CN102875586A - Method for preparing key intermediate of limaprost - Google Patents
Method for preparing key intermediate of limaprost Download PDFInfo
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- CN102875586A CN102875586A CN201110193352XA CN201110193352A CN102875586A CN 102875586 A CN102875586 A CN 102875586A CN 201110193352X A CN201110193352X A CN 201110193352XA CN 201110193352 A CN201110193352 A CN 201110193352A CN 102875586 A CN102875586 A CN 102875586A
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- 0 CCC[C@](C)CC([C@]1C)C1(*)C=C[C@@](C)([C@@](CCCCCC*)[C@](C1)OC(*)=O)[C@@]1O* Chemical compound CCC[C@](C)CC([C@]1C)C1(*)C=C[C@@](C)([C@@](CCCCCC*)[C@](C1)OC(*)=O)[C@@]1O* 0.000 description 4
- XECMNJDAJPRBJK-DSQDFUFQSA-N CCCCCCOC(CCCCCC[C@@H](C(CC1OC2OCCCC2)OC(CCCCC)=O)[C@H]1/C=C/C(C[C@@H](C)CCCC)=O)=O Chemical compound CCCCCCOC(CCCCCC[C@@H](C(CC1OC2OCCCC2)OC(CCCCC)=O)[C@H]1/C=C/C(C[C@@H](C)CCCC)=O)=O XECMNJDAJPRBJK-DSQDFUFQSA-N 0.000 description 1
- CELWCAITJAEQNL-UHFFFAOYSA-N OC1OCCCC1 Chemical compound OC1OCCCC1 CELWCAITJAEQNL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for preparing the key intermediate of limaprost, particularly provides a chiral compound of formula I and a preparation method thereof. The method comprises the following steps: (1) reacting a compound of formula 3 with a compound of formula 4 to obtain a compound of formula 5; (2) reacting a compound of formula 6 with the compound of formula 5 to obtain a compound of formula 7; (3) mixing the compound of formula 7 with a compound of formula 8 to obtain the compound of formula 1; (4) reacting the compound of formula 1 with a reducing agent to obtain a raw product, separating and purifying the raw product by column chromatography to obtain a compound of formula 2; (5) reacting the compound of formula 2 with a protector reduction agent to obtain a compound of formula 9, wherein each structural formula and substituent are defined as the specification. According to the invention, the method has mild reaction conditions, and the high-purity chiral compound can be conveniently and efficiently prepared.
Description
Technical field
The present invention relates to a kind of preparation method of chipal compounds, be specifically related to a kind of preparation method of limaprost intermediate.
Background technology
The limaprost chemical name is: (E)-and 7-[(1R, 2R, 3R)-3-hydroxyl-2-[(3S, 5S)-(E)-3-hydroxy-5-methyl base-1-nonene base]-the 5-oxocyclopentyl]-2-enanthic acid ((E)-7-[(1R, 2R, 3R)-3-hydroxy-2-[(3S, 5S, E)-3-hydroxy-5-methylnon-1-enyl]-5-oxocyclopentyl] hept-2-enoic acid), structure is suc as formula shown in 10 compounds.
Limaprost has vasodilation, increases the effect of blood flow and anti-platelet aggregation, is used for clinically improving all kinds of ischemia symptoms that thromboangiitis obliterans causes, and such as ulcer, pain, creeping chill; And the subjective symptom and the locomotor activity that improve the acquired character lumbar spinal stenosis.Limaprost is because it is oral effective, and drug effect is good, and medication is convenient, thereby has broad application prospects.The limaprost alpha-cylodextrin is the oral PGE1 derivative of little wild medicine and the exploitation of large Japanese drugmaker, is used for the treatment of ulcer, pain and the subjective symptom of improving the acquired character lumbar spinal stenosis.
Limaprost (formula 10 compounds) is prepared by limaprost key intermediate (formula 9a compound).At present, the synthesis technique by the preparation limaprost key intermediate (formula 9a compound) of document US 4294849 report take formula 8a compound as starting raw material, adopts the synthetic method of achirality to prepare formula 9a compound, and yield is extremely low.The pure formula 9a ' compound for preparing just can obtain formula 9a compound after must removing hydroxyl isomer and methyl isomer through twice column chromatographic isolation and purification.
This technique adopts the synthetic method of achirality take non-chiral compound as starting raw material, and the intermediate of formation is non-chiral compound.Preparation process must be passed through the separating for several times purifying, just can obtain the limaprost intermediate of high-optical-purity, causes this technique to expend a large amount of solvents, and production efficiency is extremely low, and it is larger to expand large-scale difficulty, does not meet the requirement of suitability for industrialized production.
Therefore, this area is low in the urgent need to developing a kind of production cost, and is efficient, convenient, is fit to the limaprost key intermediate compound of suitability for industrialized production, and the technique for preparing accordingly limaprost.
Summary of the invention
Purpose of the present invention provides a kind of production cost low, and is efficient, convenient, is fit to the limaprost key intermediate compound of suitability for industrialized production, and the technique for preparing accordingly limaprost.
In a first aspect of the present invention, a kind of formula I chipal compounds is provided,
Wherein,
R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl; With
X is O or OH, and supplementary condition are: when X is O, being two keys between X and the adjacent C, and when X is OH, is singly-bound between X and the adjacent C.
In a preference, the structure of described compound as shown in Equation 1:
In a preference, the structure of described compound as shown in Equation 2:
In a preference, described compound has and is selected from one or more features of lower group:
R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl;
R
2Be C
1-C
4The straight or branched alkyl; And/or
R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl.
In another preference, R
1Be methyl.
In another preference, R
2Be methyl.
In another preference, R
3Be THP trtrahydropyranyl.
In a preference, R
1Be methyl, R
2Be methyl, and/or R
3Be THP trtrahydropyranyl.
Second aspect present invention provides a kind of method of preparation formula I chipal compounds, comprises step:
(a) under acidic conditions, in inert solvent, with formula 3 compounds and the reaction of formula 4 compounds, form formula 5 compounds;
(b) under alkaline condition, in inert solvent, with formula 5 compounds and the reaction of formula 6 compounds, form formula 7 compounds;
(c) under alkaline condition, in inert solvent, with formula 7 compounds and the reaction of formula 8 compounds, form formula 1 compound;
(d) randomly, with the reduction of formula 1 compound, form formula 2 compounds:
Wherein, above-mentioned various in,
R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl;
R
4Be C
1-C
6The straight or branched alkyl;
R
5Be C
1-C
4The straight or branched alkyl;
R
6Be C
1-C
4The straight or branched alkyl.
