CN103145689B - Method for combining Fingolimod intermediate - Google Patents
Method for combining Fingolimod intermediate Download PDFInfo
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- CN103145689B CN103145689B CN201310026669.3A CN201310026669A CN103145689B CN 103145689 B CN103145689 B CN 103145689B CN 201310026669 A CN201310026669 A CN 201310026669A CN 103145689 B CN103145689 B CN 103145689B
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- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960000556 fingolimod Drugs 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 17
- 229940125898 compound 5 Drugs 0.000 claims abstract description 11
- 239000004342 Benzoyl peroxide Substances 0.000 claims abstract description 10
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019400 benzoyl peroxide Nutrition 0.000 claims abstract description 10
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract 4
- 238000007239 Wittig reaction Methods 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 239000002904 solvent Substances 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- 238000005406 washing Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 9
- 238000004587 chromatography analysis Methods 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000000638 solvent extraction Methods 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000003054 catalyst Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940125904 compound 1 Drugs 0.000 abstract description 3
- 229940125782 compound 2 Drugs 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- 125000001033 ether group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- -1 boron ester Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000000463 material 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
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
Abstract
The invention provides a method for combining a Fingolimod intermediate. The method includes that: a. compound 1 and a compound 2 conduct Wittig reaction to produce a compound 3; b. the compound 3 conducts hydrogenation reaction under a condition that catalyst Pd/C exists to produce a compound 4; c. the compound 4 reacts with bisdiboron, benzoyl peroxide and t-BuONO to produce a compound 5; d. the compound 5 and a iodo-object 6 conduct Suzuki reaction to produce a compound 7; and e. the compound 7 conducts hydrogenation reaction under the catalysis of Pd/C to produce a compound 8. The method for combining the Fingolimod intermediate is simple and short in synthetic route, easy and convenient to operate, low in cost, high in rate of production and easy for industrialized production.
Description
Technical field
The present invention relates to compound preparing technical field, particularly FTY720 key intermediate preparing technical field, more specifically refers to a kind of novel method of synthetic FTY720 key intermediate.
Background technology
FTY720 is developed by Japanese Mitsubishi drugmaker at first, later stage, whole world transfer of management right was to Switzerland Novartis drugmaker, take the lead in being approved listing by U.S. FDA on September 21st, 2010, become the first neotype immunosuppressant that is used for the treatment of relapsing remitting multiple sclerosis disease that can oral administration administration, be mainly used in treating recurrent multiple sclerosis, reduce the clinical frequency increasing the weight of and delay the savings of physical disabilities.
Compound
8it is the key intermediate of synthetic FTY720.At present, compound
8synthetic method mainly by several below:
(1) with toluene
9for starting raw material, through five step reactions, obtain target product, its route following (WO2012056458A2).This route, at synthetic compound
10process in to use friedel-crafts acylation, due to the generation of aluminium salt, pollute large; This synthetic overall yield is lower, is unsuitable for scale operation.
(2) with compound
15for starting raw material, through seven step reactions, obtain target product, its route following (Synlett. 2007,2841 – 2846).The weak point of this route is that part material is expensive, makes total cost higher.
(3) with compound
2starting raw material, obtains target product through four-step reaction, route following (SYNTHESIS, 2006,753-755).At synthetic compound
20process in, use more expensive (2-oxygen propyl group) dimethyl phosphonate and p-toluene sulfonyt azide reagent, so synthetic route cost is higher, be difficult to industrialization.
Summary of the invention
The object of this invention is to provide a kind of synthetic FTY720 key intermediate
8novel method, that the method has advantages of is easy and simple to handle, cost is low, yield is high.
