CN103509044A - Beraprost sodium intermediates and preparation method thereof - Google Patents
Beraprost sodium intermediates and preparation method thereof Download PDFInfo
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- CN103509044A CN103509044A CN201210209052.0A CN201210209052A CN103509044A CN 103509044 A CN103509044 A CN 103509044A CN 201210209052 A CN201210209052 A CN 201210209052A CN 103509044 A CN103509044 A CN 103509044A
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- 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
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Abstract
The invention discloses beraprost sodium intermediates and a preparation method thereof. Specifically, provided is the beraprost sodium intermediate compounds represented by the formula I and the preparation method thereof. The preparation method comprises the steps: (a) protecting hydroxyl of a compound represented by the formula II, and thus generating a compound represented by the formula Ia; optionally (b) carrying out a deprotection reaction of the compound represented by the formula Ia to obtain a compound represented by the formula Ib; optionally (c) oxidizing the compound represented by the formula Ib to obtain a compound represented by the formula Ic; and optionally (d) carrying out a reaction of the compound represented by the formula Ic and phosphate ester to obtain a compound represented by the formula Id. Structures and definitions of substituent groups are defined as described in the specification. The method disclosed by the invention is mild in reaction conditions and high in yield, can avoid the use of toxic reagents, and is suitable for industrialized production.
Description
Technical field
The present invention relates to beraprost sodium intermediate and preparation method thereof.
Background technology
Beraprost sodium, by toray Co., Ltd. (Toray) exploitation, is contained in Discussion on Chinese Listed with trade(brand)name moral.The structure of the beraprost sodium of listing, suc as formula shown in V, is 4 racemic compounds that isomer forms.
Beraprost sodium belongs to prostacyclin class medicine (prostacyclin, PGI
2).Prostacyclin is the vaso-active substance being synthesized by vascular endothelial cell, has the effect of antiplatelet and vasodilation, simple PGI
2transformation period is shorter, and pharmacological action is very limited.1992, activated form PGI
2analogue oral medicine is that beraprost sodium is succeeded in developing, and due to its Stability Analysis of Structures, the transformation period is longer, is widely used in clinically treatment chronic lower limb occlusive disease (ASO).
Patent EP084856, EP463162A1 and Tetrahedron; 55 (1999); 2449-2474 describes the synthetic of beraprost sodium in detail, synthetic route as shown below, wherein; primary hydroxyl is protected through TERT-BUTYL DIMETHYL CHLORO SILANE; secondary hydroxyl is protected through ethanoyl, then through hydrochloric acid hydrolysis, by DCC/DMSO, is oxidized; carry out Witting-Horner-Emmon reaction, through CeCl
3/ NaBH
4reduction, hydrolysis, then become sodium salt.
There is following shortcoming in this synthetic route: oxidizing reaction adopts the toxicity of DCC (dicyclohexylcarbodiimide) larger, and the by product urea derivative that reaction generates is difficult to remove from system, thereby affected the quality of product.After reduction, also need to remove ethanoyl in addition, whole piece route yield is low.
Patent CN1680351A has reported the route of another synthetic beraprost sodium; its schematically as follows shown in; this route is through chlorotriethyl silane protection primary hydroxyl and secondary hydroxyl; by Swern oxidizing reaction oxidation of primary hydroxyl optionally; carry out again Witting-Horner-Emmon reaction; DIBAL-H reduction, hydrolysis, finally becomes sodium salt.
The step of this reaction scheme is shorter; before reduction, removed the protecting group on secondary hydroxyl, but its Swern oxidation and reduction two-step reaction all need-70～-80 ℃ of low temperature, also need anhydrous and oxygen-free operation; and to having relatively high expectations of equipment, be difficult to further suitability for industrialized production.
Therefore, this area is easy to industrialization amplification in the urgent need to developing one, and yield is high, and avoids using the operational path of toxic reagent.
Summary of the invention
The object of the present invention is to provide a kind of beraprost sodium intermediate and preparation method thereof, develop one and be easy to industrialization and amplify, yield is high, and avoids using the preparation technology of the beraprost sodium of toxic reagent.
A first aspect of the present invention, provides a kind of formula I compound, and structure is shown below,
In formula, R
1for methyl or ethyl;
R
2for H, C
1-4alkoxyalkyl or THP trtrahydropyranyl;
R is siloxy ,-the CHO ,-CH that trialkyl replaces
2oH or
Described alkyl is selected from: C
1-6alkyl (being preferably methyl, ethyl, the tertiary butyl), C
6-10aryl (being preferably phenyl) or its combination.
