CN102351901A - 25-hydroxy vitamin D2 series medicament side chain and its preparation method - Google Patents

25-hydroxy vitamin D2 series medicament side chain and its preparation method Download PDF

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CN102351901A
CN102351901A CN2011102317027A CN201110231702A CN102351901A CN 102351901 A CN102351901 A CN 102351901A CN 2011102317027 A CN2011102317027 A CN 2011102317027A CN 201110231702 A CN201110231702 A CN 201110231702A CN 102351901 A CN102351901 A CN 102351901A
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compound
phosphorus
preparation
reaction
formula
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高强
薛吉军
郑保富
刘荣
李海峰
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SHANGHAI HAOYUAN CHEMICAL TECHNOLOGY Co Ltd
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SHANGHAI HAOYUAN CHEMICAL TECHNOLOGY Co Ltd
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Priority to PCT/CN2011/001406 priority patent/WO2013023327A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Abstract

The invention relates to a 25-hydroxy vitamin D2 series medicament side chain and its preparation method. The invention provides a novel compound 1, the structure of which is shown in formula 1, and a synthetic method thereof. The synthetic method provided by the invention comprises the following steps of: using (S)-2-methyl-3-hydroxypropionic acid methyl ester as an initial raw material, performing a reaction between (S)-2-methyl-3-hydroxypropionic acid methyl ester and a methyl metal reagent, carrying out selective halogenation or sulfonate esterification, followed by selective halogenation and protection of tertiary alcohols, and performing a reaction with a metallic compound of diaryl phosphine or trialkoxyl phosphine to obtain the target compound.

Description

25-hydroxy-vitamin D 2 medicine series side chains and preparation method thereof
Technical field
The present invention relates to a kind of organic compound and preparation method thereof, say it is one type of chain P contained compound and preparation method thereof definitely.
Background technology
Formula 1
Suc as formula a series of 25-hydroxy-vitamin Ds shown in 1 2The class medicine all has a common side chain.These medicines comprise 25-hydroxy-vitamin D 2,1 α, 25-dihydroxyvitamin D 2, Zemplar, or the like.These medicines all are the conditioning agents 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 derivative of vitamins D side chain, different hydroxyl models, the analogue of different steric configurations; Deng; 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
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.
Disease 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 side chain method that is used to construct this compounds mainly is to construct side chain through two keys of constructing on the side chain, and reaction commonly used has the Wittig reaction, Julia coupling olefination and Wiitig-Horner reaction.Wherein, Julia coupling olefination mainly uses suc as formula the compound shown in 24 as the side chain fragment, and the Wittig reaction is then used suc as formula the compound shown in 25 as side chain fragment (patent documentation US4847012, US5260290 etc.).Wherein, compound 4 is when a series of similar medicines that are used for compound 2 synthetic, and yield is very low, and will construct through the desulfurization alkylene of coupling and Na-Hg through two-step reaction, and operation inconvenience is polluted big.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.
Figure BSA00000556071900021
Formula 2
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 31, and the present invention also provides the synthesis method of this compound.Provided by the present invention suc as formula synthesizing of the compound shown in 31 not seeing bibliographical information as yet.
Formula 3
Wherein, R is hydrogen atom or alkyl or trialkyl silyl or the substituted alkyl of alkoxyl group or acyl group or THP trtrahydropyranyl or tetrahydrofuran base; R 1And R 2Be respectively a kind of in aryl or the alkoxyl group.
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?2009，61pp.WO2009124210.