To achieve these goals, the present invention adopts cheap raw material compound
1and compound
2for starting raw material, through Wittig (Wittig) reaction, hydrogenation, the reaction of generation boron ester, Suzuki (Suzuki) reaction, hydrogenation, finally obtain compound
8, it can obtain FTY720 through hydrolysis.Route of the present invention is as follows:
Synthesis step is as follows:
A, make compound
1with
2in solvent, add mineral alkali, there is Wittig (Wittig) reacting generating compound
3;
B, make compound
3under palladium/carbon (Pd/C) catalysis, pass into hydrogen, there is hydrogenation and obtain compound
4;
C, make compound
4react with connection boric acid pinacol ester, benzoyl peroxide and nitrite tert-butyl, obtain compound
5;
D, make compound
5with iodo thing
6in solvent, add alkali and catalyzer, there is Suzuki (Suzuki) reacting generating compound
7;
E, make compound
7under palladium/carbon (Pd/C) catalysis, pass into hydrogen, there is hydrogenation and obtain compound
8.
In step a, the alkali that described Wittig reacts used is NaOH, Na
2cO
3or K
2cO
3, solvent is the mixed solution of THF and DMF, at 70～150 ℃ of temperature, reacts 4～8 hours; Compound
2with compound
1mol ratio be 1: 1.0～1.5; Compound
2be 1: 2.5～3.0 with adding the mol ratio of mineral alkali, after having reacted, with appropriate solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying.The solvent that extraction is used comprises methylene dichloride, chloroform, ethyl acetate; The solvent that chromatography column purifying is used comprises the mixture that ethyl acetate and sherwood oil or ether form.
In step b, described hydrogenation solvent used is methyl alcohol, ethanol, dioxane or THF, and catalyzer is Pd/C, and temperature of reaction is 0～50 ℃; After having reacted, filter solvent evaporated.
In step c, the solvent of described reaction is methylene dichloride, ethyl acetate, toluene or acetonitrile, and connection boric acid pinacol ester and benzoyl peroxide are dissolved in solvent, add compound
4and nitrite tert-butyl, temperature, at 10～50 ℃, is reacted 2～8 hours; After having reacted, with solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying; The solvent that extraction is used comprises methylene dichloride, chloroform, ethyl acetate, and the solvent that chromatography column purifying is used comprises the mixture that ethyl acetate and sherwood oil or ether form.Wherein: described compound
4with the mol ratio of connection boric acid pinacol ester be 1: 1.0～1.5: compound
4with the mol ratio of benzoyl peroxide be 1: 0.01～0.05; Compound
4with the mol ratio of nitrite tert-butyl be 1: 1.2～1.8.
In steps d, the alkali that described Suzuki reacts used is K
2cO
3, NaOH, CsF or CH
3cOOK, catalyzer is Pd (PPh
3)
4, PdCl
2or PdCl (dppf)
2(PPh
3)
2, solvent is the mixed solvent that toluene, dioxane and tetrahydrofuran (THF) or they and water form, temperature, at 70～120 ℃, is reacted 10～15 hours; Compound
5with iodo thing
6mol ratio be 1: 1.2～1.8; Compound
5 withthe mol ratio that adds alkali is 1: 1.5～2.5; Compound
5 withthe mol ratio that adds catalyzer is 1: 0.02～0.10; After having reacted, with solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying.The solvent that extraction is used comprises methylene dichloride, chloroform, ethyl acetate, and the solvent that chromatography column purifying is used comprises the mixture that ethyl acetate and sherwood oil or ether form.
In step e, the solvent of described hydrogenation is methyl alcohol, ethanol, dioxane or THF, and catalyzer is Pd/C, and temperature of reaction is 0～50 ℃; After hydrogenation completes, filtration, solvent evaporated.
The compound that the present invention is used
1that reference < < Bioorg. Med. Chem. Lett.. 2011,19,3156 – 3172 > > obtain; Compound
2be reference < < J. Org. Chem. 2004,69,7765-7768 > > obtains.
Beneficial effect of the present invention is as follows:
(1), the present invention adopts compound
1with
2for raw material, through Wittig, hydrogenation, generation boron ester, Suzuki, hydrogenation five step reactions, obtain compound
8, synthetic route is brief, and yield is 36.6%.
(2), the present invention do not relate to the use of expensive reagent, reduced cost.