In another preference, described C
1-4alkoxyalkyl is methoxyl methyl or ethoxyethyl group.
In another preference, the siloxy that described trialkyl replaces is the siloxy that trialkyl that an alkyl is the tertiary butyl replaces.
In another preference, the siloxy that described trialkyl replaces is tertiary butyl dimethyl Si base or tert-butyl diphenyl siloxy.
In another preference, described formula I compound is:
In various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl; Preferred methoxyl methyl, ethoxyethyl group or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl; The siloxy that the trialkyl that preferably alkyl is the tertiary butyl replaces; More preferably be selected from tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
In another preference, R
1for methyl; R
2for THP trtrahydropyranyl.
In another preference, R ' is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
A second aspect of the present invention, provides a kind of preparation method of formula I compound, comprises the following steps:
(a) take formula II compound is raw material, the hydroxyl of formula II compound is protected to the formula I compound of structure shown in production Ia; And optionally
(b) formula Ia compound is sloughed protecting group R ', obtains the formula I compound of structure shown in formula Ib; And optionally
(c) formula Ib compound, through oxidation, obtains the formula I compound of structure shown in formula Ic; And optionally
(d) formula Ic compound reacts with the phosphoric acid ester shown in formula X, obtains the formula I compound of structure shown in formula Id,
In formula, Ri, Rii are independently selected from C
1-4alkyl;
During above-mentioned reaction scheme is various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl; The siloxy that the trialkyl that preferably alkyl is the tertiary butyl replaces; More preferably be selected from tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
In another preference, Ri, Rii are independently selected from methyl or ethyl.
In another preference, R
1for methyl or ethyl; R
2for methoxyl methyl, ethoxyethyl or THP trtrahydropyranyl; R ' is tertiary butyl dimethyl Si base or tert-butyl diphenyl siloxy.
In another preference, R
1for methyl; R
2for THP trtrahydropyranyl.
In another preference, R ' is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
A third aspect of the present invention, provides the formula I purposes of compound, as the intermediate of beraprost sodium, or for the preparation of beraprost sodium or its intermediate.
A fourth aspect of the present invention, provides a kind of preparation method of beraprost sodium, comprises step:
(a) formula Id compound is removed to R
2group, obtains the beraprost sodium intermediate of structure shown in formula III;
(b) formula III compound reduces through reductive agent, obtains the beraprost sodium intermediate of structure shown in formula IV;
(c) formula IV compound obtains described beraprost sodium through alkaline condition hydrolysis;
In various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl.
In another preference, R
2for methoxyl methyl, ethoxyethyl or THP trtrahydropyranyl.
In another preference, described reductive agent is sodium borohydride/seven water cerous chlorate reductive agent; Or diisobutyl aluminium hydride DIBAL-H reductive agent.
Method of the present invention, reaction conditions is gentle, can avoid using toxic reagent, and yield is high, is suitable for suitability for industrialized production.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, at this, tire out and state no longer one by one.
Embodiment
Present inventor is through extensively and in depth research; it is unexpected that discovery adopt the group of ethers or acid labile to protect the secondary hydroxyl of raw material; not only react completely; and following adopted quaternary ammonium salt can only remove primary hydroxyl protecting group and the group of ethers protecting group or acid labile is not affected; the further like this unicity that guarantees subsequent reactions; can significantly improve yield, and it is all gentleer respectively to walk reaction conditions, is easy to suitability for industrialized production.On this basis, completed the present invention.
Beraprost sodium
As used herein, " formula V compound ", " beraprost sodium ", " suc as formula the beraprost sodium shown in V " or " beraprost sodium V " can Alternates, refer to that structure is suc as formula shown in V, the racemic compound being comprised of 4 isomer.
Formula I compound
As used herein, " formula I compound ", " suc as formula the compound shown in I ", " compound of structure shown in formula I " or " Compound I " can Alternates, refer to that structure is suc as formula the compound shown in I:
In formula, R
1for methyl or ethyl;
R
2for H, C
1-4alkoxyalkyl or THP trtrahydropyranyl;
R is siloxy ,-the CHO ,-CH that trialkyl replaces
2oH or
In another preference, described R
2for methoxyl methyl, ethoxyethyl group or THP trtrahydropyranyl.
