CN101671288B - Preparation method of intermediate of paricalcitol - Google Patents
Preparation method of intermediate of paricalcitol Download PDFInfo
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- CN101671288B CN101671288B CN 200910207308 CN200910207308A CN101671288B CN 101671288 B CN101671288 B CN 101671288B CN 200910207308 CN200910207308 CN 200910207308 CN 200910207308 A CN200910207308 A CN 200910207308A CN 101671288 B CN101671288 B CN 101671288B
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- 0 C[C@](COC(C)=O)[C@@](CC1)[C@@](C)(CCC2)[C@@]1C2=CC=C(C[C@](C[C@]1OC(C)=O)OC(C)=O)[*@]1OC([n]1cncc1)=S Chemical compound C[C@](COC(C)=O)[C@@](CC1)[C@@](C)(CCC2)[C@@]1C2=CC=C(C[C@](C[C@]1OC(C)=O)OC(C)=O)[*@]1OC([n]1cncc1)=S 0.000 description 3
- OCKXELWONHWZRX-VQURKFAASA-N C[C@H](COC(C)=O)[C@@H](CC1)[C@@](C)(CCC2)[C@@H]1/C2=C/C=C(C[C@H](C1)OC(C)=O)C[C@H]1OC(C)=O Chemical compound C[C@H](COC(C)=O)[C@@H](CC1)[C@@](C)(CCC2)[C@@H]1/C2=C/C=C(C[C@H](C1)OC(C)=O)C[C@H]1OC(C)=O OCKXELWONHWZRX-VQURKFAASA-N 0.000 description 1
Abstract
The invention discloses a preparation method of an intermediate of paricalcitol. The preparation is shown as the following formula, hydroxyl in a compound 3 is used for protection to obtain a compound 4, and then the compound 4 is subject to reduction to obtain a compound 1.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, is the preparation method about the synthetic intermediate of Zemplar exactly, and its structure is as shown in the formula shown in 1:
Formula 1
Background technology
The Zemplar structure is as shown in the formula shown in 2, it is the medicine for prevention and treatment secondary hyperparathyroidism (SHPT), it demonstrates prevention and treats curative effect accepting III before dialysis and the transplantation and IV phase chronic renal disease (CKD) patient's SHPT, the most widely used SHPT prevention of dialysis patients and medicine have been become, by easily oral administration reduction Rat parathyroid hormone 1-34 (PTH) level, simultaneously blood calcium and serium inorganic phosphorus level are had minimum influence, and the PTH reduction is a critical index of SHPT treatment curative effect.
Formula 2
Compound as shown in Equation 11 involved in the present invention is the key intermediate of synthetic Zemplar, and existing synthetic this compound method only has a kind of, i.e. the disclosed method of US Patent No. 5281731 and US5086191 is shown in 3.This patent obtains target compound, wherein R by the Wittig reaction of segment one and segment two
1=R
2=TBS, R
3=Ac.The used segment one synthetic very trouble of the method, reagent is expensive, and route is long; Segment is second from VD
2Ozonization, lack Atom economy.The joint efficiency of segment one and segment two is not high simultaneously, severe reaction conditions.
Formula 3
In the method for the disclosed synthetic Zemplar of Chinese invention patent application CN200910136441.3, the method for the intermediate shown in the synthesis type 1 is provided, referring to formula 4, namely the method by Lithium Aluminium Hydride reduction sulphonate obtains the compound suc as formula 1, wherein R
1, R
2Be respectively TBS and MOM, R
3Be hydrogen atom.Because the strongly-acid of sulfonylation agent and the high reductibility of Lithium Aluminium Hydride, so that byproduct of reaction is more, reaction yield is very low in the method, and the simultaneously use of Lithium Aluminium Hydride is not easy to produce and amplifies so that should reaction very dangerous.
Formula 4
Summary of the invention
The invention provides a kind of method that overcomes compound 1 shown in the not enough synthesis type 1 of prior art.
