CN1310869C - 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method - Google Patents
2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method Download PDFInfo
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- CN1310869C CN1310869C CNB2005100957663A CN200510095766A CN1310869C CN 1310869 C CN1310869 C CN 1310869C CN B2005100957663 A CNB2005100957663 A CN B2005100957663A CN 200510095766 A CN200510095766 A CN 200510095766A CN 1310869 C CN1310869 C CN 1310869C
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Abstract
The present invention provides a preparation method for 2-amido-2-[2-(4-alkylphenyl) ethyl]-1, 3-trimethylene glycol as shown in a general formula (I). The method uses alkyl benzene II as initial raw materials which react with 3-propanediol through Friedel-Crafts acidylation with lewis acids in order to generate beta-halogenated alkylpropiophenone (III); the III reacts with sodium nitrite to generate a beta-nitro alkyl alkylpropiophenone IV as a key intermediate product. The IV is restored by a composire hydrogen compound to prepare 3-nitro-1-(4-alkyl phenyl) propanol V, and then, 2-nitro-2-methylol-4-(4-alkyl phenyl)-1, 4 butanediol VI is prepared by hydroxymethylation; the intermediate product VI simultaneously eliminates benzyl alcohol calcium bhydroxybmethylbutyrate to obtain the target compound of 2-amino-2-[2-(4-alkylphenyl)dithiophosphate]-1, 3-trimethylene glycol I after nitryl is hydrogenated and restored.
Description
Technical field
The present invention relates to 2-amino-2-[2-(4-alkyl phenyl) ethyl of general formula (I)]-1, the preparation method of ammediol, and the method that in this product of preparation, prepares intermediate product.
In the formula: R is C
1-10Alkyl, be preferably n-octyl.
Background technology
2-amino-2-[2-(4-octyl phenyl) ethyl]-1, the ammediol hydrochloride, be called for short FTY-720, it is micromolecular compound to the structural modification preparation of Cordyceps sinensis main component myriocin, has good immunosuppressive activity, the clinical diseases such as organ transplantation immunologic rejection and multiple sclerosis that are used for.
The synthetic head of this compound sees WO9408943 (priority date: on October 21st, 1992), journal of medicinal chemistry in 2000 (J.Med.Chem.43 (15): 2946-61) with the Japanese chemical pharmacology circular (Chem.Pharm.Bull.53 (1): 100-2) synthesized this compound of WO0053569 and 2005 by different approach, though these methods all have characteristics separately, but, still have insufficient place, the starting material that use as some method are relatively more expensive, the reaction conditions that some method is used is relatively harsher, a lot of intermediate products in some method are liquid oils, need column chromatography purification, not too be fit to the large-scale industrialization preparation.
Summary of the invention
The objective of the invention is provides a kind of 2-amino-2-[2-(4-alkyl phenyl) ethyl at above-mentioned weak point]-1, the preparation method of ammediol, be 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, the preparation of ammediol provides the method for simpler and more direct a, more convenient operation, has reaction conditions gentleness, low cost and other advantages.
2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, the preparation method of ammediol takes following scheme to realize: the 2-amino-2-[2-of the following general formula of a kind of preparation (I) (4-alkyl phenyl) ethyl]-1, the method for ammediol:
In the formula: R is C
1-10Alkyl;
It is characterized in that this method may further comprise the steps:
1), alkylbenzene (II)
With 3-halo propionyl chloride (IX)
In the presence of Lewis acid, carry out the F-C acylation reaction, generation β-halo-to alkylbenzene acetone (III);
In the formula: R is C
1-10Alkyl, X is halogen atom Cl or Br;
2), β-halo-to alkylbenzene acetone (III) and Sodium Nitrite reaction, generation β-nitro-to alkylbenzene acetone (IV);
In the formula: R is C
1-10Alkyl;
3), β-nitro-reduction forms 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) to alkylbenzene acetone (IV);
In the formula: R is C
1-10Alkyl;
4), 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) generates 2-nitro-2-methylol-4-(4-alkyl phenyl)-1,4 butyleneglycol (VI) with formaldehyde condensation under alkaline condition;
In the formula: R is C
1-10Alkyl;
5), the reduction of 2-nitro-2-methylol-4-(4-alkyl phenyl)-1,4 butyleneglycol (VI), hydrogenolysis form target compound 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, ammediol (I).
Wherein, R is a n-octyl.
