WO2007049124A1

WO2007049124A1 - Method of making 8-fluoro-naphthalen-1-ylamine and related compounds

Info

Publication number: WO2007049124A1
Application number: PCT/IB2006/002979
Authority: WO
Inventors: Zhijian Zhu
Original assignee: Pfizer Products Inc.
Priority date: 2005-10-24
Filing date: 2006-10-13
Publication date: 2007-05-03
Also published as: AR056154A1; TW200800890A; JP2007119461A

Abstract

A process is described for preparing 8-flouro-napthalen-l-ylamine comprising reacting lH-naphtlio[l,8-de][l,2,3]triazine with hydrogen fluoride or a complex of hydrogen fluoride and an n-donor base. A process is also set forth for using 8-fluoro- naphthalen-1-ylamine produced as described above in the preparation of l-(8-fluoro- napthalen-l-yl)-piperazine, which can be used as an intermediate in the production of 7- { 4- [4-(8-fluoro-napthalen- 1 -yl)-piperazin- 1 -yl] -butoxy } -3 ,4-dihydro- IH- [l,8]naphthyridin-2-one, a D2 partial agonist indicated for possible use in the treatment of schizophrenia.

Description

METHOD OF MAKING δ-FLUORO-NAPHTHALEN- 1 -YLAMINE AND RELATED

COMPOUNDS FIELD OF THE INVENTION

[0001] The present invention relates to methods of preparing 8-fluoro-naphthalen-l- ylamine, an 8-halo-naphthalen-l-ylamine, and to the use of such compounds as intermediates in the synthesis of 7-{4-[4-(8-fluoro-napthalen-l-yl)-piperazin-l-yl]- butoxy } -3 ,4-dihydro- IH- [ 1 ,8]naphthyridin-2-one.

BACKGROUND

[0002] US Patent Application Publication 2005/0043309Al (Example A66) discloses a process for synthesis of 7-{4-[4-(8-fluoro-napthalen-l-yl)-piρerazin-l-yl]-butoxy}-3,4- dihydro-lH-[l,8]naphthyridin-2-one, a dopamine D₂ partial agonist indicated for use in the treatment of schizophrenia, in which l-(8-fluoro-naphthalen-l-yl)-piperazine is used as an intermediate. Unfortunately, the synthesis process used to make that particular intermediate is not suitable for making large quantities of the product due to its high cost and difficulties in controlling the operation. Specifically, in the first step of the process 8- bromo-naphthalene-1-carboxylic acid, a very expensive compound, was used to make 8- bromo-naphthalene-1-ylamine through a Curtis rearrangement reaction. The large amount of heat released in the process makes safe operation difficult. A Schiemann diazotization/fluoro-dediazotization reaction was used in the second step of the process to produce l-bromo-8-fluoro-naphthalene. The product of that reaction was then used to make the l-(8-fluoro-naphthalen-l-yl)-piperazine intermediate.

[0003] One could contemplate making l-(8-fluoro-naphthalen-l-yl)-piperazine from another 8-halo-naphthalen-l-ylamine intermediate, 8-fluoro-naphthalen-l-ylamine, by the formation of piperazine with the use of inexpensive compounds. However, methods for making that particular intermediate disclosed in the literature involve numerous steps, produce many impurities, or utilize labile compounds. Figure 1, below, illustrates several methods for making 8-fluoro-naphthalen-l-ylamine (1) disclosed in the literature. One such reference describes the preparation of compound 1 from l-fluoro-8-nitronaphthalene (3) by iron reduction (Bull. Soc. Chim. BeIg, 1966, 75, 577-581). Figure 1 also illustrates methods for making compound 1 from compound 4 disclosed in the literature. [0004] Figure 1

[0005] In one method illustrated in Figure 1, compound 3 was prepared by nitration of 1-fluoronaphthalene (6) {Israel Journal of Chemistry, 1977, 16, 299-303). However, the nitration gave a mixture of l-fluoro-2-nitronaphthalene, l-fluoro-4-nitronaphthalene and 3, and the products were separated by column chromatography.