In another preference, also comprise in step (d): the thick product that reduction is formed carries out separation and purification through column chromatography, obtains formula 2 pure compounds.
In a preference, above-mentioned various in, each substituting group has and is selected from one or more features of lower group:
R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl;
R
2Be C
1-C
4The straight or branched alkyl;
R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl;
R
4Be C
1-C
4The straight or branched alkyl;
R
5Be C
1-C
2Alkyl; And/or
R
6Be C
1-C
2Alkyl.
In a preference, R
1Be methyl; R
2Be methyl; R
3Be THP trtrahydropyranyl; R
4Be methyl; R
5Be methyl; R
6Be methyl.
In a preference, in the step (a), described acid is selected from lower group: the vitriol oil, concentrated hydrochloric acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, sulfonic resin or its combination; And/or
In the step (b), described alkali is selected from lower group: lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium or its combination; And/or
In the step (c), described alkali is selected from lower group: sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, potassium tert.-butoxide, sodium methylate, sodium ethylate or its combination; And/or
In the step (d), reduce with the reductive agent that is selected from lower group: sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, zinc borohydride or its combination.
Third aspect present invention provides a kind of preparation method, comprises step:
(i) slough R in formula 2 compounds
3Group forms formula 9 compounds,
In various, R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl;
In another preference, slough R with the reagent that is selected from lower group in the step (i)
3Group: p-methyl benzenesulfonic acid, para-methylbenzenepyridinsulfonate sulfonate, acetic acid, hydrochloric acid, hydrofluoric acid, tetrabutyl ammonium fluoride or its combination.
In a preference, also comprise step:
(ii) formula 9 compounds are carried out hydroxyl protection, hydrolysis, two keys, oxidation removes hydroxyl protecting group, thereby forms limaprost:
In another preference, described method also comprises before in step (i): with the reduction of formula 1 compound, form formula 2 compounds:
In another preference, step (i) is carried out in inert solvent.
In another preference, described inert solvent comprises: methyl alcohol, ethanol, tetrahydrofuran (THF), water or its combination.
In another preference, step (i) reaction conditions is-50-50 ℃, reacted 0.1-24 hour.
Fourth aspect present invention provides the purposes of formula I chipal compounds, for the preparation of the intermediate of limaprost.
In a preference, described chipal compounds is for the preparation of the intermediate shown in the formula 9:
In the formula, R1 is selected from C
1-C
10Straight or branched alkyl, trifluoromethyl, trichloromethyl; R2 is selected from C
1-C
10The straight or branched alkyl.
In another preference, R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl; R
2Be C
1-C
4The straight or branched alkyl.
In a preference, described chipal compounds is for the preparation of limaprost.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus consist of new or preferred technical scheme.As space is limited, this tired stating no longer one by one.
Description of drawings
Fig. 1 has shown that the formula 9a compound H PLC of Comparative Examples 2 preparations detects collection of illustrative plates;
Fig. 2 has shown that the formula 9a compound H PLC of embodiment 5 preparations detects collection of illustrative plates.
Embodiment
The inventor by repetition test, is surprised to find that first that through extensive and deep research novel formula I chipal compounds is suitable as the intermediate of preparation limaprost very much.Utilize formula I compound, can be efficient, easily preparation formula 9 intermediates, and then preparation limaprost.Finished on this basis the present invention.
Concrete, adopting chipal compounds compound as shown in Equation 3 is that starting raw material can well prepare high optically pure formula 9 compounds.Experimental result shows, the phenomenon of racemization does not occur the chirality methyl of compound shown in the hold mode 3 well in the reaction process substantially.The optical purity of formula 9 compounds that prepare is up to more than 99%, even 100%.And calculate with formula 1 compound, molar yield brings up to 49% by 16.7%, than the document marked improvement, and owing to reduced the step of column chromatography, and reduced in a large number the use of organic solvent, save the industrialization cost, avoided the defective of half female ring of document as the waste material reject, improved the utilization ratio of atom.Simultaneously, prepare a series of new chipal compounds through behind the process optimization, can be used for the research of other prostatitis elements, for the new drug development of other kinds has been laid certain basis.
Intermediate
Intermediate refers to work in-process, is to produce the product that forms in the needed product process.Usually, the contriver can carry out from intermediate the production of product as starting raw material.Therefore, screening suitable intermediate can optimized process flow, and then reaches the raising yield, saves time, the purpose of cost.
Intermediate of the present invention refers to the described midbody compound suc as formula I.
Wherein, R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl; With
R
3Be silylation or THP trtrahydropyranyl;
X is O or OH, and supplementary condition are: when X is O, being two keys between X and the adjacent C, and when X is OH, is singly-bound between X and the adjacent C.
In a preference, described compound has and is selected from one or more features of lower group:
R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl;
R
2Be C
1-C
4The straight or branched alkyl;
R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl.
In another preference, R
1Be methyl.
In another preference, R
2Be methyl.
In another preference, R
3Be THP trtrahydropyranyl.
The preparation of formula 1 intermediate and formula 2 intermediates
Formula 1 intermediate of the present invention and formula 2 intermediates can make by following method, yet the condition of the method is not limited to following explanation such as the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc.The compounds of this invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
In preparation method of the present invention, each reaction is carried out in inert solvent usually, and the reaction times is generally 0.1-48 hour, preferably is 0.5-24 hour.
Take formula 2 intermediates as example, a kind of preferred method comprises:
(1) under acidic conditions, in inert solvent, with formula 3 compounds and the reaction of formula 4 compounds, forms formula 5 compounds;
(2) under alkaline condition, in inert solvent, with formula 5 compounds and the reaction of formula 6 compounds, form formula 7 compounds;
(3) under alkaline condition, in inert solvent, with formula 7 compounds and the reaction of formula 8 compounds, form formula 1 compound;
(4) with the reduction of formula 1 compound, form formula 2 compounds:
The preparation of formula 9 intermediates
A kind of preferred method is R in the formula of sloughing 2 compounds
3Group forms formula 9 compounds,
The preparation of limaprost
Formula 9 compounds are carried out hydroxyl protection, hydrolysis, two keys, oxidation removes hydroxyl protecting group, thereby forms limaprost.
