TW200831478A - Chromane derivatives, synthesis thereof, and intermediates thereto - Google Patents

Abstract

Methods of preparing compounds of formula I or pharmaceutically acceptable salts thereof are provided: wherein each of R1, R2, R3, R4, x, m, n, and Ar are as defined, and described in classes and subclasses herein, which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

Description

200831478 IX. Invention Description: [Improve the technology of the technology ^ field ^] The cross-references of the relevant application request the US provisional patent application No. 60/854,382 application 曰 5 2006 1 〇 $ 25 priority, the case The full text is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to 5-HT2C receptor agonists or partial agonists, methods for their preparation, and uses thereof. 10 [Prior Art] Background of the Invention There are about 5 million people with schizophrenia. The most popular treatment for schizophrenia is the "atypical" antipsychotic, which combines dopamine (DO and serotonin (5-HT2A) receptor antagonism. Although 15 has reported atypical antipsychotics Relative to the improvement in efficacy and side effects of typical antipsychotic agents, but these atypical antipsychotic agents are clearly insufficient to treat all symptoms of schizophrenia, with side effects such as weight gain (Allison, D·B· Et al., American Journal of Psychiatry, 156: 1686-1696; Masand, P. S. 'Exp. Opin· Pharmacother· I : 20 377-389, 2000 ; Whitaker, R., Spectrum Life Sciences, Decision Resources, 2: 1-9, 2000) Atypical antipsychotic agents also bind to the 5-HT2C receptor with high affinity and act as 5-HT2C receptor antagonists or inverse agonists. Weight gain is an atypical antipsychotic such as Crozapine The side effects caused by (clozapine) and olanzapine 200831478 (olanzapine) have suggested that 5-Ht2c antagonism causes weight gain. Conversely, it is known that stimulating 5-HT2C receptors will lead Reduction and weight reduction of food intake (Walsh et al., Psychopharmacology ill: 57-73,1996; Cowen, P · J., et al, Human Psychopharmacology

5 Μ : 385-391, 1995 ; Rosenzweig-LipSon, s·, et al. ASPET Abstract, 2000). Several lines of evidence suggest that 5-HT2c receptor agonism or partial agonism can be used for the treatment of schizophrenia. Studies suggest that 5_ht2C antagonists increase the dopamine concentration of synapses and are effective in the study of Parkinson's disease 10 (DiMatteo, V., et al., Neuropharmacology, Cry: 265-272, 1998; Fox, SH , et al., Experimental Neurology: 35_49, 1998). Since the positive symptoms of schizophrenia are associated with increased dopamine concentrations, compounds with opposite effects to 5-HT2c antagonists, such as 5-HT2c agonists and partial agonists, should reduce synaptic dopamine 15 degree. Recent studies have demonstrated that 5-HT2c agonists increase dopamine concentrations in the prefrontal cortex and vestibular cochlear nucleus (Millan, J. J., et al., Neuropharmacology 21: 953-955, 1998, DiMatteo, V., Et al., Neuropharmacology Μ: 1195-1205, 1999; Di Giovanni, G., et al., Neurosynaptic 35: 53-61, 2000), prefrontal cortex and vestibular cochlear nucleus are mediators such as The brain area of clinical antipsychotic efficacy of Croza Equality. However, 5-HT2C agonists do not reduce dopamine concentrations in the striatum, which is the brain region most closely associated with extrapyramidal side effects. In addition, recent studies have demonstrated that 5-HT2c agonists can reduce the emission of the ventral tegmental area (VTA), but do not reduce the emission of substantia nigra. The differential effect of 5-HT2c agonist on the cerebral rim pathway compared to the substantia nigra 200831478 striatum pathway suggests that 5-HT2C agonists are marginally selective and less likely to produce extrapyramidal side effects associated with typical antipsychotics . SUMMARY OF THE INVENTION As described herein, the present invention provides a process for the preparation of a compound having activity as a 5-111^:agonist or partial agonist. These compounds are useful in the treatment of schizophrenia, schizophrenic disorders, schizoaffective disorders, paranoia, substance-induced psychosis, left-dopa (L-DOPA)-induced psychosis, psychosis caused by Alzheimer's dementia, Mental illness caused by Parkinson's disease, psychosis caused by Lewy body disease, dementia, memory impairment, intelligent deficiency caused by Alzheimer's disease, bipolar disorder, depression, emotional exacerbation, anxiety disorder, adjustment disorder , eating disorders, epilepsy, sleep disorders, migraine, sexual dysfunction, gastrointestinal disorders, obesity and its comorbidities, or central nervous system defects caused by trauma, stroke or spinal cord injury. These compounds include a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2; 20 η is 0 or 1; = represents a single bond or a double bond;

Ar is a thienyl group, a furyl group, an acridinyl group or a phenyl group, wherein Ar may be substituted with one or more R* groups as required; 200831478 each R* is -Ph, _, _CN, -R or - 〇R ; each R is a hydrogen, a Cl 6 aliphatic group or a Ci 6 haloaliphatic group; X is 0 to 3; each R1 is -R, _CN, halogen or _0R; 5 r2 is hydrogen, Ci -3 alkyl or - fluorene ((^_3 alkyl); and each of R3 and R4 is each hydrogen, Ci6 aliphatic or fluorenyl fluoroaliphatic. The invention also provides synthetic intermediates for the preparation of such compounds [Embodiment; j 10 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The process and intermediates of the present invention can be used to prepare a compound as described in U.S. Patent Application Serial No. 11/409,467, filed on Apr. 21, 2006, the entire disclosure of The manners are incorporated herein. In several embodiments, the present compounds are prepared substantially according to the reaction schemes I, II, and III shown below, wherein Ri, R2, R, Ra, 15 Rb, CG1, CG2, X, and y are as The following definitions and the categories and subclass definitions as described herein. In one aspect, the invention provides steps as described in the reaction diagrams J, :^ and the claws Preparation of enantiomerically rich forms of formulas A, B, II and II · HX for palm 2,8-disubstituted bite compounds. 20 skilled artisans are aware of reactions I, II and III, As described in steps Sb to S-10, a wide variety of reaction conditions can be employed to facilitate various synthetic transformations; therefore, the present invention encompasses a wide variety of broad reaction conditions (generally reference to March's Advanced Organic Chemistry: Reactor Transfer and Structural Formula, Μ·B Smith and J. March, 5th edition, John Wiley & Sons, 2001; and Integrated Organic Conversion, R. 200831478

C. Larock, 2nd edition, John Wiley & Sons, 1999). Reaction diagram I

A 11 IIHX Csp2_Csp2 coupling reaction between a compound of formula K having a coupling group CG and a compound of formula L having an even 5-group CG2 in a carbon atom carrying a complementary coupling group (ie, CG1 and CG2) in step S-1 To provide a compound of formula j. Suitable coupling reactions are well known to those skilled in the art. The coupling reaction is typically one of CGi or CG, which is an electron withdrawing group (for example, c 〇 Ts, OMs, etc.), and the resulting polar carbon _ CG bond is derived from electron-rich metals. (eg, low-cost 1 〇 palladium species or recorded species) oxidative addition sensitivity, complementary coupling groups are positively charged groups (eg, monoterpene quinones, di-based vinegars, deodorized, tin-fired) Classes, decyl species, zinc species, red, species, magnesium species, zirconium species, etc.), so the carbon carrying the positively coupled coupling is dry to sputum to other positively charged species (eg Pdn-iv 200831478 or NiII_IV) Species) sensitive. Dihydroxyboronic acid with different aryl groups! The Suzuki coupling reaction is typically carried out using a palladium catalyst ruthenium (triphenylphosphine) palladium (ruthenium) or other suitable source such as trans-dichloropurine (tri-o-tolylphosphine) palladium (II),

Pd(II)Cl2(PPh3)2, Pd(II)Cl2(dppb)2, Pd(II)(OAc)2 + PPh3,

5 Pd(II)(OAc)2 + tris(o-tolyl)phosphine (palladacycle), or Pd/C is carried out under basic conditions. Typically, the reaction base is sodium hydroxide, potassium hydroxide or barium hydroxide, sodium hydrogencarbonate or potassium hydrogencarbonate, sodium carbonate, potassium carbonate, barium carbonate or barium carbonate, fluorinated planer or potassium fluoride, third butoxide Sodium or potassium tert-butoxide, potassium phosphate or triethylamine; and solvents include DMF, ethanol, 10 tetrahydroethylene, and hydrazine. Mountains, ethylene glycol dimethyl scales, water, toluene, benzene, and mixtures thereof; and phase shifting reagents such as Bu4NC1 or 18-crown-6 are used. Examples of reactions include metal-catalyzed cross-linking reactions. A. de Meijere and F. Diederich, ed., 2nd ed., John Wiley & Sons, 2004; and Handbook of Organic Palladium Chemistry for Organic Synthesis, Negishi, E., de Meijere, A. Editor, John Wiley's father 15 subsidiary, New York State, 2002. In several embodiments, the CG1 in the compound of Formula K is dihydroxyboronic acid, dihydroxyborate or borane. In other embodiments, CG1 in the compound of formula K is a dihydroxy boronate. According to one aspect of the invention, the CG1 of the compound of formula K is dihydroxyboronic acid. In some embodiments, the CG2 in the compound of formula L is Br, I, OTf, OMs or OTs. According to one aspect of the invention, the CG2 in the compound of formula L is Br. In step S-2, the compound of formula J is deprotected by removal of the Ra group to obtain a hydrazine compound wherein Ra is a hydroxy protecting group. Hydroxyl protecting groups and their accompanying, *·· ' 10 200831478 The removal of the latter is well known to the art world, including the details of Greene and Wuts Organic Synthetic " 蒦基' John Wiley & Sons, 1999, full text of the document Incorporate here by bow. Examples of suitably protected hydroxyl groups further include, but are not limited to, esters, carbonates, phthalates, propenyl ethers, 5 ethers, decyl ethers, alkyl ethers, aryl alkyl ethers, And alkoxy yard-based scales. Examples of suitable esters include formates, acetates, propionates, pentamidine esters, crotonates, and benzoates. Specific examples of suitable esters include alpha fluorene, arachidyl ester, acetate, gas acetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, _ gas phenoxyacetic acid 1 〇 曰, 笨 propyl propionate, 4 keto valerate, 4,4-(extended * ethyl disulfide) pentose quinone valproate (dimethyl Base acetate), crotonate, 4-methoxy-croton, benzoate, p-benzyl benzoic acid _, 2,4,6-trimethyl benzoate. Examples of suitable carbonated vinegars include W-based methyl vinegar, ethylene carbonate, 2,2,2-tris-ethylene carbonate, 2-(trimethyl sulphate) acetonate, and L-phenyl benzene. Base) B, ethylene carbonate _, propylene carbonate _, and carbonic acid on the nitro section S. Examples of suitable Shixiyuan ethers include trimethyl sulphide, triethyl sulphate, t-butyl dimethyl sulphate, t-butyl diphenyl sulphate, Triisopropyl rock shochu base, and other three burning base stone kiln base scale. Examples of suitable alkyl groups include methyl scale 1 ether, p-methoxy group 2〇, 3,4-dimethoxy group, triphenylmethyl, tert-butyl scale, and Propenyl or its derivatives. Alkoxy-based scalys include acyl acids such as methoxymethyl-, methylthiomethyl ether, Amethoxyethoxy)methyl, ethoxymethyltrimethyl-weilc)ethoxy Methyl ether, and tetrachlorine british puzzle. Examples of suitable aryl silk ethers include benzyl ether, p-methoxyl 200831478 ether (MPM), 3,4-dimethoxybenzyl ether, o-nitrobenzyl ether, p-mercapto Benzyl ether, p-ibenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2- and 4-methylpyridyl ether. In several embodiments, the Ra group is a Cl 6 alkyl group. In yet another embodiment, the Ra group is a methyl group. The removal of the group can be facilitated, for example, by reaction with a base (e.g., sodium hydroxide, tetrabutylammonium hydroxide, etc.) or with an acid (e.g., hydrochloric acid, hydrobromic acid, acetic acid). , sulfuric acid, acetic acid, camphorsulfonic acid, TFA, p-toluenesulfonic acid, or Lewis acid (such as BBr3, BC13, A1C13), etc.; use fluoride anion source (such as tetrabutylammonium fluoride, potassium fluoride, 10 fluorinated pyridinium 11 iron, triethylammonium fluoride, tetrabutyltriphenyldifluoroantimonate, etc.); or hydrogenation reaction to promote the removal of Ra groups. In several embodiments, the removal of the Ra group can be facilitated by reaction with BB1 VBCI3 or AICI3. In several embodiments, the deprotection reaction is carried out in a suitable medium. In several embodiments, the conversion is carried out using acetic acid, diphenyl ether, di 417 mountain, anisidine, acetone, tetrahydrofuran, acetic acid, ethyl acetate, dimethylformamidine. Amine, ethylene glycol, toluene, benzene, DMS0, water, diisopropylethylamine, triethylamine, pyridine, N-mercaptoporphyrin, acetonitrile, N-methylpyrrolidine, and a mixture thereof. In several embodiments, the removal of the Ra groups is facilitated by reaction with BB1.3 in toluene or hydrobromic acid in acetic acid. In several embodiments, the reaction is carried out at a temperature between about 0 ° C and about 100 ° C. In the step S-3, the hydrazine compound is reacted with the compound of the formula G by conjugate addition to obtain a compound of the formula F. In some embodiments, the foregoing reaction step can be carried out with or without heating in the presence or absence of a base. In some embodiments, the conjugate addition reaction is carried out in a carbonic acid clock, potassium hydroxide, sodium hydroxide, 12 200831478 tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, triethylbenzylammonium hydroxide. 1,1,3,3-tetradecyl fluorene, eucalyptus diterpene bicyclo[5·4·〇]undecene, N-methylporphyrin diisopropylethylamine, tetradecyl The reaction is carried out in the presence of a diamine, acridine or triethylamine. In several embodiments, the conjugate addition reaction system 5 is carried out in the presence of triethylamine. In several embodiments, the incorporation reaction is carried out in a suitable medium. A suitable medium is a solvent or mixture of solvents which, when combined with the reaction with a reagent or a reagent, aids in the reaction therebetween. In some embodiments, the conversion reaction is carried out in diphenyl ether, dioxane, mountain, 1 anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene. It is carried out in water, diisopropylethylamine, triethylamine, hydrazine, N-methyl phthalocyanine, acetonitrile, N-fluorenyl hydrazine or a mixture thereof. In several embodiments, the reaction is carried out in ethyl acetate. In other embodiments, no additional solvent was added. In still other embodiments, 15 excess phenol (corresponding to the hydrazine compound) is employed as the solvent. In other embodiments, the reaction is carried out at a temperature between about 25 ° C and about 11 ° C. In still other embodiments, the reaction is carried out at about 50 °C. In other embodiments, the vehicle addition system is similar to Ruhemann, S. J. Chem. Soc. 1990, 77, 1121, Gudi, Μ·Ν·, et al., Indian Chemical Journal, 1969, 7, 97, Cairns , 20 Η · Specialized by J. Med. Chem. 1972 ' 15 ' 583 ' Stoermer, MJ and Fairlie, D. R Aust J. Chem. 1995, 48, 677 and British Patent No. GB1262078. In step S-4 and step S-5, the following reaction scheme (previously) and reaction diagram 11 (described later) illustrate that the compound of formula F is reduced (step S-4) followed by deprotection (step 13 200831478 S-4) The compound of formula E is obtained, and then the compound of formula E is cyclized (step S-5) to form a compound of formula D. However, those skilled in the art will recognize that there are other ways in which a compound of formula D can be made from a compound of formula F, and such means are intended to be encompassed within the scope of the invention. For example, a compound of formula F can be deprotected first, then reduced, and then cyclized to form a compound of formula D. Alternatively, the compound of formula D can be deprotected, then cyclized, and then reduced to form a compound of formula D.

