SYNTHESIS OF INTERMEDIATES FOR MACROCYCLIC MCL-1 INHIBITORS BY MEANS OF A RING CLOSURE.

Abstract

Processes for synthesizing Mcl-1 inhibitors and intermediates such as compound F, which can be used to prepare them, are provided herein, where the variable PG is as defined herein. In particular, processes for synthesizing compound A1 and its salts or solvates, and compound A2 and its salts and solvates, are provided herein. (See Formulas).

Description

SYNTHESIS OF INTERMEDIATES FOR MACROCYCLIC MCL-1 INHIBITORS G BY MEANS OF A RING CLOSURE BACKGROUND CROSS REFERENCES TO RELATED APPLICATIONS This application claims the benefit over U.S. Provisional Application No. 63 / 020 958, submitted on May 6, 2020, which is incorporated herein by reference in its entirety and for all purposes as if it were fully set forth herein. TECHNICAL FIELD This disclosure relates to processes for synthesizing useful intermediates in the preparation of 13',13'-dioxide of (1 S,3'ñ,6'ñ,7'S,8'E,1 TS,12'F?)-6-chloro-7'-methoxy-11',12'dimethyl-3,4-dihydro-2 / - / ,15' / - / -spiro[naphthalene1,22'

[20] oxa

[13] thia[1,14]diazatetrachloro[14.7.2.03'6.019'24]pentacose [8,16,18,24]tetraen]-15'-one (compound A1; AMG 176), one of its salts or solvates, and in the preparation of 13',13'-dioxide of (1 S,3' / 7,6'R,7'ñ,8'E,11'S,12'f?)-6-chloro-7'-methoxy-11',12'dinet¡l-7'-((9aE)-octahydro-2 / 7-p¡hdo[1,2-a]pyraz¡n-2-¡lmethyl)-3,4-dihydro-2 / 7,15' / - / -spiro[naphthalene1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.03'6.019'24]pentacose[8,16,18,24]tetraen]-15'-one (compound A2; AMG 397), one of its salts or solvates. These compounds are inhibitors of myeloid cell leukemia protein 1 (Mcl-1). DESCRIPTION OF RELATED TECHNOLOGY The compound, 13', 13'-dioxide of (1 S,3'ñ,6'ñ,7'S,8'E,11'S,12'ñ)-6-chloro-7'-methoxy 11',12'-dimethyl-3,4-dihydro-2 / 7,15' / 7-spiro[naphthalene-1,22'

[20] oxa

[13] ta[1,14]diazatetrachloro[14.7.2.03'6.019'24]pentacose[8,16,18,24]tetraen]-15'-one (compound A1), is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): OMe The compound, 13',13'-dioxide of (1S,3'ñ,6' / :?,7'fí,8'E,irS,12'ñ)-6-chloro-7'-methoxy11',12'-dinetyl-7'-((9afí)-octahydro-2 / - / -pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2 / - / , 15Ήspiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.03'6.019'24]pentacose[8,16,18,24]tetraen]-15'-one (compound A2), is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): r / or Ln / zznz / E / YiAi A common feature of human cancer is the overexpression of Mcl-1. Overexpression of Mcl-1 prevents cancer cells from undergoing programmed cell death (apoptosis), allowing the cells to survive despite widespread genetic damage. Mcl-1 is a member of the Bcl-2 protein family. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) which, when activated, form a homooligomer on the outer mitochondrial membrane, leading to pore formation and leakage of mitochondrial contents—a step involved in triggering apoptosis. Anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit additional regulatory functions. Research has shown that Mcl-1 inhibitors may be useful for treating various types of cancer. Mcl-1 is overexpressed in numerous cancers. U.S. Patent No. 9,562,061, which is incorporated herein by reference in its entirety, describes compound A1 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods resulting in higher yields and purity of compound A1 are desired, particularly for the commercial production of compound A1. U.S. Patent No. 10,300,075, which is incorporated herein by reference in its entirety, describes compound A2 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods resulting in higher yields and purity of compound A2 are desired, particularly for the commercial production of compound A2. COMPENDIUM The present document provides a compound that has the structure of compound D: ίη / 77Π7 / E / YΙΛΙ (D), or one of its salts or solvates, where PG is a protecting group of alcohols. In several embodiments, PG is an ether, a silyl ether, an acetal or ketal, or an acyl group. In some cases, PG is an acyl group. In some cases, the acyl group is acetyl, pivaloyl, benzoyl (Bz), 4-bromobenzoyl (Br-Bz), 4-chlorobenzoyl, 4-iodobenzoyl, 4-fluorobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, or 2-naphthoyl. In some cases, PG is acetyl. In some cases, PG is pivaloyl. In some cases, PG is benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, or 2-naphthoyl. In some cases, PG is 4-bromobenzoyl. In some cases, PG is an ether. In some cases, the ether is methoxy, ethoxy, propoxy, butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), methoxypropyl ether (MOP), benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB), or 2-naphthylmethyl ether (Nap). In some cases, PG is an acetal or ketal. In some cases, PG is a tetrahydropyranilic acetal (THP).In some cases, PG is a silicyl ether. In some cases, PG is triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), or tert-butyldiphenylsilyl ether (TBDPS). This document also provides processes for synthesizing a compound D or one of its salts or solvates: which include: Mix a compound C, an activating agent, an amine-type base, and a compound E in the presence of a solvent to form compound D or one of its salts or solvates Ln / Zznz / E / YIAI OPG where PG is a protective group of alcohols. In several embodiments, the processes further comprise synthesizing compound C by mixing compound B and a protecting group introduction reagent to form compound C: OH (B) In some cases, compound B and the protecting group introduction reagent are mixed with a base. In some cases, the base comprises pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), NaH, KH, K2CO3, Na2CO3, Li2CO3, CS2CO3, or a combination thereof. In several embodiments, PG is an ether, a silyl ether, an acetal or ketal, or an acyl group. In some cases, PG is an acyl group. In some cases, the acyl group is acetyl, pivaloyl, benzoyl (Bz), 4-bromobenzoyl (Br-Bz), 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, or 2-naphthoyl. In some cases, PG is acetyl. In some cases, PG is pivaloyl. In some cases, PG is benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, or 2-naphthoyl. In some cases, PG is 4-bromobenzoyl. In some cases, PG is an ether. In some cases, the ether is methoxy, ethoxy, propoxy, butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), methoxypropyl ether (MOP), benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB), or 2-naphthylmethyl ether (Nap). In some cases, PG is an acetal or ketal. In some cases, PG is a tetrahydropyranilic acetal (THP). In some cases, PG is a silyl ether.In some cases, PG is triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), or tert-butyldiphenylsilyl ether (TBDPS). In some cases, PG is acetyl, and the synthesis of compound C comprises mixing compound B, acetic anhydride, triethylamine, and 4-dimethylaminopyridine (DMAP) in the absence of solvent. ίη / 77Π7 / E / YΙΛΙ In several embodiments, PG is 4-bromobenzoyl and the synthesis of compound C comprises mixing compound B, 4-bromobenzoyl chloride, and pyridine in a solvent. In some cases, the solvent comprises tetrahydrofuran (“THF”), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, dichloromethane, 1,2-dichloroethylene, or a combination thereof. In several embodiments, the mixing of compound B and the protecting group introduction reagent is carried out for 30 minutes to 48 hours. In some cases, the mixing is carried out for 1.5 hours. In several embodiments, the mixing of compound B and the protecting group introduction reagent is carried out at a temperature of 0 °C to 40 °C. In several embodiments, compound B, prior to mixing with the protecting group introducer, is prepared as a free acid (free acid of compound B) from a salt form (salt of compound B). In some embodiments, the salt of compound B is an ammonium salt. In some cases, the salt of compound B comprises a cation of In some embodiments, the free acid of compound B is prepared by mixing the salt of compound B and phosphoric acid in a solvent to form the free acid of compound B. In some cases, the solvent comprises 2-methyltetrahydrofuran (2-MeTHF) or toluene. In several embodiments, the activating agent comprises an acid anhydride, an acid chloride-type agent, a carbodiimide-type agent, a uranium-type agent, an ammine-type agent, a phosphonium-type agent, or a combination thereof. In some cases, the activating agent is SOCl₂, oxalyl chloride, propanophosphonic acid anhydride, or a combination thereof. In several embodiments, the amine-type base for mixing compound C and compound E comprises pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof. In some cases, the amine-type base comprises diisopropylethylamine, triethylamine, or a combination thereof. In several embodiments, compound E and compound C are present in a molar ratio of 1:1 to 1.5:1 of compound C:compound E. In several embodiments, the mixture of compound C, compound E, the activating agent, and the amine-type base is produced in a solvent. In some cases, the solvent comprises tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, dichloroethane, 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, L-dimethylformamide, L-dimethylacetamide, L-methyl-2-pyrrolidone, or a combination thereof. In some cases, the solvent comprises toluene. This document also provides processes for synthesizing a compound A or one of its salts or solvates: Me. Or that include: mix an organometallic catalyst and a compound D Me. O (D) or one of its OPG salts or solvates in a solvent, for Me. Or form a compound F (F) or one of its salts. In several embodiments, compound D is synthesized by the processes described herein. In several embodiments, the organometallic catalyst comprises molybdenum or ruthenium. In some cases, the organometallic catalyst comprises a 1st generation Grubbs catalyst, 2nd generation Grubbs catalyst, 3rd generation Grubbs catalyst, 1st generation Hoveyda-Grubbs catalyst, 2nd generation Hoveyda-Grubbs catalyst Ln / Zznz / E / YIAI generation or a combination of these. In some cases, the organometallic catalyst is In several embodiments, the solvent comprises a nonpolar organic solvent. In some cases, the solvent is toluene, hexane, heptane, 1,4-dioxane, or a combination thereof. In several embodiments, the mixing of compound D and the organometallic catalyst is carried out at a temperature of approximately 50 °C to approximately 115 °C. In some cases, the mixing of compound D and the organometallic catalyst is carried out at a temperature of approximately 80 °C. In several embodiments, the processes also include deprotecting compound F to form compound A. In several embodiments, compound A is used to synthesize compound A1 or one of its salts or solvates. OMe (A1). In several embodiments, compound A is used to synthesize compound A2 or one of its salts or solvates. (A2) Other aspects and advantages will become apparent to those skilled in the art from a review of the following detailed description. The description from this point onward includes specific embodiments, it being understood that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION Herein, processes are proposed for synthesizing Mcl-1 inhibitors and corresponding intermediates for macrocyclic Mcl-1 inhibitors. En particular, se proporcionan procesos para sintetizar 13',13'-dióxido de (Ιδ,δΉ,βΉ,ϊ'δ,δ'Ε,ΙΙ'δ,^'^-β-οΙοΓΟ7'-metoxi-11',12'-d¡met¡l-3,4-d¡hidro-2 / - / ,15'H-esp¡ro[naftalen1,22'

[20] oxa

[13] tia[1,14]diazatetrac¡clo[14.7.2.03'6.019'24]pentacosa [8,16,18,24]tetraen]-15'-ona (compuesto A1), o una de sus sales o solvatos, y para sintetizar 13',13'-dióxido de (1S,3Έ,6Έ,7Ή,8Έ,1TS, 12'fí)-6-cloro-7'-metox¡-11', 12'-dinet¡l-7'-((9afí)octahidro-2 / - / -pir¡do[1,2-a]piraz¡n-2-¡lmet¡l)-3,4-d¡h¡dro-2 / - / ,15' / - / -espiro[naftalen-1,22'

