CN102850319A - Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester - Google Patents

Abstract

The present invention relates to the preparation method of fingolimod intermediate, in particular to {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane The preparation method of -5-base} tert-butyl carbamate comprises the steps of: the Grignard reagent made by n-octyl haloalkane and 4-halogenated benzoate undergo cross-coupling reaction, and the 4-n-octyl group generated Benzoic acid ester is reduced to generate 4-n-octylbenzyl alcohol, and then through halogenation reaction to obtain 4-n-octylbenzyl halide, which reacts with triphenylphosphine to generate (4-n-octylbenzyl ) triphenylphosphonium halide, which reacts with (5-formyl-2,2-dimethyl-1,3-dioxane-5-yl)carbamate tert-butyl ester to produce { 5-[2-(4-n-octylphenyl)ethenyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamate tert-butyl ester, then hydrogenation reduction The title compound was obtained.

Description

A method for preparing tert-butyl {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamate

technical field

The invention relates to the field of pharmacy, in particular to {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamic acid Preparation method of tert-butyl ester. the

Background technique

Fingolimod, whose trade name is Gilenya, has the structure of 2-amino-2-[2-(4-n-octylphenyl)ethyl]-1,3-propanediol. On September 22, 2010, the US FDA approved the use of fingolimod as a first-line drug for relapsing multiple sclerosis, becoming the first approved oral drug for the treatment of the disease. Currently, the drug has been approved for marketing in the United States, Canada, Europe, Russia, and Australia. the

{5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamic acid tert-butyl as shown in formula I Esters are important intermediates in the synthesis of fingolimod and its derivatives. At present, there are only 2 documents reporting the preparation method of the compound of formula I. Kim et al. (Synthesis, 2006, 5, 753-755) reported a preparation method of a compound of formula I, using 4-n-octyl iodide benzene as a raw material, which has a higher price and is not easy to obtain; the method also uses cost Higher azide, and dangerous; In addition, the production cost of the palladium-catalyzed cross-coupling reaction adopted is high, and is not suitable for large-scale production. (Synlett, 2007, 18, 2841-2846) reported the preparation method of formula I compound, its step is loaded down with trivial details, and adopts highly toxic carbon tetrachloride to make solvent, and total yield is not high, thus also not suitable for industrialization Production. the

Contents of the invention

The technical problem to be solved by this invention is to overcome the above-mentioned {5-[2-(4-n-octylphenyl) ethyl]-2,2-dimethyl-1,3-dioxane-5-yl } The deficiencies in the preparation method of tert-butyl carbamate (compound of formula I) provide a preparation method that is low in cost, easy to operate, high in yield and environmentally friendly and can be implemented industrially. the

The preparation method of the compound of formula I provided by the invention is shown in the following formula:

The preparation method of the formula I compound provided by the invention specifically comprises the following steps:

(1) 1-halogenated n-octane (compound of formula II)

First make Grignard reagent, and then with 4-halogenated benzoic acid ester (compound of formula III)

A cross-coupling reaction occurs to generate 4-n-octylbenzoic acid ester (compound of formula IV)

In formula II, X is halogen, preferably chlorine or bromine;

In formula III, R is an alkyl group of C1～10, preferably methyl or ethyl; Y is a halogen, preferably chlorine or bromine;

In formula IV, the definition of R is the same as the definition in above-mentioned formula III;

(2) Formula IV compound is reduced to generate 4-n-octyl benzyl alcohol (formula V compound)

(3) The compound of formula V is subjected to halogenation reaction to generate 4-n-octylbenzyl halide (compound of formula VI)

In formula VI, Z is halogen, preferably chlorine or bromine;

(4) react the compound of formula VI with triphenylphosphine to generate (4-n-octylbenzyl) triphenylphosphonium halide (compound of formula VII)

In formula VII, the definition of Z is the same as the definition in the above-mentioned formula VI;

(5) (5-formyl-2,2-dimethyl-1,3-dioxane-5-yl) tert-butyl carbamate (compound of formula VIII)

Wittig (Wittig) reaction occurs with the compound of formula VII under the effect of base to generate {5-[2-(4-n-octylphenyl) vinyl]-2,2-dimethyl-1,3- Dioxane-5-yl}carbamate tert-butyl ester (compound of formula IX)

(6) The compound of formula IX is hydrogenated and reduced to obtain the compound of formula I

In the above-mentioned step (1), the compound of formula II is first prepared as a Grignard reagent, and then cross-coupling with 4-halogenated benzoate (compound of formula III) to obtain 4-n-octyl benzoate (Compound of formula IV), the specific preparation method refers to the patent document US7026478. the