Reaction diagram II

It is to be understood that any of the intermediates shown in Reaction Schemes I or II can be isolated and/or purified prior to the subsequent steps of 10. Alternatively, any of the intermediates shown in Scheme I or II can be used in subsequent steps without isolation and/or purification. Variations in these steps are also intended to be encompassed within the scope of the invention. In several embodiments, the conjugate addition step S-3 followed by the reduction and deprotection step S-4 to form the compound of formula E can be carried out without isolation and/or purification of the intermediate compound. In some embodiments, the reduction reaction is a hydrogenation reaction carried out in the presence of hydrogen and a metal catalyst. In several embodiments, the metal catalyst is palladium on carbon or contains ZnBr2, Pt/C, RU/C, Rh/C, Pt〇2. Still another 14 200831478 In the examples, the palladium catalyst is palladium hydroxide (π). In still other embodiments, the hydrogenation reaction can be carried out in methanol, ethanol, ethyl acetate, or acetic acid, TjjF, isopropanol. In still other embodiments, the hydrogenation is carried out in the presence of sulfuric acid, acetic acid, or one. In still other embodiments, the hydrogenation reaction is carried out as described in 5 Witiak' D. Τ. et al., J. Med. Chem. 1975, 18, 934. In still other embodiments, the hydrogenation reaction described above and herein is carried out at a pressure of about 5 Torr Psi (3⁄4) or more; and in some embodiments, the hydrogenation reaction is carried out by heating the reaction mixture. In other embodiments, the hydrogenation is carried out at a temperature of from about 30 ° C to about 50 ° C. In other embodiments, the reduction reaction is a chemical reduction reaction of zinc powder in the presence of acetic acid. Surprisingly, it has been found that reduction step S-4 is carried out by hydrogenation in an acidic medium to obtain or be a more efficient reaction and reduction of the undesired dehalogenated e-compound. Thus, according to another embodiment, the present invention provides a method of synthesizing a compound of formula E as shown in Figures I and II and a compound of formula E-1 as shown in Figure 13 of the following reaction, which is via the formula or The H-1 compound is reacted with a compound of formula G, followed by hydrogenation in an acidic medium to obtain a compound of formula Ε or formula Ε-1. In several embodiments, the acidic medium comprises acetic acid, sulfuric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, phosphoric acid, or mixtures thereof. In the examples, the acidic medium is a sulfuric acid/acetic acid mixture.

20 Reaction Diagram III (10) Rb〇(〇)C-"^^^Q)QRb ><^5, ^C(0)0R Reduction; &><% ^co2h S-3a S-4a Η · 1 F · 4 Ε · 1 Each of the Rb groups of the G and F compounds and the reactions shown in Figures H and HI. Each of the Rb groups of the compound of 200831478 is a suitable carboxylic acid protecting group and is selected from It is not limited to an alkyl group, an alkenyl group, a phenyl group, a benzyl group, or a trialkyl decyl group. In some embodiments, each Rb group is selected from methyl, ethyl, t-butyl, propenyl, benzyl, phenyl, trimethyldecyl, or tert-butyl 5 dimethyl, respectively. Shi Xi burning base. In other embodiments, each Rb is ethyl. Removal of the Rb group can, for example, facilitate the reaction via reaction with a base (e.g., sodium hydroxide, tetrabutylammonium hydroxide, etc.) or via an acid (e.g., hydrochloric acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid). , reaction to _toluenesulfonic acid, etc.; use of fluoride anion source (such as tetrabutylammonium fluoride, potassium fluoride, acridine fluoride, trisodium monoethylammonium fluoride, tetrabutyltriphenyldifluorofluorene) Ammonium phosphate, etc.; or by hydrogenation to promote removal of the Rb group, and optionally heating the reaction mixture. In some of the examples, the removal of the Rb group is enhanced by reaction with sodium hydroxide. In other embodiments, the reaction can be promoted by reaction with hydrochloric acid. In still other embodiments, the reaction is promoted by reaction with HCl/AcOH. In the dry embodiment, the deprotection reaction is carried out in a suitable medium. In some embodiments, the conversion is carried out using ethanol, methanol, isopropanol, acetic acid or tetrazolium as a solvent, or using a mixture of the foregoing solvents and/or water. In several embodiments, the reaction is It is carried out at a temperature of from about 40 ° C to about 100 ° C. 20 In step S-5, the compound of formula E is cyclized to give the compound of formula D. In the case of the above, the cyclization reaction is promoted by treating the compound of the formula E with an appropriate brownies acid. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, tripolyphosphoric acid, methanesulfonic acid, Eaton's reagent (P205/MeS03H), gassulfonic acid, camphorsulfonic acid, and p-toluenesulfonic acid. In other embodiments, additional test 16 200831478 may be employed, including, for example, pentoxide, triple gas, disc, pentachlor, grass, chlorine, helium or acetic anhydride. Those skilled in the art will appreciate that a number of conditions will result in the formation of an intermediate product of chlorine prior to the ongoing cyclization of Fedel-Cmfts by a Lewis acid such as AICI3. In still another embodiment, the reaction is carried out using acetonitrile or water as a solvent. In still other embodiments, the cyclization system is Ruhemann, sj chem s 1990, 77, im, Gudi, Μ·Ν· et al. Indian Chemical Journal 1969, 7, 971, Cairns, Η· et al. J. Med Chem. 1972, 15, 583, Stoermer, MJ and Fairlie, D. P. Aust. J. Chem. 1995, 48, 677, and British Patent No. GB1262078. In step S-6, the ketone functional group of the compound of formula D is reduced to a methylene group to obtain a compound of formula C. Those skilled in the art understand that a wide variety of reaction conditions can be used to facilitate this reduction; therefore, a wide range of reaction conditions are included (a broad reference to March's advanced organic chemistry: reaction, machine rotation and structural formula, Μ. Ββ 15 Smith and J. March, pp. 5th edition, John Wiley & Sons, 2001; and Integrated Organic Conversion, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999). In step S-6, the reaction is carried out using a reducing reducing agent. Suitable reducing agents include, but are not limited to, H2 (gas) and palladium catalysts or platinum catalysts, cyclohexene and Pd/C (catalyzed transfer hydrogenation), Zn/rhodium, Li/NH3, monidene 20 nickel, trialkylsulfonyl hydrogen (eg Et3SiH), sodium borohydride or lithium aluminum hydride. In several embodiments, the reaction is carried out in trifluoroacetic acid, acetic acid, ethyl acetate, tetrahydrofuran, dioxane or diethyl ether. In other embodiments, the reaction is carried out at a temperature of from about -25 ° C to 80 ° C. In step S-7, the carboxylic acid of formula C is subjected to optical separation using the appropriate palm species 17 200831478 to obtain an enantiomerically enriched compound of formula B. In several embodiments, the appropriate palm species is palmitic amine. In several embodiments, the palmitic amine is (R)-;!-phenyl-propylamine, (a) cinchonidine, R7)-adrenalin, (+)-cinchonine (a) strychnine, or -(a)+...naphthyl)-ethyl-5-amine. In still other embodiments, the palmitic amine is (_)-cinchonidine. According to one aspect of the invention 'a mixture of enantiomers of formula C and enantiomerically enriched for palmitic amine, the diastereomeric excess of the resulting salt can be achieved by one of the diastereomers The other is increased by selective crystallization. According to still another aspect of the present invention, the 10th palmitic amine used in the crystallization described above is (a)-cinchonidine. In several embodiments, the non-oblating salt is formed by the enantiomeric enantiomer of Formula B and enantiomerically enriched with palmitic amine in methanol, ethanol, isopropanol, dichlorodecane. , acetonitrile, acetic acid, dimethylformamide, isopropyl acetate, burned, money, tetranitrogen, cyclohexane, benzene, benzene, dimethyl, yt, tertiary butyl The combination is tested in water, water, or a mixture thereof; and then heated as needed to: reach the reflux temperature of the solvent used. In other embodiments, the aforementioned diastereomeric salts are formed via refluxing acetonitrile and water.于若 =Example: The diastereomeric salt of the compound of formula B is due to methanol, ethanol, j 20 = leaven: di-methane, acetonitrile, ethyl acetate, dimethylformamide, acetic acid Bismuth, hexanes, heptane, tetrahydrofuran, cyclohexane, stupid: benzene, B, tributylmethyl, water, or liquid crystals. In other embodiments, the crystallization is due to the crystallization of the B. In still other embodiments, the crystallization occurs when the turbid liquid is cooled by the addition. In several embodiments, the solution is heated up to the reflux temperature of the container 18 200831478 and cooled to a lower plate. The acid is obtained from the diastereomer by treatment with a suitable solvent: do not:: by: appropriate use = a wide range of solvents suitable for use in this project, in methanol, ethanol, 1 propionate 7 is 夂, suitable solvent is selected from ~ Isopropanol, acetic acid, butyl, diethyl ether, dibutyl sulfonate, water, or a mixture thereof. In the other way, the Aaπ used in the above-mentioned selection is very according to the present hair-step. Enantiomeric excess or diastereomer of a compound of Ba 10 15 20 The enrichment of the enantiomerically rich structure of the compound of formula B (i.e., ent_B) is understood. Thus, (4) reflection pre-enantiomers can be enriched: the formula is passed. Thus, in another aspect of the invention, the mixture of the enantiomers of formula C is dissolved in a suitable solvent, and the opposite kine isomer (ent_B) is crystallized therein to obtain a mono-enantiomer. The enriched crystalline product: and the enantiomer B enriched mother liquor. In addition, in the present invention: a mixture of the enantiomers of the formula C is dissolved in a suitable solvent, and the enantiomer B is crystallized therefrom to obtain a single enantiomer. The mother product of the crystalline product B and the opposite enantiomer em_B. In the examples, suitable solvents are selected from the group consisting of methanol, ethanol, isopropanol, methylene chloride, acetonitrile, ethyl acetate, isopropyl acetate, hexane, heptane, tetrahydrofuran, cyclohexane. , benzene, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof. In other embodiments, the enantiomer of formula c is dissolved in a suitable solvent at a temperature of from about 70 ° C to about 9 (TC). In several embodiments, the crystallization occurs in a heated enantiomer of formula C. When the solution is cooled, 19 200831478 mother liquor is collected to obtain the "isomer B rich form. In addition, in some real-time, heated C-isomer solution cooling