[20] oxa

[13] tia[1,14]diazatetrac¡clo[14.7.2.03'6.019'24]pentacosa[8,16,18,24]tetraen]-15'-ona (compuesto A2), o una de sus sales o solvatos: OMe U.S. Patent No. 9,562,061, which is incorporated herein by reference in its entirety, describes compound A1, or one of its salts or solvates, as an Mcl-1 inhibitor and provides a process for its preparation. U.S. Patent No. 9,562,061 also describes a process for synthesizing intermediates for a macrocyclic Mcl-1 inhibitor, which are shown below and used in the synthesis of compound A. ίη / 77Π7 / E / YΙΛΙ U.S. Patent No. 10,300,075, which is incorporated herein by reference in its entirety, describes compound A2, or one of its salts or solvates, as an Mcl-1 inhibitor and provides a process for its preparation. The disclosure of salts and solvates of compound A2 in U.S. Patent No. 10,300,075 is incorporated herein by reference in its entirety. This patent also describes a process for synthesizing intermediates for macrocyclic Mcl-1 inhibitors, shown below, used in the synthesis of compound A. In particular, patent '061 describes a process for synthesizing compound A, which is shown in Scheme 1 below, in, for example, columns 93-94 of patent '061. Scheme 1 - Previous synthesis of compound A The process shown above has several disadvantages. The processes in Scheme 1 cannot be adequately scaled up. Although the yields stated in patent O61 for the steps in Scheme 1 are adequate, these yields are for small scale. When these processes are scaled up, the yields are dramatically reduced. For example, when the processes in Scheme 1 are scaled up to larger quantities (e.g., 20 g or more), the yield of the first step (sulfonamide coupling) that is The yield of Ln / Zznz / E / YIAI shown in Scheme 1 is approximately 35%, and the yield of the second step (metathesis reaction) of Scheme 1 is approximately 60%, giving an overall yield for the two steps of approximately 21%. In particular, the first step of Scheme 1 exhibits a low yield and many impurities when scaled up, which must be removed before the subsequent metathesis step. Chromatography is required to purify the product after the first step. Furthermore, the metathesis reaction without a protected alcohol, as shown in Scheme 1, requires a high catalyst loading (e.g., 10 mol%, based on the moles of product from the first step) and dilute conditions in an environmentally undesirable solvent (e.g., 1,2-DCE), which limits the product yield when scaling up this reaction to larger quantities.The second step of Scheme 1 exhibits low yield and many impurities (e.g., isomerized and dimeric byproducts) when scaled up. Chromatography is also required to purify the product after the second step. Favorably, the processes described herein utilize more favorable reaction conditions (e.g., they use more environmentally friendly solvents), have a higher yield than the process in Scheme 1, and produce fewer byproducts. For example, the yield of the sulfonamide addition can be improved from 35% in Scheme 1 to 76%–90% in the processes described herein. Furthermore, the processes described herein use more environmentally benign solvents and reagents and do not require chromatography to purify the products of each step. The processes described herein have improved yields compared to the prior art due to the use of an allyl alcohol protecting group, which minimizes dimeric and isomeric impurities in both the sulfonamide coupling step and the ring-closing metathesis step.The processes described herein utilize intermediates with protected allyl alcohol, which renders these intermediates crystalline, thus facilitating scale-up, long-term storage, and purification. Processes are provided herein for synthesizing compound A or one of its salts or solvates. ίη / 77Π7 / E / YΙΛΙ OH (A); comprising: mixing a compound C, an activating agent, an amine-type base, and a compound E in the presence of a solvent to form compound D or one of its salts or solvates where PG is a protecting group of alcohols, as explained in detail below. As will be seen, the disclosed processes involve the formation of an intermediate with a protected vinyl alcohol, compound D, by the addition of compound E to compound C. Furthermore, a compound having the structure of compound D is provided herein: (D), or one of its salts or solvates, where PG is a protecting group of alcohols. This document also provides processes for synthesizing a compound A or one of its salts or solvates: OH comprising: mixing an organometallic catalyst and a compound D ίη / 77Π7 / E / YΙΛΙ salts or solvates in a solvent, to form a compound F or its (D) or one of OPG (F) or one of its salts. The following diagram provides a general reaction scheme for the processes described herein: General process for the synthesis of macrocyclic Mcl-1 inhibitor intermediates OH Compound B Compound C Compound D Compound F OH Compound A Protection of compound B The disclosure processes may include protecting compound B to provide compound C. The process herein may comprise synthesizing compound C by mixing compound B and a protecting group introduction reagent to form compound C. In some embodiments, compound B and the protecting group introduction reagent may be mixed with a base. As provided herein, compound B has the structure of OH r / or Ln / zznz / E / YiAi (B). In some embodiments, compound B is a salt. A salt of compound B, or any other compound described herein, may be prepared, for example, by reacting the compound in its free base form with a suitable organic or inorganic acid and optionally isolating the salt thus formed. Non-limiting examples of suitable salts for any one or more of the compounds described herein include salts of the hydrobromide, hydrochloride, sulfate, bisulfate, sulfonate, camphorsulfonate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and amino acid salts and the like. In some embodiments, the salt of compound B comprises an ammonium cation. In some embodiments, the ammonium cation is .In some embodiments, compound B, prior to mixing with the protecting group introduction reagent, is prepared as a free acid from a salt form, compound B':. ίη / 77Π7 / E / YΙΛΙ Compound B is reacted with an alcohol protecting group introducer, which thereby protects the alcohol in compound B. Alcohol protecting groups are groups that mask a hydroxyl functional group and are well known in the art. The preparation of compounds may involve the protection and deprotection of various hydroxyl groups. The need for protection and deprotection, and the selection of suitable protecting groups and protecting group introducer reagents, can be readily determined by someone skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety.Adjustments to the alcohol protecting groups and the methods of formation and cleavage described herein may be made as necessary, taking into account different substituents. Non-limiting examples of suitable alcohol protecting group introduction reagents include acyl halides (e.g., acetyl chloride, pivaloyl chloride, 4-bromobenzoyl chloride, etc.), acyl anhydrides (e.g., acetic anhydride, maleic anhydride, etc.), silyl halides (e.g., trimethylsilyl chloride, chlorotriethylsilane, triisopropylsilyl chloride, etc.), and sulfonyl halides (e.g., methanesulfonyl chloride, etc.). Other alcohol protecting group introduction reagents that may be used to provide the alcohol protecting group, PG, as described herein are also contemplated. As described above, alcohol protecting groups are groups that mask a hydroxyl functional group and are well known in the art. In some embodiments, the alcohol protecting group (PG) may be an ether, a silyl ether, an acetal or ketal, or an acyl group. In some embodiments, PG is an ether. Ether-type protecting groups comprise an alkyl moiety, either substituted or unsubstituted, attached to the oxygen of the hydroxyl group being protected (e.g., masked as an ether). Examples of suitable ethers include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), and methoxypropyl ether (MOP). Other examples of ethers considered include, but are not limited to, benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB), and 2-naphthylmethyl ether (Nap). In some embodiments, PG is an acetal or ketal. Acetals that act as an OH / OR group Protecting R groups have a general structure of °PG' and can take the form of acetals (such as OR', where R' is, for example, an alkyl group) or hemiacetals (such as OH), where R-0 comes from the hydroxyl group being protected and PG' is the remainder of the (hemi)acetal-type protecting group. Ketals acting as protecting groups have a general structure of PG', where R-0 comes from the hydroxyl group being protected and can take the form of ketals (such as OR', where R' is, for example, an alkyl group) or hemiacetals (such as OH), and each PG' comes from the remainder of the (hemi)ketal-type protecting group that masks the hydroxyl group (i.e., R-OH) and can be substituted or unsubstituted. An example of a suitable acetal includes, but is not limited to, tetrahydropyranilic acetal (THP). In some embodiments, PG is an acyl group. The term “acyl,” as used herein, refers to a protecting group of alcohols in which the oxygen atom of the alcohol -R-O is bonded to an acyl group -R-O, where R-O is derived from the hydroxyl group being protected and PG' is derived from the remainder of the acyl protecting group. In some embodiments, the acyl protecting group is selected from the group consisting of acetyl, pivaloyl, benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, 2-naphthoyl, 4-methoxybenzoyl, and isobutyryl. r / or Ln / zznz / E / YiAi In some embodiments, PG is a silyl ether. The term “silyl ether,” as used herein, refers to a protecting group of alcohols in which the oxygen atom The PG' I ^PG' R Si^ of the alcohol is attached to a silyl ether group - °PG', where R-0 comes from the hydroxyl group being protected and each PG' comes from the remainder of the silyl ether protecting group. In some embodiments, the silyl ether protecting group is selected from the group consisting of OSiEts (triethylsilyl ether, TES), OSi('Pr)3 (triisopropylsilyl ether, TIPS), OSiMes Ln / Zznz / E / YIAI (trimethylsilyl ether, TMS), OSÍMesfiu (tert-butyldimethylsilyl ether, TBS) and OSiPhs'Bu (tert-butyldiphenylsilyl ether, TBDPS). In some embodiments, PG is a sulfonyl-type protecting group. The expression “sulfonyl-type protecting group,” as used herein, refers to a protecting group of alcohols in which the oxygen atom of the alcohol is bonded to a sulfonyl group. IYo °PG', where R-0 comes from the hydroxyl group being protected and PG' comes from the remainder of the sulfonyl protecting group. In some embodiments, the sulfonyl protecting group is selected from the group consisting of mesyl, tosyl, nosyl, and trifyl. yOMe In some embodiments, PG is selected from the group consisting of * (methoxy), yO^OMe Y°^°^^OMe I (tert-butyl ether), ' (methoxymethyl acetal, MOM), *e (2-methoxyethoxymethyl ether, MEM),Me(ethoxyethyl acetal, ΈΕ), (methoxypropyl acetal, MOP), (benzyloxymethyl acetal, BOM), (ether 4(benzyl ether, Bn), methoxybenzyl, PMB), (acetyl, Ln / Zznz / E / YIAI (4-phenylbenzoyl), (1-naphthoyl ester), (4-methoxybenzoyl), e (2-naphthoyl ester), 0(isobutyryl). In some embodiments, PG is 0. In some realizations, PG es0 In general, the protecting group introducing reagent can be any suitable protecting group introducing reagent known to a person skilled in the art that is used to protect an alcohol (hydroxyl group). In some embodiments, the protecting group introducing reagent may comprise acetic anhydride or acetyl chloride. In some embodiments, the protecting group introducing reagent may comprise 4-bromobenzoyl chloride. In some embodiments, the mixing of compound