CN103086937A - Method for synthesizing paricalcitol - Google Patents
Method for synthesizing paricalcitol Download PDFInfo
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- CN103086937A CN103086937A CN2013100056271A CN201310005627A CN103086937A CN 103086937 A CN103086937 A CN 103086937A CN 2013100056271 A CN2013100056271 A CN 2013100056271A CN 201310005627 A CN201310005627 A CN 201310005627A CN 103086937 A CN103086937 A CN 103086937A
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- 0 C[C@@]([C@@](CC1)[C@@](C)(CCC2)C1C2=CC=C(C[C@](C1)O)C[C@]1O)C=C[C@](C)C(C)(C)* Chemical compound C[C@@]([C@@](CC1)[C@@](C)(CCC2)C1C2=CC=C(C[C@](C1)O)C[C@]1O)C=C[C@](C)C(C)(C)* 0.000 description 3
- BPKAHTKRCLCHEA-QEBMNFNLSA-N C[C@@H]([C@@H](CC1)[C@@](C)(CCC2)C1/C2=C/C=C(C[C@H](C1)O)C[C@H]1O)/C=C/[C@H](C)C(C)(C)O Chemical compound C[C@@H]([C@@H](CC1)[C@@](C)(CCC2)C1/C2=C/C=C(C[C@H](C1)O)C[C@H]1O)/C=C/[C@H](C)C(C)(C)O BPKAHTKRCLCHEA-QEBMNFNLSA-N 0.000 description 1
- FJBWUMAFVDROLG-OAHRJWNUSA-N C[C@H](C(C)(C)O)/C=C/[C@@H](C)[C@@](C)(CC1)[C@@](C)(CCC2)C1/C2=C/C=C(/C[C@H](C1)N=O)\C[C@H]1O Chemical compound C[C@H](C(C)(C)O)/C=C/[C@@H](C)[C@@](C)(CC1)[C@@](C)(CCC2)C1/C2=C/C=C(/C[C@H](C1)N=O)\C[C@H]1O FJBWUMAFVDROLG-OAHRJWNUSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a new method for synthesizing paricalcitol, comprising the following steps of: a. reacting a compound II with alkali, then adding a compound I, carrying out a Julia reaction to generate a compound III; b. reacting the compound III with a fluorine-containing reagent to remove the protecting group so as to obtain a compound IV; c. removing the protecting group of the compound IV under acidic condition to obtain the product of paricalcitol. The method for synthesizing paricalcitol disclosed the invention has the advantages of low cost and high yield, and is simple in operation and easy in industrial production.
Description
Technical field
The present invention relates to the compound preparing technical field, particularly the preparing technical field of Zemplar.
Background technology
Zemplar is by a kind of prevention of Abbott's research and development and treatment secondary hyperparathyroidism, and injection was in listing in 1998, and capsule preparations was in listing in 2005.Zemplar has become the most popular hyperparathyroidism prevention of dialysis patients and medicine.
The synthetic method of report Zemplar has some at present, but all synthetic routes are all take vitamin D2 as raw material, carry out structural modification and obtain on the parent nucleus of vitamin D2.
(Drugs of the Future 1998, p.602) vol.23 has summed up the synthetic method of Zemplar to document.The method obtains through multistep is synthetic take 25-OH Vintamin D2 as raw material.This route Main Problems is to comprise several aspects: (1) raw material 25-OH Vintamin D2 is expensive, (2) intermediate that in synthetic route, some step produces is the mixture of a plurality of diastereomers, makes the evaluation of compound very difficult.
Patent (WO2010009879A2) has also been reported the synthetic method of several Zemplars.The method is take vitamin D2 as raw material, transforms to obtain on its structure.The intermediate that the route of this patent report also can exist some step to obtain is the situation of several mixtures, causes to such an extent that the evaluation of compound is very difficult.