Rich form

. - See "Japanese artisans understand that the mother liquor enriched with the opposite enantiomer ent_B circulates the stereocenter of the stereocenter, thereby forming a racemic of this mouthpiece, which can again be described as step s. In a number of embodiments, such a method is performed as described in Example 8 (see below). The advantage of this method is that it can improve the atomic economy and cost effectiveness of the total synthesis process. In an embodiment, the invention provides a method of formulating a compound of formula B from a compound of formula ent-B, comprising the step of forming a stereogenic exogenous compound into a compound of formula C-indole; and isolating the compound of formula 6 as described herein. The skilled artisan understands that the enantiomeric enrichment of the compound of formula c can be achieved using the 15th method, including the aforementioned optical segmentation techniques. Examples of methods include (a) separation of enantiomers by palm chromatography. (b) one enantiomer is selectively crystallized than the other enantiomer, optionally by sowing the enantiomeric mixture solution by enriching the crystal with the desired enantiomer (c) one enantiomer compared to the other enantiomer 20 and the enantiomeric enrichment reaction to the palm; and (d) facilitated conversion via a palm catalyst, one enantiomer More selective reaction (including enzyme-catalyzed conversion: Pseudomonas fluorencens (also 20 200831478: Amano lipolytic enzyme AK)). Stereochemistry, Ε. L. Eliel and s. Ή silen, 1994; enantiomers, racemic mixtures and optical segmentation, deduction (2), etc. A 'Willie Technology, New York' Lantern; Wilen' s H et al., four pentahedrons 1977, 33, 2725; optical partitioning and optical segmentation, %^11, Yi 11. (EL Eliel, editor), Notre Dame University, Indiana, Notre Dame, In 1972, skilled artisans understand that the two enantiomers of a compound of interest are chemically converted to different chemical entities, requiring a subsequent step (or subsequent step) to recapture the initial compound. 10 As used above, Enantiomeric rich" or " Enantiomerically pure "denotes one enantiomer of at least 75% Composition of the article. In several embodiments, the term means that one enantiomer constitutes at least 8% of the article. In other examples, the term means that one enantiomer constitutes at least 9% of the article. In other embodiments, the term refers to an enantiomeric composition of at least 95% 15 articles. In still other embodiments, the term indicates that one enantiomer constitutes at least 97.5% of the preparation. In yet another embodiment, the term is used to indicate that the article consists of a single enantiomer to the detection limit (also referred to as "enantiomerically pure"). As used herein, "enantiomerically rich" or "enantiomerically abundant" is used to describe a singular noun (eg, an enantiomer of r form 6). 2 Oops, you must know "compound" or " The acid may be enantiomerically pure or may actually be an enantiomerically enriched mixture of enantiomers. Similarly, when "racemic" is used to describe a singular noun (such as "racemic compound"), it is understood that the term actually describes a mixture of enantiomers of 丨··丨. Those skilled in the art are aware of the formulae E, D, c, B, a, π & η · HXization 21 200831478 The composition contains stereogenic carbon. Thus, the invention encompasses enantiomers of the compounds E, D, C, B, A, II and II HX and mixtures thereof. Although single stereochemical isomers are illustrated for Formulas B, A, II, and II · HX in Reaction Scheme I, it is to be understood that the present invention encompasses those chemical formulas in which one of the enantiomeric 5 constructs is enriched by the method of the present invention. a mixture of enantiomers. In step S-8, the carboxylic acid of formula B is subjected to guanidation to provide a compound of formula A. In several embodiments, the guanidation is carried out by reacting a carboxylic acid with a suitable reactant (eg, via reaction with sulfoximine gas, oxaloquinone chloride, etc.) to form an activated carbonyl group and subsequently treating the activated species with an ammonia source. . In a number of implementations of 10 cases, the source of cyanide was ammonia or ammonia in a suitable solvent. Suitable solvents include tetrahydrofuran, toluene, heptane, tert-butyl methyl ether, diethyl ether, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, di-hexane, or water (e.g., nh4oh). In other embodiments, the present reaction is carried out by first activating the 15 carboxylic acid to aid in the oximation reaction, by deuteration by reaction with chlorophyll chloride, and subsequently treating the activated species using NH4 〇H. In still other embodiments, the reaction is carried out in toluene, benzene, ethyl acetate, dichloromethane, gas, dioxane, and combinations thereof. In other embodiments, the reaction is carried out at a temperature between about 1.00 (TC and 150 ° C. In still other embodiments, the reaction is carried out at a temperature between about 0 ° C and about 20 50 ° C. In other embodiments, the reaction is substantially similar to that of Zhang et al., Tetrahedron Letter 45: 5229 (2004); Benz, "Synthesis of Indoleamine and Related Compounds", Organic Synthesis, Tr〇st, Β·M., Editor's Pergam〇n press: New York, New York, Issue 6; Bailey et al., "Indoleamine" in Integrated Organic Functional Conversion, Katritzky, 22 200831478 et al., edited by Pogman In New York, New York, No. 5; and pCT Bulletin W005037817. In step S-9, the amine of the formula A is reduced to form the guanamine. In several embodiments, the reduction step is It is carried out by treating the compound of the formula a with Red-Al [贰(2-methoxyethoxy) 5 hydride sodium], BH3_THF, acetonitrile or hydrogenation. In other examples, the reduction step is carried out in toluene. , in benzene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, or a mixture thereof. In an embodiment, the reduction step is carried out at a temperature of from about -40 ° C to about 100 ° C. In other embodiments, the reduction step is about 4 ° C (the temperature of TC is 10 rows. In the examples, the reduction is carried out in a manner substantially similar to that described in Gross, Tetrahedron Letter 44: 8563 (2003); W005037817; W003040382; W002020507; or DE 10120619. In several embodiments, the reduction of indoleamine to an amine can be used. Borane amines such as triethylamine shed, trimethylamine borane, tert-butylamine borane, diisopropylethylamine boron 15 alkane, diethylphenylamine borane (DEANB), acridine Borane, and porphyrin borane are achieved. Other suitable amine boranes are well known in the art. In several embodiments, the amine borane is DEANB or triethylamine borane. In several embodiments, the reaction can be amine The borane is carried out neat or the reaction can be carried out in an organic solvent such as acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran. In several embodiments, the temperature of the reaction is in the range of from 20 ° C to 100 ° C. In the examples, the temperature system was > 60 ° C. The reaction was usually completed in > 20 hours. The typical procedure is to add the amine borane to the guanamine starting material using a solvent or no solvent. The mixture is heated to a temperature of 60 ° C or above until the reaction is complete. Additional amine borane can be added to drive the reduction reaction to completion. In several embodiments, when the reaction is completed 23 200831478 5 'the free state is not separated, but the free base is directly converted to its hydrochloride as described above. Formulas 〖, 】, ^, £, 〇, (:, 34 And 11 and 11. Each of the R groups is halogen, _CN, _R or _〇R, wherein each R is hydrogen, Cl_0 aliphatic or Cl. 6 haloaliphatic, and X is 0 to 3. Examples of suitable R1 groups include hydrogen, methyl, ethyl, isopropyl, gas, and fluorine. SJ, H, F, E, D, C, B, A, IIH.HX: ^^li] R2 10 groups are respectively Ph, _, -CN, -R or -OR, wherein each R is wind , a Cl-6 aliphatic group or a Cwi aliphatic group, and y is from 0 to 5. Examples of suitable R groups include methyl, ethyl, isopropyl, chloro, fluoro, methoxy, monofluoromethylphenyl, cyano, ethoxy, trifluoromethoxy, and isopropoxy . According to the invention of the invention, R2 is gas. According to another aspect of the present invention, at least one of the loops of the formula J, Η, F, E, D, C, B, 15 A, II, and II ΗΧ compounds is in the position of the two rings. The one in it. According to still another aspect of the invention, the R2 groups are tethered at various positions in the two adjacent ring positions. In several embodiments, '% secret 4' is from the portion of Table 1 below, one of which represents the attachment point of ring B to ring A. 20 The v/member knows that the atropisomer of the compound may be present. Thus, the July stipulations are in the definitions and tables of the texts and in the above-mentioned and the classes and subclasses described herein, and the isomeric forms of the formula 11 and formula II·HX compounds. 24 200831478 Table 1

Vii viii ix x vi vAA/

ν/VV» J\i\j MeO 丄 F3C,

5 xi xii xiii

Xviii xix

Xiv vATU xv xx

25 200831478

Those skilled in the art will recognize that Compound 5 of Formula II prepared by the process of the present invention can be treated with a suitable Brownsian acid as described in Step S-10 to form a salt thereof (represented by Formula II.HX) wherein 乂° is the acid Alkaloids. Examples of the acid include hydrogen halides, ferulic acid, acid, sulfuric acid, and acid. According to one aspect of the invention, the compound of formula II is treated with hydrochloric acid to form a hydrazine compound of the formula II wherein 乂[] is a functional anion. In several embodiments, the acid herein is a salt 10 acid and the hydrochloric acid is introduced into the compound of formula II in gaseous form. In other embodiments, the acid is introduced into a solution containing a compound of formula II. Suitable solutions include, but are not limited to, methanol, ethanol, isopropanol, water, or mixtures thereof. In still another embodiment, the acid is introduced into a solution comprising a compound of formula II and isopropanol. As used herein, the terms "aliphatic" or "aliphatic" mean a straight-chain (ie unbranched) or branched hydrocarbon chain that is completely saturated or contains one or more unsaturation units, or is fully saturated or contains one or A single cyclic hydrocarbon of a plurality of unsaturated units, but non-aromatic (also referred to herein as "carbocyclic" or "cycloaliphatic"), which has a single attachment point attached to the remainder of the molecule. In several embodiments, the aliphatic group contains 1-6 carbon atoms; in yet other embodiments, the 'aliphatic group contains 1-3 carbon atoms. In some embodiments, "cycloaliphatic" (or rabbit loop) refers to a monocyclic CVC6 hydrocarbon that is fully saturated or contains one or more unsaturation units, but a non-aromatic ring, one attached to the remainder of the molecule 5 Point of attachment. Such groups include cycloalkyl, cycloalkenyl, and cycloalkynyl. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl, and mixtures thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "unsaturated" as used herein means that one part has one or more units of unsaturation. The term "alkyl" as used herein, refers to a hydrocarbon chain containing up to 6 carbon atoms. The term "alkyl" includes, but is not limited to, straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl Base, isoamyl, 1-methyl-butyl, 2-methyl-butyl, n-hexyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, Or 4-methyl 15-pentyl. The terms "halogen" or "halogen" as used herein mean a chlorine (_q), a desert (_Br), a fluorine (-F) or an iodine (-1) atom. The term "haloaliphatic" as used herein refers to an aliphatic radical as defined herein having one or more substituents. In several embodiments, each hydrogen atom on the aliphatic 20 aliphatic group is replaced by a halogen atom. Such a lipid group includes -cf3. The term "fluoroaliphatic" as used herein, denotes an aliphatic radical having one or more substituents as defined herein. In the right-handed example, the gas-moon group is a gas-burning base. 27 200831478 The term "fluoroalkyl" as used herein, refers to an alkyl group, as defined herein, having one or more fluoro substituents. In several embodiments, each hydrogen atom on the alkyl group is replaced by a fluorine atom. The term "Ph" is used herein to mean phenyl. The term "alkenyl" as used herein, refers to an aliphatic straight or branched hydrocarbon chain containing from 1 to 3 double bonds containing from 2 to 8 carbon atoms. Examples of alkenyl groups include ethenyl, prop-1-enyl, propenyl, methacryl, but-1-enyl, but-2-enyl, but-3-enyl, or 3,3- Dimethylbut-1-enyl. In some embodiments, the alkenyl group is preferably a branched alkenyl group having from 3 to 8 carbon atoms. The words "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" include acid addition salts which are salts derived by treating a compound of formula II with the following organic or inorganic acids, Such acids are, for example, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, butyl butyric acid, malonic acid, citric acid, malic acid, oxalic acid, propionic acid, hydrochloric acid. 15 hydrogen HCl, acid, citric acid, sulfuric acid, glycolic acid, pyruvic acid, methyroic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, or a similarly known acceptable acid. When the compound of formula I contains an acidic substituent, the term also includes salts derived from bases such as the sodium salt. In several embodiments, the invention provides the hydrochloride salt of a compound of formula II. According to another aspect, the present invention provides a method of preparing a compound of the formula II·HX: ,*>·.