B and the protecting group introduction reagent can be carried out in the presence of an organic solvent. Generally, the organic solvents are known in the art. Non-limiting examples of organic solvents that can be used for the protection of the hydroxyl group of compound B include acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, benzotrifluoride, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,2-dichloroethane (1,2-DCE), 1,4-dioxane, cyclopentyl methyl ether (CPME), chloroform, carbon tetrachloride, dichloromethane (DCM), methanol, ethanol, propanol, and 2-propanol. tert-butanol.In some embodiments, the organic solvent comprises toluene. The organic solvent may be present in an amount of 5 L / kg of compound B to 50 L / kg of compound B, for example, at least 5, 10, 15, 20, 25 or 30 L / kg of compound B and / or up to a maximum of 50, 45, 40, 35, 30, 25 or 20 L / kg of compound B, such as 10 to 40 L / kg of compound B, 15 to 30 L / kg of compound B, or 15 L / kg to 20 L / kg of compound B. B. ίη / 77Π7 / E / YΙΛΙ Compound B and the protecting group introducing reagent may be present in a molar ratio of 1:1 to 1:5, for example, a molar ratio of at least 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:3.5 and / or up to a maximum of 1:5, 1:3, 1:2.75, 1:2.5, 1:2.25, 1:2 or 1:1.5, such as 1:1 to 1:2.5, 1:1 to 1:2, 1:1 to 1:1.5, 1:1.25 to 1:2 or 1:1.25 to 1:1.75. In some embodiments, the molar ratio of compound B to the protecting group introducing reagent is 1:3. In some embodiments, the molar ratio of compound B to the protecting group introducer is 1:1.5. In some cases, the protecting group introducer is acetic anhydride and the molar ratio of compound B to the protecting group introducer is 1:1.25 to 1:5.In some cases, the protecting group introducing reagent is bromobenzoyl chloride and the molar ratio of compound B to the protecting group introducing reagent is from 1:1.5 to 1:5. The protection of compound B can be carried out in the presence of a base, for example, an amine-type base (for example, mono-, di-, or trialkylamines, substituted or unsubstituted piperidines, substituted or unsubstituted pyridines). In some embodiments, the base comprises pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), NaH, KH, K2CO3, Na2CO3, Li2CO3, Cs2CO3, or a combination thereof. In some embodiments, the base is selected from the group consisting of triethylamine, diisopropylethanolamine, α-methylpyrrolidine, β-ethylpiperidine, pyridine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine, 2,6-lutidine, and a combination thereof. In some embodiments, the base is triethylamine. In some embodiments, the base is pyridine. When a base is present in the mixture of compound B and the protecting group introducing reagent, compound B and the base may be present in a molar ratio of 1:1 to 1:15, for example, at least 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12.5, 1:15, and / or up to a maximum of 1:10, 1:9, 1:8, 1:7 or 1:6, such as 1:1 to 1:10, 1:1.5 to 1:5, or 1:5 to 1:10, 1:5 to 1:15, or 1:4 to 1:8, or 1:4 to 1:6. In some embodiments, the molar ratio of compound B to the base is 1:5. In some embodiments, the molar ratio of compound B to the base is 1:1.5. In some cases, the base is triethylamine and the molar ratio of compound B to the base is from 1:1.25 to 1:3. In some cases, the base is pyridine and the molar ratio of compound B to the base is from 1:5 to 1:15. In some embodiments, compound B and the protecting group introduction reagent may be further mixed with 4-dimethylaminopyridine (DMAP). When DMAP is present in the mixture of compound B and the protecting group introduction reagent, compound B and DMAP may be present in a molar ratio of 1:0.05 Ln / Zznz / E / YIAI to 1:5, for example, from at least 1:0.05, 1:0.01, 1:0.05, 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, such as from 1:0.05 to 1:1, from 1:1 to 1:5 or from 1:0.1 to 1:3. In some embodiments, the molar ratio of compound B to DMAP is 1:0.2. In some embodiments, the molar ratio of compound B to DMAP is 1:2. The protection of compound B can occur at a temperature of 0 °C to 40 °C, for example, at least 0, 5, 10, 15, 20, 25, 30 or 40 °C and / or up to a maximum of 10, 20, 30, 35 or 40 °C, such as 0 °C to 30 °C, 0 °C to 25 °C, 15 °C to 30 °C, 10 °C to 40 °C or 20 °C to 40 °C. In some embodiments, the protection of compound B occurs at a temperature of 40 °C. In some embodiments, the mixing of compound B and the protecting group introduction reagent can be carried out for 30 minutes to 6 hours. For example, the mixing can be carried out for 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In some embodiments, compound B is provided as a salt. In some embodiments, compound B is provided as a salt of a carboxylic acid. In some embodiments, compound B is provided as a free acid. In some embodiments, compound B, prior to mixing with the protecting group introduction reagent, is prepared as a free acid from a salt form. In some embodiments, the free acid of compound B is prepared by mixing the salt of compound B and an acid in a solvent to form the free acid of compound B. In some embodiments, the acid comprises phosphoric acid, HCl, citric acid, acetic acid, sulfuric acid, or a combination thereof. In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is present at a concentration of 1 L / (kg of salt of compound B) to 20 L / (kg of salt of compound B). In some embodiments, the solvent comprises 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran, or toluene. Synthesis of compound D The disclosure processes include mixing a compound C, an activating agent, an amine-type base, and a compound E in the presence of a solvent to form compound D or one of its salts or solvates ίη / 77Π7 / E / YΙΛΙ Conveniently, the disclosure processes provide protection of the vinyl alcohol before the addition of compound E, which differs from the synthesis procedure used in the prior art process of U.S. Patent No. 9,562,061. The protection of the alcohol provides higher yields and greater efficiency. For example, the yield of the sulfonamide addition can be improved from 35%, as in the prior synthesis shown in Scheme 1, to 76% in the processes described herein. Furthermore, the processes described herein utilize a protecting group that provides crystalline intermediates, which simplifies purification attempts, eliminates the need for chromatography, and provides long-term stability. As provided herein, compound C has a structure of OPG (C), where PG is an alcohol protecting group as described herein. In some embodiments, compound C is a salt. The salts of compound C may be similar to those described herein for compound B. In some embodiments, PG is acetate (Ac). In some embodiments, PG is bromobenzoate (Br-Bz). ίη / 77Π7 / E / YΙΛΙ As provided herein, compound E has the structure of H2NO2S MeE|compound C and compound E may be present in a molar ratio of 1:1 to 1:1.5, compound C:compound E, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5. In some embodiments, the molar ratio of compound C to compound E is 1:1.1. In some embodiments, the molar ratio of compound C to compound E is 1:1.3. In general, the activating agent may comprise an acid anhydride, acid chloride, carbodiimide-type agent, uranium-type agent, amminium-type agent, phosphonium-type agent, or a combination thereof. Acid anhydrides considered include acetic anhydride, propanoic anhydride, benzoic anhydride, succinic anhydride, butyric anhydride, hexanoic anhydride, and cyclohexanecarboxylic anhydride. Non-limiting examples of acid chlorides include ethanoyl chloride, propanoyl chloride, butanoyl chloride, and benzoyl chloride. Non-limiting examples of phosphonium-type agents include (hydroxymethylphosphonium chloride). In some embodiments, the activating agent may comprise SOCl2, oxalyl chloride, propanephosphonic acid anhydride (T3P®), or a combination thereof. In some embodiments, the activating agent is an acid chloride-type agent. In some embodiments, the acid chloride-type agent comprises SOCl2. In some embodiments, the activating agent is an acid anhydride. In some embodiments, the acid anhydride comprises propanephosphonic acid anhydride (T3P®). Compound C and the activating agent may be present in a molar ratio of 1:1 to 1:5, for example, at least 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, such as 1:1 to 1:5, 1:1.5 to 1:5, 1:1 to 1:3, or 1:3 to 1:5. In some embodiments, the molar ratio of compound C to the activating agent is 1:1.5. In some embodiments, the molar ratio of compound C to the activating agent is 1:1.05. In some embodiments, the activating agent is SOCl₂ or oxalyl chloride, and the molar ratio of compound C to the activating agent is 1:1 to 1:1.2. In some embodiments, the activating agent is T3P and the molar ratio of compound C to the activating agent is from 1:1 to 1:2. The synthesis of compound D can be carried out in the presence of a base, for example, an amine-type base (for example, mono-, di-, or trialkylamines, substituted or unsubstituted piperidines, substituted or unsubstituted pyridines). In some embodiments, the amine-type base may comprise pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyl[5.4.0]undec-7-ene (DBU), 1,4-diazabicylyl[2.2.2]octane (DABCO), or a combination thereof. In some embodiments, the amine base is selected from the group consisting of triethylamine, diisopropylethylamine, β-methylpyrrolidine, α-ethylpiperidine, pyridine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine, 2,6-lutidine, and a combination thereof. In some embodiments, the amine base is triethylamine. In some embodiments, the amine base is diisopropylethylamine. Compound C and the amine-type base may be present in a molar ratio of 1:1 to 1:15, for example, at least 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12.5, 1:15 and / or up to a maximum of 1:10, 1:9, 1:8, 1:7 or 1:6, such as 1:1 to 1:10, 1:1.5 to 1:5, 1:5 to 1:10, 1:5 to 1:15, 1:4 to 1:8, or 1:4 to 1:6. In some embodiments, the molar ratio of compound C to the amine-type base is 1:5. In some embodiments, the molar ratio of compound C to the base is 1:3.5. In some embodiments, the base is triethylamine or diisopropylethylamine and the molar ratio of compound C to the base is 1:2 to 1:5. The synthesis of compound D can take place in the presence of a solvent. Non-limiting examples of solvents that can be used for the synthesis of compound D from compound C, an activating agent, a base, and compound E include acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, benzotrifluoride, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,2-dichloroethane (1,2-DCE), 1,4-dioxane, cyclopentyl methyl ether (CPME), chloroform, carbon tetrachloride, and dichloromethane (DCM). A / ,AAd¡methylacetam¡de (DMAc) and / V-methyl-2pyrrolidone (NMP).In some embodiments, the solvent comprises tetrahydrofuran (“THF”), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane (DCM), dichloroethane (DCE), 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, or a combination thereof. In some embodiments, the organic solvent comprises toluene, MeTHF, THF, DCM, or DCE. In some embodiments, the solvent comprises toluene and DMF. In some embodiments, compound C and DMF may be present in a molar ratio of 1:0.01 to 1:0.5, such as 1:0.05, 1:0.1, or 1:0.5. The solvent may be present in an amount of 3 L / kg of compound C to 50 L / kg of compound C, for example, at least 3, 5, 10, 15, 20, 25, 30, 40 or 50 L / kg of compound C and / or up to a maximum of 50, 45, 40, 35, 30, 25 or 20 L / kg of compound C, such as 3 to 20 L / kg of compound C, 15 to 30 L / kg of compound C or 5 L / kg to 50 L / kg of compound C. In some embodiments, the synthesis of compound D may further comprise mixing it with a nucleophilic