AU2012202178B2 - Method for the preparation of 1-acetyl-6-amino-3, 3-dimethyl-2, 3 -dihydroindole - Google Patents

Abstract

The present invention relates to processes for preparing indoline derivatives, particularly I-acetyl-6-amino-3,3-dimethyl-2,3-dihydroindole.

Description

- 1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL :Name-of Applicant: Amgen lnc. Actual'Inventors: Anthony:King and Robert'Larsen and Tij'Li and Yuelie'Lu Address for Service is: SHELSTON IP 60 Margaret Street Telephone'No: \(02) 9777 111.1 SYDNEY NSW 2000 Facsimile.No. (02) 9241 4666 CCN: 3710000352 Attorney Code: SW Invention Title: Method for the preparation of 1-acetyl-6-amino-3, 3-dimethyl-2, 3 dihydroindole Details of Original Application No. 2009327349 dated 18 Dec 2009 The following statement is a full description of this invention, including the best method of performing it known to me/us: File: 70747AUP01 METHOD FOR THE PREPARATION OF 1-ACETYL-6-AMINO-3,3-DIMETHYL-2,3-DIHYDROINDOLE CROSS REFERENCES TO RELATED APPLICATIONS 5 The present application is a divisional application of Australian Application No. 2009327349, which is incorporated in its entirety herein by reference. 100011 This application claims the benefit of United States Provisional Application No. 61/139,152, filed on December 19, 2008, of which is hereby 10 incorporated by reference in its entirety and for all purposes as if specifically and fully set forth herein. FIELD OF THE INVENTION [0002] The present invention relates to processes for preparing indoline derivatives, particularly 1-acetyl-6-amino-3,3-dimethyl-2,3-dihydroindole. 15 BACKGROUND OF THE INVENTION [0003a] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. 100031 Indole derivatives have been and continue to be important intermediates 20 for dyestuffs and pharmaceuticals. Since it's discovery in the 1880's, Emil Fischer's synthetic method has been one of the most widely used methods for preparing indoles from aryl hydrazines. Various catalysts have been used to effect the cyclization of arylhydrazones derived from the reaction of aryl hydrazines and ketones/aldehydes. Bronsted acids including H 2

SO

4 , HCl, PPA, TFA, oxalic acid, formic acid, HI, HBr, 25 propionic acid, and AcOH, Lewis acids including ZnC1 2 , ZnBr 2 , TiCl 4 , SnCl 2 , CuCI, CuBr, and PCl 3 , and solid acids including zeolites, and montmorillonite clay, Lewis acidic ionic liquids such as 1 -butyl-pyridium chloride-3AlC1 3 and choline chloride-2ZnCI 2 and Bronsted acidic ionic liquids including BMImHSO 4 , BMImH 2

PO

4 , HMImTA, HMImBF 4 , HMImNO 3 and HMImOTf, among others, have been used. 30 [00041 However, because of the complex mechanism involved, there exists high variability in the preferred conditions for specific indoles. In other words, one set of reagents and conditions does not work best for all indoles. 10005] US Pat. No. 5179211 describes a process of preparing indoles from phenylhydrazine and ketones in the presence of less than 5 equivalents of an acid having I n a pK of 1.3-4.5 and an aqueous medium. The process preferably is carried out at a temperature of 80-110 "C. Preferably 2-4 equivalents of acid are used. 100061 Liu and Robichaud (Tet Lett. 48, 461 (2007)) describe that the use of acetic acid and a temperature of 60 "C gave indolenines in good yield. Elevated 5 temperatures led to significant side products and rearrangements. [0007] Liu et al (Org. Lett, 8, 5769 (2006)) describe that a mixture of AcOH and MsOH also functioned in a reaction with cyclohexanecarbaldehyde and phenyihydrazine whereas ZnC 2 and H 2 SO4 11, did not perform as well. A mixture of HCl in AcOH in a reaction with isobutylaldehyde led to rearrangement to form 2,3-substituted indoles. [0008] Edwards et al (Bio and Med Chem Lett, 8, 745 (1998)) describe the use of Fischer protocol (AcOH, 60 "C), reduction of indoles to indolenines, nitration and 5 hydrogenation to the amino-substituted compounds. [00091 Certain substituted indoline compounds, such as those disclosed in US Patent No. 6995162, including motesanib, have been found to be useful in treating conditions associated with angiogenesis, including the treatment of cancers. In addition, US Patent No. 6878714 describes the method of making I-acetyl-6-amino-3,3-dimethyl 10 2,3-dihydroindole using reductive Heck conditions. This route generally involves the palladium-catalyzed cyclization of allylacetamide. Liu et al. (Tet Lett, 48, 2307 (2007)) describe the synthesis of substituted indolines using the Heck cyclization. The use of palladium in such reactions adds an undesired expense that would be advantageous to avoid. Thus, there is an ongoing need for more facile and higher yielding processes for 15 preparing indoline derivatives. SUMMARY OF THE INVENTION 100101 The present invention is generally directed to processes for preparing indoline derivatives using modified Fischer indole conditions. [0010a] According to a first aspect, the present invention provides a process for 20 the formation of