[0006] In another method illustrated in Figure 1, compound 3 was prepared from 8- nitro-1-naphthalylamine (5) through a Schiemann reaction (Bull. Soc. CMm. BeIg, 1966, 75, 577-581). However, the nitration of 1-naphthylamine (8) gave only 38% yield of 5, together with the generation of 5-nitro- 1-naphthylamine (Journal of the Chemical Society, 1939, 348). Compound 5 has also been prepared by mono-reduction of 1,8- dinitronaphthalene (7) (Collection of Czechoslovak Chemical Communications, 1929, 1, 360). Compound 7 is both heat and shock sensitive, which limits its utility, particularly, in large scale preparations.

[0007] In another method illustrated in Figure 1, compound 1 could be prepared from 8-fluoro-l-naphthalenecarboxylic acid (2) through a Curtis or Hoffmann rearrangement reaction. However, one reference discloses that it took five synthesis steps to prepare compound 2 from ethyl (o-fluorophenyl)acetate (4) (Journal of Organic Chemistry, 2002, 67, 1171-1177).

[0008] As can be seen, none of the reaction schemes illustrated or described above are suitable for a practical, safe, and economic preparation of 8-fluoro-naphthalen-l-ylamine, a useful intermediate that could be used in the synthesis of compounds such as l-(8- fluoro-naphthalen- 1 -yl)-piperazine or 7- { 4- [4-(8-fluoro-napthalen- l-yl)-piperazin- 1 -yl]- butoxy } -3,4-dihydro- lH-[ 1 ,8]naphthyridin-2-one.

[0009] German patent DE 147852 disclosed that lH-naphtho[l,8-de][l,2,3]triazine could be converted to 8-chloro-l-aminonaphthalene upon exposure to concentrated hydrochloric acid and hydrogen chloride gas in the presence of copper with heating. However, one would not expect to be able to modify that process to displace the triazine with fluoride to make 8-fluoro-napthalen-l-ylamine, given the fact that fluoride is less nucleophilic than chloride.

BRIEF SUMMARY OF THE INVENTION

[0010] The present invention relates to a method of preparing 8-flouro-napthalen-l- ylamine. The method comprises reacting lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or with a complex of hydrogen fluoride and an n-donor base. The present invention further relates to a method of preparing l-(8-fluoro-napthalen-l-yl)-piperazine from 8-fluoro-naphthalen-l-ylamine.

[0011] The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Examples of "alkyl" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0012] The term "alkoxy", as used herein, unless otherwise indicated, means "alkyl-O- ", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.

[0013] The terms "halo" and "halogen", as used herein, unless otherwise indicated, include, fluoro, chloro, bromo and iodo.

DETAILED DESCRIPTION OF THE INVENTION

[0014] In one embodiment, the present invention relates to a method of preparing 8- flouro-napthahlen-1-ylamine from lH-naphtho[l,8-de][l,2,3]triazine by reacting the triazine with hydrogen fluoride or with a complex of hydrogen fluoride and an n-donor base. [0015] In another embodiment, the n-donor base is selected from the group consisting of tetrahydrofuran, an amine, an amide, a carbamic acid, an ester, a trialkylphosphine, or an alcohol. The n-donor base is more preferably a compound of formula 1:

wherein R¹ is hydrogen, hydroxyl, amino, nitro, halo, C₁-C₅ alkyl, or C₁-C₅ alkoxy. The compound of formula 1 is preferably pyridine. For a discussion of methods of using hydrogen fluoride and complexes of hydrogen fluoride and n-donor bases as fluorinating reagents of other compounds see Journal of Organic Chemistry, 1979, 44, 3872 and references cited therein.

[0016] As illustrated in Example 2, below, the conversion of lH-naphtho[l,8- de][l,2,3]triazine to 8-flouro-napthahlen-l-ylamine according to the method of the present invention can be accomplished using a complex of hydrogen fluoride and pyridine under more mild reaction conditions than were used to convert the same triazine to 8-chloro- napthalen-1-ylamine as described in DE 147852. This is surprising because fluoride is less nucleophilic than chloride. Additionally, it appears that in the process of the present invention, lH-naphtho[l,8-de][l,2,3]triazine behaves like a stabilized diazonium compound, allowing the introduction of a fluoro group but with much reduced thermo instability. The differential scanning calorimetry ("DSC") analysis of lH-naphtho[l,8- de][l,2,3]triazine carried out as described in Example 1, below, showed an onset temperature of 24O⁰C with energy of 817J/g. This indicates that the compound has a much greater safety margin for handling than other diazonium compounds. Additionally, no column purification is required in order to complete the conversion from lH-naphtho[l,8- de][l,2,3]triazine to 8-flouro-napthahlen-l-ylamine.

