CN105384765A - Quinic acid lactone derivative preparation method - Google Patents
Quinic acid lactone derivative preparation method Download PDFInfo
- Publication number
- CN105384765A CN105384765A CN201410448980.1A CN201410448980A CN105384765A CN 105384765 A CN105384765 A CN 105384765A CN 201410448980 A CN201410448980 A CN 201410448980A CN 105384765 A CN105384765 A CN 105384765A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- lower group
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CCN*1=CC1 Chemical compound CCN*1=CC1 0.000 description 3
- GAASGTOOMWIDNB-FSDSQADBSA-N C[C@H](CC[C@H]1O)C[C@H]1O Chemical compound C[C@H](CC[C@H]1O)C[C@H]1O GAASGTOOMWIDNB-FSDSQADBSA-N 0.000 description 1
Classifications
-
- 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 present invention relates to a quinic acid lactone derivative preparation method, which comprises: in an organic solvent, carrying out a reaction with a compound 1 to obtain a compound 2. According to the method of the present invention, the solubility of the reactant in the solvent is increased so as to substantially improve the yield of the product and provide convenience and economy. The structures of the compounds 1 and 2 are defined in the specification.
Description
Technical field
The present invention relates to medicine intermediate synthesis field, particularly, the invention provides a kind of preparation method of Ergocalciferols compound lactone intermediate fragments.
Background technology
Ergocalciferols compound is applicable to protect against osteoporosis, kidney originality osteopathy (rachitis renalis, the rickets and osteomalacia etc. of the rickets that hyperparathyroidism (with bone patient), hypoparathyroidism, nutrition and malabsorption cause and osteomalacia, false calcium deficiency (D-dependent form I).
Due to its drug effect and effect disease, determine Ergocalciferols compound and there is the very large market requirement.But to carry out volume production to Ergocalciferols compound, the demand for upstream intermediate will be very large, and this area is in the urgent need to improving the preparation efficiency of upstream intermediate, and the method for simplification of flowsheet.
In the method for the ossified alcohol compound of synthesis disclosed in WO2010/120698A1, provide the synthetic method of midbody compound 3, see formula 7, namely pull out hydrogen by the organic bases with pyridines, the compound 3 in the method synthesis type 7 that silicon protective material is protected, wherein R
1for H or TBDMS, R
2for H, R
3for H or alkyl.And react complete, with ethyl acetate and normal hexane, crystallization is carried out to compound 3, obtain product.Therefore, compound 2 is key intermediates of the ossified alcohol compound of synthesis.
In the method for existing synthetic compound 2, WO2010/120698A1 and document Elliotetal., 1981, J.Chem.Soc.Perkintrans1,1782-1789 are take toluene as solvent, and tosic acid is catalyzer, reflux dewatering and obtaining.Because the solubleness of toluene to compound 1 is lower, reaction yield is lower.But target product Ergocalciferols compound all needs just can be obtained by the operation of compound 1 more than 10 steps, so will be very large to the demand of this step of compound 1.Therefore improve yield, to reduce costs be a problem that must solve.
In sum, this area still lack a kind of can high-level efficiency, prepare the method for compound 2 hypotoxicity.
Summary of the invention:
The object of this invention is to provide a kind of can high-level efficiency, prepare the method for compound 2 hypotoxicity.
A first aspect of the present invention, provides a kind of preparation method of compound 2 as shown in Equation 2, it is characterized in that, comprise step:
In organic solvent, carry out reaction 1 with compound, obtain compound 2;
Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
In formula, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMSOTf, TIPSOTf or TESOTf.
In another preference, described organic solvent is the mixing solutions of DMF and hexanaphthene.
In another preference, R
2for H, R
3for H or alkyl.
In another preference, described reaction is carried out in presence of an acid catalyst; Preferably, described acid catalyst is selected from lower group: organic acid, mineral acid, or its combination.
In another preference, described acid catalyst is selected from lower group: tosic acid, benzene methanesulfonic acid, methylsulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, or its combination; Preferably, described acid catalyst is tosic acid.