CH

3

CH

3 N

H

2 N 0

H

3 C comprising -2- 0 H- CH 3 HN NH2 a) reacting H 3 C and H to form a hydrazone; b) cyclization of the hydrazone in the presence of a Fischer catalyst to form a 3H-indole, wherein the temperature of the cyclization is between -1 5*C and 5 about 30'C; c) reduction of the 3H-indole to form a 2,3-dihydro-indole; d) nitration of the 2,3-dihydro-indole to form a 6-nitro-2,3-dihydro-indole; e) acylation of the 6-nitro-2,3-dihydro-indole to form the protected 6-nitro-2,3 dihydro-indole; and 10 f conversion of the nitro group to form 6-amino-2,3-dihydro-indole. [0010b] According to a second aspect, the present invention provides a product when prepared according to the process of the first aspect. [0011] In some embodiments, the present invention is directed to processes for preparing indoline compounds, comprising the steps of: 15 0

CH

3 H

NH

2 a) reacting H3c and H to form a hydrazone; b) cyclization of the hydrazone in the presence of a Fischer catalyst to form a 3H indole; c) reduction of the 3H-indole to form a 2,3-dihydro-indole; 20 d) nitration of the 2,3-dihydro-indole to form a 6-nitro-2,3-dihydro-indole; e) acylation of the 6-nitro-2,3-dihydro-indole to form the protected 6-nitro-2,3 dihydro-indole; and f) conversion of the nitro group to form 6-amino-2,3-dihydro-indole. - 2a - 10012] In other embodiments, the processes further directed to processes for preparing a mixture

CH

3 CH, N N N of hydrazones of the formula H [(E/Z)- I -(2-methylpropylidene)-2 phenylhydrazine]. [0013] In other embodiments, the processes further directed to processes for preparing the following compound CH,

CH

3 H2N O

H

3 c [00 14] In other embodiments, the invention is directed to a non-aqueous cyclization of a mixture

CH

3 N of hydrazones of the formula H [0015] The following definitions are provided for the full understanding of terms and abbreviations used in this specification. [0016] As used heroin and in the appended claims, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "an antagonist" includes a plurality of such antagonists, and a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth. The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements. [0017] The abbreviations in the specification correspond to units of measure, techniques, properties, or compounds as follows: "min" means minutes, "h" means hour(s), "gL" means microliter(s), "mL" means milliliter(s), "mM" means millimolar, "M" means molar, "mmole" means millimole(s), "cm" means centimeters, "SEM" means standard error of the mean and "IU" means International Units. -3- [00181 It is believed the chemical formulas and names used herein correctly and accurately reflect the underlying chemical compounds. However, the nature and value of the present invention does not depend upon the theoretical correctness of these formulas, in whole or in part. Thus it is understood that the formulae uscd herein, as well as the chemical names attributed to the correspondingly indicated compounds, are not intended to limit the invention in any way, including restricting it to any specific tautomeric form or to any specific optical or geometric isomer. [00191 When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations, and subcombinations of ranges specific embodiments therein are intended to be included. [00201 When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence. GENERAL PROCEDURE 100211 Scheme A