The present invention in the formula 3 used compound 3 as starting raw material, by method as shown in Equation 5, preparation compound 1: at first, the hydroxyl protection in the compound 3 is obtained compound 4, then compound 4 is reduced and obtain compound 1.Protection compound 3 used protecting groups can be the thiono base class functional groups such as the former acyl group of sulphur, amino thiocarbonyl, that is to say that R can be (R in the compound 4
4)
2N-or R
4O-or R
4S-, wherein R
4Be alkyl or aryl or 1-imidazolyl.R in the compound 3
1, R
2And R
3Can be alkyl silyl or-oxyl or alkoxy methyl or acyl group.Thereby used protection reagent can be CS among the present invention
2/ MeI/NaH, 1,1 '-thio-carbonyldiimidazole, sulfo-phenyl chloroformate or their analogue that is to say that the R in the formula 5 can be amino, alkylamino, alkoxyl group, alkyl thiol, imidazoles and similarly contain heteroatomic functional group.The reduction of compound 4 uses gentle negative hydrogen reagent as reductive agent, as: tin hydrogen reagent or boron hydrogen reagent or aluminium hydrogen reagent, etc.; Reaction can be carried out under condition of free radical, also can carry out under common reductive condition.
Formula 5
The present invention has the following advantages: 1.Institute's mild condition among the present invention, easily control; 2.Method yield provided by the invention is higher; 3.Raw material in present method is easy to get.
Embodiment
Embodiments of the invention below are provided.
Embodiment one:
We are take compound 3a as starting raw material, and with 3a and 1, the reaction of 1 '-thio-carbonyldiimidazole obtains compound 4a, and then reduction obtains compound 1a to compound 4a with lithium triethylborohydride.Reaction as shown in Equation 6.
Formula 6
Get compound 3a (550mg, 1mmol) be dissolved in the methylene dichloride, add suitably excessive 1 in the reaction solution, 1 '-thio-carbonyldiimidazole, stirring at room react to the raw material disappearance, add the water washing reaction solution, organic phase is through super-dry, filter, after concentrating, resistates gets compound 4a with purification by silica gel column chromatography.When 1, when 1 '-thio-carbonyldiimidazole consumption was 1.2 times of molar weights of substrate 3a, the yield of 4a was 85%.
Compound 4a is dissolved among the anhydrous THF, to wherein adding excessive lithium triethylborohydride, after room temperature reaction disappears to raw material 4a, the pressure reducing and steaming solvent, resistates obtains compound 1a with purification by silica gel column chromatography.When the lithium triethylborohydride consumption was 4 times of molar weights of substrate, yield was 60%.
Embodiment two:
Present embodiment is used NaH, CS take 3b as starting raw material successively with 3b
2Obtain 4b after processing with MeI, then 4b is obtained compound 1a with the diisobutyl aluminum hydrogen reduction.Reaction as shown in Equation 7.
Formula 7
Get compound 3b (550mg, 1mmol) and be dissolved in the tetrahydrofuran (THF), in reaction solution, add suitably excessive NaH, stirring at room reaction 1h, to wherein adding dithiocarbonic anhydride, reacting by heating is after 3 hours again, to wherein adding methyl iodide, continue reacting by heating 6 hours, and added the shrend reaction of going out, extracted with diethyl ether, organic phase is through super-dry, filter, after concentrating, resistates gets compound 4b with purification by silica gel column chromatography.When the NaH consumption is 1.5 times of molar weights of substrate 3b, dithiocarbonic anhydride is 2 times of molar weights of substrate, and methyl iodide is 1.2 times of molar weights of substrate, during 55 degrees centigrade of temperature of reaction, and the yield 75% of this reaction.
Compound 4b is dissolved in the dry toluene, to wherein adding excessive diisobutyl aluminum hydrogen, after room temperature reaction disappears to raw material 4b, tartarize potassium sodium water solution cancellation reaction, mixture stirred after 3 hours, used ethyl acetate extraction, drying, after filtering evaporate to dryness, resistates obtains compound 1b with purification by silica gel column chromatography.When diisobutyl aluminum hydrogen consumption was 4 times of molar weights of substrate, yield was 51%.