In another preference, described R is the siloxy that the alkyl trialkyl that is the tertiary butyl replaces.
In another preference, described R is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
In another preference, described R
1for methyl; R
2for THP trtrahydropyranyl.
In another preference, formula I compound of the present invention is preferably:
In various, R
1for methyl or ethyl;
R
2for methoxyl methyl, ethoxyethyl group or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl; The siloxy that the trialkyl that preferably alkyl is the tertiary butyl replaces; Be more preferably tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
Formula I compound of the present invention, can be as the intermediate of beraprost sodium, or for the preparation of beraprost sodium or its intermediate.
The preparation method of formula I compound
The preparation method of formula I compound provided by the invention, comprises the following steps:
(a) take formula II compound is raw material, the hydroxyl of formula II compound is protected to the formula I compound of structure shown in production Ia; And optionally
(b) formula Ia compound is sloughed protecting group R ', obtains the formula I compound of structure shown in formula Ib; And optionally
(c) formula Ib compound, through oxidation, obtains the formula I compound of structure shown in formula Ic; And optionally
(d) formula Ic compound reacts with the phosphoric acid ester shown in formula X, obtains the formula I compound of structure shown in formula Id,
In formula, Ri, Rii are independently selected from C
1-4alkyl;
During above-mentioned reaction scheme is various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl; The siloxy that the trialkyl that preferably alkyl is the tertiary butyl replaces; Be more preferably tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
In another preference, Ri, Rii are independently selected from methyl or ethyl.
In another preference, described C
1-4alkoxyalkyl is methoxyl methyl or ethoxyethyl group.
In another preference, described R ' is tertiary butyl dialkyl group siloxy.
In another preference, R
1for methyl or ethyl; R
2for methoxyl methyl, ethoxyethyl or THP trtrahydropyranyl; R ' is tertiary butyl dimethyl Si base or tert-butyl diphenyl siloxy.
In another preference, R
1for methyl; R
2for THP trtrahydropyranyl.
In the present invention, formula Z compound passes through document Tetrahedron, and 55 (1999), the preparation method of 2449-2474 is prepared, and adopts silicon ether protecting group optionally to protect primary hydroxyl to obtain formula II compound, R Z compound
1group is methyl or ethyl, and R ' is the siloxy that trialkyl replaces, the siloxy that the trialkyl that preferably alkyl is the tertiary butyl replaces; Be more preferably tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
Adopt protecting group to protect the hydroxyl of formula II compound and obtain formula Ia compound, wherein R
1for methyl or ethyl; R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl; The siloxy that R ' replaces for trialkyl.
In another preference, R
1group is methyl or ethyl, and R ' is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base, R
2for methoxyl methyl, ethoxyethyl or THP trtrahydropyranyl.
In another preference, described R
1for methyl; R
2for methoxyl methyl or THP trtrahydropyranyl.More preferably, R
2for THP trtrahydropyranyl.
By quaternary ammonium salt, remove in compound formula Ia siloxy protecting group in R ' group, wherein as mentioned above, quaternary ammonium salt is preferably tetrabutyl ammonium fluoride to R ' group.
Formula Ib compound is oxidized and obtains formula Ic compound, R through oxygenant
1, R
2definition as previously mentioned, wherein oxygenant is preferably Dess-Martin oxygenant, in formula Y compound, R
3for acetoxyl group.
By formula Ic compound and general formula X compound, (its Ri, Rii group are independently selected from C
1~ C
4alkyl) carry out Witting-Honer-Emmon reaction and obtain formula Id compound, wherein R
1, R
2the definition of group as mentioned above, formula X compound reference (Heterocycles, 53,5,2000.1085-1110) preparation.
The purposes of beraprost sodium intermediate compound I d
Formula Id compound removes R through corresponding acid again
2protecting group group obtains formula III compound, and its acid of using can be strong acid or weak acid, and strong acid can be hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and Hydrogen bromide is preferably hydrochloric acid or Hydrogen bromide, and the best is hydrochloric acid.
The key intermediate that formula III compound is beraprost sodium, formula III compound is reduced through corresponding reductive agent, obtain formula IV compound, its reductive agent using is sodium borohydride and seven water cerous chlorate systems, or the DIBAL-H reduction system in referenced patent CN1680351.
The preparation method of beraprost sodium
The preparation method of beraprost sodium provided by the invention, comprises that employing formula III compound prepares the step of beraprost sodium, and wherein, formula III compound adopts the aforesaid method preparation of the present invention.