In addition, also have many pieces of patents (US7491712, EP2085380, WO2008053961, US5587497, WO7900513, US5246925, EP0387077) and document (Tetrahedron 2009, and p.10002-10008) vol.65 has reported the synthetic method of Zemplar.These synthetic methods are all to carry out structure of modification on the parent nucleus of vitamin D2, exist yield low, and the intermediate complicated difficult is to identify the similarly problem such as what purifying.Therefore above-mentioned these synthetic methods all are not suitable for being applied to the suitability for industrialized production of Zemplar.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings for above existence, and a kind of method of more efficiently synthetic Zemplar is provided.The method adopts the synthetic strategy of convergence type.Starting compound I is the relative simple known small molecules of structure with Compound I I, and easily a large amount of preparations, also easily carry out the Structural Identification structure.Raw material I can be by known synthetic method (Tetrahedron, 1992,48,9283-9294; EP2011781; Journal of Organic Chemistry, p.1264-1269) 1986, vol.51, obtains easily take vitamin D2 as raw material.In addition, raw material II also can be passed through currently known methods (Tetrahedron 2001, vol.57, p.681-694) synthetic the obtaining take the D-quininic acid as raw material.By two fragments are spliced, thereby the Zemplar key intermediate III of composite structure relative complex can obtain Zemplar finally by crossing simple deprotection reaction.This synthetic route has advantages of that synthetic operation is easy, cost is low, productive rate is high.And each intermediate is one matter, easily carries out Structural Identification and purifying.Therefore this route is more easily realized suitability for industrialized production.
To achieve these goals, the technical solution used in the present invention comprises the following steps:
A. with Compound I I and alkali reaction, then add Compound I, Julia reacting generating compound III occurs;
B. compound III and fluorine-containing reagent are reacted, deprotection base t-Butyldimethylsilyl obtains compound IV;
C. making compound IV issue unboiled water solution reaction at acidic conditions removes the R group and obtains Zemplar V;
Wherein, in Compound I, compound III and compound IV, the R group is hydroxyl protecting group, and this class protecting group is stable under alkaline condition, is easy to remove, for example methoxymethyl, benzyloxymethyl, 2-methoxy ethoxy methyl under acidic conditions.
Preferably, in step a, the temperature of described reaction is-60 ℃ ~-40 ℃; The solvent of described reaction is tetrahydrofuran (THF), ether, glycol dimethyl ether; Described alkali is lithium diisopropylamine (LDA), lithium hexamethyldisilazide (LHMDS), two trimethyl silicon based amido sodium (NaHMDS).The mol ratio of Compound I and Compound I I is 1:1 ~ 1.5.The mol ratio of Compound I I and alkali is 1:1 ~ 1.5.Reacted 3 ~ 5 hours at the temperature of-60 ℃ ~-40 ℃.
Preferably, in step a, after described reaction is completed, also comprise step: be warmed up to room temperature, add saturated ammonium chloride easy, add ethyl acetate extraction, use the dried over sodium sulfate ethyl acetate layer, decompression steams organic solvent, then passes through column chromatography purification; Column chromatography stationary phase used is silica gel, and elutriant is the mixture of ethyl acetate and sherwood oil.
Preferably, in step b, the temperature of described reaction is 50 ℃ ~ 70 ℃; The solvent of described reaction is tetrahydrofuran (THF), methyl alcohol, ethanol, dioxane, acetonitrile or its mixture; Described fluorine-containing reagent is anhydrous tetrabutyl ammonium fluoride, 4-butyl ammonium fluoride trihydrate, Potassium monofluoride, Sodium Fluoride, cesium fluoride, and the mol ratio of compound III and fluorine-containing reagent is 1:3 ~ 5; The described reaction times is 6 ~ 18 hours.
Preferably, in step b, after described reaction finishes, also comprise step: decompression steams organic solvent, then adds ethyl acetate, washs ethyl acetate layer with clear water, through solvent evaporated after dried over sodium sulfate, through column chromatography purification; Column chromatography stationary phase used is silica gel, and elutriant is the mixture of ethyl acetate and sherwood oil.
Preferably, in step c, the temperature of described reaction is 0 ℃ ~ 70 ℃, and preferred temperature is 20 ℃ ~ 50 ℃; The solvent of described reaction is methyl alcohol, ethanol, water or its mixture; The acid that described acidic conditions adopts is hydrochloric acid, sulfuric acid, tosic acid, trifluoroacetic acid, acetic acid; The described reaction times is 3 ~ 5 hours.
Preferably, in step c, after described reaction finishes, also comprise step: add a little triethylamine to transfer pH to neutral, then decompression steams organic solvent, then add ethyl acetate, wash ethyl acetate layer with clear water, through solvent evaporated after dried over sodium sulfate, through column chromatography purification; Column chromatography stationary phase used is silica gel, and elutriant is the mixture of ethyl acetate and sherwood oil.
