EA042082B1 - SYNTHESIS OF POLYCYCLIC CARBAMOYL PYRIDONE COMPOUNDS - Google Patents

Description

Technical field

New methods for the synthesis of polycyclic carbamoylpyridone compounds have been proposed. Intermediates in the synthesis of polycyclic carbamoylpyridone compounds have also been proposed.

Description of the prior art

Human Immunodeficiency Virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) codes for three enzymes that are required for virus replication: reverse transcriptase, protease, and integrase. Despite the widespread use of drugs targeting reverse transcriptase and protease, which have shown their effectiveness, in particular when used in combination, toxicity and the development of resistant strains limit their use (Palella, et al. N. Engl. J Med. ( 1998) 338:853-860; Richman, D.D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit HIV replication and minimize PXR activation when co-administered with other drugs.

Certain polycyclic carbamoylpyridone compounds have been found to have antiviral activity as described in PCT/US2013/076367. Accordingly, there is a need for methods for the synthesis of such compounds.

Brief description of the invention

The present invention relates to a new synthetic method for the preparation of polycyclic carbamoylpyridone compounds of formula I using the synthetic steps described herein. The present invention also relates to specific individual steps of this method and specific individual intermediates used in this method. According to one embodiment of the present invention, there is provided a process for the preparation of a compound of formula I.

In another embodiment, a process for preparing a compound of formula I is provided.

according to the following general scheme VI reaction of B-1.J-1 in the presence of acid to obtain C-1, including suspending B-1.J-1 in a solvent, treating the resulting solution with acid, carrying out the reaction for from about 12 to about 24 hours at about 20-80° C. and recovering C-1;

reacting C-1 with an alkylated formamide acetal to give D-1, comprising adding the alkylated formamide acetal to a solution of C-1 and an acid in a solvent and reacting at about 0-75° C. for about 0.1 to about 12 hours;

reacting D-1 with K-1 to give E-1, comprising adding K-1 to a solution of D-1 in a solvent and reacting at about 10-60° C. to give E-1;

interaction of E-1 with M-1 in the presence of a base to obtain F-1, including the addition of M-1

- 1 042082 and base to the reaction mixture containing E-1, stirring the specified reaction mixture at about 20-80°C for about 1 to about 24 h and extracting F-1;

reacting F-1 with at least one acid to form FF-1, comprising adding at least one acid to a solution of F-1 in a solvent, stirring the reaction mixture at about 20-120° C. for about 1 to about 24 hours and product extraction;

interaction of FF-1 with N-1 or its salts in the presence of an additive to obtain G-1, including the combination of FF-1, N-1 or their salts and the specified additive with a solvent, stirring the reaction mixture at about 0-40 ° C and extraction G-1; and reacting G-1 with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof to give a compound of formula I, said reacting comprising adding at least one reagent to a solution of G-1 in a suitable solvent, stirring the resulting suspension at about 40-100° C. for about 10 minutes to 3 hours, quenching the reaction by adding acid, and extracting the compound of formula I;

where Hal is a halogen, which may be the same or different;

n is 1, 2 or 3;

L is -C(R ^c )2-, -C(R ^c )2C(R ^c )2-, -C(R ^c )2C(R ^c )2C(R ^c )2- or -C(R ^c )2C(R ^c )2C(R ^c )2C(R ^c )2-;

each R ^c is independently hydrogen, halogen, hydroxyl, or C1- _C4 alkyl;

each R ^b is independently C1-C ₄ alkyl and each Ra, R ¹ and R ² are independently (C1-C ₄ )alkyl, (C6-C10)aryl, or ( _C6 - _C10 )aryl( _C1C4 ) alkyl.

Other embodiments and features are set forth in the following detailed description of the embodiments, and in part will become apparent from the description, or may be learned by practice of the claimed invention. It should be understood that the above summary, which should be considered as a condensed and general summary of some of the embodiments proposed in this application, is offered solely for the convenience and assistance of the reader and does not limit in any way the scope or range of equivalents that, in accordance with the law defined by the claims.

Detailed description of the invention

For a more complete understanding of the various embodiments of the invention, the following is a detailed description. However, those skilled in the art will appreciate that the invention may be practiced without these details. It should be understood that the following description of certain embodiments should be considered as an example of the claimed subject matter, and not as limiting the appended claims to the particular illustrated embodiments. The headings used in this specification are for convenience only and should not be construed as limiting the claims in any way. Embodiments illustrated after any heading may be combined with embodiments illustrated after any other heading.

Definitions.

Unless the context suggests otherwise, in the present description and claims, the word contain and its various forms, such as contains and containing, should be considered in an open and non-exclusive sense, that is, as including, but not limited to.

A prefix such as C _u - _v or (C _u -C _v ) indicates that the subsequent group contains u to v carbon atoms. For example, (C1-C ₆ )alkyl means that the alkyl group contains from 1 to 6 carbon atoms and (C ₆ -C ₁₀ )aryl(C1-C ₆ )alkyl means that the aryl portion in said group contains from 6 to 10 carbon atoms and the alkyl part in the specified group contains from one to six carbon atoms.

Reference to one embodiment or embodiment in the present specification means that a particular feature, structure, or characteristic described in an embodiment is included in at least one embodiment of the present invention. Thus, the use of phrases in one implementation or according to an implementation variant in various places in this description does not necessarily refer to one implementation variant. In addition, certain features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Amino refers to the -NH ₂ radical.

Cyano refers to the -CN radical.

Hydroxy or hydroxyl refers to the -OH radical.

Imino refers to the =NH substituent.

Nitro refers to the -NO2 radical.

Oxo refers to the =O substituent.

Thioxo refers to the =S substituent.

BzOH refers to benzoic acid or V'

- 2 042082

Alkyl refers to a straight or branched saturated hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing from one to twelve carbon atoms (C1- _C12 alkyl) or from one to eight carbon atoms (C1- _C8 alkyl) or one up to six carbon atoms (C ₁ -C ₆ alkyl), or from one to four carbon atoms (C 1 -C ₄ alkyl), which is attached to the rest of the molecule through a single bond, for example, to methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1- enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated herein, the alkyl group may be optionally substituted. In some embodiments, alkyl refers to a straight or branched saturated hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing one to twelve carbon atoms (C1- _C12 alkyl), or one to eight carbon atoms (C1- _C8 alkyl). ), or from one to six carbon atoms (C ₁ -C 6 alkyl), or from one to four carbon atoms (C 1 -C ₄ alkyl), and which is attached to the rest of the molecule through a single bond, for example, to methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise specifically stated herein, the alkyl group may be optionally substituted.

Aryl refers to a radical in the form of a monocyclic hydrocarbon ring system containing hydrogen and 6 to 18 carbon atoms, or 6 to 10 carbon atoms, or 6 to 8 carbon atoms. Aryl radicals include, but are not limited to, aryl radicals derived from benzene. Unless otherwise specifically stated in the specification, the term aryl or the prefix ar- (as in aralkyl) includes optionally substituted aryl radicals that are optionally substituted. Arylalkyl (also aralkyl) refers to a radical of the formula -R ^{B -RC} where R ^B is an alkyl group as defined above and _RC is one or more aryl radicals as defined above, eg benzyl. Arylalkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, and the like. An arylalkyl group contains from 6 to about 30 carbon atoms, for example an alkyl group may contain from 1 to about 10 carbon atoms and an aryl group may contain from 5 to about 20 carbon atoms. Unless the specification specifically states otherwise, the aralkyl group may be optionally substituted.

In some embodiments, arylalkyl (also aralkyl) refers to a radical of the formula -R ^{B -RC} where R ^B is an alkyl group as defined above and _RC is one or more aryl radicals as defined above, such as benzyl. Arylalkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, and the like. An arylalkyl group contains from 6 to about 30 carbon atoms, for example an alkyl group may contain from 1 to about 10 carbon atoms and an aryl group may contain from 6 to about 20 carbon atoms. Unless the specification specifically states otherwise, the aralkyl group may be optionally substituted. Halogen or halogen refers to bromine, chlorine, fluorine or iodine. As used herein, the term alkylated formamide acetal refers to a compound of the formula:

_R v2 where each R ^b is independently (C1-C4) alkyl, R ^v1 and R ^v2 are independently (C1-C6) alkyl, or R ^v1 and R ^v2 together with the atoms to which they are attached form 5-10- membered heterocyclyl.

Alkylated formamide acetal includes, but is not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal.

As used herein, the term acyl donor refers to a reactive compound that transfers a -CO-R ^x group to another molecule, where R ^x is (C1-C6)alkyl R ^y and R ^y is selected from the group consisting of H, CN, - NR ^z1 R ^z2 , C(O)R ^z1 , -C(O)OR ^z1 , -C(O)NR ^z1 R ^z2 , -OC(O)NR ^z1 R ^z2 , -NR ^z1 C(O)R ^z2 , -NR ^z1 C(O)NR ^z2 -NR ^z1 C(O)OR ^z2 , -SR ^z1 , -S(O)i.2R ^z1 , -S(O)2NR ^z1 R ^z2 , -NR ^z1 S(O) 2R ^z2 , NR ^z1 S(O)2R ^z2 and OR ^z1 . R ^z1 and R ^z2 are independently selected from the group consisting of H, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 heteroalkyl, C3_10 cycloalkyl, 3-12 membered heterocyclyl, C6_10 aryl, and 5-10 membered heteroaryl. In some embodiments, R ^y is H. In some embodiments, R ^z1 and R ^z2 are independently selected from the group consisting of H and C1. ₆ alkyl. Acyl donors include, but are not limited to, anhydrides, esters, and acid chlorides such as succinic anhydride, glutaric anhydride, acetic anhydride, vinyl acetate, isopropenyl acetate, 4-chlorophenyl acetate, ethyl methoxyacetate, acetyl chloride, and benzoyl chloride.

One skilled in the art will appreciate from the present application, and in particular Schemes IVI, that Compound E-1 may exist in the E or Z configuration, or as a mixture of the E and Z configurations. Accordingly, in some embodiments, Compound E-1 exists in

E- or Z-configuration or mixtures thereof. In some embodiments, the E-1 connection exists in an E configuration. In some embodiments, the E-1 connection exists in a Z configuration. In some embodiments, compound E-1 exists in a mixture of Z and E configurations.

(E-1) (E)-configuration (E-1) (7)-configuration

A person skilled in the art will understand from this application that compound B-1.J-1 is a salt

The term protecting group as used herein refers to a labile chemical moiety known in the art used to protect reactive groups, including without limitation hydroxyl and amino groups, from undergoing unwanted interactions during a synthesis process. Protected hydroxyl and amino groups are referred to herein as protected hydroxyl groups and protected amino groups, respectively. Protecting groups are typically used to selectively and/or orthogonally protect sites when conducting interactions on other reactive sites, which can then be removed to obtain the original unprotected group or to conduct additional interactions. Protective groups known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). In general, the groups are protected or provided as a precursor that is inert to interactions that result in modification of other portions of the parent molecule and that is converted to the final group at the appropriate time. Exemplary protecting or precursor groups are further discussed in Agrawal, et al., Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26p. 1-72. Examples of hydroxyl protecting groups include, but are not limited to, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2 ,6dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoyl formate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate. Examples of amino protecting groups include, but are not limited to, carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teos), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bloc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trihaloacetyl, benzoyl and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imide protecting groups such as phthalimido and dithiasuccinoyl.