Embodiment three:
Present embodiment is take 3c as starting raw material, 3c and the reaction of sulfo-phenyl chloroformate are obtained 4c after, 4c obtains 1c with the tricyano sodium borohydride reduction.Reaction as shown in Equation 8.
Formula 8
Get compound 3c (550mg, 1mmol) be dissolved in the methylene dichloride, in reaction solution, add suitably excessive sulfo-phenyl chloroformate and the 4-dimethylamino pyridine of catalytic amount, stirring at room is reacted to raw material and is disappeared, add the water washing reaction solution, organic phase is filtered through super-dry, after concentrated, resistates gets compound 4c with purification by silica gel column chromatography.When the consumption of sulfo-phenyl chloroformate was 1.2 times of molar weights of substrate 3c, the yield of 4c was 72%.
Compound 4c is dissolved in the anhydrous tetrahydro furan, after being cooled to subzero 40 degrees centigrade, to wherein adding excessive sodium cyanoborohydride, stir lower nature and rise to room temperature, behind raw material hour, add the shrend reaction of going out, extracted with diethyl ether, the organic phase drying is filtered, behind the evaporate to dryness, resistates obtains compound 1c with purification by silica gel column chromatography.When the sodium cyanoborohydride consumption was 2 times of molar weights of substrate, yield was 60%.
Embodiment four:
Compound 4a is dissolved in the dry toluene, and to wherein adding excessive tributyl tin hydrogen and the Diisopropyl azodicarboxylate of catalytic amount, reflux is cooled to room temperature after disappearing to raw material 4a, the pressure reducing and steaming solvent, and resistates obtains compound 1a with purification by silica gel column chromatography.When tributyl tin hydrogen consumption is 6 times of molar weights of substrate, when Diisopropyl azodicarboxylate was 0.15 times of molar weight of substrate, yield was 45%.
Embodiment five:
Compound 4c is dissolved in the dry toluene, and to wherein adding excessive tributyl tin hydrogen and the Diisopropyl azodicarboxylate of catalytic amount, reflux is cooled to room temperature after disappearing to raw material 4c, the pressure reducing and steaming solvent, and resistates obtains compound 1c with purification by silica gel column chromatography.When tributyl tin hydrogen consumption is 7 times of molar weights of substrate, when Diisopropyl azodicarboxylate was 0.10 times of molar weight of substrate, yield was 52%.
Embodiment six:
Compound 4b is dissolved in the anhydrous tetrahydro furan, after being cooled to subzero 40 degrees centigrade, to wherein adding excessive lithium triethylborohydride, stir lower nature and rise to room temperature, behind raw material hour, add the shrend reaction of going out, extracted with diethyl ether, the organic phase drying is filtered, behind the evaporate to dryness, resistates obtains compound 1b with purification by silica gel column chromatography.When the lithium triethylborohydride consumption was 3 times of molar weights of substrate, yield was 48%.
The preparation method of the intermediate of Zemplar provided by the present invention is not limited to the implementation process described in above-described embodiment.
Claims (6)
1. preparation is characterized in that reaction suc as formula shown in the I suc as formula the method for the 1a of compound shown in the I, and the compound 3a suc as formula shown in the I of 1mmol is dissolved in the methylene dichloride, and it is suitably excessive to add in the reaction solution
1,1 '-thio-carbonyldiimidazole, stirring at room is reacted to raw material and is disappeared, add the water washing reaction solution, organic phase is filtered through super-dry, after concentrating, resistates must be suc as formula the compound 4a shown in the I with purification by silica gel column chromatography, compound 4a is dissolved among the anhydrous THF, to wherein adding excessive lithium triethylborohydride, after room temperature reaction disappears to raw material 4a, the pressure reducing and steaming solvent, resistates obtains compound 1a with purification by silica gel column chromatography.