Beneficial effect of the present invention comprises: yield is higher, and is easy and simple to handle, do not relate to the use of expensive reagent, and each intermediate is one matter, easily carries out Structural Identification and purifying.In addition, starting compound I is the relative simple known small molecules of structure with Compound I I, and easily a large amount of preparations, also easily carry out the Structural Identification structure.In general, the present invention more easily realizes the suitability for industrialized production of Zemplar.
Embodiment
In order more clearly to understand technology contents of the present invention, now further illustrate in conjunction with the embodiments as follows:
Embodiment 1
1.1 the preparation of compound III a
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-65 ℃; 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then with Compound I a(0.3g) be dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-57 ℃ reaction 3 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III a 0.45g, yield 74%.
1H?NMR(CCl
3,400MHz):δ＝-0.04(s,6H),0.00(s,6H),0.60(s,3H),0.83(s,18H),0.95(m,6H),1.10(s,3H),1.14(s,3H),1.21(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.15(m,4H),2.38(m,1H),3.34(s,3H),4.00(m,2H),4.68(s,2H),5.25(m,2H),6.03(d,J=12Hz,1H),6.20(d,J=12Hz,1H)。
MS(EI):m/e=688。
1.2 the preparation of compound III a
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-70 ℃; 1 milliliter of lithium diisopropylamine (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then with Compound I a(0.3g) be dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-50 ℃ reaction 3 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III a 0.42g, yield 70%.
1H?NMR(CCl
3,400MHz):δ＝-0.04(s,6H),0.00(s,6H),0.60(s,3H),0.83(s,18H),0.95(m,6H),1.10(s,3H),1.14(s,3H),1.21(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.15(m,4H),2.38(m,1H),3.34(s,3H),4.00(m,2H),4.68(s,2H),5.25(m,2H),6.03(d,J=12Hz,1H),6.20(d,J=12Hz,1H)。
MS(EI):m/e=688。
1.3 the preparation of compound III a
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous diethyl ethers; reduce the temperature to-65 ℃; 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then with Compound I a(0.3g) be dissolved in 2 milliliters of anhydrous diethyl ethers; be added drop-wise in above-mentioned reaction system; keep Nei Wen-45 ℃ reaction 4 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III a 0.43g, yield 73%.
1H?NMR(CCl
3,400MHz):δ＝-0.04(s,6H),0.00(s,6H),0.60(s,3H),0.83(s,18H),0.95(m,6H),1.10(s,3H),1.14(s,3H),1.21(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.15(m,4H),2.38(m,1H),3.34(s,3H),4.00(m,2H),4.68(s,2H),5.25(m,2H),6.03(d,J=12Hz,1H),6.20(d,J=12Hz,1H)。
MS(EI):m/e=688。
1.4 the preparation of compound III a
under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous glycol dimethyl ethers, reduce the temperature to-78 ℃, 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution, stirred 10 minutes, then with Compound I a(0.3g) be dissolved in 3 milliliters of anhydrous glycol dimethyl ethers, be added drop-wise in above-mentioned reaction system, keep Nei Wen-45 ℃ reaction 3 hours, after reaction finishes, be warmed up to room temperature, add ethyl acetate and ammonium chloride solution, tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification, get compound III a 0.40g, yield 65%.
1H?NMR(CCl
3,400MHz):δ＝-0.04(s,6H),0.00(s,6H),0.60(s,3H),0.83(s,18H),0.95(m,6H),1.10(s,3H),1.14(s,3H),1.21(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.15(m,4H),2.38(m,1H),3.34(s,3H),4.00(m,2H),4.68(s,2H),5.25(m,2H),6.03(d,J=12Hz,1H),6.20(d,J=12Hz,1H)。
MS(EI):m/e=688。
1.5 the preparation of compound III b
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-75 ℃; 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then compounds ib (0.37g) is dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-45 ℃ reaction 5 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III b 0.48g, yield 70%.
1H?NMR(CCl
3,400MHz):δ＝-0.02(s,6H),0.01(s,6H),0.61(s,3H),0.82(s,18H),0.98(m,6H),1.11(s,3H),1.15(s,3H),1.23(m,3H),1.55(m,3H),1.70(m,2H),1.91(m,7H),2.13(m,4H),2.39(m,1H),4.01(m,2H),4.61(s,2H),4.70(s,2H),5.25(m,2H),6.02(d,J=11Hz,1H),6.21(d,J=11Hz,1H),7.30(m,5H)。
MS(EI):m/e=764。
1.6 the preparation of compound III b
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-78 ℃; 1 milliliter of lithium diisopropylamine (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then compounds ib (0.37g) is dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-45 ℃ reaction 5 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III b 0.50g, yield 73%.