28 200831478 wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 5 each R2 is -Ph, a halogen atom, -CN, -R or - OR; each R is a nitrogen, Ci_6 aliphatic or Ci_6 13⁄4 aliphatic group; and χθ is a suitable acid test, the method comprises the following steps: (a) providing a compound of formula II:

Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 15 each R2 is -Ph, a halogen atom, -CN, -R or -OR; Each R is independently a nitrogen, a Ci-6 aliphatic or a Ci_6 13⁄4 aliphatic group; and (b) contacting the compound of formula II with a suitable HX acid to form a compound of formula II. 20 As defined above, in the compounds of formula II and II · HX, X is 0 to 3, y is 0 to 5, and each R1 is a halogen atom, -CN, _R, OR; each R is a mouse, C1 _6 fat a group or a C1 _6 13⁄4 aliphatic group; and each R2 is 29 200831478 -Ph, a halogen atom, _CN, _R or _〇R. In several embodiments, it is again 〇2. In other embodiments, X is zero. In other embodiments, y is 2 to 3. In other embodiments, y is two. In several embodiments, R1 is fluoro or chloro. In other embodiments, R1 is fluorine. In several embodiments, R2 is fluoro, gas or Cl-35 aliphatic. In other embodiments, R2 is gas. As defined above, in the formula π and Η · HX compounds, ring A is substituted with a Ri group at the open meta position relative to the carbon carrying ring B. In other practical examples, %B is substituted with ortho R relative to the ortho position of the carbon carrying ring a. In still other embodiments, ring B is substituted with an r2 group at each ortho position of the (7) stone opposite to ring A. In still other embodiments, Ring B is selected from the group shown in Table 1 above, one of which represents the attachment point of Ring B to Ring A. In the above reaction step, HX is an appropriate brownies acid, and X□ is the test of the car. Examples of the Browns acid include a functional hydrogen, a tickic acid, a 15 sulfonic acid, sulfuric acid, and phosphoric acid. In the case of the right scallop, the following conjugates of the appropriate Bronze acid: acetic acid, lactic acid, hydrazine; secret, t ^ ® 夂, cinnamic acid, tartaric acid, succinic acid, anti-butene-1 ♦ butyl - Acid, @二酸, is a peach acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrogen desert acid, hydroquinic acid, Gu, Gu, sulfuric acid, ethanol 2 citric acid, pyruvic acid, methanesulfonic acid, formic acid. In other embodiments, tartaric acid, toluene acid, salicylic acid, or benzene, Χθ is chlorine. According to one aspect of the invention, the compound of formula 11 is treated with hydrochloric acid to form a hydrazine compound of the formula II wherein Xegci. In several embodiments, when the appropriate acid is hydrochloric acid, the acid is introduced into a medium containing a compound of formula π in gaseous form 30 200831478. In other embodiments, the acid is introduced into a medium containing a compound of formula π in a solution comprising methanol, ethanol, isopropanol, or water, or a mixture thereof. In still other embodiments, the acid is introduced into a medium comprising a compound of formula IHb and isopropanol. In some embodiments, the compound of formula II. HX is selected from the group consisting of compounds formed by combining a compound of formula II shown in Table 2 with a suitable brownies acid. In other embodiments, the HX compound is selected from the group consisting of the compound formed by the combination of the hydrazine and the appropriate brownies acid. In yet another embodiment, the hydrazine compound is an HCl salt of a compound of formula II-1, 10 (e.g., compound π_ι · HC1). In several embodiments, the hydrazine compound of formula II is isolated by crystallization. Those skilled in the art will recognize that a compound of formula II or a hydrazine compound can be purified by crystallization from the following standard organic media, such as methanol, ethanol 'isopropanol, di-methane, acetonitrile, ethyl acetate, hexanes, heptane. , tetrahydrofuran, 15 cyclohexane, stupid, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water or a mixture thereof. Those skilled in the art will appreciate that varying the crystallization conditions can provide a comparison of the purity of the compound of formula II or the purity of the ruthenium compound prior to crystallization, as determined by analytical methods (eg, NMR, LCMS or HPLC), with higher or lower pairs. Isomerization purity or isomer purity. Therefore, in other embodiments, crystallization may be repeated as needed until the Π·ΗΧ compound has a desired purity. In yet another embodiment, crystallization increases the enantiomeric excess of the crystalline product, optionally via one or more crystals enriched in the desired enantiomeric form, The solution is seeded to crystallize. In yet another embodiment, the crystallization step is as the only separation step or purification step of the compound of the formula (2008). Examples of the compound of formula II are listed in Table 2 below. Table 2

II-1

,nh2

ΙΙ-7

ΙΙ-8 ΙΙ-9

ΙΜΟ 5 Π-6

1丨丄,一ΝΗ:丨丨

, ΝΗ? 11-12

,ΝΗ2

11-14

,νη2 11-15 ΙΙ-11

Ci f3c.

,νη2 11-17

MeO.

11-22

11-13

.νη2 cf3

Cl

11-18 11-19 Cl, Ck people, /NH2 F3C, A MeO, A u MeO〆 11-23 11-24 Cl, CO,.nh2 oc a Φ person,, /ΝΗ2

Cl ΙΙ-20 Cl

,nh2 Cl 11-25 10 Π-31

11-32 11-33 11-35 32 200831478

II-36

II-37

.nh2 II-38

,ΝΗ, ΙΙ-41

ΙΙ-42 νη2 Τ

ΝΗ〇 ΝΗ, ΙΙ-44 W/NH2 '人/ΝΗ2 cu 々α ci ΙΙ-45

Ph

.ΝΗ?

11-43

ΙΙ-46 II-47 11-48 乂ν/ΝΗ2 ^γ^〇>ν,/ΝΗ2 ^^0 person, /NH2 into Cl ci^^ci ci^^ci VV OMe ocf3 11-51 11-52 11 -53 νη2 .νη2

w/NH2

, /ΝΗ2 .νη2

Cl cf3 11-56 11-57 11-58 乂 v/NH2 person z/NH2 V1 ci^^ci cl>^rcl V V OMe 〇cf3 CN 11-61 11-62 11-63

ΙΙ-59 ΙΙ-55 w/NH2

ΆΗ2 ΙΙ-60

Ηη2

W/NH2

Ηη2

Ph

,νη2 11-67

.νη2 ΙΙ-69

ΙΙ-70 33 . 200831478

II-76

11-77

II-78

Nh2 11-74

ΙΙ-79

ΙΙ-91 9〇,. , /ΝΗ2 fw ,,/ΝΗ2 0rCF3 ΐ1 V 1 OMe ΙΙ-92 ΙΙ-93 11-94

ΙΙ-95

ΙΙ-101

MeO

34 200831478 In several embodiments, the compound of formula II is selected from the group consisting of compounds 11-1, II-8 and 11-47. In still other embodiments, the compound of formula II is compound II-1. According to another embodiment, the invention provides a method of preparing a compound of formula II:

Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 10 each R2 is -Ph, a halogen atom, -CN, -R or -OR; And each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group; comprising the steps of: (a) providing a compound of formula A:

15 wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, a halogen atom, _CN, _R or -OR; Each R is independently a nitrogen, a Ci-6 aliphatic group or a Ci_6 13⁄4 aliphatic group; 35 200831478 and (b) reducing the compound of formula A to obtain the compound of formula II. For the compound of formula A, X, y, R1 and R2 are each as defined above for the examples and sub-embodiments of the compounds of formula η and II · HX. 5 In the above reaction step, the indoleamine of the compound of formula A is partially reduced to an amine. Skilled artisans understand that a wide variety of reaction conditions can be used to reduce guanamine, and thus the present invention encompasses a wide variety of reaction conditions; generally reference to March, (2001) and Larock (1999). Suitable reducing agents include, but are not limited to, Red-Al [sodium (2-methoxyethoxy)aluminum hydride], BH3-THF, diborane, and lithium aluminum hydride. In other embodiments, the reducing step is carried out in toluene, benzene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, or a mixture thereof. In some embodiments, the reducing step is carried out at a temperature of from about -40 ° C to about 10 ° C. In other embodiments, the reducing step is carried out at a temperature of from about 0 °C to about 80 °C. In still other embodiments, the reduction is substantially similar to 15 Gross 'J. L. Tetrahedron Letters 2003, 44, 8563; Mayweg, A. et al., U.S. Patent Application Publication No. US 05250769 (2005); Devant, R. et al. 'International Patent Application Bulletin WO 05037817 (2005); Mitsuda, M. et al., International Patent Application Bulletin WO 03040382 (2003); Bokel 'Η· et al., International Patent Application Bulletin w〇02020507 ( 20) or in the manner described in Bokel, Η et al., German Patent Application Publication No. DE 10120619 (2002). In several embodiments, the reduction of the guanamine to an amine may use a degraded amine such as triethylamine borane, trimethylamine borane, tributylamine borane, diisopropylethylamine borane, Diethylaniline borane (DEANB), mouth ratio sigma side burning, and porphyrin borane. Other suitable amine boranes are well known to those skilled in the art. In several embodiments, the amine borane is DEANB or triethylamine boron. In several embodiments, the reaction can be carried out neat in the amine borane or the reaction can be carried out in an organic solvent such as acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran. In several embodiments, the reaction temperature is in the range of from 20 ° C to 100 ° C. In several embodiments, the temperature system is > 60 °C. The reaction is usually completed in >20 hours. A typical procedure is to add an amine borane to the amine starting material using a solvent or no solvent. The mixture is heated to a temperature of 60 ° C or above until the reaction is completed. Additional amine borane can be added to drive the reduction reaction to completion. In the examples, when the reaction is complete, the free base is not isolated, but instead is converted from its base to its hydrochloride as directly described above. According to another embodiment of the invention, the invention provides a method of preparing a compound of formula A:

Wherein: 15 X is 0 to 3; y is 〇 to 5; each R1 is -R, -CN, a halogen atom or _0R; each R2 is Ρ1ι, _ atom, -CN, -R or -〇R And each R is hydrogen, a Cw aliphatic group or a Cw haloaliphatic group; 20 comprises the following steps: (a) providing a compound of formula B: 37 200831478

Wherein = X is 0 to 3; y is 0 to 5; 5 each R1 is -R, -CN 'halogen atom or each; R2 is -Ph, _ atom, or -OR, respectively; and each R is hydrogen, a Cw aliphatic group or a Ci 6 haloaliphatic group; and (b) amidoxime of the compound of the formula B to obtain the compound of the formula a. 10 For the compounds of formulas 8 and 6, x'y'R1 and R2 are each as defined above for the examples and sub-embodiments of the compounds of formula II and II. HX. In the above reaction step, the compound of the formula B is subjected to guanidation to obtain the formula VIII compound. Skilled artisans understand that a wide variety of reaction conditions can be used to amamine a compound of formula G, and thus the present invention encompasses a wide variety of reaction conditions; roughly 15 references to March (2001); Larock (1999); Benz, G "decamine and related Synthesis of Compounds." In Integrated Organic Synthesis, Tr〇st, Β·M• ed., Pogman Press: New York, New York, No. 6; and Bailey, ρ·D· et al. Organic Functional Conversion, Katrhzky, et al., Pomeranian Press: New York, New York, No. 5. In several embodiments, 2 an alkalization is carried out by first reacting decanoic acid with a suitable reagent (eg, via sub-(tetra) gas, light chlorine particles) (iv) to activate the filament, and then treating the activation with an ammonia source. Species. In several embodiments, the ammonia source is 38 200831478 ammonia or a solution of ammonia in a suitable solvent. Suitable solvents include tetrahydrofuran, toluene, heptane, tert-butyl methyl ether, diethyl ether, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane or water (e.g., NH4〇H). In other embodiments, the reaction is carried out by assisting deuteration by first activating the carboxylic acid by reaction with 5 S0C12, and subsequently treating the activated species with nh4oh. In still other embodiments, the reaction is carried out in toluene, benzene, ethyl acetate, dioxane, chloroform, dioxane, and combinations thereof. In other embodiments, the reaction is carried out at a temperature of from about -10 °C to 150 °C. In still other embodiments, the reaction is carried out at a temperature of from about 50 ° C to about 100 ° C. In still other embodiments, the reaction is substantially similar to that of Zhang et al., Tetrahedron Letter 45: 5229 (2004); Benz, "Synthesis of Indoleamine and Related Compounds" in Integrated Organic Synthesis, Trost, Β· M., ed., Pogman Press: New York, New York, No. 6; Bailey et al., "Indoleamine" in Integrated Organic Functional Conversion, Katritzky, et al., ed., Pogman: New State, New York, Issue 5; and PCT Bulletin W005037817. According to another embodiment, the invention provides a method of preparing a compound of formula B:

20 wherein: X is 0 to 3; y is 0 to 5; 39 200831478 Each R1 is -R, -CN, i atom or -OR; each R2 is -Ph, a halogen atom, -CN, -R or - OR; and each R is hydrogen, Cw aliphatic or Cwi aliphatic, respectively; comprising the following steps: 5 (a) providing a compound of formula C-1:

Wherein: X is 0 to 3; y is 0 to 5; 10 each R1 is _R, -CN, a halogen atom or -OR; each R2 is -Ph, a halogen atom, -CN, -R or -OR; And each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 ifi aliphatic group; and (b) treating the compound of formula C-1 with a non-racemic palmitic amine to obtain a mixture of diastereomeric 15 salts; c) selectively crystallizing one of the diastereomeric salts to obtain a mixture of diastereomerically rich salts; and (d) being rendered in a diastereomeric salt thereof The 20 formula B compound is recovered in a heterogeneous rich form. For the compounds of formula B and C-1, each of x'y'R1 and R2 is as defined above for the examples and sub-embodiments of the compounds of formula II and II. HX. 40 200831478 In the foregoing reaction step, the carboxylic acid of the formula is optically partitioned to obtain an enantiomerically enriched compound of formula B. Skilled artisans understand that a wide variety of optical segmentation conditions can be employed, and thus the present invention encompasses a wide variety of reaction conditions; generally reference is made to March, (2001) and Larock (1999). In several embodiments, 5 the palmitic amine in the optical splitting step is (R)-l-phenyl-propylamine, (-)-cinchonidine, R-(a) adrenaline, (+ ) _ Cinchonine, (a) _ strychnine, or - (-)-1-(1-naphthyl)-ethylamine. In still other embodiments, the palmitoylamine is (-)-cinchonidine. In still other embodiments, the palmitic amine is (_)-cinchonidine. In several embodiments, the content of palmitic amine relative to the racemic acid is from 3 to 2 molar equivalents, and preferably from 5 to 1 equivalent. In some embodiments, the crystallization of step (c) is carried out in acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, diethyl ether, tert-butyl methyl ether, benzene, toluene, dichloromethane. , water, etc. or a mixture thereof. In several embodiments, the acid is released in step (d) by treating the salt with hydrochloric acid or sulfuric acid. In still other embodiments, step (d) is carried out in isopropyl acetate, water or a mixture thereof. In other embodiments, the optical segmentation step is substantially similar to that of Wigerinck, P. Τ·Β·P. et al., International Patent Application No. 9929687 A1 (1999); Van Lommen, G. RE et al., European Patent The application is made in the manner described in EP 145 067 A2 (1985); or in the manner described by Schaff, T. K. et al. J. Med. Chem. 20 1983 '26 '328. In several embodiments, the invention provides a process for the preparation of a compound of formula b from a compound of formula ent-B, which comprises the step of racemizing the stereocenter to form a compound of formula C-i, as described herein. According to another embodiment, the invention provides a method of preparing a compound of formula C-ι: 41 200831478

