CN101955498B - Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof - Google Patents
Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof Download PDFInfo
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- CN101955498B CN101955498B CN2010102208491A CN201010220849A CN101955498B CN 101955498 B CN101955498 B CN 101955498B CN 2010102208491 A CN2010102208491 A CN 2010102208491A CN 201010220849 A CN201010220849 A CN 201010220849A CN 101955498 B CN101955498 B CN 101955498B
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Abstract
The invention relates to a preparation of organic compounds, in particular to a preparation method of a common side chain of a series of 25-hydroxyitamin D2 medicines. The structure of the compounds is represented in the formula 1. The compounds have wide application and are more stable than the traditional compounds with the same application, so that the compounds are convenient to storage and use. The method for synthesizing the target compounds (1) has high yield, short synthesis route and easily purified products.
Description
Technical field
The present invention relates to a kind of preparation method of organic cpds, is that its structure is as shown in the formula shown in 1 about the preparation method of the common side chain of 2 types of medicines of a series of 25-hydroxy-vitamin Ds exactly.
Formula 1
Wherein, R be Wasserstoffatoms perhaps-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or hydrocarbyl substituted, they can be identical, also can be different.
Background technology
Formula 2
Formula 3
Suc as formula 2 types of medicines of a series of 25-hydroxy-vitamin Ds shown in 2 a common side chain is arranged all, these medicines can be synthesized through the process shown in the formula 3 by compound 1.These medicines comprise 25-hydroxy-vitamin D 2,1a, and 25-dihydroxyvitamin D 2, Zemplar, or the like.These medicines all are the regulators of calcium phosphorus running balance in animal and human's body
1,2Their activity in cell recognition have also been found in nearest research
3,4,5Therefore; Various types of novel vitamin D analogues have caused investigator's extensive interest, the for example analogue of the verivate of vitamins D side chain, different hydroxyl models, the analogue of different steric configurations, etc.; All be widely used in polytype active testing; A plurality of known these compounds have all been showed good active in external body, shown effect good in multiple disease treatment and potential using value, like the rickets of the dysplasia of treatment sclerotin, anti-vitamins D
6, osteoporosis
7, vitamin D deficiency such as psoriasis
8For example; Zemplar is the medicine of prevention and treatment secondary hyperparathyroidism (SHPT); It demonstrates prevention and treatment curative effect to III and IV phase chronic renal disease (CKD) patient's the SHPT that accepts before dialysis and the transplantation, has become the most widely used SHPT of dialysis patients and has prevented and medicine.
The existing compound that is used to construct above-mentioned 25-hydroxy-vitamin D 2 medicine series side chains mainly contains suc as formula two kinds shown in 4, i.e. the Yelide salt 5 of the sulfone 4 of patent (US4847012, US5260290 etc.) report and other bibliographical informations.Wherein, compound 4 is when a series of similar medicines that are used for compound 2 synthetic, and yield is very low.Compound 5 not only be used for medicine when synthetic yield low, and the synthetic and purifying of compound 5 itself are difficult to, its building-up process also causes some limitations for the basic R of protection functional group.
Formula 4
Summary of the invention
The present invention provides a kind of new can overcome above-mentioned insufficient compound, and its structure is suc as formula compound shown in 11, and the present invention also provides the compound method of this compound.Provided by the present invention suc as formula the compound shown in 1
1Hafner，V.；Rutsch，C.；Ding，R.；Heinrich，T.；Diedrichs，L.；Schmidt-Gayk，H.；Walter-Sack，I.；Bommer，J.；Mikus，G.Int.J.Clin.Pharm.Therap.2008，46(3)，131-135.
2Nakane，Masaki；Ma，Junli；Rose，Andrew?E.；Osinski，Mark?A.；Wu-Wong，J.Ruth.J.Steroid?Biochem.Mol.Biology?2007，103(1)，84-89
3Coyne，D.W.；Grieff，M.；Ahya，S.N.；Giles，K.；Norwood，K.；Slatopolsky，E.Am.J.Kidney?Diseases?2002，40(6)，1283-1288
4Slatopolsky，E.；Cozzolino，M.；Finch，J.L.Kidney?International?2002，62(4)，1277-1284.
5Rown，A.J.；Finch，J.；Slatopolsky，E.J.Lab.Clin.Med.2002，139(5)，279-284.
6Puschett?J.B.；Genel?M.；Rastegar?A.；Anast?C.；DeLuca?H.F.；Friedman?A.Clin.pharm.Thera.1975，17(2)，202-11.
7Balint，E.；Marshall，C.F.；Sprague，S.M.Am.J.Kidney?Diseases?2000，36(4)，789-796.