[0017] When pyridine is used as the n-donor base in a hydrogen fluoride/n-donor base complex in the embodiment of the present method described above, the ratio of hydrogen fluoride to pyridine used in the complex is preferably from 70% hydrogen fluoride and 30% pyridine to 57% hydrogen fluoride and 43% pyridine, more preferably 70% hydrogen fluoride and 30% pyridine, (w/w, relative to the total weight of the complex) [0018] In another embodiment of the present invention, when lH-naphtho[l,8- de][l,2,3]triazine is reacted with hydrogen fluoride or a complex of hydrogen fluoride and an n-donor base as described above, it is preferably done at a temperature between -30⁰C to 150°C, more preferably at a temperature of about 5°C to 55°C, even more preferably at a temperature of about 2O⁰C to 3O⁰C.

[0019] In another embodiment, the reaction of lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or a complex of hydrogen fluoride and an n-donor base is carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of 2-methoxyethanol, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydofuran, 1,2- dimethoxyethane, diethyleneglycol dimethyl ether, toluene, chlorobenzene, dichlorobenzene, and dichloromethane, dichloroethane.

[0020] Any one of a number of methods known in the art are suitable for use in making the lH-naphtho[l,8-de][l,2,3]triazine used in the present invention. The IH- naphtho[l,8-de][l,2,3]triazine is preferably prepared from 1,8-diaminonaρhthalene. A suitable procedure for preparing lH-naphtho[l,8-de][l,2,3]triazine from 1,8- diaminonaphthalene is described in Journal of the Chemical Society, 1969, 756. 1,8- Diaminonaphthalene is an inexpensive starting material for making 8-flouro-napthahlen-l- ylamine (via a lH-naphtho[l,8-de][l,2,3]triazine intermediate) compared to 8-bromo- naphthalene-1-carboxylic acid, the starting material in the process for making l-(8-fluoro- naphthalen-l-yl)piperazine disclosed in Example A66 of US2005/0043309A1. Furthermore, the synthesis of 8-fluoro-naphthalen-l-ylamine using the method of the present invention requires fewer synthesis steps, fewer purification steps, and milder reaction conditions than methods described in the literature.

[0021] In another embodiment, the process of the present invention further comprises reacting the 8-fluoro-l-aminonaphthalene, produced as described above, with bis(2- chloroenthylamine hydrochloride to produce l-(8-fluoro-naphthalen-l-yl)piperizine. A preferred embodiment of this process, starting with 1,8-diaminonaphthalene, is illustrated in the reaction scheme of Figure 2, below:

[0022] Figure 2

NH₂ NH₂

[0023] In the process of making 8-flouro-napthahlen-l-ylamine illustrated in Figure 1 8-flouro-napthahlen-l-ylamine is reacted with the bis(2-chloroenthyl)amine hydrochloride in the presence of tetrabutylammonium iodide. This last reaction step preferably takes place in a mixture of hexylalcohol and chlorobenzene at reflux, as shown in Figure 2. [0024] The present invention is further illustrated by the following examples. These examples are intended to be illustrative of the invention and should not be used to limit or restrict its scope. In the examples below, the term "room temperature" refers to a temperature of 20°C to 27°C.