By formula III compound, prepare beraprost sodium and can adopt the usual method of using in this area, include but not limited to disclosed method in patent EP0084856.
Usefulness of the present invention is:
(1) reaction conditions is gentle, avoids using toxic reagent.
(2) secondary hydroxyl, through the radical protection of ether or acid labile, reacts completely, no coupling product.
(3) quaternary ammonium salt only remove primary hydroxyl protecting group on the group of ether or acid labile without impact, guarantee the unicity of subsequent reactions.
(4) use the o-iodobenzoic acid class oxygenant can complete oxidation, Reaction time shorten.
(5) yield is high, is easy to suitability for industrialized production.
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 use, each feature disclosing in specification sheets, can be replaced by any alternative characteristics of identical, impartial or similar object that provide.Therefore except there being special instruction, the feature disclosing is only the general example of equalization or similar features.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition or the condition of advising according to manufacturer.
Unless otherwise defined, the same meaning that all specialties of using in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
The preparation of formula II compound
(R wherein
1for methyl, R ' is tert-butyl diphenyl siloxy)
In 500ml four-necked bottle, by 15g formula Z compound (R
1for methyl) be dissolved in 100ml methylene dichloride, add 5ml triethylamine, 0.34g DMAP, under nitrogen protection, be cooled to 0 ℃, splash into the dichloromethane solution that 50ml contains 12.8g tert-butyl diphenyl chlorosilane, stir 2 hours, react completely.Add the rare aqueous citric acid solution washing of 75ml for several times, adopt the saturated NaCl solution washing of 300ml, through anhydrous sodium sulfate drying, filter, concentrate to obtain micro-yellow liquid.After column chromatography purification, obtain 26.1g, yield: 97.9%.This step reaction product can not purified next step reaction of input.
MS:567.5[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH：0.75(9H,s),1.75-2.84(11H,m),3.52(3H,s),3.59(1H,m),3.67-4.15(3H,m),5.04(1H,m),6.80(1H,m),6.97(2H,m),7.34-7.59(10H,m)
Embodiment 2
The preparation of formula II compound
(R wherein
1for ethyl, R ' is tertiary butyl dimethyl Si base)
In 500ml four-necked bottle, by 15g formula Z compound (R
1for ethyl) be dissolved in 100ml methylene dichloride, add 5ml triethylamine, 0.33g DMAP, under nitrogen protection, be cooled to 0 ℃, splash into the dichloromethane solution that 50ml contains 11.6g TERT-BUTYL DIMETHYL CHLORO SILANE, stir 2 hours, react completely.Add the rare aqueous citric acid solution washing of 75ml for several times, adopt the saturated NaCl solution washing of 300ml, through anhydrous sodium sulfate drying, filter, concentrate to obtain micro-yellow liquid.After column chromatography purification, obtain 20.2g, yield: 99.3%.This step reaction product can not purified next step reaction of input..
MS:457.5[M+Na]
+
Embodiment 3
The preparation of formula Ia compound
(R wherein
1for methyl, R
2for THP trtrahydropyranyl, R ' is tert-butyl diphenyl siloxy)
1000ml four-necked bottle, in 800ml methylene dichloride, adds 13.66g 3 by the formula II compound dissolution in 36.52g embodiment 1 under room temperature, 4-dihydropyrane under nitrogen protection, adds 0.5g tosic acid, room temperature reaction 1h.Through about 95ml saturated sodium bicarbonate aqueous solution washing, saturated nacl aqueous solution washing, dry concentrated, obtain micro-yellow thick liquid 48.02g.After column chromatography purification, obtain 41.6g, yield: 98.7%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 3:1)=0.8
MS:651.7[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm):0.78(9H,s),1.77-2.85(16H,m),3.49(3H,s),3.52(1H,m),3.59-4.16(5H,m),4.93(1H,m),5.01(1H,m),6.81(1H,J=7.0HZ),6.97(2H,m),7.33-7.56(10H,m)
Embodiment 4
The preparation of formula Ia compound
(R wherein
1for methyl, R
2for methoxyl methyl, R ' is tert-butyl diphenyl siloxy)
250ml four-necked bottle, in 200ml trichloromethane, adds Vanadium Pentoxide in FLAKES 2g by the formula II compound dissolution in 10.71g enforcement 1, and the about 2.9g of methylal, under nitrogen protection, and room temperature reaction 8h.Through washing, then through ethyl acetate extraction (100ml*2), saturated aqueous common salt washing, dry concentrated, obtain micro-yellow thick liquid 13.08g.After column chromatography purification, obtain 10.9g, yield: 113%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 3:1)=0.6