CH

3 H 2 CH 3 H

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3 "'C N N N 02N H H

OH

3

CH

3

CH

3

CH

3 0 2 N N

H

2 N N

H

3 0 -4- [0022] For a review on the Fischer Indole Synthesis, see B. Robinson, Chem. Rev. 1963, 63, 373-401. One method of preparing the desired compounds is shown in Scheme A above. Formation of the Hydrazone and Cyclization [00231 Embodiments of the process include cyclization of the compound resulting from treatment of isobutyraldehyde with phenyihydrazine. [0024] In the process, it is possible to solubilize the phenylhydrazine first or the aldehyde first or added simultaneously. In certain embodiments of this step of the process, the phenyihydrazine is first diluted in solvent prior to the addition of the aldehyde. In certain embodiments of this step of the process, the phenythydrazine cooled to a solid prior to the addition of the aldehyde. The invention also relates to a process where an excess of isobutyraldehyde is added to the phenylhydrazine. The invention also relates to a process in an atmosphere where minimal oxygen is present, such as in a nitrogen environment. The process may include hydrazone formation carried out at a temperature range of about 10 "C and about 30 *C. Embodiments of the process include a hydrazone formation carried out at a temperature below about 20 to about 25 *C. [0025] The present invention also relates to a process where the phenylhydrazone is isolated prior to the cyclization step. The appropriate isolated phenylhydrazonc can be cyclized to form the indole as described above by treatment with acid, e.g. methanesulfonic acid. [00261 Alternatively, the hydrazone is not isolated prior to treatment with the acid. [0027] The cyclization with Fischer indole chemistry involves using a Bronsted acid as a catalyst. Suitable acids include trifluoroacetic acid (TFA), acetic acid, toluenesulfonic acid, methanesulfonic acid, difluoroacetic acid and sulfuric acid. The invention also relates to the use of methanesulfonic acid as a catalyst. [00281 Embodiments of the process include acid compounds in an amount of more then 5 equivalents per mole of the hydrazine employed. The invention also relates to the use of about 8 equivalents of acid. [00291 Embodimcnts of the process include cyclization in a non-aqueous solvent environment. Such solvents include heptane, hexane, toluene, benzene, xylenes, isopropyl alcohol, dioxane, dichloromethane, ethanol, acetonitrile and tetrahydrofuran. Alternatively, some of the catalyst acids could be used neat, without additional solvent, where the acid played the role of solvent too. Such acids include acetic acid and formic acid. The present invention also relates to a process where non-polar solvents are used, e.g. heptane, hexane, toluene, benzene and xylenes. The present invention also relates to a process where a mixture of solvents is utilized. In certain embodiments of the invention, heptane is used as the solvent. Where the term "non-aqueous" is used, it is not to intend that water is not generated by a reaction step. -5- 10030] Embodiments of the process include a cyclization carried out at a temperature of above about -15 *C and the temperature of reflux of the solution. Embodiments of the process include a cyclization carried out at a temperature of above about -15 *C and about 30 "C. The invention also relates to a cyclization carried out at a temperature of above about room temperature. The invention also relates to a cyclization carried out at a temperature that is above the melting point of the catalyst acid. The invention also relates to a process in an atmosphere where minimal oxygen is present, such as in a nitrogen environment. Formation of the indoline [00311 In certain embodiments of this step of the process, the reduction involves the use of a reducing agent that is not water sensitive. For example sodium borohydride, NaBH(OAc) 3 and sodium cyanoborohydride are acceptable. In certain embodiments of this step of the process, an excess of reducing agent is used. In certain embodiments of this step of the process, >1 to about 2 equivalents of reducing agent is used. In certain embodiments of this step of the process, about 1.2 to about 1.8 equivalents of reducing agent is used. In certain embodiments of this step of the process, about 1.2 or about 1.8 equivalents of reducing agent is used. [0032] Embodiments of the process include a reduction carried out at a temperature of above about 15 *C and about 25 *C. In certain embodiments of this step of the process, the reaction can be performed at a temperature of about room temperature. Basification can be accomplished with NaOH, ammonium hydroxide or the like. 100331 The indoline can be isolated as a salt by treatment with an acid, such as HC . Nitration [0034] Nitration of the dihydro-indole ring such as with H 2 S0 4 and fuming HNO 3 at a temperature below RT, further at a temperature of about -15 "C to about 10 *C, and preferably at about 0 *C, gives the 6-nitro-3,3-dimethyl indoline. Other methods of nitration would be acceptable too. Protection of the dihydro-ndole [00351 The free amine of the indoline can be protected such as by acetylation. The acetylation can be accomplished such as with acetyl chloride or acetic anhydride, under standard coupling chemistry, such as with DIEA, and DMAP, at a temperature of about RT, in a suitable solvent, such as DCM, DMF and/or DMAC. Conversion of the nitro group to an amine [0036] The conversion of the nitro group to an amine can be accomplished by methods known to one skilled in the art such as by reduction including by hydrogenation, such as with catalytic -6hydrogenation including treatment with hydrogen in the presence of a transition metal catalyst, e.g. Pt or sulfided Pt supported on carbon or alumina, Pd supported on carbon, barium sulfate, calcium carbonate or Raney sponge nickel. In certain embodiments of this step of the process, catalysts include 10% Pd/C. [00371 In certain embodiments of this step of the process, the hydrogenation occurs in the presence of a solvent, such as an alcohol, e.g. MeOH or EtOH, cyclic ethers, e.g. THF, and EtOAc. [0038] Alternatively, reduction of the nitro compound with iron powder, preferably at a temperature above about 50 *C, and more preferably at about 80 *C, yields the amine. Alternatively one can use 10% Pd/C in the presence of an excess of NH 4