The invention provided herein is also intended to cover all pharmaceutically acceptable compounds of formula I and compounds of formula II labeled with isotopes wherein one or more atoms are replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be introduced into the proposed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine atoms, such as ² H, ³ H, ^H C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. These labeled compounds may be suitable for determining or measuring the efficacy of compounds by characterizing, for example, site and mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula I and compounds of formula II, for example containing a radioactive isotope, are suitable for drug and/or substrate tissue distribution studies. Radioactive isotopes such as tritium, i.e. ³ H, and carbon-14, i.e. ^14C are particularly suitable for this task due to their ease of administration and rapid detection.

Substitution by heavier isotopes such as deuterium, i.e. ² H, may provide certain therapeutic benefits, determined by the higher metabolic stability. For example, the in vivo half-life may be increased or the required dosage may be reduced. Thus, in some cases, heavier isotopes may be preferred.

Substitution with positron-emitting isotopes such as 11C, ^18F , ^15O , and ^13N may be suitable for positron emission tomography (PET) studies in determining the degree of substrate receptor occupancy. Isotopically labeled compounds of formula I and compounds of formula II can generally be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described in the examples below, using the appropriate isotopically labeled reagent. instead of the unlabeled reagent used previously.

It is also understood that the invention described in the present description, covers the products of metabolism in vivo of the proposed compounds. These products can be obtained, for example, as a result of oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly through the action of enzymatic processes. Accordingly, the invention includes compounds prepared by a method comprising administering a compound of the present invention to a mammal for a period of time sufficient to produce a metabolite. These products are typically detected by administering a labeled compound described in the embodiments herein at a detectable dose to an animal such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the products conversions from urine, blood or other biological samples.

A stable compound and a stable structure is meant to mean a compound that is strong enough to undergo isolation from a reaction mixture until the desired purity is achieved and formulated into an effective therapeutic agent. A Lewis acid refers to a group that can accept a lone pair of electrons, that is, an electron pair acceptor. Lewis acids can react with a Lewis base to form a Lewis adduct by exchanging an electron pair provided by the Lewis base. Mammal includes human and domesticated animals such as laboratory animals and domestic animals (eg cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and undomesticated animals such as wild animals.

Optional or optional means that the event or condition described below may or may not occur, and the description includes cases in which the specified event or condition occurs and cases in which it does not occur. For example, optionally substituted aryl means that the aryl radical may be substituted or unsubstituted, and the description includes substituted aryl radicals and unsubstituted aryl radicals.

A pharmaceutically acceptable carrier, diluent or excipient includes, without limitation, any additives, carriers, excipients, lubricants, sweeteners, diluents, preservatives, colorants/colorants, flavor enhancers, surfactants, humectants, dispersing agents, suspending agents, stabilizers , isotonic agents, diluents, or emulsifiers approved by the United States Food and Drug Administration for use in humans or domesticated animals.

A pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and possesses (or can be converted into a form that possesses) the intended pharmacological activity of the parent compound. Examples of pharmaceutically acceptable salts of the compounds provided herein include salts derived from an appropriate base such as alkali metal (eg sodium), alkaline earth metal (eg magnesium), ammonium and NX4+ (wherein X is C1- _C4 alkyl ). Pharmaceutically acceptable nitrogen or amino salts include, for example, salts of organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic, malic, mandelic, isethionic, lactobionic, succinic, 2naphthalenesulfonic acid, oleic, palmitic, propanoic, stearic and trimethylacetic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of the hydroxy group of a compound include the anion of said compound in combination with a suitable cation such as Na ⁺ and NX4 ⁺ (wherein X is independently selected from H or a C1-C4 alkyl group). Pharmaceutically acceptable salts also include salts obtained by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordination with an organic base such as diethanolamine, triethanolamine, N-methylglucamine, etc. Also included in this definition are ammonium and substituted or quaternary ammonium salts. Exemplary non-limiting lists of pharmaceutically acceptable salts can be found in B SM Berge et al., J. PharmaSci., 66(1), 1-19(1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, tab. 38-5, the contents of each of which are incorporated into the present application by reference. For therapeutic use, the salts of the active ingredients of the compounds provided herein, as a rule, must be pharmaceutically acceptable, i. they must be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I, a compound of formula II, or another compound described herein. All salts derived from a physiologically acceptable acid or base, or derived from another acid or base, are included within the scope of the present invention.

Metal salts refer to salts in which the cation is a metal, such as those formed when an acidic proton present in a compound is replaced by either a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when the metal ion is coordinated to an organic base such as diethanolamine, triethanolamine, N-methylglucamine, and the like.

The metal may be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. Non-limiting examples of suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, and zinc.

Non-limiting examples of suitable metal salts include lithium salts, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt and zinc salt.

In addition, salts can be obtained by adding certain organic and inorganic acids, for example, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , or organic sulfonic acids to basic sites, usually amines. Finally, it should be understood that the compositions described in this application contain the compounds proposed in the present description, in non-ionized form, as well as in the form of a zwitterion, and combinations with stoichiometric amounts of water in the form of hydrates.

Often, crystallization yields a solvate of the compound described in the embodiments described herein. As used herein, the term solvate refers to an aggregate containing one or more molecules of a compound described in the embodiments described herein and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds described in the embodiments described herein may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as the corresponding solvated forms. The compound described in the embodiments described herein may be a true solvate, while in other cases, the compound of the present invention may contain solely introduced water or a mixture of soda and some introduced solvent.

A pharmaceutical composition refers to a composition containing a compound described herein and a medium generally accepted in the art for delivering a biologically active compound to a mammal, eg, a human. Said medium includes all pharmaceutically acceptable carriers, diluents or excipients.

An effective amount or therapeutically effective amount refers to an amount of a compound of the present invention which, when administered to a patient in need thereof, is sufficient to effectively treat the disease states, conditions, or disorders for which the compounds may be used. The amount indicated should be sufficient to produce the biological or medical response in the tissue system or patient intended by the researcher or physician. The amount of a compound of the present invention corresponding to a therapeutically effective amount may vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease state, or the disorder being treated and its severity, drugs used in combination or concomitantly with the compounds described herein, and the patient's age, weight, general health, sex, and diet. Those skilled in the art can determine the indicated therapeutically effective amount using conventional methods based on their own knowledge, the prior art and the present description.

The compounds described herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thereby allowing the formation of enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- in the case of amino acids. It is intended that the present invention include all of these possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be obtained using chiral synthons or chiral reagents or separated using conventional methods, for example, by chromatography and fractional crystallization. Conventional methods for the preparation/isolation of individual enantiomers involve chiral synthesis from the appropriate

- 6 042082 th optically pure precursor or separation of the racemate (or racemate salt or derivative), for example, by chiral high performance liquid chromatography (HPLC). When the compounds described in this application contain olefinic double bonds or other centers of geometric asymmetry, and unless specifically indicated otherwise, it is understood that the compounds include E - and Z geometric isomers. In addition, all tautomeric forms are intended to be included. Stereoisomers refer to compounds that are made up of the same atoms linked by the same bonds but have different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof, and includes enantiomers that refer to two stereoisomers whose molecules are incompatible mirror images of each other. Tautomer refers to a molecule made by transferring a proton to another atom of the same molecule. The present invention includes tautomers of any of these compounds.

An enantiomerically enriched compound refers to a compound that contains more than 50% of one of the pairs of enantiomers. An enantiomerically enriched compound may have an enantiomeric excess (%ee) of greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90% , more than 95%, more than 99% or more than 99.9%. Throughout this document, reference to an exemplary value or parameter includes (or describes) embodiments that refer to such value or parameter per se. For example, a description referring to about X includes a description of X. Also, the singular form includes the plural form, unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds, and a reference to an assay includes a reference to one or more assays or equivalents known to those skilled in the art.

General schemes

Some implementation options relate to multi-stage General methods of synthesis, described below, namely General schemes I-VI. All substituent groups in the steps described below are as defined as follows:

Hal is a halogen which may be the same or different;

n is 1, 2 or 3;

L is -C(R ^c )2-, -C(R ^c )2C(R ^c )2-, -C(R ^c )2C(R ^c )2C(R ^c ) ₂ - or -C(R ^c )2C(R ^c )2C(R ^c )2C(R ^c )2-;

each R ^c is independently hydrogen, halogen, hydroxyl, or C1- _C4 alkyl;

each Ra, R ¹ and R ² is independently (C1-C ₄ )alkyl, (C ₆ -C1 ₀ )aryl, or (C ₆ -C1 ₀ )aryl (C _g C4) alkyl and each R ^b is independently ( C1- _C4 )alkyl.

General scheme VI.

According to some implementation options, the method according to General Scheme I is proposed

General Scheme VI wherein said method comprises the following steps:

interaction of B-1.J-1 in the presence of an acid to obtain C-1, including suspending B1.J-1 in a solvent, treating the resulting solution with acid, carrying out the reaction for from about 12 to about 24 hours at about 20-80 ° C and extract C-1;

reacting C-1 with an alkylated formamide acetal to give D-1, comprising adding the alkylated formamide acetal to a solution of C-1 and an acid in a solvent and reacting at about 0-75° C. for about 0.1 to about 12 hours;

- 7 042082 interaction of D-1 with K-1 to obtain E-1, including adding K-1 to a solution of D-1 in a solvent and carrying out the reaction at about 10-60°C to obtain E-1;

interaction of E-1 with M-1 in the presence of a base to obtain F-1, including adding M-1 and base to the reaction mixture containing E-1, stirring said reaction mixture at about 20-80°C for from about 1 to about 24 h and extract F-1;

reacting F-1 with at least one acid to form FF-1, comprising adding at least one acid to a solution of F-1 in a solvent, stirring the reaction mixture at about 20-120° C. for about 1 to about 24 hours and product extraction;

interaction of FF-1 with N-1 or its salts in the presence of an additive to obtain G-1, including the combination of FF-1, N-1 or their salts and the specified additive with a solvent, stirring the reaction mixture at about 0-40 ° C and extraction G-1; and reacting G-1 with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof to give a compound of formula I, said reacting comprising adding at least one reagent to a solution of G-1 in a suitable solvent, stirring the resulting suspension at about 40-100° C. for about 10 minutes to 3 hours, quenching the reaction by adding acid, and extracting the compound of formula I;

Hal is a halogen which may be the same or different;

n is 1, 2 or 3;

L is -C(R ^c )2-, -C(R ^c )2C(R ^c )2-, -C(R ^c )2C(R ^c )2C(R ^c )2- or -C(R ^c )2C(R ^c )2C(R ^c )2C(R ^c )2-;

each R ^c is independently hydrogen, halogen, hydroxyl, or C1- _C4 alkyl;

each Ra, R ¹ and R ² is independently (C1-C ₄ )alkyl, (C ₆ -C ₁₀ )aryl, or (C ₆ -C ₁₀ )aryl(C1C ₄ )alkyl and each R ^b is independently (C1 -C ₄ )alkyl.