EXAMPLES [0025] Example 1 - Preparation of lH-Naphtho[l,8-de][l,2,3]triazine

[0026] 1,8-diaminonaphthalene (25Og, 1.58 mole) was dissolved in a mixture of acetic acid (500 mL) and ethanol (2500 mL) under nitrogen at room temperature. Isoamyl nitrite (208.1 mL, 1.55 mole, 0.98 eq) was then added dropwise over a period of 3.5 hours with the temperature of the reaction mixture maintained between 18⁰C and 21°C. After the addition, the resulting red suspension was stirred at room temperature for 19 hours. The solid was collected by filtration, washed with ethanol (2 x 500 mL) and dried under vacuum to give lH-naphtho[l,8-de][l,2,3]triazine as a red crystalline solid (235.86g, 88%). IH NMR (400 MHz, OMSO-D6) δ ppm 13.24 (s, IH), 7.24 (m, 2H), 7.11 (m, IH), 7.01 (d, J = 8.40 Hz, IH), 6.86 (dd, /= 5.37, 2.64 Hz, IH), 6.10 (d, / = 7.23 Hz, IH). CHN analysis: calc. for C₁₀H₇N₃: C% 70.99, H% 4.17, N% 24.84; found: C% 70.62, H% 4.06, N% 24.46.

[0027] Example 2 - Preparation of 8-FIuoro-naphthalen-l-ylamine:

HF/pyridine

[0028] Hydrogen fluoride-pyridine (70% HF/30% pyridine, 400 niL) was placed in a container and cooled in an ice bath. lH-Naphtho[l,8-de][l,2,3]triazine (100 g, 0.59 mole) was added slowly. After the addition, the container was rinsed with additional 100 g of hydrogen fluoride-pyridine to wash down the solid on the sidewall of the container. The container was sealed and connected to a nitrogen line. The solution was stirred under nitrogen at room temperature for 7 days. High pressure liquid chromatography ("HPLC") analysis showed all starting material had disappeared by the end of that period, with 94% product purity. The reaction was cooled in ice bath. Once the temperature was below 10°C, potassium hydroxide ("KOH") (45w%, 1.35 L) was slowly added with temperature maintained below 35°C. The final pH was about 11.

[0029] The resulting mixture was diluted with ethyl acetate ("EtOAc") (500 mL) and stirred for 20 minutes, and product isolated from the mixture through a series of separation steps. The mixture was transferred to a 6-L separatory funnel through suction. The aqueous layer was separated and removed. The organic layer and emulsion interface were filtered through Celite^® (diatomaceous earth) to remove solid. The filtering cake was washed with ethyl acetate (2 X 200 mL). The bi-layer filtrate (now nicely separated) was separated. The organic layer was washed twice with a mix of saturated sodium chloride (300 mL), water (300 mL) and saturated sodium bicarbonate (300 mL); then saturated sodium chloride (300 mL). The organic layer was then degassed by bubbling nitrogen for 20 minutes to remove oxygen and prevent oxidation. The solution was stirred under nitrogen with activated carbon (Sigma-Aldrich, 242276, Darco, G-60, 100 mesh, 50 g) for 5 hours, and additional activated carbon (50g) overnight. The activated carbon was removed by filtration through Celite^®, the solid cake was washed with EtOAc (2 x 300 mL). The filtrate (red-wine color) was concentrated to give an oil, which was azeotroped with chlorobenzene twice (2 x 500 mL). The oil was solidified after sitting at room temperature overnight. The solid was further dried under vacuum to give 8-fluoro- naρhthalen-1-ylamine as a red-brown solid (86.1g, 90.4%). IH NMR (400 MHz, DMSO- D6) δ ppm 7.48 (dd, J = 8Hz, IH), 7.27 (m, IH), 7.19 (t, IH), 7.03 (m, 2H), 6.65 (dd, J = 8Hz, IH), 5.66 (s, 2H). CHN Analysis: calc. for C₁₀H₈FN: C% 74.52, H% 5.00, N% 8.69; Found: C% 74.36, H% 4.92, N% 8.79.

[0030] Example 3 - Preparation of l-(8-Fluoro-naphthalen-l-yl)piperazine Hydrochloride

Bis(chloroethyl)amine HCI Bu₄NI (0.5eq), hexyl alcohol chlorobenzene, reflux

[0031] 8-Flouro-napthahlen-l-ylamine (168.86 g, 1.048 mole) was mixed with bis(2- chloroethyl)amine hydrochloride (Aldrich, B38503, 202.O g, 1.13 mol, 1.08 eq), tetrabutylammonium iodide (Aldrich, 140775, 193.5 g, 0.524 mmol, 0.5 eq) and hexyl alcohol (Aldrich, 100 mL) in anhydrous chlorobenzene (Aldrich, 1950 mL). The mixture was degassed by bubbling nitrogen for 20 minutes. The mixture was then heated to reflux under nitrogen for 74 hours to give a light brown suspension. The progress of the reaction was checked by HPLC. The suspension was slowly cooled to room temperature with gentle stirring overnight to give a nice brown suspension.