Wherein, alkylbenzene (II) is 1: 1～1.5 with the mole ratio that 3-halo propionyl chloride (IX) reacts in the step 1); The preferred aluminum trichloride (anhydrous) of Lewis acid, with the mole ratio of alkylbenzene (II) be 2～5: 1.
Wherein, β-halo step 2)-to the mole ratio of alkylbenzene acetone (III) and Sodium Nitrite is 1: 1～5; The reaction solvent for use is non-proton property polar solvent DMF or DMSO.
Wherein, used reductive agent is the multiple hydride of aluminium or boron in the step 3); Used solvent is water or alcohol.
Wherein, described multiple hydride is LiAlH
4, NaBH
4, KBH
4, LiBH
4Described alcohol is C
1-6Fatty Alcohol(C12-C14 and C12-C18).
Wherein, the mole ratio of 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) and formaldehyde is 1: 2～10 in the step 4); The solvent that reacts used is tetrahydrofuran (THF) or dioxane; Reacting employed basic catalyst is triethylamine, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium alkoxide or potassium alcoholate; 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) and catalyzer 1: 1～3.
Wherein, the used hydrogen pressure of step 5) is 1～30kg/cm
2Reduction, the employed solvent of hydrogenolysis are alcohol; Catalyzer is 10% palladium carbon.
Wherein, step 5) also can divide for two steps carried out, 2-nitro-2-methylol-4-(4-alkyl phenyl)-1, the first hydrogenolysis of 4 butyleneglycols (VI) is 2-nitro-2-[2-(4-alkyl phenyl) ethyl]-1, ammediol, reduction becomes 2-amino-2-[2-(4-alkyl phenyl) ethyl then]-1, ammediol (I).
2-amino-2-[2-of the present invention (4-alkyl phenyl) ethyl]-1, the preparation method of ammediol I improves atom utilization, reduces the three wastes, is the target that " green synthetic " pursued.The method of the present invention and prior art relatively; all reagent of the present invention and group substantially all are the needed groups of target compound; the protection or the deprotection reaction that do not have group; therefore; method of the present invention is 2-amino-2-[2-(4-alkyl phenyl) ethyl of more effective, simpler and more direct, more economical a, more convenient operation]-1, the preparation method of ammediol.
Embodiment
The detailed description of invention
The present invention prepares 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, the method for ammediol I can be represented with following reaction formula:
Shown in above-mentioned reaction formula, preparation method of the present invention is to be starting raw material with alkylbenzene II, and alkyl R wherein is C
1-10The straight or branched alkyl, be preferably n-octyl.Alkylbenzene II and 3-halo propionyl chloride carry out the Friedel-Crafts acylation reaction by the ordinary method that those skilled in the art know in the presence of Lewis acid, generate β-halo to alkylbenzene acetone III, wherein: the aforesaid alkyl of R; X is Br or Cl, is preferably Br.β-halo with the Sodium Nitrite reaction, generates crucial intermediate product β-nitro to alkylbenzene acetone IV to alkylbenzene acetone III.β-nitro can make 3-nitro-1-(4-alkyl phenyl) propyl alcohol V, the wherein aforesaid alkyl of R through multiple hydrogen compound reduction earlier to alkylbenzene acetone IV.3-nitro-1-(4-alkyl phenyl) propyl alcohol V makes 2-nitro 2-methylol-4-(4-alkyl phenyl)-1 through methylolation, 4 butyleneglycol VI, intermediate VI takes off the benzylalcohol hydroxyl hydro-reduction nitro time again and obtains target compound 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, ammediol I, the wherein aforesaid alkyl of R.
According to the present embodiment, being reflected in the polar aprotic solvent of compound III and Sodium Nitrite carried out, and is preferably DMF or DMSO; Temperature of reaction 10-100 ℃; The mole ratio of compound III and Sodium Nitrite is 1: 1-5.
β-nitro (4-alkyl) Propiophenone IV reduces with multiple hydrogen compound, and used reductive agent is the multiple hydride and the derivative thereof of aluminium or boron, as LiAlH
4, NaBH
4, KBH
4And LiBH
4, be preferably NaBH
4Or KBH
4The reaction solvent for use is water or alcohol, and employed alcohol is C
1-6Fatty Alcohol(C12-C14 and C12-C18), be preferably ethanol or Virahol.
3-(4-alkyl phenyl)-3-hydroxyl-nitropropane V, the aforesaid alkyl of R wherein, under alkaline condition, with formaldehyde condensation, reacting employed alkali is organic bases or mineral alkali; The organic bases that uses comprises pyridine, triethylamine, sodium alkoxide or potassium alcoholate; Mineral alkali comprises yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide.