In some embodiments, reacting F-1 with at least one acid results in the following aldehyde:

which is hydrogenated to give FF-1.

General schemes - separate stages.

Additional embodiments relate to the individual steps of the multi-step general synthesis methods described above, namely the general scheme VI. These individual steps and intermediates of the present invention are described in detail below. All substituent groups in the steps described below are as defined in the multi-step method above.

1. Formation of C-1 through salt B-K-1

Alternatively, in some embodiments, C-1 is obtained by forming a B-1·J-1 salt according to the procedure below.

A. Salt formation B-1^J-1 by adding J-1 to B-1

Free acid B-1 (about 1 eq.) is dissolved in the solvent, followed by the addition of J-1 (from about 1 to about 5 eq.). In some embodiments, the salt is aged up to 12 hours, up to 10 hours, up to 8 hours, up to 6 hours, up to 4 hours, or up to 3 hours. The salt is obtained by any suitable methods known in the art, including, but not limited to, filtration with solvents, extraction, crystallization and chromatography on silica gel.

In some embodiments, the solvent for the above interaction is a polar aprotic solvent or an aromatic solvent. In some embodiments, the solvent for the above interaction is a polar aprotic solvent. In some embodiments, the solvent for the above interaction is an aromatic solvent. Examples of polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. Examples of aromatic solvents for the above interaction include, but are not limited to, pyridine, toluene, xylene, benzene or chlorobenzene. According to other additional implementation options, the solvent is a mixture containing at least one of the above solvents. For example, in some embodiments, the solvent is a mixture of up to three or

- 8 042082 to two polar aprotic solvents selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane and N-methyl-2-pyrrolidinone. In other embodiments, the solvent is a mixture of up to three or up to two aromatic solvents selected from the group consisting of pyridine, toluene, xylene, benzene, and chlorobenzene. In one embodiment, the solvent is a mixture of up to three or up to two solvents selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In an additional embodiment, the solvent is acetonitrile.

In some embodiments, B-1.J-1 is

Oh..Oh

In some embodiments, the reaction mixture is stirred at about 1530°C, about 20-70°C, about 20-60°C, about 20-50°C, about 20-40°C, about 2030°C, about 30-80°C , about 30-70°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-80°C, about 40-70°C, about 40-60°C, about 40- 50°C, about 5080°C, about 50-70°C, about 50-60°C, about 60-80°C, about 60-70°C, about 70-80°C, or any subrange in between. In additional embodiments, the reaction proceeds at about 15 to about 25°C.

In some embodiments, the solvent is acetonitrile and the reaction proceeds at about 18 to about 25°C.

b. Formation of C-1 from salt B-1 J-1

B-1 J-1

Salt B-1J-1 (about 1 eq.) suspended in a suitable solvent. The resulting solution is treated with about 0.1-1 eq. suitable acid. The reaction is allowed to proceed for about 12 to about 24 hours at about 20-80°C, after which the solvent is removed and C-1 is recovered and purified from the residue using any suitable technique known in the art, such as, but not limited to them, solvent extraction, silica gel chromatography, crystallization and filtration.

In some embodiments, the solvent for the above interaction is a polar aprotic solvent or an aromatic solvent. In some embodiments, the solvent for the above interaction is a polar aprotic solvent. In some embodiments, the solvent for the above interaction is an aromatic solvent. Examples of polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. Examples of aromatic solvents for the above interaction include, but are not limited to, pyridine, toluene, xylene, benzene or chlorobenzene. According to other additional implementation options, the solvent is a mixture containing at least one of the above solvents. For example, in some embodiments, the solvent is a mixture of up to three, or up to two, polar aprotic solvents selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2- pyrrolidinone. In other embodiments, the solvent is a mixture of up to three or up to two aromatic solvents selected from the group consisting of pyridine, toluene, xylene, benzene, and chlorobenzene. In one embodiment, the solvent is a mixture of up to three or up to two solvents selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In an additional embodiment, the solvent is acetonitrile.

In specific embodiments, the acid is an inorganic acid, an organic acid, or a halogenated organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid. Examples of organic acids include, but are not limited to, formic acid

- 9 042082 slot and acetic acid. In other embodiments, the organic acid is a halogenated organic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In some embodiments, the acid is trifluoroacetic acid. In other further embodiments, the acid is a mixture containing one or more organic acids and one or more inorganic acids. In some embodiments, the acid is a mixture containing up to three or up to two organic acids. In some embodiments, the acid is a mixture containing up to three or up to two halogenated organic acids. In some embodiments, the acid is a mixture containing up to three or up to two inorganic acids. In a specific embodiment, the acid is a mixture of up to three or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In a specific embodiment, the acid is trifluoroacetic acid.

In some embodiments, after addition is complete, the reaction mixture is heated to about 20-70°C, about 20-60°C, about 20-50°C, about 20-40°C, about 2030°C, about 30-80°C , about 30-70°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-80°C, about 40-70°C, about 40-60°C, about 40 -50°C, about 5080°C, about 50-70°C, about 50-60°C, about 60-80°C, about 60-70°C, about 70-80°C, or any subrange in between. According to additional variants of implementation of the interaction takes place at about 60°C.

In specific embodiments, the solvent is acetonitrile, the acid is trifluoroacetic acid, and the reaction proceeds at about 60°C.

B. Alkylation of C-1 to give E-1

A solution of approximately 1 eq. C-1 in a suitable solvent is treated with about 1 to 1.5 eq. alkylated formamide acetal and stirred at about 0-60°C for about 10 hours to about 18 hours. The reaction mixture is treated with about 1 eq. K-1 and the reaction is left to proceed for about 1 to about 4 hours, and then quenched by adding acid. E-1 is then extracted and purified by any suitable means known in the art, including but not limited to solvent extraction, crystallization, and silica gel chromatography.

In a specific embodiment, the solvent is an aprotic polar organic solvent such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone or mixtures thereof. In an additional embodiment, the solvent is 2-methyltetrahydrofuran.

In some embodiments, the alkylated formamide acetal is selected from the group consisting of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

According to specific implementation options 1 EQ. C-1 is treated with approximately 1.1 eq. alkylated formamide acetal.

In some embodiments, R ¹ is (C1-C4)alkyl, (C2-C10)aryl, or (C2-C10)aryl(C1-C4)alkyl. In some embodiments, R ¹ is (C1C4)alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl(C1- _C4 )alkyl. In some embodiments, R ¹ is C1-C4 alkyl. In additional embodiments, R ¹ is -CH3, ie K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, the reaction is quenched with an inorganic acid, an organic

- 10 042082 acid or halogenated organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is a halogenated organic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid. Examples of organic acids include, but are not limited to, formic acid and acetic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In other further embodiments, the acid is a mixture containing one or more organic acids, one or more inorganic acids, and/or one or more halogenated organic acids. In some embodiments, the acid is a mixture containing up to three or up to two organic acids. In some embodiments, the acid is a mixture containing up to three or up to two halogenated organic acids. In some embodiments, the acid is a mixture containing up to three or up to two inorganic acids. In a specific embodiment, the acid is a mixture of up to three or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In a specific embodiment, the acid is trifluoroacetic acid. In specific embodiments, the reaction is quenched with hydrochloric acid. In specific embodiments, the reaction is quenched with 2 N HCl. In some embodiments, the reaction is not quenched.

In some embodiments, the reaction proceeds at about 10-60°C, about 10-50°C, about 10-40°C, about 10-30°C, about 10-20°C, 20-60°C, about 2050 °C, about 20-40°C, about 20-30°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-60°C, about 40-50°C, about 50-60°C or any subrange in between. In specific embodiments, the reaction proceeds at room temperature. In additional embodiments, the reaction proceeds at about 15 to about 25°C.

In specific embodiments, the solvent is 2methyltetrahydrofuran, the alkylated formamide acetal is N,Ndimethylformamide dimethylacetal, R ¹ is —CH ₃ , and the reaction proceeds at about 18 to about 23°C.

C. Cyclization of E-1 to F-1 o

E-1

In specific embodiments, a solution of about 1 eq. E-1 and about 1 to 5 eq. M-1 in the first suitable solvent is combined and cooled to about 0-5°C. In some embodiments, the base is slowly added to the reaction mixture while keeping the internal temperature of the reaction mixture cold during the addition (e.g., below room temperature, or below about 25°C, or below about 20°C, or below about 15°C). After addition is complete, the reaction mixture is heated to about 20-80°C for at least about 14 hours.

After this time, the reaction mixture can be diluted with an aqueous acidic solution and an additional suitable organic solvent, and the product is extracted and purified by any suitable means known in the art, including, but not limited to, solvent extraction, crystallization, and silica gel chromatography. In some embodiments, the aqueous acidic solution is hydrochloric acid and acetic acid. For example, in some embodiments, the aqueous acidic solution is glacial acetic acid.

In specific embodiments, the first solvent is one or more alcohols, one or more polar organic solvents, or a mixture of one or more alcohols and one or more polar organic solvents. In some embodiments, the first solvent is up to three alcohols, up to three polar organic solvents, or mixtures thereof (ie, a mixture of up to three or up to two alcohols and up to three or up to two polar organic solvents). In some embodiments, the first solvent is one or two alcohols, one or two polar organic solvents, or mixtures thereof (ie, a mixture of one or two alcohols and one or two polar organic solvents). According to some variations

- 11 042082 antham implementation of the first solvent is an alcohol. In some embodiments, the first solvent is a polar organic solvent. Examples of alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and t-butanol. Examples of polar organic solvents include, but are not limited to, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidinone. In some embodiments, the first solvent is methanol, ethanol, n-propanol, 2-propanol, butanol, t-butanol, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone . In a specific embodiment, the first solvent is methanol.

In specific embodiments, the base is a metal hydride, an alkoxide, or a bis(trialkylsilyl)amide. In some embodiments, the base is a metal hydride. In some embodiments, the base is an alkoxide. In some embodiments, the base is a bis(trialkylsilyl)amide. Examples of metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, sodium t-pentoxide, and lithium t-butoxide. Examples of bis(trialkylsilyl)amide bases include, but are not limited to, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. In other additional embodiments, the base is a mixture of at least one of the above bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is a mixture of up to three or up to two metal bis(trialkylsilyl)amides. In some embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, sodium t-pentoxide, t-butoxide lithium, lithium bis-(trimethylsilyl)amide, sodium bis-(trimethylsilyl)amide or potassium bis-(trimethylsilyl)amide. In specific embodiments, the base is sodium methoxide.