MS:611.5[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm):0.84(9H,s),1.64-2.72(10H,m),3.25(3H,s),3.44(3H,s),3.51(1H,m),3.74-4.08(2H,m),4.79(2H,s),5.05(1H,m),6.75(1H,J=5.2HZ),6.98(2H,m),7.30-7.49(10H,m)。
Embodiment 5
The preparation of formula Ia compound
(R wherein
1for methyl, R
2for ethoxyethyl group, R ' is tert-butyl diphenyl siloxy)
250ml four-necked bottle, is dissolved in 180ml ether by 4.2g vinyl ethyl ether ether, adds 2.1mg tosic acid, and prepared formula II compound 10.5g in embodiment 1, room temperature reaction 12h.Water-soluble through washing, then through ethyl acetate extraction (100ml*2), saturated aqueous common salt washing, dry concentrated, obtain micro-yellow thick liquid 6.02g.After column chromatography purification, obtain 4.63g, yield: 97.4%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 3:1)=0.8
1H-NMR(400MHz,CDCl
3),δH(ppm)：0.84(9H,s),1.64-2.72(10H,m),3.15(3H,s),3.42(3H,s),3.50(1H,m),3.68-3.72(4H,t),3.74-4.08(2H,m),4.79(2H,s),5.02(1H,m),6.71(1H,J=5.2HZ),6.92(2H,m),7.32-7.42(10H,m)
Embodiment 6
Preparation (the R of formula Ib compound
1for methyl, R
2for ethoxyethyl group)
500ml three-necked flask, is dissolved in the formula Ia compound in 4.00g embodiment 5 in 75ml anhydrous tetrahydro furan, under nitrogen protection, is cooled to 0 ℃, drips 125ml containing the THF solution of 4g tetrabutyl ammonium fluoride, rises to 30 ℃ to reaction end.Add 50ml water, water layer, through ethyl acetate 75ml extraction 2 times, merges organic layer, washs anhydrous sodium sulfate drying, dense dry micro-yellow oil that to obtain through 200ml saturated nacl aqueous solution.After column chromatography purification, obtain 2.33g, yield: 96.4%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 1:1)=0.3
1H-NMR(400MHz,CDCl
3),δH(ppm)：1.61-2.71(10H,m),3.31(3H,s),3.34-3.38(4H,m),3.42(3H,s),3.51(1H,m),3.72-4.09(2H,m),4.78(2H,s),5.04(1H,m),6.75(1H,J=5.0HZ),6.84(2H,m)
Embodiment 7
Preparation (the R of formula Ib compound
1for methyl, R
2for THP trtrahydropyranyl)
1000ml three-necked flask, is dissolved in 750ml anhydrous tetrahydro furan by the formula Ia compound in 38.41g embodiment 3, under nitrogen protection, is cooled to 0 ℃, drips 125ml containing the THF solution of 24g tetrabutyl ammonium fluoride, rises to 30 ℃ to reaction end.By 300ml water and 450ml ethyl acetate, extract, water layer, through 250ml ethyl acetate extraction 2 times, merges organic layer, through 200ml saturated nacl aqueous solution, wash anhydrous sodium sulfate drying, dense dry micro-yellow oil that to obtain, after column chromatography purification, obtain 22.48g, yield: 94.2%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 1:1)=0.3
MS:413.5[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm):1.61-2.71(16H,m),3.34-3.38(4H,m),3.42(3H,s),3.51(1H,m),3.72-4.09(4H,m),4.92(1H,m),5.05(1H,m),6.74(1H,J=4.8HZ),6.8?8(2H,m)
Embodiment 8
Preparation (the R of formula Ib compound
1for methyl, R
2for methoxyl methyl)
500ml three-necked flask, is dissolved in 75ml anhydrous tetrahydro furan by the formula Ia compound in 5.12g embodiment 4, under nitrogen protection, is cooled to 0 ℃, drips 125ml containing the THF solution of 4.5g tetrabutyl ammonium fluoride, rises to 30 ℃ to reacting 12h.Add 60ml water, water layer, through ethyl acetate 85ml extraction 2 times, merges organic layer, through the washing of 250ml saturated nacl aqueous solution, and anhydrous sodium sulfate drying, dense doing to obtain micro-yellow oil, obtains 2.84g, yield: 93.0% after column chromatography purification.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 1:1)=0.3
MS:373.2[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm)：1.62-2.71(11H,m),3.23(3H,s),3.41(3H,s),3.55(1H,m),3.71-4.05(2H,m),5.01(1H,m),4.87(2H,s),6.68(1H,J=5.0HZ),6.92(2H,m)
Embodiment 9
Preparation (the R of formula Ic compound
1for methyl, R
2for THP trtrahydropyranyl)
2.25g Dess-Martin oxygenant is dissolved in to 210ml methylene dichloride, is cooled to 10 ℃, drip 60ml containing the dichloromethane solution of the formula Ib compound of preparation in 3.26g embodiment 7, rise to stirring at room 1h.Add 460ml to contain 1.04gNa
2s
2o
3and 0.55gNaHCO
3the aqueous solution, stir 15min, solution becomes clarification, layering, water layer, through 200ml methyl chloride extraction 2 times, merges organic layer, anhydrous sodium sulfate drying, the concentrated yellow oil that to obtain, after column chromatography purification 2.51g, yield: 100%.This step reaction product can not purified next step reaction of input.