The concrete preparation method of formula 1 compound provided by the invention and formula 2 compounds may further comprise the steps:
The first step stirs formula 3 compounds, formula 4 compounds, acid and toluene, and after back flow reaction was extremely complete, reaction solution was through Na
2CO
3Aqueous solution cancellation, extraction, the saturated nacl aqueous solution washing, underpressure distillation obtains formula 5 compounds behind the anhydrous sodium sulfate drying.
After the tetrahydrofuran solution cooling of second step with formula 6 compounds, be added dropwise to alkyl lithium solution and formula 5 compounds, keep temperature in the dropping process, drip insulation reaction.After reacting completely, reaction solution extracts through water and glacial acetic acid cancellation, and the saturated nacl aqueous solution washing is concentrated behind the anhydrous sodium sulfate drying, obtains formula 7 compounds through column chromatography.
The 3rd step dripped above-mentioned formula 7 compound solutions and formula 8 compound solutions with the alkaline solution cooling.React complete after, reaction solution is through the glacial acetic acid cancellation, concentrating under reduced pressure, extraction, saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, dense doing behind the anhydrous sodium sulfate drying, then the silicagel column separation and purification obtains formula 1 compound.
The 4th step added the reductive agent reaction with the methanol solution cooling of formula 1 compound.React complete afterreaction liquid through the glacial acetic acid cancellation, extraction, saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, then dense doing behind the anhydrous sodium sulfate drying separate obtaining formula 2 compounds through silica gel column chromatography.
Preferably, in the first step, R
4Be C
1-C
6The straight or branched alkyl; Preferably, R
4Be C
1-C
4The straight or branched alkyl; More preferably, R
4Be methyl.
Described inert solvent is toluene, and temperature of reaction is for refluxing.
Described acid is selected from: the vitriol oil, concentrated hydrochloric acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, sulfonic resin or its combination.
In the second step, R
5Be C
1-C
4The straight or branched alkyl; R
6Be C
1-C
4The straight or branched alkyl;
Preferably, R
5Be C
1-C
2Alkyl; R
6Be C
1-C
2Alkyl; Better, R
5Be methyl; R
6Be methyl.
Described alkali is selected from: lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium or its combination.
In the 3rd step, R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl; R
2Be C
1-C
10The straight or branched alkyl; R
3Be silylation or THP trtrahydropyranyl;
Preferably, R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl; R
2Be C
1-C
4The straight or branched alkyl; R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl;
More preferably, R
1Be methyl; R
2Be methyl; R
3Be THP trtrahydropyranyl.
Described alkali is selected from: sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, potassium tert.-butoxide, sodium methylate, sodium ethylate or its combination.
In the 4th step, described reductive agent is selected from: sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, zinc borohydride or its combination.
Above-mentioned formula 2 compounds can be for the preparation of formula 9 compounds, and its preparation method may further comprise the steps:
With the solution of formula 2 compounds, the reagent react required with the deprotection base.Reacting complete, is 8.0 with saturated sodium bicarbonate solution to the pH value of reaction solution, the dense dry reaction liquid that reduces pressure, through extraction, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrated after, obtain formula 9 compounds with silica gel column chromatography.
Preferably, the used reagent that is selected from lower group is sloughed R
3Group: p-methyl benzenesulfonic acid, para-methylbenzenepyridinsulfonate sulfonate, acetic acid, hydrochloric acid, hydrofluoric acid, tetrabutyl ammonium fluoride or its combination.
Wherein, among the present invention, term " column chromatography " mainly refers to silica gel column chromatography.The separation principle of silica gel chromatography is to separate according to different the obtaining of the adsorptive power of material on silica gel, the material that polarity is larger generally speaking is easily by silica gel adsorption, the weak material of polarity is difficult for by silica gel adsorption, and whole chromatography process namely is Adsorption and desorption, again absorption, desorption process again.Silica gel column chromatography is habitually practised 300-400 order silica gel.
Among the present invention, term " TLC " full name tlc is that suitable stationary phase is coated on sheet glass, plastics or the aluminium substrate, becomes an even thin layer.After point sample, expansion, according to Rf value (R
f) with the suitable contrast Rf value (R of the color atlas of gained by the same method
f) compare, in order to the method for the discriminating, determination of foreign matter or the assay that carry out medicine.Tlc is a kind of very important experimental technique of sharp separation and a small amount of material of qualitative analysis, also is used for following the tracks of reaction process.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and usefulness, each feature that discloses in the specification sheets can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore except special instruction is arranged, the feature that discloses only is the general example of equalization or similar features.
Major advantage of the present invention is:
1, the invention provides a kind of new chipal compounds and preparation method thereof.Preparation method's reaction conditions of compound provided by the invention is gentle, purification condition is simple, yield also is significantly increased.Chipal compounds provided by the invention can be used for preparing the limaprost key intermediate, and the configuration of each compound of reservation that can be good in the preparation process, and greatly degree has reduced the difficulty of separation and purification of products.
2, the invention provides a kind of preparation method of limaprost key intermediate.Method reaction conditions provided by the invention is gentle, the difficulty of separation and purification is low, yield significantly improves than prior art, has alleviated to a great extent the technological operation degree-of-difficulty factor and to equipment requirements, has significantly reduced production cost.Method provided by the invention is take commercially available chipal compounds formula 3 compounds as starting raw material, the synthesis step of process can be good the reservation configuration, avoid occuring the racemization phenomenon, be conducive to the quality control of intermediate and finished product, be conducive to suitability for industrialized production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that better implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
The preparation of raw material formula 8a compound
Take commercially available Corey lactone as starting raw material, the method for reference literature GB1579464A1 and US3992439A1 report prepares.
Reference examples 2
The preparation of formula 9a compound
The method of reference literature US4294849A1 report; take racemic form 7a ' compound as starting raw material; under the effect of NaH; formula 1a ' the compound that the Wittig condensation obtains 17 methyl racemizations occurs with formula 8a compound; then obtain the formula 2a ' compound of 17 methyl racemizations through sodium borohydride reduction; again under the condition of tosic acid; the deprotection base obtains the formula 9a ' compound of 17 methyl racemizations; obtain formula 9a compound finally by crossing twice column chromatography; calculate with formula 1a ', yield is 16.7%.HPLC shows that purity is 90.75%, and the content of methyl isomer 17-(R)-9a accounts for 9.25%.See Fig. 1, the data such as the retention time at its each peak and area thereof are as shown in table 1.