activator. In some embodiments, the nucleophilic activator comprises DMAP, pyridine, or a combination thereof. In some embodiments, the nucleophilic activator is pyridine. In some embodiments, the nucleophilic activator is DMAP. When DMAP is present in the mixture, compound C and DMAP may be present in a molar ratio of 1:0.05 to 1:3, for example, at least 1:0.05, 1:0.01, 1:0.05, 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, such as 1:0.05 to 1:1, 1:1 to 1:5, or 1:0.1 to 1:3. In some embodiments, the molar ratio of compound C to DMAP is 1:0.1. In some embodiments, the molar ratio of compound C to DMAP is 1:0.05 to 1:1. In some embodiments, the molar ratio of compound C to DMAP is 1:0.25 to 1:2. In the synthesis of compound D, the mixture can be produced at a temperature from 0 °C to 115 °C, for example, at 10, 15, 20, 25, 30, 40, 50, 75, 90, 100, 110, or 115 °C. In some embodiments, the mixture can be produced at a temperature from 0 °C to 35 °C. In some embodiments, the mixture can be produced at a temperature from 75 °C to 115 °C. In some embodiments, the mixing of compound C and the activating agent can occur before the addition of compound E. In some embodiments, the mixing of compound C and the activating agent can occur over a period of 30 minutes to 72 hours. For example, the mixing can be carried out over 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 10 hours, 12 hours, 15 hours, 20 hours, 24 hours, 48 ​​hours, or 72 hours. In some embodiments, the mixing of compound C, compound E, the activating agent, and the amine-type base can be carried out for 2 to 24 hours. For example, the mixing can be carried out for 2, 3, 4, 5, 6, 8, 10, 20, 15, or 24 hours. In some cases, compound D is formed as a salt. The salts of compound D may be similar to those described herein for compound B. In some embodiments, compound D is formed as a piperazine salt or a dicyclohexylamine salt. In some cases, compound D is formed as a solvate. The solvates of compound D may include, but are not limited to, hydrates such as a monohydrate or dihydrate. In some embodiments, compound D is formed as a monohydrate. Compound D Γ / QQI η / 77Π7 / Β / ΥΙΛΙ ίη / 77Π7 / Ε / ΥΙΛΙ In addition, a compound having a structure of compound D is provided herein. (D), or one of its salts or solvates, wherein PG is a protecting group of alcohols as described herein. In some embodiments, PG is an ether, a silyl ether, an acetal or ketal, or an acyl group. In some embodiments, the acyl group is acetyl, pivaloyl, benzoyl (Bz), 4-bromobenzoyl (Br-Bz), 4-chlorobenzoyl, 4-iodobenzoyl, 4-fluorobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, or 2-naphthoyl. In some embodiments, the ether is methoxy, ethoxy, propoxy, butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), methoxypropyl ether (MOP), benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB), or 2-naphthylmethyl ether (Nap). In some embodiments, the acetal or ketal is tetrahydropyranilic acetal (THP).In some embodiments, the silyl ether is triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), or tert-butyldiphenylsilyl ether (TBDPS). In some embodiments, PG is acetyl. In some embodiments, PG is 4-bromobenzoyl. In some embodiments, compound D is a salt. The salts of compound D may be similar to those described herein for compound B. In some cases, compound D is a piperazine salt. In some cases, compound D is a dicyclohexylamine salt. In some embodiments, compound D is a solvate. In some cases, compound D is a hydrate. In some cases, compound D is in a free form (neither as a salt nor as a solvate). Ring closure metathesis The processes of the disclosure of the present may include mixing an organometallic catalyst and a compound D form a compound F (D) or one of its salts or solvates in a solvent, for ίη / 77Π7 / E / YΙΛΙ OPG (F) or one of its salts. In some embodiments, compound D is synthesized by the processes described herein. Conveniently, the disclosure processes provide protection of the vinyl alcohol prior to ring-closing metathesis, which differs from the synthesis procedure described in U.S. Patent No. 9,562,061. As provided herein, compound D has the structure of (D). In some embodiments, compound D is provided in free form. In some embodiments, compound D is provided as a solvate. In some embodiments, compound D is provided as a hydrate. In some embodiments, compound D is provided as a salt. The salts of compound D may be similar to those described herein for compound B. In some embodiments, the salt of compound D comprises an ammonium cation. In some embodiments, the ammonium cation is a piperazine cation. In some embodiments, compound D is provided as compound D', a compound having a structure of (Dj. In some embodiments, compound D' can be converted into the free form of compound D before mixing with the organometallic catalyst. In some embodiments, the salt form of compound D is mixed with an acid (e.g., aqueous hydrochloric acid, phosphoric acid, citric acid, or sulfuric acid) to form compound D as a free form. The free form of compound D is then subjected to the ring-closing metathesis reaction with the organometallic catalyst. In some embodiments, compound D is provided as a monohydrate form that is first dried (e.g., by azeotropic distillation) to remove water from the hydrated form before using compound D in the ring-closing metathesis reaction with the organometallic catalyst. In general, the organometallic catalyst can be any ring-closing metathesis catalyst known to the person skilled in the art. In some embodiments, the organometallic catalyst comprises molybdenum or ruthenium. In some embodiments, the organometallic catalyst may comprise one or more Grubbs catalysts. Numerous Grubbs catalysts are known in the art (e.g., 1st generation Grubbs catalyst, 2nd generation Grubbs catalyst, 3rd generation Grubbs catalyst, 1st generation Hoveyda-Grubbs catalyst, 2nd generation Hoveyda-Grubbs catalyst, etc.). Grubbs catalysts are ruthenium-based. A person skilled in the art will appreciate that other organometallic ring-closing metathesis catalysts, such as Schrock-type catalysts (which are molybdenum-based) or Grela's catalyst, can be used instead of or in addition to Grubbs' catalysts according to some embodiments.In some embodiments, the organometallic catalyst comprises the Hoveyda-Grubbs M730 catalyst (M73-SIMes), which has a structure of. In some embodiments, the organometallic catalyst is the Hoveyda-Grubbs M730 catalyst (M73-SIMes). Conveniently, when the Hoveyda-Grubbs M73-SIMes catalyst is used in ring-closure metathesis, both the yield and efficiency are improved compared to the process described in U.S. Patent No. 9,562,061, which uses a Hoveyda-Grubbs II catalyst. The Hoveyda-Grubbs M73-SIMes catalyst provides improved stability in this process compared to the previous synthesis shown in Scheme 1, thereby extending the lifetime of the organometallic catalyst. The Hoveyda-Grubbs M73-SIMes catalyst is more catalytically active compared to the previous catalyst used, allowing for the use of a lower catalyst loading while maintaining comparable or even higher yields.Furthermore, the Hoveyda-Grubbs M73-SIMes catalyst provides higher selectivity, improving not only the yield but also the purity profile, thus enabling improved isolation of compound F and eliminating the need for chromatography. The organometallic catalyst can be present in an amount from 0.01 mol% to 20 mol% (depending on compound D). The ring-closing metathesis reaction can take place in the presence of a solvent. In some embodiments, the solvent is a nonpolar solvent. In some embodiments, the solvent comprises toluene, hexane, heptane, 1,4-dioxane, 1,2-dichloroethylene, dichloromethane, or a combination thereof. In some embodiments, the solvent comprises toluene. The solvent may be present in an amount of 5 L / kg of compound D to 800 L / kg of compound D, for example, at least 3, 5, 10, 15, 20, 25, 30, 40, 50 L / kg or 150 L / kg of compound D and / or up to a maximum of 800, 700, 600, 500, 400, 300, 200 or 150 L / kg of compound D, such as 5 to 700 L / kg of compound D, 20 to 100 L / kg of compound D, or 20 L / kg to 200 L / kg of compound D, or 100 L / kg to 800 L / kg of compound D. The mixing can be done at a temperature of 50 °C to 115 °C, for example, at 50, 60, 70, 75, 80, 90, 100, 110 or 115 °C. In some embodiments, the mixing can be done at a temperature of 80 °C. In some embodiments, the mixing of compound D and the organometallic catalyst can be carried out for 30 minutes to 24 hours. For example, the mixing can be carried out for 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 20 hours, or 24 hours. In some embodiments, the mixing of compound D and the organometallic catalyst can be carried out for at least 1 hour. In some embodiments, the ring-closing metathesis reaction can be carried out in an inert atmosphere. In some embodiments, the inert atmosphere may comprise N2, Ar, or a combination thereof. In some embodiments, the ring-closing metathesis can be carried out in a nitrogen atmosphere. In some embodiments, the ring-closing metathesis reaction can be carried out under vacuum (at reduced pressure). In some embodiments, the ring-closing metathesis reaction can be carried out at a pressure of 200 to 500 torr. In some embodiments, the ring-closing metathesis reaction can be carried out at atmospheric pressure in combination with bubbling of an inert gas. In some embodiments, the ring-closing metathesis reaction can be carried out by a continuous flow process. In some embodiments, the continuous flow process may comprise one or more continuous stirred-tank reactors (CSTRs). In some embodiments, the continuous flow process comprises two CSTRs. In some embodiments, compound D and the organometallic catalyst are flowed into a CSTR to mix them. In some embodiments, prior to the addition of compound D and the organometallic compound to the CSTR, the CSTR is purged with an inert gas such as N2 or Ar. In some embodiments, compound D, the organometallic catalyst, or both may be dissolved in a nonpolar organic solvent as described herein prior to addition to the CSTR. In some embodiments, the nonpolar organic solvent is toluene. In some embodiments, the flow rate of addition of compound D, the organometallic catalyst, or both, to the CSTR may be from 0.1 mL / min to 50 mL / min. For example, the flow rate of addition of compound D, the organometallic catalyst, or both, to the CSTR can be from 0.1 mL / min to 25 mL / min, or from 0.1 mL / min to 10 mL / min, from 0.5 mL / min to 5 mL / min, such as 0.1 mL / min, 0.5 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min, 3 mL / min, 4 mL / min, 5 mL / min, 10 mL / min, 25 mL / min, 50 mL / min, 100 mL / min, 200 mL / min or 500 mL / min or higher. In some embodiments, compound D is dissolved in a solvent in a first CSTR to form a first solution, and the organometallic catalyst is dissolved in a solvent in a second CSTR to form a second solution. In some embodiments, the first and second solutions are flowed in a third CSTR for a period of 30 minutes to 24 hours or more. For example, the first and second solutions are flowed in a third CSTR for a period of 1 hour to 24 hours, or 2 hours to 20 hours, or 5 hours to 12 hours. In some embodiments, compound D is dissolved in a solvent in a first CSTR to form a first solution, and the first solution is flowed into a second CSTR. In some embodiments, the organometallic catalyst is added as a solid, in portions, to the second CSTR. In some embodiments, the first solution and the organometallic catalyst as a solid are added over a period of 30 minutes to 24 hours. For example, the first solution and the organometallic catalyst as a solid are added over a period of 1 hour to 24 hours, or 2 hours to 20 hours, or 5 hours to 12 hours. In some embodiments, the organometallic catalyst can be added as a solid in increments of 10 minutes, 20 minutes, 30 minutes, 1 hour, or 2 hours, where each increment comprises one-half, one-quarter, or one-eighth of the total amount of the organometallic catalyst. Deprotection of compound F The processes for synthesizing compound A, or one of its salts or solvates, may involve mixing compound F Ln / Zznz / E / YIAI deprotection to form compound A. As provided herein, compound F has a structure of It is provided in free form. In some embodiments, compound F is provided as a salt. The salts of compound F may be similar to those described herein for compound B. In some embodiments, the deprotecting agent includes acetyl chloride, an enzyme, an acid, a base, a metal hydride, or a combination of these. In some embodiments, the deprotecting agent includes acetyl chloride and an alcohol. As described herein, non-limiting examples of solvents that are alcohols include methanol, ethanol, propanol, 2-propanol, and tert-butanol. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, and a combination thereof. In some embodiments, the alcohol is methanol. In some embodiments, the deprotecting agent includes a base. Non-limiting examples of bases include an alkali metal hydroxide or an alkali metal alkoxide (e.g., methoxide, ethoxide, propoxide, etc.). In some embodiments, the base may comprise a lithium, sodium, or potassium cation, or a combination thereof. In some embodiments, the base may comprise a hydroxide or methoxide anion. In some embodiments, the base is sodium methoxide. In some embodiments, the base is sodium hydroxide. Compound F and the base may be present in a molar ratio of 1:1 to 1:10, for example, at least 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and / or up to a maximum of 1:10, 1:9, 1:8, 1:7 or 1:6, such as 1:1 to 1:10, 1:1.5 to 1:5 or 1:2 to 1:10, 1:2 to 1:6.In iη / 77P7 / E / YILI compound A is heated to a temperature of 40 °C to 50 °C, then the solution is cooled to a temperature of 15 °C to 25 °C (e.g., 20 °C) and a crystallization solvent is added to the cooled solution to form crystals of compound A. In some embodiments, the solution of compound A comprises toluene, THF, or a combination thereof, and the crystallization solvent comprises heptane. In some embodiments, the solution of compound A comprises 2-MeTHF and the crystallization solvent comprises heptane. The process for synthesizing compounds C, D, F, and A can be used to synthesize compounds A1 and A2. As shown in Scheme 4, compound A can be used to synthesize compound A1 and its salts and solvates, and as shown in Scheme 5, compound A can also be used to synthesize compound A2 and its salts and solvates. Conversion of compound A into compound A1 As shown above and described in U.S. Patent No. 9,562,061, compound A can be used to synthesize compound A1 and its salts and solvates. As described herein, compounds C, D, E, and F can be used to prepare compound A. As set forth in U.S. Patent No. 9,562,061, compound A can be methylated to provide compound A1. Conversion of compound A into compound A2 Ln / Zznz / E / YIAI As shown above and described in U.S. Patent No. 10,300,075, compound A can be used to synthesize compound A2 and its salts and solvates. Compound A can be oxidized to yield cyclic enone I, as described in U.S. Patent No. 10,300,075. Enone I can then be converted to epoxide J using the procedures described in U.S. Patent No. 10,300,075. Epoxide J can then be reacted with bicyclic compound K to yield hydroxy-type compound L. Finally, methylation of compound L yields compound A2 as described in U.S. Patent No. 10,300,075. It should be understood that, although the disclosure is read in conjunction with the detailed description thereof, the foregoing description and the following example are intended to illustrate, and not limit, the scope of the disclosure, which is defined by the scope of the appended claims II / 77P7 / E / YILI. Other aspects, advantages, and modifications are within the scope of the following claims. EXAMPLES The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention. Example 1: Formation of compound A using an acetyl-type PG Compound B' Compound B Compound c (where PG is Ac) 1. SOCI2, DMF, toluene 2. EbN DMAP Compound E, toluene 3. 2-ProH. NaCl 4. AcOH entrainment, AcOH / FeO isolation Me Me Compound E 1,M73-SiMes (4% mol), C. toluene (200 L / kg) 2. silica trap Compound D Hydrated Compound (where PG is Ac) OAc Compound F (where PG is Ac) NaOMe. MeOH citric acid (aq.) THF / heptane OH Compound A Synthesis of compound C (where PG is Ac) (S)-5-(((1 R,2R)-2-((S)-1 -acetoxyallyl)cyclobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepin-3,r-naphthalene]-7-carboxylic acid (compound C, where PG is Ac): In a jacketed 2 L glass reactor, compound B' (50 g, 84 mmol, 1.0 eq.) was introduced, followed by 2-MeTHF (350 mL, 7 L / kg). The suspension was stirred at room temperature and 1 M phosphoric acid (200 mL, 4 L / kg) was added. Note: An exothermic reaction of 20.7 to 24.1 °C was observed after the addition of phosphoric acid. The mixture was vigorously stirred for 1 hour, then brine (50 mL, 1 L / kg) was added. The mixture was stirred for an additional 5 minutes, then stirring was stopped and the phases were allowed to separate. The lower phase was discharged and 20% brine (250 mL, 5 L / kg) was introduced into the reactor. The mixture was stirred for > 5 minutes, then stirring was stopped and the phases were allowed to stabilize.The lower phase was discharged and water (250 mL, 5 L / kg) was introduced into the reactor. The mixture was stirred for 5 min, then the stirring was stopped and the phases were allowed to stabilize. The lower phase was discharged and the upper phase was azeotropically distilled at 60 °C under reduced pressure to remove the water. The distillation was completed after taking samples of the solution and analyzing them to determine its water content. In a separate jacketed reactor at 22 °C, dimethylaminopyridine (DMAP) (2.057 g, 16.84 mmol, 0.20 eq.) was introduced, followed by anhydrous 2-MeTHF (250 mL, 5 L / kg). The mixture was stirred for 5 min, then triethylamine (17.6 mL, 126 mmol, 1.5 eq.) was added, followed by acetic anhydride (11.94 mL, 126 mmol, 1.5 eq.). The mixture was stirred for 5 min at room temperature, then compound B was added in its free form as a solution in 2-MeTHF from the salt cleavage. The mixture was stirred for 1.5 min, and then samples were taken to determine the conversion. After the reaction was complete, water (250 mL, 5 L / kg) was introduced, followed by a lamp of 1 M dibasic sodium phosphate (150 mL, 3 L / kg). A 1 M NaOH solution (150 mL, 3 L / kg) was then introduced and stirred. Samples of the two-phase mixture were taken to determine the pH (expected pH 9-10. If the pH is > 13, it should be adjusted to a pH of 9-10 with 2 M HCl).The two-phase mixture was then vigorously stirred for > 6 h. Stirring was stopped, and samples of the upper phase were taken to determine the conversion. After the reaction was complete, 2 M HCl (250 mL, 5 L / kg) was introduced. The two-phase mixture was vigorously stirred. Stirring was stopped, and the phases were allowed to equilibrate. The lower phase was discharged, and toluene (400 mL, 8 L / kg) was introduced into the reactor, followed by water (250 mL, 5 L / kg). The mixture was vigorously stirred, and then stirring was stopped, and the phases were allowed to equilibrate. The lower phase was discharged, and 20% brine (250 mL, 5 L / kg) was introduced into the reactor. The mixture was vigorously stirred, and then stirring was stopped, and the phases were allowed to equilibrate. The lower phase was discharged and the upper phase was distilled at 60 °C under reduced pressure to remove 2-MeTHF, H2O and acetic acid.The stream of compound C (where PG is Ac) in toluene was transported directly to the next step with an analytical yield of 100% molar. LRMS(ESI): Calculated for C29H32CINO5+Na: 532.2, observed: 532.2. Synthesis of compound D (where PG is Ac) Compound c (where PG is Ac) Compound Do CompoundD hydrate (where PG is Ac) r / or Ln / zznz / E / YiAi 1. SOCI2, DMF, toulene -----------► 2. EbN DMAP Compound E, toluene 3. 2-PrOH, NaCl entrainment with AcOH isolation with AcOH / HO Compound E (S)-1-((1 ff,2R)-2-(((S)-6'-chloro-7-((((2fi,3S)-3-methylhex-5-en-2 yl)sulfonyl)carbamoyl)-3',4'-dihydro-2H,2'H-spiro[benzo[b][1,4]oxazepin-3,1'-naphthalene]5(4H)-yl)methyl)cyclobutyl)allyl acetate (compound D, where PG is Ac): To a solution of compound C (where PG is Ac) in toluene at 20 - 25 °C, a catalytic amount of anhydrous dimethylformamide (DMF, 0.652 mL, 8.42 mmol, 0.1 eq.) was added. The reactor was fitted with a NaOH trap and a collection tank, and a strong N2 purge was initiated. In a separate container under a nitrogen atmosphere, toluene (44 mL, 0.86 L / kg) was added, followed by thionyl chloride (6.45 mL, 88 mmol, 1.05 eq). The thionyl chloride solution in toluene was then added to the reaction mixture. The mixture was stirred for 4 hours, and samples were taken to determine the conversion. After the reaction was complete, compound E (19.4 g, 109 mmol, 1.3 eq) and DMAP (1.028 g, 8.05 eq) were added to a separate reactor.42 mmol, 0.1 eq.), followed by toluene (350 mL, 7 L / kg). The mixture was azeotropically distilled at 70 °C under reduced pressure to remove water. The solution was distilled to approximately 150 mL (3 L / kg), then diluted to approximately 400 mL (8 U / kg) with anhydrous toluene and distilled again, ending with 250 mL (5 L / kg). This solution was added to the reactor containing the acid chloride in toluene at 20 °C. Triethylamine (41.1 mL, 295 mmol, 3.5 eq.) was then added to the reactor. The mixture was then allowed to be stirred overnight. Samples of the mixture were taken to determine the conversion. After the reaction was complete, isopropanol (200 mL, 4 L / kg) was added, followed by 20% brine (300 mL, 6 L / kg). The mixture was vigorously stirred for 10 min, then stirring was stopped and the phases were allowed to stabilize. The lower phase was discharged, and 20% brine (300 mL, 6 L / kg) was introduced into the reactor. The mixture was vigorously stirred for 10 min, then stirring was stopped and the lower phase was discharged. The upper phase was then distilled at 65 °C under reduced pressure and accreted with acetic acid. The solution was then heated to 85 °C. Once the temperature was reached, 65 mL of water were added with vigorous stirring to achieve a 94:6 acetic acid / water ratio. After the addition was complete, the solution was heated again to 85 °C and a 2% w / w crystallization nucleus of compound D was added to the mixture.126 g) as a suspension in 90 / 10 acetic acid / water. The resulting suspension was maintained at 85 °C before cooling to 22 °C in 5 h. The suspension was maintained at 22 °C for > 2 h, then filtered and washed using 20 mL (5 L / kg) of 90 / 10 acetic acid / water followed by 750 mL of water (15 L / kg). The wet mass retained on the filter was dried on the filter using vacuum and nitrogen. 