In some embodiments, R ² is (C1-C4)alkyl, (C2-C10)aryl, or (C2-C10)aryl(C1-C4)alkyl. In some embodiments, R ² is (C1C4)alkyl, (C6- _C10 )aryl, or (C6- _C10 )aryl(C1- _C4 )alkyl. In some embodiments, R ² is C1- _C4 alkyl. In some embodiments, R ² is -CH3.

In some embodiments, after addition is complete, the reaction mixture is heated to about 20-70°C, about 20-60°C, about 20-50°C, about 20-40°C, about 2030°C, about 30-80°C , about 30-70°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-80°C, about 40-70°C, about 40-60°C, about 40 -50°C, about 5080°C, about 50-70°C, about 50-60°C, about 60-80°C, about 60-70°C, about 70-80°C, or any subrange in between.

In specific embodiments, the first solvent is an alcohol, the base is an alkoxide, after addition is complete, the reaction mixture is heated to about 40 to about 50° C. and R ² is (C 1 -C ₄ )alkyl.

In specific embodiments, the first solvent is methanol, the base is sodium methoxide, after addition is complete, the reaction mixture is heated to about 40 to about 50° C. and R ² is -CH3.

D. Alkylation and cyclization of C-1 to give F-1 alkylated formamide acetal

ABOUT

S-1 M-1

In some embodiments, about 1 eq. C-1 and from about 1 to about 5 eq. alkylated formamide acetal is combined in the reaction vessel and the reaction mixture is stirred for approximately 30 minutes. In some embodiments, about 1 eq. C-1 and from about 1 to about 3 eq. alkylated formamide acetal is combined in a reaction vessel. The first suitable solvent and approximately 1 eq. K-1 is added to this mixture and the reaction is allowed to proceed for several hours, after which the first solvent is removed by any suitable means known in the art.

The resulting material is dissolved in a second suitable solvent and about 1 to about 5 eq. M-1. The reaction mixture is cooled to about 0 to about 5°C and then from about 1.5 to 2 eq. bases are slowly added to the reaction mixture. internal temperature

The reaction mixture is kept cold during the addition (eg below room temperature, or below about 25°C, or below about 20°C, or below about 15°C). After addition is complete, the reaction mixture is heated to about 20-80°C for about 8 to about

h.

After the specified time has elapsed, the reaction mixture is cooled to room temperature, quenched by adding acid and diluted by adding an organic solvent. Product F-1 can then be extracted and purified by any suitable means known in the art, including, but not limited to, solvent extraction, crystallization, and silica gel chromatography.

In some embodiments, R ^a is (C1-C4)alkyl, (C2-C10)aryl, or (C2-C10)aryl(C1-C4)alkyl. In some embodiments, R ^a is (Cp C4) alkyl, (C ₆ -C ₁₀ ) aryl, or (C ₆ -C ₁₀ ) aryl (C 1 -C ₄ ) alkyl. In some embodiments, R ^a is C1-C4 alkyl. In some embodiments, R ^a is -CH3.

In a specific embodiment, the first solvent is an aprotic polar organic solvent such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1 ,4-dioxane, N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment, the first solvent is 2-methyltetrahydrofuran.

In some embodiments, the alkylated formamide acetal is selected from the group consisting of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In some embodiments, R ¹ is (C1-C4)alkyl, (C2-C10)aryl, or (C2-C10)aryl(C1-C4)alkyl. In some embodiments, R ¹ is (Cp C4) alkyl, (C ₆ -C ₁₀ ) aryl, or (C ₆ -C ₁₀ ) aryl (C 1 -C ₄ ) alkyl. In some embodiments, R ¹ is C1-C4 alkyl. In additional embodiments, R ¹ is -CH3, ie K-1 is aminoacetaldehyde dimethyl acetal.

In specific embodiments, the base is a metal hydride, a bis(trialkylsilyl)amide base, or an alkoxide. In some embodiments, the base is a metal hydride. In specific embodiments, the base is a bis(trialkylsilyl)amide base. In specific embodiments, the base is an alkoxide.

Examples of metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Examples of bis-(trialkylsilyl)amide bases include, but are not limited to, lithium bis-(trimethylsilyl)amide, sodium bis-(trimethylsilyl)amide, and potassium bis-(trimethylsilyl)amide. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, sodium t-pentoxide, and lithium t-butoxide. In other additional embodiments, the base is a mixture of at least one of the above bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two bis(trialkylsilyl)amide bases. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is a mixture of up to three or up to two bases selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, lithium bis-(trimethylsilyl)amide, sodium bis-(trimethylsilyl)amide, bis-(trimethylsilyl) )potassium amide, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide and lithium tert-butoxide. In specific embodiments, the base is sodium methoxide. In specific embodiments, a solution of base in alcohol is added to the reaction mixture. Suitable alcohol includes, but is not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, or t-butanol. In a specific embodiment, the base is sodium methoxide. In a specific embodiment, the base is added as a 30% solution of sodium methoxide in methanol.

In specific embodiments, the second solvent is an alcohol or a polar solvent. In some embodiments, the second solvent is an alcohol. In some embodiments, the second solvent is a polar solvent. Examples of alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and t-butanol. Examples of polar organic solvents include, but are not limited to, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidinone. In a specific embodiment, the second solvent is methanol.

In some embodiments, R ² is (C1-C ₄ )alkyl, (C ₂ -C ₁₀ )aryl, or (C ₂ -C ₁₀ )aryl(C1-C ₄ )alkyl. In some embodiments, R ² is (C1C ₄ )alkyl, (C6-C ₁₀ )aryl, or (C ₆ -C ₁₀ )aryl(C1-C ₄ )alkyl. In some embodiments, R ² is C1- _C4 alkyl. In some embodiments, R ² is -CH ₃ .

In some embodiments, after addition is complete, the reaction mixture is heated to about 20-70°C, about 20-60°C, about 20-50°C, about 20-40°C, about 2030°C, about 30-80°C , about 30-70°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-80°C, about 40-70°C, about 40-60°C, about 40 -50°C, about 5080°C, about 50-70°C, about 50-60°C, about 60-80°C, about 60-70°C, about 70-80°C, or any subrange in between.

In specific embodiments, R ^a is (C1-C4) alkyl, the first solvent is 2-methyltetrahydrofuran, the alkylated acetalformamide is N,N-dimethylformamideα dimethyl acetal, R ¹ is (C1-C4) alkyl, the base is an alkoxide, the second solvent is an alcohol, after completion of the addition, the reaction mixture is heated to from about 40 to about 50° C. and R ² is (C ₁ C4) alkyl.

In specific embodiments, R ^a is -CH3, the first solvent is 2-methyltetrahydrofuran, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, R ¹ is _-CH3 , the base is sodium methoxide, the second solvent is methanol , after addition is complete, the reaction mixture is heated to from about 40 to about 50° C., and R ² is -CH3.

E. Condensation of F-1 with N-1 to give G-1

G-1

F-1 equiv. F-1 and the appropriate solvent are combined in the reaction vessel, add about 5-8 eq. the first acid and from about 0.2 to about 0.5 eq. second acid. The interaction can be carried out at from about 20 to about 100°C.

The reaction is left to proceed for about 2 to about 5 hours, after which about 1.5 eq. N-1 and from about 2 to about 3 eq. the bases are slowly introduced into the reaction vessel. After the addition is complete, the reaction is allowed to proceed for at least about 1 hour.

Water and additional solvent are added to the reaction vessel, and G-1 is extracted and purified by any suitable method known in the art, including, but not limited to, solvent extraction, silica gel chromatography, and crystallization.

In specific embodiments, the solvent is an aprotic polar organic solvent such as, but not limited to, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4- dioxane or N-methyl-2-pyrrolidinone or mixtures thereof. In some embodiments, the solvent is a mixture of one, two, or three, or in some embodiments, a mixture of one or two of the following solvents: tetrahydrofuran, acetonitrile, diisopropyl ether, methyl t-butyl ether, N,N-dimethylformamide, N,N- dimethylacetamide, 1,4-dioxane or Nmethyl-2-pyrrolidinone. In additional embodiments, the solvent is acetonitrile.

In some embodiments, the first acid is an organic acid, an organic carboxylic acid, or an inorganic acid. In some embodiments, the first acid is an organic acid. In some embodiments, the first acid is an organic carboxylic acid. In some embodiments, the first acid is an inorganic acid. Examples of organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid. Examples of organic carboxylic acids include, but are not limited to, acetic acid, formic acid, butyric acid, propionic acid, and benzoic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, or sulfuric acid. In other additional embodiments, the first acid is acetic acid.

In some embodiments, the second acid is an organic acid, an organic carboxylic acid, or an inorganic acid. In some embodiments, the second acid is an organic acid. According to some options

- 14 042082 implementation of the second acid is an organic carboxylic acid. In some embodiments, the first acid is an inorganic acid. Examples of organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and sulfuric acid. Examples of organic carboxylic acids include, but are not limited to, acetic acid, formic acid, butyric acid, propionic acid, or benzoic acid. In specific embodiments, the second acid is methanesulfonic acid or formic acid.

In some embodiments, the first acid is acetic acid and the second acid is methanesulfonic acid.

In some embodiments, the first acid and the second acid are the same acid. In other embodiments, the first acid and the second acid are formic acid or acetic acid.

In some embodiments, N-l is in the form of a solution when added to the reaction mixture.

In additional embodiments, L is -CH ₂ -CH ₂ - i.e. N-1 is (lR,3S)-3-aminocyclopentane-Pol

In some embodiments, N-l is but

(3-aminocyclopentanol).

In specific embodiments, N-l is a salt or a co-crystal. Suitable salts or co-crystals of N-l include, but are not limited to, oxalic acid, hydrochloric acid, mandelic acid, R-mandelic acid, and S-mandelic acid. Suitable salts or co-crystals of N-l include, but are not limited to, benzoic acid, naproxen, S-naproxen, and R-naproxen.

According to other additional implementation options, N-l is

^but ^\ ^but ^-\

VVNH ₂ HCI ζΑ^ΝΗ ₂ HCI o

According to other additional implementation options, N-l is or

- 15 042082

In some embodiments, after adding the acid(s), the reaction mixture is maintained at about 20 to about 90°C, about 20 to about 80°C, about 20 to about 70°C, about 20 to about 60°C. about 20 to about 50°C, about 20 to about 40°C, from about 20 to about 30°C, from about 30 to about 100°C, from about 30 to about 90°C, from about 30 to about 80°C, from about 30 to about 70°C, from about 30 to about 60°C, from about 30 to about 50°C, from about 30 to about 40°C, from about 40 to about 100°C, from about 40 to about 90°C, from about 40 to about 80°C, from about 40 to about 70°C, from about 40 to about 60°C, from about 40 to about 50°C, from about 50 to about 100 °C, from about 50 to about 90°C, from about 50 to about 80°C, from about 50 to about 70°C, from about 50 to about 60°C, from about 60 to about 100°C, from about 60 to about 90°C, from about 60 to about 80°C, from about 60 to about 70°C, from about 70 to about 80°C, or any subrange in between. In other further embodiments, after addition of the acid(s), the reaction mixture is maintained at about 65 to about 70°C, about 70 to about 75°C, about 75 to about 80°C, or any subrange in between.