Each peak retention time of table 1 and area, height and area percentage
| Retention time | Area | Highly | Area percentage (%) |
| 27.041 | 6694671 | 209104 | 90.75 |
| 29.852 | 682233 | 23877 | 9.25 |
Embodiment 3
The preparation of formula 1a compound
Formula 3 compounds (8.23g), formula 4a compound (6.6g), the vitriol oil (0.2ml) and toluene (40ml) are stirred, be warming up to reflux dewatering reaction 5h, TLC follows the tracks of reaction.Reduce temperature of reaction after the complete reaction, add 10%Na
2CO
3(4ml) cancellation reaction, normal hexane (20ml*4) aqueous layer extracted is washed underpressure distillation behind the anhydrous sodium sulfate drying after organic layer merges with saturated nacl aqueous solution (50ml), collect 120-126 ℃ cut, obtain formula 5a compound (13.9g).
Under the nitrogen protection; formula 6a compound (14.2g) and tetrahydrofuran (THF) (83ml) are mixed; stir and cool to below-70 ℃; splash into the hexane solution (45.7ml of n-Butyl Lithium (n-Butyl lithium); 2.5M); drip process control temp and be lower than-70 ℃, dropwise insulation reaction 1h.Then dropping type 5a compound (13.9g) dropwises, and keeps thermotonus 1h.TLC follows the tracks of reaction.After the complete reaction, add glacial acetic acid cancellation reaction, add entry (20ml), with ethyl acetate (50ml*3) aqueous phase extracted.After merging, washs with saturated nacl aqueous solution (50ml*1) organic layer, anhydrous sodium sulfate drying, and the concentrated thick product (15.88g) that obtains of underpressure distillation, then column chromatography obtains formula 7a compound (11.78 gram).
Under the nitrogen protection; with NaH (1.31g; 60%) and tetrahydrofuran (THF) (280ml) mix and to be chilled to below-5 ℃; drip tetrahydrofuran (THF) (30ml) solution of above-mentioned formula 7a compound (9.38g); stir 1h in 14 ℃ after dropwising; methylene dichloride (150ml) solution that adds above-mentioned formula 8a compound (13.0g), 14 ℃ are stirred 1h, and TLC follows the tracks of reaction.React complete after, add glacial acetic acid (25.8ml) cancellation reaction, be evaporated to driedly, add ethyl acetate (450ml) and saturated sodium bicarbonate solution (150ml), stir fully rear separatory.Then organic layer continues with saturated sodium bicarbonate solution (150ml), saturated nacl aqueous solution (120ml*2) washing, and underpressure distillation is concentrated behind the anhydrous sodium sulfate drying does, and then the silicagel column separation and purification obtains formula 1a compound (11.91g).
MS(ESI)：545.36(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ6.73-6.63(m，1H)，6.26-6.18(m，1H)，5.15-5.12(t，1H)，4.58-4.52(d，1H)，4.12-3.97(m，1H)，3.83-3.73(m，1H)，3.66(s，3H)，3.45-3.39(m，1H)，2.58-2.49(m，3H)，2.37-2.26(m，3H)，2.06(s，3H)，1.58-1.26(m，25H)，0.91-0.87(m，6H)。
Embodiment 4
The preparation of formula 2a compound
Under the nitrogen protection; formula 1a compound (0.76g) and methyl alcohol (10ml) are chilled to-40--30 ℃; add sodium borohydride (0.44g); in-40--30 ℃ stirring 2h; TLC detects to the rear adding glacial acetic acid cancellation reaction that reacts completely; and adding ethyl acetate (20ml) and saturated sodium bicarbonate solution (10ml); separatory after stirring fully; organic layer continues with saturated sodium bicarbonate solution (10ml); saturated nacl aqueous solution (10ml*2) washing; underpressure distillation is concentrated behind the anhydrous sodium sulfate drying does, and then obtains formula 2a compound (0.38g) through silica gel column chromatography separating purification.
MS(ESI)：547.37(M+Na
+)；563.37(M+K
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.68-5.60(m，1H)，5.46-5.40(m，1H)，5.16-5.11(t，1H)，4.59-4.53(d，1H)，4.12-3.89(m，2H)，3.83-3.72(m，1H)，3.67(s，3H)，3.42-3.38(m，1H)，2.59-2.46(m，3H)，2.38-2.24(m，3H)，2.08(s，3H)，1.59-1.27(m，25H)，0.90-0.88(m，6H)。
Embodiment 5
The preparation of formula 9a compound
Formula 2a compound (0.36g) is dissolved in methyl alcohol (10ml), tosic acid (0.015g), be warmed up to 40 ℃ of reaction 2h, TLC detect to react complete after, being added dropwise to saturated sodium bicarbonate solution to the pH value of reaction solution is 8.0 o'clock, stop to drip, concentrating under reduced pressure dry reaction liquid, add ethyl acetate (20ml) and water (10ml), stir separatory, then organic layer continues with saturated nacl aqueous solution (10ml*1) washing, the concentrated dried formula 9a compound (0.6g) that obtains behind the anhydrous sodium sulfate drying.Then adopt silica gel column chromatography separating purification to obtain formula 9a compound (0.30g), calculate with formula 1a, molar yield is that 49.4%, HPLC shows that purity is 99.54%, and methyl isomer 17-(R)-9a is 0.46%, sees accompanying drawing 2.The data such as the retention time at each peak that it relates to and area thereof are as shown in table 2.
MS(ESI)：463.27(M+Na
+)；479.26(M+K
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.68-5.46(m，2H)，5.19-5.16(t，1H)，4.22(s，1H)，3.90(s，1H)，3.66(s，3H)，2.50-2.42(m，1H)，2.32-2.25(m，1H)，2.05(s，3H)，1.70-1.51(m，8H)，1.43-1.18(m，15H)，0.93-0.88(m，6H)。
Each peak retention time of table 2 and area, height and area percentage
| Retention time | Area | Highly | Area percentage (%) |
| 26.965 | 16599431 | 505650 | 99.54 |
| 29.790 | 77428 | 2934 | 0.46 |
Embodiment 6
The preparation of formula 1b compound
With formula 3 compounds (10.0g), formula 4b compound (methyl alcohol, 40ml), concentrated hydrochloric acid (0.2ml) and toluene (40ml) stirs, and is warming up to back flow reaction.TLC detects after react completely, and reduces temperature of reaction, adds 10%Na
2CO
3(4ml) cancellation reaction adds entry (20ml), then normal hexane (20ml*4) aqueous layer extracted, organic layer washs with saturated nacl aqueous solution (50ml), 130-136 ℃ cut is collected in underpressure distillation behind the anhydrous sodium sulfate drying, obtains formula 5b compound (10.2g).