8Petkovich, P.M.; Helvig, C.F.; Melnick, J.Z.PCT Int.Appl.2009, bibliographical information is not seen in synthesizing of 61pp.WO2009124210. 1 as yet.
The present invention is a starting raw material with (R)-2-methyl-3-hydroxy methyl propionate (being compound 6), through suc as formula the method shown in 5, prepares compound 1: at first, compound 6 and methylmetal reagents reaction are obtained compound 7.Optionally the primary alconol in the compound 7 is carried out halo or the sulphonyl esterification can obtain compound 8, protect the tertiary alcohol in 8 to obtain compound 9 then, the metallic compound reaction with compound 9 and diaryl phosphine obtains target compound again.Here the methylmetal reagents with compound 6 reactions can be lithium methide, methylmagnesium-halide, methyl zinc.Compound 7 is converted into compound 8 can obtain halogenide 8 through the direct exchange of alcohol and halogen; Also can alcohol and sulfonylation agent reaction be obtained sulphonate 8, can also the primary alconol acyl in the compound 7 be protected with alkylsulfonyl and carry out halo with metal halide again and obtain halogenide 8.Three grades of hydroxyls of protection compound 8 can be used silicon ether, acyl group, alkyl, alkoxyalkyl, tetrahydropyrans, THF.
Formula 5
Wherein, R ' is an alkyl, and X is halogen or sulfonyloxy R " SO
2O-, R here " be alkyl.R be Wasserstoffatoms perhaps-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or hydrocarbyl substituted, they can be identical, also can be different.
The present invention has the following advantages: 1.The present invention provides the compound of one type of new Synthetic 2 5-HEC medicine series side chain, and this use of a compound is extensive, and more stable than the compound of existing same purposes, is convenient to preserve and use; 2.The method yield of synthesising target compound 1 provided by the invention is high, and route is brief, and product is easy to purifying.
Embodiment
Specific embodiment of the present invention below is provided, to show possible implementation process.
Embodiment one: compound 1a, its molecular structure is following, R1=R2=OCH2CH3 wherein, R=CH2OCH3.
Its synthetic route is following:
Get (R)-3-hydroxy-2-methyl methyl propionate (11.8g 100mmol) is dissolved in the ether, under the zero degrees celsius, in the argon atmospher to wherein splashing into MeMgBr (3M; 100mL 300mmol), after dripping off, continues to stir 6 hours; To wherein slowly splashing into 1M hydrochloric acid cancellation reaction, ethyl acetate extraction (300mL is each) three times merges organic phase; Anhydrous magnesium sulfate drying, filtering and concentrating obtain colorless oil 11 (10.7g), yield 90%.
1H?NMR(300MHz，δ，ppm)0.81(3H，d，J＝6.9Hz)，1.14(3H，s)，1.22(3H，s)，1.77(1H，m)，3.58(1H，b)，3.66(2H，m)，3.84(1H，b).
13C?NMR(75MHz，δ，ppm)12.9，23.9，29.6，43.9，66.1，74.5.ESI-HRMS(m/z)[M
+]118.0，100.0，85.0，59.0.
Above-mentioned gained colorless oil is dissolved in methylene dichloride (100mL) and the pyridine (10mL), to wherein adding 4-(N, N-dimethyl amido) pyridine (1g) and Tosyl chloride (20g; 105mmol), stirred overnight at room temperature, treat that raw material disappears after; Reaction solution is slowly poured in the frozen water solution (200mL) of NaHCO3 (15g) into stirring at room 30 minutes, separatory; Water merges organic phase and washes anhydrous sodium sulfate drying with 1M hydrochloric acid (20mL) with dichloromethane extraction (200mL) three times; After the filtering and concentrating, purification by silica gel column chromatography obtains colorless oil compound 12 (20g), yield 82%.
1H?NMR(300MHz，δ，ppm)0.93(3H，d，J＝6.9Hz)，1.09(3H，s)，1.16(3H，s)，1.83(1H，m)，2.42(3H，s)，3.89(1H，dd，J＝7.5，9.6Hz)，4.22(1H，dd，J＝4.5，9.6Hz)，7.32(2H，d，J＝7.5Hz)，7.76(2H，d，J＝7.5Hz).
13C?NMR(75MHz，δ，ppm)12.6，21.6，26.0，28.5，43.4，71.9，72.6，127.8，129.8，132.9，144.7.