Wherein: χ is 0 to 3; y is 0 to 5; 5 each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, _ atom, _CN, _R or -OR; R is a nitrogen, a Ci_6 aliphatic group or a Ci_6_ aliphatic group, respectively; and comprises the following steps: (a) providing a compound of formula D:

Wherein: χ is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 15 each R2 is -Ph, i atom, -CN, _R or -OR; Each R is a chlorine, a Ci_6 aliphatic group or a Ci_6_aliphatic group; and (b) a compound of the formula D is reduced to obtain the compound of the formula C-1. For the compounds of formula C-1 (e.g., C) and D, χ, y, R1 and R2 are each as defined above for the examples and sub-embodiments of the compounds of formula II and II. HX. 42 200831478 In a reaction step, the ketone moiety of the compound of formula D is reduced to sub-, and, g. Those skilled in the art understand that a wide variety of reaction conditions can be used to shift the ketone to a methylene group, thus the present invention covers a wide range of reaction conditions. In general, take the exams of March, (2〇〇1) and Larock (I"9). The appropriate reducing agent for the above reaction step 5 includes H2 (gas) with palladium or platinum catalyst, cyclohexene with Pd/C (catalyzed transfer hydrogenation), Zn/HCl, Li/NH3, Raney nickel, trialkylsulfonium House based hydrogen (eg Et3SiH), sodium borohydride or lithium aluminum hydride. Suitable solvents for the foregoing reaction steps in several embodiments are ethyl acetate, tetrahydrofuran, di "baut", or diethyl ether. In other embodiments, the reaction is carried out at a temperature of from about -25 °C to 80 °C. According to another embodiment of the invention, the invention provides a method of preparing a compound of formula D:

Wherein: X is 〇 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is _Ph, a halogen atom, -CN, -R or -〇R; And each R is hydrogen, a Cw aliphatic group or a Cwi aliphatic group; 20 comprises the following steps: U) providing a compound of formula E. 43 200831478

Wherein: x is 0 to 3; y is 0 to 5; 5 each Rl is -r, -cn, a halogen atom or _(^; each R2 is -Ph, south atom, -CN, -R or -OR And each R is hydrogen, a Cy aliphatic group or an aliphatic group; and (b) cyclizing the compound of the formula E to obtain the compound of the formula D. 10 a compound of the formula, X, y, R1 and R2 Each is as defined above for the examples and sub-embodiments of the compounds of formula II and II. HX. In this cyclization step, the compound of formula is cyclized to obtain the compound of formula D. Those skilled in the art understand that a wide variety of compounds can be used. The reaction conditions are used to cyclize the compound of formula E. Thus, the present invention encompasses a wide variety of conditions; generally reference is made to Smith 15 and March '(2001) and Larock (1999). In several embodiments, via treatment with an appropriate brownies acid The compound E can promote cyclization. Examples of the brownbinder acid include hydrochloric acid, sulfuric acid, acid-filling, trimeric acid, methic acid, and Eaton's reagent (P2 (VMeS03H), chlorosulfonic acid, camphorsulfonic acid, and - Toluenesulfonic acid. In other embodiments, additional reagents may be employed, including, for example, pentoxide 20 cans, phosphorus trichloride Five gasified phosphorus, acetyl chloride or acetic anhydride. Those skilled in the art will appreciate that certain conditions will facilitate the formation of the sulfhydryl group of the intermediate product prior to cyclization. In yet another embodiment, the reaction system uses ethyl chloroformate. Or water for 44 200831478 for solvent. In still other embodiments, the cyclization system is substantially similar to Ruhemann (1990), Gudi (1969), Cairns (1972), Stoermer (I995) or Fitzmaudce, C. Further, in accordance with another embodiment of the present invention, a method of preparing a compound of formula D is carried out in accordance with the method of U.S. Patent No. 1,262,078, filed on May 24, 1968.

Wherein: X is 0 to 3; 10 y is 〇 to 5; each R1 is -R, -CN, _ atom or -〇r; each R2 is -Ph, _ atom, _CN...foot or -〇11; And each R is hydrogen, a Cw aliphatic group or a Ci 6 nonaliphatic group; and comprises the following steps: 15 (a) providing a compound of formula F:

Wherein: X is 0 to 3; y is 〇 to 5; 20 each R1 is -R, -CN, a halogen atom or _〇R; 45 200831478 Each R2 is -Ph, i atom, -CN, -R or -OR ; each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 13⁄4 aliphatic group, and Rb is a suitable carboxylic acid protecting group; (b) removing the Rb group from the compound of the formula F to obtain the compound of the formula F-2:

Wherein = X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 10 each R2 is -Ph, i atom, -CN, _R or -OR; Each R is independently hydrogen, a Cw aliphatic group or a Ci_6 haloaliphatic group; (c) cyclizing the compound of formula F-2 to obtain a compound of formula F-3:

15 (d) Reduction of the compound of formula F-3 to obtain the compound of formula D. According to another embodiment of the invention, the invention provides a method of preparing a compound of formula E:

46 200831478 wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 5 each R2 is _Ph, a halogen atom, -CN, _R or -OR And each R is a chlorine, a Ci_6 aliphatic group or a Ci_6_ aliphatic group; and comprises the following steps: (a) providing a compound of formula F:

10 wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is _Ph, a halogen atom, _CN, _R or -OR; Each R is a nitrogen, a Ci_6 aliphatic or a Ci_6 nonaliphatic group; and Rb is a suitable carboxylic acid protecting group; (b) reducing the compound of formula F to obtain a compound of formula F-1:

Wherein: 20 X is 0 to 3; 47 200831478 y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, i atom, _CN, -R or -OR And each R is hydrogen, a Cw aliphatic group or a Cwi aliphatic group; and 5 Rb is a suitable carboxylic acid protecting group; and (c) removing the Rb group from the compound of the formula F-1 to obtain the compound of the formula E. Additionally, in accordance with another embodiment of the present invention, the present invention provides a method of preparing a compound of formula E:

Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; 15 each R2 is -Ph, i atom, -CN, -R or -OR; And each R is a nitrogen, a Ci_6 aliphatic group or an aliphatic group; and comprises the following steps: (a) providing a compound of formula F:

20 where: 48 200831478 X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is _Ph, a halogen atom, -CN, -R or - OR; 5 each R is hydrogen, a Ck aliphatic or aliphatic group; and Rb is a suitable carboxylic acid protecting group; (b) removing the Rb group from the compound of formula F to obtain the compound of formula F-2:

Where = 10 X is 0 to 3; y is 0 to 5; each R1 is -R, _CN, i atom or -OR; each R2 is -Ph, i atom, _CN, _R or _OR; and each R The compound of the formula E is obtained by respectively reducing chlorine, a Ci_6 aliphatic group or a Ci_6_aliphatic group; 15 and (c) reducing the compound of the formula F-2. For the compounds of the formulae E, F, Fd, F-2, and F-3, X, y, R1 and R2 are each as defined above for the examples and sub-embodiments of the compounds of the formula II and II. HX. In the foregoing reaction step, the double bond of the compound of the formula F is reduced to obtain a compound of the formula F-1. Further, the double bond of the compound of the formula F-2 is reduced to obtain the compound of the formula E. Alternatively, the double bond of the compound of formula F-3 is reduced to provide a compound of formula D. 49 200831478 Skilled artisans understand that a wide variety of reaction conditions can be used to reduce double bonds to single bonds, so the present invention covers a wide variety of conditions; generally reference to March, (2001) and Larock (1999). In some embodiments, the appropriate reducing agent for the foregoing reaction step is hydrogen and a palladium catalyst. Properly include, but is not limited to, palladium on carbon and palladium (II) hydroxide. In several embodiments, the hydrogenation reaction can be carried out in methanol, ethanol, ethyl acetate, or acetic acid. In still other embodiments, the hydrogenation is carried out in the presence of sulfuric acid, acetic acid, or both. In several embodiments, the hydrogenation is carried out in the presence of sulfuric acid. In still other embodiments, the hydrogenation is carried out as described in Witak, D. T. et al. J. Med. Chem. 1975, 10 18, 934. In still other embodiments, the hydrogenation reaction as previously described and illustrated herein is carried out at a pressure of about 50 psi or more; in several embodiments, the hydrogenation is carried out with heating of the reaction mixture. In other embodiments, the hydrogenation is carried out at a temperature of from about 3 ° C to about 5 (TC). In the foregoing reaction, the decanoic acid protecting group in the formula F-fluorene compound is removed by 15 to obtain the formula E. In addition, the protecting group Rb in the lamp compound is removed to obtain the compound of the formula 17_2. Those skilled in the art understand that a wide variety of reaction conditions can be used to reduce the double bond to a single bond, and thus the present invention covers a wide variety of conditions; Reference above March, (2〇〇1^LaiOck(i999). In the right-hand embodiment, the appropriate carboxylic acid protecting group for the Rb group includes, but is not limited to, fluorenyl, ethyl, tert-butyl, propylene a base, a phenyl group, a phenyl group, a trimethyl group or a second butyl dimethyl group. In other embodiments, each Rb is an ethyl group. The removal of the Rb group can, for example, facilitate the reaction by By reaction with a base (eg, sodium hydroxide, tetrabutylammonium hydroxide, etc.); or by reaction with an acid (eg, hydrochloric acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid, p--50 200831478 toluenesulfonic acid, etc.); Source of fluoride anion (eg tetrabutylammonium fluoride, fluorinated Potassium, fluorinated acridine, triethylammonium fluoride, tetrabutyltriphenyldifluoride, etc.); or by hydrogenation to promote the removal of Rb groups. In several embodiments, Rb groups The removal of the mass is enhanced by reaction with sodium hydroxide. In other embodiments, the reaction can be promoted by reaction with hydrochloric acid. In other embodiments, the reaction is promoted by reaction with HCl/AcOH. In one embodiment, the reaction is carried out at a temperature of from about 4 (TC to about 10 ° C. In several embodiments, the deprotection reaction is carried out in a suitable medium. In several embodiments, the conversion is carried out using ethanol, Methanol, isopropanol, acetic acid or tetrachloromethane is carried out as a granule or a mixture of the aforementioned solvents and/or water. In some examples, the removal of R and the reduction of olefins are carried out simultaneously. * A person understands that a number of R protecting groups can be removed by hydrogenation conditions. Thus, according to another embodiment, the preparation of the compound of formula E provides a deprotection step and the original step is carried out in one step under the same conditions.

