and the solid was washed with IPA (4 mL) and dried overnight in a vacuum oven (65°C, ~50 mbar) to provide the desired product tafamidate (0.298 g, 74.1% yield) as a light pink solid. 1H NMR and HPLC of the solid obtained from the reaction were consistent with tafamidate.

[0322] Table 6:

[0323]

[0324] The reaction in IPA proceeded faster than that in methanol, and the reaction in IPA was nearly complete at 19.75 h.

[0325] Embodiment 52

[0326]

[0327] 4-amino-3-hydroxybenzoic acid (401 mg, 2.62 mmol) and 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (795 mg, 2.89 mmol) followed by TFA (30 μL, 0.388 mmol) were added to 8 mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12 h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2 h. The resulting solid was collected by filtration and rinsed with IPA (2x4 mL) for cleaning the reaction vessel. The resulting pink solid was dried at 60°C for 12 h under vacuum (50 mbar) to provide tafamid (637 mg, 2.068 mmol, 79% yield). When compared to standards, 1H NMR, LC-MS and LC-MS / MS were obtained and met the desired product tafamid. LC-MS used to monitor the reaction completion before separation showed 76.7% tafamidis peak area.

[0328] Embodiment 53

[0329]

[0330] 4-amino-3-hydroxybenzoic acid (402mg, 2.62mmol) and 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane (832mg, 2.88mmol) followed by TFA (30μL, 0.388mmol) were added to 8mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2h. The resulting solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The resulting pink solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamid (564mg, 1.83mmol, 69.9% yield). When compared with standards, 1H NMR, LC-MS and LC-MS / MS were consistent with the desired product tafamid. LC-MS used to monitor the reaction completion before separation showed 65.4% tafamidis peak area.

[0331] Embodiment 54

[0332]

[0333] 4-amino-3-hydroxybenzoic acid (405mg, 2.65mmol) and 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane (974mg, 2.89mmol) followed by TFA (30μL, 0.388mmol) were added to 8mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2h. The resulting solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The resulting pink solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamid (591mg, 1.92mmol, 72.5% yield). When compared with standards, 1H NMR, LC-MS and LC-MS / MS were consistent with the desired product tafamid. LC-MS used to monitor the reaction completion before separation showed 65.5% tafamidis peak area.

[0334] Embodiment 55

[0335]

[0336] 4-amino-3-hydroxybenzoic acid (402mg, 2.62mmol) and 2-(3,5-dichlorophenyl)-2-methoxy-1,3-dioxolane (735mg, 2.95mmol) were added to 8mL of IPA at 20°C under stirring followed by TFA (30μL, 0.388mmol). The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2h. The resulting solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The resulting pink solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamid (701mg, 2.28mmol, 86.7% yield). When compared with standards, 1H NMR, LC-MS and LC-MS / MS were consistent with the desired product tafamid. LC-MS used to monitor the reaction completion before separation showed 88.9% tafamidis peak area.

[0337] Embodiment 56

[0338]

[0339] 4-amino-3-hydroxybenzoic acid (402mg, 2.65mmol) and 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane (761mg, 2.91mmol) followed by TFA (30μL, 0.388mmol) were added to 8mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2h. The resulting solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The resulting pink solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamid (679mg, 2.20mmol, 84.0% yield). When compared with standards, 1H NMR, LC-MS and LC-MS / MS were consistent with the desired product tafamid. LC-MS used to monitor the reaction completion before separation showed 78.5% tafamidis peak area.

[0340] Embodiment 57

[0341]

[0342] 4-Amino-3-hydroxybenzoic acid (400 mg, 2.61 mmol) and 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane (842 mg, 2.93 mmol) followed by TFA (30 μL, 0.388 mmol) were added to 8 mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12 h. The mixture was then cooled to 20°C and granulated in batches at 20°C for 2 h. The resulting solid was collected by filtration and rinsed with IPA (2x4 mL) for washing the reaction vessel. The resulting solid was dried at 60°C for 12 h under vacuum (50 mbar) to provide a solid (692 mg). This solid was analyzed by 1H NMR and LC-MS indicating that it was mainly the above-mentioned open-ring 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane as the main component, and LC-MS / MS analysis indicated that the desired product tafamidide was present as a minor component. It is hypothesized that the ring strain of the starting 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane causes hydrolysis of this material, favoring the reaction leading to the formation of tafamidil.

