WO2018108954A1

WO2018108954A1 - Process for the preparation of 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol

Info

Publication number: WO2018108954A1
Application number: PCT/EP2017/082493
Authority: WO
Inventors: Francis Gosselin; Xin Linghu
Original assignee: F. Hoffmann-La Roche Ag; Genentech, Inc.
Priority date: 2016-12-12
Filing date: 2017-12-12
Publication date: 2018-06-21
Also published as: AR110356A1

Abstract

Methods of making 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol 9, an intermediate useful for the synthesis of estrogen receptor modulating compounds are described.

Description

PROCESS FOR THE PREPARATION OF 2-(3-(FLUOROMETHYL)AZETIDIN-l-

YL)ETHAN- 1 -OL CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. provisional application no. 62/432837, filed on 12 December 2016, the entire disclosures of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to methods of making 2-(3-(fluoromethyl)azetidin- 1 -yl)ethan- 1 - ol 9, an intermediate useful for the synthesis of estrogen receptor modulating compounds.

BACKGROUND OF THE INVENTION

The estrogen receptor ("ER") is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β (beta)-estradiol and estrones. ER has been found to have two isoforms, ER-a (alpha) and ER-β (beta). Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, as well as others diseases or conditions.

The estrogen receptor is a critical driver in breast cancer (Di Cosimo, S. & Baselga, J.

(2010) Nat. Rev. Clin. Oncol). Since about 60-70% of breast cancer (BC) is estrogen receptor positive (ER+), modulation of estrogen activity and/or synthesis is the main therapeutic strategy in the treatment of ER+ BC. Effective hormonal therapies are used across many lines of therapy to decrease estrogen/ligand (ovarian suppression, aromatase inhibitors). Selective Estrogen Receptor Modulators (SERM) bind to ER, downregulate ER levels and antagonize ER transcriptional activity. Selective Estrogen Receptor Degraders (SERD) bind to ER and degrade ER.

Many breast cancer patients relapse or develop resistance in their tumors, which are often still dependent on the ER. There is a need for new ER-a targeting agents that have activity in the setting of metastatic disease and acquired resistance.

SUMMARY OF THE INVENTION The invention relates to methods of making intermediate 2-(3-(fluoromethyl)azetidin- l-yl)ethan-l-ol 9:

H

and salts thereof.

An aspect of the invention is a process for the preparation of 2-(3- (fluoromethyl)azetidin-l-yl)ethan-l-ol 9 comprising reacting 3-(fluoromethyl)azetidine 7, ethyl glyoxalate, and a first hydride reducing agent to form ethyl 2-(3-(fluoromethyl)azetidin- l-yl)acetate 8

reacting 8 with a second hydride reducing agent to form 9.

In some embodiments, the first and second hydride reducing agent is independently selected from sodium triacetoxyborohydride, Red-Al, lithium aluminum hydride (LAH), sodium borohydride and diisobutylaluminum hydride (DIBAL).

In some embodiments, the process further comprises reacting tert-butyl 3- (fluoromethyl)azetidine- 1 -carboxylate 6 :

6

with an acidic reagent to form 7.

In some embodiments, the acidic reagent is selected from para-toluenesulfonic acid, trifluoroacetic acid, and acetic acid.

In some embodiments, the process further comprises reacting tert-butyl 3- (((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate 5a or tert-butyl 3- ((tosyloxy)methyl)azetidine- 1 -carboxylate 5b :

Boc 5a Boc 5b

with a fluorinating reagent to form 6. In some embodiments, the fluorinating reagent is selected from tetra-butylammonium fluoride (TBAF) and hydrogen fluoride/trimethylamine.

In some embodiments, about 1% to 5% of tert-butyl 3-(chloromethyl)azetidine-l- carboxylate is formed with 6.

In some embodiments, the process further comprises reacting the mixture of 6 and about 1% to 5% of tert-butyl 3-(chloromethyl)azetidine-l-carboxylate with 1,4- diazabicyclo[2.2.2]octane (DABCO) and then purifying 6 by aqueous extraction in an organic solvent whereby tert-butyl 3-(chloromethyl)azetidine-l-carboxylate is decreased to less than about 1%.

In some embodiments, the process further comprises reacting tert-butyl 3- (hydroxymethyl)azetidine- 1 -carboxylate 4 :

with a sulfonylation reagent and an amine base to form 5a or 5b.

In some embodiments, the sulfonylation reagent is selected from para-toluenesulfonic anhydride, para-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride,

methanesulfonic anhydride, and methanesulfonyl chloride.

In some embodiments, the amine base is selected from triethylamine,

diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In some embodiments, the process further comprises reacting 1 -(tert-butyl) 3-methyl azetidine-l,3-dicarboxylate 3:

Boc 3

with a hydride reducing agent to form 4.

In some embodiments, the hydride reducing agent is selected from Red-Al and sodium borohydride.

In some embodiments, the process further comprises reacting methyl azetidine-3- carboxylate hydrochloride 2:

HCI 2 with Boc anhydride and an amine base to form 3.

In some embodiments, the amine base is selected from triethylamine,

diisopropylethylamine, and DBU.

In some embodiments, the process further comprises reacting azetidine-3-carboxylic acid 1 :

with thionyl chloride and methanol to form 2.