TLC-R
f(normal hexane: ethyl acetate 5:1)=0.6
MS:413.3[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm)：1.63-2.78(16H,m),3.42(3H,s),3.51(1H,m),3.70-4.05(4H,m),5.06(1H,m),4.90(1H,m),6.70(1H,J=5.3HZ),6.89(2H,m),9.87(1H,s)
Embodiment 10
Preparation (the R of formula Id compound
1for methyl, R
2for THP trtrahydropyranyl)
0.35gNaH is dissolved in to 200ml methylene dichloride, be cooled to 10 ℃, drip 180ml containing the dichloromethane solution of 0.22g formula X compound, 10-15 ℃ is stirred 1h, again mixed solution is cooled to-10 ℃, the 2.31g formula Ic compound of preparation in embodiment 9 is dissolved in to 200ml methylene dichloride, this solution is slowly dripped in above-mentioned mixed solution, drip and finish, stirring at room 1h.The citric acid solution that adds 100ml 10% under ice bath, add again 150ml water, stir layering, water layer is through 150ml methyl chloride extraction 2 times, and combined dichloromethane layer, successively through 200ml water and the washing of 200ml sodium chloride solution, anhydrous sodium sulfate drying, concentrate to obtain yellow oily liquid, column chromatography purification obtains 2.83g, yield: 96.3%.
TLC-R
f(normal hexane: ethyl acetate 3:1)=0.6
MS:517.5[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm)：1.21(3H,s),1.63-3.02(21H,m),3.59(3H,s),3.68(2H,m),3.72-3.89(1H,m),4.92(1H,m),5.03(1H,q,5.8Hz),5.23-5.26(1H,m),6.25(1H,dd,J=15.2HZ),6.73(1H,t,J=7.1HZ),6.85(1H,dd,J=15.2HZ，8.7Hz),6.99(1H,d,J=7.1HZ),7.04(1H,d,J=7.1HZ)
Embodiment 11
Preparation (the R of formula III compound
1for methyl)
The formula Id compound room temperature that 2.00g embodiment 10 is prepared is dissolved in 25ml methyl alcohol, adds 0.05ml10% (mass percent) the HCl aqueous solution, and temperature control, at 30 ℃, stirs 2h.Add sodium bicarbonate powder 1g, stir 10min, add 10ml water, through 15ml ethyl acetate extraction 4 times, the washing of 20ml saturated nacl aqueous solution, after anhydrous sodium sulfate drying, filtering and concentrating, obtains yellow solid, and the further purifying of this step reaction, obtains white solid.