The present invention is a starting raw material with (S)-2-methyl-3-hydroxy methyl propionate (being compound 6), through suc as formula the method shown in 4, prepares compound 1: at first, compound 6 and methylmetal reagents reaction are obtained compound 7.Selectivity is carried out halo with the one-level hydroxyl of this diol compound or sulfonate compound that the one-level hydroxyl sulfoacid esterification of this diol compound is obtained and halogen negative ion generation substitution reaction are carried out halo and can be obtained compound 8; Protect three grades of hydroxyls in 8 to obtain compound 9 then, metallic compound or the tri-alkoxy phosphorus reaction with compound 9 and diaryl phosphine obtains target compound 1 again.Here the methylmetal reagents with compound 6 reactions can be lithium methide or methylmagnesium-halide or methyl zinc.Compound 7 is converted into compound 8 and can obtains through the direct halogenation of hydroxyl, the one-level hydroxyl in the compound 7 can also be converted into sulphonate and carry out halo with halogen anion again and obtain halogenide 8.Used halide reagent phosphorus trihalide or three oxyhalogen phosphorus or halogenation sulfoxide or phosphorus pentahalides or carbon tetrahalide or iodine when compound 7 direct halogenations prepare compound 8 are like sulfur oxychloride or phosphorus tribromide or phosphorus pentachloride or phosphorus trichloride or phosphorus oxychloride or carbon tetrabromide or tetracol phenixin or iodine.The used reagent of compound 7 sulfonylations can be methylsulfonyl chloride or ether or Tosyl chloride or benzene sulfonyl chloride or trifluoromethanesulfanhydride anhydride; The used halogen anion of halogenation comes from lithium salts or sodium salt or the sylvite or the magnesium salts of chlorine or bromine or iodine, like lithium chloride or lithiumbromide or Sodium Bromide or Potassium Bromide or magnesium bromide or magnesium chloride or sodium iodide or lithium iodide or potassiumiodide or magnesium iodide.The protection of 8 three grades of hydroxyls of compound can be with alkyl silyl or benzoyl or alkoxyalkyl or THP trtrahydropyranyl or tetrahydrofuran base, and used reagent is trialkyl silicon chlorides or Benzoyl chloride or alkoxyalkyl chlorine or dihydropyrane or dihydrofuran.The metallic compound of the diaryl phosphine here can be diphenylphosphine lithium or di-p-tolyl phosphine lithium or corresponding sodium reagent or potassium reagent.Here used tri-alkoxy phosphorus can be trimethoxy phosphorus or triethoxy phosphorus or three butoxy phosphorus
Figure BSA00000556071900031
Formula 4
Wherein, R is hydrogen atom or alkyl or trialkyl silyl or the substituted alkyl of alkoxyl group or acyl group or THP trtrahydropyranyl or tetrahydrofuran base; R 1And R 2Be respectively a kind of in aryl or the alkoxyl group.
What use when constructing the such drug molecule of compound 2 with compound 1 is the Wittig-Horner reaction.With compound 1 usefulness highly basic (as, butyllithium, potassium tert.-butoxide, etc.) handle after, 3 reactions obtain compound 2 with compound again, remove R protection base at last after, just can obtain drug molecule 2a-2c.
Figure BSA00000556071900041
Formula 5
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.Through preferred; R in the compound 1 protection base is can be for tertiary butyl dimethyl silica-based or trimethyl silicon based or triethyl is silica-based or methoxyl methyl or benzyloxymethyl or 2-tetrahydrofuran base or 2-THP trtrahydropyranyl or hydrogen atom or benzoyl, and R1 and R2 can be methyl or ethyl or butyl.
Embodiment one: compound 1a, its molecular structure is following, wherein R 1=R 2=-OEt, R=-CH 2OCH 3, its molecular structure is as shown in the formula shown in 6:
Figure BSA00000556071900042
Formula 6
Its synthetic route is as shown in the formula shown in 7:
Figure BSA00000556071900051
Formula 7
(11.8g 100mmol) is dissolved in the ether, under the zero degrees celsius to get (S)-2-methyl-3-hydroxy methyl propionate; In the argon atmospher to wherein splash into MeMgBr (3M, 100mL, 300mmol); After dripping off; Continue to stir 6 hours, to wherein slowly splashing into 1M hydrochloric acid cancellation reaction, ethyl acetate extraction (300mL is each) three times; Merge organic phase; Anhydrous magnesium sulfate drying, filtering and concentrating obtain colorless oil 11 (10.7g), yield 90%.
The structure elucidation data: 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 11 is dissolved in CH 2Cl 2(100mL) and in the pyridine (10mL), to wherein add 4-(N, N-dimethyl amido) pyridine (1g) and Tosyl chloride (20g, 105mmol), stirred overnight at room temperature, treat that raw material disappears after, slowly pour reaction solution into NaHCO 3In the frozen water solution (200mL) (15g), 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%.