52.53 g of compound D (where PG is Ac) were obtained in 90% yield.1H NMR (400 MHz, DMSO) δ 11.74 (s, 1 H), 7.63 (d, J = 8.50 Hz, 1 H), 7.15 - 7.36 (m, 4 H), 6.92 (d, J = 8.29 Hz, 1 H), 5.67 - 5.81 (m, 2 H), 5.03 - 5.25 (m, 5 H), 4.04 (s, 2 H), 3.77 - 3.88 (m, 1 H), 3.37 - 3.49 (m, 3 H), 3.28 - 3.37 (m, 3 H), 2.66 - 2.82 (m, 2H), 2.29 - 2.42 (m, 2 H), 2.01 - 2.13 (m, 2 H), 1.95 - 1.90 (m, 5 H), 1.77 - 1.85 (m, 3 H), 1.50 - 1.74 (m, 3 H), 1.24 (d, J = 7.05 Hz, 3 H), 1.01 (d, J=6.84 Hz, 3 H).13C NMR (101 MHz, DMSO-d6):5 170.0, 166.4, 153.2, 141.8, 140.1, 139.5, 136.6, 135.4, 131.4, 130.0, 128.75, 126.7, 126.6, 120.8, 120.0, 117.6, 117.1, 116.0, 79.5, 77.2, 61.1, 59.6, 58.0, 42.3, 41.7, 39.5, 36.2, 31.8, 30.1, 29.0, 25.0, 21.1, 21.0, 18.8, 14.9, 8.1. LRMS (ESI): Calculated for Cse^sCI^OeS+Na: 691.2, observed: 691.2. Synthesis of compound F (where PG is Ac) r / oe Ln / zznz / E / YiAi (1S,11'R,12'S,16'S,16a'f,18a'R,E)-6-chloro-11',12'-dimethyl-10,10'dioxide-8'-oxo-3,4,8',9',12,13,16',16a',17',18,18a',19'-dodecahydro-1'H,2H,3'H,1VHespiro[naphthalene-1,2'-[5,7]ethenecyclobuta[i][1,4]oxazepino[3,4f][1]thia[2,7]diazacyclohexadecin]-16'-yl (compound F, where PG is Ac): In a 20 L reactor, compound D (where PG is Ac) (200 g) was introduced followed by toluene (3 L, 15 L / kg) The mixture was heated under reflux and dried azeotropically using a Dean-Stark trap. It is worth noting that the starting diene was supplied in Step 2 as a monohydrate and that removing water and residual solvents by distillation was important. Ln / Zznz / E / YIAI azeotropic. The diene was then diluted to a total of 50 L / kg with toluene (10 L). In a 60 L reactor, 30 L of toluene (150 L / kg, loading relative to the starting compound D (where PG is Ac)) was introduced and heated to 80 °C. Nitrogen bubbling was initiated, and the reactor was placed under partial vacuum (500 torr). Under these conditions, condensation of toluene should be observed in the condenser. These conditions should allow for efficient removal of ethylene from the reaction solution. Four equivalent portions of the M73-SIMes catalyst, each 1 mol% (2.3 g each), were prepared and set aside. A solution of compound D (where PG is Ac) in toluene was added continuously to the 60 L reactor for approximately 2 h. At the beginning of the substrate addition, a portion of the catalyst was suspended in 50 mL (20 L / kg) of toluene relative to the catalyst and added to the reactor.The other three portions of catalyst were prepared similarly and added at 30-minute intervals. After the substrate addition was complete, the reaction was stirred at 80 °C and a partial vacuum for > 1 h. The reaction was cooled to 50 °C and deactivated with diethylene glycol monovinyl ether and stirred for > 15 minutes at 40–50 °C. The batch was then concentrated to approximately 4 L (20 L / kg) and transferred to a clean drum. The material was transferred to a 5 L reactor and 200% w / w of the scavenger SiliaMet-Tiol (loading relative to compound D) was introduced. The mixture was stirred at 40–50 °C for > 12 hours, cooled, and then filtered to remove the scavenger. Three 400 mL toluene washes (2 L / kg) were also performed. The batch was further concentrated in a 5 L reactor to a total volume of approximately 2 L (10 L / kg). 7.05 (dd, J = 8.1, 1.9 Hz, 1H), 6.86 (d, J= 1.9 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 5.86 (bddd, J = 14.3, 7.9, 4.5 Hz, 1H), 5.67 (dd, J= 14.3, 8.9 Hz, 1H), 5.20 (dd, J = 8.9, 3.7 Hz, 1H), 4.04 (d, J= 12.3 Hz, 1H), 3.99 (d, J= 12.3 Hz, 1H), 3.97 (ca, J=7.2 Hz, 1H), 3.73 (d, J = 14.9 Hz, 1H), 3.56 (d, J = 14.2 Hz, 1H), 3.18 (d, J= 14.2 Hz, 1H), 3.04 (dd, J= 14.9, 10.0 Hz, 1H), 2.78 (dt, J = 16.4, 3.3 Hz, 1H), 2.69 (ddd, J= 16.4, 10.6, 6.2 Hz, 1H), 2.37 (bqd, J = 8.2, 3.6 Hz, 1H), 2.24 (bqui, J=8.2 Hz, 1H), 2.02 (m, 2H), 1.97 (dt, J = 14.2, 3.6 Hz, 1H), 1.93 (S, 3H), 1.89 (m, 1H), 1.89 (m, 1H), 1.83 (m , 2H), 1.72 (m, 1H), 1.72 (m, 1H), 1.38 (ddd, J = 14.2, 12.7, 3.9 Hz, 1H), 1.25 (d, J= 7.2 Hz, 3H), 0.92 (d, J= 6.8 Hz, 3H).13C NMR (150 MHz, DMSO) δ 169.2, 168.6, 151.2, 139.8, 139.6, 139.4, 135.5, 130.8, 129.6, 129.0, 128.1, 126.3, 125.3, 119.5, 118.0, 114.7, 79.7, 74.6, 59.8, 57.2, 55.6, 41.3, 40.8,36.4, 32.8, 32.6, 29.5, 27.7, 26.2, 21.1, 18.9, 18.4, 15.1, 5.5. LRMS (ESI): Calculated for C34H4iCIN2O6S+Na: 663.2, observed: 663.2. Ln / Zznz / E / YIAI Síntesis del compuesto A Compuesto F (Donde PG es Ac) 10',1O'-dioxide of (1 S,11 ' R,12'S,16'S,16a'H,18a'fí,E)-6-chloro-16'-hydroxy-11',12'dimethyl-3,4,12',13', 16',16a',17',18',18a',19'-decahydro-1 Ή,2H,3Ή,11 'H-spiro[naphthalen-1,2'[5,7]ethenecyclobuta[i][1,4]oxazepino[3,4-f][1]t¡a[2,7]diazacyclohexadecin]-8'(9'H)-one (compound A): To a solution of 200 g of compound F (where PG is Ac) in 10 L / kg of MeOH, sodium methoxide (2 eq.) was added In methanol, the mixture was diluted with 1 volume of MeOH (followed by a 1 V MeOH wash) and stirred for > 2 hours at 20 °C. The batch was heated to 40–50 °C and 2 L (10 L / kg) of toluene was added. 4 M citric acid (3.0 eq.), further diluted with 4 volumes of water, was added, and the phases were vigorously stirred at 40–50 °C for > 15 minutes. It is important to note that effective mixing and a high temperature (40–50 °C) are necessary to minimize precipitation of the product as an amorphous solid.The phases were separated at 40–50 °C, and any solids at the aqueous-organic phase interface were retained with the organic phase. The organic components were diluted with an additional 1 L (5 L / kg) of MeOH and washed with 5 additional volumes of water at 40–50 °C for > 15 minutes. The phases were separated again at 40–50 °C, and any solids at the aqueous-organic phase interface were retained with the organic phase. The mixture was vigorously stirred for > 5 minutes. The batch, after treatment, was then concentrated to approximately 1 L (5 L / kg), an additional 1.2 L (6 L / kg) of toluene was added, and the mixture was further concentrated to a total of 1 L (5 L / kg) and diluted with an additional 1.2 L (6 L / kg) of toluene. This mixture was then purified by filtration again to remove salts (the filter was then rinsed with 400 ml (2 L / kg) of toluene). The batch was then concentrated to approximately 1 L (5 L / kg).Next, tetrahydrofuran (1 L / kg) was added, followed by a crystallization nucleation. The crystallization nucleation bed was maintained for > 1 hour at 40–50 °C, and an additional 2 L / kg of THF was added for 1 hour. The batch was then cooled to 20 °C for at least 2 hours. Heptane (6 L / kg) was added for > 2 hours, and the mixture was maintained under these conditions for at least 1 hour. The wet mass retained on the resulting filter was then washed with 2X2 L / kg of heptane:THF 2:1 and dried to a constant weight.1H NMR (600 MHz, CDCh) δ 8.53 (s, 1H), 7.70 (d, J= 8.6 Hz, 1H), 7.17 (dd, J= 8.6, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.00 (dd, J = 8.1,2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.85 (ddd, J = 15.3, 8.4, 4.6 Hz, 1H), 5.72 (ddd, J = 15.3, 8.1, 1.6 Hz, 1H), 4.28 (qd, J= 7.2, 1.3 Hz, 1H), 4.25 (dd, J = 8.1,4.0 Hz, 1H), 4.09 (d, J = 12.1 Hz, 1H), 4.07 (d, J= 12.1 Hz, 1H), 3.84 (da, J= 14.8 Hz, 1H), 3.69 (d, J= 14.1 Hz, 1H), 3.23 (d, J= 14.1 Hz, 1H), 3.01 (dd, J= 14.8, 9.6 Hz, 1 H), 2.83. - 2.77 (m, 1H), 2.77 - 2.72 (m, 1H), 2.44 (qd, J = 9.6, 4.0 Hz, 1 H), 2.32 (quid, J = 9.6, 1.6 Hz, 1H), 2.14-2.04 (m, 2H), 2.05 - 1.98 (m, 3H), 1.98- 1.92 (m, 1H), 1.88 (ca, J = 10.4 Hz, 1H), 1.85 - 1.75 (m, 2H), 1.66 (here, J = 9.6 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H), 1.39 (ta, J = 12.8 Hz, 1H), 1.04 (d, J = 6.7 Hz, 3H);13C NMR (151 MHz, CDCI3) δ 166.5, 152.9, 140.9, 139.3, 138.8, 132.2,132.1,130.8,129.6, 128.5,126.7, 126.3,120.9,116.2, 115.2, 80.1,73.3, 59.9, 58.2, 57.8, 43.6, 41.7, 37.1,33.7, 33.6, 30.1,28.3, 27.1, 19.2, 19.1, 15.3, 5.7. LRMS (ESI): Calculated for CszHsgCINgOsS+Na: 621.2, observed: 621.2. Example 2: Formation of compound A with 4-bromobenzoyl as PG ρ / ρρίη / ζζηζ / Ε / γίΛΐ Composed B BrBzC . pyridine, toulene filter 3. pyridine, H2O, DMAP, 60°C (ac.); 5M HCI (ac.); OF H2O 4. NaHCOa 5. Crystallization in toluene / heptane EITHER (where PG is 4-bromobenzoyl) silica trapper 1, M73-SiMes (4 mol %). 80 °C, toluene (200 Ukg) Compound F (where PG is 4-bromobenzoyl) Compound A Synthesis of compound C (where PG is 4-bromobenzoyl) 1. BrBzCI, pyridine, toluene 2. Filter 3. pyridine, H2O, DMAP, 60°C (aq.); 5M HCl (ac); DI H2O 4. NaHCO3 5. Crystallization in toluene / heptane Compound C (where PG is 4-bromobenzoyl) (S)-5-(((1 / ?,2R)-2-((S)-1 -((4-bromobenzoyl)oxy)allyl)cyclobutyl)methyl)-6'-chloro3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepin-3,1'-naphthalene]-7-carboxylic acid (compound C, where PG is 4-bromobenzoyl): In a 5 L glass reactor jacketed with a jacket, 143 g of compound B' (243 mmol) were introduced, followed by toluene (15 L / kg). 1 M H3PO4 (aq.) (4 L / kg) was added to the resulting suspension. The mixture was stirred for 60 minutes at 20 °C, then stirring was stopped and the phases were allowed to stabilize. The lower aqueous phase was discharged and 5 L / kg of dilute water was added to the toluene mixture. The mixture was stirred for at least 5 minutes at 20 °C, then stirring was stopped and the phases separated. The lower phase was discharged and 5 L / kg of dilute water was introduced into the reactor. The mixture was stirred for at least 5 minutes, then stirring was stopped and the lower phase was discharged.The organic mixture was distilled to a concentration of 5 L / kg. After confirming that the H₂O concentration was < 500 ppm, the mixture was diluted with toluene (6.25 L / kg) and cooled to 25 °C. Then, 4-bromobenzoyl chloride (3.0 eq., 146 g, 729 mmol) was added, followed by a toluene rinse. Next, pyridine (10 eq., 2430 mmol, 192 g) was added, and the mixture was stirred at 25–30 °C for at least 12 hours. After confirming that the reaction was complete by UPLC, the suspension was filtered to remove bromobenzoic anhydride and rinsed with toluene. Water (10 L / kg) was added to the toluene solution, followed by DMAP (2.0 eq., 486 mmol, 59 g) and pyridine (5.0 eq., 1215 mmol, 96 g). The two-phase mixture was stirred at 60 °C for at least 7 hours. After this time, stirring was stopped and a sample of the upper phase was taken to determine the conversion.After confirming that hydrolysis was complete, the mixture was cooled to 50 °C and the phases were separated. The organic phase was washed with a saturated aqueous solution of NaHCO3 (5 L / kg) at 50 °C. The phases were separated, and then 5 M HCl (aq.) (6 L / kg) was added to the toluene. The mixture was stirred and the phases separated, and the organic phase was washed a final time with DI water (5 L / kg). The toluene phase was distilled to 4 L / kg and then cooled to 20 °C. A crystallization nucleus of compound C (where PG is 4-bromobenzoyl) was then added to the mixture. The resulting suspension was maintained for at least 2 hours at 20 °C, and then 9 L / kg of n-heptane was added. The suspension was cooled to 0 °C, held under these conditions for 2 hours, and then filtered and washed with toluene / heptane. The wet mass of product retained on the filter was dried at 25–40 °C. Isolated yield: 75%. 