1H?NMR(CCl
3,400MHz):δ＝-0.02(s,6H),0.01(s,6H),0.61(s,3H),0.82(s,18H),0.98(m,6H),1.11(s,3H),1.15(s,3H),1.23(m,3H),1.55(m,3H),1.70(m,2H),1.91(m,7H),2.13(m,4H),2.39(m,1H),4.01(m,2H),4.61(s,2H),4.70(s,2H),5.25(m,2H),6.02(d,J=11Hz,1H),6.21(d,J=11Hz,1H),7.30(m,5H)。
MS(EI):m/e=764。
1.7 the preparation of compound III c
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-64 ℃; 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then compounds ib (0.34g) is dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-53 ℃ reaction 4 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III c 0.47g, yield 72%.
1H?NMR(CCl
3,400MHz):δ＝-0.03(s,6H),0.02(s,6H),0.60(s,3H),0.82(s,18H),0.95(m,6H),1.12(s,3H),1.15(s,3H),1.20(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.16(m,4H),2.38(m,1H),3.34(s,3H),3.55(m,4H),4.01(m,2H),4.70(s,2H),5.25(m,2H),6.01(d,J=11.6Hz,1H),6.21(d,J=11.6Hz,1H)。
MS(EI):m/e=732。
1.8 the preparation of compound III c
Under nitrogen protection with Compound I I(0.51g) be dissolved in 4 milliliters of anhydrous tetrahydro furans; reduce the temperature to-65 ℃; 1 milliliter of lithium hexamethyldisilazide (1M) is added drop-wise in mentioned solution; stirred 10 minutes; then compounds ib (0.34g) is dissolved in 2 milliliters of tetrahydrofuran (THF)s; be added drop-wise in above-mentioned reaction system; keep Nei Wen-40 ℃ reaction 2 hours, reaction is warmed up to room temperature after finishing; add ethyl acetate and ammonium chloride solution; tell organic layer, evaporate to dryness after dried over sodium sulfate, column chromatography purification; get compound III c 0.48g, yield 74%.
1H?NMR(CCl
3,400MHz):δ＝-0.03(s,6H),0.02(s,6H),0.60(s,3H),0.82(s,18H),0.95(m,6H),1.12(s,3H),1.15(s,3H),1.20(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.16(m,4H),2.38(m,1H),3.34(s,3H),3.55(m,4H),4.01(m,2H),4.70(s,2H),5.25(m,2H),6.01(d,J=11.6Hz,1H),6.21(d,J=11.6Hz,1H)。
MS(EI):m/e=732。
Embodiment 2
2.1 the preparation of compound IV a
The compound III a(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 7ml, 4-butyl ammonium fluoride trihydrate (0.73g) is warmed up to 60 ℃ of reaction 8h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVa 0.23g yield 88% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H),6.47(d,J=11.2Hz,1H)。
MS(EI):m/e=460。
2.2 the preparation of compound IV a
The compound III a(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 3ml, methyl alcohol 5ml, Potassium monofluoride (0.14g) are warmed up to 60 ℃ of reaction 16h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVa 0.21g yield 81% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H),6.47(d,J=11.2Hz,1H)。
MS(EI):m/e=460。
2.3 the preparation of compound IV a
The compound III a(0.40g that adds embodiment 1 to obtain under room temperature), dioxane 6ml, 4-butyl ammonium fluoride trihydrate (0.73g) is warmed up to 70 ℃ of reaction 7h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVa 0.22g yield 86% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H),6.47(d,J=11.2Hz,1H)。
MS(EI):m/e=460。
2.4 the preparation of compound IV a
The compound III a(0.40g that adds embodiment 1 to obtain under room temperature), acetonitrile 5ml, methyl alcohol 5ml, Sodium Fluoride (0.12g) are warmed up to 70 ℃ of reaction 7h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVa 0.19g yield 76% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H),6.47(d,J=11.2Hz,1H)。
MS(EI):m/e=460。
2.5 the preparation of compound IV a
The compound III a(0.40g that adds embodiment 1 to obtain under room temperature), ethanol 6ml, cesium fluoride (0.35g) are warmed up to 50 ℃ of reaction 9h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVa 0.20g yield 80% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H),6.47(d,J=11.2Hz,1H)。
MS(EI):m/e=460。
2.6 the preparation of compound IV b
The compound III b(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 6ml, 4-butyl ammonium fluoride trihydrate (0.66g) is warmed up to 62 ℃ of reaction 9h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVb 0.24g yield 86% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.64(s,3H),1.02(m,6H),1.10(s,3H),1.14(s,3H),1.23-1.57(m,3H),1.83-2.12(m,14H),2.15-2.23(m,3H),4.09(m,2H),4.61(s,2H),4.70(s,2H),5.30(m,2H),6.12(d,J=11.2Hz,1H),6.41(d,J=11.2Hz,1H),7.30(m,5H)。
MS(EI):m/e=536。
2.7 the preparation of compound IV b