In accordance with another embodiment of the present invention, the present invention provides a method of preparing a compound of formula F:

Wherein: X is 0 to 3; 20 y is 〇 to 5; each is -R, -CN, a halogen atom or _〇R; each R2 is _Ph, _ atom, _CN, _R or s, respectively; 200831478 Each R is hydrogen, a Ci_6 aliphatic group or a Ci_6 dentate group; the following steps are included: (a) Providing a compound of formula H:

5 wherein: X is 0 to 3; y is 0 to 5; each R1 is _R, -CN, i atom or -OR; each R2 is -Ph, a halogen atom...CN, 士 or -〇R; 10 each R is hydrogen, a Ci-6 aliphatic group or a Cl_6 haloaliphatic group, and (b) the hydrazine compound is contacted with a compound of formula G: C(0)0Rb ι|ι g C(0)0Rb to obtain The compound of formula F wherein Rb is hydrogen or a suitable carboxylic acid protecting group. In the foregoing reaction step, a compound of the formula F is obtained by a conjugate addition reaction with a compound of the formula g. Those skilled in the art understand that a wide variety of reaction conditions can be used for the conjugate addition reaction, and thus the present invention covers a wide variety of conditions; generally reference is made to March, (2〇〇1) and Larock (1999). In some embodiments, the foregoing reaction step can be carried out with or without heating in the presence or absence of a base. In some embodiments, the conjugate addition reaction is carried out in potassium carbonate, chlorination, sodium hydroxide, tetrabutylammonium hydroxide, benzyltrimethyl hydroxide 52 200831478, and triethylbenzylammonium hydroxide. M3-tetramethylguanidine, 込^二丫丫bicyclo[5·4·〇]undec-7-ene, methyl phthalocyanine, diisopropylethylamine, tetramethylethylideneamine, The reaction is carried out in the presence of hydrazine or triethylamine. In the examples, the conjugate addition reaction is carried out in the presence of triethylamine. 5 In several embodiments, the conjugate addition reaction is carried out in a suitable medium. A suitable medium is a solvent or mixture of solvents which, when combined with a reaction partner or reagent, facilitates the reaction therebetween. In some embodiments, the conversion reaction is carried out in diphenyl ether, dioxane, mountain, anisole, propyl iq, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethyl 10 decylamine, ethylene glycol, toluene. It is carried out in water, diisopropylethylamine, triethylamine, acridine, N-methylporphyrin 'acetonitrile, N-methylpyrrolidine or a mixture thereof. In several embodiments, the reaction is carried out in ethyl acetate. In other embodiments, no additional solvent was added. In still other embodiments, an excess of phenol (corresponding to the hydrazine compound) is employed as the solvent. In other embodiment 15, the reaction is carried out at a temperature between about 25 ° C and about 110 ° C. In still other embodiments, the reaction is carried out at about 50 °C. In other embodiments, the conjugated addition is similar to Ruhemann, SJ Chem. Soc. 1990, 77, 1121, Gudi, Μ·Ν· et al., Indian Chemical Journal, 1969, 7, 971, Cairns, Η· Specialized by J. Med. Chem. 1972 ' 15,583, Stoermer, Μ J. and 20 Fairiie, DP Aust J. Chem. 1995, 48, 677 and British Patent No. GB1262078. According to another embodiment, the invention provides a method of preparing a compound of formula: 53 200831478

Wherein: X is 0 to 3; y is 0 to 5; 5 each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, _ atom, -CN, -R or -OR; And each R is a chlorine, a Ci_6 aliphatic group or a Ci_6_ aliphatic group; and comprises the following steps: (a) providing a compound of formula K:

Wherein: X is 0 to 3; each R1 is -R, -CN, i atom or -OR; each R is a chlorine, a Ci_6 aliphatic group or a Ci_6 oxime group; 15 Ra is a suitable hydroxy protecting group; CG1 is a suitable coupling that facilitates the coupling of a Csp2-Csp2 coupling reaction with a transition metal medium between a Csp2 carbon bearing a CG2 coupling group; (b) contacting the compound of formula K with a compound of formula L:

20 where: 54 200831478 y is 0 to 5; each R2 is -Ph, a tooth atom, _cn, -R or -OR; and each R is hydrogen, a Cw aliphatic group or a haloaliphatic group; and CG is assisted a coupling between a Csp2 carbon attached to a csp2 carbon carrying a c〇i coupling group and a Csp:2-Csp2 coupling reaction of a transition metal medium; and (c) a compound of the formula K and the compound of the formula L The intermediate reaction product removes the Ra group to obtain the hydrazine compound. For the ruthenium, osmium and L compounds, x, y ' Ri & R2 are each as defined above for the examples and sub-embodiments of the formula 10 and the HX compound. In some embodiments, the appropriate hydroxy protecting group Ra of the compound of formula K includes esters, carbonates, sulfonates, propenyl ethers, ethers, sec-alkyl ethers, alkyl ethers, aryl olefins. Alkyl ethers and alkoxyalkyl ethers. Examples of suitable classes include formic acid S, acetic acid, propionic acid, valeric acid, crotonate, and benzoate. Specific examples of suitable esters include formic acid, benzalkonate, acetate, chloroacetate, trifluoroacetate, methoxyacetate, tris-methoxyacetate, p-Gaphenoxyacetate, 3-Pyrylpropionate, 4-ketovalerate, 4,4-(Exoethyldithio)pentanoate, pivalic acid (Trimethyl B) Acidate), crotonate, 4-methoxy-crotonate, benzoate 20, p-mentylbenzoate, 2,4,6-trimethoxybenzoate. Examples of suitable carbonates include 9-mercaptodecyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(tridecyldecyl)ethyl carbonate, 2-(phenylsulfonate) Ethyl) ethyl ester, ethylene carbonate, propylene carbonate, and p-nitrobenzyl carbonate. Examples of suitable decyl ethers include trimethyl decyl ether, triethyl sulfonyl group 55 200831478 ether, tert-butyl dimethyl decyl ether, tert-butyl diphenyl decyl ether, triisopropyl Base alkyl ethers, and other trialkyl alkyl ethers. Examples of suitable alkyl ethers include mercapto ether, benzyl ether, p-nonyloxybenzyl ether, 3,4-dimethoxy benzyl ether, triphenyl decyl ether, third butyl ether, and Propenyl ether or 5 derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2. methoxyethoxy) methyl ether, benzyloxy methyl ether, β-( Trimethyldecyl)ethoxymethyl ether, and tetrahydropyran-2-yl ether. Examples of suitable aryl ketones include benzyl ether, p-methoxy benzyl ether (ΜΡΜ), 3,4-dimethoxy benzyl bond, ortho-succinyl fluorenyl bond, p-end fluorenyl group 10 Ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2- and 4-mercaptoacridyl ether. In several embodiments, the Ra group is an aliphatic group or a Q-6 haloaliphatic group. In yet another embodiment, the Ra group is a methyl group.

Removal of the Ra group can be facilitated, for example, by reaction with a base such as sodium hydroxide, tetrabutylammonium hydroxide, or the like; or via 15 with an acid such as hydrochloric acid, acetic acid, sulfuric acid, acetic acid, Reaction of camphorsulfonic acid, TFA, p-toluenesulfonic acid or Lewis acid (eg BBrs, BC13, A1C13), etc.; use of fluoride anion sources (eg tetrabutylammonium fluoride, potassium fluoride, pyridinium fluoride, Triethylammonium fluoride, tetrabutyltriphenyldifluoroantimonate, etc.); or hydrogenation reaction to promote the removal of Ra groups. In several embodiments, the deprotection counter 20 should be carried out in a suitable medium. In some embodiments, the conversion is carried out using diphenyl ether, dioxonium, anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene, benzene. , DMSO, water, diisopropylethylamine, triethylamine, acridine, hydrazine-methylporphyrin, acetonitrile, hydrazine-methylpyrrolidine, or a mixture thereof. In several embodiments, 56 200831478

Removal of the Ra group can be facilitated by reaction with BBr3, BC13 or A1C13. In several embodiments, the removal of Ra groups is facilitated by reaction with BBr3 in toluene. In several embodiments, the reaction is carried out at a temperature between about 〇 ° C and about 10 ° C. Suitable coupling groups CG1 of the compound of formula K are selected from, but not limited to, dihydroxyboronic acids, dihydroxyborates, boranes, decanes, decyl species, zinc species, aluminum species, magnesium species, or zirconium species. In some embodiments, the CG1 of the compound of formula K is dihydroxyboronic acid, dihydroxyborate or borane. In other embodiments, the CG1 of the compound of formula K is a dihydroxyborate. Root 10 According to one aspect of the invention, CG1 in the compound of formula K is dihydroxyboronic acid. Suitable coupling groups CG2 of the compound of formula L are selected from, but not limited to, _Ch-Br, -1, and -OTf. In several embodiments, the CG2 in the compound of formula L is -Br, -I or -OTf. According to one aspect of the invention, the CG2 in the compound of formula L is -Br. According to another embodiment of the invention, there is provided a process for the preparation of a compound of formula E-1:

Wherein: X is 0 to 3; 20 each R1 is -R, -CN, a halogen atom or -OR; and each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6_ aliphatic group, respectively; comprising the following steps: 57 200831478 ( a) Providing a compound of formula F-4:

Wherein: X is 0 to 3; 5 each R1 is -R, _CN, a halogen atom or -OR; and each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group; and wherein Rb is a suitable carboxylic acid protection (b) reducing the compound of formula F-4 in an acidic medium to obtain the compound of formula F-5:

Wherein: X is 0 to 3; each R1 is _R, -CN, a halogen atom or -OR; and each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 13⁄4 aliphatic group; and 15 wherein Rb is a suitable carboxylic acid a protecting group; and (c) deprotecting the compound of formula F-5 to give the compound of formula E-1. Suitable acidic media include acetic acid, sulfuric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, squaric acid or mixtures thereof. 20 Example 58 200831478 NMR spectra were recorded on a Varian Inova 300 at 300 MHz^H and 13C), and the chemical shifts are indicated in ppm relative to the TMS internal standard. HPLC conditions for R acid versus palm purity: Column: Cairo CHIRALCEL OD-H 250x4.6^ meters, #〇DHOCE EF033 at 5 35 °C. Phase: Hexane: IPA: TFA=950: 50 Moule:! . Flow rate: 1.0 ml/min. Ultraviolet light detector: 220 nm injection volume: 1 〇 microliter. Instrument: Detector: WATERS PDA 996. Pump: Allanance 2690 System G. Equal gradient: time from 〇 minute to 3 〇 minutes. Mass spectra were recorded on a Finnigan mass spectrometer. 10 Example 1 Preparation of 2,6-dichloro-2'-methoxybiphenyl (110):

2-methoxybenzene dihydroxy-decanoic acid (1〇9) (3.51 kg, 23.1 mol, 1.37 equivalent) and 2-bromo-i,3-diphenylbenzene (1〇8) were fed in a 100 liter reactor. ) in a solution of 15 dimethoxyethane (DME, 7.64 kg, 50 w/w 〇 / 0, 16.9 mol). Dimethoxyethane (DME, 29 kg) was added to the mixture. The reaction contents were stirred to obtain a solution, and then the solution was heated to 50 °C. Into this solution, a 4·4 Μ aqueous sodium hydroxide solution (3·55 kg of sodium hydroxide in 19.0 kg of water, 5.0 eq.) was added over a period of 20 minutes, and maintained at 5 〇 ±5. The temperature of 〇. 2〇 The reaction was then heated to 70 °C over a period of 15 minutes, followed by the addition of Pd(PPh3)4 (0.41 kg, 〇35 mol, 2 mol%). The mixture was heated to reflux (heated to 80 ° C) with 15 minutes 59 200831478 hours and then stirred at 8 ° ± 2 ° C for 18 hours. At this time, the reaction was cooled to room temperature (22-25 ° C), the DME layer/water layer was separated, and the organic layer was concentrated under reduced pressure to give a brown oil. To this brown oil was added tert-butyl mercapto ether (ΤΒΜΕ) (15.0 kg) and water (12.0 kg). The mixture was heated at 5 to 33 ± 2 ° C and filtered using a R53-SP Zeta filter for 4 hours (carbonization). The amber TBME organic layer was separated. The organic layer was washed with water (2 x 12.0 kg). The TBME was removed by atmospheric distillation to obtain 16 ± 2 liters. IPA (2 x 8.0 kg) was then added to replace the TBME, and the IPA solution (8 ± 2 liters) was cooled to 〇t to 1 °C to induce crystallization. The crystals were filtered and washed with IPA (2 x 5.0 kg).

Dry at 10 45 ° C for 20 hours to obtain 3.4 kg (76%) of compound (110). 4 NMR (300 MHz, DMSOO 5 7.54 (dd, J = 0.9, 7. 8 Hz, 2H) 7.46-7.37 (m, 2H), 7.15-7.02 (m, 3H). Example 2 2', 6'- Preparation of chloro-biphenyl-2-phenol (111):

ΌΜβ Cl BBrd1.1 eq>/toluene 〇 to 5 °C, 18 h

2,6·Dichloro-2,-methoxybiphenyl (11 Å) (3 千 kg, 11.9 mol) and toluene (ΐ3·〇 kg) were added to a 5 liter reactor. The reaction was cooled to _5 ± 3. 〇, in the solution, add bbq (3·3 kg, 132 m, labor field), and hold in the solution for 30 minutes, and the dish is at _5±3C. The reaction mixture was stirred at _5 ± 3 °c for 3 Torr for 20 hrs and then slowly warmed to 2 hunger and lining for 18 hours in H, hour time (shortest time period). The reaction mixture was cooled to (iv) and carefully treated as minute time. 200831478 sterol (12·〇 kg) was added, the temperature was maintained at 5 ° C to 15 ° C, and then the reaction was heated to 40 ± 2. (: 3 hours. & The mixture should be concentrated under reduced pressure to obtain a liter, add methanol (1 〇. 〇 kg), the reaction mixture is re-concentrated, and added ethyl acetate (16 〇 kg) and water (15· 〇kg). The organic layer and the water layer are separated. The organic layer is washed with 8% NaHC〇3 (0.40 kg in 5·00 kg water), and reduced to 5±3 liters under reduced pressure, followed by decompression. Azeotrope with heptane (1 〇〇 kg χ 2) to 5 ± 3 liters. The resulting suspension was slowly cooled to 〇_5 C in a minimum of 丨 hours and maintained at this temperature for 1 hour. Washing with cold heptane (2 χ 3. 〇 kg), drying at 45 ° C for 2 hrs to give the compound (ill) (2·6 1 〇, 94 〇 / 〇). lR NMR (300 MHz, DMSO-d6) 5 9.53 (s,1H), 7.54-7.51 (m,2H), 7.41-7.35 (m,1H), 7.26-7.21 (m,1H), 7·〇2-6·85 (m,3H) 〇 Example 3 Preparation of 2-(2',6'-dichloro-biphenyl)-2-(succinic acid)ether (115):