(19.0g 70mmol) is dissolved among the exsiccant CH3CN (50mL), to wherein adding anhydrous Na I (11g with above-mentioned p-toluenesulfonic esters; 73mmol), reflux concentrated and removes CH3CN after 5 hours; Add ether (100mL) and filter, with ether (200mL) washing leaching cake, merging filtrate is with sodium thiosulfate solution washing (50mL); Organic phase is through anhydrous magnesium sulfate drying, crosses the elimination siccative, directly is used for next step after concentrated.
Get above-mentioned iodide 13 (16g 70mmol) is dissolved among the dry CH2Cl2 (300mL), ice-water bath cooling down, to wherein add diisopropyl ethyl amine (10g, 100mmol) with methoxyl methyl chlorine (7g, 85mmol).Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 14 (13.6g) with purification by silica gel column chromatography, two step total recoverys 71%.
1H?NMR(300MHz，δ，ppm)1.08(3H，d，J＝5.7Hz)，1.12(3H，s)，1.23(3H，s)，1.97(1H，m)，2.85(1H，dd，J＝9.3，11.1Hz)，3.35(3H，s)，3.68(1H，dd，J＝1.8，9.3Hz)，4.67(2H，m).
13C?NMR(75MHz，δ，ppm)。
Get above-mentioned gained and look for oily matter 14 (11g) to mix with triethyl-phosphite (20g), reflux is after 5 hours, the triethyl-phosphite that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1a (9g), yield 79% with the silica gel column chromatography fast purifying.
Embodiment two: 1b's is synthetic.R1=R2=OMe wherein, R=THP, molecular structure is as follows:
Its synthetic route is following:
Get (R)-3-hydroxy-2-methyl ethyl propionate (11.8g 100mmol) is dissolved in the ether, under the zero degrees celsius, in the argon atmospher to wherein splashing into MeLi (1M; 300mL 300mmol), after dripping off, continues to stir 6 hours; To wherein slowly splashing into 1M hydrochloric acid cancellation reaction, ethyl acetate extraction (300mL is each) three times merges organic phase; Anhydrous magnesium sulfate drying, filtering and concentrating obtain colorless oil 11 (10.1g), yield 85%.
Above-mentioned gained colorless oil is dissolved in methylene dichloride (100mL) and the triethylamine (10mL), cryosel bathe cooling down to wherein add methylsulfonyl chloride (11.4g, 100mmol); After continuation is stirred and was treated that raw material disappeared in 2 hours; Add the shrend reaction of going out, separatory, water is with dichloromethane extraction (200mL) three times; Anhydrous sodium sulfate drying directly is used for next step after the filtering and concentrating.
Above-mentioned methanesulfonates 16 is dissolved among the exsiccant CH3CN (100mL), to wherein add anhydrous Na I (15g, 100mmol); After the reflux 5 hours, concentrate and remove CH3CN, add ether (100mL) and filter; With ether (200mL) washing leaching cake, merging filtrate is with sodium thiosulfate solution washing (50mL), and organic phase is through anhydrous magnesium sulfate drying; Cross the elimination siccative, concentrate, two step yields 60% after the silica gel column chromatography purifying obtains iodide 13 (13.7g).
1H?NMR(300MHz，δ，ppm)1.08(3H，d，J＝6.3Hz)，1.14(3H，s)，1.23(3H，s)，1.85(1H，m)，2.89(1H，dd，J＝9.3，11.1Hz)，3.65(1H，dd，J＝1.5，9.3Hz).
13C?NMR(75MHz，δ，ppm)11.1，16.0，25.1，28.5，47.6，73.1.
Get above-mentioned iodide 13 (11.4g 50mmol) is dissolved among the dry CH2Cl2 (100mL), ice-water bath cooling down, to wherein adding tosic acid (0.5g), then slowly to wherein splash into dihydropyrane (5g, 60mmol).Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 17 (13g), yield 82% with purification by silica gel column chromatography.
Get above-mentioned gained and look for oily matter 17 (9.4g) to mix with trimethyl phosphite (20g), reflux is after 5 hours, the trimethyl phosphite that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1a (7.9g), yield 81% with the silica gel column chromatography fast purifying.
Embodiment three: 1c's is synthetic.R1=R2=Ph wherein, R=Bz, its molecular structure is shown in the following figure:
Its synthetic route is following:
(13.6g 50mmo1) is dissolved among the dry CH2C12 (100mL), under the ice-water bath cooling, to wherein adding pyridine (10g) and 4-(N, N-dimethyl amido) pyridine, then slowly to wherein splashing into Benzoyl chloride 99min. (10g) to get above-mentioned p-toluenesulfonic esters 12.Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains product 18 (13g), yield 78% with purification by silica gel column chromatography.