(3), synthetic method of the present invention easy and simple to handle, the condition that relate to easily control, and is easy to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is schema of the present invention.
Embodiment
In order more clearly to understand technology contents of the present invention, existing further illustrate as follows in conjunction with the embodiments, but embodiment is not construed as limiting the invention.
Embodiment 1
1.1 compound
3preparation
Under nitrogen protection condition, by compound
2(9.9g, 38.18mmol), compound
1(21.9g, 45.82mmol) and anhydrous K
2cO
3(14.8g, 106.9mmol) joins in the there-necked flask of 500mL, then the mixed solvent that adds the anhydrous THF of 150mL and 50mL dry DMF to form, and is slowly heated to 80 ℃, reaction 5h.After cooling, add water, ethyl acetate (100 mL * 3) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry, column chromatography obtains the corresponding olefin(e) compound of 12.3g
3; Compound
3for mixture, there is Cis-trans structures, yield is 85.1%.
1.2 compound
3preparation
Under nitrogen protection condition, by compound
2(9.9g, 38.18mmol), compound
1(21.9g, 45.82mmol) and anhydrous Na
2cO
3(11.3g, 106.9mmol) joins in the there-necked flask of 500mL, then the mixed solvent that adds the anhydrous THF of 150mL and 50mL dry DMF to form, and is slowly heated to 80 ℃, reaction 5h.After cooling, add water, ethyl acetate (100 mL * 3) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry, column chromatography obtains the corresponding olefin(e) compound of 12.0g
3; Compound
3for mixture, there is Cis-trans structures, yield is 83.1%.
Embodiment 2
2.1 compound
4preparation
By compound
3(12.0 g, 31.71mmol) is dissolved in 150mL methyl alcohol, adds 1.2g Pd/C((10 wt%), room temperature reaction 12 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure and obtains 10.3g white solid product
4, productive rate is 92.7%.
Mp: 160-163 oC;
1H NMR (500MHz, CDCl
3):
δ 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 9 H), 1.92 (t, 2 H), 2.44-2.48 (m, 2 H), 3.55 (s, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 6.61 (d,
J = 8 Hz, 2 H), 6.96 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
19H
30N
2O
4 [M]
+: 350.2206, found: 350.2203。
2.2 compound
4preparation
By compound
3(12.0 g, 31.71mmol) is dissolved in 150mL ethanol, adds 1.2g Pd/C((10 wt%), room temperature reaction 12 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure and obtains 10.0g white solid product
4, productive rate is 90.0%.
Mp: 160-163 oC;
1H NMR (500MHz, CDCl
3):
δ 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 9 H), 1.92 (t, 2 H), 2.44-2.48 (m, 2 H), 3.55 (s, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 6.61 (d,
J = 8 Hz, 2 H), 6.96 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
19H
30N
2O
4 [M]
+: 350.2206, found: 350.2203。
2.3 compound
4preparation
By compound
3(12.0 g, 31.71mmol) is dissolved in 150mL tetrahydrofuran (THF), adds 1.2g Pd/C((10 wt%), room temperature reaction 12 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure and obtains 9.6 g white solid product
4, productive rate is 86.4%.
Mp: 160-163 oC;
1H NMR (500MHz, CDCl
3):
δ 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 9 H), 1.92 (t, 2 H), 2.44-2.48 (m, 2 H), 3.55 (s, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 6.61 (d,
J = 8 Hz, 2 H), 6.96 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
19H
30N
2O
4 [M]
+: 350.2206, found: 350.2203。
Embodiment 3
3.1 compound
5preparation
To join boric acid pinacol ester (7.25g, 28.53mmol) and benzoyl peroxide (0.14g, 0.57mmol) is dissolved in 150mL CH
3in CN, after add successively compound
4(10.0g, 28.53mmol) and nitrite tert-butyl (4.42g, 42.80mmol), room temperature reaction 6h after feeding in raw material.Add water termination reaction, ethyl acetate (100 mL * 3) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 7.76g white solid product, yield 60%.