The compound III b(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 2ml, methyl alcohol 4ml, Potassium monofluoride (0.13g) is warmed up to 60 ℃ of reaction 12h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVb 0.22g yield 82% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.64(s,3H),1.02(m,6H),1.10(s,3H),1.14(s,3H),1.23-1.57(m,3H),1.83-2.12(m,14H),2.15-2.23(m,3H),4.09(m,2H),4.61(s,2H),4.70(s,2H),5.30(m,2H),6.12(d,J=11.2Hz,1H),6.41(d,J=11.2Hz,1H),7.30(m,5H)。
MS(EI):m/e=536。
2.8 the preparation of compound IV c
The compound III c(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 5ml, 4-butyl ammonium fluoride trihydrate (0.80g) is warmed up to 55 ℃ of reaction 10h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVc 0.23g yield 85% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.64(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.21-1.54(m,3H),1.85-2.11(m,14H),2.14-2.25(m,3H),3.34(s,3H),3.55(m,4H),4.10(m,2H),4.70(s,2H),5.34(m,2H),6.11(d,J=11.4Hz,1H),6.41(d,J=11.4Hz,1H)。
MS(EI):m/e=504。
2.9 the preparation of compound IV c
The compound III c(0.40g that adds embodiment 1 to obtain under room temperature), tetrahydrofuran (THF) 2ml, methyl alcohol 6ml, Potassium monofluoride (0.15g) are warmed up to 62 ℃ of reaction 14h.Reaction finishes to add ethyl acetate.Saturated brine washing, anhydrous sodium sulfate drying, filtration concentrate to get crude product, obtain IVc 0.21g yield 79% through column chromatography purification.
1H?NMR(CCl
3,400MHz):δ＝0.64(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.21-1.54(m,3H),1.85-2.11(m,14H),2.14-2.25(m,3H),3.34(s,3H),3.55(m,4H),4.10(m,2H),4.70(s,2H),5.34(m,2H),6.11(d,J=11.4Hz,1H),6.41(d,J=11.4Hz,1H)。
MS(EI):m/e=504。
Embodiment 3
3.1 compound V is the preparation of Zemplar
Compound IV a(0.20g with embodiment 2 preparations) be dissolved in 3ml methyl alcohol, add tosic acid (83mg), 25 ℃ of reaction 8h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(0.14g through column chromatography purification, yield 75%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.2 compound V is the preparation of Zemplar
Compound IV a(0.20g with embodiment 2 preparations) be dissolved in 5ml methyl alcohol, add concentrated hydrochloric acid (50mg), 25 ℃ of reaction 10h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(0.12g through column chromatography purification, yield 67%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.3 compound V is the preparation of Zemplar
Compound IV a(0.20g with embodiment 2 preparations) be dissolved in the mixed solvent of 3ml ethanol and 1ml water, add sulfuric acid (23mg), 45 ℃ of reaction 5h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(0.13g through column chromatography purification, yield 72%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.4 compound V is the preparation of Zemplar
Compound IV a(0.20g with embodiment 2 preparations) be dissolved in the mixed solvent of 3ml methyl alcohol and 1ml water, add acetic acid (43mg), 55 ℃ of reaction 8h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(0.12g through column chromatography purification, yield 65%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.5 compound V is the preparation of Zemplar
Compound IV b(0.20g with embodiment 2 preparations) be dissolved in 3ml methyl alcohol, add tosic acid (71mg), 25 ℃ of reaction 12h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(93mg through column chromatography purification, yield 60%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.6 compound V is the preparation of Zemplar
Compound IV b(0.20g with embodiment 2 preparations) be dissolved in 3ml methyl alcohol, add concentrated hydrochloric acid (45mg), 25 ℃ of reaction 11h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(0.10g through column chromatography purification, yield 65%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.7 compound V is the preparation of Zemplar
Compound IV c(0.20g with embodiment 2 preparations) be dissolved in 3ml methyl alcohol, add tosic acid (75mg), 25 ℃ of reaction 10h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(101mg through column chromatography purification, yield 65%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
3.8 compound V is the preparation of Zemplar
Compound IV c(0.20g with embodiment 2 preparations) be dissolved in 3ml methyl alcohol, add concentrated hydrochloric acid (55mg), 25 ℃ of reaction 8h of room temperature.Add triethylamine to regulate pH to 7 ~ 8 after reaction finishes, add ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate and get compound V(91mg through column chromatography purification, yield 60%).
