TW200800890A - Method of making 8-fluoro-naphthalen-1-ylamine and related compounds - Google Patents

Abstract

A process is described for preparing 8-flouro-napthalen-l-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. 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

200800890 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing 8·fluoro·naphthalene-based amines and amines, and the compounds are in the form of 7_{4 cases of 8 denaphthalenes). Use of an intermediate as a compound in the synthesis of a small base]_butyl lactyl}-3,4-dihydro-1/f_n,8]^_2. ketone. [Prior Art]

U.S. Patent Application Publication No. 2〇〇5/〇〇433〇9A1 (Example A66) discloses a method for synthesizing 7-{4-[4m-i-yl)-pyridin-1-yl]-butoxy}_ 3,4-Dihydrolu-n, 8Mm (a method for the determination of a dopamine quinone 2 moiety promoter for the treatment of schizophrenia), in this method] ♦ gas · Cai _ 1-base) - azine As an intermediate. Unfortunately, the synthesis of this particular intermediate is costly and difficult to control and therefore not suitable for use in the manufacture of large quantities of product. Specifically, in the first step of the process, 8-bromo-naphthylamine is produced by a Curtis rearrangement reaction using 8_/odor-na-l-carboxylic acid (a very expensive compound). The large amount of heat released in this method makes it difficult to ensure safe operation. In the second step of the process, a Schiemann diazonium/fluorine-deazotization reaction is used to produce bromobromine-fluoro-naphthalene. After the use of the product of the hydrazine reaction to produce 1 _(8_fluoro-naphthalene-丨-yl)_slightly intermediate 0, we can imagine the formation of piperazine by using an inexpensive compound to give another 8_halo-naphthalen-1-yl group The amine intermediate (8-fluoro-naphthalen-1-ylamine) produces 1-(8-fluoro-birthazine. However, the process disclosed in this document for making this particular intermediate involves many steps and produces many impurities. Or use the unstable compound I15347.doc 200800890. The following Scheme 1 illustrates several methods for producing 8-fluoro-naphthalene-1-ylamine (1) disclosed in this document. A reference description is made by iron. Reduction of compound 1 by I-fluoro 8~ Shi Xiao Ji Qin (3) (eg "c/^. 1966, 577-581). Flow! Also disclosed in this document for use in the manufacture of compound 4 Method of Compound 1. Scheme 1

In one of the processes illustrated in Scheme 1, compound 3 is prepared by nitration of fluoronaphthalene (6) (Israel Journal 〇f Chemistry, 1977, 16, 299-303). However, nitration produces a mixture of 1-fluoro-2-nitronaphthalene, fluoropropanyl and a mixture and the product is isolated by column chromatography. In another method illustrated in Scheme 1, compound 3 is prepared from 8-nitronaphthylamine (5) via a Schiemami reaction (e.g. " Μ 1966, 75, 577-581). However, the nitration of 1-naphthylamine (8) yielded only 38% yield of 5, while producing 5-stone Schottyl-neglandamine "μ 1939, 348". Also by 丨^ dinitronaphthalene (7) Single reduction system I15347.doc 200800890 Preparation compound ^ (Collection of Czechoslovak Chemical Communicatiom, 1929, 1, 360). Compound 7 is heat sensitive and impact sensitive, which (especially) limits the use of compound 7 in large scale preparation In another method illustrated in Scheme 1, compound i can be prepared from a fluoro-1-naphthoic acid (2) by Curtis or Hoffmann rearrangement reaction. However, a reference discloses ethyl (o-fluorophenyl)acetate. (4) Five compounds are required to prepare compound 2

Step (J(10)7, (10) CTzembir;;, 2002, 67, 1171-1177) As seen above, none of the reaction schemes described or described above are suitable for practical, female and economical preparation of 8-fluoro-naphthalene-1 Alkylamine which is useful for the synthesis of, for example, 1-(8-fluoro-naphthalen-1-yl)-piperazine or 7-{4-[4-(8-indole-naphthalene-^-piperazine-l-yl) Useful intermediates for compounds of -butoxy}-3,4-dihydro-1-[1,8]-naphthalene-2-one. German Patent DE 147 852 discloses exposure in the presence of steel and heating When concentrated hydrochloric acid and hydrogen chloride gas, If naphtho[l58_de][1,2,3] triazine can be converted to 8-chloro-1_1-aminonaphthalene. However, fluoride is weaker than chloride. The fact that we do not expect to be able to replace the triazine with fluoride to modify the process to produce 8-den-naphthalene-i-ylamine. [Invention] The present invention relates to a process for preparing 8-fluoro-naphthalene-i-ylamine. Including the reaction of 1 -naphtho[1,8'[1,2,3]. with IU 匕 hydrogen or gasification gas and alkaloid. The present invention further relates to the species by 8_ Method for preparing 1-(8-|L-naphthalen-1-yl)-pyridazine from fluorocentric 1-ylamine c Unless otherwise stated, The term "alkyl" as used includes 115347.doc 200800890 = (9) mono (tetra)yl groups of the chain, branch or ring moiety or combinations thereof. "alkyl groups" Examples include, but are not limited to, methyl, ethyl, Propyl, isopropyl, butyl; dibutyl, t-butyl and tert-butyl, pentyl, hexyl, heptyl, :::yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, norminyl, and the like. Unless otherwise stated, the term "alkoxy" as used herein means base-〇·", where "burning base" is as above Examples of oxime, "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentyloxy. Unless otherwise stated, the term as used herein , "halogen" and "halogen" include fluorine, chlorine, bromine and iodine. [Embodiment] In the embodiment, the present invention relates to a method for making a triple call with a gas or with hydrogen fluoride and η. A method for preparing 8-fluoro-naphthalen-1-ylamine from naphtho[H(^][1'2,3]dioxin by reacting a complex of alkaloid. In another embodiment, η donor base Selected from a group consisting of the following groups: tetrahydrofuran, amine, decylamine, amino decanoic acid, vinegar, trialkylphosphine or alcohol. The η donor base is more preferably a compound of formula 1: i wherein R1 is hydrogen, hydroxy, amine a nitro group, a halogen, a Cl_c5 alkyl group or a cKc5 alkoxy group. The compound of the formula 1 is preferably a pyridine. A method for using a hydrogen fluoride and a complex of hydrogen fluoride and a η donor base as a fluorinating reagent for other compounds is discussed. , refer to the Journal of Organic Chemistry, \9Ί9, 3 private η2& references cited therein. 115347.doc 200800890 As illustrated in Example 2 below, the conversion of indole naphtho 8'[1,2,3] trisonic to 8|naphthalene small amine can be accomplished using a fluorinated gas as follows: The complex is achieved under conditions which are used to temper the same three: chloro-naphthylamine, as described in 147852. This is surprising because the compound is weaker than the chloride nucleophile. In addition, in

In the process, it is expected that the performance of bismuthazine is: 匕 diazonium compound, thereby allowing the introduction of a fluorine group, but the introduction of the fluorine II greatly reduces the thermal instability. As described in Example i Differential scanning calorimetry performed by [l,8-de]n,2,3]triazine ((10)q analysis shows initial temperature, energy 817 J/g. This means that the compound has more than other diazonium compounds. Large safe treatment range. In addition, in order to complete the conversion of (10) naphtho-n,8_de][1,2,3]triazine to 8-naphthalene-based amine, = column purification is required. When the intermediate (4) is used as hydrogen fluoride & for the experience of η in the complex, the ratio of hydrogen to the bite used in the complex is preferably 70% hydrogen fluoride and 30% D bite to 57. % gasified chlorine and acridine, more preferably 7% hydrogen fluoride and 3% pyridene (w/w, relative to the total weight of the complex). As mentioned above, in another embodiment of the invention When i扒naphthalene de][l,2,3]^嘻 is reacted with hydrogen fluoride or a complex with hydrogen fluoride and n donor base, preferably at -3 (TC to 15 (temperature between TC, Better at about 5 it to 55° The temperature of C, even more preferably, is about 2 (rc to 3 (temperature of rc). In another embodiment, 1/? naphthalene is used in the presence of a solvent. 115347.doc 200800890 Π, 2, 3 Dioxazine and hydrogen fluoride or a complex of w-w, gas and 11 for the experience of the complex. The bath is preferably selected from the group consisting of various solvents: 2_methoxy oxime Know, tetrahydrofuran, !, heart dioxin, oxime acetophenone, di n, methyl tetracycline, m chloromethyl chloro, dichloro ethane, chlorpyrifos, dichlorobenzene and two The cups of many known methods, such as the ones used in the production of this month, are suitable for the production of 1 naphthene, [8-de]n, 2, 3] Triazine. Preferably by J 8·

Monoamine naphthalene (4). Naphthyl from mcan. A suitable procedure for the preparation of naphthyl and w]n,2, from the amine amine-based C., is described in lang, 0/ca- 吟, 1969, 756. The 1,8-diamine group is not used in the manufacture of 8 naphthalene-based amines compared to 8^, odor, naphthyl, and acenamic acid (via the [l,8-de][l,2,3]triazine intermediate The inexpensive starting material, 8_bromo-naphthalene-1-carboxylic acid, is disclosed in the example A" of US 2 〇〇 5/〇〇 433 〇 9 A1 for the manufacture of M8-fluoro-naphthalene small group) The starting material in the method. The synthesis of 8-fluoro-naphthalen-1-ylamine using the process of the present invention requires less synthesis steps, less purification steps, and milder reaction conditions than the methods described in the literature. In another embodiment, the process of the present invention further comprises reacting 8-fluoro-1-aminonaphthalene produced as described above with bis(2-chloroethylamine) hydrochloride to produce 1-(8-fluoro) - Nai-1-ki) Travel. A preferred embodiment of the process (starting with 1,8-diaminonaphthalene) is illustrated in the reaction scheme of Scheme 2 below: • 10 - 115347.doc 200800890 Scheme 2, 2 pentylene nitrite _ ElDM, Such as OH, room temperature

(82-88%)

cS (87 Nor 4) NH2 F HB pyridine, room temperature

M Methyl _s_, 己 ®

Cl-benzene, all over

In the process for producing 8-fluoro-naphthalen-1-ylamine described in Scheme 1, 8-fluoro-naphthalen-1-ylamine is bis(2-chloroethyl) in the presence of tetrabutylammonium iodide Amine hydrochloride reaction. As shown in Scheme 2, this final reaction step is preferably carried out in a mixture of hexanol and chlorobenzene under reflux. The invention is further illustrated by the following examples. The examples are intended to illustrate the invention and should not be used to limit or limit the scope thereof. In the following examples, the term "room temperature' refers to a temperature of from 20 °C to 27 °C. Instance

Example 1 - Preparation of 1H-naphtho[l,8-de][l,2,3]triazine

Iso-nitrite, although Earn is sincere

1,8-Diaminonaphthalene (250 g, 1.58 mol) was dissolved in a mixture of acetic acid (500 ml) and ethanol (2500 ml) in nitrogen at room temperature. Subsequently, isoamyl myristate (208.1 mL, 1.55 mol, 0.98 equivalent) was added dropwise over a period of 3.5 hours while maintaining the temperature of the reaction mixture between 18 ° C and 21 t. After the addition, the resulting red suspension was stirred at room temperature for 19 hours. The solid was collected by filtration 115347.doc -11 - 200800890, washed with ethanol (2×500 ml) and dried under vacuum to yield 1H-naphtho[l,8-de][l,2,3] as a red crystalline solid. Triazine (235.86 g, 88%). 1H NMR (400 MHz, DMSO-D6) δ ppm 13·24 (s, m), 7·24 (m, 2H), 7.11 (m, 1H), 7·01 (d, J=8/40 Hz, 1H),6·86 (dd? J 5.37? 2.64 Hz, 1H), 6.10 (d, J-7.23 Hz, 1H) ° CHN Analysis: Calculated value of C1gH7N3: c% 70.99, H% 4.17, N% 24.84; Experimental values: c% 7〇.62, H〇/〇4 〇6, 24.46. Example h Preparation of 8-fluoro-naphthalen-1-ylamine