In some embodiments, the process further comprises reacting 9 and 2-(4-iodophenyl)- 4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)- 2H-chromene 47

to form 3-(fluoromethyl)-l-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3- ((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)azetidine 48:

In some embodiments, the process further comprises reacting 48 with aqueous acetic acid to form 2-(4-(2-(3-(fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl- -chromen-6-ol 46:

In some embodiments, the process further comprises separating the racemic mixture of 46 into (S)-2-(4-(2-(3-(fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol and (R)-2-(4-(2-(3-(fluoromethyl)azetidin- 1 -yl)ethoxy)phenyl)-3- (3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol.

DEFINITIONS

The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers (stereocenters), and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane -polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include

interconversions by reorganization of some of the bonding electrons.

The phrase "pharmaceutically acceptable salt" as used herein, refers to

pharmaceutically acceptable organic or inorganic salts of a compound of the invention.

Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, and pamoate (i.e., 1 , Γ-methylene-bis -(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

The phrase "pharmaceutically acceptable salt" as used herein, refers to

PREPARATION OF 2-(3 -(FLUOROMETHYL) AZETIDIN- 1 - YL)ETH AN- 1 -OL 9

The present invention includes processes, methods, reagents, and intermediates for the synthesis of 2-(3-(fluoromethyl)azetidin-l-yl)ethan-l-ol 9, an intermediate useful for the synthesis of estrogen receptor modulating compounds, including 2-(4-(2-(3- (fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol 46 (CAS Registry Number 1443983-86-5) and the (R) and (S) enantiomers (Example 10), which are described in: US 9475798; WO 2016/097071; WO 2016/097073; WO

2016/097072; WO 2014/205136; WO 2014/205138; WO 2013/090836, all of which are expressly incorporated by reference). Other reaction conditions and reagents may be used with 9 to form 46, or to react 9 with other aryl iodide compounds to incorporate the fluoromethyl(azetidin- 1 -yl)ethoxy group.

As used herein, 2-(3-(fluoromethyl)azetidin-l-yl)ethan-l-ol 9 includes all

stereoisomers, geometric isomers, tautomers, and salts thereof.

It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

The compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The compounds of the invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or

"tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine- enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

The compounds of the invention also include isotopically-labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ^UC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated ( H) and carbon- 14 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography

(PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Starting materials and reagents for the preparation of 2-(3-(fluoromethyl)azetidin-l- yl)ethan-l-ol 9 are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y.

(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-

Verlag, Berlin, including supplements (also available via the Beilstein online database).

The following Schemes and Examples illustrate the chemical reactions, processes, and methodology for the synthesis of 2-(3-(fluoromethyl)azetidin- 1 -yl)ethan- 1 -ol 9, and certain intermediates and reagents.

Scheme 1 :

Scheme 1 shows the preparation of 2-(3-(fluoromethyl)azetidin-l-yl)ethan-l-ol 9. Azetidine-3-carboxylic acid 1 was treated with thionyl chloride in methanol to give methyl azetidine-3-carboxylate hydrochloride 2 (Example 2). The nitrogen of 2 was protected with the Boc (tert-butyloxycarbonyl) group with Boc anhydride and an amine base, such as triethylamine, diisopropylethylamine, and DBU, to give 3 (Example 3). Reduction of the methyl ester of 3 with a hydride reducing agent, such as sodium borohydride or Red-AI, gave the alcohol 4 (Example 4), which was converted to the methanesulfonyl (mesyl) leaving group with methanesulfonyl chloride 5a (Example 5) or the para-toluenesulfonate (tosyl) with para-toluenesulfonyl chloride 5b in an amine base such as triethylamine,

diisopropylethylamine, and DBU. Other leaving groups such as halide: CI, Br, and I, can be employed as alternatives to mesylate and tosylate. The reactions to form 5a and 5b can be conducted in solvents such as dichloromethane (DCM), tetrahydrofuran (THF), or 2- methyltetrahydrofuran (MeTHF). Solvent MeTHF has the advantage of poorly solubilizing the Et₃N.HCl salt by-product which can displace mesylate to form the CI analog, tert-butyl 3- (chloromethyl)azetidine-l-carboxylate (Example 6) in the next step to form the fluoro intermediate 6. Thus chloride can be effectively removed from 5a and 5b by filtration.

Treatment of 5a or 5b with triethylamine trihydrofluoride gave tert-butyl 3- (fluoromethyl)azetidine-l-carboxylate 6 (Example 6). Other fluorination reagents such as tetrabutylammonium fluoride (TBAF) can be used to prepare 6, although about 5-15% hydrolysis by-product, tert-butyl 3-(hydroxymethyl)azetidine-l-carboxylate, is formed when using TBAF as fluorination reagent since TBAF contains water. Using 3HF.Et₃N/DBU, the hydrolysis by-product can be controlled to around 1%. Alternatively, fluoro intermediate 6 can be obtained directly from alcohol 4 with PSF/HF/TEA. Production of 6 may be accompanied by small amounts of the chloro analog, tert-butyl 3-(chloromethyl)azetidine-l- carboxylate (Example 6). Crude 6 is heated in DMF with l,4-diazabicyclo[2.2.2]octane (DABCO), potassium iodide, and potassium carbonate, converting the chloro analog to the quaternary ammonium salt which is removed by aqueous extraction.