1H NMR (600 MHz, CDCI3) δ 7.86 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 8.2, 1.9 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.84 (ddd, J = 17.1, 10.6, 6.4 Hz, 1H), 5.49 (t a, J = 6.4 Hz, 1H), 5.36 (dt, J = 17.1, 1.2 Hz, 1H), 5.22 (dt, J = 10.6, 1.2 Hz, 1H), 4.12 (d, J= 12.1 Hz, 1H), 4.08 (d, J= 12.1 Hz, 1H), 3.59 (dd, J = 14.8, 4.1 Hz, 1H), 3.52 (d, J = 14.4 Hz, 1H), 3.35 (dd, J = 14.8, 9.0 Hz, 2H), 3.32 (d, J= 14.4 Hz, 1H), 2.78-2.75 (m, 1H), 2.75-2.71 (m, 2H), 2.47 (qui, J= 8.5 Hz, 1H), 2.12-2.02 (m, 1 H), 2.00 - 1.92 (m, 1H), 1.93- 1.85 (m, 2H), 1.85- 1.77 (m, 1H), 1.7841 ίη / 77Π7 / Ε / ΥΙΛΙ. 1.69 (m, 2H), 1.56 (ta, J= 11.0 Hz, 1H);13C NMR (151 MHz, CDCI3) δ 171.8, 165.1, 153.7, 141.0, 139.0, 138.8, 134.3, 132.1, 131.7, 131.0, 129.5, 129.1, 128.6, 128.1, 126.6, 123.7, 121.7, 120.8, 117.5, 117.0, 79.4, 78.0, 60.9, 58.8, 43.0, 41.8, 36.2, 30.2, 29.0, 25.9, 21.2, 19.0. LRMS (ESI): Calculated for C34H33BrCINO5+Na: 672.1, observed: 672.1. Synthesis of compound D (whence PG is 4-bromobenzoyl) ((S)-5-(((1F?,2fi)-2-((S)-1-((4-bromobenzo¡l)ox¡)allyl)cyclobut¡l)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H piperazine salt spiro[benzo[b][1,4]oxazepin-3,T-naphthalen]-7-carbonyl)(((2R,3S)-3-methylhex-5-en-2yl)sulfonyl)amide (compound D, piperazine salt): In a flask, compound C (PG is 4-bromobenzoyl (10 g, 85% wt, 13.2 mmol)), toluene was introduced (50 mL) and DIPEA (6.0 mL, 3.5 eq.). To the homogeneous solution, 50% w / w T3P in toluene (13.6 mL, 1.5 eq.), compound E (2.6 g, 1.1 eq.), and DMAP (1.6 g, 1.0 eq.) were added. The resulting mixture was then heated under reflux overnight. The reaction was cooled to room temperature and deactivated with 1 M aq HCl (50 mL). The aqueous phase was separated, and the organic phase was washed twice with 1 M aq HCl (50 mL) and once with water (50 mL). The organic phase was purified by filtration, washed with toluene (50 mL), and concentrated to approximately 50 mL. Piperazine (1.14 g, 1.0 eq.) was added.The mixture was stirred at 60 °C for 1 hour. The solution was then cooled to room temperature, and a crystallization nucleus of the piperazine salt of compound D was added. The suspension was stirred, and 22 mL of heptane was added. After the addition was complete, the suspension was heated to 50 °C, and an additional 21 mL of heptane was added. The suspension was cooled to room temperature, filtered, and the wet mass retained on the filter was washed twice with 1:1 toluene / heptane (50 mL) and dried to provide the piperazine salt of compound D as a whitish crystalline solid (11.4 g, 85% w / w, 82% yield):1H NMR (600 MHz, DMSO-de): δ 7.79 (d, 8.6 Hz, 2H), 7.67 (d, 8.6 Hz, 2H), 7.53 (d, 1.9 Hz, 1H), 7.48 (d, 8.5 Hz, 1 H). Ln / Zznz / E / YIAI 7.31 (dd, 8.2,1.9 Hz, 1H), 7.14 (dd, 8.5,2.4 Hz, 1 H), 7.12 (d, 2.4 Hz, 1H), 6.76 (d, 8.2 Hz, 1H), 5.86 (ddd, 17.2,10.7,6.4 Hz, 1H), 5.71 (ddt, 17.1,10.2,7.0 Hz, 1H), 5.41 (t a, 6.4 Hz, 1H), 5.27 (dt, 17.2,1.4 Hz, 1H), 5.15 (dt, 10.7,1.4 Hz, 1H), 5.00 (de, 17.1,1.5 Hz, 1H), 4.95 (ddt, 10.2,2.4,1.5 Hz, 1H), 3.95 (d, 12.0 Hz, 1 H), 3.87 (d, 12.0 Hz, 1H), 3.38 (dd, 14.2,8.0 Hz, 1H), 3.37 (qd, 7.1,2.6 Hz, 1H), 3.30 (dd, 14.2,5.5 Hz, 1H), 3.20 (d, 14.1 Hz, 1H), 3.15 (d, 14.1 Hz, 1H), 2.90 (s, 8H), 2.66 (t a, 6.4 Hz, 2H), 2.59 (td, 8.0,5.5 Hz, 1H), 2.49 (qui, 8.0 Hz, 1H), 2.34 (sxtd, 7.0,2.6 Hz, 1H), 1.97 (m, 3H), 1.85 (m, 2H), 1.73 (m, 2H), 1.66 (m, 2H), 1.55 (ddd, 13.5,9.8,4.0 Hz, 1 H), 1.08 (d, 7.1 Hz, 3H), 0.94 (d, 7.0 Hz, 3H);13C RMN (150 MHz, DMOS-d6): δ 169.8, 164.4, 150.9, 140.7, 139.6, 138.8, 137.3,134.6, 134.4, 131.9, 131.0, 130.7, 129.4, 128.8, 128.2, 127.3,125.9, 119.8, 119.5, 117.2,116.4, 116.0, 78.7, 77.6, 61.2, 58.2, 57.2, 43.2, 42.3, 41.4, 40.0, 35.8, 31.4, 29.6, 28.5, 24.2, 20.2, 18.2, 14.5, 8.4; LRMS (ESI): Calculated for C4iH46BrCIN2O6S+Na: 831.2, observed: 831.2. Synthesis of compound F (where PG is 4-bromobenzoyl) (where PG is 4-bromobenzoyl) 1. HCl(aq.)1M 2. M73-S¡Mes (2 mol%), 80 °CCIBrtoluene or Me O '0 compound F (where PG is 4-bromobenzoyl) 3. Acetone, silica trapper 4. Crystallization in toluene / heptane 10',1 θ'-dioxide (1 S,11 'R,12'S,16'S,16a'R,18a'R,E)-16'-((4-bromobenzyl)ox¡)-6chloro-11 ',12'-dimethyl-3,4,12', 1316',16a',17',18', 18a',19'-decahydro-1 Ή,2Η,3Ή,11 'Hespiro[naphthalen-1,2'-[5,7]ethenocyclobuta[¡][1,4]oxazepino[3,4f][1]thia[2,7]diazacyclohexadec¡n]-8'(9'H)-one (compound F where PG is 4-bromobenzoyl) : In a jacketed container, the piperazine salt was stirred Compound D (70 g) was dissolved in toluene (1.4 L, 20 L / kg) in the presence of 1 N aqueous HCl (0.35 L) at room temperature for 1 hour. After phase separation, the organic phase was washed twice more with 1 N HCl (2 x 0.35 L, 10 L / kg) to completely remove residual piperazine. The resulting organic phase was washed twice with deionized water (2 x 0.35 L, 10 L / kg). The organic phase containing the free form of compound D was concentrated under vacuum to a volume of 700 mL. In a second vessel, a solution of the M73-SIMes catalyst (1.287 g, 1.734 mmol, 0.022 eq.) was prepared.The catalyst solution and the toluene solution of compound D were simultaneously introduced for 60–90 minutes into the toluene container at 80 °C with a pressure of 300–500 torr. After the addition was complete, the solution was stirred for 1 hour before sampling to determine the conversion. After the reaction was complete (monitored by LC), the batch was pressurized to 1 atm with a nitrogen flow and cooled to 45 °C. Diethylene glycol monovinyl ether (256 µL, 1.874 mmol, 0.024 eq.) was added to deactivate the remaining active catalyst.After 1 hour, the batch was vacuum distilled to approximately 700 mL of toluene. The mixture was then cooled to room temperature and diluted with acetone (0.7 L, 10 L / kg) to obtain a 1:1 toluene / acetone solution. The Silia-MetS-Thiol trapper (35.0 g) was then added to the mixture, and the suspension was heated to 50 °C with stirring to trap the ruthenium metal. After 16 hours of stirring, the batch was filtered, and the spent silica was washed twice with 1:1 toluene / acetone (2 x 0.63 L, 18 L / kg). The filtrate and washings were combined and concentrated under vacuum to reduce the total volume to approximately 700 mL. The batch was held at 45 °C for 2 hours to induce self-formation of crystallization nuclei. Heptane (0.28 L, 4 L / kg) was supplied to the suspension at 45°C for 3 hours and then progressive cooling was carried out to 20-25°C.The suspension was filtered in the vacuum and the residual liquid above the filter was washed twice with tolueno:heptane 2:1 (2 x 0.21 L, 6 L / kg). The solid is dried in a vacuum at 40 °C to proportion the composition F, whereby PG is 4-bromobenzoyl as a white solid (48.9 g, 8085% yield).1H RMN (600 MHz, CDCI3) δ 8.46 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.56 (d, J= 8.5 Hz, 2H), 7.54 (d, J= 8.7 Hz, 1H), 7.16 (dd, J = 8.7, 2.3 Hz, 1H), 7.10 (d, J=2.0 Hz, 1 H), 7.07 (d, J = 2.3 Hz, 1 H), 7.01 (dd, J = 8.1,2.0 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1 H), 5.97 (ddd, J = 15.2, 9.1, 4.4 Hz, 1 H), 5.73 (ddt, J = 15.2, 8.2, 1.4 Hz, 1 H), 5.59 (dd, J = 8.2, 4.8 Hz, 1 H), 4.30 (qd, J= 7.3, 1.2 Hz, 1 H), 4.08 (d, J = 12.4 Hz, 1H), 4.06 (d, J= 12.4 Hz, 1H), 3.97 (dd, J = 15.5, 3.2 Hz, 1H), 3.57 (d, J = 14.4Hz, 1H), 3.17 (d, J= 14.4 Hz, 1 H), 3.03 (dd, J= 15.5, 9.1 Hz, 1H), 2.81 -2.76 (m, 1H), 2.77 - 2.72 (m, 1H), 2.67 (qd, J= 9.2, 4.7 Hz, 1H), 2.46 (quid, J=9.1, 3.2 Hz, 1 H), 2.14 - 2.04 (m, 3H), 2.04 - 1.99 (m, 2H), 2.00 - 1.88 (m, 3H), 1.85 - 1.74 (m, 1 H), 1.69 (de, J = 10.6, 9.1 Hz, 1H), 1.45 (d, J = 7.3 Hz, 3H), 1H), 1.02 (d, J = 6.7 Hz, 3H).13C NMR (151 MHz, CDCI3) δ 129.6, 129.4, 128.5, 127.9, 126.7, 126.4, 126.3, 120.9, 116.0, 115.7, 80.2, 75.9, 59.4, 58.1,57.8, 37.7, 37.7. 33.4, 30.1,28.2, 26.6, 19.8,19.0, 15.4, 5.9. LRMS (ESI): Calculated for C39H42BrCIN2O6S+Na: 803.1, observed: 803.1. r / or Ln / zznz / E / YiAi Ln / Zznz / E / YIAI Ongoing manufacturing: Synthesis of compound F (where PG is 4-bromobenzoyl) compound D (where PG is 4-bromobenzoyl) or 1. HCI (ac.) 1 M 2. M73-SIMs (2% mol), 80 °C toluene I THEIR O compound f (where PG is 4-bromobenzoyl) acetone, silica trap crystallization in toluene / heptane 10',10'-dioxide of (1S,1Tfi,12'S,16'S,16a' / ?,18a'fi,E)-16'-((4-bromobenzyl)ox¡)-6chloro-11 ',12'-di met i l-3,4,12', 1316',16a',17',18',18a',19'-decahydro-1Ή,2Η,3Ή,11Ήspiro[naphthalen-1,2'-[5,7]ethenocyclobuta[¡][1,4]oxazepino[3,4f][1]thia[2,7]diazacyclohexadecin]-8'(9'H)-one, compound F (where PG is 4bromobenzoyl): Stage 1 of a 2-stage continuous stirred tank reactor (CSTR) was connected to Two inlet feeds. Stage 1 and 2 CSTRs were each connected to a nitrogen gas purge. In both CSTRs, 50 mL of toluene was introduced, and both CSTRs were subjected to an internal temperature of 90–95 °C. Both CSTRs were equipped with a condenser cooled to 1 °C. Stage 1 and 2 CSTRs were connected to each other using a third pump, with a flow rate of 1.0 mL / min. Stage 2 CSTR was connected to a crude collection vessel using a fourth pump, with a flow rate of 0.0 mL / min. The free form of compound D (2.11 grams, prepared from 2.46 g of piperazine salt breakage) dissolved in toluene (100 mL, 40 L / kg) (feed 1) was pumped at a flow rate of 0.50 mL / min using peristaltic pump 1 into CSTR 1. The M73-SiMes catalyst (40.7 mg, 2.0 mol%) dissolved in toluene (100 mL) (feed 2) was pumped at a flow rate of 0.50 mL / min using peristaltic pump 2 into CSTR 1. The feeds to both pumps were started simultaneously. The reagent bottles for feeds 1 and 2 were maintained at 25 °C, with a gaseous nitrogen feed. After pumping the reaction streams, the solution entering the collection vessel was collected in fractions every 35 minutes for 3.33 hours of processing time. After 140 minutes of pumping, the fractions were analyzed by liquid chromatography (LC) to assess conversion. Results: Purity according to LC (PenumBrBz) = 86.18%. Purity according to LC (RCMPRE) = 2.32%. Ln / Zznz / E / YIAI Synthesis of compound A EITHER . compound A compound F (where PG is 4-bromobenzoyl) 10',10'-dioxide Ή,2Η,3Ή,11 'H-spiro[naphthalen-1,2'[5,7]ethenocyclobuta[i][1,4]oxazepino[3,4-f][1]thia[2,7]diazacyclohexadecin]-8'(9' / - / )-one (compound A): In a 2 L jacketed glass reactor, compound F (PG was 4-bromobenzoyl (60 g, 76.7 mmol)), followed by 600 mL of 2-MeTHF (10 L / kg) was added. The resulting mixture was stirred at 20 °C for 30 min. Then, 5 M NaOH (92.05 mL, 6 eq.) was introduced into the reactor with stirring. The reaction was stirred at 55 °C for 5 hours. 1200 mL of 2-MeTHF (20 L / kg) was added to the reaction mixture, followed by 276 mL (4.6 L / kg, 9 eq.) of 2.5 M H3PO4 at 50 °C, and the mixture was stirred at 50 °C for 10 min. The aqueous phase was removed after phase separation.Next, 300 mL of water (5 L / kg) at 50 °C was introduced into the reactor containing the organic phase, and the resulting mixture was stirred at 50 °C for 10 minutes. The aqueous phase was removed after phase separation. The water wash was repeated once more. Then, 100% w / w SiliaMet-Tiol was added, and the mixture was stirred at 20–45 °C for 18 hours. The mixture was then filtered and washed with 2-MeTHF. Finally, the batch was concentrated under reduced pressure to a yield of 9 L / kg (540 mL). The batch was cooled to 45 °C and held for 1 h to induce self-formation of crystallization nuclei. The resulting suspension was then cooled to 20 °C and 450 mL of heptane (7.5 L / kg) was introduced into the reactor. After the addition, the suspension was stirred at 20 °C for one hour. A white crystalline solid (compound A) was obtained after filtration and washing with a 1 / 1 mixture of 2-MeTHF / heptane.1H NMR (600 MHz, CDCh) δ 8.53 (s, 1H), 7.70 (d, J= 8.6 Hz, 1H), 7.17 (dd, J = 8.6, 2.4 Hz, 1H), 7.09 (d, J= 2.4 Hz, 1H), 7.00 (dd, J = 8.1,2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.85 (ddd, J = 15.3, 8.4, 4.6 Hz, 1H), 5.72 (ddd, J = 15.3, 8.1, 1.6 Hz, 1H), 4.28 (qd, J = 7.2, 1.3 Hz, 1H), 4.25 (dd, J = 8.1, 4.0 Hz, 1H), 4.09 (d, J= 12.1 Hz, 1H), 4.07 (d, J= 12.1 Hz, 1H), 3.84 (d a, J= 14.8 Hz, 1H), 3.69 (d, J = 14.1 Hz, 1H), 3.23 (d, J = 14.1 Hz, 1H), 3.01 (dd, J = 14.8, 9.6 Hz, 1H), 2.83 -2.77 (m, 1H), 2.77 - 2.72 (m, 1H), 2.44 (qd, J = 9.6, 4.0 Hz, 1H), 2.32 (quid, J = 9.6, 1.6 Hz, 1H), 2.14. 2.04 (m, 2H), 2.05-1.98 (m, 3H), 1.98- 1.92 (m, 1H), 1.88 (ca, J = 10.4 Hz, 1H), 1.85-1.75 (m, 2H), 1.66 (qu¡, J= 9.6 Hz, 1H), 1.47 (d, J= 7.2 Hz, 3H), 1.39 (ta, J= 12.8 Hz, 1H), 1.04 (d, J= 6.7 Hz, 3H);13C NMR (151 MHz, CDCI3) δ 166.5, 152.9, 140.9, 139.3, 138.8, 132.2, 132.1, 130.8, 129.6, 128.5, 126.7, 126.3, 120.9, 116.2, 115.2, 80.1,73.3, 59.9, 58.2, 57.8, 43.6, 41.7, 37.1, 33.7, 33.6, 30.1, 28.3, 27.1, 19.2, 19.1, 15.3, 5.7. LRMS (ESI): Calculated for C32H39CIN2O5S+Na: 621.2, observed: 621.2. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A compound having a structure of compound D: OPG η Me. O (D), or one of its salts or solvates, where PG is an alcohol protecting group.

