CN107325122A - Prepare new intermediate of beraprost and preparation method thereof - Google Patents
Prepare new intermediate of beraprost and preparation method thereof Download PDFInfo
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- CN107325122A CN107325122A CN201710012228.6A CN201710012228A CN107325122A CN 107325122 A CN107325122 A CN 107325122A CN 201710012228 A CN201710012228 A CN 201710012228A CN 107325122 A CN107325122 A CN 107325122A
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- 0 CCCN(*)C[C@@](C(C*)O)C1C(C)C(CC(CCC*)=CC)OC1 Chemical compound CCCN(*)C[C@@](C(C*)O)C1C(C)C(CC(CCC*)=CC)OC1 0.000 description 13
- FAWVBUMPRVURFJ-UHFFFAOYSA-N C=CCNc(c(Br)ccc1)c1C(C(C1)=O)=CC1O Chemical compound C=CCNc(c(Br)ccc1)c1C(C(C1)=O)=CC1O FAWVBUMPRVURFJ-UHFFFAOYSA-N 0.000 description 1
- KJMKOIAHBIUMOZ-VWBXGBJLSA-N CC(CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1OC(c1ccccc1)=O)O Chemical compound CC(CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1OC(c1ccccc1)=O)O KJMKOIAHBIUMOZ-VWBXGBJLSA-N 0.000 description 1
- NLHGQDYZKFXUTA-FHLARSPXSA-N CC(O)OC[C@@H]1[C@H]2c(cc(cc3Br)Br)c3O[C@H]2CC1 Chemical compound CC(O)OC[C@@H]1[C@H]2c(cc(cc3Br)Br)c3O[C@H]2CC1 NLHGQDYZKFXUTA-FHLARSPXSA-N 0.000 description 1
- PWICBAIESJWBCS-JCOFBHIZSA-N CC(OC[C@@H]1[C@H]2c3cc(Br)cc(Br)c3O[C@H]2CC1)=O Chemical compound CC(OC[C@@H]1[C@H]2c3cc(Br)cc(Br)c3O[C@H]2CC1)=O PWICBAIESJWBCS-JCOFBHIZSA-N 0.000 description 1
- XZEBLFSWEFWAQM-AGRKJWEESA-N CC(O[C@@H]1C2)O[C@H]3[C@]12[C@H]1C(C=CCC2CCCC(O)=O)=C2O[C@H]1C3 Chemical compound CC(O[C@@H]1C2)O[C@H]3[C@]12[C@H]1C(C=CCC2CCCC(O)=O)=C2O[C@H]1C3 XZEBLFSWEFWAQM-AGRKJWEESA-N 0.000 description 1
- DWLHYKVIAPGXIJ-SUMVWBOSSA-O C[C@H](C(C)[SH+]C[C@@H]1[C@H]2c(cccc3Br)c3O[C@H]2CC1)c1ccccc1 Chemical compound C[C@H](C(C)[SH+]C[C@@H]1[C@H]2c(cccc3Br)c3O[C@H]2CC1)c1ccccc1 DWLHYKVIAPGXIJ-SUMVWBOSSA-O 0.000 description 1
- ZISUALSZTAEPJH-UHFFFAOYSA-N C[SiH](C)c1ccccc1 Chemical compound C[SiH](C)c1ccccc1 ZISUALSZTAEPJH-UHFFFAOYSA-N 0.000 description 1
- FNVUXGHSLWMLKI-DADVEIPYSA-N OC[C@@H]1[C@H]2c(cc(cc3Br)Br)c3O[C@H]2CC1 Chemical compound OC[C@@H]1[C@H]2c(cc(cc3Br)Br)c3O[C@H]2CC1 FNVUXGHSLWMLKI-DADVEIPYSA-N 0.000 description 1
- FCJFLHNBEPKCFG-XBFCOCLRSA-O O[C@H]1C=C(C2CC2)[C@@H](C[SH2+])[C@@H]1c(cccc1Br)c1O Chemical compound O[C@H]1C=C(C2CC2)[C@@H](C[SH2+])[C@@H]1c(cccc1Br)c1O FCJFLHNBEPKCFG-XBFCOCLRSA-O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides compound and preparation method thereof shown in Formulas I.Compound shown in Formulas I is the intermediate that can be used for the structure for preparing beraprost brand-new.It can significantly shorten the synthesis step of prostaglandin using intermediate synthesis beraprost sodium, improve combined coefficient, production cost significantly reduced, so as to possess significant economic benefit and social value.