Deprotection of the nitrogen by removal of the Boc group from 6 with a slight molar excess (1.1 equiv.) of para-toluenesulfonic acid hydrate in methyl tert-butylether (MTBE) gives the non-hygroscopic and easy to handle para-toluene sulfonate salt (TsOH) of 3- (fluoromethyl)azetidine 7 (Example 7). The HC1 salt of 7 is a highly hygroscopic and gummy solid, not suitable for scale up. Other salts of 7 may be useful such as sulfate or organic sulfonates. Naphthalene-l,5-disulfonic acid also forms a crystalline, non-hygroscopic salt of 7. Reductive amination of 7 by condensing ethyl glyoxalate in toluene and DCM, and reducing the imine intermediate with sodium triacetoxyborohydride (NaBH(OAc)₃), as the first hydride reducing agent, gave the ethyl ester, ethyl 2-(3-(fluoromethyl)azetidin-l- yl)acetate 8 (Example 8). Other glyoxalate reagents can be used such as methyl glyoxalate, ethyl glyoxalate, and isopropyl glyoxalate. Other first hydride reducing agents can be used such as reduction of the ester with a second hydride reducing agent gave the alcohol 9. Red- Al® (sodium bis(2-methoxyethoxy)aluminum hydride in toluene provided an efficient reaction and allowed large scale distillation of 9 after aqueous workup with efficient removal of by-products 2-methoxyethanol and ethylene glycol (Example 9). Other hydride reducing agents can be used to reduce 8 to 9, including sodium triacetoxyborohydride, lithium aluminum hydride (LAH), sodium borohydride and diisobutylaluminum hydride (DIBAL). Alternatively, alcohol 9 can be obtained directly from 3-(fluoromethyl)azetidine 7 by alkylation with 2-bromoethanol or ethylene oxide. Scheme 2:

Scheme 2 shows the preparation of azetidine-3-carboxylic acid 1.

Diphenylmethanamine (benzhydrylamine) and 2-oxopropane-l,3-diyl dimethanesulfonate were reacted to give l-benzhydrylazetidin-3-one 10 (Example 1). Reduction of the ketone of 10 with a hydride reducing agent gave l-benzhydrylazetidin-3-ol 11. Alternatively, 11 can be prepared by cyclization of benzhydrylamine and epichlorohydrin in diisopropylethylamine and ethanol. Mesylation of 11 with methanesulfonyl chloride gave l-benzhydrylazetidin-3-yl methanesulfonate 12. Displacement of the mesyl group with cyanide ion gave 1- benzhydrylazetidine-3-carbonitrile 13. Hydrolysis of 13 with aqueous acid gave 1- benzhydrylazetidine-3-carboxylic acid 14. Deprotection of 14 by hydrogenolysis gave 1.

Scheme 3:

EtO Et

24

Scheme 3 shows an alternative route for the preparation of 2-(3- (fluoromethyl)azetidin-l-yl)ethan-l-ol 9. Bis-triflation of diethyl 2,2- bis(hydroxymethyl)malonate 15 with triflic anhydride and diisopropylethylamme (DIPEA) gave diethyl 2,2-bis((((trifluoromethyl)sulfonyl)oxy)methyl)malonate 16. Displacement of both triflate groups and cyclization of 16 with 2-(benzyloxy)ethan-l -amine gave diethyl l-(2- (benzyloxy)ethyl)azetidine-3,3-dicarboxylate 17. Saponification of the ester groups of 17 with aqueous sodium hydroxide gave bis sodium salt of l-(2-(benzyloxy)ethyl)azetidine-3,3- dicarboxylate 18. Acidification of 18 with aqueous hydrochloric acid gave l-(2- (benzyloxy)ethyl)azetidine-3,3-dicarboxylic acid 19. Heating of 19 caused loss of carbon dioxide to form l-(2-(benzyloxy)ethyl)azetidine-3-carboxylic acid 20. Reaction of 20 with thionyl chloride and methanol form the methyl ester, methyl l-(2-(benzyloxy)ethyl)azetidine- 3-carboxylate 21. Reduction of the methyl ester with a hydride reducing agent such as lithium aluminum hydride gave (l-(2-(benzyloxy)ethyl)azetidin-3-yl)methanol 22. Sulfonylation of 22 gave mesylate, (l-(2-(benzyloxy)ethyl)azetidin-3-yl)methyl methanesulfonate 23a, or tosylate, (l-(2-(benzyloxy)ethyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate 23b.

Fluorination of 23a or 23b with triethylamine trihydrofluoride gave l-(2-(benzyloxy)ethyl)- 3-(fluoromethyl)azetidine 24. Reductive removal of the benzyl group with palladium catalysis and hydrogen gas of 24 gave 9.

Scheme 4:

Scheme 4 shows another alternative route for the preparation of 2-(3- (fluoromethyl)azetidin-l-yl)ethan-l-ol 9. Reaction of ethyl acrylate and formaldehyde with l,4-Diazabicyclo[2.2.2]octane (DABCO) in dioxane and water gave ethyl 2- (hydroxymethyl)acrylate 25. Michael addition of 2-(benzyloxy)ethan-l -amine to 25 in methanol gave ethyl 3-((2-(benzyloxy)ethyl)amino)-2-(hydroxymethyl)propanoate 26.