In specific embodiments, the solvent is acetonitrile, the first acid is an organic carboxylic acid, the second acid is an organic carboxylic acid, and after addition of the acids, the reaction mixture is maintained at about 70 to about 75°C.

In specific embodiments, the solvent is acetonitrile, the first acid is acetic acid, the second acid is methanesulfonic acid, the reaction mixture is maintained at about 70 to about 75°C after addition of the acids, and N-1 is

F. Deprotection of G-1 to give a compound of formula I

G-1 |

The reaction vessel is charged with approximately 1 eq. G-1 and a suitable solvent. Approximately 2 to 3 eq. a metal salt, Lewis acid or other reagent is added to said solution. The resulting suspension is stirred at about 40 to about 100° C. for about 10 minutes to about 3 hours. The reaction is quenched by the addition of acid and then the compound of formula I is extracted and purified using any suitable technique known in the art, such as but not limited to solvent extraction, preparative HPLC, and crystallization.

In a specific embodiment, the solvent is an aprotic polar organic solvent such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, K-methyl-2-pyrrolidinone or a mixture thereof. In an additional embodiment, the solvent is acetonitrile.

In some embodiments, G-1 is reacted with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof.

In additional embodiments, the metal salt is selected from the group consisting of magnesium bromide, lithium chloride, lithium bromide, and lithium iodide. In other additional embodiments, the metal salt is lithium chloride.

In specific embodiments, the Lewis acid is selected from the group consisting of boron trifluoride methyl etherate, boron trifluoride diethyl etherate, boron trifluoride dibutyl etherate, aluminum chloride, aluminum bromide, boron trichloride, boron tribromide, chlorotrimethylsilane, iodotrimethylsilane, palladium, and boron trifluoride diethyl etherate. In some embodiments, the Lewis acid is selected from the group consisting of chlorotrimethylsilane, iodotrimethylsilane, sodium ethanethiolate, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl etherate, and trifluoroacetic acid.

In specific embodiments, other reagents suitable for facilitating the conversion are sodium ethanethiolate, sodium hexamethyldisiloxane, and trifluoroacetic acid.

According to particular embodiments, deprotecting G-1 to obtain a compound of the

- 16 042082 mules I is carried out in the presence of from about 2 to about 3 eq. a reagent selected from the group consisting of magnesium bromide, lithium chloride, lithium bromide, lithium iodide, boron trifluoride methyl etherate, boron trifluoride diethyl etherate, boron trifluoride dibutyl etherate, aluminum chloride, aluminum bromide, boron trichloride, boron tribromide, chlorotrimethylsilane, iodotrimethylsilane, palladium, boron trifluoride diethyl etherate, chlorotrimethylsilane, iodotrimethylsilane, sodium ethanethiolate, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl etherate and trifluoroacetic acid.

In some embodiments, the reaction proceeds at about 40 to about 50°C, from about 40 to about 60°C, from about 40 to about 70°C, from about 50 to about 60°C, from about 50 to about 70° C, from about 50 to about 80°C, from about 60 to about 70°C, from about 60 to about 80°C, or any subrange in between. In specific embodiments, the reaction proceeds at about 50°C.

In specific embodiments, the solvent is acetonitrile, the metal salt is magnesium bromide, and the reaction proceeds at about 50°C.

G. Getting C-1 from B-1.J-1

B-1.J-1, solvent and acid are combined in a reactor under conditions effective to obtain C1.

In some embodiments, no acid is present. In some embodiments, the acid is a protic acid or a Lewis acid. In some embodiments, protic acids include, but are not limited to, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, acetic acid, formic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, and methanesulfonic acid. In some embodiments, Lewis acids include, but are not limited to, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, and scandium triflate. In specific embodiments, the acid is trifluoroacetic acid.

In some embodiments, about 10 eq., about 5 eq., about 1 eq. or about 0.1 eq. acids are used in the reaction B-1.J-1 to give C-1.

In some embodiments, the solvent is toluene, heptane, water, 2-methyltetrahydrofuran, isopropyl acetate, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, methyl tert-butyl ether, dimethyl sulfoxide, n-butanol, acetonitrile, acetone, or mixtures thereof. . In a specific embodiment, the solvent is acetonitrile.

In some embodiments, the concentration of B-1.J-1 is about 2-40 ml/g, about 2-20 ml/g, about 5-15 ml/g. In a specific embodiment, the concentration of B1.J-1 is about 10 ml/g.

In some embodiments, the reaction mixture is heated to a temperature of from about 20 to 110°C, from about 30 to 90°C, from about 40 to 80°C, from about 50 to 70°C, from about 55 to 65°C, or from about 58 to 61 ° C. In a particular embodiment, the reaction mixture is heated to about 60°C.

In some embodiments, other additives are added to the reaction mixture. In some embodiments, the additives include, but are not limited to, lithium chloride, sodium chloride, and potassium chloride.

In some embodiments, B-1.J-1 is loaded into the reactor in one portion at about 20° C., followed by heating.

In some embodiments, B-I.J-1 is loaded into the reactor in batches over 1 hour during heating.

In some embodiments, the reaction mixture is heated for about 1-24 hours, for about 2-12 hours, or for about 3-6 hours. In a specific embodiment, the reaction mixture is heated for about 2.5 hours.

In some embodiments, the product formed is extracted and optionally purified using any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the reaction mixture is cooled and the contents of the reactor partially distilled.

In some embodiments, the organic phase is washed at least once with an aqueous solution. In some embodiments, the aqueous solution contains about 23% NaCl, about 1.5% H ₂ SO ₄ , and about 76% water. According to some options for the implementation of water

- 17 042082 The solution contains approximately 20% NaCl.

In some embodiments, the product solution is seeded with C-1, which has been previously isolated. In some embodiments, solid C-1 is isolated by filtration.

In specific embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F. In some embodiments, n=1-3. In some embodiments, n=2. In some embodiments, n=3. In additional embodiments, J-1 is . In some embodiments, J-1 is In additional embodiments, J-1 is ^X.

In some embodiments, R ^a is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ^a is (C1C4)alkyl. In some embodiments, R ^a is methyl.

In specific embodiments, R ^a is (C1-C ₄ )alkyl, the solvent is acetonitrile, the reaction mixture is heated to about 60°C, and J-1 is

7%

In specific embodiments, R ^a is methyl, the solvent is acetonitrile, the reaction mixture is heated to about 60°C, and J-1 is

H. Formation of enamine from C-1 to give D-1

To a solution of C-1 and acid in a solvent from about 0.5 to about 1.5 eq. alkylated formamide acetal is added under conditions effective to obtain D-1.

According to specific implementation options 1 EQ. C-1 is combined with about 1.1 eq. alkylated formamide acetal.

In some embodiments, the alkylated formamide acetal is selected from the group consisting of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In a specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In some embodiments, the solvent is dichloromethane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, or N-methyl-2-pyrrolidone. In a specific embodiment, the solvent is 2-methyltetrahydrofuran.

In some embodiments, the acid is an organic acid. In some embodiments, the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In some embodiments, the acid is a mixture containing up to three or up to two organic acids. In a specific embodiment, the acid is trifluoroacetic acid.

In some embodiments, the reaction mixture is heated to an internal temperature of about 40° C. prior to the addition of the alkylated formamide acetal.

In some embodiments, the reaction proceeds at about 0-75°C, about 10-60°C, about 20-50°C, about 40-50°C, or about 30-40°C. In specific embodiments, the reaction proceeds at room temperature. According to additional variants of implementation of the interaction takes place at about 40°C.

In some embodiments, the reaction proceeds for about 0.1 to about 12 hours, for about 0.1 to about 6 hours, for about 0.1 to about 3 hours, for about 0.1 to about about 1 hour, or for about 0.2 to about 0.5 hours.

In some embodiments, D-1 is extracted and purified by any suitable means known in the art, including, but not limited to, solvent extraction, crystallization, and chromatography.

In some embodiments, seed D-1 is added and the mixture is agitated. In some embodiments, the mixture is stirred at about 40°C for at least 1 hour.

- 18 042082

In some embodiments, about 0.2-0.6 eq. alkyl formamide acetal and the reaction mixture is stirred for at least about 25 minutes. The reaction mixture was cooled to room temperature and allowed to stir for about 12 hours.

In some embodiments, the contents of the reactor are filtered and the filter cake is washed with solvent and dried to give D-1. In some embodiments, the solvent is a combination of 2-methyltetrahydrofuran and heptanes.

In specific embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F. In some embodiments, n=1-3. In some embodiments, n=2. In some embodiments, n=3.

In some embodiments, Ra is (C ₁ -C ₄ )alkyl, (C ₆ -C ₁₀ )aryl, or (C ₆ -C ₁₀ )aryl(C1 -C ₄ )alkyl. In some embodiments, Ra is (C1C ₄ )alkyl. In some embodiments, Ra is methyl.

In some embodiments, each R ^b is independently (C1C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, each R ^b is independently (C1-C4) alkyl. In some embodiments, R ^b is methyl.

In specific embodiments, R ^b is (C1-C ₄ )alkyl, Ra is (C1-C ₄ )alkyl, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the reaction proceeds at about 10 to about 60° C., the acid is trifluoroacetic acid, each Hal is -F and n=3.

In specific embodiments, R ^b is methyl, Ra is methyl, the alkylated formamide acetal is N,Ndimethylformamide dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the reaction is from about 40° C., the acid is trifluoroacetic acid, Hal is -F and n=3.

I. Formation of F-1 from D-1 through E-1

oh oh, R ^a

To a solution of D-1 in a solvent add about 1.1 eq. K-1 under conditions effective to obtain E-1.

In some embodiments, the solvent is an alcoholic solvent such as, but not limited to, ethanol, n-propanol, 2-propanol, butanol, methanol, and t-butanol, or aprotic polar organic solvents such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran , acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane and N-methyl-2-pyrrolidinone. In specific embodiments, the solvent is methanol.

In some embodiments, K-1 is an aminoacetaldehyde acetal, such as, but not limited to, aminoacetaldehyde diethyl acetal, aminoacetaldehyde dipropyl acetal, aminoacetaldehyde dimethyl acetal, and aminoacetaldehyde dibutylacetal. In some embodiments, K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, the reaction proceeds at about 10-60°C, about 10-50°C, about 10-40°C, about 10-30°C, about 10-20°C, 20-60°C, about 2050 °C, about 20-40°C, about 20-30°C, about 30-60°C, about 30-50°C, about 3040°C, about 40-60°C, about 40-50°C, about 50-60°C or any subrange in between. In specific embodiments, the reaction proceeds at room temperature. In additional embodiments, the reaction proceeds at about 16 to about 23°C.