CO

2 H. Alternatively, reduction of the nitro compound, such as with acid, for example AcOH, and zinc yields the amine. [0039] The reaction mixtures and solid samples are analyzed on an Agilent HPLC system using a Waters Symmetry Cis (150 X 4.6 cm) column with the detector set at 254 nm. The gradient eluting solvent mixture is water and MeOH containing 0.1% of TFA and starting from 90% aqueous MeOH to 60% aqueous MeOH over 15 min and then increased to 65% aqueous MeOH over the next 5 minutes at a flow rate of 1.0 mL/min. [00401 The present invention is further defined in the following Examples, in which all parts and percentages are by weight and area percent (A%) and degrees are Celsius, unless otherwise stated. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. EXAMPLES 100411 Abbreviations IPAC isopropyl acetate IPA isopropyl alcohol ACN acetonitrile NaOH sodium hydroxide Et 3 N, TEA tricthylaminc HCI hydrochloric acid Pd/C palladium/carbon THF tetrahydrofuran

H

2 hydrogen

H

2

SO

4 sulfuric acid

HNO

3 nitric acid -7- MSA, MeSO 3 H, MsOH methanesulfonic acid DCM dichloromethane, methylene chloride TFA trifluoroacetic acid

F

2 HCCOOH difluoroacetic acid PPA phosphoric acid HI hydrogen iodide HBr hydrogen bromide AcOH acetic acid ZnCI2 zinc chloride ZnBr 2 zinc bromide TiCl4 titanium tetrachloride SnCl 2 stannous chloride CuCI cuprous chloride CuBr cuprous bromide

PC

3 phosphorous trichloride A% area per cent MeOH methanol EtOH ethanol DIEA di-isopropylethylamine DMAP 4-dimcthylaminopyridino RT room temperature DMF dimethylformamide DMAC dimethylacetamide EtOAc ethyl acetate