2. The compound of claim 1, wherein the PG is an ether, a silicic ether, an acetal or ketal, or an acyl.

3. The compound of claim 2, wherein PG is an acyl.

4. The compound of claim 3, wherein the acyl is acetyl, pivaloyl, benzoyl (Bz), 4-bromobenzoyl (Br-Bz), 4-chlorobenzoyl, 4-iodobenzoyl, 4-fluorobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl or 2-naphthoyl.

5. The compound of claim 4, wherein PG is acetyl.

6. The compound of claim 4, wherein PG is pivaloyl.

7. The compound of claim 4, wherein PG is benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl or 2-naphthoyl.

8. The compound of claim 7, wherein PG is 4-bromobenzoyl.

9. The compound of claim 2, wherein PG is an ether.

10. The compound of claim 9, wherein the ether is methoxy, ethoxy, propoxy, butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), methoxypropyl ether (MOP), benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB) or 2-naphthylmethyl ether (Nap).

11. The compound of claim 2, wherein PG is an acetal or ketal.

12. The compound of claim 11, wherein PG is tetrahydropyranilic acetal (THP).

13. The compound of claim 2, wherein PG is a silyl ether.

14. The compound of claim 13, wherein PG is triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), or tert-butyldiphenylsilyl ether (TBDPS). ίη / 77Π7 / E / YΙΛΙ 15. A process for synthesizing compound D or one of its salts or solvates: comprising: mixing a compound C, an activating agent, an amine-type base and a compound E in the presence of a solvent to form compound D or one of its salts or solvates OPG where PG is an alcohol protecting group.

16. The process of claim 15, further comprising synthesizing compound C by mixing compound B and a protecting group introduction reagent to form compound C: OH 17. The process of claim 16, wherein compound B and the protecting group introduction reagent are mixed with a base.

18. The process of claim 17, wherein the base comprises pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), NaH, KH, K2CO3, Na2CO3, IJ2CO3, CS2CO3 or a combination of these.

19. The process of claim 18, wherein the base comprises pyridine, triethylamine, or a combination thereof. ίη / 77Π7 / E / YΙΛΙ 20. The process of claim 15, wherein the PG is an ether, a silicic ether, an acetal or ketal, or an acyl.

21. The process of claim 20, where PG is an acyl.

22. The process of claim 21, wherein the acyl is acetyl, pivaloyl, benzoyl (Bz), 4-bromobenzoyl (Br-Bz), 4-chlorobenzoyl, 4-iodobenzoyl, 4-fluorobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl or 2-naphthoyl.

23. The process of claim 22, wherein PG is acetyl.

24. The compound of claim 23, wherein PG is pivaloyl.

25. The process of claim 22, wherein PG is benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl or 2-naphthoyl.

26. The process of claim 25, wherein PG is 4-bromobenzoyl.

27. The process of claim 20, where PG is an ether.

28. The process of claim 27, wherein the ether is methoxy, ethoxy, propoxy, butoxy, methoxymethyl acetal (MOM), 2-methoxyethoxymethyl ester (MEM), ethoxyethyl acetal (EE), methoxypropyl ether (MOP), benzyloxymethyl acetal (BOM), benzyl ether (Bn), 4-methoxybenzyl ether (PMB) or 2-naphthylmethyl ether (Nap).

29. The process of claim 20, wherein PG is an acetal or ketal.

30. The process of claim 29, wherein PG is tetrahydropyranilic acetal (THP).

31. The process of claim 20, wherein PG is a silicic ether.

32. The process of claim 31, wherein PG is triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), ferf-butyldimethylsilyl ether (TBS) or tert-butyldiphenylsilyl ether (TBDPS).

33. The process of claim 16, wherein PG is acetyl and the synthesis of compound C comprises mixing compound B, acetic anhydride, triethylamine and 4-dimethylaminopyridine (DMAP) in the absence of solvent.

34. The process of claim 16, wherein PG is 4-bromobenzoyl and the synthesis of compound C comprises mixing compound B, 4-bromobenzoyl chloride and pyridine in a solvent.

35. The process of claim 34, wherein the solvent comprises tetrahydrofuran (“THF”), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene, hexane, heptane, 1,4-dioxane, dichloromethane, 1,2-dichloroethylene or a combination thereof.

36. The process of claim 15, wherein the mixing of compound B and the protecting group introduction reagent is carried out for 30 minutes to 48 hours.

37. The process of claim 36, wherein the mixing is carried out for 1.5 hours.

38. The process of claim 16, wherein the mixing of compound B and the protecting group introduction reagent is carried out at a temperature of 0 °C to 40 °C.

39. The process of claim 15, wherein compound B, prior to mixing with the protecting group introduction reagent, is prepared as a free acid (free acid of compound B) from a salt form (salt of compound B).

40. The process of claim 39, wherein the salt of compound B is an ammonium salt.

41. The process of claim 40, wherein the salt of compound B comprises an r / or Ln / zznz / E / YiAi 42. The process of claim 39, wherein the free acid of compound B is prepared by mixing the salt of compound B and phosphoric acid in a solvent to form the free acid of compound B.

43. The process of claim 42, wherein the solvent comprises 2-methyltetrahydrofuran (2-MeTHF) or toluene.

44. The process of claim 15, wherein the activating agent comprises an acid anhydride, an acid chloride-type agent, a carbodiimide-type agent, a uronium-type agent, an ammine-type agent, a phosphonium-type agent, or a combination thereof.

45. The process of claim 44, wherein the activating agent is SOCI2, oxalyl chloride, propanephosphonic acid anhydride or a combination thereof.

46. ​​The process of claim 15, wherein the amine-type base for mixing compound C and compound E comprises pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyl[5.4.0]undec-7-ene (DBU), 1,4-diazabicylyl[2.2.2]octane (DABCO) or a combination thereof.

47. The process of claim 46, wherein the amine-type base comprises diisopropylethylamine, triethylamine, or a combination thereof.

48. The process of claim 15, wherein compound E and compound C are present in a molar ratio of 1:1 to 1.5:1 of compound C:compound E.

49. The process of claim 15, wherein the mixture of compound C, compound E, the activating agent and the amine-type base is produced in a solvent.

50. The process of claim 49, wherein the solvent comprises tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, dichloroethane, 1,2-dimethoxylane, toluene, hexane, heptane, 1,4-dioxane, L / ,L / Z dimethylformamide, L / ,V-dimethylacetamide, A / -methyl-2-pyrrolidine or a combination thereof.

51. The process of claim 50, wherein the solvent comprises toluene.

52. A process for synthesizing compound A or one of its salts or solvates: comprising: mixing an organometallic catalyst and a compound D or one of its salts or solvates in a solvent, to form a compound F (F) or one of its salts, and deprotecting compound F to form compound A.

53. The method of claim 52, wherein compound D is synthesized by the process of any of claims 15-51.

54. The process of claim 52, wherein the organometallic catalyst comprises molybdenum or ruthenium.

55. The process of claim 52, wherein the organometallic catalyst comprises a 1st generation Grubbs catalyst, 2nd generation Grubbs catalyst, 3rd generation Grubbs catalyst, 1st generation Hoveyda-Grubbs catalyst, 2nd generation Hoveyda-Grubbs catalyst, or a combination thereof. ίη / 77P7 / E / YΙΛΙ 56. The process of claim 52, wherein the organometallic catalyst is ^-O'Bu NH 57. The process of claim 52, wherein the solvent comprises a nonpolar organic solvent.

58. The process of claim 57, wherein the solvent is toluene, hexane, heptane, 1,4-dioxane or a combination thereof.

59. The process of claim 52, wherein the mixing of compound D and the organometallic catalyst occurs at a temperature of approximately 50 °C to approximately 115 °C.

60. The process of claim 59, wherein the mixture of compound D and the organometallic catalyst is produced at a temperature of approximately 80 °C.

61. The process of claim 52, wherein compound A is used to synthesize compound A1 or one of its salts or solvates Me' O 62. The process of claim 52, wherein compound A is used to synthesize compound A2 or one of its salts or solvates