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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- nitro
- alkyl phenyl
- alkylbenzene
- ethyl
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000004996 alkyl benzenes Chemical class 0.000 claims abstract description 30
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- -1 hydrogen compound Chemical class 0.000 claims abstract description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910010082 LiAlH Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 239000004411 aluminium Substances 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N 1,4-butanediol Substances OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 abstract description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 5
- 239000013067 intermediate product Substances 0.000 abstract description 5
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 238000007031 hydroxymethylation reaction Methods 0.000 abstract 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- SUSUNJZIRVZIIO-UHFFFAOYSA-N 3-(hydroxymethyl)-3-nitro-1-(4-octylphenyl)butane-1,4-diol Chemical compound CCCCCCCCC1=CC=C(C(O)CC(CO)(CO)[N+]([O-])=O)C=C1 SUSUNJZIRVZIIO-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ZZIKIHCNFWXKDY-UHFFFAOYSA-N Myriocin Natural products CCCCCCC(=O)CCCCCCC=CCC(O)C(O)C(N)(CO)C(O)=O ZZIKIHCNFWXKDY-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 241001248610 Ophiocordyceps sinensis Species 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- ZZIKIHCNFWXKDY-GNTQXERDSA-N myriocin Chemical compound CCCCCCC(=O)CCCCCC\C=C\C[C@@H](O)[C@H](O)[C@@](N)(CO)C(O)=O ZZIKIHCNFWXKDY-GNTQXERDSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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| WO2012056458A3 (en) * | 2010-10-28 | 2013-07-18 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of fingolimod |
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