Description
Technical field
The present invention relates to the field of chemical synthesis.Specifically, the present invention relates to a kind of knot for being used to prepare beraprost
Brand-new intermediate of structure and its preparation method and application.
Background technology
Beraprost sodium can be by the prostanoid medicine (Prostacyclin that oral way is used
PGI2).Effect with antiplatelet and expansion blood vessel, is clinically widely used in treatment chronic lower limb obliteran.
Beraprost sodium structure is the racemic compound for including four kinds of stereoisomers.
Patent US5202447, JP59134787 and JP2003002885 describe beraprost sodium synthetic method (see
Route 1), this method is using cyclopentadiene as starting material, and synthesis step is more, and yield is extremely low.
Route 1：
Patent WO2004/005274 and JP07238046 describe another synthetic route (see route 2), and the route is with benzene
Phenol is starting material, by bromination, after bromopropene protection, with obtaining product through series reactions such as rearrangements after furans reaction, the mistake
Journey yield is high compared with route 1, but the yield of wherein Isosorbide-5-Nitrae-addition reaction is not high, and wherein needs to use the toxicity such as osmium tetroxide larger
Chemical substance carries out the fracture oxidation of double bond, the shortcomings of security protection of reaction pairing into personnel require high, there is operation inconvenience.
Route 2：
Therefore, this area need to develop a kind of low production cost, processing efficient, it is easy to operate, be adapted to industrialized production
Key intermediate compound, this intermediate can be applied to the synthetic route of beraprost sodium.
The content of the invention
It is an object of the invention to provide a kind of intermediate synthesized suitable for beraprost sodium.
Another object of the present invention is to provide the method that beraprost sodium is synthesized using the intermediate.
In a first aspect, the present invention provides the compound shown in Formulas I：
In formula, R1For silicon-based protecting group；Wherein R2And R3It is each independently the alkyl of 1~6 carbon atom；R4For pi-allyl
Or aryl.
In a particular embodiment, R1For t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate；R2
And R3Each stand alone as methyl or ethyl；R4For pi-allyl or phenyl.
In a particular embodiment, compound shown in Formulas I is with compound shown in following formula I a or Ib：
In formula, R1、R2、R3And R4As described above.
In second aspect, the present invention provides the preparation method of compound shown in Formulas I, for example following reaction process institute of methods described
Show：
In formula, R1、R2、R3And R4As described above.
In a particular embodiment, it the described method comprises the following steps：
Step 1：Formula III with halo is cuprous is formed in THF in -60 DEG C~-20 DEG C reactions after organic copper salt, then at -60
DEG C~-20 DEG C with Formula II react to obtain formula IV；
Step 2：Formula IV is dissolved in methanol, with four (triphenyl) phosphine palladiums removing acrylic protect, at -10 DEG C~0 DEG C with gold
Category hydride reduction obtains Formula V；
Step 3：Formula V is dissolved in THF, adds triphenylphosphine, and azo condensing agent is added in -50 DEG C~-20 DEG C, and in equality of temperature
Formula IV is reacted to obtain under degree；
Step 4：Bicyclic (3,3, the 1)-nonane (9-BBN) of 9- boron in -10 DEG C~10 DEG C with 3- methyl butyrates reaction after the completion of,
Add triphenylarsine, PdCl2(dppf)2, Formula IV, sodium methoxide, react to obtain Formulas I in 50 DEG C~60 DEG C.
In a particular embodiment,
In step 1, halo cuproine is protobromide ketone, cuprous iodide or stannous chloride, preferably cuprous iodide；
In step 2, metal hydride is lithium borohydride, potassium borohydride or sodium borohydride, preferably sodium borohydride；
In step 3, azo condensing agent is diethylazodicarboxylate, azodicarboxy dimethyl phthalate or azo-2-carboxylic acid two
Isopropyl ester, preferably diisopropyl azo-2-carboxylic acid.