In some embodiments, the reaction mixture is stirred for about 0.1 to about 12 hours, about 0.5 to about 4 hours, about 1 to about 2 hours.

After successful completion of the reaction to obtain E-1, M-1 is added to the reaction mixture.

- 19 042082

In some embodiments, about 1 to about 10 or about 1 to about 5 eq. M-1. According to a specific implementation variant add about 5 eq.

M-1.

In some embodiments, M-1 is dimethyl oxalate, diethyl oxalate, dipropyl oxalate, or dibutyl oxalate. In a specific embodiment, M-1 is dimethyl oxalate.

The reaction mixture is stirred at a temperature sufficient to achieve dissolution of M1. In some embodiments, the reaction mixture is stirred at about 2080°C, at about 20-70°C, at about 20-60°C, at about 30-60°C, at about 40-50°C, or at about 45°C. .

In some embodiments, the base is added to the reaction mixture after the addition of M-1.

In some embodiments, the base is a metal hydride, an alkoxide, an inorganic carbonate, or a bis(trialkylsilyl)amide. In some embodiments, the base is a metal hydride. In some embodiments, the base is an alkoxide. In some embodiments, the base is an inorganic carbonate. In some embodiments, the base is bis(trialkylsilyl)amide. Examples of metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, sodium t-pentoxide, and lithium t-butoxide. Examples of bis(trialkylsilyl)amide bases include, but are not limited to, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. Examples of carbonates include, but are not limited to, lithium, sodium, potassium and cesium carbonate.

In other additional embodiments, the base is a mixture of at least one of the above bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is a mixture of up to three or up to two metal bis(trialkylsilyl)amides. In some embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, sodium t-pentoxide, t-butoxide lithium, lithium bis-(trimethylsilyl)amide, sodium bis-(trimethylsilyl)amide and potassium bis-(trimethylsilyl)amide.

In specific embodiments, the base is sodium methoxide. In specific embodiments, the base is sodium methoxide in methanol solution.

In some embodiments, after adding the base, the reaction mixture is heated to about 20-80°C, 20-70°C, about 20-60°C, about 20-50°C, about 20-40°C, about 20-30 °C, about 30-80°C, about 30-70°C, about 30-60°C, about 30-50°C, about 30-40°C, about 40-80°C, about 40-70° C, about 40-60°C, about 40-50°C, about 50-80°C, about 50-70°C, about 50-60°C, about 60-80°C, about 60-70°C , about 70-80°C or any sub-range between them. In a particular embodiment, the reaction mixture is heated to about 42-48°C. In a particular embodiment, the reaction mixture is heated to about 45°C.

In some embodiments, the reaction mixture is stirred for about 1 to about 24 hours, about 6 to about 24 hours, about 12 to about 20 hours, about 14 to about 18 hours.

In some embodiments, the reaction mixture is diluted with an aqueous solution, and F1 is extracted and purified by any suitable means known in the art, including, but not limited to, solvent extraction, crystallization, and silica gel chromatography.

In some embodiments, the temperature is lowered to about 34-37°C over about 1 hour, F-1 seeds are optionally loaded and allowed to stand for about 1-2 hours. Water is then added and the temperature is lowered to about 18-22°C. C for 1 hour. The resulting suspension is filtered.

In some embodiments, the liquids are reused to displace the solids remaining in the reactor. The solids collected on the filter are then washed with a 1:1 mixture of water and methanol, followed by washing with water. The collected wet filter cake is dried in a vacuum oven at about 36-42° C. for about 16 hours to give F-1.

In some embodiments, R ¹ is (C ₁ -C ₄ )alkyl, (C ₆ -C ₁₀ )aryl, or

- 20 042082 (C ₆ -C ₁₀ )aryl(C1-C ₄ )alkyl. In some embodiments, R ¹ is

C1- _C4 alkyl. In additional embodiments, R ¹ is -CH3, ie K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, R ² is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ² is C1-C4 alkyl. In some embodiments, R ² is -CH3.

In specific embodiments, each Hal is independently -F or -Cl. In a particular implementation, Hal is -F. In some embodiments, n=1-3. In some embodiments, n=2. In some embodiments, n=3.

In some embodiments, R ^a is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ^a is (C1-C4)alkyl. In some embodiments, R ^a is methyl.

In some embodiments, each R ^b is independently (C1C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, each R ^b is independently (C1-C4) alkyl. In some embodiments, R ^b is methyl.

In specific embodiments, R ^b is methyl, R ^a is (C1-C4) alkyl, each Hal is -F, n=3, R ² is (C1-C4) alkyl, R ¹ is (C1- C ₄ )alkyl, the solvent is an alcoholic solvent, K-1 is aminoacetaldehyde dimethyl acetal, the first reaction proceeds at about 2 to about 40°C, the second reaction is heated to about 20 to about 80°C, the base is an alkoxide and M-1 is dimethyl oxalate.

In specific embodiments, R ^b is methyl, R ^a is methyl, Hal is -F, n=3, R ² is -CH3, R ¹ is -CH3, the solvent is methanol, K-1 is aminoacetaldehyde dimethyl acetal, the first reaction is from about 16 to about 23°C, the second reaction is heated to about 45°C, the base is sodium methoxide and M-1 is dimethyl oxalate.

J. Hydrolysis of F-1 acetal to give FF-1

To a solution of F-1 in a solvent add about 0.1-1 eq. the first acid and about 2-20 eq. the second acid under conditions effective to obtain FF-1.

In some embodiments, about 0.1-0.5 eq. first acid. According to specific implementation options add about 0.1 EQ. first acid.

In some embodiments, the solvent is a polar organic solvent or a weak protic acid. In some embodiments, the polar organic solvent includes, but is not limited to, propionitrile, tetrahydrofuran, 1,4-dioxane, acetonitrile, and ethyl acetate. In some embodiments, the weak protic acid includes, but is not limited to, formic acid, propionic acid, and butyric acid. In a specific embodiment, the solvent is acetonitrile.

In some embodiments, the first acid is a strong protonic acid including, but not limited to, methanesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

In a specific embodiment, the first acid is ptoluenesulfonic acid. In a specific embodiment, the first acid is p-toluenesulfonic acid monohydrate.

In some embodiments, the second acid is a weak protic acid, including but not limited to acetic acid, formic acid, propionic acid, and butyric acid. In a specific embodiment, the second acid is acetic acid.

The interaction is then heated to about 20-120°C, about 40-100°C, about 60-80°C, or about 70-80°C. In a particular embodiment, the reaction mixture is heated to about 75°C.

In some embodiments, the reaction mixture is stirred for about 1 to about 24 hours, for about 4 to about 14 hours, for about 8 to about 10 hours.

- 21 042082

In some embodiments, water is added to the reaction mixture.

In some embodiments, the product formed is extracted and optionally purified using any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the mixture is concentrated under reduced pressure to remove the solvent. The resulting suspension is then kept at room temperature for about 2 hours, filtered and washed with water. The precipitate is dried in a vacuum oven at 50°C for at least 10 hours to obtain FF-1.

In some embodiments, R ¹ is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ¹ is C1-C4 alkyl. In additional embodiments, R ¹ is -CH3.

In some embodiments, R ² is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ² is C1-C4 alkyl. In some embodiments, R ² is -CH3.

In specific embodiments, each Hal is independently -F or -Cl. In a particular implementation, Hal is -F. In some embodiments, n=1-3. In some embodiments, n=2. In some embodiments, n=3.

In some embodiments, R ^a is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl. In some embodiments, R ^a is (C1C4)alkyl. In some embodiments, R ^a is methyl.

In specific embodiments, R ^a is (C1-C4)alkyl, each Hal is -F, n=3, ^R2 is (C1- _C4 )alkyl, ^R1 is (C1- _C4 )alkyl, the reaction mixture is heated to about 20 to about 120° C., the first acid is ptoluenesulfonic acid, the second acid is acetic acid, and the solvent is acetonitrile.

In specific embodiments, R ^a is methyl, Hal is -F, n=3, R ² is -CH3, R ¹ is -CH3, the reaction mixture is heated to about 75°C, the first acid is p-toluenesulfonic acid, the second acid is acetic acid and the solvent is acetonitrile.

K. Cyclization of FF-1 and N-1 to give G-1

FF-1

The starting material FF-1, N-1, or a salt or co-crystal thereof, and an additive are combined with a solvent under conditions effective to obtain G-1.

In some embodiments, the additive is a carboxylate salt such as, but not limited to, sodium acetate, potassium acetate, lithium acetate, sodium propionate, and potassium propionate. In some embodiments, the additive is a carbonate such as, but not limited to, sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate. In some embodiments, the additive is a water scavenger such as, but not limited to, molecular sieves, trimethyl orthoacetate, and trimethyl orthoformate. In specific embodiments, the additive is potassium acetate.

In some embodiments, about 1 to about 2, or about 1 to about 1.5 eq. N-1 or its salt or co-crystal.

In some embodiments, about 1 to about 5 eq. additives. According to specific implementation options add about 2.5 eq. additives.

In some embodiments, the solvent is acetonitrile, ethyl acetate, toluene, 2-methyltetrahydrofuran, isopropyl acetate, dichloromethane, or mixtures thereof. In specific embodiments, the solvent is dichloromethane.

In some embodiments, the reaction mixture is stirred at about 0 to about 40°C, about 10 to about 30°C, about 15 to about 25°C, about 20°C.

In some embodiments, G-1 is extracted and optionally purified using any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In specific embodiments, the reaction mixture is washed with an aqueous solution and evaporated to dryness. In specific embodiments, the residue is dissolved in dimethylformamide and the resulting solution is added to water over about 2 hours with stirring. The product suspension is held at about 20° C. for about 12 hours and filtered. Filtration

- 22 042082 the residue of the product is washed with water and dried to obtain G-1.

In some embodiments, N-1 is in the form of a solution when added to the reaction mixture.

In additional embodiments, L is -CH2-CH2-.

In specific embodiments, N-1 is (1R,3S)-3-aminocyclopentan1-ol

In specific embodiments, N-1 is a free base or synthesized and used without isolation.

In specific embodiments, N-1 is a salt or a co-crystal. Suitable N-1 salts or co-crystals include, but are not limited to, benzoic acid, acetic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, hydrochloric acid, naproxen, S-naproxen, R-naproxen, mandelic acid, R-mandelic acid and S-mandelic acid.

In other additional embodiments, N-1 is

In specific embodiments, N-1 is a salt or co-crystal with benzoic acid.

In specific embodiments, N-1 is but.

BzOH nh ₂

In specific embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F. In some embodiments, n=1-3. In some embodiments, n=2. In some embodiments, n=3.

In some embodiments, R ² is (C1-C4)alkyl, (C6-C10)aryl, or (C6-C1o)aryl(C1-C4)alkyl. In some embodiments, R ² is C1-C4 alkyl. In some embodiments, R ² is -CH ₃ .