In another preference, described reaction is carried out at 50-150 DEG C, preferably carries out at 80-130 DEG C.
In another preference, the described reaction times is 5-35h, is preferably 10-25h.
In another preference, the productive rate of described method is >=85%, is preferably >=90%.
A second aspect of the present invention, provide a kind of preparation method of compound 3 as shown in Equation 3, described method comprises step:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain formula 3 compound;
In formula, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl, or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf.
In another preference, R
1for H or TBDMS, R
2for H, R
3for H or alkyl.
In another preference, in described step (i), described reaction is carried out in presence of an acid catalyst; Preferably, described acid catalyst is selected from lower group: organic acid, mineral acid, or its combination.
In another preference, in described step (i), described acid catalyst is selected from lower group: tosic acid, benzene methanesulfonic acid, methylsulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, or its combination; Preferably, described acid catalyst is tosic acid.
In another preference, in described step (i), described reaction is carried out at 50-150 DEG C, preferably carries out at 80-130 DEG C.
In another preference, after described step (i) is terminated, product is not purified, directly as the raw material of step (ii).
In another preference, after step (i) reaction is carried out, product, without purifying, is directly used in next step reaction.
In another preference, described method also comprises: carry out recrystallization purifying to formula 3 compound that step (ii) obtains, thus obtain the compound 3 of purifying; Preferably, described recrystallization purifying comprises: be dissolved in the mixed solvent of ethyl acetate and normal hexane by the compound 3 that step (ii) obtains, then carry out crystallization.
A third aspect of the present invention, provide a kind of preparation method of Ergocalciferols compound, described method comprises:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain compound 3;
In formula, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf; With
(iii) Ergocalciferols compound is prepared with compound 3.
In another preference, after described step (i) is terminated, product is not purified, directly as the raw material of step (ii).
In another preference, described Ergocalciferols compound has as shown in the formula the structure shown in 5:
Wherein
R
1for=CH
2, or R
1for being selected from the group of lower group: C
1-7alkyl, C
1-7silylation, or C
2-7acyl group;
R
2and R
3be selected from lower group: H or C independently of one another
1-12alkane;
R
4and R
5be selected from lower group independently of one another: H, C
1-12alkyl, C
1-12alkoxyl group, C
1-12haloalkyl, C
1-12halogenated alkoxy, C
1-12alkyl-hydroxyl, C
1-12haloalkyl-hydroxyl;
R
6be selected from lower group: C
1-12alkyl, C
1-12haloalkyl;
X is selected from lower group: O, S, or N;
A is 0,1,2,3,4,5;
Wherein, described halo refer to one or more hydrogen atoms on group replace by halogen atom.
In another preference, R
1for being selected from the group of lower group: C
3-7alkyl, C
3-7silylation, or C
3-7acyl group.
In another preference, described Ergocalciferols compound is selected from lower group:
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor finds in the preparation process of key intermediate compound 2 through long-term and deep research, replaces existing toluene solvant system to be prepared, can obtain compound 2 with higher yield and good selectivity by DMF/ cyclohexane solution system.Based on above-mentioned discovery, contriver completes the present invention.
Term
Unless stated otherwise, term " C1-C6 alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, as methyl, ethyl, propyl group, butyl, or similar group.
Term " C1-C6 alkoxyl group " refers to the straight or branched alkoxyl group with 1-6 carbon atom, as methoxyl group, oxyethyl group, propoxy-, butoxy, or similar group.
Term " C
1-7silylation " silane that refers to have 1-7 carbon atom loses the group that a hydrogen atom is formed, as silicomethane, trimethyl silane, or similar group.
Term " C
2-7acyl group " refer to have the acid removing hydroxyl of 2-7 carbon atom after remaining group, as ethanoyl, propionyl, or similar group.
Compound 2 and preparation thereof
The invention provides a kind of preparation method of the compound 2 be shown below, it is characterized in that, comprise step:
I () in organic solvent, is reacted with compound 1, obtain compound 2;
Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination.
In formula, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl, or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf.
In another preference, R
2for H, R
3for H or alkyl.