NH

4

CO

2 H ammonium formate BMmHSO 4 1-butyl-3-methyl-imidazolium hydrogen sulphate BMImH 2

PO

4 I -butyl-3-methyl-imidazolium dihydrogen phosphate HMImTA 1-methylimidazolium hydrogen trifluoracetate HMImBF 4 I -methylimidazolium hydrogen boron tetrafluoride HMImNO 3 1-methylimidazolium hydrogen nitrate HMImOTf I-methylimidazolium hydrogen triflate -8 - EXAMPLE 1 Preparation of 3,3-dimethyl-3H-indole [the Fischer indole reaction] [0042]

CH

3 N'NH2 O N N CH3 MeSO 3 H H H 8 eq. 1eq. 1.1 eq. eq. Material / CAS# MW Quantity Mol Equiv Amount Unit phenylhydrazine /100-63-0 108.14 200 g 1.85 1.0 isobutyraldehyde/75-79-2 72.11 146.7 g 2.04 1.1 Methanesulfonic acid/78-84-2 96.1 1.422 kg 14.8 8.0 Heptane/142-82-5 114 600 mL *Based on the assay of the indolinc. [0043] Phenylhydrazine (200 g) and heptane (600 mL) were charged to a 2L dry RB-flask under nitrogen at 10- 12*C, and the vessel was degassed three times with nitrogen/vacuum, followed by the addition of isobutyraldehyde (146.7 g) dropwise at temperature <20 *C. The resulting mixture was stirred for 1 h at 18-20 *C or until 99 A% conversion. To a 5 L reactor, MSA (1.422 kg) was charged followed by slow addition of the reaction mixture prepared in the 2L RB-flask. The reaction mixture was stirred overnight at 18-20 "C to afford a crude mixture of 3,3-dimethyl-3H-indole. (<2 A% for the starting material, Assay: 91% yield). [0044] The following Fischer indole reaction studies (Example IA-IS) were prepared by the method described above, unless changes in solvents, acids and temperatures which are specifically described. For examples 1 A-I D, I J- 1K and 10 - IS, the hydrazone was generated in situ. [0045] A: TFA/DCM/35 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (5.41 g), 400 mL DCM, isobutyraldehyde (4.69 g), TFA (11.5 mL), 17h at 35 *C, only 5 A% desired product. [00461 B: TFA/ACN/35 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (5.41 g), 50 mL ACN, isobutyraldehyde (4.69 g), TFA (11.5 mL), 17h at 35 *C, only 15 A% desired product. [00471 C: TFA/THF/35 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (5.41 g), 50 mL ACN, isobutyraldehyde (4.69 g), TFA (11.5 mL), 17h at 35 *C, only 10 A% desired product. -9- [00481 D: AcOH/60 "C: The same procedure as the above Fischer indole reaction, phenylhydrazine (5.40 g), isobutyraldehyde (3.97 g), AcOH (9 g), 17h at 60 *C, only 57 A% desired product. [0049] J: MSA/toluene/20*C: The same procedure as the above Fischer indole reaction, phenylhydrazine (2.16 g), isobutyraldehyde (1.59 g), 40 mL toluene and MSA (5.77 g), 17h at 20 *C, there is 90 A% desired product. [0050] K: MSA/heptane/20 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (8.64 g), isobutyraldehyde (6.36 g), 24 mL heptane and MSA (38.4 g), 2 days at 20 "C, there is 92 A% desired product. [00511 0: TFA/DCM/25 "C: The same procedure as the above Fischer indole reaction, phenylhydrazine (2.163 g), 50 mL DCM, isobutyraldehyde (1.59 g), TFA (4.62 mL), 17h at rt, provided <1 A% desired product. [0052] P: Formic Acid/THF/20 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (2.163 g), isobutyraldehyde (1.59 g), 40 mL THF and formic acid (2.76 g, 3g Sieve), 17h at 20 "C, 2h at 35 *C, there is 3 A% desired product. [0053] Q: MSA/heptane/25 "C: The same procedure as the above Fischer indole reaction, phcnylhydrazine (100 g), 300 mL heptane, isobutyraldehyde (73.35 g), MSA (711.14 g), 17h at 18-25 "C, 91 A% desired product. [0054] R: MSA/heptane/30 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (4.32 g), 12 mL heptane, isobutyraldehyde (3.18 g), MSA (19.2 g), 17h at 30 "C, 85 A% desired product. [0055] S: TFA/60 *C: The same procedure as the above Fischer indole reaction, phenylhydrazine (5.40 g), isobutyraldehyde (3.97 g), TFA (17 g), 17h at 60 "C provided <I A% desired product. EXAMPLE 2 Preparation of hydrazone [0056] Phenylhydrazine (21.64 g), 10 g of molecular sieve and THF (100 ml) were charged to a 240 mL dry RB-flask under nitrogen at 0-5 'C, and the vessel was then degassed three times with nitrogen/vacuum, followed by the addition of isobutylaldehyde (15.86 g). The resulting reaction mixture was stirred for 0.5 h (99A% conversion). The sieve was filtered off and the THF was removed under vacuum to afford the hydrazone as an oil (38g). [0057] For examples lE-1I and IL-IN, the cyclization was performed on isolated hydrazone from Example 2 directly. [0058] E: TFA/IPAC/40 *C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 20 mL IPAC, TFA (3.42 g), 17h at 40 "C provided <I A% desired product. - 10 - [00591 F: HgSO 4 /THF/40 *C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 15 mL THF and 50% H 2