2. preparation is characterized in that reaction suc as formula shown in the II suc as formula the method for the 1b of compound shown in the II, will
The compound 3b suc as formula shown in the II of 1mmol is dissolved in the tetrahydrofuran (THF), in reaction solution, add suitably excessive NaH, after the stirring at room reaction again to wherein adding dithiocarbonic anhydride, after the reacting by heating 3 hours, to wherein adding methyl iodide, continue reacting by heating 6 hours, and then added the shrend reaction of going out, extracted with diethyl ether, organic phase is through super-dry, filter, after concentrating, resistates must be suc as formula the 4b of compound shown in the II with purification by silica gel column chromatography, compound 4b is dissolved in the dry toluene, to wherein adding excessive diisobutyl aluminum hydrogen, after room temperature reaction disappeared to raw material 4b, the cancellation of tartarize potassium sodium water solution was reacted again, use again ethyl acetate extraction, drying, behind the filtration evaporate to dryness, resistates obtains compound 1b with purification by silica gel column chromatography.
3. preparation is such as the method for compound 1c as shown in formula III, it is characterized in that reaction is shown in formula III, the compound 3c as shown in formula III of 1mmol is dissolved in the methylene dichloride, add suitably excessive sulfo-phenyl chloroformate and the 4-dimethylamino pyridine of catalytic amount in reaction solution, stirring at room is reacted to the raw material disappearance, adds the water washing reaction solution, organic phase is through super-dry, filter, after concentrating, the resistates purification by silica gel column chromatography
Compound 4c that must be as shown in formula III, again compound 4c is dissolved in the anhydrous tetrahydro furan, be cooled to subzero 40 degrees centigrade after, to wherein adding excessive sodium cyanoborohydride, stir lower nature and rise to room temperature, after raw material disappears, add the shrend reaction of going out, extracted with diethyl ether, the organic phase drying, filter, behind the evaporate to dryness, resistates obtains compound 1c with purification by silica gel column chromatography.
4. preparation is characterized in that and will be dissolved in the dry toluene suc as formula the 4a of compound shown in the IV, to azo two isobutyls that wherein add excessive tributyl tin hydrogen and catalytic amount suc as formula the method for the compound 1a shown in the IV
Nitrile, reflux are cooled to room temperature after disappearing to raw material 4a, the pressure reducing and steaming solvent, and resistates obtains compound 1a with purification by silica gel column chromatography.
5. preparation is suc as formula the method for the compound 1c shown in the V, it is characterized in that and to be dissolved in the dry toluene such as the 4c of compound as shown in the formula III, to wherein adding excessive tributyl tin hydrogen and the Diisopropyl azodicarboxylate of catalytic amount, after reflux disappears to raw material 4c, be cooled to room temperature, the pressure reducing and steaming solvent, the resistates silicagel column
Chromatography purification obtains compound 1c.
6. preparation is suc as formula the method for the compound 1b shown in the VI, it is characterized in that and to be dissolved in the anhydrous tetrahydro furan suc as formula the 4b of compound shown in the VI, after being cooled to subzero 40 degrees centigrade, to wherein adding excessive lithium triethylborohydride, stir lower nature and rise to room temperature, after raw material disappears, add the shrend reaction of going out, second
The ether extraction, the organic phase drying is filtered, and behind the evaporate to dryness, resistates obtains compound 1b with purification by silica gel column chromatography.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910207308 CN101671288B (en) | 2009-10-14 | 2009-10-14 | Preparation method of intermediate of paricalcitol |
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|---|---|---|---|
| CN 200910207308 CN101671288B (en) | 2009-10-14 | 2009-10-14 | Preparation method of intermediate of paricalcitol |
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|---|---|
| CN101671288A CN101671288A (en) | 2010-03-17 |
| CN101671288B true CN101671288B (en) | 2013-10-30 |
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| CN 200910207308 Expired - Fee Related CN101671288B (en) | 2009-10-14 | 2009-10-14 | Preparation method of intermediate of paricalcitol |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5086191A (en) * | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
| US5281731A (en) * | 1991-05-28 | 1994-01-25 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
-
2009
- 2009-10-14 CN CN 200910207308 patent/CN101671288B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5086191A (en) * | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
| US5281731A (en) * | 1991-05-28 | 1994-01-25 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
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| CN101671288A (en) | 2010-03-17 |
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