Deprotonation and cyclization of 26 with tert-butylmagnesium chloride in THF gave l-(2- (benzyloxy)ethyl)-3-(hydroxymethyl)azetidin-2-one 27. Fluorination of 27 with triethylamine trihydrofluoride, perfluoro-l-butanesulfonyl fluoride, CF₃(CF₂)₃S0₂F (PBSF, CAS Reg. No. 375-72-4 Zhao, X. et al (2009) Synlett, No. 5, 779-782), and DBU gave l-(2- (benzyloxy)ethyl)-3-(fluoromethyl)azetidin-2-one 28. Other f uorinating reagents such as Diethylaminosulfur trifluoride (DAST, CAS Reg. No. 38078-09-0) and 2-Pyridinesulfonyl Fluoride (PyFluor, CAS Reg. No. 878376-35-3) may be useful in converting 27 to 28. Reduction of the beta-lactam carbonyl of 28 with lithium aluminum hydride gave 24, followed by conversion to 9 following Scheme 3.

Scheme 5

Scheme 5 shows an alternative route for the preparation of 28. Bromination of 25 with phosphorus tribromide gave ethyl 2-(bromomethyl)acrylate 29. Fluorination of 29 with tetrabutylammonium fluoride (TBAF) gave ethyl 2-(fluoromethyl)acrylate 30. Michael addition of 2-(benzyloxy)ethan-l -amine to 30 gave ethyl 3-((2-(benzyloxy)ethyl)amino)-2- (fluoromethyl)propanoate 31. Deprotonation and cyclization of 31 with tert-butylmagnesium chloride in THF gave 28.

Scheme 6

THF/H20 34 THF 35

Scheme 6 shows an alternative route for the preparation of 24. Reduction of the carboxylic acid of 14 with borane in THF gave (l-benzhydrylazetidin-3-yl)methanol 32. Reductive removal of the benzhydryl group with hydrogen gas and palladium catalysis in methanol in the presence of para-toluene sulfonic acid gave the para-toluene sulfonate salt, azetidin-3-ylmethanol 4-methylbenzenesulfonate 33. Acylation of 33 with 2- (benzyloxy)acetyl chloride and dipotassium hydrogen phosphate in THF and water gave 2- (benzyloxy)-l-(3-(hydroxymethyl)azetidin-l-yl)ethan-l-one 34. Fluorination of 34 with triethylamine trihydrofluoride and PBSF in THF gave 2-(benzyloxy)-l-(3-

(fluoromethyl)azetidin-l-yl)ethan-l-one 35. Reduction of the amide carbonyl of 35 with borane in THF gave 24. cheme 7:

Scheme 7 shows another alternative route for the preparation of 24. Reduction of trimester, triethyl methanetricarboxylate 36 with borane/trimethylsulfide in THF gave triol, 2- (hydroxymethyl)propane-l,3-diol 37. Acetonide formation of 37 with 2,2-dimethoxypropane and para-toluene sulfonic acid hydrate in THF gave (2,2-dimethyl-l,3-dioxan-5-yl)methanol 38. Sulfonylation of 38 with methanesulfonyl chloride and triethylamine in dichloromethane (DCM) gave (2,2-dimethyl-l,3-dioxan-5-yl)methyl methanesulfonate 39. Fluorination of 39 with triethylamine trihydrofluoride gave 5-(fluoromethyl)-2,2-dimethyl-l,3-dioxane 40. Acidic hydrolysis in aqueous sulfuric acid or an organic sulfonic acid of the acetonide group of 40 gave 2-(fluoromethyl)propane-l,3-diol 41. The alcohol groups of 41 were converted to sulfonyl leaving groups: bis-mesylate, 2-(fluoromethyl)propane-l,3-diyl dimethanesulfonate 42a, bis-triflate, 2-(fluoromethyl)propane-l,3-diyl bis(trifluoromethanesulfonate) 42b, or bis- tosylate, 2-(fluoromethyl)propane-l,3-diyl bis(4-methylbenzenesulfonate) 42c. Cyclization of 42a, 42b, or 42c with 2-(benzyloxy)ethan-l -amine gave 24. cheme 8

Scheme 8 shows an alternative route for the preparation of 3-(fluoromethyl)azetidine 4-methylbenzenesulfonate 7. Fluorination of 39 with triethylamine trihydrofluoride gave in situ intermediate 40 which was hydrolyzed to diol 41. Triflation of 41 with triflic anhydride and diisopropylethylamine gave in situ intermediate 42b which was cyclized with diphenylmethanamine to give l-benzhydryl-3-(fluoromethyl)azetidine 43. Deprotection by removal of benzhydryl from 43 with hydrogen gas under palladium catalysis and in the presence of para-toluenesulfonic acid gave para-toluene sulfonate salt 7. Scheme 9:

Scheme 9 shows another alternative route for the preparation of l-benzhydryl-3- (fluoromethyl)azetidine 43. The carboxylic acid of 14 was converted to methyl ester, methyl l-benzhydrylazetidine-3-carboxylate 44 with thionyl chloride and methanol. Reduction of 44 with sodium borohydride gave 32. Methanesulfonylation of 32 with methanesulfonyl chloride and triethylamine in DCM gave (l-benzhydrylazetidin-3-yl)methyl methanesulfonate 45. Fluorination of 45 with triethylamine trihydrofluoride gave 43. EXAMPLES

Example 1 Azetidine-3-carboxylic acid 1

A solution of diphenylmethanamine (benzhydrylamine) and 2-oxopropane-l,3-diyl dimethanesulfonate were reacted to give l-benzhydrylazetidin-3-one 10 (Scheme 2).