In the above-mentioned step (2), the compound of formula IV is reduced to generate 4-n-octylbenzyl alcohol (compound of formula V), and the reaction is carried out by conventional methods known to those skilled in the art. Aluminum lithium, sodium borohydride or potassium borohydride, preferably a sodium borohydride/lithium chloride or potassium borohydride/lithium chloride reducing system. the

In the above-mentioned step (3), the compound of formula V is subjected to a halogenation reaction to generate 4-n-octylbenzyl halide (compound of formula VI), and the reaction is carried out according to a conventional method known to those skilled in the art. The halogenating reagent can be thionyl chloride, hydrogen chloride, concentrated hydrochloric acid, hydrogen bromide solution, phosphorus tribromide, phosphorus pentachloride or triphenylphosphine/carbon tetrachloride. the

In the above-mentioned step (4), the compound of formula VI is reacted with triphenylphosphine to generate (4-n-octylbenzyl) triphenylphosphonium halide (compound of formula VII). The conventional method is used, and the reaction solvent can be toluene, dichloromethane, N, N-dimethylformamide or tetrahydrofuran; the reaction temperature can be selected between 30°C and the reflux temperature of each solvent. the

In the above step (5), (5-formyl-2,2-dimethyl-1,3-dioxane-5-yl) tert-butyl carbamate (compound of formula VIII) and compound of formula VII A Wittig reaction occurs under the action of a base to generate {5-[2-(4-n-octylphenyl)vinyl]-2,2-dimethyl-1,3-dioxane -5-base} carbamic acid tert-butyl ester (formula IX compound), this reaction is carried out by conventional methods known to those skilled in the art, and the mol ratio of formula VII compound and formula VIII compound is preferably 1～1.5: 1; Adopted The base can be sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium carbonate or triethylamine, preferably sodium methoxide, sodium ethoxide or sodium hydroxide; The ratio is preferably 1:1~3; the solvent used can be tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or methylene chloride; the reaction temperature can be selected between -78 ° C and the reflux temperature of each solvent The compound of formula VIII can be prepared with reference to the literature method (Synthesis, 2006, 5, 753-755). the

In the above step (6), the compound of formula IX is subjected to hydrogenation reduction to obtain the compound of formula I. The reaction is carried out by conventional methods known to those skilled in the art, and the catalyst used is palladium carbon, Raney nickel or platinum Catalyst, preferred palladium carbon; Reaction solvent is water, ethanol, methyl alcohol, acetic acid, ethyl acetate, toluene, tetrahydrofuran or N, N-dimethylformamide, preferred toluene, tetrahydrofuran, methyl alcohol or ethanol; Reaction temperature can be at room temperature to Choose between the reflux temperature of each solvent. the

The remarkable effect of the present invention is that the preparation method provided by the present invention can be conveniently used to prepare {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3 -Dioxane-5-yl}carbamate tert-butyl ester, and then the drug fingolimod can be prepared conveniently. Compared with the existing literature methods, the preparation method provided by the present invention has the following advantages: raw materials are cheap and easy to obtain, the total yield is high, the production cost is low, the reaction conditions are mild and the post-treatment is convenient, so it can be implemented industrially. the

Detailed ways

The present invention is further described by the following examples, but these examples are only used to illustrate the present invention, rather than limiting the scope of the present invention. the

Example 1

Synthesis of methyl 4-n-octylbenzoate

Preparation of Grignard reagent: under nitrogen protection, add 1,2-dibromoethane (0.3mL, 3.6mmol) to a closed three-necked flask containing magnesium chips (1.728g, 72.0mmol) and tetrahydrofuran (20mL) to initiate. After the initiation started, a solution of 1-bromo-n-octane (11.58g, 60mmol) in tetrahydrofuran (100mL) was added dropwise to the reaction flask, and the dropping rate was controlled to maintain the slight boiling of the reaction solution. After stirring vigorously at room temperature for about 30 minutes, , the magnesium chips are greatly reduced, and cooled to room temperature for later use. the

Cross-coupling reaction: while Grignard reagent was being prepared, methyl p-chlorobenzoate (8.5295 g, 50 mmol), iron acetylacetonate (950 mg, 2.69 mmol, 5.4%) were dissolved in tetrahydrofuran (300 mL) and N-methyl In a mixed solvent of pyrrolidone (16 mL), the mixture was stirred under ice-cooling. Under the protection of nitrogen, the above-mentioned Grignard reagent that had been cooled to room temperature was added dropwise in about 1 minute, and the stirring was continued for 30 minutes under ice-cooling, and then stirred at room temperature for 10 minutes. The reaction solution was poured into ethyl acetate (200 mL), quenched with 1M hydrochloric acid, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.02 g of a slightly yellow oil with a yield of 86.7%. ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.7Hz, 3H), 1.2-1.42(br d, J=9.5Hz, 10H), 1.62(t, 2H, J=7.4Hz) , 2.68(t, J=7.7Hz, 2H), 3.91(s, 3H), 7.24(d, J=8.3Hz, 2H), 7.93(d, J=8.2Hz, 2H).

Example 2

Synthesis of 4-n-octylbenzyl alcohol

Add methyl 4-n-octylbenzoate (3.1 g, 12.5 mmol), anhydrous lithium chloride (2.1 g, 50 mmol), sodium borohydride (1.89 g, 50 mmol) to ethylene glycol dimethyl ether (80 mL) In, reflux reaction for 6 hours. The reaction solution was quenched with 1M hydrochloric acid, adjusted to near neutral pH, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution (25mL) and saturated brine (30mL×3), and dried over anhydrous sodium sulfate. , and concentrated under reduced pressure to obtain 2.62 g of a colorless oil, with a yield of 95%. ¹ HNMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.7Hz, 3H), 1.19-1.42(br d, J=8.4Hz, 10H), 1.58(t, J=7.4Hz, 2H), 1.87(s, 1H), 2.59(t, J=7.7Hz, 2H), 4.61(s, 2H), 7.15(d, J=7.8Hz, 2H), 7.25(d, J=7.9Hz, 2H).

Example 3

Synthesis of 4-n-octylbenzyl bromide

Dissolve 4-n-octylbenzyl alcohol (2.2g, 10mmol) in dichloromethane (40mL), add phosphorus tribromide (0.9g, 3.33mmol) dropwise, stir at room temperature for 30 minutes, then quench the reaction with ice water , and then extracted with dichloromethane, the organic layer was washed successively with saturated sodium bicarbonate solution (20mL×3) and saturated brine (30mL×3), dried over anhydrous sodium sulfate, and concentrated under pressure to obtain 2.60g of light yellow oil, Yield 92%. ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.5Hz, 3H), 1.19-1.42(br d, J=9.5Hz, 10H), 1.59(t, J=7.4Hz, 2H) , 2.59(t, J=7.7Hz, 2H), 4.49(s, 2H), 7.14(d, J=8.0Hz, 2H), 7.29(d, J=8.1Hz, 2H).

Example 4

Synthesis of (4-n-octylbenzyl)triphenylphosphonium bromide

Dissolve 4-n-octylbenzyl bromide (2.55g, 9mmol) and triphenylphosphine (2.60g, 10mmol) in toluene (50mL), heat and react at 100°C for 5 hours, and a white solid precipitates, which is filtered and used for After washing with toluene and drying, 4.8 g of white powdery solid was obtained with a yield of 98%. ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.5Hz, 3H), 1.26(s, 10H), 1.52(s, 2H), 2.19(s, 1H), 2.50(t, J =7.4Hz, 2H), 5.22(d, J=14.0Hz, 2H), 6.94(d, J=8.4Hz, 2H), 6.96(d, J=8.6Hz, 2H), 7.51-7.82(m, 15H ).

Example 5

Synthesis of tert-butyl {5-[2-(4-n-octylphenyl)vinyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamate

(5-formyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamate tert-butyl ester (0.227g, 0.875mmol), (4-n-octylbenzyl) Triphenylphosphonium bromide (0.519g, 0.955mmol) was dissolved in dichloromethane (15mL), sodium hydroxide solution (3.75M, 0.64mL) was added dropwise at room temperature, after vigorous stirring for 12 hours, saturated saline ( 15 mL), the organic layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL×3). The organic layers were combined, washed successively with saturated ammonium chloride solution (20 mL×3) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purified by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 0.35 g of a purplish transparent viscous substance with a yield of 90% (trans:cis = 1:5). Cis isomer: ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.7Hz, 3H), 1.28(m, 10H), 1.38(s, 9H), 1.44(s, 3H) , 1.46(s, 3H), 1.59(m, 2H), 2.45(t, J=7.7Hz, 2H), 3.75(d, J=11.7Hz, 2H), 3.89(d, J=11.0Hz, 2H) , 5.18(br s, 1H), 5.58(d, J=12.6Hz, 1H), 6.66(d, J=12.6Hz, 1H), 7.10(d, J=8.0Hz, 2H), 7.15(d, J =8.0Hz, 2H); trans isomer: ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.7Hz, 3H), 1.28(m, 10H), 1.38(s, 9H) , 1.44(s, 3H), 1.46(s, 3H), 1.59(m, 2H), 2.45(t, J=7.7Hz, 2H), 3.75(d, J=11.7Hz, 2H), 3.89(d, J=11.0Hz, 2H), 5.18(br s, 1H), 6.16(d, J=17.4Hz, 1H), 6.50(d, J=17.4Hz, 1H), 7.27(d, J=6.6Hz, 4H ).

Example 6

Synthesis of tert-butyl {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamate

Tert-butyl {5-[2-(4-n-octylphenyl)vinyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamate (220mg, 0.5 mmol) was dissolved in tetrahydrofuran (10mL), and 5% palladium carbon (30mg) was added to carry out atmospheric pressure catalytic hydrogenation reaction. After 12 hours of reaction at room temperature, the palladium carbon was filtered off with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a white solid 220 mg, 99% yield. Mp: 60-61°C (literature value: 63°C). ¹ H NMR (300MHz, CDCl ₃ ): δ0.87(t, J=6.7Hz, 3H), 1.28(m, 10H), 1.41(s, 3H), 1.43(s, 3H), 1.47(s, 9H ), 1.58(m, 2H), 1.97(m, 2H), 2.50-2.58(m, 4H), 3.67(d, J=12.0Hz, 2H), 3.90(d, J=12.0Hz, 2H), 4.97 (br s, 1H), 7.08(s, 4H).

Claims (6)

1. the method for { 5-[2-(4-n-octyl phenyl) ethyl]-2, the 2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate shown in the preparation formula I,

The method may further comprise the steps:

(1) with the 1-halo octane shown in the formula II

Make first Grignard reagent, again with the 4-halogenated benzoic acid ester shown in the formula III

Cross-coupling reaction occurs, the 4-n-octyl manthanoate shown in the production IV

Wherein, the X among the formula II is halogen, preferred chlorine or bromine; R in the formula III is the alkyl of C1～10, preferable methyl or ethyl; Y is halogen, preferred chlorine or bromine; The definition of R among the formula IV is with the definition in the above-mentioned formula III;

(2) with the 4-n-octyl methyl alcohol shown in the formula IV compound reduction production V

(3) formula V compound is carried out halogenating reaction, the 4-n-octyl benzyl halides shown in the production VI

Wherein, the Z among the formula VI is halogen, preferred chlorine or bromine;

(4) with formula VI compound and triphenylphosphine reaction, (4-n-octyl benzyl) the triphenyl phosphonium halide shown in the production VII

Wherein, the definition of the Z among the formula VII is with the definition among the above-mentioned formula VI;

(5) with (5-formyl radical-2, the 2-dimethyl-1,3-dioxane-5-yl) t-butyl carbamate shown in the formula VIII

Wittig (Wittig) reaction occurs under the effect of alkali with formula VII compound, shown in the production IX 5-[2-(4-n-octyl phenyl) vinyl] and-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate

(6) formula IX compound is carried out the catalytic hydrogenation reduction, make formula I compound

2. preparation method according to claim 1, it is characterized in that, in the step (2) of claim 1, the reduction of formula IV compound is generated 4-n-octyl methyl alcohol, the reductive agent that adopts can be Lithium Aluminium Hydride, sodium borohydride or POTASSIUM BOROHYDRIDE, the reduction system of preferred sodium borohydride/lithium chloride or POTASSIUM BOROHYDRIDE/lithium chloride.

3. preparation method according to claim 1, it is characterized in that, in the step (3) of claim 1,4-n-octyl methyl alcohol is carried out halogenating reaction, generate 4-n-octyl benzyl halides, the halide reagent that adopts can be sulfur oxychloride, hydrogenchloride, concentrated hydrochloric acid, hydrogen bromide solution, phosphorus tribromide, phosphorus pentachloride or triphenylphosphine/tetracol phenixin.

4. preparation method according to claim 1, it is characterized in that, in the step (5) of claim 1, with (5-formyl radical-2,2-dimethyl-1,3-dioxane-5-yl) Wittig reaction occurs, the mol ratio preferred 1～1.5: 1 of formula VII compound and formula VIII compound with formula VII compound in t-butyl carbamate (VIII compound) under the effect of alkali; The alkali that adopts can be sodium hydride, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, salt of wormwood or triethylamine, particular methanol sodium, sodium ethylate or sodium hydroxide; The mol ratio of formula VII compound and alkali preferred 1: 1～3; The solvent that adopts can be tetrahydrofuran (THF), DMF, methyl-sulphoxide or methylene dichloride; Temperature of reaction can be selected between-78 ℃～each solvent refluxing temperature.

5. preparation method according to claim 1 is characterized in that, the catalyzer that adopts in the step (6) of claim 1 is palladium carbon, Raney's nickel or platinum class catalyzer, preferred palladium carbon; Reaction solvent is water, ethanol, methyl alcohol, acetic acid, ethyl acetate, toluene, tetrahydrofuran (THF) or DMF, preferred toluene, tetrahydrofuran (THF), methyl alcohol or ethanol.

6. { 5-[2-(4-n-octyl phenyl) vinyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate shown in the formula IX

Wherein, formula IX compound comprises the cis-trans-isomer of alkene.