The structure elucidation data: 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 in exsiccant CH with above-mentioned gained p-toluenesulfonic esters 12 3Among the CN (50mL), (11g, 73mmol), reflux concentrated and removes CH after 5 hours to wherein adding anhydrous Na I 3CN adds ether (100mL) and filters, and with ether (200mL) washing leaching cake, merging filtrate is with sodium thiosulfate solution washing (50mL), and organic phase is through anhydrous magnesium sulfate drying, and mistake elimination siccative directly is used for next step after concentrated.
(16g 70mmol) is dissolved in dry CH to get above-mentioned gained iodide 13a 2Cl 2(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 CH 2Cl 2Extraction.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 14a (13.6g) with purification by silica gel column chromatography, two step total recoverys 71%.
The structure elucidation data: 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 14a (11g) to mix with triethoxy phosphorus (20g), reflux is after 5 hours, the triethoxy phosphorus 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.R wherein 1=R 2=OMe, R=THP, molecular structure is as shown in the formula shown in 8:
Figure BSA00000556071900061
Formula 8
Its synthetic route is as shown in the formula shown in 9:
Figure BSA00000556071900071
Formula 9
(40.0mmol) is dissolved in CH with compound 11 2Cl 2(100mL) and in the pyridine (4.0g); Cryosel is bathed cooling down to wherein slowly splashing into sulfur oxychloride (5.1g; 50mmol); After continuation is stirred and was treated that raw material disappeared in 1 hour; 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.
(11.4g 50mmol) is dissolved in dry CH to get above-mentioned muriate 13b 2Cl 2(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 CH 2Cl 2Extraction.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 14b (13g), yield 82% with purification by silica gel column chromatography.
Get above-mentioned gained and look for oily matter 14b (9.4g) to mix with trimethoxy phosphorus (20g), reflux is after 5 hours, the trimethoxy phosphorus that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1b (7.9g), yield 81% with the silica gel column chromatography fast purifying.
Embodiment three: 1c's is synthetic.R wherein 1=R 2=Ph, R=Bz, its molecular structure is as shown in the formula shown in 10:
Figure BSA00000556071900072
Formula 10
Its synthetic route is as shown in the formula shown in 11:
Figure BSA00000556071900081
Formula 11
Glycol 11 (11.8g) is dissolved in the exsiccant ether (100mL), and the ice-water bath cooling is down to wherein adding anhydrous PBr 3(30g), add continued and stir 1h, add shrend and go out, extracted with diethyl ether, the organic phase anhydrous magnesium sulfate drying is crossed the elimination siccative, concentrates after the silica gel column chromatography purifying obtains iodide 13c (7g), yield 70%.
13c (2g) is dissolved in CH 2Cl 2(20mL), to wherein adding pyridine (1g) and DMAP (100mg), then to wherein splashing into Benzoyl chloride (1.7g); After adding continued stirring 2h, add shrend and go out, behind the separatory; Organic phase concentrates after silica gel column chromatography obtains compound 14c (2.3g), yield 70% through drying.
Phenylbenzene phosphatization hydrogen (3.72g) is dissolved among the anhydrous THF; After being cooled to subzero 78 degrees centigrade under the argon atmospher; To the hexane solution (2.8M that wherein slowly splashes into butyllithium; 7ml), stirring reaction is after 30 minutes, to the THF solution that wherein adds iodide 14c (4.5g); Continue to stir 2 hours; To wherein adding the shrend reaction of going out, then to wherein add ydrogen peroxide 50 (30%, 3ml); Continue to stir and heat up naturally; After 5 minutes, separatory, water ethyl acetate extraction; Merge 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.R wherein 1=R 2=Ph, R=SiEt 3, its molecular structure is as shown in the formula shown in 12:
Figure BSA00000556071900082
Formula 12
Its synthetic route is as shown in the formula shown in 13:
Figure BSA00000556071900091
Formula 13
Compound 11 (1.18g) is dissolved in ether (20mL) and the acetonitrile (12mL), to wherein adding triphenyl phosphorus (3.12g), then in batches to wherein adding iodine (2.54g); Behind the stirring at room 3h, add shrend and go out, extracted with diethyl ether; Organic phase is filtered through super-dry, obtains compound 13d after concentrating.