Reduction of the ketone of 10 with a hydride reducing agent gave l-benzhydrylazetidin-3-ol 11. Alternatively, 11 can be prepared by cyclization of benzhydrylamine and epichlorohydrin in diisopropylethylamine and ethanol. Mesylation of 11 with methanesulfonyl chloride gave l-benzhydrylazetidin-3-yl methanesulfonate 12. Displacement of the mesyl group with cyanide ion gave l-benzhydrylazetidine-3-carbonitrile 13. Hydrolysis of 13 with aqueous acid gave l-benzhydrylazetidine-3-carboxylic acid 14. Deprotection of 14 by hydrogenolysis gave 1 (CAS Reg. No.: 36476-78-5 zwitterion; 102624-46-4 hydrochloride salt; 106887-11-0 sodium salt; 1282041 potassium salt).

Example 2 Methyl azetidine-3-carboxylate hydrochloride 2

A 5000 liter reactor was charged with azetidine-3-carboxylic acid 1 (CAS Reg. No. 36476-78-5, 256.5 kg, 2540 mol, 1.0 eq.) and MeOH (1026 kg, 4 wt) and purged with nitrogen gas, and cooled to 5-15 °C. Thionyl chloride (362 kg, 3043 mol, 1.20 eq.) was added dropwise at 5-25 °C giving a violent exothermic reaction over about 3.5 hrs. The mixture was stirred at about 15-20 °C for 16 hrs to give crude 2 (CAS Reg. No.. 100202-39-9 HC1 salt, 343238-58-4 free base), used directly in Example 2. A sample showed by 1H NMR that all starting material was consumed.

Example 3 l-(tert-Butyl) 3-methyl azetidine-l,3-dicarboxylate 3

Triethylamine (TEA, 560 kg, 5544 mol, 2.18 eq) was added dropwise to the crude solution of 2 at 5-10 °C giving a vigorous exothermic reaction over about 7 hrs. The mixture was cooled to 5-15 °C. More triethylamine was added (210 kg, 2082 mol, 0.82 eq). Oi-tert- butyl dicarbonate (boc anhydride, Boc₂0, CAS Reg. No. 24424-99-5 (587 kg, 2690 mol, 1.06 eq.) dropwise at 5-15 °C, giving a slightly exothermic reaction with gas generated for about 7 hrs. The mixture was stirred at 15-20 °C for 16 hrs. Methanol was removed by evaporation at 50 °C over about 5 hrs. Toluene (1360 kg, 5.3 wt) and water (1750 kg, 6.8 wt) were added and stirred for 20 min. The organic phases were separated. The water phase was extracted with toluene. The combined organic phases were washed with brine and dried over MgS0₄ (150 kg, 0.58 wt) for 30 min, and filtered. The filter cake was washed with toluene. The combined organic phases were evaporated at 50-60 °C under vacuum, (vacuum: about 0.08 Mpa, about 40 hrs) to give 3 (CAS Reg. No. 610791-05-4, 582 kg 90.4 w% by qNMR assay) in 96.4% corrected yield.

Example 4 tert-Butyl 3-(hydroxymethyl)azetidine-l-carboxylate 4

A 5000 liter reactor was charged with sodium borohydride (NaBH₄, 72kg, 1902 mol, 1.2 eq.) and tetrahydrofuran (THF, 2240 kg, 6.6 wt), purged with nitrogen gas, and heated to 60-65 °C. A solution of 3 (377 kg, 90.4 wt%, 1585 mol, 1.0 eq) in methanol (MeOH, 70 kg, 2188 mol, 1.40 eq) was added dropwise at 60-65 °C with hydrogen gas evolution. Stirring was continued at 60-65 °C for 4 to 6 hrs. Gas chromatography sampling indicated all 3 was consumed. More methanol (70 kg, 2188 mol, 1.40 eq) was added dropwise at 60-65 °C to quench the excess NaBH₄. The reaction mixture was cooled to 30-35 °C.

A second 5000 liter reactor was charged with water (H₂0, 1700 kg) and heated to 30 to 40 °C. The reaction mixture in the first reactor containing 3 was transferred to the second reaction under vacuum to quench the reaction, and stirred at 50 °C for 1 hrs. Both the organic phase and aqueous phase turned clear. The mixture was cooled to 25-30 °C and the phases separated. The organic phase was concentrated under vacuum. (60 °C, Vacuum: -0.08 Mpa, over about 10 hrs. The aqueous phase was extracted with DCM (1300 kg). The organic phases were combined and washed with 10 w% aq. K₂CO₃ (500 kg x 2) and brine (650 kg), dried with MgS0₄ (200 kg), and filtered. The filter cake was washed with DCM (260 kg). The wash and filtrate organic phases were combined and concentrated under vacuum to give 4 (CAS Reg. No. 142253-56-3, 170 kg, 99.9 % GC purity) as a light yellow oil in 91% yield (uncorrected). The obtained oil became white solid after cooling to room temperature.