1H?NMR(CCl
3,400MHz):δ＝0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H),4.03-4.10(m,2H),5.28-5.40(m,2H),6.11(d,J=11.6Hz,1H),6.44(d,J=11.6Hz,1H)。
MS(EI):m/e=416。
In sum, the method for synthetic Zemplar of the present invention has advantages of that synthetic operation is easy, productive rate is high, is easy to suitability for industrialized production.
Need to prove, all quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read above-mentioned teachings 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 (7)
1. the method for a synthetic Zemplar, is characterized in that, comprises the following steps:
A. with Compound I I and alkali reaction, then add Compound I, Julia reacting generating compound III occurs;
B. compound III and fluorine-containing reagent are reacted, deprotection base t-Butyldimethylsilyl obtains compound IV;
C. making compound IV issue unboiled water solution reaction at acidic conditions removes the R group and obtains Zemplar V;
Wherein, in Compound I, compound III and compound IV, the R group is hydroxyl protecting group, and this class protecting group is stable under alkaline condition, is easy to remove, for example methoxymethyl, benzyloxymethyl, 2-methoxy ethoxy methyl under acidic conditions.
2. synthetic method according to claim 1, is characterized in that, in step a, the temperature of described reaction is-70 ℃ ~-30 ℃, and preferred temperature is-60 ℃ ~-40 ℃; The solvent of described reaction is tetrahydrofuran (THF), ether, glycol dimethyl ether; Described alkali is lithium diisopropylamine, lithium hexamethyldisilazide, two trimethyl silicon based amido sodium.
3. synthetic method according to claim 1, it is characterized in that, in step a, after described reaction finishes, also comprise step: be warmed up to room temperature, add saturated ammonium chloride easy, add ethyl acetate extraction, use the dried over sodium sulfate ethyl acetate layer, decompression steams organic solvent, then passes through column chromatography purification.
4. synthetic method according to claim 1, is characterized in that, in step b, the temperature of described reaction is 40 ℃ ~ 80 ℃, and preferred temperature is 50 ℃ ~ 70 ℃; The solvent of described reaction is tetrahydrofuran (THF), methyl alcohol, ethanol, dioxane, acetonitrile or its mixture; Described fluorine-containing reagent is tetrabutyl ammonium fluoride, 4-butyl ammonium fluoride trihydrate, Potassium monofluoride, Sodium Fluoride, cesium fluoride.
5. synthetic method according to claim 1, is characterized in that, in step b, after described reaction finishes, also comprise step: decompression steams organic solvent, then adds ethyl acetate, wash ethyl acetate layer with clear water, through solvent evaporated after dried over sodium sulfate, through column chromatography purification.
6. synthetic method according to claim 1, is characterized in that, in step c, the temperature of described reaction is 0 ℃ ~ 70 ℃, and preferred temperature is 20 ℃ ~ 50 ℃; The solvent of described reaction is methyl alcohol, ethanol, water or its mixture; The acid that described acidic conditions adopts is hydrochloric acid, sulfuric acid, tosic acid, trifluoroacetic acid, acetic acid.
7. synthetic method according to claim 1, it is characterized in that, in step c, after described reaction finishes, also comprise step: add a little triethylamine to transfer pH to neutral, then decompression steams organic solvent, then add ethyl acetate, wash ethyl acetate layer with clear water, through solvent evaporated after dried over sodium sulfate, through column chromatography purification.
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