Under the nitrogen protection; above-mentioned formula 6b compound (15.2g) and tetrahydrofuran (THF) (80ml) are mixed; stir and cool to below-70 ℃; splash into the hexane solution (178ml, 0.56M) of lithium methide (Methyl lithium), the control temperature is lower than-70 ℃ in the dropping process; after dropwising; insulation reaction 1h, then dropping type 5b compound (9.45g) dropwises rear insulation reaction 1h.TLC detects after react completely, add glacial acetic acid cancellation reaction, add entry (20ml), with ethyl acetate (50ml*2) aqueous phase extracted, after merging, washs with saturated nacl aqueous solution (50ml) organic layer, anhydrous sodium sulfate drying concentrates and obtains the 15.88g sample, and then column chromatographic isolation and purification obtains formula 7b compound (9.0g).
Under the nitrogen protection; the aqueous solution (0.44g with sodium hydroxide; 30%)) and methylene dichloride (5ml) mix; be chilled to below-5 ℃; methylene dichloride (5ml) solution of dropping formula 7b compound (1.04g); drip complete rear in 14 ℃ of stirring 1h; 14 ℃ of stirrings of methylene dichloride (5ml) the solution 1h that adds above-mentioned formula 8b compound (1.49g); TLC detects after react completely; add glacial acetic acid (2.5ml) cancellation reaction; be evaporated to dried; add ethyl acetate (45ml) and saturated sodium bicarbonate solution (15ml), stir separatory, organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (12ml*2) washing; concentrated doing behind the anhydrous sodium sulfate drying, then the silicagel column separation and purification obtains formula 1b compound (1.15g).
MS(ESI)：603.42(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ6.75-6.63(m，1H)，6.27-6.19(m，1H)，5.16-5.12(t，1H)，4.12-3.97(m，1H)，3.83-3.73(m，1H)，3.66(m，2H)，3.45-3.38(m，1H)，2.58-2.49(m，2H)，2.30-2.0(m，6H)，2.01-1.30(m，17H)，1.29(m，3H)，1.14(m，3H)，1.0-0.87(m，15H)，0.21(s，6H)。
Embodiment 7
The preparation of formula 2b compound
Under the nitrogen protection; formula 1b compound (0.50g) and methyl alcohol (6ml) are chilled to-40--30 ℃; add POTASSIUM BOROHYDRIDE (0.48g); in-40--30 ℃ stirring 2h; TLC detects to reacting complete rear adding glacial acetic acid cancellation reaction; and adding ethyl acetate (15ml) and saturated sodium bicarbonate solution (8ml); stir separatory; organic layer continues with saturated sodium bicarbonate solution (8ml); saturated nacl aqueous solution (8ml*2) washing; through concentrated doing behind the anhydrous sodium sulfate drying, then separate obtaining formula 2b compound (0.15g) through silica gel column chromatography.
MS(ESI)：583.43(M+1
+)；605.43(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.69-5.60(m，1H)，5.46-5.39(m，1H)，，5.18-5.12(t，1H)，4.59-4.54(d，1H)，4.12-3.97(m，1H)，3.85-3.73(m，1H)，3.66(m，2H)，3.43-3.39(m，1H)，2.58-2.49(m，2H)，2.32-2.0(m，6H)，2.02-1.31(m，17H)，1.29(m，3H)，1.14(m，3H)，1.01-0.88(m，15H)，0.21(s，6H)。
Embodiment 8
The preparation of formula 9b compound
0.15g formula 2b compound is dissolved in tetrahydrofuran (THF) (1ml), add entry (1ml) and glacial acetic acid (3ml) and be warmed up to 40-50 ℃ of reaction 3h, TLC detect to react complete after, the reaction solution concentrating under reduced pressure is done, add ethyl acetate (20ml) and water (10ml), stir separatory, organic phase with saturated sodium bicarbonate solution wash to the pH value be 8.0 o'clock, stop washing, then organic layer continues with saturated nacl aqueous solution (10ml) washing, and concentrated doing obtains formula 9b compound (0.13g) through silica gel column chromatography separating purification again behind the anhydrous sodium sulfate drying, calculate with formula 1b, molar yield is 32.2%.HPLC shows that purity is 100%, does not find methyl isomer 17-(R)-9b.
MS(ESI)：469.35(M+1
+)；491.35(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.70-5.61(m，1H)，5.47-5.40(m，1H)，5.18-5.13(t，1H)，4.60-4.55(d，1H)，4.04-3.88(m，1H)，3.86-3.72(m，1H)，3.67(m，2H)，3.45-3.36(m，1H)，2.58-2.50(m，2H)，2.32-2.02(m，6H)，2.0-1.32(m，16H)，1.30(m，3H)，1.15(m，3H)，1.02-0.88(m，5H)。
Embodiment 9
The preparation of formula 1c compound
Formula 3 compounds (8.23g), formula 4c compound (10.0g), tosic acid (0.5g) and toluene (40ml) are stirred, be warming up to back flow reaction, behind the 5h, the TLC detection reaction is complete.Reduce temperature of reaction, add 10%Na
2CO
3(4ml) cancellation reaction, normal hexane (20ml*4) aqueous layer extracted, organic layer washs with saturated nacl aqueous solution (50ml), and 132-136 ℃ cut is collected in underpressure distillation behind the anhydrous sodium sulfate drying, obtains formula 5c compound (7.6g).
Under the nitrogen protection; formula 6c compound (10.3g) and tetrahydrofuran (THF) (40ml) are mixed; stir and cool to below-70 ℃; splash into the pentane solution (43.8ml of tert-butyl lithium (t-Butyl lithium); 1.3M); drip process control temp and be lower than-70 ℃, after dropwising, insulation reaction 1h.Then dropping type 5c compound (6.9g) dropwises rear insulation reaction 1h.TLC detects after react completely, add glacial acetic acid cancellation reaction, add entry (10ml), with ethyl acetate (25ml*3) extracted products, after merging, washs with saturated nacl aqueous solution (25ml) organic layer, concentrate behind the anhydrous sodium sulfate drying and obtain the 15.88g sample, then obtain formula 7c compound (6.5g) behind the column chromatographic isolation and purification.
Under the nitrogen protection; lithium chloride (0.32g) is dissolved in the tetrahydrofuran (THF) (20ml); adding formula 7c compound (1.15g) and triethylamine (0.52ml); the temperature of mixture is reduced to-10 ℃; slowly drip tetrahydrofuran (THF) (15ml) solution of above-mentioned formula 8c compound (1.71g); joining day is about 2h;-10 ℃ are stirred 20h; TLC detect to react complete after; add glacial acetic acid (2.5ml) cancellation reaction; be evaporated to dried; add ethyl acetate (45ml) and saturated sodium bicarbonate solution (15ml), stir separatory, then organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (120ml*2) washing; dense doing behind the anhydrous sodium sulfate drying, then the silicagel column separation and purification obtains formula 1c compound (1.2g).
MS(ESI)：649.40(M+1
+)；671.40(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ6.74-6.63(m，1H)，6.26-6.19(m，1H)，4.58-4.54(d，1H)，4.12-3.95(m，1H)，3.86(d，2H)，3.73-3.63(m，1H)，3.45-3.39(m，1H)，2.58-1.26(m，24H)，1.12-1.20(m，6H)，0.97-0.92(m，12H)，0.90(m，9H)。
Embodiment 10
The preparation of formula 2c compound
Under the nitrogen protection; formula 1c compound (1.0g) and methyl alcohol (612ml) are chilled to-40--30 ℃; add lithium borohydride (0.50g); in-40--30 ℃ stirring 2h; TLC detects to reacting complete rear adding glacial acetic acid cancellation reaction; and adding ethyl acetate (30ml) and saturated sodium bicarbonate solution (16ml); stir separatory; organic layer continues with saturated sodium bicarbonate solution (16ml); saturated nacl aqueous solution (16ml*2) washing; through concentrated doing behind the anhydrous sodium sulfate drying, then obtain formula 2c compound (0.45g) through silica gel column chromatography separating purification.
MS(ESI)：651.42(M+1
+)；673.42(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.68-5.60(m，1H)，5.46-5.40(m，1H)，4.64-4.52(d，1H)，4.22-4.18(m，1H)，4.14-3.97(m，1H)，3.88(d，2H)，3.83-3.73(m，1H)，3.48-3.39(m，1H)，2.72-1.25(m，24H)，1.12-1.20(m，6H)，0.97-0.93(m，12H)，0.90(m，9H)。
Embodiment 11
The preparation of formula 9c compound
0.30g formula 2c compound is dissolved in methyl alcohol (5ml), the hydrochloric acid (1ml) that adds 2N, then in 15-20 ℃ of reaction 0.1h, TLC detect to react complete after, the reaction solution concentrating under reduced pressure is done, add ethyl acetate (20ml) and water (10ml), stir separatory, organic phase with saturated sodium bicarbonate solution wash to organic phase pH value be 8.0 o'clock, stop washing, then organic layer continues with saturated nacl aqueous solution (15ml*1) washing, concentrated doing behind the anhydrous sodium sulfate drying, separate obtaining formula 9c compound (0.22g) through silica gel column chromatography again, calculate with formula 1c, molar yield is 39.9%.HPLC shows that purity is more than 99.0%, and wherein the content of methyl isomer 17-(R)-9c is 1.0%.
MS(ESI)：537.33(M+1
+)；559.33(M+Na
+)；575.34(M+K
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.69-5.60(m，1H)，5.46-5.41(m，1H)，4.64-4.50(d，1H)，4.24-4.18(m，1H)，4.12-3.97(m，1H)，3.88(d，2H)，3.83-3.73(m，1H)，3.49-3.39(m，1H)，2.72-1.20(m，24H)，0.97-0.93(m，12H)。
Embodiment 12
The preparation of formula 1d compound
Formula 3 compounds (10.0g), formula 4d compound (40ml), concentrated hydrochloric acid (0.2ml) and toluene (40ml) are stirred, be warming up to back flow reaction, TLC detects after react completely, and reduces temperature of reaction, adds 10%Na
2CO
3(4ml) cancellation reaction, concentrated removal formula 4d compound, add entry (20ml), then normal hexane (20ml*4) aqueous layer extracted, organic layer washs with saturated nacl aqueous solution (50ml), 152-156 ℃ cut is collected in underpressure distillation behind the anhydrous sodium sulfate drying, obtains formula 5d compound (10.2g).
Under the nitrogen protection; formula 6d compound (12.1g) and tetrahydrofuran (THF) (42ml) are mixed; stir and cool to below-70 ℃; splash into the hexane solution (22.9ml, 2.5M) of n-Butyl Lithium (n-Butyl lithium), drip process control temp and be lower than-70 ℃; after dropwising; insulation reaction 1h, then dropping type 5d compound (5.94g) dropwises rear insulation reaction 1h.TLC detects after react completely, add glacial acetic acid cancellation reaction, add entry (10ml), with ethyl acetate (25ml*3) aqueous phase extracted, after merging, washs with saturated nacl aqueous solution (25ml) organic layer, anhydrous sodium sulfate drying concentrates and obtains the 17.1g sample, and then column chromatographic isolation and purification obtains formula 7d compound (7.5g).
Under the nitrogen protection; tetrahydrofuran solution (3.2ml with potassium tert.-butoxide; 1M) and tetrahydrofuran (THF) (5ml) mix; be chilled to below-5 ℃; tetrahydrofuran (THF) (5ml) solution of dropping formula 7d compound (1.25g); drip complete rear in 10-15 ℃ of stirring 1h; tetrahydrofuran (THF) (15ml) solution that adds above-mentioned formula 8d compound (1.35g); 10-15 ℃ is stirred 1h; TLC detect to react complete after; add glacial acetic acid (2.5ml) cancellation reaction; be evaporated to dried; add ethyl acetate (45ml) and saturated sodium bicarbonate solution (15ml); stir separatory; then organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (12ml*2) washing, concentrated doing behind the anhydrous sodium sulfate drying, then the silicagel column separation and purification obtains formula 1d compound (1.1g).
MS(ESI)：539.37(M+1
+)；561.37(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ6.76-6.60(m，1H)，6.25-6.19(m，1H)，4.50-4.45(d，1H)，4.10-3.85(m，1H)，3.76(d，1H)，3.73-3.60(m，1H)，3.45-3.35(m，1H)，2.58-1.35(m，26H)，1.32(m，6H)，0.97-0.92(m，6H)，0.21(s，9H)。
Embodiment 13
The preparation of formula 2d compound
Under the nitrogen protection; formula 1d compound (1.0g) and methyl alcohol (612ml) are chilled to-50--40 ℃; add sodium borohydride (0.60g); in-50--40 ℃ stirring 2h; TLC detects to reacting complete rear adding glacial acetic acid cancellation reaction; and adding ethyl acetate (25ml) and saturated sodium bicarbonate solution (15ml); stir separatory; organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (15ml*2) washing; through concentrated doing behind the anhydrous sodium sulfate drying, then separate obtaining formula 2d compound (0.44g) through silica gel column chromatography.
MS(ESI)：541.38(M+1
+)；563.38(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.68-5.62(m，1H)，5.48-5.40(m，1H)，4.50-4.40(d，1H)，4.18-3.85(m，2H)，3.76(d，1H)，3.74-3.60(m，1H)，3.45-3.33(m，1H)，2.58-1.34(m，26H)，1.33(m，6H)，0.98-0.92(m，6H)，0.21(s，9H)。
Embodiment 14
The preparation of formula 9d compound
0.30g formula 2d compound is dissolved in tetrahydrofuran (THF) (5ml), cool to 0-5 ℃, the tetrahydrofuran solution (0.56ml) that adds the tetrabutyl ammonium fluoride of 1M, in 0-5 ℃ of reaction 2-3h, TLC detects to reacting complete no, the reaction solution concentrating under reduced pressure is done, add ethyl acetate (20ml) and water (10ml), stir separatory, then organic layer continues to wash with saturated nacl aqueous solution (15ml) with 10% sodium dihydrogen phosphate (10ml) washing, concentrated doing behind the anhydrous sodium sulfate drying, separation obtains formula 9d compound (0.25g) through silica gel column chromatography, calculates with formula 1d, and molar yield is 42.1%.HPLC shows that purity is more than 98.5%, and wherein the content of methyl isomer 17-(R)-9c is 1.5%.
MS(ESI)：469.35(M+1
+)；491.35(M+Na
+)；507.35(M+K
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.68-5.62(m，1H)，5.38-5.25(m，1H)，4.52-4.40(d，1H)，4.18-3.88(m，2H)，3.75(d，1H)，3.76-3.60(m，1H)，3.45-3.30(m，1H)，2.59-1.35(m，26H)，1.34(m，6H)，0.99-0.92(m，6H)。
Embodiment 15
The preparation of formula 1e compound
Formula 3 compounds (10.0g), formula 4e compound (40ml), the vitriol oil (0.2ml) and toluene (40ml) are stirred, be warming up to back flow reaction, TLC detects after react completely, and reduces temperature of reaction, adds 10%Na
2CO
3(10ml) cancellation reaction, concentrated removal formula 4e compound, add entry (20ml), then normal hexane (20ml*4) aqueous layer extracted, organic layer washs with saturated nacl aqueous solution (50ml), 120-126 ℃ cut is collected in underpressure distillation behind the anhydrous sodium sulfate drying, obtains formula 5e compound (9.21g).
Under the nitrogen protection; formula 6a compound (3.15g) and tetrahydrofuran (THF) (42ml) are mixed; stir and cool to below-70 ℃; splash into the hexane solution (25.0ml, 1.0M) of s-butyl lithium (s-Butyl lithium), drip process control temp and be lower than-70 ℃; after dropwising; insulation reaction 1h, then dropping type 5e compound (2.45g) dropwises rear insulation reaction 1h.TLC detects after react completely, add glacial acetic acid cancellation reaction, add entry (10ml), with ethyl acetate (25ml*3) aqueous phase extracted, after merging, washs with saturated nacl aqueous solution (25ml) organic layer, anhydrous sodium sulfate drying concentrates and obtains the 17.1g sample, and then column chromatographic isolation and purification obtains formula 7a compound (2.2g).
Under the nitrogen protection; with n-butyllithium solution (1.32ml; 2.5M) and tetrahydrofuran (THF) (5ml) be chilled to below-70 ℃; tetrahydrofuran (THF) (5ml) solution of dropping formula 7a compound (1.0g); drip Bi Houyu-70 ℃ ℃ and stir 1h; tetrahydrofuran (THF) (10ml) solution that adds above-mentioned formula 8e compound (1.68g);-70 ℃ are stirred 1h; then be warmed up to 10-15 ℃ and stir 1h; TLC detect to react complete after; add glacial acetic acid (2.5ml) cancellation reaction; be evaporated to dried; add ethyl acetate (45ml) and saturated sodium bicarbonate solution (15ml); stir separatory; then organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (12ml*2) washing, concentrated doing behind the anhydrous sodium sulfate drying, then the silicagel column separation and purification obtains formula 1e compound (1.60g).
MS(ESI)：649.50(M+1
+)；
1H-NMR(500.13MHz，CDCl
3)δ6.79-6.60(m，1H)，6.26-6.19(m，1H)，5.16-5.11(t，1H)，4.51-4.45(d，1H)，4.12-3.85(m，1H)，3.75(m，2H)，3.73-3.62(m，1H)，3.45-3.36(m，1H)，2.78-1.10(m，47H)，0.90-0.95(m，12H)。
Embodiment 16
The preparation of formula 2e compound
Under the nitrogen protection; formula 1e compound (1.0g) and methyl alcohol (6ml) are chilled to-40--30 ℃; add sodium borohydride (0.50g); in-40--30 ℃ stirring 2h; TLC detects to reacting complete rear adding glacial acetic acid cancellation reaction; and adding ethyl acetate (25ml) and saturated sodium bicarbonate solution (15ml); stir separatory; organic layer continues with saturated sodium bicarbonate solution (15ml); saturated nacl aqueous solution (15ml*2) washing; through concentrated doing behind the anhydrous sodium sulfate drying, then separate obtaining formula 2e compound (0.50g) through silica gel column chromatography.
MS(ESI)：651.51(M+1
+)；673.51(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.69-5.62(m，1H)，5.38-5.25(m，1H)，5.16-5.10(t，1H)，4.51-4.44(d，1H)，4.13-3.86(m，2H)，3.77(m，2H)，3.73-3.60(m，1H)，3.45-3.37(m，1H)，2.78-1.09(m，47H)，0.91-0.95(m，12H)。
Embodiment 17
The preparation of formula 9e compound
0.30g formula 2e compound is dissolved in tetrahydrofuran (THF) (2ml), add entry (2ml) and glacial acetic acid (6ml) in 10-20 ℃ of reaction 24h, TLC detects to reacting complete, dense dry reaction liquid reduces pressure, add ethyl acetate (40ml) and water (20ml), stir separatory, organic phase is 8.0 o'clock with saturated sodium bicarbonate solution to pH value, stop washing, then organic layer continues with saturated nacl aqueous solution (20ml) washing, and concentrated doing behind the anhydrous sodium sulfate drying separates obtaining formula 9e compound (0.26g) again through silica gel column chromatography, calculate with formula 1e, molar yield is 49.6%.HPLC shows that purity is more than 99.7%, and wherein the content of methyl isomer 17-(R)-9b is 0.3%.