Feed 2',6'-di-biphenyl-2-one ((111) 'W3 g, 0.431 mol), triethylamine (72 ml, 0. 518 Mo) in a 12 liter multi-neck round bottom bottle Ear, I·2 when 61 200831478 篁) and THF (1.0 liters). Ethyl methyl diester (112) (80 ml, 〇·646 mol, 1.5 eq.) was added to the mixture over a period of time. The mixture was stirred overnight (> 12 hours) at 50 C and then concentrated to one-fifth of its original amount. To the reaction mixture was added 800 ml of ethyl acetate. The organic solution was washed with 5200 ml of 10% aqueous hydrochloric acid and 3 liters of 20 ml of water, dried over anhydrous sodium sulfate and concentrated to give (113) as a brown oil (yield of oxime isomers and oxime isomers by iH NMR) 1 : 1 mixture). The crude product (113) was dissolved in 1.5 liters of ethyl acetate, and the resulting solution was hydrogenated at 50 psi (hydrogen) at 20-25 ° C using Pd(〇H) 2 (32.8 g, 20% w/w). Overnight (> 24 hours). The catalyst was removed by filtration and the filtrate was concentrated to give the crude diester (114) as a brown oil. iH NMR (300 MHz, DMSO-d6) 5 7.55-7.50 (m, 2H), 7.42-7.36 (m, 2H), 7.12-7.04 (m, 3H), 5.18-5.14 (m, 1H), 3.64 (s) , 3H), 3.49 (s, 3H), 2.88-2.56 (m, 2H). MS 383.04 [M], 400.07 [M+NH/], 15 421.00 [M+K+] A mixture of the crude product diester (114), 1.0 liters of glacial acetic acid and liter of concentrated hydrochloric acid was refluxed (90-95 ° C) for 2 hours. . After cooling to 〇 -5 ° C, and the temperature was maintained for s hrs, the precipitate was filtered and washed with 3×500 ml of water to give compound (115) (118 g, 77%) as pale white solid. 1H NMR (300 MHz, 20 DMSO-d6) 5 7.54-7.48 (m, 2H), 7.42-7.36 (m, 2H), 7.12-7 02 (m, 3H), 4.99-4.95 (m, 1H), 2.75 -2.46 (m, 2H). Example 4 Preparation of 8-(2,6-dioxa-phenyl)-4-indolyl-biting σ-end-2-weilic acid (116): 62 200831478

2. AICI3 (2.05 eq) -15 to-10° 1 h

In a 12 liter multi-necked round bottom flask (115) (867 g, 2.44 mol, 1.0 eq.), DMF (38 ml, 0.491 mol, 0.2 eq.) and 5.2 liters of dioxane. Grass mash (450 5 ml, 5.16 mol, 2.11 eq.) was added dropwise to the mixture at 0-5 ° C over 1 hour, and the mixture was stirred overnight (> 12 hours) at 20 ° C to 25 ° C. . The resulting solution was cooled to -15 ° C, and A1C13 (667 g, 5.00 mol, 2.05 equivalent) was added in portions over 30 minutes, and the reaction temperature was maintained at -15 ° C to -10 °C. The mixture was stirred at -15 ° C to -10 ° C for 30 minutes. 1.7 L of a 1.2 N aqueous hydrochloric acid solution was added dropwise to the reaction mixture to maintain the temperature below 10 °C. After complete addition, the organic phase and the aqueous phase were separated, and the organic phase was washed with 3 x 3.5 liters of water, dried over anhydrous sodium sulfate and concentrated to afford (116) as a white solid (600 g, 81%). Compound (116) was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) (57.93 (dd, J=1.8, 7·8 Hz, 1H), 7.37-7.25 (m, 3H), 7.15-7.08 (m, 2H), 15 4.82 (m, 1H), 2.91 (s, 2H). MS 334.9 [MH]. Example 5 Preparation of (±)-8-(2,6-dichloro-phenyl)-pyridin-2-carboxylic acid decylamine (117) :

(116)

Et3SiH (6 eq) THF, 65 to 70 °C 4h

(117) 63 200831478 Feed (116) (1.0 kg, 2.97 mol, 1·〇 equivalent) and TFA (5.0 liter) in a 5-liter multi-neck round bottom bottle. Triethyldecane (1.66 liters, 10.4 moles, 3.5 equivalents) was added to the mixture at 65 ° C over a period of 2.5 hours, and the reaction temperature was maintained at 65-70 °C. The mixture was stirred at the same temperature for 4 hours. After cooling to room temperature (20 ° C to 5 25 ° C) and overnight (> 12 hours), the reaction mixture was filtered, washed with 4 x 1.0 liters of heptane and dried to give (117) ( 929 g, 97%), as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 12.86 (s, 1U), 7.54-7.49 (m, 2H), 7.40-7.35 (m, 1H), 7.15-7.12 (m, 1H), 6.94-6.92 (m , 2H), 4.71-4.68 (m, 1H), 2.90-2.67 (m, 2H), 10 2.12-2.05 (m, 2H). MS 321.0 [M-H]. Example 6 Preparation of (R)-8-(2,6-dioxaphenyl)-acridine-2-carboxylic acid decylamine (R)_(118):

(ΛΗ117} Feed the racemate (117) in a 12-liter multi-neck round bottom bottle (8 gram, not 15 ears), (·)-cinchonidine (729 g, 2.48 mol, 1. 〇 )) and acetonitrile / water (9: / 4 · 8 liters). Mix the mixture to INC Η, when cooled, after hunger, form a crystal suspension, add more acetonitrile / water (9: Bu 16 liters ) to the suspension. The solution is cooled to 20-25 Χ: and maintained at this temperature for 12 hours. The crystals are washed and acetonitrile/water (9: 2 χ 2.5 liters) and suspended in i-Pr 〇Ac (ethyl 20 propylene vinegar, 4 liters), followed by the addition of aqueous 1% Ηα. The organic layer was separated to the residue. 1. (COCl) 2 (0.5 eq) EtOAc 2. NH4OH (10 eq) heptane — 30% (2 steps) 100% βθ

Loose solution (1 liter X2) was washed, then washed with water (10) and concentrated to a low amount of d. 6 liters) to obtain a suspension. For analysis, the whole sample was taken and evaporated to give a white solid (98% ee). lHNMR (300 MHz, DMSo_d6) ά 12.84 (s, iH), 7.54-7.49 (m, 2H), 7.40-7.35 (m, 1H), 7.15-7.11 (m5 1H)? 6.94-6.92 (m9 2H)? 4.71 -4.68 (m? 1H)? 2.91-2.67 (m, 2H), 2·12_2·〇5 (m, 2H). MS 321.0 [M-H]. 5 Feed DMF (38 pens, 0.496 m, 〇 2 equivalents) in a suspension of the above optically rich (R)-(117) and cool to 〇_1 (rc. Add grass in 4 minutes) Brewed chlorine (108 ml, 124 mmol, 〇·5 eq.), maintained the temperature below 15 C, then the mixture was stirred for 2 hours. In another 12 liter flask, ammonium hydroxide was fed (1·72 liters, 28 %, 12.4 moles, 5.0 equivalents) and heptanes (2.75 10 liters) 'cooled to 0-5 ° C. The acid gas solution was added to the ammonium hydroxide solution and the reaction temperature was maintained below 10 ° C. After that, the reaction was warmed to 20-25 ° C, the pH of the mixture was adjusted to pH 9-10, and the mixture was stirred for 30 minutes. The precipitate was filtered and washed with water (0.1 liters of X 2 ) and heptane ( 〇 1 liter X 2 ). The crude product (R)-(118), the crude product was re-slurried in i-Pr〇Ac (2.77 liters) at 85 ° C for 15 2 hours to obtain (R) _ (l 18), grayish white Solid (238 g, 30%, 100% ee). 4 NMR (300 MHz, DMSO-d6) 5 7.60-7.39 (m, 4H), 7·20_7·16 (m, 1H), 6.98-6.96 (m, 2H), 6.34 (s, 1H), 4.49 (dd, J = 3.6, 8.1 Hz, 1H), 2.95-2.69 (m, 2H), 2 19-1 · 85 (m, 2H) .MS 321.8 [M + H] 20 Example 7 upgrade the enantiomeric excess of (117):

65 200831478 A method for upgrading the enantiomeric excess (R)_(117) by upgrading the enantiomeric excess of cinchonidine salt prior to conversion to free acid. In order to ensure that compound II-1 (HC1) can be produced in an enantiomeric excess of more than 99%, it is desirable to optically partition the racemate (117) to obtain (R)-(>98% enantiomeric 5 excess. U7). Enantiomeric excess < 98%, enantiomeric excess < 99% of the final product II-1 (HC1). The conversion of (R)_(117) to n-i (HCl) requires an additional 5 steps. However, an upgrade of the enantiomeric excess was not achieved during this additional step. A simple method was developed to make >98% enantiomeric excess of (R)-(117). (117) Optically divided by cinchonidine to produce a salt having an enantiomeric 10 excess of about 95%. The enantiomeric excess was upgraded to > 98% by slurrying the salt in 7 parts of 9: acetonitrile: water. After filtration and drying, an enantiomeric excess was found to be 98.4%. A typical procedure is as follows: 30.0 grams (117) is dissolved in 6 parts of 9: 1 acetonitrile: water at 70-75 °C. Add 1 equivalent of (1) cinchonidine in several portions. The resulting solution was maintained for 2 hours and then cooled to room temperature. The mixture was filtered and washed with 9: 1 acetonitrile: water (4 portions). The material was dried at 60 ° C for about 4-5 hours. The HPLC of this material was shown to be about 94.9% ee. Obtained 26 5 grams of material. This material was transferred to 500 liters of simmered ’. Add 7 parts of 9: 1 acetonitrile: water. The white liquid is heated to 70_75 C ' to maintain a slurry. The mixture was maintained for 20 minutes, then cooled to room temperature over 30 minutes and stirred for another 15 minutes. The mixture was filtered and washed with 4 (2 x 2) portions of 9: 1 acetonitrile: water. After the filter cake was dried at 60 ° C for about 15 hours, the % ee of the solid was about 98.4%. The % ee of the combined mother liquor and lotion is estimated to be approximately 86.1%. After drying, the material weighed about 23.5 grams (82%). The theoretical yield is 28.66 g. Example 8 66 200831478 (±)-8-(2,6·Dichloro-phenyl)-indole-2-carboxylic acid (117) recycling:

1) NaH/THF 2) MeOH 3) 30% NaOH water/heptane

Feeding mother liquor of 8-(2,6-dichlorophenyl)-2-indolecarboxylic acid (-)-cinchonidine salt in a 100 liter reactor (46 kg in 21% solids solution, 15.6 mol) . The solution 5 was concentrated to 16 ± 2 liters under reduced pressure. Isopropyl acetate (40 kg) and bottled water (18.4 kg) were added. Hydrochloric acid 20 °Be (degree Baume, also known as muriatic acid, 32% HCl in water) was added to the mixture to adjust the pH to 1 to 2 (3.3 kg). The biphasic mixture was stirred at 20 ° C to 30 ° C for 5 minutes. Separate the layers. The organic layer was washed with dilute hydrochloric acid (1 kg of hydrochloric acid 20 ° Be in 18 kg of water) and washed three times with water (18 kg). The washed organic layer was concentrated to 12 ± 2 liters under reduced pressure. The heptanes (9.4 kg) were fed and the suspension was stirred at 19 ° C to 25 ° C for 3 hours. The solid was filtered, washed with heptane (5 kg) and dried at 50t for 10 hr to afford 4.5 g (yield: 89%) of Compound (S) - (117). 8-(2,6-Dichlorophenyl)-2-indolecarboxylic acid 15 (117) (4.5 kg, 13.9 mol) and methanol (17.1 kg) were fed in a 100 liter reactor. Sulfuric acid 66 QBe (77 g, 0.01 mol, 0.07 mol%) was added and heated to reflux for 5 h. The solution was cooled to -15 ° C to -5 ° C and maintained for 30 minutes. The solid was filtered, washed with cold methanol (3.8 kg) and dried at <RTI ID=0.0>> A suspension of 37% dispersion of sodium hydride (G83 kg, 12·8 mol, L3 equivalent) in THF (5.8 kg) was prepared in a 100 liter reactor. 8_(2,6_di-phenyl)-2-mercaptocarboxylic acid methyl ester (u7a) (3·3 kg, 9·8 mol, 丄〇5 equivalent) in THF (8·7 kg) Time was added to the hemp suspension and the mixture was maintained for hunger for i hours. Add methanol at a time (1.5 kg sodium oxide 30% (5.9 kg), mixture at 19 (: to 25) (: maintain for 3 minutes, then add bottled water (33 kg). The solution is concentrated under reduced pressure to 39 liters. Add 10 heptanes (14 kg), and the mixture is acidified to ΡΗ 12 with 2〇〇Be (5·8 kg). The suspension is held in the pit for 1 hour, then filtered and filtered. Water (5 kg) was washed twice and washed with heptane (5 kg). The filter cake was dried at 6 (TC for 12 hours to obtain 3.4 kg (67% from mother liquor): (117). (300 MHz, DMSO-d6) 5 12.86 (s, 1H), 15 7.54-7.49 (m? 2H)? 7.40-7.35 (m? 1H)? 7.15-7.12 (m9 1H)? 6.94-6.92 (m, 2H) ), 4.71-4.68 (m, 1H), 2·90_2·67 (m, 2H), 2.12-2.05 (m, 2H). MS 321.0 [MH]. Example 9 (R)-[8-(2,6) -monochloro-bens)-bito-2-yl]-methylamine and (r)_[8_(2,6-di-20 gas-stupyl)-σ克ϋ基基]-methylamine Preparation of hydrochloride (ii_i and h_i(hci)):