SO

4 (2.94 g), 3h at 40 *C, there is 40 A% desired product. [0060] G: p-Toluenesulfonic acid/THF/40 *C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 15 mL THF and p-toluenesulfonic acid (5.7 g), 3h at 40*C, there is 58 A% desired product. [0061] H: MSA/THF/40 "C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 15 mL THF and MSA (1.45 g), 3h at 40 "C, there is 60 A% desired product. [0062] 1: F2CHCOOHJTHF/40 *C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 15 mL THF and F 2 CHCOOH (1.44 g), 3h at 40 "C, there is 20 A% desired product. [00631 L: AcOH/40 'C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), AcOH (5 mL), lh at T, 24h at 40 "C, provided 20 A% desired product. [0064] M: Formic acid/70 "C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), formic acid (5 mL), 17h at 70 "C provided <1 A% desired product. [00651 N: TFA/Toluene/48 "C: The same procedure as the above Fischer indole reaction, phenylhydrazone (1.62 g), 20 mL toluene, TFA (3.42 g), 17h at 48 *C provided <1 A% desired product. - 11 - Table I # Solvent Catalyst Temp *C A% Yield I heptane MSA 20 98 1A DCM TFA 35 5 1B ACN TFA 35 15 1C THF TFA 35 10 ID none AcOH 60 57 1E IPAC TFA 40 <1 IF THF H 2

SO

4 40 40 1 G THF p-Toluenesulfonic acid 40 58 1H THF MSA 40 60 11 THF F 2 CHCOOH 40 20 IJ toluene MSA 20 90 1K heptane MSA 20 92 IL. none AcOH 40 20 1M. none Formic acid 70 <1 IN toluene TFA 48 <1 10 DCM TFA rt <1 IP. THF Formic acid 20/35 3 1Q heptane MSA 25 91 IR heptane MSA 30 85 iS none TFA 60 <1 -12 - EXAMPLE 3 Preparation of 3, 3-dimethylindoline HCI salt [00661 NaBH 4 1.2 eq.