In some embodiments, Ra is (C ₁ -C ₄ )alkyl, (C6-C ₁₀ )aryl, or (C6-C ₁₀ )aryl(C ₁ -C ₄ )alkyl. In some embodiments, Ra is (C1C ₄ )alkyl. In some embodiments, Ra is methyl.

In specific embodiments, Ra is (C1- _C4 ) alkyl, each Hal is HCX -F, n=3, ^R2 is _-CH3 , N-1 is C/ ^NH2 * ^z , the solvent is dichloromethane , the reaction mixture is stirred at from about 0 to about 40°C and the additive is potassium acetate.

In specific embodiments, Ra is methyl, Hal is -F, n=3, R ² is -CH ₃ , N-1 is ^ΝΗ · ^Βζ0Η , the solvent is dichloromethane, the reaction mixture is stirred at about 20° C. and the additive is potassium acetate.

- 23 042082

Examples

In order to provide a more complete understanding of the invention, the following examples are given. These examples are provided for the purpose of illustrating embodiments and should not be construed as limiting the scope of the present disclosure in any way. The reagents used in the examples below may be prepared either as described herein or, if not described herein, are commercially available or may be prepared from commercially available materials by methods known in the art. .

In one embodiment, a multi-step synthetic route for preparing a compound of Formula I is provided below. In some embodiments, each individual step of the schemes below is provided. Examples and any combination of two or more successive steps of the examples below are provided.

L. Salt Formation B-1a J-1a

Free acid B-1a (4.4 g) was dissolved in 50 ml of acetonitrile and J-1a (3.3 g, 1.0 eq.) in 30 ml of acetonitrile was added. The desired salt was obtained and kept for about 1 hour at room temperature. The solids were filtered and the precipitate was washed with 2 x 10 ml of acetonitrile to give the product.

¹ H NMR (400 MHz, DMSO-d6) δ 7.40 (bs, 3H), 6.11 (t, J=7.7 Hz, 2H), 3.12 (s, 2H), 2.92 ( s, 2H), 2.08 (s, 3H), 0.35 (s, 6H). ¹³ C NMR (101 MHz, DMSOCH) δ 191.98, 164.66, 163.06 (dt, J=248.6, 16.2 Hz), 161.82 (ddd, J=250.4, 15, 8, 10.4 Hz), 107.39 (td, J=20.0, 4.7 Hz), 101.16 (m), 100.01, 87.01, 77.71, 58.39, 30 .45, 26.37.

M. Salt Formation B-1a J-1a

Meldrum's acid (10.1 g, 1.1 eq.) and DMAP (0.6 g, 0.08 eq.) were dissolved in 300 ml of acetonitrile. Methoxyacetic acid (5.8 g, 1 eq) and 17.6 g (2.1 eq) Hunig's base were added. The solution was heated to about 45°C and 8.4 g (1.1 eq.) of pivaloyl chloride in 30 ml of acetonitrile was added over about 1 hour.

After about 2.5 hours at about 45°C, the solution was cooled to room temperature and concentrated in vacuo. The resulting oil was dissolved in 110 ml of dichloromethane, cooled in an ice bath and extracted with 50 ml of 1 N HCl. The layers were separated and the aqueous layer was extracted with 40 ml dichloromethane. The combined organic layer was concentrated and diluted in acetonitrile and again evaporated. The substance was dissolved in 220 ml of acetonitrile.

After cooling in an ice bath, trifluorobenzylamine (11.4 g, 1.1 eq.) and the mixture at about 9° C. were allowed to warm to room temperature and stirred as the suspension thickened. After about 2 hours, 220 ml of MTBE was added slowly and the suspension was kept overnight. The suspension was cooled in an ice bath for about 3 hours and filtered, washed with 50 ml of cold 1:1 acetonitrile/MTBE and dried overnight in a vacuum oven to give the product.

N. Amidation using B-1a J-1a salt to give C-1a

X °F

V ^h a ^tfa ~ Λοόι oJO ³ * ----* °

C-1a

B-1a * J-1a

Salt B-1a·J-1a (3.7 g, 1.0 eq.) was suspended in 50 ml of acetonitrile and then treated with trifluoroacetic acid (0.1 ml, 0.1 eq.). The reaction mixture was heated to about 40 to about 50° C. for about 18 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting residue was suspended in 5 volumes of 2-methyltetrahydrofuran and 5 volumes of hexanes were added dropwise over 1 hour. The resulting mixture was allowed to stir for at least 24 hours and then the resulting suspension was filtered to obtain the product.

- 24 042082

O. Amidation of B-1a.J-1a to C-1a

B-a1.J-1a C-1 a

B-1a.J-1a (75.077 g, 198.97 mmol, 1.0 eq.), acetonitrile (750 ml) and trifluoroacetic acid (1.5 ml, 20 mmol, 0.1 eq.) were combined in a reactor. The reactor was heated until the internal temperature reached about 58°C and the contents of the reactor were held at about 58-61°C for about 3.5 hours. The jacket temperature was then brought to about 45°C and a vacuum was applied. The contents of the reactor were distilled to about 150 ml of residue. Then isopropyl acetate (300 ml) was charged into the reactor and distillation was continued until a volume of about 150 ml was reached. Then isopropyl acetate (150 ml) was loaded into the reactor, the temperature of the jacket was brought to about 20°C and the contents were left to reach an internal temperature of <25°C. The wash solution (22.8% NaCl, 1.5% H ₂ SO ₄ , 75.7% water, 300 ml) was charged to the reactor and the contents were stirred for about 30 minutes. The lower phase was separated and the second wash solution (22.8% NaCl, 1.5% H ₂ SO ₄ , 75.7% water, 300 ml) was loaded into the reactor. After stirring for about 15 minutes, the lower phase was separated and 20% aqueous NaCl (300 ml) was charged into the reactor and stirred for about 15 minutes. The lower phase was separated. Heptane (150 ml) was loaded into the reactor followed by seeding (51 mg, 0.1 wt.%). The mixture was held for about 30 minutes, during which a suspension formed. Additional heptane (450 ml) was then charged over at least 30 minutes. The jacket temperature was then brought to about 29° C. and the solvent was distilled off in vacuo to reach a content volume of about 450 ml. The slurry was then cooled to an internal temperature of about 5°C for at least 1 hour. The contents of the reactor were discharged and the solids were collected by filtration. The mother liquors were recycled twice to force the solids out of the reactor, each time allowing the internal temperature to reach <6° C. before discharge. Then a solution of heptane/isopropyl acetate (75% v/v, 225 ml) was loaded into the reactor and when the internal temperature reached <6° C., the slurry was washed with a filter cake. The wet filter cake was then dried in vacuo at about 40° C. for about 18 hours to give C-1a.

¹ H NMR (400 MHz, CDCl3): δ 7.12 (br, 1H), 6.66 (app t, J=8.1 Hz, 2H), 4.50 (app d, J=5.7 Hz , 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³ C NMR (100 MHz, CDC^): δ 203.96, 164.90, 162.37 (ddd, J=250.0, 15.7, 15.7 Hz), 161.71 (ddd, J= 250.3, 14.9, 10.9 Hz), 110.05 (ddd, J=19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41 , 45.71, 31.17 (t, J=3.5 Hz). LCMS, calculated: 275.23, found: 275.97 (M).

P. Formation of enamine D-1a from C-1a

C-1 a D-1a

C-1a (8.4 g, 1.0 eq.) was loaded into the reactor followed by the addition of 2-methyltetrahydrofuran (166.7 ml, 20 vols, 0.18 M) and trifluoroacetic acid (231.9 μl, 0.1 equiv.). The reaction mixture was heated to an internal temperature of about 40° C. and DMF-DMA (3.0 ml, 0.75 eq.) was added rapidly. The reaction mixture was stirred for several minutes, followed by the addition of seed D-1a (20 µg, 0.002 eq.) at about 40°C. The homogeneous mixture was kept at 40° C. for about 1 hour. An additional portion of DMF-DMA (1.5 ml, 0.37 eq.) was added and the reaction mixture was stirred for about 25 minutes. Added one last portion of DMF-DMA (1.5 ml, 0.37 eq.) and the reaction mixture was cooled from about 40°C to room temperature and homogeneous left to stir over night.

The contents of the reactor were filtered and the filter cake was washed with a solvent combination of 2-methyltetrahydrofuran and heptanes (67.1 ml, 8 volumes) to give D-1a. 1H NMR (400 MHz, CDCl ₃ ): δ 8.34 (br, 1H), 7.83 (s, 1H), 6.63 (m, 2H), 4.53 (s, 2H), 4.12 (s, 2H), 3.34 (s, 3H), 3.10 (s, 6H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 192.33, 165.85, 163.03, 160.54, 158.00, 110.89, 103.50, 100.05, 76.11, 58, 77, 44.74, 30.61. LCMS, calculated: 330.12, found: 330.91 (M).

Q. Condensation and cyclization of D-1a to give F-1a via E-1a

D-1a (70.0 g, 212 mmol, 1.0 eq.) was loaded into an inert 1 L reactor. Methanol (420 mL, 6 vols) and aminoacetaldehyde dimethyl acetal (1, 28.8 mL, 233 mmol, 1.1 eq.) were then charged to said reactor. The temperature of the jacket of the reactor was maintained at about 16-23°C.

- 25 042082

After keeping the reaction mixture for about 1-2 hours, dimethyl oxalate (2, 125 g, 1.06 mol, 5.0 eq.) was loaded into the reactor and the temperature of the reactor jacket was increased to about 42-48°C.

After complete dissolution of the dimethyl oxalate was achieved, the reactor was charged with sodium methoxide as a solution in methanol (84.7 g, 25.197 mmol, 1.85 eq.). The reactor jacket temperature was maintained at about 42-48°C for about 14-18 hours.

The temperature of the reactor jacket was lowered to about 34-37° C. over about 1 hour. about 1-2 hours. After that, water (420 ml, 6 volumes) was loaded into the reactor over about 2-3 hours. The temperature of the reactor jacket was lowered to about 18-22°C over about 1 hour.

The resulting slurry was discharged from the reactor and the solids were collected by filtration. The liquids were recycled to displace the solids remaining in the reactor. The solids collected on the filter were then washed with a 1:1 mixture of water and methanol (420 ml, 6 vols) followed by washing with water (420 ml, 6 vols). The collected wet filter cake was dried in a vacuum oven at about 36-42° C. for about 16 hours to give F-1a.

¹ H NMR (400 MHz, CDCl3): δ 10.28 (t, J=5.5 Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H), 4 .58 (d, J=5.6 Hz, 2H), 4.43 (t, J=4.7 Hz, 1H), 4.00 (d, J=4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 173.08, 163.81, 162.17, 162.14 (ddd, J=249.2, 15.6, 15.6 Hz), 161.72 ( ddd, J=250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 110.53 (ddd, J=19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, calculated: 458.39, found: 459.15 (M+H).