In another preference, described organic solvent is the mixing solutions of DMF and hexanaphthene.
Described reaction can optionally be carried out under suitable dehydrating condensation agent exists.In a preferred embodiment of the invention, described reaction is carried out in presence of an acid catalyst; Preferably, described acid catalyst is selected from lower group: organic acid, mineral acid, or its combination.
In another preference, described acid catalyst comprises (but being not limited to): tosic acid, benzene methanesulfonic acid, methylsulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, or its combination; Preferably, described acid catalyst is tosic acid.
Described temperature of reaction is not particularly limited, can according to reactant concrete structure, and the solvent of use or practical condition determine preferred temperature range.Preferably, described reaction is carried out at 50-150 DEG C, preferably carries out at 80-130 DEG C.
The described reaction times is not particularly limited, and can pass through this area ordinary method, as TLC method determination reaction end.In preferred embodiments more of the present invention, the described reaction times is 5-35 hour, is preferably 10-25 hour.
Compound 3 and preparation thereof
The invention provides one and can overcome prior art deficiency, the method for synthetic compound 3.The present invention is with described compound 1 for starting raw material particularly, prepares compound 3 by method as shown in Equation 9: first being carried out lactonizing by compound 1 obtains compound 2, then carries out hydroxyl protection to compound 2 and crystallization obtains compound 3.
Lactonize in process, solvent can (but being not limited to) be selected: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination; The good solvent of effect has benzene, normal hexane, hexanaphthene, DMF, and some mixed solvents wherein as, DMF and normal hexane, DMF and toluene etc.
Step of lactonization can be carried out under acid catalysis, as organic acid or mineral acid.The acid catalyst that preferably lactonizes comprises (but being not limited to): tosic acid, sulfur oxychloride etc.Preferably the reaction times is 10-16 hour.Preferably temperature of reaction is 80-130 DEG C.Then carried out with reference to method disclosed in PCT application WO2010/120698A1 by the synthesis of compound 2 to compound 3.
Particularly, the preparation method of compound as shown in Equation 9 provided by the invention, comprises step:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain compound 3;
In formula, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl, or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf.
In another preference, R
1for H or TBDMS, R
2for H, R
3for H or alkyl.
In another preference, after step (i) reaction is carried out, product, without purifying, is directly used in next step reaction.
In another preference, described method also comprises: carry out recrystallization purifying to the compound 3 that step (ii) obtains, thus obtains formula 3 compound of purifying; Preferably, described recrystallization purifying comprises: be dissolved in the mixed solvent of ethyl acetate and normal hexane by the compound 3 that step (ii) obtains, then carry out crystallization.
In a preferred embodiment of the invention, described method comprises step:
A (), with compound 1 for starting raw material, compound 1 is formed lactone by acid-catalyzed dehydration and obtains compound 2, compound is purifying not, is directly used in next step after being steamed by solvent.Wherein, the good solvent of effect has normal hexane, hexanaphthene, DMF, etc., and some mixed solvents wherein as, DMF and normal hexane, DMF and toluene.
In the process that lactonizes, acid catalyst is respectively organic acid and mineral acid, and wherein organic acid is tosic acid, benzene methanesulfonic acid, methylsulfonic acid, acetic acid; Mineral acid is sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI etc.
Reaction times is 5-35 hour, and preferably the reaction times is 10-25 hour.
In dehydration, temperature controls at 50-150 DEG C, is preferably 80-130 DEG C in temperature of reaction.
B the crude product of compound 2 is dissolved in DMF by (), add on silicon protective material and protect, crystallization obtains compound 3.Recrystallisation solvent used is the mixed solvent of ethyl acetate and normal hexane.Above-mentioned steps is not particularly limited, and can adopt literature method, the method as described in WO2010/120698A1.