Example 5 tert-Butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l-carboxylate 5a

A reactor was charged with 4 (430 kg, 2300 mol, 1.0 eq.), TEA (350 kg, 3450 mol, 1.5 eq) and DCM (2750 kg, 6.4 wt). The mixture was cooled to 0 to 5 °C. Methanesulfonyl chloride (MsCl, 303 kg, 2645 mol, 1.15 eq) was added at 0 to 5 °C. The mixture was agitated at 0 to 5 °C for 1 hrs, then warmed to 10-15 °C and stirred for 4 hrs. Gas chromatography sampling indicated all 4 was consumed. The reaction was quenched with H₂0 (2000 kg, 4.65 wt) and the inner temperature was maintained below 20 °C. After stirring at 15-20 °C for 30 minutes, the phases were separated. The aqueous phase was extracted with DCM (500 kg, 1.16 wt). The combined organic phases were washed with 5 w%> aq. citric acid (1500 kg, 3.5 wt) and water (1500 kg x 2, 7 wt), dried over Na₂S0₄ (100 kg, 0.23 wt) and filtered. The filter cake was washed with DCM (250 kg, 0.58 wt). The combined organic phases were evaporated at 40-50 °C under vacuum to give 5a (CAS Reg. No. 142253-57-4, 630 kg, 99.4 % GC purity) as a brown oil. 5a 1H NMR (300 MHz, DMSO-d₆): δ 4.33 (d, 2H), 3.92 (m, 2H), 3.62 (m, 2H), 3.21 (s, 3H), 2.91 (m, 1H), 1.41 (s, 9H)

Example 6 tert-butyl 3 -(fluoromethyl)azetidine- 1 -carboxylate 6

A 5000 liter reactor was charged with 5a (630 kg, 2354 mol, 1.0 eq) and triethylamine trihydrofluoride (hydrogen fluoride triethylamine, TREAT-HF, Et₃N.3HF, CAS Reg. No. 73602-61-6, 700 kg, 4348 mol, 1.8 eq) to 5000L reactor. The mixture was agitated under N₂ atmosphere while l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, CAS Reg. No. 6674-22-2, 1000 kg, 6579 mol, 2.8 eq.) was added dropwise at 25-55 °C. The mixture was agitated at 90-100 °C for 16 hrs. Gas chromatography sampling indicated all 5a was consumed. The mixture was cooled to 30-40 °C and quenched with water (1900 kg, 3.0 wt). The mixture was extracted with petroleum ether (PE, 790 kg x 2, 1.25 wt). The combined organic phases were washed with H₂0 (1300 kg, 2 wt) and brine (1300 kg, 2 wt), dried over Na₂S0₄ (100 kg, 0.16 wt), and filtered. The filter cake was washed with PE (132 kg, 0.2 wt). The combined organic phases were concentrated under vacuum at 45 °C to give 6 (CAS Reg. No. 1443983- 85-4, 408 kg, 98.8 % GC purity, 97 w% by qNMR assay) as light yellow oil in 88.0% isolated yield, containing about 1-3% of the chloro analog, tert-butyl 3- (chloromethyl)azetidine-l-carboxylate. 6 ¹H NMR (300 MHz, CD30D): δ 5.41, 5.40, 5.29, 5.28 (dd, 2H), 4.72 (m, 2H), 4.43 (m, 2H), 3.67 (m, 1H), 2.19 (s, 9H)

Removal of chloro analog, tert-butyl 3 -(chloromethyl)azetidine-l -carboxylate in 6:

1 % KI

A 5000 liter reactor was charged with crude 6 (408 kg, 2072 mol, containing 0.8-1.3%) of tert-butyl 3-(chloromethyl)azetidine-l-carboxylate; 397 kg, 2037 mol) and DMF (2000 kg, 2.5 w). l,4-Diazabicyclo[2.2.2]octane (DABCO, CAS Reg. No. 280-57-9, (8.4 kg, 75 mol, 2.0 eq), potassium iodide (KI, 6.5 kg, 39 mol, 1.0 eq) and potassium carbonate (K₂C0₃, 16 kg, 116 mol, 3.0 eq). Note: the amounts of DABCO, KI and K₂C0₃ are based on the amount of the chloro analog (1.0 eq.) and the volume of the solvent is based on the amount of crude 6 (1.0 wt). The mixture was stirred at 115-120 °C for 16 hours. Gas chromatography sampling indicated about 0.1% of the chloro analog remained. Additional DABCO (8.4 kg, 75 mol, 2.0eq), KI (6.5 kg, 39 mol, 1.0 eq) and K₂C0₃ (16 kg, 116 mol, 3.0 eq) were added to the reaction mixture and stirred at 115-120 °C for 5 hours. Gas chromatography sampling indicated less than about 0.03% of the chloro analog remained. The mixture was cooled to 20-30 °C. and 10 w% aq. NaCl (1500 kg) was added. The reaction mixture was extracted with PE (660 kg x 5). The combined organic phases were washed with saturated NaCl (1000 kg x 2), dried with anhydrous Na₂S0₄ (150 kg) and filtered. Presumably the quaternary salt, 1 -((1 -(tert-butoxycarbonyl)azetidin-3-yl)methyl)- 1 ,4-diazabicyclo[2.2.2]octan-l -ium chloride, formed by reaction of the chloro analog with DABCO, is removed in the aqueous washes. The filter cake was washed with petroleum ether (PE, 120 kg). The combined organic phases were concentrated under vacuum at 40-50 °C to give 6 (750 kg, 98.2 A% GC purity, 97 w% by qNMR assay) as a light yellow oil in 93.7% isolated yield, containing less than about 0.01% of the chloro analog, tert-butyl 3-(chloromethyl)azetidine-l-carboxylate.