R. Hydrolysis of F-1a acetal to give FF-1a

(90% yield)

To a solution of F-1a (10.0 g, 1.0 eq.) and acetonitrile (50 ml) was added ptoluenesulfonic acid monohydrate (0.414 g, 0.10 eq.) and acetic acid (16.3 ml, 12 eq.) . The reaction mixture was then heated to about 75° C. and held for about 8-10 hours. After completion of the reaction, confirmed by HPLC, the reaction mixture was cooled to room temperature and water (60 ml) was added. The mixture was then concentrated under reduced pressure to remove acetonitrile. Then the resulting suspension was kept at room temperature for about 2 h, filtered, washed with water (2x30 ml). The precipitate was dried in a vacuum oven at about 50° C. for about 10 hours to give FF-1a.

1H NMR (400 MHz, DMSO-d6): δ 10.34 (t, J=8.0 Hz, 1H), 8.45 (s, 1H), 7.19 (m, 2H), 6.37 ( m, 2H), 4.96 (m, 1H), 4.55 (d, J=4.0 Hz, 2H), 3.95 (m, 2H), 3.93 (s, 3H). 3.79 (s, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ 172.32, 163.47, 162.10, 161.93 (dt, J=246, 15.0 Hz), 161.41 (ddd, J= 247, 15.0, 11.0 Hz), 148.01, 145.57, 135.84, 118.32, 111.48 (td, J=20.0, 5.0 Hz), 101.17 ( m), 87.99, 60.55, 60.50, 53.98, 30.37. LCMS, calculated: 431.1061, found: 431.1062 (M+H).

S. Cyclization of FF-1a and N-1a.BzOH to give G-1a

G-1a

FF-1a (90.0 g, 1.0 eq.), N-1a.BzOH (60.7 g, 1.3 eq.) and potassium acetate (51.3 g, 2.5 eq.) were loaded into reactor. Dichloromethane (DCM, 1.1 L) was charged and the mixture was stirred at about 20° C. until the reaction was complete. A 5% aqueous NaHCO3 solution (540 ml) was loaded into the reactor and the mixture was stirred until the solids were completely dissolved. The phases were separated and the lower organic phase was loaded back into the reactor. Water (450 ml) was charged to the reactor and the mixture was stirred for about 15 minutes. The phases were separated and the organic phase was distilled to dryness.

Crude G-1a was dissolved in dimethylformamide (DMF, 180 mL) and the resulting solution was charged to a reactor containing water (1.1 L) over about 2 hours with water stirring. The product slurry was held at about 20° C. for about 12 hours and then filtered. The filtration residue of the product was washed with water (360 ml) and dried to obtain G-1a.

1H NMR (400 MHz, CDCl3): δ 10.23 (t, J=5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J=8.1 Hz, 2H) , 5.29 (dd, J=9.5, 3.7 Hz, 2H), 4.57 (d, J=5.4 Hz, 3H), 4.33 (dd, J=12.8, 3 .8 Hz, 1H), 4.02-3.87 (m, 1H), 3.94 (s, 3H), 2.06-1.88 (m, 4H), 1.78 (dd, J= 17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 174.53, 163.75, 162.33 (dd, J=249.4, 15.7, 15.7 Hz), 161.86 (ddd, J= 250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75, 118.88, 110.58 (ddd, J=19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, calculated: 463.14, found: 464.15 (M+H).

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T. Deprotection of G-1a to give a compound of formula Ia

G-1a la

G-1a (14 g) was suspended in acetonitrile (150 ml) and dichloromethane (150 ml). MgBr ₂ (12

G). The reaction mixture was heated to 40-50° C. for about 10 min before cooling to room temperature. The reaction mixture was poured into 0.5 M HCl (140 ml) and the layers were separated. The organic layer was washed with water (70 ml) and then the organic layer was concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane to 6% ethanol/dichloromethane) to give Ia.

Each of the references, including all patents, patent applications and publications cited in this application, is incorporated into the present description by reference in its entirety, as if each of them were included separately. In addition, based on the above description of the invention, a person skilled in the art can make certain changes or modifications to the present invention, and these equivalents will still be within the scope of the invention defined by the appended claims.

Claims (38)

CLAIM 1. Process for the preparation of a compound of formula I according to the following General Scheme VI wherein said method comprises the following steps: interaction of B-1.J-1 in the presence of an acid to obtain C-1, which includes suspending B1.J-1 in a solvent, treating the resulting solution with acid, carrying out the reaction for 12 to 24 hours at 20-80°C and extracting C -1; interaction of C-1 with an alkylated formamide acetal to obtain D-1, which includes adding an alkylated formamide acetal to a solution of C-1 and an acid in a solvent and carrying out the reaction at 0-75 ° C for 0.1 to 12 hours; interaction of D-1 with K-1 to obtain E-1, including adding K-1 to a solution of D-1 in a solvent and carrying out the reaction at 10-60°C to obtain E-1; interaction of E-1 with M-1 in the presence of a base to obtain F-1, which includes adding M-1 and base to the reaction mixture containing E-1, stirring said reaction mixture at 20-80°C for 1 to 24 hours and extracting F-1; interaction of F-1 with at least one acid to obtain FF-1, including adding at least one acid to a solution of F-1 in a solvent, stirring the reaction mixture at 20-120°C for 1 to 24 hours and extracting the product ; - 27 042082 interaction of FF-1 with N-1 or its salts in the presence of an additive to obtain G-1, including the combination of FF-1, N-1 or its salts and the specified additive with a solvent, stirring the reaction mixture at 0-40 ° C and extracting G-1; and reacting G-1 with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof to give a compound of formula I, said reacting comprising adding at least one reagent to a solution of G-1 in a suitable solvent, stirring the resulting suspension at 40-100° C. for 10 minutes to 3 hours, quenching the reaction by adding acid, and recovering the compound of formula I; where Hal is a halogen, which may be the same or different; n is 1, 2 or 3; L is -C(R ^c ) ₂ -, -QR^CCRV, -CCRbCRcbCRV or -CR^CRcbCR^CRV; each R ^c is independently hydrogen, halogen, hydroxyl, or C ₁ -C ₄ alkyl; each Ra, R ¹ and R ² is independently (C1-C ₄ )alkyl, (C6-C10)aryl, or ( _C6 - _C10 )aryl( _C1C4 )alkyl and each ^Rb is independently (C1-C ₄ ) alkyl. 2. Process according to claim 1, characterized in that B-1.J-1 is reacted in the presence of an acid selected from the group consisting of an inorganic acid, an organic acid, a halogenated organic acid, a Lewis acid, and mixtures thereof. 3. The method according to claim 1 or 2, characterized in that said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, dichloroacetic acid, chloroacetic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, scandium triflate, and mixtures thereof. 4. Method according to any one of claims 1 to 3, characterized in that the acid is trifluoroacetic acid. 5. The method according to claim 1, wherein the alkylated formamide acetal is selected from the group consisting of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal and dimethyl acetal N,Ndiisopropylformamide. 6. The method according to any one of claims 1 to 5, characterized in that the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 7. Process according to any one of claims 1 to 6, characterized in that C-1 is reacted with an alkylated formamide acetal in the presence of an acid. 8. The method of claim 7, wherein said acid is selected from the group consisting of trifluoroacetic acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. 9. Method according to any one of claims 7 or 8, characterized in that said acid is trifluoroacetic acid. 10. The method according to any one of claims 1 to 9, wherein K-1 is selected from the group consisting of aminoacetaldehyde diethyl acetal, aminoacetaldehyde dipropylacetal, aminoacetaldehyde dimethyl acetal and aminoacetaldehyde dibutylacetal. 11. The method according to any one of claims 1 to 10, characterized in that K-1 is aminoacetaldehyde dimethyl acetal. 12. The method according to any one of claims 1 to 11, characterized in that M-1 is selected from the group consisting of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and dibutyl oxalate. 13. The method according to any one of claims 1 to 12, characterized in that M-1 is dimethyl oxalate. 14. The method according to any one of claims 1 to 13, characterized in that E-1 is subjected to interaction with M-1 in the presence of a base selected from the group consisting of a metal hydride, an alkoxide, an inorganic carbonate, a bis-(trialkylsilyl)amide base and their mixtures. 15. The method of claim 14, wherein said base is selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium ethoxide, t- sodium pentoxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof. 16. The method according to any one of claims 14 or 15, characterized in that said base is sodium methoxide. 17. The method according to any one of claims 1 to 16, characterized in that F-1 is subjected to interaction with at least one acid selected from the group consisting of organic acid, inorganic acid, organic carboxylic acids and mixtures thereof. - 28 042082 18. The method according to claim 17, characterized in that said at least one acid is selected from the group consisting of methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid , formic acid, butyric acid, propionic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid and mixtures thereof. 19. The method according to any one of claims 17 or 18, characterized in that said at least one acid is p-toluenesulfonic acid. 20. The method according to any one of claims 1 to 19, characterized in that L is -CH ₂ -CH ₂ -. 21. The method according to any one of claims 1 to 20, characterized in that N-l is 22. The method according to any one of claims 1 to 21, characterized in that N-l is in the form of a salt. 23. The method according to claim 22, characterized in that Ν-l is Ό- ^η ·· 24. Method according to any one of claims 1 to 23, characterized in that N-l is in the form of a solution. 25. The method according to any one of claims 1 to 24, characterized in that said additive is selected from the group consisting of a carboxylate salt, an inorganic carbonate, a metal hydride, an alkoxide, a water scavenger, and mixtures thereof. 26. The method according to any one of claims 1 to 25, characterized in that said additive is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, tert- sodium butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide, lithium tert-butoxide, sodium propionate, potassium propionate, molecular sieves, trimethylorthoacetate, potassium acetate, sodium acetate, lithium acetate and trimethylorthoformate. 27. The method according to any one of claims 1 to 26, characterized in that said additive is potassium acetate. 28. The method according to any one of claims 1 to 27, characterized in that said at least one reagent is selected from the group consisting of magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, chlorotrimethylsilane, iodotrimethylsilane, boron trichloride, boron tribromide, sodium ethanethiolate, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl etherate, and trifluoroacetic acid. 29. The method of claim 28, wherein said at least one reactant is magnesium bromide. 30. The method according to any one of claims 1 to 29, characterized in that each R ^a , R ^b , R ¹ and R ² independently represents C 1 -C ₄ alkyl. 31. The method according to any one of claims 1 to 30, characterized in that R ² is -CH ₃ . 32. The method according to any one of claims 1 to 31, characterized in that R ¹ is -CH ₃ . 33. The method according to any one of claims 1 to 32, characterized in that R ^a is -CH ₃ . 34. The method according to any one of claims 1 to 33, characterized in that R ^b is -CH ₃ . 35. The method according to any one of claims 1 to 34, wherein each Hal is independently -F or -C1. 36. The method according to any one of claims 1 to 35, characterized in that Hal is F. 37. The method according to any one of claims 1 to 36, characterized in that η is 3. 38. The method according to any one of claims 1 to 37, characterized in that J-1 is CA