Mp: 145-148 oC;
1H NMR (500MHz, CDCl
3):
δ 1.33 (s, 12 H), 1.41 (s, 3 H),1.43 (s, 3 H), 1.47 (s, 9 H), 1.98 (t, 2 H), 2.56-2.60 (m, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 7.19 (d,
J = 8 Hz, 2 H), 7.71 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
25H
40BNO
6 [M]
+: 461.2949, found: 461.2950。
3.2 compound
5preparation
To join boric acid pinacol ester (7.25g, 28.53mmol) and benzoyl peroxide (0.14g, 0.57mmol) and be dissolved in 150mL methylene dichloride, after add successively compound
4(10.0g, 28.53mmol) and nitrite tert-butyl (4.42g, 42.80mmol), room temperature reaction 6h after feeding in raw material.Add water termination reaction, methylene dichloride (100 mL * 3) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 7.21g white solid product, yield 54.8%.
Mp: 145-148 oC;
1H NMR (500MHz, CDCl
3):
δ 1.33 (s, 12 H), 1.41 (s, 3 H),1.43 (s, 3 H), 1.47 (s, 9 H), 1.98 (t, 2 H), 2.56-2.60 (m, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 7.19 (d,
J = 8 Hz, 2 H), 7.71 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
25H
40BNO
6 [M]
+: 461.2949, found: 461.2950。
3.3 compound
5preparation
To join boric acid pinacol ester (7.25g, 28.53mmol) and benzoyl peroxide (0.14g, 0.57mmol) and be dissolved in 150mL toluene, after add successively compound
4(10.0g, 28.53mmol) and nitrite tert-butyl (4.42g, 42.80mmol), room temperature reaction 6h after feeding in raw material.Add water termination reaction, ethyl acetate (100 mL * 3) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 7.15g white solid product, yield 54.3%.
Mp: 145-148 oC;
1H NMR (500MHz, CDCl
3):
δ 1.33 (s, 12 H), 1.41 (s, 3 H),1.43 (s, 3 H), 1.47 (s, 9 H), 1.98 (t, 2 H), 2.56-2.60 (m, 2 H), 3.66 (d,
J = 12 Hz, 2 H), 3.88 (d,
J = 11 Hz, 2 H), 4.98 (s, 1 H), 7.19 (d,
J = 8 Hz, 2 H), 7.71 (d,
J = 8 Hz, 2 H); HRMS (EI):
m/z calcd for C
25H
40BNO
6 [M]
+: 461.2949, found: 461.2950。
Embodiment 4
4.1 compound
7preparation
By compound
6(1.93g, 8.1mmol) and compound
5(2.5g, 5.4mmol) is dissolved in toluene/dioxane (10:1 v/v, 22 mL), then adds NaOH solid (0.44g, 10.8mmol), adds catalyst P dCl under nitrogen protection condition
2(dppf) (0.2g, 0.27mmol), is slowly heated to 100 ℃, and reaction 12h. is chilled to room temperature, adds 10mL water, with ethyl acetate (3 * 20 ml) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 1.87 g compounds
7. compound
7for mixture, there is Cis-trans structures, yield is 77.7%.
4.2 compound
7preparation
By compound
6(1.93g, 8.1mmol) and compound
5(2.5g, 5.4mmol) is dissolved in toluene/dioxane (10:1 v/v, 22 mL), then adds NaOH solid (0.44g, 10.8mmol), adds catalyst P d (PPh under nitrogen protection condition
3)
4(0.31g, 0.27mmol), is slowly heated to 100 ℃, and reaction 12h. is chilled to room temperature, adds 10mL water, with ethyl acetate (3 * 20 ml) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 1.67 g compounds
7. compound
7for mixture, there is Cis-trans structures, yield is 69.4%.