The preparation method of Ergocalciferols compound
As used herein, term " Ergocalciferols compound " refers to the analogue of vitamins D, preferably has as shown in the formula the structure shown in 10:
Wherein
R
1for=CH
2, or R
1for being selected from the group of lower group: C
1-7alkyl, C
1-7silylation, or C
2-7acyl group;
R
2and R
3be selected from lower group: H or C independently of one another
1-12alkane;
R
4and R
5be selected from lower group independently of one another: H, C
1-12alkyl, C
1-12alkoxyl group, C
1-12haloalkyl, C
1-12halogenated alkoxy, C
1-12alkyl-hydroxyl, C
1-12haloalkyl-hydroxyl;
R
6be selected from lower group: C
1-12alkyl, C
1-12haloalkyl;
X is selected from lower group: O, S, or N;
A is 0,1,2,3,4,5;
Wherein, described halo refer to one or more hydrogen atoms on group replace by halogen atom.
In another preference, R
1for being selected from the group of lower group: C
3-7alkyl, C
3-7silylation, or C
3-7acyl group.
In another preference, described Ergocalciferols compound is selected from lower group:
The preparation method of Ergocalciferols compound provided by the invention comprises the step shown in formula 11:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain compound 3;
In formula 11, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl, or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf; With
(iii) Ergocalciferols compound is prepared with compound 3.
The present invention has the following advantages:
1. mild condition used in the present invention, easily controls, and compound 2 yield is high, and after having prepared, can carry out subsequent step without the need to being separated the compound 2 obtaining purifying, production efficiency is significantly improved;
2. use method of the present invention, the productive rate of compound 2 and compound 3 improves greatly, particularly the yield of important intermediate compound 3 has been increased to about 48% from average about 34%, and this has great importance for the longer Ergocalciferols compound of production line;
3. the present invention uses low-toxic solvent, and environmental pollution is little, and low for the requirement of production unit, personnel protection, is applicable to suitability for industrialized production.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
In each embodiment, after prepared by compound 2, product is not purified, directly carries out next step reaction.
Embodiment 1
With compound 1 for starting raw material, join in normal hexane by compound 1, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.Reaction as shown in Equation 12, is then carried out with reference to WO2010/120698A1 by the synthesis of compound 2 to compound 3.Two step yields are 25%.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 2:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.As shown in Equation 13, then carried out with reference to the method disclosed in PCT application WO2010/120698A1 by the synthesis of compound 2 to compound 3, two step yields are 48% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 3:
With compound 1 for starting raw material, joined in DMF and hexanaphthene by compound 1, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.Reaction as shown in Equation 14, is then carried out with reference to WO2010/120698A1 by the synthesis of compound 2 to compound 3.Two step yields are 41%.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 4:
With compound 4 for starting raw material, join in normal hexane by compound 4, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.As shown in Equation 15, then carried out with reference to WO2010/120698A1 by the synthesis of compound 5 to compound 6, two step yields are 22% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for CH
3.
Embodiment 5:
With compound 4 for starting raw material, joined by compound 4 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.As shown in Equation 16, by the synthesis then reference WO2010/120698A1 of compound 5 to compound 6, two step yields are 45% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for CH
3.
Embodiment 6:
With compound 4 for starting raw material, joined in DMF and hexanaphthene by compound 4, add catalyzer tosic acid, 90 DEG C are reacted 18 hours.As shown in Equation 17, then carried out with reference to WO2010/120698A1 by the synthesis of compound 5 to compound 6, two step yields are 41% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for CH
3.
Embodiment 7:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add the catalyzer vitriol oil, 90 DEG C are reacted 18 hours.As shown in Equation 18, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 40% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 8:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyst methanesulfonic acid, 90 DEG C are reacted 18 hours.As shown in Equation 19, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 38% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 9:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 80 DEG C are reacted 18 hours.As shown in Equation 20, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 42% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 10:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 100 DEG C are reacted 18 hours.As shown in Equation 21, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 46% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 11:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 90 DEG C are reacted 10 hours.As shown in Equation 22, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 34% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 12:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyzer tosic acid, 100 DEG C are reacted 15 hours.As shown in Equation 23, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 44% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
Embodiment 13:
With compound 1 for starting raw material, joined by compound 1 in the mixed solution of DMF and normal hexane, add catalyst methanesulfonic acid, 100 DEG C are reacted 20 hours.As shown in Equation 18, by the synthesis then reference WO2010/120698A1 of compound 2 to compound 3, two step yields are 48% in reaction.Wherein R
1for TBDMS, R
2for H, R
3for H.