NH

4 0H 5.5 eq. H 1eq. 1 eq. HCI 1.3 eq. CN H HCI 1 eq. Material / CAS# MW Quantity Mol Equiv Amount Unit 3,3-dimethyl-3H-indole Sodium borohydride/16940-66-2 37.83 84 g 2.22 1.2 Ammonium hydroxide/1336-21-6 35.05 943 mL 15.7 8.5 IPAC/110-19-0 116.16 600 mL Heptane/142-82-5 114 800 mL 5 N HCI/IPA/7647-01- 36.5 364 mL 1.85 1.3* IPA/67-63-0 62.11 236 mL D I water 18 1.18 L Brine 58.5 80 mL [00671 The resulting mixture from Example 1 was treated with a slow addition of a solution of NaBH 4 (84 g) in 400 mL DI basified with 5N NaOH (pH.-l3) water in 3h at a temperature below 10 "C, then warmed to about room temperature. The reaction was worked up by adjusting pH to 8 with 14.5N

NH

4 0H and the phases were then separated. The aqueous phase was extracted with IPAC (300 mL x 2). The combined organic phase was washed with DI water (80 mL) and saturated brine (80 mL) to give the corresponding indoline solution (containing 231 g of 3,3-dimethylindoline, 85% assay yield.) [00681 To this indoline solution (in heptane/IPAC) was added 194 mL propan-2-ol, followed by the addition of 5 N HCI in IPA (408 mL) to form a suspension, which was stirred for 2h before filtration. The wet cake was then washed with heptane (100 mL x2) to afford the 3,3-dimethylindoline HCI salt. (255.6 g, 75.5% yield, 98.4 A% for the HCI salt). - 13 - Example 4 Preparation of 3, 3-dimethyl-6-nitroindoline [0069] + H 2

SO

4 + HNO3 -15 - 0 OC H HCI H (1 eq.) (13.3 eq.) (1.1 eq.) (1 eq.) Material / CAS# MW Quantity Mol Equiv Amount Unit 3,3-dimethylindoline HCI 183.7 200 g 1.089 1.0

H

2 SO4/7664-93-9 98 1419 g 14.48 13.3 HN03/7697-37-2 63 75.6 g 1.20 1.1 IPAC/110-19-0 116.16 800 mL Ammonium hydroxide/1336-21-6 35.05 2184 mL 31.66 29.1 D.I. Watcr 18 600 mL Brine 58.5 400 mL [00701 H 2