Above-mentioned methanesulfonates 18 (11.3g) is dissolved among the exsiccant CH3CN (100mL), and to wherein adding anhydrous Na I (5g), reflux is after 5 hours; Concentrate and remove CH3CN, add ether (100mL) and filter, with ether (200mL) washing leaching cake; Merging filtrate is with sodium thiosulfate solution washing (50mL), and organic phase is crossed the elimination siccative through anhydrous magnesium sulfate drying; Concentrate after the silica gel column chromatography purifying obtains iodide 19 (7g), yield 70%.
Phenylbenzene phosphatization hydrogen (3.72g) is dissolved among the anhydrous THF, be cooled to subzero 78 degrees centigrade under the argon atmospher after, to the hexane solution that wherein slowly splashes into butyllithium (2.8M, 7ml); Behind the stirring reaction 30 minutes,, continue to stir 2 hours, to wherein adding the shrend reaction of going out to the THF solution that wherein adds iodide 19 (4.5g); (30%, 3ml), continuation is stirred and is heated up naturally, after 5 minutes to wherein adding ydrogen peroxide 50 then; Separatory, water is used ethyl acetate extraction, merges organic phase; Use anhydrous sodium sulfate drying, resistates obtains target compound 1c with purification by silica gel column chromatography, yield 75% behind the filtration evaporate to dryness.
Embodiment four: 1d's is synthetic.R1=R3=Ph wherein, R=SiEt3, its molecular structure is shown in the following figure:
Its synthetic route is following:
Iodohydrin 13 (2.72g) is dissolved in the methylene dichloride (20ml), under the room temperature to wherein adding triethylamine (3ml) and chlorotriethyl silane (5g), stirred overnight at room temperature; In reaction solution, add the shrend reaction of going out, separatory, water is used dichloromethane extraction; Merge organic phase; Use anhydrous sodium sulfate drying, resistates obtains silicon ether 20 (3g), yield 80% with purification by silica gel column chromatography behind the filtration evaporate to dryness.
Phenylbenzene phosphatization hydrogen (3.72g) is dissolved among the anhydrous THF, be cooled to subzero 78 degrees centigrade under the argon atmospher after, to the hexane solution that wherein slowly splashes into butyllithium (2.8M, 7ml); Behind the stirring reaction 30 minutes,, continue to stir 2 hours, add the shrend reaction of going out to the THF solution that wherein adds iodide 20 (4.5g); (30%, 3ml), continuation is stirred and is heated up naturally, after 5 minutes to wherein adding ydrogen peroxide 50 then; Separatory, water is used ethyl acetate extraction, merges organic phase; Use anhydrous sodium sulfate drying, resistates obtains target compound 1d with purification by silica gel column chromatography, yield 85% behind the filtration evaporate to dryness.
Claims (3)
1. suc as formula compound shown in 11:
Formula 1
Wherein, R be Wasserstoffatoms perhaps-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or hydrocarbyl substituted, they can be identical, also can be different.
2. in the compound 1 according to claim 1, R
1And R
2Be respectively aryl or alkoxyl group or alkyl.
3. the preparation method of compound 1 according to claim 1, this preparation method pass through suc as formula the process shown in 2:
Wherein, R ' is an alkyl, and X is halogen or sulfonyloxy R " SO
2O-, R here " be alkyl, R be Wasserstoffatoms perhaps-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or hydrocarbyl substituted, they can be identical, also can be different; Compound 2 promptly obtains compound 3 with the methylmetal reagents reaction through step a; Compound 3 obtains compound 4 through step b, and step b can be through through obtaining compound 4 after the sulfonic acid esterification and then with the metal halide reactant salt, also can be directly and halogen react and obtain compound 4, perhaps obtain compound 4 through the sulfonic acid esterification; Compound 4 promptly protects the tertiary alcohol in the compound 4 to obtain compound 5 through step c; Compound 5 promptly obtains target compound 1 through the metallic compound reaction with the diaryl phosphine through steps d.
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| CN102351901A (en) * | 2011-08-15 | 2012-02-15 | 上海皓元化学科技有限公司 | 25-hydroxy vitamin D2 series medicament side chain and its preparation method |
| CN102643302A (en) * | 2012-04-06 | 2012-08-22 | 上海皓元化学科技有限公司 | Preparation method of synthetic intermediate of 25-hydroxyvitamin D2and 1α, 25-dihydroxyvitamin D2 |
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| US4847012A (en) * | 1988-04-29 | 1989-07-11 | Wisconsin Alumni Research Foundation | Vitamin D related compounds and processes for their preparation |
| US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
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