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
Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester Download PDFInfo
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Abstract
The present invention relates to a preparation method of fingolimod intermediate, specifically relates to a preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester. The method includes performing cross-coupling reaction of a Grignard reagent prepared from n-octyl alkylogen with 4-halogen-benzoate, reducing the generated 4-n-octyl benzoate to 4-n-octyl benzyl alcohol, performing halogenation reaction to give 4-n-octyl benzyl halide, reacting the halide with triphenylphosphine to generate (4-n-octyl benzyl) triphenylphosphonium halide, performing Wittig reaction of the compound with (5-formyl-2,2-dimethyl-1,3-dioxane-5-yl) carbamic acid tert-butyl ester, generating {5-[2-(4-n-octyl-phenyl)-vinyl]-2,2-dimethyl-1,3-dioxane-5-yl}-carbamic acid tert-butyl ester, and preparing the compound by hydrogenation reduction.
Description
Technical field
The present invention relates to pharmacy field, be specifically related to the preparation method of { 5-[2-(4-n-octyl phenyl) ethyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate.
Background technology
FTY720 (Fingolimod), commodity are called Gilenya, structure is 2-amino-2-[2-(4-n-octyl phenyl) ethyl]-1,3-PD.On September 22nd, 2010, drugs approved by FDA uses FTY720 as a line medication of recurrence type multiple sclerosis, becomes the medicine that first granted oral administration is treated this disease.At present, this medicine has been got permission in the U.S., Canada, Europe, Russia, Australia's listing.
The important intermediate of synthetic FTY720 and derivative thereof suc as formula { 5-[2-(4-n-octyl phenyl) ethyl]-2, the 2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate shown in the I.At present, the preparation method of formula I compound that only had 2 pieces of bibliographical informations.Kim etc. (Synthesis, 2006,5,753-755) reported a kind of preparation method of formula I compound, adopting 4-n-octyl benzene iodide is raw material, its price is higher, and is difficult for obtaining; The method is the higher trinitride of use cost also, and has danger; In addition, the production cost of the palladium catalysis cross-coupling reaction that adopts is high, is not suitable for scale operation.Balasubramaniam etc. (Synlett, 2007,18, the preparation method of the formula I compound of 2841-2846) reporting, its complex steps, and adopt the tetracol phenixin of severe toxicity to make solvent, total recovery is not high, thereby is unsuitable for suitability for industrialized production yet.
Summary of the invention
Technical problem to be solved by this invention be to overcome above-mentioned 5-[2-(4-n-octyl phenyl) ethyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate (formula I compound) preparation method's deficiency, a kind of cost is low, easy to operate, yield is high and the preparation method of the industrializing implementation of environmental protection but provide.
The preparation method of formula I compound provided by the invention is shown below:
The preparation method of formula I compound provided by the invention specifically may further comprise the steps:
(1) with 1-halo octane (formula II compound)
Make first Grignard reagent, again with 4-halogenated benzoic acid ester (formula III compound)
Cross-coupling reaction occurs, and generates 4-n-octyl manthanoate (formula IV compound)
In formula II, X is halogen, preferred chlorine or bromine;
In formula III, R is the alkyl of C1～10, preferable methyl or ethyl; Y is halogen, preferred chlorine or bromine;
In formula IV, the definition of R is with the definition in the above-mentioned formula III;
(2) reduction of formula IV compound is generated 4-n-octyl methyl alcohol (formula V compound)
(3) formula V compound is carried out halogenating reaction, generate 4-n-octyl benzyl halides (formula VI compound)
In formula VI, Z is halogen, preferred chlorine or bromine;
(4) with formula VI compound and triphenylphosphine reaction, generate (4-n-octyl benzyl) triphenyl phosphonium halide (formula VII compound)
In formula VII, the definition of Z is with the definition among the above-mentioned formula VI;
(5) with (5-formyl radical-2,2-dimethyl-1,3-dioxane-5-yl) t-butyl carbamate (formula VIII compound)
Wittig (Wittig) reaction occurs under the effect of alkali with formula VII compound, generate 5-[2-(4-n-octyl phenyl) vinyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate (formula IX compound)
(6) formula IX compound is carried out hydro-reduction, make formula I compound
In above-mentioned steps (1), formula II compound is made first Grignard reagent, carry out cross-coupling reaction with 4-halogenated benzoic acid ester (formula III compound) again and make 4-n-octyl manthanoate (formula IV compound), concrete preparation method refers to Patent Document US7026478.
In above-mentioned steps (2), the reduction of formula IV compound is generated 4-n-octyl methyl alcohol (formula V compound), this reaction is undertaken by ordinary method well known by persons skilled in the art, 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.
In above-mentioned steps (3), formula V compound is carried out halogenating reaction, generate 4-n-octyl benzyl halides (formula VI compound), this reaction is undertaken by ordinary method well known by persons skilled in the art, and the halide reagent that adopts can be sulfur oxychloride, hydrogenchloride, concentrated hydrochloric acid, hydrogen bromide solution, phosphorus tribromide, phosphorus pentachloride or triphenylphosphine/tetracol phenixin.
In above-mentioned steps (4), with formula VI compound and triphenylphosphine reaction, generate (4-n-octyl benzyl) triphenyl phosphonium halide (formula VII compound), this reaction is undertaken by ordinary method well known by persons skilled in the art, reaction solvent can be toluene, methylene dichloride, DMF or tetrahydrofuran (THF); Temperature of reaction can be selected between 30 ℃～each solvent refluxing temperature.
In above-mentioned steps (5), with (5-formyl radical-2,2-dimethyl-1,3-dioxane-5-yl) Wittig (Wittig) reaction occurs with formula VII compound in t-butyl carbamate (formula VIII compound) under the effect of alkali, generate 5-[2-(4-n-octyl phenyl) vinyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate (formula IX compound), this reaction is undertaken by ordinary method well known by persons skilled in the art, the mol ratio preferred 1～1.5: 1 of formula VII compound and formula VIII compound; 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; But formula VIII compound reference literature method (Synthesis, 2006,5,753-755) preparation.
In above-mentioned steps (6), formula IX compound is carried out hydro-reduction, make formula I compound, this reaction is undertaken by ordinary method well known by persons skilled in the art, and the catalyzer that adopts 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; Temperature of reaction can be selected between each solvent refluxing temperature in room temperature.
Remarkable effect of the present invention is, preparation method provided by the present invention can be advantageously used in the preparation of 5-[2-(4-n-octyl phenyl) ethyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate, and then can prepare easily the medicine FTY720.Compare with existing literature method, preparation method provided by the present invention has following advantage: raw material is cheap and easy to get, total recovery is high, production cost is low, reaction conditions is gentle and convenient post-treatment, thereby can carry out industrializing implementation.
Embodiment
Further describe by the following examples the present invention, still, these embodiment only are for explanation the present invention, rather than limitation of the scope of the invention.
Embodiment 1
Synthesizing of 4-n-octyl methyl-formiate
The preparation of Grignard reagent: under the nitrogen protection, in the airtight three-necked bottle that magnesium chips (1.728g, 72.0mmol) and tetrahydrofuran (THF) (20mL) are housed, add glycol dibromide (0.3mL, 3.6mmol) and cause.After the beginning to be triggered, tetrahydrofuran (THF) (100mL) solution of 1-bromine octane (11.58g, 60mmol) is dropwise added in reaction flask, reaction solution is little to boil built in keeping to drip speed control, after about 30 minutes of the room temperature vigorous stirring, magnesium chips reduces in a large number, and it is for subsequent use to be chilled to room temperature.
Cross-coupling reaction: in the Grignard reagent preparation, with Chlorodracylic acid methyl esters (8.5295g, 50mmol), ferric acetyl acetonade (950mg, 2.69mmol, 5.4%) is dissolved in the mixed solvent of tetrahydrofuran (THF) (300mL) and N-Methyl pyrrolidone (16mL), under the ice bath cooling, stirs.Under the nitrogen protection, the above-mentioned Grignard reagent that is chilled to room temperature was dropwise added in about 1 minute, the ice bath cooling is lower to be continued to stir after 30 minutes, and stirring at room is 10 minutes again.In reaction solution impouring ethyl acetate (200mL), with the cancellation of 1M hydrochloric acid, tell organic phase, water is used ethyl acetate extraction (50mL * 3) again.Merge organic phase, with saturated common salt water washing (50mL * 3), anhydrous sodium sulfate drying, concentrating under reduced pressure get little yellow oil 11.02g, productive rate 86.7%.
1H?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).
Embodiment 2
Synthesizing of 4-n-octyl methyl alcohol
4-n-octyl methyl-formiate (3.1g, 12.5mmol), Lithium chloride (anhydrous) (2.1g, 50mmol), sodium borohydride (1.89g, 50mmol) are joined in the glycol dimethyl ether (80mL) back flow reaction 6 hours.Reaction solution 1M hydrochloric acid cancellation, and transfer pH closely neutral, use again ethyl acetate extraction, organic layer is used respectively saturated sodium bicarbonate solution (25mL) and saturated aqueous common salt (30mL * 3) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure get colorless oil 2.62g, productive rate 95%.
1HNMR(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).
Embodiment 3
Synthesizing of 4-n-octyl bromobenzyl
With 4-n-octyl methyl alcohol (2.2g, 10mmol) be dissolved in the methylene dichloride (40mL), drip phosphorus tribromide (0.9g, 3.33mmol), stirring at room is after 30 minutes, react with the frozen water cancellation, use dichloromethane extraction, organic layer is used saturated sodium bicarbonate solution (20mL * 3) and saturated aqueous common salt (30mL * 3) washing, anhydrous sodium sulfate drying successively again, pressurization concentrates to get faint yellow oily thing 2.60g, productive rate 92%.
1H?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).
Embodiment 4
Synthesizing of (4-n-octyl benzyl) three phenyl phosphonium bromides
4-n-octyl bromobenzyl (2.55g, 9mmol) and triphenylphosphine (2.60g, 10mmol) are dissolved in the toluene (50mL), in 100 ℃ of reacting by heating 5 hours, separate out white solid, filter, white solid is dry after with toluene wash, gets white powder solid 4.8g, productive rate 98%.
1H?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).
Embodiment 5
{ 5-[2-(4-n-octyl phenyl) vinyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate synthetic
With (5-formyl radical-2; 2-dimethyl-1; 3-dioxane-5-yl) t-butyl carbamate (0.227g, 0.875mmol), (4-n-octyl benzyl) three phenyl phosphonium bromides (0.519g, 0.955mmol) are dissolved in the methylene dichloride (15mL); splash into sodium hydroxide solution (3.75M under the room temperature; 0.64mL), vigorous stirring added saturated aqueous common salt (15mL) after 12 hours; tell organic layer, water layer extracts with methylene dichloride (15mL * 3).Merge organic layer, use successively the washing of saturated ammonium chloride solution (20mL * 3) and saturated aqueous common salt (30mL * 3), anhydrous sodium sulfate drying, concentrating under reduced pressure get thick product.(eluent is sherwood oil: ethyl acetate=30: 1) purifying gets purplish transparent thick material 0.35g, and productive rate 90% is (trans: cis=1: 5) through column chromatography.Cis-isomeride:
1H NMR (300MHz, CDCl
3): δ 0.87 (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(ide):
1H NMR (300MHz, CDCl
3): δ 0.87 (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).
Embodiment 6
{ 5-[2-(4-n-octyl phenyl) ethyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate synthetic
Will 5-[2-(4-n-octyl phenyl) vinyl]-2,2-dimethyl-1,3-dioxane-5-yl } t-butyl carbamate (220mg, 0.5mmol) be dissolved in the tetrahydrofuran (THF) (10mL), add 5% palladium carbon (30mg), carry out the normal pressure catalytic hydrogenation, behind the room temperature reaction 12 hours, with the filtering of palladium carbon, get white solid 220mg, productive rate 99% after filtrate decompression is concentrated with diatomite.M.p.:60-61 ℃ (literature value: 63 ℃).
1H?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.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145689A (en) * | 2013-01-24 | 2013-06-12 | 华东师范大学 | Method for combining Fingolimod intermediate |
| CN103275123A (en) * | 2013-05-23 | 2013-09-04 | 浙江肯特化工有限公司 | Preparation method of triphenylmethylphosphonium chloride |
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| US4613622A (en) * | 1983-09-09 | 1986-09-23 | Henkel Kommanditgesellschaft Auf Aktien | Sebosuppressive preparations containing benzyl alcohol derivatives |
| EP0225602A2 (en) * | 1985-12-06 | 1987-06-16 | Ciba-Geigy Ag | Alpha-hydroxythio ethers |
| CN1266844A (en) * | 1999-03-11 | 2000-09-20 | 杭州中美华东制药有限公司 | Process for preparing alkylphenylethyl aminopropanediol and intermediate obtained therein |
| CN1814583A (en) * | 2006-03-01 | 2006-08-09 | 徐州师范大学 | Method for preparing 2-P-octyl-phenenl-2-amino-propanediol hydrochloride |
| WO2011009634A2 (en) * | 2009-07-24 | 2011-01-27 | Ratiopharm Gmbh | Process for producing fingolimod salts |
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| US4613622A (en) * | 1983-09-09 | 1986-09-23 | Henkel Kommanditgesellschaft Auf Aktien | Sebosuppressive preparations containing benzyl alcohol derivatives |
| EP0225602A2 (en) * | 1985-12-06 | 1987-06-16 | Ciba-Geigy Ag | Alpha-hydroxythio ethers |
| CN1266844A (en) * | 1999-03-11 | 2000-09-20 | 杭州中美华东制药有限公司 | Process for preparing alkylphenylethyl aminopropanediol and intermediate obtained therein |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145689A (en) * | 2013-01-24 | 2013-06-12 | 华东师范大学 | Method for combining Fingolimod intermediate |
| CN103145689B (en) * | 2013-01-24 | 2014-07-16 | 华东师范大学 | Method for combining Fingolimod intermediate |
| CN103275123A (en) * | 2013-05-23 | 2013-09-04 | 浙江肯特化工有限公司 | Preparation method of triphenylmethylphosphonium chloride |
| CN103275123B (en) * | 2013-05-23 | 2016-07-06 | 肯特催化材料股份有限公司 | A kind of preparation method of trityl group chlorination |
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Application publication date: 20130102 |