Compound VI is reduced under acidic conditions and hydrogenolysis can directly obtain target compound I, wherein can use the catalyzer of catalytic amount well known by persons skilled in the art, and as Pd-C, and hydrogen pressure is 1-30kg/cm
2
According to embodiment of the present invention, compound VI also can first hydrogenolysis form compound VI I, and restoring becomes target compound I.
Further describe the present invention by the following examples, still, these embodiment are used to illustrate the present invention, rather than limitation of the scope of the invention.
Embodiment 1,
Synthesizing of right-octyl group-3-brom-acetophenone
121g (0.637mol) octyl group benzene and 124g (0.727mol) 3-bromo propionyl chloro, the 800ml normal hexane adds and to be equipped with in the 2l three-necked bottle that the condensation drying is used to, and the external application frozen water is chilled to 3 ℃, adds the anhydrous AlCl of 97g (0.73mol)
3Stirring reaction half an hour removes ice-water bath and stirred 1 hour, reheat back flow reaction half an hour, finishes.Stirring to pour in the 1500ml frozen water down has solid to separate out, filtration, and the normal hexane recrystallization, the white plates crystallization, 159.5g (yield: 77%), mp:53～4 ℃.
1HNMR(CDCl
3)：δ7.87(d，2H，J＝8.4Hz，ArH)，7.27(d，2H，J＝8.4Hz，ArH)，3.76(t，2H，J＝6.87Hz，CH
2)，3.55(t，2H，J＝6.87Hz，CH
2)，2.66(t，2H，J＝7.72Hz，CH
2)，1.65-1.56(m，2H)，1.30-1.26(m，10H)，0.88(t，3H，J＝6.7Hz)。
Embodiment 2,
Right-octyl group-3-oil of mirbane acetone must synthesize
70g (0.216mol) is right-and octyl group 3-brom-acetophenone and 340mlDMF mix, and the external application frozen water is chilled to below 20 ℃, adds 61g (0.884mol) Sodium Nitrite, 20 ℃ of insulation reaction 2 hours are poured in the 1200ml water under stirring, and separate out little yellow solid, filter washing, vacuum suck drying, crude product 450ml normal hexane, 1g gac reflux is decoloured half an hour, filters crystallisation by cooling, filter, room temperature vacuum-drying gets white solid 45.5g.Mp.60～2 ℃, yield 72.4%.
1HNMR(CDCl
3)：δ7.87(d，2H，J＝8.16Hz，ArH)，7.27(d，2H，J＝8.16Hz，ArH)，4.82(t，2H，J＝6.0Hz，CH
2)，3.65(t，2H，J＝6.0Hz，CH
2)，2.68(t，2H，J＝7.72Hz，CH
2)，1.66-1.61(m，2H)，1.30-1.26(m，10H)，0.88(t，3H，J＝6.7Hz)。
Embodiment 3,
Synthesizing of right-octyl group-β-oil of mirbane propyl alcohol
13g (0.045mol) is right-and octyl group 3-oil of mirbane acetone and 500ml ethanol mixes, and after the dissolving, room temperature adds 2.0g (0.053mol) sodium borohydride, stirring reaction spends the night, pour in the 100ml frozen water, transfer PH to 5, use ether extraction three times with dilute hydrochloric acid, united extraction liquid, washing twice, anhydrous magnesium sulfate drying, pressure reducing and steaming solvent, get oily liquids 13g, can directly make the next step.
1HNMR (CDCl
3): δ 7.26～7.13 (m, 4H, ArH), 4.78 (t, 1H, J=6.6Hz, CH), 4.63～4.40 (two groups of quintets, 2H, J=6.87Hz, CH
2), 2.60 (t, 2H, J=7.7Hz, CH
2), 2.42～2.34 (m, 2H), 2.15 (s, br, 1H, OH), 1.60 (t, 2H, J=6.87, CH
2), 1.30-1.19 (m, 10H), 0.88 (t, 3H, J=6.45Hz).
Embodiment 4,
2-methylol-2-nitro-4-(4-octyl phenyl)-1,4-butyleneglycol synthetic
7g (0.233mol) Paraformaldehyde 96, the 70ml1.4-dioxane, the 4ml triethylamine is mixed in the three-necked bottle, stir add down 15g right-octyl group-3-oil of mirbane propyl alcohol, slowly be heated to 70 ℃, insulation reaction 2 hours, pressure reducing and steaming solvent, raffinate are thick, put into and to, crystallisation by cooling filters, and filter cake is refining with 80ml tetracol phenixin and 2ml chloroform mixed solution, activated carbon decolorizing, crystallisation by cooling filters, 50 ℃ of dryings get white solid 9g.Yield 56.6%.mp.81～83℃。
1HNMR (CDCl
3): δ 7.26 (d, 2H, J=7.9Hz, ArH), 7.13 (d, 2H, J=7.9Hz, ArH), 4.78 (t, 1H, J=6.6Hz, CH), 4.63～4.40 (two groups of quintets, 2H, J=6.87Hz, CH
2), 2.60 (t, 2H, J=7.7Hz, CH
2), 2.42～2.34 (m, 2H), 2.15 (s, br, 1H, OH), 1.60 (t, 2H, J=6.87, CH
2), 1.30-1.19 (m, 10H), 0.88 (t, 3H, J=6.45Hz).
Embodiment 5,
2-amino-2-[2-(4-octyl phenyl) ethyl]-1, ammediol;
14.1g the methylol of 2-(0.04mol)-2-nitro 4-(4-octyl phenyl)-1, the 4-butyleneglycol, 250mL methyl alcohol, the 31mL concentrated hydrochloric acid in the 500mL autoclave pressure, adds 4.8g10% palladium-carbon, 20kg/cm
2Stirring at room 48 hours is filtered, and distillation for removing methanol is regulated pH8 with saturated sodium bicarbonate, ethyl acetate extraction (200mL * 3), merge, dried over mgso is filtered, the filtrate distillation, the residue re-crystallizing in ethyl acetate, white plates crystallization 8.1g, yield: 66.2%, mp:122～4 ℃.
1HNMR(DMSO-D
6)：δ7.06(s，4H，ArH)，4.46(s，br，2H，NH
2)，3.21-3.27(m，4H，CH
2OHx2)，2.48-2.56(m，4H)，1.44-1.50(m，4H)，1.24-1.26(m，12H)，0.85(t，J＝6.7Hz，3H)。
Embodiment 6,
2-nitro-2-[2-(4-octyl phenyl) ethyl]-1, ammediol:
3.4g the methylol of 2-(0.0096mol)-2-nitro-4-(4-octyl phenyl)-1, the 4-butyleneglycol places the 250mL there-necked flask, adds 180mL ethanol, 1.24g10% palladium-carbon, the 3mL concentrated hydrochloric acid, 60 ℃ of normal pressures led to hydrogen 48 hours, filtered distillation, residue normal hexane recrystallization, white plates crystallization 2.0g, yield: 63%, mp:100～2 ℃.
1HNMR(CDCl
3)：δ7.11～7.04(m，4H，ArH)，4.26～4.23(m，2H，CH
2)，4.05～4.01(m，2H，CH
2)，2.74(s，br，2H，OH)，2.58～2.51(m，4H，2×CH
2)，2.19～2.14(m，2H，CH
2)，1.57(m，2H，CH
2)，1.30～1.26(m，10H，CH
2)，0.88(t，3H，J＝6.87Hz，CH
3)。
Embodiment 7,
2-amino-2-[2-(4-octyl phenyl) ethyl]-1, ammediol;
10.89 2-nitro-2-[2-(0.032mol) (4-octyl phenyl) ethyl]-1, ammediol, 250mL methyl alcohol, the 15mL glacial acetic acid solution in the 500mL autoclave pressure, adds 3.8g10% palladium-carbon, 20kg/cm
2Stirring at room 20 hours is filtered, and filtrate is regulated pH8 with saturated sodium bicarbonate, distillation for removing methanol, ethyl acetate extraction (200mL * 3) merges dried over mgso, filter, the filtrate distillation, the residue re-crystallizing in ethyl acetate gets white plates crystallization 4.1g, yield: 41.7%, fusing point is identical with embodiment 5 with proton nmr spectra.
Embodiment 8,
2-amino-2-[2-(4-octyl phenyl) ethyl]-1, the ammediol hydrochloride:
4.18g 2-amino-2-[2-(0.0137mol) (4-octyl phenyl) ethyl]-1, ammediol adds 40mL ethanol, add saturated ether solution of hydrogen chloride to pH4, distillation, residue alcohol-ether recrystallization, white plates crystallization 3.0g, yield: 65.5%, mp:106～8 ℃.
1HNMR(CDCl
3)：δ7.87(br，3H，NH
3 +)，7.03(d，2H，J＝7.9Hz，ArH)，6.94(d，2H，J＝7.9Hz，ArH)，4.96(br，2H，OH)，3.77(br，4H，CH
2)，2.57(br，2H，CH
2)，2.42(t，2H，J＝7.1Hz，CH
2)，1.94(br，2H，CH
2)，1.48(br，2H，CH
2)，1.25(br，10H，CH
2)，0.87(t，3H，J＝6.66Hz，CH
3)。
Claims (9)
1, the 2-amino-2-[2-of the following general formula of a kind of preparation (I) (4-alkyl phenyl) ethyl]-1, the method for ammediol:
It is characterized in that this method may further comprise the steps:
1), alkylbenzene (II)
With 3-halo propionyl chloride (IX)
In the presence of Lewis acid, carry out the F-C acylation reaction, generation β-halo-to alkylbenzene acetone (III);
X is halogen atom Cl or Br in the formula;
2), β-halo-to alkylbenzene acetone (III) and Sodium Nitrite reaction, generation β-nitro-to alkylbenzene acetone (IV);
3), β-nitro-reduction forms 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) to alkylbenzene acetone (IV);
4), 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) generates 2-nitro-2-methylol-4-(4-alkyl phenyl)-1,4 butyleneglycol (VI) with formaldehyde condensation under alkaline condition;
5), the reduction of 2-nitro-2-methylol-4-(4-alkyl phenyl)-1,4 butyleneglycol (VI) forms target compound 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1, ammediol (I);
R in the above-mentioned general formula is C
1-10Alkyl.
2, method according to claim 1 is characterized in that wherein, and R is a n-octyl.
3, method according to claim 1 is characterized in that wherein, and alkylbenzene in the step 1) (II) is 1: 1～1.5 with the mole ratio of 3-halo propionyl chloride (IX) reaction; The preferred aluminum trichloride (anhydrous) of Lewis acid, with the mole ratio of alkylbenzene (II) be 2～5: 1.
4,, it is characterized in that wherein step 2 according to the method for claim 1) in β-halo-to the mole ratio of alkylbenzene acetone (III) and Sodium Nitrite be 1: 1～5; The reaction solvent for use is non-proton property polar solvent DMF or DMSO.
5, method according to claim 1 is characterized in that wherein, and used reductive agent is the multiple hydride of aluminium or boron in the step 3); Used solvent is water or alcohol.
6, method according to claim 5 is characterized in that wherein, and described multiple hydride is LiAlH
4, NaBH
4, KBH
4, LiBH
4Described alcohol is C
1-6Fatty Alcohol(C12-C14 and C12-C18).
7, method according to claim 1 is characterized in that wherein, and (4-alkyl phenyl) propyl alcohol of 3-nitro-1-in the step 4) (V) is 1: 2～10 with the mole ratio of formaldehyde; The solvent that reacts used is tetrahydrofuran (THF) or dioxane; Reacting employed basic catalyst is triethylamine, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium alkoxide or potassium alcoholate; 3-nitro-1-(4-alkyl phenyl) propyl alcohol (V) and catalyzer 1: 1～3.
8, method according to claim 1 is characterized in that wherein, and the used hydrogen pressure of step 5) is 1～30kg/cm
2Reduction, the employed solvent of hydrogenolysis are alcohol; Catalyzer is 10% palladium carbon.
9, method according to claim 1, it is characterized in that wherein, reduction in the step 5) divided for two steps carried out, 2-nitro-2-methylol-4-(4-alkyl phenyl)-1,4 butyleneglycol (VI) is reduced to 2-nitro-2-[2-(4-alkyl phenyl) ethyl earlier]-1, ammediol, reduction becomes 2-amino-2-[2-(4-alkyl phenyl) ethyl then]-1, ammediol (I).
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| WO2012041359A1 (en) | 2010-10-01 | 2012-04-05 | Synthon B.V. | Process for making fingolimod |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5604229A (en) * | 1992-10-21 | 1997-02-18 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
| 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 |
-
2005
- 2005-11-22 CN CNB2005100957663A patent/CN1310869C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5604229A (en) * | 1992-10-21 | 1997-02-18 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
| 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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012041359A1 (en) | 2010-10-01 | 2012-04-05 | Synthon B.V. | Process for making fingolimod |
| WO2012041707A1 (en) | 2010-10-01 | 2012-04-05 | Synthon Bv | Process for making fingolimod |
| WO2012041405A1 (en) | 2010-10-01 | 2012-04-05 | Synthon B.V. | Process for making fingolimod |
| WO2012056458A3 (en) * | 2010-10-28 | 2013-07-18 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of fingolimod |
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