Example 7 3-(Fluoromethyl)azetidine 7

A 5000 liter reactor was charged with methyl tert-butylether (MTBE, 1480 kg, 3.7 wt), 6 (400 kg, 97 w%>, 2053 mol, 1.0 eq) and para-toluenesulfonic acid hydrate (TsOH.H₂0, 430 kg, 2258 mol, 1.1 eq). The mixture was purged and agitated under N₂ atmosphere at 20- 30 °C for 2 hrs with isobutene and C0₂ gas generation. The mixture was further agitated at 30-40 °C for 2 hrs, at 40-50 °C for 2 hrs, and then at 50-55 °C for 12 hrs. Gas

chromatography sampling indicated less than 0.5% 6 remained. The reaction mixture was cooled to 10- 15 °C, filtered and washed with MTBE (300 kg). About 675 kg wet product para-toluene sulfonate salt of 7 (CAS Reg. No. 1443983-83-2 (free base), 80-82 w%) was obtained in quantitative yield as a light yellow solid, and used in the next step directly without further drying. 7 para-toluene sulfonate salt 1H NMR (400 MHz, DMSO-d₆): δ 8.63 (br, 2H), 7.51 (d, 2H), 7.13 (d, 2H), 4.45-4.63 (dd, 2H), 3.90 (m, 2H), 3.75 (m, 2H), 3.06 (m, 1H), 2.48 (s, 3H).

Example 8 Ethyl 2-(3-(fluoromethyl)azetidin-l-yl)acetate 8

A reactor was charged with DCM (1890 kg), 7 (256 kg, 82 w%, 804 mol, 1.0 eq) and ethyl glyoxalate (CAS Reg. No. 924-44-7, 197 kg, 965 mol, 1.2 eq, 50 w% toluene solution). The mixture was agitated at 15-20 °C for 2 hrs until the reaction mixture became clear. After cooling to 5-15 °C, sodium triacetoxyborohydride (NaBH(OAc)₃, CAS Reg. No. 56553-60-7, 340 kg, 1608 mol, 2.0 eq) was added in 34 portions to keep the internal temperature (IT) between 5-20 °C). The mixture was agitated at 15-25 °C for 16 hrs. Gas chromatography sampling indicated all starting material 7 was consumed. Water (1900 kg, 9wt) was added to the reaction mixture, with hydrogen gas evolution. The mixture was charged with 12 M HCl (61 kg) to adjust pH to 4-5 and agitated for 30 min. The phases were allowed to separate. The aqueous phase was extracted with DCM (500 kg, 2.4 wt). The organic phases were extracted with 0.1 M HC1 (250 kg x 2). The combined aqueous phases were adjusted to pH to 8-9 with K₂C0₃ (450 kg, 2.26 wt) with C0₂ evolution. Solid NaCl (450 kg, 2.38 wt) and MTBE (300 kg, 1.43 wt) were added and stirred for 30 min. whereupon a white solid precipitated. The white solid was removed by centrifugation and the solid was washed with MTBE (300 kg, 1.43 wt). The aqueous and organic phases were combined and stirred for 20 min. The phases were separated and the aqueous phase was extracted with MTBE (300 kg x 4,). The combined organic phases were dried over anhydrous Na₂S0₄ (100 kg, 0.5 wt) and filtered. The filter cake was washed with MTBE (250 kg x 2, 1 wt). The combined organics were concentrated under vacuum at 40 °C to give 8 (131 kg, 88 w% by qNMR assay, 82% yield) as light yellow oil. 8 1H NMR (400 MHz, CDC13): δ 4.57 (d, 1H), 4.46 (d, 1H), 4.19 (q, 2H), 3.55 (m, 2H), 3.26 (s, 2H), 3.20 (m, 2H), 2.91 (m, 1H), 1.27 (t, 3H)

Example 9 2-(3-(Fluoromethyl)azetidin-l-yl)ethan-l-ol 9

A 5000 liter reactor was charged with THF (1067 kg) and purged twice with N₂. A solution of Red-Al® (sodium bis(2-methoxyethoxy)aluminum hydride solution, 745 kg, 2582 mol, 70 w% toluene solution) the pipeline was rinsed with THF (45 kg). The reaction mixture was cooled to 0-5 °C. Two batches of 8 (124kg, 80 w%, 567 mol and 131kg, 88 w%, 659 mol) and THF (89 kg) were added to the elevated tanker. The mixture in the tanker of 8 and THF was introduced into the reactor under the N₂ flow at 0-10 °C. The mixture in the reactor was stirred at 15-20 °C for 12 hrs. Gas chromatography sampling indicated all starting material 8 was consumed. The reaction mixture was cooled to 0-5°C and 20 w% aq. NaOH (1075 kg, 5 wt) was added at 10-20 °C (H₂ generated). The mixture was stirred for 30 min at 15-25 °C and the phases were allowed to separate. The aqueous phase was extracted with Me- THF (344 kg x2). TLC analysis showed no 8 residue in aqueous phase. The organic phases were combined, washed with 33 w% aq. K₂C0₃ (516 kg x 4), dried over MgS0₄ (225 kg) and filtered. The filter cake was washed with Me-THF (170 kg). The combined organics were concentrated under vacuum at 45-50 °C to give 9 (243 kg crude product, 71.9 % GC purity, 2-methoxyethanol: 27.0 %) as brown oil. The crude product was further concentrated under vacuum to remove 2-methoxyethanol and purified by vacuum distillation (oil bath: 80-90 °C, vacuum: about 1 mbar, collected 60-75 °C fractions to give 250 kg of pure 9 (73% yield, 99.6-99.9 % GC purity). 1H NMR (300 MHz, CD30D): δ 4.52 (d, 1H), 4.41 (d, 1H), 3.51 (m, 2H), 3.44 (m, 2H), 3.11 (t, 2H), 2.80 (m, 1H), 2.59 (t, 2H). ¹³C NMR (400 MHz, CD30D): δ 84.27, 82.62, 60.50, 59.36, 55.76. F NMR: δ 225.27. Mass Spec. (M+H/l): 134.09