[0343] Embodiment 58

[0344]

[0345] 4-amino-3-hydroxybenzoic acid (402mg, 2.62mmol) and 1-(3,5-dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane (2.88mmol) followed by TFA (30μL, 0.388mmol) were added to 8mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was cooled to 20°C and granulated in batches at 20°C for 2h. The obtained solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The obtained solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamidy. 1H NMR, LC-MS and LC-MS / MS were compared with tafamidy standard samples.

[0346] Embodiment 59

[0347]

[0348] 4-amino-3-hydroxybenzoic acid (402mg, 2.62mmol) and 4-(tert-butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane (2.88mmol) followed by TFA (30μL, 0.388mmol) were added to 8mL of IPA at 20°C under stirring. The reaction mixture was heated to 85°C and stirred at this temperature for 12h. The mixture was cooled to 20°C and granulated in batches at 20°C for 2h. The obtained solid was collected by filtration and rinsed with IPA (2x4mL) for cleaning the reaction vessel. The obtained solid was dried at 60°C for 12h under vacuum (50 mbar) to provide tafamidy. 1H NMR, LC-MS and LC-MS / MS were compared with tafamidy standard samples.

Claims

1. A method for preparing 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia, The method comprises reacting 1.0 equivalent of 4-amino-3-hydroxybenzoic acid of Formula IIIa with 1.0-1.1 equivalent of 3,5-dichlorophenyl orthoester compound of Formula II to provide 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of Formula Ia Where R 2a , R 2b and R 2c Each is methyl, or R 2a , R 2b and R 2c Together they are CH3C(CH2-)3; wherein the reaction of the compound of formula IIIa and the compound of formula II used to provide the compound of formula Ia is carried out in a solvent and in the presence of 0.05, 0.10 or 0.25 equivalents of an acid catalyst, the solvent being selected from: methanol and isopropanol, the acid catalyst being selected from: trifluoroacetic acid, hydrochloric acid and methanesulfonic acid, and wherein the reaction is carried out at a temperature of room temperature to 65°C for a time of 0.25 hour to 40 hours.

2. The method of claim 1, wherein the acid catalyst is trifluoroacetic acid.

3. The method of claim 1, wherein the acid catalyst is hydrochloric acid.

4. The method of claim 1, wherein the acid catalyst is methanesulfonic acid.

5. The method of any one of claims 1 to 4, wherein the reaction of the compound of formula IIIa with the compound of formula II to provide the compound of formula Ia is carried out in the presence of 0.10 or 0.25 equivalents of an acid catalyst.

6. The method of claim 1, wherein R 2a , R 2b and R 2c Each is a methyl group.

7. The method of claim 1, wherein the compound of formula II is 8. The process of any one of claims 1 to 4, further comprising the step of isolating the compound of formula Ia.

9. The process of claim 8, wherein the compound of formula Ia is isolated by filtration.

10. A process for preparing 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia, The method comprises reacting one molar equivalent of 4-amino-3-hydroxybenzoic acid of formula IIIa with one molar equivalent of 3,5-dichlorophenyl orthoester compound of formula IIa in a suitable solvent in the presence of 0.25 equivalent of an acid catalyst to provide 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole of formula Ia The solvent is isopropanol, the acid catalyst is selected from trifluoroacetic acid, hydrochloric acid and methanesulfonic acid, and the reaction is carried out at a temperature of 60° C. for a period of 0.25 hours to 40 hours.

11. A method for preparing a 6-carboxy-2-(3,5-dichlorophenyl)benzoxazole compound of formula I, The method comprises reacting 1.0 equivalent of a 4-amino-3-hydroxybenzoic acid compound of formula III with 1.05 equivalent of a 3,5-dichlorophenyl orthoester compound of formula II to provide the compound of formula I Where R 1 is hydrogen, and the reaction is carried out in isopropanol in the presence of 0.10 or 0.25 equivalents of methanesulfonic acid at a temperature of 60° C. for a period of 0.25 to 40 hours, and the compound of formula II is selected from: 1,3-Dichloro-5-(trimethoxymethyl)benzene; 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane; 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane; 2-(3,5-dichlorophenyl)-2-methoxy-1,3-dioxolane; 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane; 3-(3,5-dichlorophenyl)-2,4,10-trioxadamantane; 1-(3,5-Dichlorophenyl)-4-isopropyl-2,6,7-trioxabicyclo[2.2.2]octane; and 4-(tert-Butyl)-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane.

12. A method for preparing a compound of formula IIa-2, Where R 3 is selected from: isopropyl, tert-butyl and neopentyl, The method comprises reacting a compound of formula IV with 3,5-dichlorobenzoic acid in toluene in the presence of methanesulfonic acid 13. The method of claim 12, wherein R 3 is isopropyl or tert-butyl.

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