4.3 compound
7preparation
By compound
6(1.93g, 8.1mmol) and compound
5(2.5g, 5.4mmol) is dissolved in toluene/dioxane (10:1 v/v, 22 mL), then adds K
2cO
3solid (1.49g, 10.8mmol), adds catalyst P dCl under nitrogen protection condition
2(dppf) (0.2g, 0.27mmol), is slowly heated to 100 ℃, and reaction 12h. is chilled to room temperature, adds 10mL water, with ethyl acetate (3 * 20 ml) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 1.51 g compounds
7. compound
7for mixture, there is Cis-trans structures, yield is 62.7%.
4.4 compound
7preparation
By compound
6(1.93g, 8.1mmol) and compound
5(2.5g, 5.4mmol) is dissolved in toluene/water (10:1 v/v, 22 mL), then adds NaOH solid (0.44g, 10.8mmol), adds catalyst P dCl under nitrogen protection condition
2(dppf) (0.2g, 0.27mmol), is slowly heated to 100 ℃, and reaction 12h. is chilled to room temperature, adds 10mL water, with ethyl acetate (3 * 20 ml) extraction, merges organic phase, first after washing, saturated common salt washing, anhydrous Na
2sO
4dry.Suction filtration, removes solvent under reduced pressure, and column chromatography obtains 1.43g compound
7.Compound
7for mixture, there is Cis-trans structures, yield is 59.4%.
Embodiment 5
5.1 compound
8preparation
By compound
7(1.60g, 3.59mmol) is dissolved in 20 mL methyl alcohol, adds 160 mg Pd/C((10 wt%), room temperature reaction 10 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure, obtains 1.60 g white solid product
8, productive rate is 99.5%.
Mp 62-64 oC;
1H NMR (500MHz, CDCl
3):
δ 0.89 (t, 3 H), 1.21 (m, 10 H), 1.43 (m, 6 H), 1.47 (s, 9 H), 1.58 (m, 2 H), 1.97 (m, 2 H), 2.52-2.57 (m, 4 H), 3.67 (d,
J = 12.0 Hz, 2 H), 3.91 (d,
J = 12.0 Hz, 2 H), 4.98 (s, 1 H), 7.08 (s, 4 H)。
5.2 compound
8preparation
By compound
7(1.60g, 3.59mmol) is dissolved in 20 mL ethanol, adds 160 mg Pd/C((10 wt%), room temperature reaction 10 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure, obtains 1.51 g white solid product
8, productive rate is 94.0%.
Mp 62-64 oC;
1H NMR (500MHz, CDCl
3):
δ 0.89 (t, 3 H), 1.21 (m, 10 H), 1.43 (m, 6 H), 1.47 (s, 9 H), 1.58 (m, 2 H), 1.97 (m, 2 H), 2.52-2.57 (m, 4 H), 3.67 (d,
J = 12.0 Hz, 2 H), 3.91 (d,
J = 12.0 Hz, 2 H), 4.98 (s, 1 H), 7.08 (s, 4 H)。
5.3 compound
8preparation
By compound
7(1.60g, 3.59mmol) is dissolved in 20 mL tetrahydrofuran (THF)s, adds 160 mg Pd/C((10 wt %), room temperature reaction 10 h under hydrogen condition.Suction filtration, removes solvent under reduced pressure, obtains 1.40 g white solid product
8, productive rate is 87.1%.
Mp 62-64 oC;
1H NMR (500MHz, CDCl
3):
δ 0.89 (t, 3 H), 1.21 (m, 10 H), 1.43 (m, 6 H), 1.47 (s, 9 H), 1.58 (m, 2 H), 1.97 (m, 2 H), 2.52-2.57 (m ,4 H), 3.67 (d,
J = 12.0 Hz, 2 H), 3.91 (d,
J = 12.0 Hz, 2 H), 4.98 (s, 1 H), 7.08 (s, 4 H)。
In sum, the synthetic FTY720 key intermediate of the present invention
8method have advantages of that synthetic route is brief, easy and simple to handle, cost is low, productive rate is high, be easy to suitability for industrialized production.