SO

4 (1.42 kg) and 3, 3-dimethylindoline HCI salt (Example 3, 200 g) were charged to a dry 5L RB-flask under nitrogen at 20-25 *C. The reaction mixture was cooled to -15 to 10 *C. A solution of HNO 3 (75.6 g) in water (18.89 g) was added drop-wise. The resulting reaction mixture was stirred for lh. The mixture was transferred into a mixture of 2.084 L of 30% NH 4 0H and 600 mL of water at 0-5 *C. The pH was adjusted to 8-9 with NH 4 0H, and after the addition of 800 mL of IPAC, phases were separated. The aqueous phase was extracted with IPAC (400 mL). The combined organic phase was washed with saturated brine (400 mL) to give a solution of 3, 3-dimethyl-6-nitroindoline. (190.5g, 91%, 94 A%). Example 5 Preparation of 1-(3, 3-dimethyl-6-nitroindoline-1 y)ethanone [0071] 0 C + Et 3 N 0-25 0 C H ~IPAC 2 N (1 eq.) (2 eq.) (2 eq.) (1 eq.) - 14 - Material / CAS# MW Quantity Mol Equiv Amount Unit 3, 3-dimethyl-6-nitroindoline 192.2 190 g 0.99 1.0 Acetyl chloride/75-36-5 78.5 155.6 g 1.98 2 Et 3 N/121-44-8 101.2 200.6 g 1.98 2 IPAC/l10-19-0 116.16 1200 mL Heptane/142-82-5 200 mL DT water 1600 mL [00721 A solution of 3, 3-dimethyl-6-nitroindoline (Example 4, 190.5 g) in 1200 mL IPAC, Et 3 N (200.6 g) was charged to a I -L jacketed reactor, followed by the drop-wise addition of acetyl chloride (155.4 g) while maintaining reaction temperature <25 *C. The reaction contents were stirred for I h at 20 25 *C. 1200 mL D.I. water was charged slowly at T<30 *C to form a suspension. The product was isolated by filtration. Wet cake was washed with D.I. water (200 mL x 2) and heptane (200 mL), and was dried at 50 "C under vacuum until constant weight. (193 g, 83.2 wt % adjusted yield, 99.15 A%, 99.5 wt% (dry)) Example 6 Preparation of 1-(6-amino-3,3-dimethyl-indoli n-1-1 y)ethanone [00731 60 *C N. + H 2 +10% Pd/C 21. 0 2 N N 30 PSI H 2 N N O O (1eq.) (3 eq.) (5 wt%) (1eq.) Material i CAS# MW Quantity Mol Equiv Amount Unit l-(3,3-dimethyl-6-nitro 234.2 50 g 213.5 1.0 indolin- I -yl)ethanone 5%Pd/C (50% wet)/ 14-22 1.0 g 10% THF/109-99-9 500 mL Hydrogen/142-82-5 2.0 0.43 g Toluene/108-88-3 200 mL DI water 200 mL [00741 1-(3, 3-Dimethyl-6-nitroindoline-]y)ethanone (Example 5, 50 g), 5% Pd/C (I g, 50% wet) and THF (200 mL) were charged to a 400 mL hydrogenation reactor. The slurry was degassed with - 15 vacuum/hydrogen three times and stirred for 6 h at 60 "C under hydrogen (30 PSI). The resulting mixture was filtered through a thin layer of CeliteTm and the cake was washed with THF (150 mL x 2). The filtrate and washes were combined and concentrated in vacuo, followed by addition of toluene (150 mL). The product was isolated by filtration and the wet cake was washed with D.I. water (100 mL x 2) and 50 mL toluene to afford l-(6-amino-3, 3-dimethyl-indolin- 1 -yl)ethanone (38.5 g, 94% yield, >99.9 A%, 100 wt%/). [00751 When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges specific embodiments therein are intended to be included. [0076] The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in their entireties. [0077] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention. - 16 -

Claims (14)

1. A process for the formation of CH 3 CH 3 N H 2 N H 3 C comprising 5 0 CH 3 H NH 2 a) reacting H 3 C and H to form a hydrazone; b) cyclization of the hydrazone in the presence of a Fischer catalyst to form a 3H-indole, wherein the temperature of the cyclization is between -15 0 C and about 30'C; 10 c) reduction of the 3H-indole to form a 2,3-dihydro-indole; d) nitration of the 2,3-dihydro-indole to form a 6-nitro-2,3-dihydro-indole; e) acylation of the 6-nitro-2,3-dihydro-indole to form the protected 6-nitro-2,3 dihydro-indole; and f) conversion of the nitro group to form 6-amino-2,3-dihydro-indole. 15

2. The process of claim 1 wherein the Fischer indole catalyst is methanesulfonic acid.

3. The process of claim I wherein the Fischer indole catalyst comprises at least one equivalent of methanesulfonic acid. 20

4. The process of claim I wherein the cyclization is at a temperature of about 20 "C.

5. The process of claim I wherein the cyclization comprises a solvent selected from heptane, hexane, toluene, benzene and xylenes. 25 - 17-

6. The process of claim 1 wherein the reduction comprises treatment with sodium cyanoborohydride or sodium borohydride.

7. The process of claim 1 wherein the reduction is at a temperature of about room 5 temperature.

8. The process of claim 1 wherein the nitration comprises treatment with HNO 3 and sulfuric acid. 10

9. The process of claim 1 wherein acylation comprises treatment with acetyl chloride.

10. The process of claim I wherein the reduction of the nitro group comprises hydrogenation. 15

11. The process of claim 5 wherein the solvent is heptane.

12. A product when prepared according to the process of any one of claims I to 11.

13. A process according to claim 1, substantially as herein described with reference to 20 any one or more of the examples but excluding comparative examples.

14. A product according to claim 12, substantially as herein described with reference to any one or more of the examples but excluding comparative examples. 25 - 18 -