In embodiments, be about between 80%-95% with the yield that compound 1 prepares compound 2.Compound 2
1hNMR (500MHz, CD
3oD) δ 1.87 (1H, brt, J11Hz, 2 α-H), 2.02 (1H, ddd, J=11.7,6.5,2.9Hz, 2 β-H), 2.22 (1H, ddd, J=11.4,6.0,2.9Hz, 8 β-H), 2.47 (1H, d, J=11.4Hz, 8 α-H), 3.70 (1H, ddd, J=11.4,6.5,4.4Hz, 3 β-H), 3.98 (1H, brt, J5Hz, 4 β-H), 4.70 (1H, brt, J5Hz, 5 α-H)
HNMR (the CDCl of compound 3
3400MHz) δ 4.80 (t, 1H), 3.90 (t, 1H), 3.80 (m, 1H), 2.85 (br, 1H), 2.55 (d, 2H), 2.20 (m, 1H), 1.90 (m, 2H), 0.80 (s, 9H), 0.00 (s, 6H).
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a preparation method for compound 2 as shown in Equation 2, is characterized in that, comprise step:
In organic solvent, carry out reaction 1 with compound, obtain compound 2;
Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
In formula, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMSOTf, TIPSOTf or TESOTf.
2. preparation method as claimed in claim 1, it is characterized in that, described reaction is carried out in presence of an acid catalyst; Preferably, described acid catalyst is selected from lower group: organic acid, mineral acid, or its combination.
3. preparation method as claimed in claim 1, it is characterized in that, described acid catalyst is selected from lower group: tosic acid, benzene methanesulfonic acid, methylsulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, or its combination; Preferably, described acid catalyst is tosic acid.
4. preparation method as claimed in claim 1, it is characterized in that, described reaction is carried out at 50-150 DEG C, preferably carries out at 80-130 DEG C.
5. preparation method as claimed in claim 1, it is characterized in that, the described reaction times is 5-35h, is preferably 10-25h.
6. preparation method as claimed in claim 1, it is characterized in that, the productive rate of described method is >=85%, is preferably >=90%.
7. a preparation method for compound as shown in Equation 3, it is characterized in that, described method comprises step:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain formula 3 compound;
In formula, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl, or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf.
8. method as claimed in claim 7, it is characterized in that, described method also comprises: carry out recrystallization purifying to formula 3 compound that step (ii) obtains, thus obtain the compound 3 of purifying; Preferably, described recrystallization purifying comprises: be dissolved in the mixed solvent of ethyl acetate and normal hexane by the compound 3 that step (ii) obtains, then carry out crystallization.
9. a preparation method for Ergocalciferols compound, is characterized in that, described method comprises:
I () in organic solvent, is reacted with compound 1, obtain compound 2; Wherein, described organic solvent is selected from lower group: normal hexane, hexanaphthene, DMF, ethyl acetate, isopropyl acetate, ethylene dichloride, or its combination;
(ii) in inert solvent, react with compound 2 and silicon protective material, obtain compound 3;
In formula, R
1, R
2, R
3be selected from lower group independently of one another: H, C1-C6 alkyl or silicon blocking group; Preferably, described silicon blocking group is selected from lower group: TBDMS-OTf, TIPS-OTf or TES-OTf; With
(iii) Ergocalciferols compound is prepared with compound 3.