Nl(HCl) 68 200831478 Feed the mixture of (8)-(118) (3〇〇5g, 〇·93m) and THF (1.50L) in a 12-liter multi-neck round bottom bottle to 6yc to at least 4 Borane-THF (1.0 M, 3.26 liters, 3.26 moles, 3.5 equivalents) was added over a period of time and the temperature was maintained between 65 °C and 68 °C. The mixture was stirred and maintained at 65 ° C to 68 ° C for 3 hours and then cooled to _10 ° C to Ot:. Concentrated hydrochloric acid (0.676 L) and water (1.5 L) were then added to the reaction mixture over a period of 10 minutes. The temperature of the mixture was adjusted to 25 C to 28 ° C and maintained at this temperature for at least 12 hours. The THF (3.40 L) was distilled off under reduced pressure, and a larger amount of water (2 liters) was added to the mixture. The aqueous layer was extracted with tert-butyl methyl ether (TBME, 2 liters χ3) and basified to pH 11 with NaOH (50%, 10 0.85 kg). The aqueous layer was then extracted with TBME (2 liters x 2). The TBME layer was combined and washed with water (slurry), dehydrated with anhydrous sodium sulfate (〇1〇 kg), filtered, and TBME was distilled off under atmospheric pressure to obtain a free amine (315 g), i.e., a compound. The free amine η] (315 g, 1 〇 2 mol) and I5 TBME (3.78 liter) were fed in a 5 liter multi-neck round bottom bottle. The mixture is heated to 45t to 5〇. To the mixture, hydrochloric acid was added to isopropanol (11.6% w/w). The resulting suspension was heated to 55_6 〇〇c & at this temperature for 1 hour. The crude product crystallized from this solution was collected and washed with TBME (3×150 mL). The crude product was transferred to a 12 liter multi-necked flask 20 equipped with a temperature probe, a nitrogen gas inlet, and a condenser. Isopropyl alcohol (IPA) (5·33 liters) was added. The mixture was heated to 65-70 ° C and clarified by a 0.2 micron cartridge. The clarified mixture solution was concentrated to a small volume (1.66 liters) under atmospheric pressure and cooled to 20. (: to 25. (:, further cooled to 5 ° C. Thus, crystals of Form II were obtained. Water (66.6 g) was added to the resulting slurry and maintained at this temperature for at least 1 hour. The crystals were collected to cool isopropyl The alcohol (300 ml) was washed and dried at 2 (rc to 69 200831478 25 ° C at 25-3 mm Hg to obtain the compound Π-1 (HC1) (287.98 g, 68.6%) as a monohydrate hydrochloride. Purity 99.6%, ee 98.0%, water content 5_15%, hydrochloric acid content 9.88% (10.0% theoretical value > Μ·Ρ· 210 ° C. [0^=-1.50. lR NMR (300 MHz, DMSO-d6) δ 8.25 (s, 2Η)? 7.550-7.547 (m5 5 2Η), 7.42-7.40 (m, 1Η), 7.20-7.17 (m, 1Η), 6.99-6.94 (m, 2Η), 4.31-4.25 (m, 1H), 2.99-2.85 (m, 4H), 2.19-2.10 (m, 1H), 1.80-1.73 (m, 1H). 13C NMR (75 MHz, DMSO-d6) 5151.3, 136.4, 135.2, 135.2, 130.9, 130.6, 129.3, 128.9, 128.8, 125.1, 123.1, 121.0, 73.0, 42.3, 24.6, 23.7. MS 307.9 [M+H]. 10 Example 10 Reduction of indoleamine to amine using boraneamines:

The reduction of indoleamine to an amine can be achieved using shed amines, such as triethylamine borane, trimethylamine borane, tert-butylamine boron, diisopropyl-15-ethylamine borane. , diethyl aniline borane (DEANB), pyridinium pyrolysis and porphyrin borane. Other suitable amine boranes are well known in the art. In several embodiments, the amine borane is DEANB or triethylamine borane. In several embodiments, the reaction can be carried out neat in the amine boron sinter or in an organic solvent such as ethyl, tetrahydrofuran or 2-methyltetrahydrofuran. In several embodiments, the temperature is in the range of from 20 °C to 10 °C. In several embodiments, the temperature > 6 〇 ° C. The reaction is usually completed in > 20 hours. A typical procedure is to add the amine borane to the guanamine starting material with or without a solvent. The mixture is heated to (9)^ or 70 200831478 until the reaction is complete. Additional amine side burns are added to drive the reduction reaction to completion. In several embodiments, when the reaction is complete, the free base is not separated, but instead is directly converted to its hydrochloride as previously described. (R)_[8-(2,6-Dichloro-phenyl)-bitite_2·yl]-methylamine H j: (and Apj) 5 HPLC conditions for palm purity: Column: Cairo Selce D-RH 15〇x 4.6 Housemy' #ODRHCD-DL023 at 30 °C. Phase: [9.22 g, KPF6 in 1 liter of water pH 3.5]: acetonitrile = 650: 350 ml. Flow rate: 1 〇 ml / min. Ultraviolet light detector: 220 nm. Injection volume: 1 〇 microliter. Instrument: Detector: Watt PDA 996. Pump: Aryan 2690 System G. Equal gradient: from 10 to 30 minutes. HPLC conditions for purity: Column: SYMMETRY SHIELD RP8 3.5 microns 150 χ 4·6 mm. Momentum: A: water: acetonitrile: IN NH4OAc = 950 : 50 : 2, Β · · water: acetonitrile · IN NH4 〇 Ac = 50 : 950 : 2. Flow rate: 1·0 ml/min. Flow rate: 1.0 ml/min. Ultraviolet light detector: 220 nm. Injection volume: 10 microliters. 15 Instrument: Detector: Watt PDA 996. Pump: Aryan 2690 System G. Gradient: time: 0 minutes, 80% moving phase A, 20% moving phase B; time: 40 minutes, 10% moving phase A, 90% moving phase B; time: 50 minutes, 10% moving phase A, 90% moving Phase B; time · · 52 minutes, 80. /. Phase A, 20% phase B; time: 60 minutes, 80% phase A, 20% phase B. 2〇 [Simple description of the diagram] (None) [Explanation of main component symbols] (None) 71

Claims (1)

200831478 X. Patent application scope: 1. A method for preparing the compound of formula II: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, a functional atom, _CN, _R or _OR; and each R Respectively nitrogen, Ci_6 aliphatic or Ci_6_ aliphatic; comprising the following steps: (a) providing a compound of formula A: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, i atom or -OR; each R2 is -Ph, a halogen atom, -CN, -R or -OR; and each R Each of which is a nitrogen, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group; and (b) a reduction of the compound of the formula A to obtain the compound of the formula II. 72 200831478 2. 3. 4. 5· 6. 7. The method of claim 1, wherein the reducing step (b) uses Red-Al [贰(2-methoxyethoxy)aluminum hydride) Sodium], BH3-THF, diborane, lithium aluminum hydride or borane amine. For example, the method of claim 1 wherein X is 〇2. For example, the method of claim 1 wherein y is 2 to 3. The method of claim 1, wherein R1 is fluorine or chlorine. The method of claim 1, wherein R2 is fluorine, chlorine, Cm aliphatic or CF3. The method of claim 1, further comprising the step of: (a) providing a compound of formula B: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, _CN, a halogen atom or -OR; each R2 is -Ph, i atom, -CN, -R or -OR; R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group, respectively; and (b) isomerizing the compound of the formula B to obtain the compound of the formula A. The method of claim 7, wherein the step (b) is carried out by first activating the carboxylic acid to assist the deuteration, and then treating the living species with ammonia. 9. The method of claim 7, further comprising the step of: (a) providing a compound of formula C-1: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, i atom, _CN, -R or _OR; R is a nitrogen, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group; and (b) a compound of the formula C-1 is treated with a non-racemic pair of palmitic amine to obtain a mixture of diastereomer salts; (c) selection Crystallizing one of the diastereomeric salts to obtain a mixture of diastereomerically rich salts; and (d) enantiomerically enriched by diastereomeric salts thereof The compound of formula B is recovered in the form. 10. The method of claim 9, wherein the non-racemic palmitic amine is selected from the group consisting of (R)-l-phenyl-propylamine, (-)-cinchonidine, a group consisting of R_(-) adrenaline, (+)_cinchonine, (-)-strophine, or -(-)-1-(1-methyl)-ethylamine . 11. The method of claim 10, wherein the non-racemic palmitic amine 74 200831478 is (-) _cinchonidine. 12. The method of claim 9, wherein the method comprises the steps of: (a) providing a compound of the formula ent-B, (b) subjecting the stereocenter of the formula ent-B to racemization to obtain the formula &丄 compound. 13. The method of claim 9, wherein m comprises the following steps: (a) providing a compound of formula D: Wherein: X is 0 to 3; y is 〇 to 5; each W is -R, -CN, a halogen atom or _〇; each R2 is -Ph, i atom, -CN, seven or _〇& And each R is hydrogen, a Cl6 aliphatic group or a Ci_aliphatic group; and (b) reducing the compound of the formula D to obtain the formula c-deuterated eight. 14. If the method of patent application (10) is applied, the “_ _ _# is carried out by using H 2 (gas) and catalyst or uranium catalyst, or by catalytic transfer hydrogenation using cyclohexene and Pd/C, Zn/HG, Li/NH3, Raney Ni, trialkyl decyl hydrogen, phenyl dialkyl sulfonium alkyl, sodium borohydride, or lithium aluminum hydride. 15 · The method of claim 13 Further comprising the following steps: 75 200831478 (a) Providing a compound of formula E: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, a halogen atom, -CN, -R or -OR; Each R is an ammonia, a Ci_6 aliphatic group or a Ci_6 haloaliphatic group; and (b) the compound of formula E is cyclized to obtain the compound of formula D. 16. The method of claim 15, further comprising the steps of: (a) providing a compound of formula F: (R)X\ \ ^ Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, _CN, a halogen atom or -OR; each R2 is -Ph, a halogen atom, _CN, -R or -OR; and each R Respectively nitrogen, Ci_6 aliphatic or Ci_6 13⁄4 aliphatic; and Rb is a suitable carboxylic acid protecting group; 76 200831478 (b) Reduction of the compound of formula F to obtain a compound of formula F-1: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, i atom, -CN, _R or -OR; R is a nitrogen, a Ci-6 aliphatic or aliphatic group, respectively; and Rb is a suitable carboxylic acid protecting group; and (c) removing the Rb group from the compound of formula F-1 to obtain the compound of formula E. 17. The method of claim 16, further comprising the step of: (a) providing a compound of the formula: Wherein: X is 0 to 3; y is 0 to 5; each R1 is -R, -CN, a halogen atom or -OR; each R2 is -Ph, a halogen atom, -CN, -R or -OR; 77 200831478 Each R is a nitrogen, a Ci_6 aliphatic or a Ci_6_aliphatic group, and (b) a bismuth compound of the formula is contacted with a compound of formula G: C(0)0Rb ι|ι g C(0)0Rb wherein Rb is The compound of formula F is obtained by appropriate carboxylic acid protecting groups. 18. The method of claim 17, further comprising the step of: (a) providing a compound of formula K: (R1)X\^ private. Ra CG1 κ wherein: X is 0 to 3; each R1 is -R, -CN, a halogen atom or -OR; each R is a nitrogen, a Ci_6 aliphatic group or a Ci_6_ aliphatic group; Ra is a suitable hydroxy protecting group. And CG1 is an appropriate coupling group for assisting the coupling of the C^2 carbon to the Csp2 carbon carrying the CG2 coupling group and the Csp2_Csp2 coupling reaction of the transition metal medium; (b) contacting the compound of the formula K with the compound of the formula L; : CG2 (R2)y_^ L where: y is 0 to 5; each R is -Ph, _ atom, -CN, _R or -OR, and 78 200831478 Each R is nitrogen, Ci_6 aliphatic group or Ci_6_ The aliphatic group, and CG2 are coupling groups for assisting the Csp2-Csp2 coupling reaction of the transition metal medium between the attached Csp2 carbon and the Csp2 carbon carrying the CG1 coupling group; (c) the compound of the formula K and the formula The reaction product between the L compounds removes the Ra group to obtain the hydrazine compound. 19. The method of claim 18, wherein the Ra group is a Cw aliphatic group or a Ci_6 haloaliphatic group. 20. The method of claim 18, wherein CG1 is dihydroxyboric acid, dihydroxyborate or borane. 21. The method of claim 18, wherein CG2 is Br, I, or OTf. 22. The method of claim 18, wherein the compound of formula K is: (R2)y-K and the compound of formula L are 79 200831478 VII. Designation of representative representatives: (1) The representative representative of the case is the picture of (·). (None) (2) A brief description of the symbol of the representative figure. · 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: