TW436474B - Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine - Google Patents

Abstract

The present invention relates to a novel process for the synthesis of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine. Moreover, the present invention also relates to a novel intermediate and an optional purification step in the novel process. Additionally, the present invention also relates to the manufacture of a pharmaceutical formulation containing isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine and the use of purified isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine in medicine.

Description

4 3 647 4 V. Description of the invention (1) Scope of the invention The present invention relates to a novel method for synthesizing isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine. Furthermore, the present invention also relates to a novel intermediate and a purification step optionally used in the method. In addition, the present invention also relates to a method for preparing a pharmaceutical formulation containing isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine, and isopropyl-fluorenyl- [ Application of 2- (3-n-propoxyphenoxy) ethyl] amine in medicine. Background and Prior Art Isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine is a compound with narcotic properties. It can be used as a topical anesthetic for the treatment of pain, including localized pain, and especially pain on non-injured skin. WO 9715548 discloses a method for preparing isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine. The method includes several steps: firstly reacting 3 -n-propoxy group with 1,2-di > styrosine to produce 1- (2-> styethoxy) -3-n-propoxyl Benzene. Next, in an ink heater, 1- (2-dihydroxyethoxy) -3-n-propoxybenzene was reacted with N-fluorenylisopropylamine. The product was then further purified by vacuum distillation, isopropyl-fluorenyl-[_ 2- (3-n-propoxyphenoxy) ethyl] amine. SUMMARY OF THE INVENTION The object of the present invention is to provide a new method for preparing isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine suitable for large-scale manufacturing. The following flow chart illustrates the main reaction that starts with 3-propoxyphenol when preparing isopropyl-methyl- [2-(3--n-propoxyphenoxy) ethyl] amine.

d 3 6 4 7 4 ′ 5. Description of the invention (2) The starting materials and reactants used in step D can be easily obtained by methods known in the art.

Scheme 1 Step 1

XT

Ethylene carbonate, solid-liquid phase-transfer catalysis XT (1)

, OH

Step 2

, 〇H halogenating or sulphonating reagent

XT ⑴ (2): halogen or ester

Step 3 χτ. ~ Χ (2) x = halogen or vinegar

Isopropyiamine

〇,

NH

Hi Page 6 d3647 4 V. Description of the Invention (3)

Step 4

Formaldehyde, H2 metal catalyst (3)

(4) The advantages of the improved method of the present invention are disclosed in the following paragraphs.

Another aspect of the present invention is to provide a method for using environmentally friendly reagents and solvents. Environmental groups within and outside the pharmaceutical industry have a general interest in ways in which the industry should develop and make appliances environmentally friendly. The method of the present invention does not use any mutagenic alkylating agents used in methods according to the prior art, such as 1,2-dibromoethane. Therefore, one of the objects of the present invention is to provide a method for preparing isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine, in which the use of 1, 2-di Ethyl bromide. 1,2-Dibromoethane is a known mutagenic compound, so its use should be limited if possible. It is especially to be avoided in mass production. Another item of the present invention is to provide a novel and optional method for purifying crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. Surprisingly, we have found that isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate is a crystalline compound. This optional purification step is shown in Scheme 2.

Page 7 436474 V. Description of the invention (4) Scheme 2 h3po4

(4) 〇,

XT

Base (5) In v1, use solid to liquid phase transfer. The reaction between base and ethylene carbonate was used to estimate the reaction. The reaction is better: J is better than 60-1 20 ° CT, long tincture or xylene). This agent (for example, aproton 1 has 1 and 1 is carried out (but not limited to) DMF, and pupa shellfish). Organic solute 'Solution = is the preferred aprotic organic solvent methyl ~: The catalyst base generates the solid-liquid phase ~ Transfer catalyst_Strain and the amount of phase transfer catalyst is not strictly required, so it can be = This test is different from phase to tooth rotation. The alkali and phase-transfer catalyst can be produced in accordance with the known conditions of this technology. The solid-liquid phase-transfer catalyst conditions can be generated. ， 合 之 测 管 · 你 丨 句. Includes (but not rr m ~ Experience 'and phase-turned fee &

"The solvent is used to carry out the reaction. The terephthalate is used as the ethylene carbonate, preferably 2-3 equivalents. The solid-liquid phase is produced by using solid secondary Xia ~ K ~ transfer catalyzed ridges and phase inversion, Shi Chengxi * Ding Pi Gong, therefore π conditions. The base and the phase ~ suitable base examples for phase-transfer catalysis conditions > λ1 is known in the art

One thousand suitable alkalemia-filament J ^ Λ J includes (but is not limited to) carbonate biphasic & transfer catalyst and potassium bicarbonate. Potassium carbonate is the phase of ‘better alkali ^ human’ sodium hydrogen acid ’carbon § 丨 〇 _ transfer catalyst

43 64 7 4 V. Description of the invention ¢ 5) Including (but not limited to) tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, and tetrabutylammonium bromide. Tetrabutylammonium bromide is the preferred phase-transfer catalyst. The phase-transfer catalyst used in step 1 may be replaced by a compound having inherent properties that can be used as the phase-transfer catalyst under the conditions used in step 1. Examples of such compounds include, but are not limited to, polyethylene glycol (PEG), such as PEG 60 00. After the reaction is complete, the reaction mixture is cooled, diluted with water, and then extracted with a suitable organic solvent (e.g., diphenylbenzene or fluorenyl tertiary-butyl ether). The organic phase was concentrated and the crude 2- (3-propoxy-phenoxy) -ethanol was purified via distillation. In step 2, the 2- (3-propoxy-phenoxy) -ethanol formed in the above step 1 is further reacted with a suitable reagent to produce a compound of formula 2,

(2) where X is bromine, chlorine, iodine or sulfonate hydrazone '. Examples of sulfonates include, but are not limited to, alkane- and aryl sulfonates, such as, for example, methanesulfonate, ethylsulfonate, p-toluene acid, p-mophenyl phenylsulfonic acid S Purpose. A preferred formula 2 is a sulfonate. Examples of reagents capable of producing preferred compounds of formula 2 include, but are not limited to, sulfenylsulfonium chloride, ethylsulfonylsulfonium chloride, p-fluorenylsulfonium chloride, and p-bromosulfonyl chloride. In step 3, an organic solvent (e.g., fluorenyl tertiary-butyl ether or toluene) of the compound of Formula 2 is further reacted with isopropylamine in the presence of water. Better than

43647 4 V. Description of the invention (6) The reaction is carried out under high temperature (preferably 60-1 10 ° C) for a long time and under high pressure (preferably 10 atmospheric pressure). Isopropylamine should be added in excess (for example, 2 to 6 equivalents, preferably 3 equivalents). Additional and non-nucleophilic tests (e.g., 'potassium carbonate or sodium carbonate) can be added to the reaction mixture as needed. The amount of water contained in the reaction mixture is not strictly regulated and can be ignored as needed. Then "the reaction mixture is cooled, and then the aqueous acid is added with vigorous stirring" until the pH of the aqueous phase reaches a constant value of 3-5 (preferably 3-3.5). The aqueous phase was separated and washed with fluorenyl tertiary-butyl ether or toluene, after which it was used in subsequent steps without any further purification '. In step 4, in the presence of palladium on charcoal, the isopropyl_methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared in the above step 3 and Formaldehyde reaction. The reaction is hydrogenated at (or higher) atmospheric pressure (for example, 1-6 bar) and the mixture is hydrogenated for several hours. Although the amount of formaldehyde is not strictly regulated, it can be between 1 and 10 equivalents. Palladium is used on charcoal in an amount of from 0.01 to .5 mol, preferably from 0.05 to 0.2. Thereafter, the reaction mixture is treated with water, (for example, sodium hydroxide) to a pH of ~ 12, and then extracted with methyl tertiary ether. The organic phase was separated and distilled to give pure isopropyl-methyl-n-propoxyphenoxy) ethyl] amine. People are surprised that we have been able to crystallize = propyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine from the reaction mixture of step 4 to the corresponding Monophosphate. The isophosphate-methyl- [2_ (3_n-propoxyphenoxy) ethyl] amine monophosphate is an isopropyl-fluorenyl- [2_ (3_n-propoxybenzene Oxy) ethyl] amine is a crystalline and stable salt, so ', you have; Isopropyl-methyl-n-propoxylate

Page 10 436474 V. Description of the invention In the method of (7) ylphenoxy) ethyl] amine, a crystalline intermediate is introduced. It is < an additional purification step that is simple and convenient to introduce into the reaction process as needed, where all intermediates are syrup. Therefore, the time-consuming and energy-consuming distillation steps used in the method according to the prior art can be omitted. Isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine mono-disc salt can be purified to produce high-purity intermediates, which can be further converted into Xingying isopropyl-methyl- [2- (3 ~ n-propoxyphenoxy) ethyl] amine. In this optional purification step, the content of the ethyl acetate solution of crude isopropyl-methyl- [2- (3 ~ n-propoxyphenoxy) ethyl] amine is tested first, and then adjusted to the above amount per gram. 6-10 ml of ethyl acetate of the crude isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine prepared in step 4. The content of the isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine in ethyl acetate is preferably per isopropyl-methyl- [2- (3 -N-propoxyphenoxy) ethyl] amine in 7-9 ml of ethyl acetate. Methanol and a methanolic solution of phosphoric acid were added to the tested solution of the isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine. The amount of dish acid should be about 0.9 to 1.0 mole equivalent, preferably 0.95 equivalent. The total amount of methanol in the tested solution should be adjusted to be equal to the amount of phosphoric acid used. The concentration of phosphoric acid in the mixture of isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine in methanol and ethyl acetate should be about 5-15% by volume, Good 9-1 1% by volume. The precipitated salt is collected via 'e.g., filtration or centrifugation, and then washed with ethyl acetate. Then, the isophosphate-methyl- [2- (3-n-propoxybenzyloxy) ethyl] amine monophosphate prepared in the above step is mixed with water, and then an aqueous sodium hydroxide solution is added to adjust the pH To ~ 11.5. Add fluorenyl tertiary-butyl ether, or other suitable

43 64 7 4 V. Description of the invention (8) Solvent solvent 'Then the two phases are separated. The organic phase was washed with water and concentrated 'to give pure isopropyl-fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine. The final distillation step of the crude isopropyl-methyl- [2- (3 ~ n-propoxyphenoxy) ethyl] amine prepared through the above step 4 can be replaced by an optional purification step, that is, isopropyl Preparation of fluorenyl- [2- (3--n-propoxyphenoxy) ethyl] amine. In these cases, it is preferable to extract the methyl isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl group] with ethyl acetate instead of methyl tert-butyl ether '. Aqueous aqueous phase of amine. Thereafter, the prepared isopropyl-methyl- [2- (3 ~ n-propoxyphenoxy) ethyl] amine monophosphate was converted into the corresponding isopropyl ~ fluorenyl group through the alkalizing step. [2_ (3-n-propoxyphenoxy) ethyl] amine. This program mode can be easily completed by a technician. The invention is described in more detail in the following non-limiting examples. Please refer to the Roman numerals in flowcharts 1 and 2. Examples Example 1 (2- (3-propoxy-phenoxyethanol (1) with ethylene glycol (20.7 kg, 234.8 moles), K2C03 (17.9 kg, 126.7 moles) , Tetrabutylammonium bromide (3.8 kg, 1.5 moles) and buprof-2--2-pyrrolidone (565 liters) to 3-propoxyphenol (179 kg, 11 7 · 4 moles) The mixture was heated to about 90 ° C. for about 0 hours, then cooled to 45 ° C. Then water (130 liters) and methyl tertiary-butane (82 liters) were added successively to separate the phases. Then, the organic phase was washed successively with 0.5 M HC1 (aqueous solution) and 0.5 M NaHCO (aqueous solution). The organic phase was concentrated under reduced pressure and then distilled (1 50 ° C / 0 · 9 5 MPa). The crude product i is purified to yield

Page 12 436474 V. Description of the invention (9) The purity of the biochromatography is more than 97% (such as I (9 kg)). MS (EI): 196 (34) '153 (13), 152 (7), 135 (4), 111 (67)' 110 (100) NMR (20 0 MHz): 5 7.15 (t, 1H) '6.5 Cm, 3H), 4.0 (m, 2H), 3.9 (m, 4H), 2.5 (s, 1 Η), 1. 7 9 (m, 2 Η), 1. (t, 3 Η). 13C NMR (50 MHz): 5 160.4, 159.8 '129.9, 107.2, 106.7' 101, 6 '69.5, 69.2, 61.4, 22.6, 10.5. Pyridoxine 3-propoxy-phenoxyacetate (2) makes 1 (17.9 kg '91 .0 mol) dissolved in methyl tertiary-butyl ether (83 liters) and trihexylamine (15.2 liters) The solution in 10.8 Molar) was reacted with Msci (7.7 liters, 99.12 Molar). The formed slurry was allowed to stand at ambient temperature for about 2 hours', water was added, the phases were separated, and then the organic phase was used in a subsequent step. MS (El): 274 (55) '232 (7), 195 mm, 153 (6), 135 (16), 123 (100), 11 (66), 79 (64). Isopropyl_ [2- (3-propanoyl-phenoxy) -ethyl] -amine (3) with K2C03 (14.0 kg '98 .1 mol), isopropylamine (36.2 liters' 4 5 5 · 9 mol) and water (31 liters) in a solution. The reactor was sealed and the mixture was heated to 90 ° C for 16 hours, creating a pressure of about 2 bar. The reaction mixture was allowed to cool to the soil temperature ', the aqueous phase was discarded, and the organic phase was washed with water. 0 5 M HgSO4 (aqueous solution) was added to the organic phase to bring the pH to ~ 3.5 'and then the phases were separated. The aqueous phase was stripped with fluorenyl tertiary-butadiene and used in subsequent steps. MS (El): 237 (7), 222 (34), 194⑴, 135⑺,

Page 13 436474 V. Description of the invention (10) 85 (80) '72 (1 0 0) NMR (2 0 0 MHz): < 5 7.1 (rn, 1H), 6.5 (m, 3H) '4.1 (t , 2H), 3.9 (t, 2H), 3.0 (t, 2H) '2.9 (m, 2H), 1.9 (m, 2H), 1.6 (m, 1H)' 1.0 (d + t, 9H) 〇13C NMR (50 MHz): (5 160.4, 160. 1, 129, 8, 107_ 0, 106 ′ 6, 101.5, 69.5, 67.6, 48.5 j46.5 > 23,0 > 22.6 > 10.5 ° isopropyl-methyl- [2- (3-propoxy-phenoxy) -ethyl] _amine (4) add wet 10% palladium on charcoal (5.2 kg, 41.1% Pd / C) and 37% Kushiro (20.3 liters' 270. 2 moles) to an aqueous acid solution of 3. The mixture was hydrogenated at a pressure of 3 bar for about 4 hours. The reaction mixture was treated with concentrated NaOH. The pH was brought to ~ 12, the solids were filtered off, and the resulting biphasic system was extracted by EAc. The phases were separated and then the organic phase was washed with water and then concentrated. The residue was made at 128-130 ° C / 0.3 MPa Distillation yielded pure isopropyl-methyl- [2- (3--n-propoxyphenoxy) ethyl] amine (18,1 kg, 72.1 moles). Crude isopropylmethyl- [2 -(3-propoxy-phenoxy) -ethyl] amine Purify the reaction at ambient temperature 'over a period of 3 hours and add MeOH (9.6 liters), followed by a solution of 1 〇4 (4.85 liters, 72.5 mol) dissolved in ^ 0 red 19.2 liters to the crude product 4 (19.0 kg '75.7 moles) of ethyl acetate (8 ml of ethyl acetate per gram of crude product) was dissolved. The isopropyl-fluorenyl- [2- (3-n-propoxyphenoxy) ethyl] amine was then filtered through a filter to fill the salt slurry, and the solid material was then passed through EtOAc. washing. In the subsequent step ^ the wet product (41.8 kg, 67.8 / mol,

Page 14 43 64 74

V. Description of the invention (11) 89% yield).

Melting point: 131-134 ° C The content of Η3Ρ04 is 27.8% (w / w), which is equivalent to a molar ratio of 1: 1 to the theoretical value of $ and & P0 w / w). 〆 Make the product (41.8 kg '67 · 6 mol) mixed with pure water (66 liters), and then add Han Na 0 Η 'to make p Η ~ 11 5 and then take 曱 基 第 = take The biphasic mixture formed. The phases were separated and the organic phase was "extracted with pure water and then concentrated under reduced pressure. Finally, a thin-film evaporator was used to remove the residual solvent; ^, which produced a chromatographic purity of more than 99%, such as oil propionate-methyl-: carboxyphenoxy) ethyl] amine 0.42 kg, ^ 6 Soil_massive MS (EI): 251 (10) -236 (9), 80 〇 / iH NMR (40 0 MHz): (J 7.1… 4.0 (t, 2H), 3.9 (t, 2H) '1 ;, 1,) 3H), (d + t, 9H). , 160. 1, 129.7, 106. 9 54, 0, 51. 7, 38, 2, 22 .., 2.3 (S, 3H), U (m, 2H) 1 U, 1H) '2.8 (ΐ, 2H) 13C NMR (50 MHz): < 5 160. 3 106. 5, 101 · 4, 69.4, 66. 8 17-9, 10.5. ’N, 5 · 7; 0, 12. 5- 57; 〇, 12.73 calculated value

Measured value%: (:, 71.5; 11, 10 ·%: C, 71. 67; H, 10. 02; N

Claims (1)

4 3 64- Page 1 2000.01.20.016 Date of Amendment Patent Application Scope Step 3 Isopropylamine ~ χχ. (2) χ = halogen or sulfonate wherein the compound of the above formula (2) and 2-6 mole equivalents of isopropylamine are in methyl-butyl ether or toluene, and in the presence of water, 60-110 ° C and Bu 10 atmospheric pressure, response under prolonged time; step 4 (3) Formaldehyde, H2'Γ metal catalyst (4) wherein the isopropyl- [2- (3-propoxy-benzyloxy) -ethyl] -amine and bu prepared from step (3) above 10 equivalents (weight) of formaldehyde is reacted in acidified water in the presence of palladium on carbon at from 0.01 to 0.5 mole equivalents at room temperature and pressure of 1-6 bar for several hours. 2. The method according to item 1 of the patent application scope, characterized in that a solid insoluble base and a phase-transfer catalyst are used in the step. 3. The method according to item 2 of the patent application, characterized in that the base is sodium carbonate, sodium carbonate, sodium bicarbonate, or hydrogen carbonate. O: \ 55 \ 55670.ptc Page 2 2000.01.20.017 4-3647 4 _Case No. 87120435_year month__ _, the scope of patent application 4. According to the method of the scope of patent application No. 2 is characterized by the phase -The transfer catalyst is PEG 600, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or tetrabutylammonium stilbene. 5. The method according to item 1 of the scope of patent application, characterized in that step 1 is performed in an aprotic organic solvent. 6. The method according to item 5 of the scope of patent application, characterized in that the aprotic organic solvent is p-methyl-2 -D ratio p.定 Ketones. 7. The method according to claim 1, wherein X is bromine, gas, iodine, sulfonate, p-toluenesulfonate or p-bromophenylsulfonate. 8. The method according to item 1 of the scope of patent application, characterized in that step 3 is performed at a pressure above atmospheric pressure. 9. The method according to item 1 of the scope of patent application, characterized in that step 3 is carried out under pressure between 10 and 10 bar. 10. The method according to item 1 of the scope of patent application, characterized in that step 3 is performed at a high temperature. 1 1. The method according to item 1 of the scope of patent application, characterized in that step 3 is performed at 6 0-11 0 ° C. 12. The method according to item 1 of the scope of patent application, characterized in that step 3 is performed using an additional base contained in the reaction mixture. 1 3. The method according to item 1 of the scope of patent application, characterized in that step 3 is performed using water as a solvent. 14. The method according to item 1 of the scope of patent application, characterized in that the metal catalyst in step 4 is palladium. 15. The method according to item 10 of the scope of patent application, characterized in that the palladium O: \ 55 \ 55670.ptc Page 3 2000.01.20.018 436474 _tW, 87120435_Year Month Day__ VI. The patented patent garden l? J is carried on charcoal. 1 G. The method according to item 1 of the scope of patent application, characterized in that the f aldehyde in step 4 is added in the form of an aqueous formaldehyde solution. 1 7 · —Isopropyl- [2- (3-propoxy-phenoxy) -ethyl] -amine. Οι'ο ^ 'οίόΤΟ.ρι: Page 4 2000.01.20. 019 4 3 64- Page 1 2000.01.20.016