MS(ESI)：567.45(M+1
+)；589.45(M+Na
+)；
1H-NMR(500.13MHz，CDCl
3)δ5.69-5.62(m，1H)，5.38-5.25(m，1H)，4.51-4.44(d，1H)，4.13-3.85(m，2H)，3.74(m，2H)，3.70-3.60(m，1H)，3.45-3.30(m，1H)，2.78-1.05(m，39H)，0.91-0.95(m，12H)。
Embodiment 18
The preparation of limaprost (formula 10 compounds)
The formula 9a compound for preparing take embodiment 5 is as starting raw material, and with reference to the method for patent US4294849 report, empirical tests prepares limaprost really.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition 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 (13)
1. a formula I chipal compounds is characterized in that,
Wherein,
R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl; With
X is O or OH, and supplementary condition are: when X is O, being two keys between X and the adjacent C, and when X is OH, is singly-bound between X and the adjacent C.
2. chipal compounds as claimed in claim 1 is characterized in that, the structure of described compound as shown in Equation 1:
3. chipal compounds as claimed in claim 1 is characterized in that, the structure of described compound as shown in Equation 2:
4. such as arbitrary described chipal compounds among the claim 1-3, it is characterized in that described compound has and is selected from one or more features of lower group:
R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl;
R
2Be C
1-C
4The straight or branched alkyl; And/or
R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl.
5. such as arbitrary described chipal compounds among the claim 1-3, it is characterized in that R
1Be methyl, R
2Be methyl, and/or R
3Be THP trtrahydropyranyl.
6. a method for preparing compound claimed in claim 1 is characterized in that, comprises step:
(a) under acidic conditions, in inert solvent, with formula 3 compounds and the reaction of formula 4 compounds, form formula 5 compounds;
(b) under alkaline condition, in inert solvent, with formula 5 compounds and the reaction of formula 6 compounds, form formula 7 compounds;
(c) under alkaline condition, in inert solvent, with formula 7 compounds and the reaction of formula 8 compounds, form formula 1 compound;
(d) randomly, with the reduction of formula 1 compound, form formula 2 compounds:
Wherein, above-mentioned various in,
R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl;
R
4Be C
1-C
6The straight or branched alkyl;
R
5Be C
1-C
4The straight or branched alkyl;
R
6Be C
1-C
4The straight or branched alkyl.
7. method as claimed in claim 6 is characterized in that, above-mentioned various in, each substituting group has and is selected from one or more features of lower group:
R
1Be C
1-C
4Straight or branched alkyl or trifluoromethyl;
R
2Be C
1-C
4The straight or branched alkyl;
R
3For triethyl is silica-based, trimethyl silicon based, t-Butyldimethylsilyl or THP trtrahydropyranyl;
R
4Be C
1-C
4The straight or branched alkyl;
R
5Be C
1-C
2Alkyl; And/or
R
6Be C
1-C
2Alkyl.
8. method as claimed in claim 6 is characterized in that,
In the step (a), described acid is selected from lower group: the vitriol oil, concentrated hydrochloric acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, sulfonic resin or its combination; And/or
In the step (b), described alkali is selected from lower group: lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium or its combination; And/or
In the step (c), described alkali is selected from lower group: sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, potassium tert.-butoxide, sodium methylate, sodium ethylate or its combination; And/or
In the step (d), reduce with the reductive agent that is selected from lower group: sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, zinc borohydride or its combination.
9. a preparation method is characterized in that, comprises step:
(i) slough R in formula 2 compounds
3Group forms formula 9 compounds,
In various, R
1Be C
1-C
10Straight or branched alkyl, trifluoromethyl or trichloromethyl;
R
2Be C
1-C
10The straight or branched alkyl;
R
3Be silylation or THP trtrahydropyranyl.
10. method as claimed in claim 9 is characterized in that, also comprises step:
(ii) formula 9 compounds are carried out hydroxyl protection, hydrolysis, two keys, oxidation removes hydroxyl protecting group, thereby forms limaprost:
11. the purposes of chipal compounds as claimed in claim 1 is characterized in that, for the preparation of the intermediate of limaprost.
12. purposes as claimed in claim 11 is characterized in that, for the preparation of the intermediate shown in the formula 9:
In the formula, R1 is selected from C
1-C
10Straight or branched alkyl, trifluoromethyl, trichloromethyl; R2 is selected from C
1-C
10The straight or branched alkyl.
13. the purposes of chipal compounds as claimed in claim 1 is characterized in that, for the preparation of limaprost.
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|---|---|---|---|
| CN201110193352XA CN102875586A (en) | 2011-07-11 | 2011-07-11 | Method for preparing key intermediate of limaprost |
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|---|---|---|---|
| CN201110193352XA CN102875586A (en) | 2011-07-11 | 2011-07-11 | Method for preparing key intermediate of limaprost |
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| CN201110193352XA Pending CN102875586A (en) | 2011-07-11 | 2011-07-11 | Method for preparing key intermediate of limaprost |
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| CN (1) | CN102875586A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014040457A1 (en) * | 2012-09-13 | 2014-03-20 | 上海源力生物技术有限公司 | Intermediate of limaprost, preparation method thereof and preparation method of limaprost therefrom |
| CN109071427A (en) * | 2016-05-09 | 2018-12-21 | Ａｇｃ株式会社 | Novel derivatives of prostaglandins |
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| US4294849A (en) * | 1979-01-29 | 1981-10-13 | Warner-Lambert Company | Prostaglandin analogues |
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| CN1126591A (en) * | 1994-06-03 | 1996-07-17 | 株式会社·R-技术上野 | Agent for treating hepato biliary diseases |
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| US4294849A (en) * | 1979-01-29 | 1981-10-13 | Warner-Lambert Company | Prostaglandin analogues |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014040457A1 (en) * | 2012-09-13 | 2014-03-20 | 上海源力生物技术有限公司 | Intermediate of limaprost, preparation method thereof and preparation method of limaprost therefrom |
| CN109071427A (en) * | 2016-05-09 | 2018-12-21 | Ａｇｃ株式会社 | Novel derivatives of prostaglandins |
| AU2017264102B2 (en) * | 2016-05-09 | 2020-09-24 | AGC Inc. | Novel prostaglandin derivative |
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