10. method as claimed in claim 9, it is characterized in that, described Ergocalciferols compound has as shown in the formula the structure shown in 5:
Wherein
R
1for=CH
2, or R
1for being selected from the group of lower group: C
1-7alkyl, C
1-7silylation, or C
2-7acyl group;
R
2and R
3be selected from lower group: H or C independently of one another
1-12alkane;
R
4and R
5be selected from lower group independently of one another: H, C
1-12alkyl, C
1-12alkoxyl group, C
1-12haloalkyl, C
1-12halogenated alkoxy, C
1-12alkyl-hydroxyl, C
1-12haloalkyl-hydroxyl;
R
6be selected from lower group: C
1-12alkyl, C
1-12haloalkyl;
X is selected from lower group: O, S, or N;
A is 0,1,2,3,4,5;
Wherein, described halo refer to one or more hydrogen atoms on group replace by halogen atom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410448980.1A CN105384765A (en) | 2014-09-04 | 2014-09-04 | Quinic acid lactone derivative preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410448980.1A CN105384765A (en) | 2014-09-04 | 2014-09-04 | Quinic acid lactone derivative preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105384765A true CN105384765A (en) | 2016-03-09 |
Family
ID=55417587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410448980.1A Pending CN105384765A (en) | 2014-09-04 | 2014-09-04 | Quinic acid lactone derivative preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105384765A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482210A (en) * | 2009-04-17 | 2012-05-30 | 维达西姆有限公司 | Vitamin d receptor agonists and uses thereof |
-
2014
- 2014-09-04 CN CN201410448980.1A patent/CN105384765A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482210A (en) * | 2009-04-17 | 2012-05-30 | 维达西姆有限公司 | Vitamin d receptor agonists and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| LAURA SA´NCHEZ-ABELLA等: ""Novel and Efficient Syntheses of (-)-Methyl 4-epi-Shikimate and 4,5-Epoxy-Quinic and Shikimic Acid Derivatives as Key Precursors to Prepare New Analogues"", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| PEI-QIANG HUANG等: ""A Novel Synthesis of 19-Nor 1α,25-dihydroxyvitamin D3 and Related Analogues"", 《TETRAHEDRON LETTERS》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20150040340A (en) | Process and intermediates for preparing integrase inhibitors | |
| CN113603568A (en) | Preparation method of cannabidiol | |
| CA3022444C (en) | Method for preparing azoxystrobin | |
| CN108558627B (en) | Method for preparing 5-hydroxy-1-indanone | |
| KR101728443B1 (en) | Method for Producing Benzyl Ester 2-aminonicotinicotinate Derivative | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| CN108689874B (en) | Method for preparing 2-aryl malonamide and application thereof | |
| KR101629561B1 (en) | Synthesis of calebin-a and its biologically active analogs | |
| CN105820174A (en) | Polysubstituted thienoindole derivative and preparation method thereof | |
| WO2016146048A1 (en) | Industrial manufacturing method for midazolam derivative | |
| CN105384765A (en) | Quinic acid lactone derivative preparation method | |
| JP2010070528A (en) | Method for producing 1,2,4-oxadiazole derivative | |
| EP2937331B1 (en) | A process for preparing an intermediate of vitamin b1 | |
| CN113336703A (en) | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives | |
| CN102336763B (en) | Synthesis method for pyranocoumarin derivatives | |
| CN101525310B (en) | The synthetic method of 1- benzoyl -3- (2- hydroxyl -1,1- dimethyl ethyl) thiocarbamide | |
| JP5448363B2 (en) | Method for producing compound | |
| CN109265431B (en) | Synthesis process of 3-acetyl-10, 11-dihydro-5H-dibenzo [ C, G ] chromen-8 (9H) -one | |
| WO2005047260A1 (en) | Process for preparing gatifloxacin | |
| CN108727179A (en) | A kind of alpha, beta-unsaturated ketone of α-allyl substitution, the synthetic method of ester or nitrile compound | |
| CN109467558B (en) | 1-hydropyrrolizine derivative and synthesis method and application thereof | |
| CN104151278B (en) | The synthetic method of 1-phenyl-2,3-naphthalene dicarboxylic acids acid anhydride and derivative thereof | |
| CN110294783B (en) | Preparation method of 16-alkene steroid compound | |
| JP6212462B2 (en) | Method for producing 3,4,5-tricaffeoylquinic acid | |
| CN111848521A (en) | Preparation method of 2-substituted-4-alkoxy imidazole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160309 |
|
| WD01 | Invention patent application deemed withdrawn after publication |