Iodohydrin 13d (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 dichloromethane extraction; Merge organic phase; Use anhydrous sodium sulfate drying, resistates obtains silicon ether 14d (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; After being cooled to subzero 78 degrees centigrade under the argon atmospher; To the hexane solution (2.8M that wherein slowly splashes into butyllithium; 7mL), stirring reaction is after 30 minutes, to the THF solution that wherein adds iodide 14d (4.5g); Continue to stir 2 hours; Add the shrend reaction of going out, then to wherein add ydrogen peroxide 50 (30%, 3mL); Continue to stir and heat up naturally; After 5 minutes, separatory, water ethyl acetate extraction; Merge 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.
Embodiment five: 1e's is synthetic.R wherein 1=R 2=-C 6H 4-Me-p, R=H, its molecular structure is as shown in the formula shown in 14:
Figure BSA00000556071900092
Formula 14
Its synthetic route is as shown in the formula shown in 15:
Equation 15
Compound 11 (1.18g) is dissolved in ether (20mL) and the acetonitrile (12mL), to wherein adding triphenyl phosphorus (3.12g), then in batches to wherein adding iodine (2.54g); Behind the stirring at room 3h, add shrend and go out, extracted with diethyl ether; Organic phase is filtered through super-dry, obtains compound 13d after concentrating.
Di-p-tolyl phosphuret-(t)ed hydrogen (3.72g) is dissolved among the anhydrous THF; After being cooled to subzero 78 degrees centigrade under the argon atmospher; To the hexane solution (2.8M that wherein slowly splashes into butyllithium; 7mL), stirring reaction is after 30 minutes, to the THF solution that wherein adds iodide 13d (2.0g); Continue to stir 2 hours; Add the shrend reaction of going out, then to wherein add ydrogen peroxide 50 (30%, 3mL); Continue to stir and heat up naturally; After 5 minutes, separatory, water ethyl acetate extraction; Merge organic phase; Use anhydrous sodium sulfate drying, resistates obtains target compound 1e with purification by silica gel column chromatography, yield 79% behind the filtration evaporate to dryness.
Embodiment six: 1f's is synthetic.R wherein 1=R 2=OBu, R=THF, molecular structure is as follows:
Figure BSA00000556071900102
Formula 16
Its synthetic route is following:
Formula 17
(40.0mmol) is dissolved in CH with compound 11 2Cl 2(100mL) and CH 3Among the CN (4.0g), cryosel bathe cooling down to wherein add PPh3 (12g, 45mmol) with CBr4 (13.2g, 40mmol), continue to stir treated the raw material disappearance in 1 hour after, add the shrend reaction of going out, separatory, water CH 2Cl 2Extraction (200mL) three times, anhydrous sodium sulfate drying, the crude product that gets compound 13f after the filtering and concentrating directly is used for next step.
(11.4g 50mmol) is dissolved in dry CH to get above-mentioned bromide 13f 2Cl 2(100mL), ice-water bath cooling down, to wherein adding tosic acid (0.5g), then slowly to wherein splash into dihydrofuran (4.7g, 60mmol).Behind the room temperature reaction 12 hours, add washing, water CH 2Cl 2Extraction.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 14f (13g), yield 81% with purification by silica gel column chromatography.
Get above-mentioned gained colorless oil 14f (9.4g) and mix with three butoxy phosphines (20g), reflux is after 5 hours, the three butoxy phosphines that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1f (7.9g), yield 81% with the silica gel column chromatography fast purifying.
Embodiment seven: the application of compound 1: under the effect of alkali, prepare compound 2b with compound 3b and 1a.