Yield: 1.59g (89%)
TLC-R
f(normal hexane: ethyl acetate 3:1)=0.3
MS:433.2[M+Na]
+
1H-NMR(400MHz,CDCl
3),δH(ppm)：1.20(3H,s),1.62-3.03(16H,m),3.57(3H,s),3.68(1H,m),3.72-3.78(1H,m),5.12(1H,m),6.25(1H,dd,J=15.1HZ),6.73(1H,t,J=7.4HZ),6.85(1H,dd,J=15.1HZ，8.3Hz),6.99(1H,d,J=7.4HZ),7.04(1H,d,J=7.4HZ)
Embodiment 12
Preparation (the R of formula III compound
1for methyl)
Formula Id compound room temperature prepared in 1.03g embodiment 10 is dissolved in 10ml acetic acid, 3.5ml water and 3.5ml tetrahydrofuran (THF), is heated to 60 ℃, reaction 6h.Decompression, by the basic evaporate to dryness of solvent, adds 15ml water, 15ml ethyl acetate extraction 2 times, and ethyl acetate layer is through 250ml saturated sodium bicarbonate washing 2 times, through saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrated, obtain yellow solid, the further purifying of this step reaction, obtains white solid.
Yield: 0.82g (95.6%).
Embodiment 13
Preparation (the R of formula IV compound
1for methyl)
In 100ml four-necked bottle, formula III compound prepared in 1.02g embodiment 11 and 1.03g seven water cerous chlorates are dissolved in to 50ml methyl alcohol, under room temperature, slowly add 0.12g SODIUM BOROHYDRIDE POWDER, stir 30min, add 6ml saturated sodium bicarbonate solution, filter, steam except methyl alcohol, through column chromatography, obtain target product.
Yield: 0.48g (47.1%)
TLC-R
f(normal hexane: ethyl acetate 1:1)=0.2
MS:435.4[M+Na]
+
H-NMR(400MHz,CDCl
3),δH(ppm)：1.21(3H,s),1.60-3.01(16H,m),3.52(3H,s),3.62(1H,m),3.71-3.78(1H,m),4.88(2H,b,OH),5.11(1H,m),6.20(1H,dd,J=15.1HZ),6.74(1H,t,J=7.4HZ),6.81(1H,dd,J=15.1HZ，8.3Hz),6.94(1H,d,J=7.4HZ),7.02(1H,d,J=7.4HZ)
Embodiment 14
The preparation of beraprost sodium
100ml four-necked bottle, drops into the prepared formula IV compound of 0.45g embodiment 13, splashes into 2N sodium hydroxide solution 5ml under cooling, and stirring at room is to reacting completely.Methyl alcohol is steamed and removed, then it is soluble in water, through 1mol/LHCl, regulate pH to 4, by the about 50ml extraction of ethyl acetate 2 times, merge concentrated organic layer, add the about 5ml of NaOH of 1mol/L, room temperature reaction is to completely, concentrated, obtains the about 0.62g of sterling of beraprost sodium.Through HPLC, detect, purity is 99.5%.
Yield: 0.44g (95.6%)
MS：443.4[M+Na]
+
1H-NMR(400MHz,DMSO-d
6),δH(ppm)：0.91,0.93(3H,d,J=6.2HZ),1.73-1.82(7H,m),1.85(2H,t,J=7.2HZ),1.90(1H,m),2.14(1H,q,J=8.6HZ),2.23(1H,m),2.41(2H,t,J=7.2HZ),2.48(1H,m),3.37(1H,t,J=8.6HZ),3.70(1H,td,J=8.6,6.0HZ),3.82,3.94(1H,t,J=6.5,6.0HZ),4.82(2H,b,OH),5.01(1H,dt,J=8.5,6.5HZ),5.45,5.49(1H,dd,J=15.5,6.2HZ),5.62,5.65(1H,dd,J=15.3,8.5HZ),6.72(1H,m,),6.91(2H,m)。
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.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 (14)
1. a formula I compound, is characterized in that, structure is shown below,
In formula, R
1for methyl or ethyl;
R
2for H, C
1-4alkoxyalkyl or THP trtrahydropyranyl;
R is siloxy ,-the CHO ,-CH that trialkyl replaces
2oH or
2. compound as claimed in claim 1, is characterized in that, the siloxy that described trialkyl replaces is the siloxy that trialkyl that an alkyl is the tertiary butyl replaces.
3. compound as claimed in claim 2, is characterized in that, the siloxy that described trialkyl replaces is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
4. compound as claimed in claim 1, is characterized in that, described formula I compound is:
In various, R
1for methyl or ethyl;
R
2for methoxyl methyl, ethoxyethyl group or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl.
5. compound as claimed in claim 4, is characterized in that, the siloxy that described trialkyl replaces is the siloxy that trialkyl that an alkyl is the tertiary butyl replaces.
6. compound as claimed in claim 5, is characterized in that, the siloxy that described trialkyl replaces is tert-butyl diphenyl siloxy or tertiary butyl dimethyl Si base.