MFP is pyridine. Hydrogen fluoride is placed in a vessel with a pyridine (70% HF/3〇% pyridine, 4 〇) and cooled in an ice bath. 1扒Naphtho[1,8-heart][1,2,3]triazine (1〇〇 g, 0.59 mol) was slowly added. After the addition, the vessel was rinsed with an additional 1 〇〇 g of hydrogen fluoride pyridine to wash away the solids on the side walls of the vessel. The vessel is sealed and connected to a nitrogen line. This solution was stirred in nitrogen for 7 days at room temperature. High pressure liquid chromatography ("HPLC") analysis showed that at the end of the period all starting materials had disappeared and the product purity was 94%. The reaction was cooled in an ice bath. Once the temperature was below ... °c, hydrogen was slowly added. Potassium oxide ("koh,,") (45 w%, 135 L) and maintained at a temperature below 35 °C. The final pH is approximately η. The resulting mixture was diluted with ethyl acetate ("EtOAc") (5 mL) and stirred for 2 min and product was isolated from the mixture by a series of separation steps. The mixture was transferred to a 6-L separatory funnel by suction. The water layer is separated and removed. The solid layer and emulsion interface were removed by CeUte8 (Shiyoshizao) to remove 115347.doc -12-200800890 solids. The filter cake was washed with ethyl acetate (2 x 200 mL). The two-layer filtrate was separated (good separation at this time). The organic layer was washed twice with a mixture of saturated sodium chloride (300 mL), water (300 mL) and saturated sodium hydrogen carbonate (300 mL); The organic layer was then degassed by bubbling nitrogen for 20 minutes to remove oxygen and prevent oxidation. The solution was stirred with activated carbon (Sigma-Aldrich, 242276, Darco, G-60, 100 mesh, 50 g) under nitrogen for 5 hours and stirred with additional active carbon (50 g) under nitrogen overnight. The activated carbon was removed by filtration through Celite® and the solid cake was washed with EtOAc (2×300 mL). The filtrate (wine) was concentrated to give an oil which was azeotroped twice with chlorobenzene (2 X 500 mL). This oil was solidified after standing at room temperature overnight. The solid was further dried in vacuo to give 8-fluoronaphthylamine (86.1 g, 90.4%) as a reddish brown solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.48 (dd, J = 8 Hz, 1H), 7.27 (m, 1H), 7.19 (t, 1H), 7.03 (m, 2H), 6.65 (dd, J = 8Hz, IH), 5.66 (s, 2H). 'CHN analysis: Calculated value of C1()H8FN: C% φ 74.52, H% 5.00, N% 8.69; Experimental value: C% 74.36, H% 4.92, N% 8.79 〇 Example 3 - Preparation of 1-(8-fluorine -Naphthalen-1-yl)piperazine hydrochloride.

Bis(Ethylethyl)amine HC1 Bll4Ni (0.5 weight) hexanol was refluxed in anhydrous chlorobenzene (Aldrich, 1950 mL). 8-Fluoro-naphthalen-1-ylamine (168.86 g, 1.048 mol) And bis(2-chloroethyl)amine hydrochloride (Aldrich, 115347.doc -13- 200800890 B38503, 202.0 g, 1.9 mol, 1.08 equivalent), tetrabutylammonium iodide (Aldrich, 140775, 193.5 g, 0.524 mmol, 0.5 eq.) and hexanol (Aldrich, 100 mL) were combined. The mixture was degassed by bubbling nitrogen for 20 minutes. The mixture was then heated to reflux for 74 hours under nitrogen to give a pale brown suspension. The progress of the reaction was checked by HPLC. The suspension was slowly cooled to room temperature while gently agitating overnight to give a good brown suspension.