Formula 18
Getting compound 1a (1.0mmol) is dissolved in the anhydrous tetrahydro furan; Be cooled to subzero 78 degree under the nitrogen protection; Then to the tetrahydrofuran solution (1.6M that wherein slowly splashes into butyllithium; 1.0mmol); Dripped off the continued stirring reaction 30 minutes; Tetrahydrofuran solution with 3b slowly splashes into wherein then, continues stirring reaction 2h.Naturally rise to room temperature, saturated ammonium chloride cancellation, ethyl acetate extraction; Organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography gets intermediate; This intermediate is dissolved in the tetrahydrofuran (THF); To wherein adding tetrabutyl ammonium fluoride, behind the stirring at room 1h, add shrend and go out; Ethyl acetate extraction; Dry concentrating obtains target compound 1 α, the 25-dihydroxyvitamin D behind the silica gel column chromatography 2(2b).

Claims (10)

1. suc as formula compound shown in 11:
Figure FSA00000556071800011
Formula 1
Wherein, R is hydrogen atom or alkyl or trialkyl silyl or the substituted alkyl of alkoxyl group or acyl group or THP trtrahydropyranyl or tetrahydrofuran base; R 1And R 2Be respectively a kind of in aryl and the alkoxyl group.
2. in the compound 1 according to claim 1, R is hydrogen atom or methyl or methoxyl methyl or methoxyethyl or trimethyl silicon based or triethyl is silica-based or 2-tetrahydrofuran base or 2-THP trtrahydropyranyl or benzoyl.
3. in the compound 1 according to claim 1, R 1And R 2Be respectively a kind of in phenyl, methoxyl group and the oxyethyl group.
4. the preparation method of compound 1 according to claim 1; Be the process through as shown in Equation 2: initiation material (S)-2- methyl-3- hydroxy methyl propionate and excessive methylmetal reagents reaction obtain diol compound; Then selectivity is carried out the one-level hydroxyl of this diol compound halo or halo is carried out in sulfonate compound and halogen anion generation substitution reaction that the one-level hydroxyl sulfoacid esterification of this diol compound obtains; Protect another hydroxyl in the gained molecule again; The metal reagent of relief gained compound and diaryl phosphorus or the reaction of tri-alkoxy phosphorus compound obtain target compound
Figure FSA00000556071800012
Formula 2
Wherein, R is hydrogen atom or alkyl or trialkyl silyl or the substituted alkyl of alkoxyl group or acyl group or THP trtrahydropyranyl or tetrahydrofuran base; R 1And R 2Be respectively a kind of in aryl and the alkoxyl group.
5. the preparation method of compound 1 according to claim 4, it is characterized in that with (S)-used methylmetal reagents was methylmagnesium-halide or lithium methide or zinc methide when the reaction of 2-methyl-3-hydroxy methyl propionate obtained diol compound.
6. the preparation method of compound 1 according to claim 4 is characterized in that it is phosphorus trihalide or three oxyhalogen phosphorus or halogenation sulfoxide or phosphorus pentahalides or carbon tetrahalide or iodine that diol compound carries out the used halide reagent of halo.
7. the preparation method of compound 1 according to claim 4; It is characterized in that diol compound carries out the such process of halogenation experience: the one-level hydroxyl to diol compound carry out sulphonateization earlier; The sulfonate compound that obtains carries out halogenation with halogen negative ion generation substitution reaction again; The sulfonic acid esterification agents useful for same here can be methylsulfonyl chloride or ether or Tosyl chloride or benzene sulfonyl chloride or trifluoromethanesulfanhydride anhydride, and the used halogen anion of halogenation comes from lithium salts or sodium salt or the sylvite or the magnesium salts of chlorine or bromine or iodine.
8. the preparation method of compound 1 as claimed in claim 7 is characterized in that said halogenation negative ion is lithium chloride or lithiumbromide or Sodium Bromide or Potassium Bromide or magnesium bromide or magnesium chloride or sodium iodide or lithium iodide or potassiumiodide or magnesium iodide.
9. the preparation method of compound 1 according to claim 4 is characterized in that used diaryl phosphine metal reagent is diphenylphosphine lithium or di-p-tolyl phosphine lithium or corresponding potassium reagent or sodium reagent.
10. the preparation method of compound 1 according to claim 4 is characterized in that used tri-alkoxy phosphorus is trimethoxy phosphorus or triethoxy phosphorus or three butoxy phosphorus.
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