7. compound as claimed in claim 4, is characterized in that, R
1for methyl; R
2for THP trtrahydropyranyl.
8. a preparation method for formula I compound, is characterized in that, comprises the following steps:
(a) take formula II compound is raw material, the hydroxyl of formula II compound is protected to the formula I compound of structure shown in production Ia; And optionally
(b) formula Ia compound is sloughed protecting group R ', obtains the formula I compound of structure shown in formula Ib; And optionally
(c) formula Ib compound, through oxidation, obtains the formula I compound of structure shown in formula Ic; And optionally
(d) formula Ic compound reacts with the phosphoric acid ester shown in formula X, obtains the formula I compound of structure shown in formula Id,
In formula, Ri, Rii are independently selected from C
1-4alkyl;
During above-mentioned reaction scheme is various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl;
The siloxy that R ' replaces for trialkyl.
9. preparation method as claimed in claim 8, is characterized in that, R
1for methyl or ethyl; R
2for methoxyl methyl, ethoxyethyl or THP trtrahydropyranyl; R ' is tertiary butyl dimethyl Si base or tert-butyl diphenyl siloxy.
10. preparation method as claimed in claim 9, is characterized in that, R
1for methyl; R
2for THP trtrahydropyranyl.
The purposes of 11. formula I compounds as described in as arbitrary in claim 1-7, is characterized in that, for the preparation of beraprost sodium or its intermediate.
The preparation method of 12. 1 kinds of beraprost sodiums, is characterized in that, comprises step:
(a) formula Id compound is removed to R
2group, obtains the beraprost sodium intermediate of structure shown in formula III;
(b) formula III compound obtains the beraprost sodium intermediate of structure shown in formula IV through reductive agent reduction;
(c) formula IV compound obtains described beraprost sodium through alkaline condition hydrolysis;
In various, R
1for methyl or ethyl;
R
2for C
1-4alkoxyalkyl or THP trtrahydropyranyl.
13. preparation methods as claimed in claim 12, is characterized in that R
2for methoxyl methyl, ethoxyethyl group or THP trtrahydropyranyl.
14. preparation methods as claimed in claim 12, is characterized in that, described reductive agent is sodium borohydride/seven water cerous chlorate reductive agent; Or diisobutyl aluminium hydride reductive agent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108463457A (en) * | 2015-08-12 | 2018-08-28 | 联合治疗学有限公司 | The method for preparing beraprost |
| CN111116530A (en) * | 2019-11-23 | 2020-05-08 | 济南康和医药科技有限公司 | Method for synthesizing beraprost |
| CN113493430A (en) * | 2020-03-19 | 2021-10-12 | 上海时莱生物技术有限公司 | Intermediate of beraprost and salt thereof and preparation method thereof |
| CN114957326A (en) * | 2022-06-28 | 2022-08-30 | 吉尔多肽生物制药(大连市)有限公司 | Synthesis method of beraprost sodium phosphine ylide intermediate |
| WO2023276983A1 (en) * | 2021-06-28 | 2023-01-05 | 大内新興化学工業株式会社 | Synthesis intermediate for beraprost or optically active form thereof, and method for producing same |
| CN115872962A (en) * | 2023-01-06 | 2023-03-31 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
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| CN108463457A (en) * | 2015-08-12 | 2018-08-28 | 联合治疗学有限公司 | The method for preparing beraprost |
| CN108463457B (en) * | 2015-08-12 | 2019-06-28 | 联合治疗学有限公司 | The method for preparing beraprost |
| CN111116530A (en) * | 2019-11-23 | 2020-05-08 | 济南康和医药科技有限公司 | Method for synthesizing beraprost |
| CN113493430A (en) * | 2020-03-19 | 2021-10-12 | 上海时莱生物技术有限公司 | Intermediate of beraprost and salt thereof and preparation method thereof |
| WO2023276983A1 (en) * | 2021-06-28 | 2023-01-05 | 大内新興化学工業株式会社 | Synthesis intermediate for beraprost or optically active form thereof, and method for producing same |
| CN114957326A (en) * | 2022-06-28 | 2022-08-30 | 吉尔多肽生物制药(大连市)有限公司 | Synthesis method of beraprost sodium phosphine ylide intermediate |
| CN115872962A (en) * | 2023-01-06 | 2023-03-31 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
| CN115872962B (en) * | 2023-01-06 | 2023-04-28 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
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