The solid was collected by filtration, washed with chlorobenzene (300 ml), toluene (30? The crude product was slurried in CH3CN (2 x 500 mL) at room temperature for 4 to 5 hours. The solid was collected by filtration, and the solid was dried under vacuo to afford 1-(8-fluoro-naphthalen-1-yl)piperazine hydrochloride (213.52 g, 76. 4%) as a yellow solid. 1H NMR (400 MHz? DMSO-D6) δ ppm 9.34 (bs5 2H), 7.70 (dd? J=8Hz5 1H)? 7.62 (m? 1H)? 7.43 (m? 2H)? 7.22 (m5 1H)? 7.10 ( Dd, J = 8 Hz, 1H), 3.33 (m, 4H), 3.11 (m, 2H), 3.00 (m, 2H). HPLC: 96.4%, purity (Tr = 10.28 min, wavelength 215 nm; YMC PackPre C18, 15 〇 x 4.6 mm, 3 μιη; Solvent A: 0.2% HCl〇4 at 90:10 water: CAN, solvent B: ACN; Gradient: 90A % to 5% A in 30 minutes, followed by 5 minutes; Flow rate: 1 · 0 mL / min. Elemental analysis: Calculated value of C14H15FN7 + 1.05HC1 + 0.6H20: C% 60.19, H% 6.22 , N% 10.03, C1% 13.32; Experimental values: C% 59.95, H% 6.09, N% 10.16, C1% 13.62 〇115347.doc • 14-

Claims (1)

200800890 X. Patent application scope: 1. A method for preparing 8-fluoro-naphthylamine, which comprises 1 仏 naphtho[1 Ue] [ 1,2,3] triterpene with hydrogen fluoride or hydrogen fluoride and donor base The complex is reacted to produce the 8-fluoro-naphthalen-1-ylamine. 2. The method according to claim 1, wherein the η donor base is selected from the group consisting of tetrahydrofuran, amine, decylamine, carbamic acid, guanidine, dicalcium phosphine and an alcohol. 3. The method of claim 2, wherein the η donor base is a compound of formula 1: R1 1 Ο wherein R1 is hydrogen C1-C5 alkoxy. A base, an amine group, a succinyl group, a halogen, a C?-C5 alkyl group or a group according to claim 3, wherein the η donor base is pyridine. 5 · For example, δ 青 项 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 6. As in Item 1 of the ancient ^,, the eight in the 1 抒-naphtho[l,8-de][l,2,3] triazine A A wind 4 or visit branch ^. The reaction of 〃, 虱 and n for the complex is at -30. Perform at a temperature between 〇 150c. 7. If the request item 6 is ancient. „ . Method / where the 1 open-naphtho[1,8-heart][1,2,3] three moles of oxygen or invites outside -U ά〇γλ ^ 虱The reaction of the η donor base complex is carried out at a temperature between 201. 8 · As requested by the project worker. Rustic gas or with fluorinated ^1 仏 并 [1,8_de][1,2, 3] Three squats are in the process of hydrogen, and the reaction of hydrogen and n is experienced in the dissolution of the solvent. 115347.doc 200800890 9. The method of claim R, wherein the group of solvents · 2, methoxy, ^ d It is selected from the group consisting of hydrogen furan, 11-t W-alkane, 2-methyltetraphenyl, acetophenone, diethylene glycol dimethyl sulfonate, methyl milk, dichlorobenzene, and bis. - a method for preparing gas _ rolling G 杌 - nai ki) piperazine, which comprises: a) according to the request item 、 /, · b) make w# 々 备 8 8H1_ ylamine, and Dingkou 8-气-奈-n 11 ^ 土私: a pair of (2_ gas ethyl) amine stepping acid 蹿 f at 11 · as requested in the paragraph 10 of the side of the sign; makeup salt I salt reaction. Reacts with the bis-amine in deuterated and ethyl hydrazine hydrochloride. II5347.doc 200800890 VII (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: • 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: ) 115347.doc