It should be noted that, all documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.In addition should understand, above-described is specific embodiments of the invention and the know-why used, after having read content described above of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (6)
1. a method for synthetic FTY720 intermediate, is characterized in that: comprise the following steps:
A, make compound
1with
2in solvent, add mineral alkali, there is Wittig reaction and generate compound
3;
B, make compound
3under the catalysis of palladium/carbon, pass into hydrogen, there is hydrogenation and obtain compound
4;
C, make compound
4react with connection boric acid pinacol ester, benzoyl peroxide and nitrite tert-butyl, obtain compound
5;
D, make compound
5with iodo thing
6in solvent, add alkali and catalyzer, there is suzuki reaction and generate compound
7;
E, make compound
7under the catalysis of palladium/carbon, pass into hydrogen, there is hydrogenation and obtain compound
8;
。
2. the method for synthetic FTY720 intermediate according to claim 1, is characterized in that the mineral alkali in described step a is NaOH, Na
2cO
3or K
2cO
3; Solvent is the mixed solution of THF and DMF; Temperature of reaction is 70～150 ℃; Compound
2with compound
1mol ratio be 1: 1.0～1.5; Compound
2be 1: 2.5～3.0 with adding the mol ratio of mineral alkali, after Wittig reaction completes, with solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying.
3. the method for synthetic FTY720 intermediate according to claim 1, is characterized in that in step b, and the solvent of described hydrogenation is methyl alcohol, ethanol, dioxane or THF, and catalyzer is palladium/carbon, and temperature of reaction is 0～50 ℃; After hydrogenation completes, filtration, solvent evaporated.
4. the method for synthetic FTY720 intermediate according to claim 1, it is characterized in that in step c, the solvent of reaction is methylene dichloride, ethyl acetate, toluene or acetonitrile, and connection boric acid pinacol ester and benzoyl peroxide are dissolved in solvent, add compound
4and nitrite tert-butyl, temperature, at 10～50 ℃, is reacted 2～8 hours; After having reacted, with solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying; Wherein: described compound
4with the mol ratio of connection boric acid pinacol ester be 1: 1.0～1.5; Compound
4with the mol ratio of benzoyl peroxide be 1: 0.01～0.05; Compound
4with the mol ratio of nitrite tert-butyl be 1: 1.2～1.8.
5. the method for synthetic FTY720 intermediate according to claim 1, is characterized in that in steps d, and described suzuki reaction alkali used is K
2cO
3, NaOH, CsF or CH
3cOOK, catalyzer is Pd (PPh
3)
4, PdCl
2or PdCl (dppf)
2(PPh
3)
2, solvent is the mixed solvent that toluene, dioxane, tetrahydrofuran (THF) or they and water form, temperature, at 70～120 ℃, is reacted 10～15 hours; Compound
5with iodo thing
6mol ratio be 1: 1.2～1.8; Compound
5 withthe mol ratio that adds alkali is 1: 1.5～2.5; Compound
5be 1: 0.02～0.10 with adding the mol ratio of catalyzer, after suzuki reaction completes, with solvent extraction, washing, dry, evaporate to dryness, then by chromatography column purifying.
6. the method for synthetic FTY720 intermediate according to claim 1, is characterized in that in step e, and the solvent of described hydrogenation is methyl alcohol, ethanol, dioxane or THF, and catalyzer is palladium/carbon, and temperature of reaction is 0～50 ℃; After hydrogenation completes, filtration, solvent evaporated.
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Non-Patent Citations (2)
| Title |
|---|
| "Iron-Catalyzed Cross-Coupling Reactions.A Scalable Synthesis of the Immunosuppressive Agent FTY720 ";Gunter Seidel, et al.;《J. Org. Chem.》;20040505;第69卷;第3950-3952页 * |
| Gunter Seidel, et al.."Iron-Catalyzed Cross-Coupling Reactions.A Scalable Synthesis of the Immunosuppressive Agent FTY720 ".《J. Org. Chem.》.2004,第69卷第3950-3952页. |
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