[0032] The solid was collected by filtration, washed with chlorobenzene (300 mL), toluene (300 mL), dried under vacuum at room temperature for 24 hours to give a yellow solid. The crude product was slurried in CH₃CN (2x500mL) at room temperature for 4 to 5 hours. The solid was collected by filtration, dried under vacuum at room temperature to give l-(8-fluoro-naphthalen-l-yl)piperazine hydrochloride as a yellow solid (213.52 g, 76.4%). IH NMR (400 MHz, DMSO-D6) δ ppm 9.34 (bs, 2H), 7.70 (dd, J = 8Hz, IH), 7.62 (m, IH), 7.43 (m, 2H), 7.22 (m, IH), 7.10 (dd, J = 8Hz, IH), 3.33 (m, 4H), 3.11 (m, 2H), 3.00 (m, 2H). HPLC: 96.4% purity (Tr = 10.28 minutes, wavelength at 215 nm; YMC PackPre C 18, 150 X 4.6 mm, 3 μm; Solvent A: 0.2% HC1O4 in 90:10 water: ACN, Solvent B: ACN; Gradient: 90% A to 5% A in 30 minutes, then hold for 5 minutes; flow rate: l.O mL/min). Elemental Analysis: calc. for Cj₄H₁₅FN₂ + 1.05HC1 + 0.6H₂O: C% 60.19, H% 6.22, H% 10.03, Cl% 13.32; Found: C% 59.95, H% 6.09, N% 10.16, Cl% 13.62.

Claims

CLAIMSWhat is claimed is:

1. A method of preparing 8-flouro-napthalen- 1 -ylamine, comprising reacting lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or a complex of hydrogen fluoride and an n-donor base to produce the 8-flouro-napthalen- 1 -ylamine.

2. The method of claim 1, wherein the n-donor base is selected from the group consisting of substituted tetrahydrofuran, amine, amide, carbamic acid, ester, trialkylphosphine, and alcohol.

3. The method of claim 2, wherein the n-donor base is a compound of formula 1:

wherein R¹ is hydrogen, hydroxyl, amino, nitro, halo, C₁-C₅ alkyl, or C₁-C₅ alkoxy.

4. The method of claim 3, wherein the n-donor base is pyridine.

5. The method of claim 4 wherein the complex of hydrogen fluoride and pyridine has about 70% hydrogen fluoride (w/w) and 30% pyridine(w/w)

6. The method of claim 1, wherein the reaction of lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or complex of hydrogen fluoride and an n-donor base is conducted at a temperature between -3O⁰C and 150°C.

7. The method of claim 6 , wherein the reaction of lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or complex of hydrogen fluoride and an n-donor base is conducted at a temperature between 2O⁰C and 3O⁰C.

8. The method of claim 1, wherein the reaction of lH-naphtho[l,8-de][l,2,3]triazine with hydrogen fluoride or complex of hydrogen fluoride and an n-donor base is carried out in the presence of a solvent.

9. The method of claim 8, wherein the solvent is selected from the group consisting of 2-methoxyethanol, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydofuran, 1,2- dimethoxyethane, diethyleneglycol dimethyl ether, toluene, chlorobenzene, dichlorobenzene, dichloromethane, and dichloroethane.

10. A method of preparing l-(8-fluoro-naphthalen-l-yl)-piperazine, comprising: a) preparing 8-flouro-napthalen-l-ylamine according to the method of claim

I, and b) reacting the 8-flouro-napthahlen-l-ylamine with bis(2-chloroenthyl)amine hydrochloride.

II. The method of claim 10, wherein the 8-flouro-napthahlen-l-ylamine is reacted with the bis(2-chloroenthyl)amine hydrochloride in the presence of tetrabutylammonium iodide.