Example 10 2-(4-(2-(3 -(fluoromethyl)azetidin- 1 -yl)ethoxy)phenyl)-3 -(3 - hydroxyphenyl)-4-methyl-2H-chromen-6-ol 46

Following the procedures in WO 2014/205138 (Example 1, Step 1, page 83, incorporated by reference herein), a mixture of 2-(3-(Fluoromethyl)azetidin-l-yl)ethan-l-ol 9, racemic 2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro- 2H-pyr -2-yl)oxy)phenyl)-2H-chromene 47 (US 9475798, col 139):

copper iodide, potassium iodide, in butyronitrile was reacted to give 3-(fluoromethyl)- l-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2- yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)azetidine 48.

Deprotection of the tetrahydropyranyl (THP) groups with aqueous acetic acid gave 2- (4-(2-(3 -(fluoromethyl)azetidin- 1 -yl)ethoxy)phenyl)-3 -(3 -hydroxyphenyl)-4-methyl-2H- chromen-6-ol 46 (WO 2014/205138, Step 2, page 84. Separation of enantiomers from the racemate gives the (R) and (S) isomers.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

What is claimed is:

1. A process for the preparation of 2-(3 -(fluoromethyl)azetidin- 1 -yl)ethan- 1 -ol 9

comprising reacting 3-(fluoromethyl)azetidine 7, ethyl glyoxalate, and a first hydride reducing agent to form ethyl 2-(3-(fluoromethyl)azetidin-l-yl)acetate 8

reacting 8 with a second hydride reducing agent to form 9.

2. The process of claim 1 wherein the first and second hydride reducing agent independently selected from sodium triacetoxyborohydride, Red-Al, lithium aluminum hydride (LAH), sodium borohydride and diisobutylaluminum hydride (DIBAL).

3. The process of claim 1 further comprising reacting tert-butyl 3- (fluoromethyl)azetidine- 1 -carboxylate 6 :

with an acidic reagent to form 7.

4. The process of claim 3 wherein the acidic reagent is selected from para- toluenesulfonic acid, trif uoroacetic acid, and acetic acid.

5. The process of claim 3 further comprising reacting tert-butyl 3- (((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate 5a or tert-butyl 3- ((tosyloxy)methyl)azetidine- 1 -carboxylate 5b :

with a fluorinating reagent to form 6.

6. The process of claim 5 wherein the fluorinating reagent is selected from tetra- butylammonium fluoride (TBAF) and hydrogen fluoride/trimethylamine.

7. The process of claim 5 wherein about 1% to 5% of tert-butyl 3- (chloromethyl)azetidine-l-carboxylate is formed.

8. The process of claim 7 further comprising reacting the mixture of 6 and about 1% to 5% of tert-butyl 3-(chloromethyl)azetidine-l-carboxylate with 1,4- diazabicyclo[2.2.2]octane and then purifying 6 by aqueous extraction in an organic solvent whereby tert-butyl 3-(chloromethyl)azetidine-l-carboxylate is decreased to less than about 1%.

9. The process of claim 5 further comprising reacting tert-butyl 3- (hydroxymethyl)azetidine- 1 -carboxylate 4:

with a sulfonylation reagent and an amine base to form 5a or 5b.

10. The process of claim 9 wherein the sulfonylation reagent is selected from para-toluenesulfonic anhydride, para-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, and methanesulfonyl chloride.

11. The process of claim 9 wherein the amine base is selected from triethylamine, diisopropylethylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

12. The process of claim 9 further comprising reacting 1 -(tert-butyl) 3-methyl azetidine-l,3-dicarboxylate 3:

with a hydride reducing agent to form 4.

13. The process of claim 12 wherein the hydride reducing agent is selected from Red-Al and sodium borohydride.

14. The process of claim 12 further comprising reacting methyl azetidine-3- carboxylate hydrochloride 2:

HCI 2 with Boc anhydride and an amine base to form 3.

15. The process of claim 14 wherein the amine base is selected from

triethylamine, diisopropylethylamine, and DBU.

16. The process of claim 14 further comprising reacting azetidine-3-carboxyl acid 1 :

with thionyl chloride and methanol to form 2.

17. The process of claim 1 further comprising reacting 9 and 2-(4-iodophenyl)-4- methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H- chrome

to form 3-(fluoromethyl)-l-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-

((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)azetidine 48:

18. The process of claim 17 further comprising reacting 48 with aqueous acetic acid to form 2-(4-(2-(3-(fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol 46:

19. The process of claim 16 further comprising separating the racemic mixture of 46 into (S)-2-(4-(2-(3 -(fluoromethyl)azetidin- 1 -yl)ethoxy)phenyl)-3 -(3 -hydroxyphenyl)-4- methyl-2H-chromen-6-ol and (R)-2-(4-(2-(3-(fluoromethyl)azetidin- 1 -yl)ethoxy)phenyl)-3- (3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol.