CN1528738A - Method for preparing 2-para octylphenyl ehtyl-2-amino propanediol - Google Patents
Method for preparing 2-para octylphenyl ehtyl-2-amino propanediol Download PDFInfo
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Abstract
The invention provides a method to prepare a compound method, including the steps: ethylbenzene and capryl chloride make Friedel-Crafts reaction to generate p-capryl chloroethylbenzene; convert capryl chloroethylbenzene under the action of sodium iodide into p-capryl iodoethylbenzene; p-capryl iodoethylbenzene and acetylamino diethyl malonate condense under the action of alkali to generate 2-(p-capryl phenethyl)-2-acetylamino diethyl malonate; or p-capryl iodoethylbenzene makes elimination reaction under the action of alkali to generate p-capryl styrene, which together with acetylamino diethyl malonate condenses under the action of alkali into 2-(p-capryl phenethyl)-2- acetylamino diethyl malonate; a compound is reduced into 2-[4-(1-hydroxyoctyl) phenethyl-]2- acetylamino propylene alcohol; the other coumpound makes hydrogenolysis to obtain 2-(p-octyl phenethyl)-acetylamino propylene alcohol; make alkali hydrolyzation and then acidifies them into salt, so as to obtain it. It also provides a method to prepare intermediate in the above preparing course.
Description
Affiliated technical field
The present invention relates to the method for a kind of 2-of preparation to octyl group styroyl-2-amino-propanediol.
Background technology
2-is an immunosuppressor to octyl group styroyl-2-amino-propanediol (being called for short FTY720) and hydrochloride thereof, is carrying out clinical study at present.Pharmacological tests shows that this compound can prolong the lifetime of animal in the test of the renal transplantation of dermatoplasty, heart transplantation and the dog of rat.Especially with immunosuppressor drug combinations such as FTY-720 and S-Neorals, use S-Neoral or FTY-720 can suppress the immunological rejection of transplant organ more significantly more separately, prolong the existence of animal.And the toxicity of this compound significantly is lower than the immunosuppressor of using clinically now, will have good prospect.
2-to the structural formula of octyl group styroyl-2-amino-propanediol hydrochloride (I) suc as formula shown in one:
Formula one:
Compound (I) is the openest in PCT/JP93/01515, and wherein the preparation method of FTY-720 is to be starting raw material with the phenylethyl alcohol, and reaction finally obtains product through ten steps.The weak point of this method is that reactions steps is long, and comprises that the yield of Friedel-Crafts reaction, reduction, hydrolysis and step such as refining is lower, causes total recovery only to have an appointment 4%.The polystep reaction agents useful for same is dangerous big, is not suitable for a large amount of preparations.A kind of new preparation method is disclosed in CN99102879.1 subsequently.This method is a starting raw material with octyl group benzene, and through seven step prepared in reaction FTY-720, total recovery is about 22%, and reactions steps is short, and yield is greatly improved than first method.But the price height of starting raw material octyl group benzene makes the cost of product also high.In addition, the intermediate with α-bromoacetophenone structure has lacrimation, has the labour protection problem.
Summary of the invention
The purpose of this invention is to provide the method for a kind of 2-of preparation to octyl group styroyl-2-amino-propanediol, it is long to overcome in the background technology reactions steps, the deficiency that total recovery is low.
In order to achieve the above object, the technical solution used in the present invention is as follows:
It is a starting raw material with chloroethyl benzene (II), and reaction obtains FTY-720 (I) through seven steps, and its step is as follows:
Formula two:
1) chloroethyl benzene (II) carries out the Friedel-Crafts reaction with capryl(yl)chloride, generates capryloyl chloroethyl benzene (III);
2) capryloyl chloroethyl benzene (III) is changed under the effect of sodium iodide capryloyl iodine ethylbenzene (IV);
3) capryloyl iodine ethylbenzene (IV) and acetamino diethyl malonate (V) condensation under the effect of alkali are generated 2-to capryloyl styroyl-2-acetamino diethyl malonate (VI);
4) capryloyl iodine ethylbenzene (IV) being eliminated reaction under the effect of alkali generates capryloyl vinylbenzene (IX); Capryloyl vinylbenzene (IX) and acetamino diethyl malonate (V) condensation under the effect of alkali are generated 2-to capryloyl styroyl acetamino diethyl malonate (VI);
5) compound (VI) reduction generate 2-[4-(1-hydroxyl octyl group) styroyl-] 2-kharophen propylene glycol (VII);
6) compound (VII) obtains octyl group styroyl kharophen propylene glycol (VIII) through hydrogenolysis;
7) compound (VIII) basic hydrolysis, the hcl acidifying salify obtains (I) then;
8) compound (I) recrystallization obtains the pure product of (I).
Method of the present invention is to be raw material with chloroethyl benzene (II), carries out the Friedle-Crafts prepared in reaction to capryloyl chloroethyl benzene (III) under the catalysis of lewis acid with capryl(yl)chloride; Preferred AlCl
3Be catalyzer, consumption is 0.7~1.0 times of chloroethyl benzene (II) weight; Chloroethyl benzene (II) is 1: 2~1: 5 with the mol ratio of capryl(yl)chloride; Reaction solution is through aftertreatment, and product (III) has enough purity, is used for the reaction with next step.Formula as follows:
The preparation of key intermediate compound of the present invention (IV) is by the iodine permutoid reaction of compound (III) in the presence of iodide, the preferred sodium iodide of iodide.Compound (III) is 1: 2~1: 5 with the molar ratio range of iodide.The iodine permutoid reaction is carried out in aprotic polar solvent, and preferred butanone is as reaction solvent.Formula as follows:
Another key intermediate of the present invention (VI) is to carry out condensation by compound (IV) and acetamino diethyl malonate (V) under alkaline condition to obtain; Compound (IV) and molar ratio range (V) are 1: 2~1: 5.The alkali that reacts used can select alkali-metal hydride, alkali-metal alkoxy compound or alkali-metal ammonia (amine) to change thing, as: hydrogen sodium, hydrogen calcium, sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium amide, two trimethyl silicane sodium amides etc., the preferred as alkali alkoxide, more preferably sodium ethylate and sodium methylate, compound (V) is 1: 1~1: 1.5 with the molar ratio range of alkali.Reaction solvent uses non-proton anhydrous solvent, preferred anhydrous tetrahydro furan.Formula as follows:
Compound (VI) obtains another key intermediate of the present invention (VII) with multiple hydride reduction.The used preferred NaBH of multiple hydride reducer
4And KBH
4, compound (VI) is 1: 5~1: 10 with the molar ratio range of multiple hydride.Reaction solvent uses the single alcohol solvent or contains the mixed solvent of alcohol, preferred alcohol, ethanol/water.Also can add damping fluid in the reaction solution, as phosphoric acid salt.Formula as follows:
Compound (VII) hydrogenolysis obtains compound (VIII).The preferred Pd-C of catalyzer that hydrogenolysis is used, its amount ranges is 3~10% of compound (VII) weight.Solvent uses methyl alcohol or ethanol.Add a spot of acid and can accelerate the carrying out of hydrogenolysis, its amount ranges is 10~15% of compound (VII) weight.Formula as follows:
Compound (VIII) is through basic hydrolysis, and hcl acidifying obtains FTY-720 subsequently.Hydrolysis is to carry out in alkaline alcohol solution.Used alkali is sodium hydroxide or potassium hydroxide.Used alcohol is methyl alcohol or ethanol.Formula as follows:
According to another kind of preparation compound (VI) method of the present invention, by shown in the formula three.Compound (IX) is the product that compound (IV) is eliminated under alkaline condition, also is one of key intermediate of the present invention; Used alkali preferred alcohol sodium, compound (IV) is 1: 2~1: 5 with the molar ratio range of alkali, solvent is an alcohols, preferred dehydrated alcohol.Compound (IX) obtains compound (VI) equally with compound (V) addition under alkaline condition; Compound (IX) is 1: 2~1: 5 with the molar ratio range of compound (V), the preferred NaH of used alkali; Compound (V) is 1: 1~1: 2 with the molar ratio range of alkali; Used solvent is an alcohols, preferred dehydrated alcohol.
Formula three
According to another scheme of the present invention, shown in four, the first hydrogenolysis of compound (VI) restores ester group, and the hydrolysis ethanoyl obtains FTY-720 too then.
Formula four
Compound (VI) hydrogenolysis obtains compound (X).The preferred Pd-C of hydrogenolysis catalyst system therefor, the catalyst consumption scope is 3~10% of compound (VI) weight.Solvent adopts ethanol or methyl alcohol.Add a spot of acid and can accelerate the carrying out of hydrogenolysis, its amount ranges is 5~15% of compound (VI) weight.。Formula as follows:
Compound (X) obtains compound (VIII) with multiple hydride reduction.Used multiple hydride is NaBH as previously mentioned
4Or KBH
4, the molar ratio range of itself and compound (X) is 4: 1~8: 1.Formula as follows:
The present invention compares with background technology, and the useful effect that has is:
According to the method for synthetic FTY-720 of the present invention, raw materials used phenylethyl alcohol is cheap, be easy to get, and only is 1/12nd of octyl group benzene price.Synthetic route is also shorter, and total recovery reaches 30~35%.In a word, the present invention is a method one easier, the more effective FTY-720 of preparation.
Embodiments of the invention only are used to illustrate the present invention, and can not cause restriction to its invention scope.
Embodiment
Embodiment:
One. compound is to the preparation of capryloyl chloroethyl benzene (III):
Under water quench, behind 365.6g (2.25mol) capryl(yl)chloride input reactor, temperature is no more than 50 ℃ and drops into the 118g aluminum trichloride (anhydrous) in batches in the control, has thrown and has stirred 30 minutes, begins slowly to drip 140.5g (1mol) chloroethyl benzene (II) when dropping to-2 ℃ with the icy salt solution cooling temperature.Add back 4 hours , Pour of insulation and pour hydrolysis in the hydrochloric acid into, with chloroform extraction twice, the combined chloroform layer.Organic layer is told chloroform layer with 10% hydrochloric acid washed twice, to neutral, use anhydrous sodium sulfate drying with the saturated brine washing, and concentrated red oil is to the about 252g of capryloyl chloroethyl benzene (III), yield 94%.
1H?NMR(CDCl
3)δ:7.89(d,J=9.6Hz,2H),7.26(d,J=9.6Hz,2H),4.15~4.13(m,2H),2.79~2.90(m,4H),1.71(m,2H),1.37~1.28(m,8H),0.88(t,J=7.8Hz,3H).
Two. to the preparation of capryloyl iodine ethylbenzene (IV):
100g (0.3752mol) dropped in the reaction flask capryloyl chloroethyl benzene (III), 112.5g (0.75mol) sodium iodide and 600g butanone refluxed 18 hours.Reflux and finish, reclaim butanone.Add the water of 3 times of amounts and the chloroform of 3 times of amounts, branch vibration layer in the raffinate.Reclaim chloroform and filter to alcohol and the gac reflux decolour that basic dried back adds 4 times of amounts, mother liquor is cooled to 0 ℃ of left and right sides crystallization, filters, and vacuum-drying gets white crystals to capryloyl iodine ethylbenzene (IV) 100g, 35~37 ℃ of mp.Yield 74%.
1H?NMR(CDCl
3)δ:7.80(d,J=9.6Hz,2H),7.22(d,J=9.6Hz,2H),3.58-3.45(m,2H),2.79~2.90(m,4H),1.71(m,2H),1.37~1.28(m,8H),0.88(t,J=7.8Hz,3H).MS(m/z)358.
Three .2-are to the preparation of capryloyl styroyl-2-acetamino diethyl malonate (VI):
175g (0.81mol) acetamino diethyl malonate (V) is put in the 50ml anhydrous tetrahydro furan after the heating for dissolving, dropped into 55g (0.81mol) sodium ethylate back flow reaction more than 1 hour.At 55-60 ℃, drop into 100g (0.2793mol) again to capryloyl iodine ethylbenzene (IV), add the back and reflux insulation after 30 hours, it is reaction end that sampling disappears with raw material (IV) spot substantially with the TLC detection reaction.Reacted, reclaimed tetrahydrofuran (THF), added chloroform and frozen water, branch vibration layer.Chloroform layer is used anhydrous sodium sulfate drying with a small amount of washing, reclaims chloroform.The residue dissolve with methanol adds the gac reflux decolour, filters, and is freezing to-5 ℃ of filtrations.Filtrate is reclaimed methyl alcohol, and residue adds the sherwood oil and the ethyl acetate mixed organic solvents recrystallization of 8 times of amounts, drying under reduced pressure, white crystals 2-to capryloyl styroyl-2-acetamino diethyl malonate (VI) 90g, mp:67~69 ℃.Yield 72%.
1H?NMR(CDCl
3)δ:7.86(d,J=9.6Hz,2H),7.23(d,J=9.6Hz,2H),6.78(s,1H),4.25~4.18(m,4H),2.92(t,J=8.0Hz,2H),2.71(t,J=8.2Hz,2H),2.54(t,J=8.2Hz,2H),1.99(s,3H),1.73~1.68(m,2H),1.36~1.24(m,14H),0.88(t,J=8.0Hz,3H).
Four .2-[4-(1-hydroxyl octyl group) styroyl-] preparation of 2-kharophen propylene glycol (VII)
90g (0.2013mol) 2-is added 360g damping fluid (solution of 180g three water dipotassium hydrogen phosphates and 180g water) to capryloyl styroyl-2-acetamino diethyl malonate (VI) after with the 1800mL dissolve with ethanol; cool to about 10 ℃; under this temperature, add 54g (1.421mol) sodium borohydride; add the 15-20 ℃ of reaction in back more than 10 hours, it is reaction end that sampling disappears with raw material (VI) spot substantially with the TLC detection reaction.Back branch sub-cloud reacts completely, PH=6 is transferred with the hydrochloric acid of 1N in the upper strata, reclaims ethanol, residual water layer ethyl acetate extraction, organic layer is washed with saturated sodium-chloride, steam to remove ethyl acetate get light yellow oil 2-[4-(1-hydroxyl octyl group) styroyl-] 2-kharophen propylene glycol (VII) 72g.
1H?NMR(CDCl
3)δ:7.24(d,J=7.8Hz,2H),7.15(d,J=7.8Hz,2H),5.99(s,1H),4.61(t,J=6.3Hz,1H),3.80(d,J=11.4Hz,2H),3.56(d,J=11.4Hz,2H),2.70~2.60(m,2H),1.95(s,3H),1.98~1.90(m,2H),1.22(m,10H),0.85(t,J=6.6Hz,3H).
Five .2-are to the preparation of octyl group styroyl-2-kharophen propylene glycol (VIII):
With above-mentioned 72g 2-[4-(1-hydroxyl octyl group) styroyl-] 2-kharophen propylene glycol (VII) oily matter is with adding 4.5g 10%Pd/C and 10ml hydrochloric acid behind the 700mL dissolve with ethanol.At 20-30 ℃, 2-3kg/cm
2Reaction is 3 hours under the condition, and it is reaction end that sampling disappears with raw material (VII) spot substantially with the TLC detection reaction.Filtering reacting liquid, filtrate neutralizes with sodium hydrogen carbonate solution, reclaims ethanol, add 200ml water in the residue, the water layer ethyl acetate extraction, the saturated sodium-chloride washing, steaming removes ethyl acetate and gets light yellow oil 2-to octyl group styroyl-2-kharophen propylene glycol (VIII) 58g.
Six .2-are to the preparation of octyl group styroyl-2-amino-propanediol hydrochloride (I):
To add 15g sodium hydroxide behind above-mentioned 58g 2-octyl group styroyl-2-kharophen propylene glycol (VIII) oily matter usefulness 200mL dissolve with methanol.Back flow reaction 4 hours, it is reaction end that sampling disappears with raw material (VIII) spot substantially with the TLC detection reaction.After reacting completely, reclaim methyl alcohol.Residue oily matter adds in the dehydrated alcohol after the dissolving, feeds exsiccant hydrogenchloride and transfer PH=4-5 in solution, concentrate white solid.Crude product gets white, needle-shaped crystals 2-to octyl group styroyl-2-amino-propanediol hydrochloride (I) 46g through the Virahol recrystallization.Yield 66% (in VI)
1H?NMR(DMSO)δ:7.97(s,3H),7.10(s,4H),5.41(s,2H),3.53(s,4H),2.58(m,2H),2.51(m,2H),1.79(m,2H),1.52(br.S,2H),1.25(m,10H),0.85(t,J=8.4Hz,3H).
Seven. to the preparation of capryloyl vinylbenzene (IX):
Method 1:
3.58 (0.01mol) to capryloyl-iodine ethylbenzene (IV), are put in the 50mL methyl alcohol after the heating for dissolving, dropped into 1.62g (0.03mol) sodium methylate back flow reaction 13 hours, it is reaction end that sampling disappears with raw material (IV) spot substantially with the TLC detection reaction.After reacting completely, reclaim methyl alcohol, add chloroform and frozen water, branch vibration layer to doing.Chloroform layer is used anhydrous sodium sulfate drying with washing neutrality on a small quantity, concentrates the residue recrystallizing methanol that obtains, and gets white crystals 4-capryloyl vinylbenzene (IX) 1.79g.Mp:62~64 ℃ yield 77.7%
Method 2:
100g (0.2793mol) is put in the 500ml dehydrated alcohol capryloyl-iodine ethylbenzene (IV); drop into 55g (0.81mol) sodium ethylate after the dissolving again; at 55-60 ℃; again; add the back and reflux insulation after 10 hours, it is reaction end that sampling disappears with raw material (IV) spot substantially with the TLC detection reaction.After reacting completely, reclaim dehydrated alcohol, add chloroform and frozen water, branch vibration layer.Chloroform layer is used anhydrous sodium sulfate drying with a small amount of washing, reclaims chloroform.The residue recrystallizing methanol, drying under reduced pressure, white crystals to capryloyl vinylbenzene (IX) 54g, mp:62~64 ℃.Yield 85%.
1H?NMR(CDCl
3)δ:7.91(d,J=9.6Hz,2H),7.47(d,J=9.6Hz,2H),4.74(dd,J=13.2,21.0Hz,1H),5.86(d,J=21.0Hz,1H),5.37(d,J=13.2Hz,1H),2.93(t,J=9.0Hz,2H),1.71(m,2H),1.40~1.20(m,8H),0.88(t,J=8.4Hz,3H).
Eight .2-are to the preparation of octyl group styroyl-2-acetamino diethyl malonate (X):
5.43g (0.025mol) acetamino diethyl malonate (V) is put in the 35mL dehydrated alcohol after the heating for dissolving, dropped into 0.6g (0.025mol) hydrogen sodium back flow reaction 1 hour.At 55-60 ℃, drop into 2.3g (0.01mol) again to capryloyl vinylbenzene (IX), add the back and reflux insulation after 35 hours, it is reaction end that sampling disappears with raw material (IX) spot substantially with the TLC detection reaction.Reacted, reclaimed ethanol, added chloroform and frozen water, branch vibration layer.Chloroform layer is used anhydrous sodium sulfate drying with a small amount of washing, reclaims chloroform.Residue is through column chromatography for separation (sherwood oil, ethyl acetate mixed solvent), white crystals 2-to capryloyl styroyl-2-acetamino diethyl malonate (VI) 1.65g, mp:67~69 ℃.Yield 37%.
1.65g (0.0037mol) 2-is added 0.1g 10%Pd/C and 0.23ml hydrochloric acid to capryloyl styroyl-2-acetamino diethyl malonate (VI) after with the 70mL dissolve with ethanol.At 20-30 ℃, 2-3kg/cm
2Reaction is 3 hours under the condition, and it is reaction end that sampling disappears with raw material (VI) spot substantially with the TLC detection reaction.Filtering reacting liquid, filtrate neutralizes with sodium hydrogen carbonate solution, reclaims ethanol, add 20ml water in the residue, the water layer ethyl acetate extraction, the saturated sodium-chloride washing is reclaimed ethyl acetate and is got light yellow oil 2-to octyl group styroyl-2-acetamino diethyl malonate (X) 1.35g.Yield 84%
1H?NMR(CDCl
3)δ:7.05(s,4H),6.74(s,1H),4.20(q,J=6.2Hz,4H),2.80~2.30(m,6H),2.95(s,3H),1.75-1.20(m,12H),1.14(t,J=6.2Hz,6H),0.86(t,J=6.0Hz,3H)。
Claims (7)
1. method for preparing 2-to octyl group styroyl-2-amino-propanediol is characterized in that:
It may further comprise the steps:
1) chloroethyl benzene (II) carries out the Friedel-Crafts reaction with capryl(yl)chloride, generates capryloyl chloroethyl benzene (III);
2) capryloyl chloroethyl benzene (III) is changed under the effect of sodium iodide capryloyl iodine ethylbenzene (IV);
3) capryloyl iodine ethylbenzene (IV) and acetamino diethyl malonate (V) condensation under the effect of alkali are generated 2-to capryloyl styroyl-2-acetamino diethyl malonate (VI);
4) capryloyl iodine ethylbenzene (IV) being eliminated reaction under the effect of alkali generates capryloyl vinylbenzene (IX); Capryloyl vinylbenzene (IX) and acetamino diethyl malonate (V) condensation under the effect of alkali are generated 2-to capryloyl styroyl acetamino diethyl malonate (VI);
5) compound (VI) reduction generate 2-[4-(1-hydroxyl octyl group) styroyl-] 2-kharophen propylene glycol (VII);
6) compound (VII) obtains octyl group styroyl kharophen propylene glycol (VIII) through hydrogenolysis;
7) compound (VIII) basic hydrolysis, the hcl acidifying salify obtains (I) then;
8) compound (I) recrystallization obtains the pure product of (I).
2. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1, it is characterized in that: step 1) is a raw material with chloroethyl benzene (II), carries out the Friedle-Crafts prepared in reaction to capryloyl chloroethyl benzene (III) under the catalysis of lewis acid with capryl(yl)chloride; Preferred AlCl
3Be catalyzer, consumption is 0.7~1.0 times of chloroethyl benzene (II) weight; Chloroethyl benzene (II) is 1: 2~1: 5 with the molar ratio range of capryl(yl)chloride; The structural formula of compound (III) is as follows:
3. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1 is characterized in that: step 2) compound (III) carries out the iodine permutoid reaction and generates compound (IV), the preferred sodium iodide of iodide in the presence of iodide; Compound (III) is 1: 2~1: 5 with the mol ratio of iodide; The iodine permutoid reaction is carried out in aprotic polar solvent, and preferred butanone is as reaction solvent; The structural formula of compound (IV) is as follows:
4. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1 is characterized in that: step 3) compound (IV) carries out condensation with acetamino diethyl malonate (V) and obtains compound (VI) under alkaline condition; Compound (IV) and molar ratio range (V) are 1: 1~1: 5; The alkali that reacts used can select alkali-metal hydride, alkali-metal alkoxy compound or alkali-metal ammonia (amine) to change thing, as: hydrogen sodium, hydrogen calcium, sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium amide, two trimethyl silicane sodium amides etc., preferred as alkali alkoxide, more preferably sodium ethylate and sodium methylate; Compound (V) is 1: 1~1.5 with the molar ratio range of alkali; Reaction solvent uses non-proton anhydrous solvent, preferred ether solvent, more preferably anhydrous tetrahydro furan; The structural formula of compound (VI) is as follows:
5. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1, it is characterized in that: step 4) compound (IX) is the product that compound (IV) is eliminated under alkaline condition, used alkali preferred alcohol sodium, compound (IV) is 1: 2~1: 5 with the molar ratio range of alkali; Solvent is an alcohols, preferred dehydrated alcohol; Compound (IX) structural formula is as follows:
Compound (IX) obtains compound (VI) equally with acetamino diethyl malonate (V) addition under alkaline condition; Compound (IX) and molar ratio range (V) are 1: 2~1: 5; The preferred NaH of used alkali; Compound (V) is 1: 1~1: 2.5 with the molar ratio range of alkali, and used solvent is an alcohols, preferably dehydrated alcohol.
6. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1 is characterised in that: step 5) compound (VI) obtains another key intermediate of the present invention (VII) with multiple hydride reduction; The used preferred NaBH of multiple hydride reducer
4And KBH
4, the molar ratio range of itself and compound (VI) is 5: 1~10: 1; Reaction solvent uses the single alcohol solvent or contains the mixed solvent of alcohol, preferred alcohol, ethanol/water.Also can add damping fluid in the reaction solution, as phosphoric acid salt; The structural formula of compound (VII) is as follows:
7. a kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol according to claim 1, it is characterized in that: step 6) compound (VII) hydrogenolysis obtains compound (VIII); The preferred Pd-C of catalyzer that hydrogenolysis is used, its amount ranges is 3~10% of compound (VII) weight; Solvent uses methyl alcohol or ethanol, adds the speed that a spot of acid can be accelerated hydrogenolysis, and its amount ranges is 5~15% of a compound VI I weight.
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CN103922943B (en) * | 2014-04-18 | 2015-04-08 | 安徽安腾药业有限责任公司 | Method for preparing fingolimod hydrochloride |
CN103922943A (en) * | 2014-04-18 | 2014-07-16 | 安徽安腾药业有限责任公司 | Method for preparing fingolimod hydrochloride |
CN106397224A (en) * | 2016-08-15 | 2017-02-15 | 东莞明日医药有限公司 | A novel synthetic method of fingolimod |
CN106397224B (en) * | 2016-08-15 | 2021-06-29 | 广州明药科技有限公司 | Novel synthesis method of fingolimod |
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