In a preferred embodiment, the reaction temperature of step 1 is -40 DEG C~-30 DEG C.
In a preferred embodiment, the reaction temperature of step 2 is -5 DEG C~0 DEG C.
In a preferred embodiment, the reaction temperature of step 3 is -35 DEG C~-30 DEG C.
In the third aspect, the present invention provides the preparation method of compound shown in Formula VII, for example following reaction process of methods described
It is shown：
In a particular embodiment, methods described includes
Compound shown in Formulas I and BFEE are obtained into intermediate state in 50 DEG C~70 DEG C reactions in acetic acid solution,
Intermediate state is dissolved in methanol and THF mixed liquor, adds saleratus, potassium fluoride and 30% hydrogen peroxide, anti-in 50 DEG C~70 DEG C
Compound shown in deserved Formula VII.
In fourth aspect, the purposes of compound shown in the Formulas I described in present invention offer first aspect present invention, it is used to make
Standby beraprost sodium or its intermediate.
At the 5th aspect, the present invention provides a kind of preparation method of beraprost sodium, and methods described is using this hair
Compound shown in preparation of compounds of formula VII shown in Formulas I described in bright first aspect, is then prepared using compound shown in Formula VII
Beraprost sodium.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Embodiment
Inventor is by in-depth study extensively, it was unexpectedly found that a kind of brand-new intermediate of structure, utilizes this
Intermediate synthesis beraprost sodium can significantly shorten the synthesis step of prostaglandin, improve combined coefficient, significantly reduce life
Cost is produced, so as to possess significant economic benefit and social value.The present invention is completed on this basis.
Compound of the present invention and preparation method thereof
To realize the purpose of the present invention, the present invention provides the compound shown in Formulas I：
In formula, R1For silicon-based protecting group, such as t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triethyl group silicon substrate；
R2And R3Each stand alone as the alkyl of 1~6 carbon atom, such as methyl or ethyl；R4For pi-allyl or aryl, such as phenyl.
The structure and beraprost sodium structure of compound shown in Formulas I based on the present invention are comprising four kinds of alloisomerisms
The racemic compound of body, those skilled in the art should know that compound of formula I of the invention is a kind of racemic modification.For example,
In a particular embodiment, compound shown in Formulas I of the invention is to include stereoisomer Ia and Ib
In formula, R1、R2、R3And R4As described above.
Compound shown in the Formulas I of the present invention can be prepared by the following method：
Wherein, R1For t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or triethyl group silicon substrate, preferably tert-butyl group diformazan
Base silicon substrate；
R2And R3It is each independently methyl or ethyl, preferably R2And R3It is methyl；
R4For pi-allyl or phenyl, preferably phenyl.
It should be appreciated by those skilled in the art that compound shown in above-mentioned formula IV, Formula V, Formula IV, Formulas I is racemic modification.
In a particular embodiment, the synthetic method of compound of formula I of the invention includes：
Step 1：Under argon gas protection, formula III and halo are cuprous to be formed after organic copper salt in THF in -60 DEG C~-20 DEG C,
Formula II is added in -60 DEG C~-20 DEG C, formula IV is obtained through post processing after reaction completely.
Step 2：Under argon gas protection, formula IV is dissolved in methanol, at room temperature, adds four (triphenyl) phosphine palladiums reaction removing acrylic
It is post-treated to obtain Formula V in being added at -10 DEG C~0 DEG C after metal hydride reduction reaction completely after protection.
Step 3：Under argon gas protection, Formula V, which is dissolved in THF, to be added after triphenylphosphine, is cooled to -50 DEG C~-20 DEG C and is added occasionally
Nitrogen condensing agent, and after synthermal lower reaction completely, it is post-treated to obtain Formula IV.
Step 4：Under argon gas protection, added in THF after 9-BBN, be cooled to -10 DEG C~10 DEG C, add 3- methyl butyrates
THF solution, be warming up to after the completion of side chain reagent reacting, add triphenylarsine, PdCl2(dppf)2, the THF for continuously adding Formula IV is molten
Liquid, is added after sodium methoxide, is warming up to 50 DEG C~60 DEG C and is reacted 16-24 hours, and reaction is completely post-treated to obtain Formulas I.
In above step：
In step 1, halo cuproine is protobromide ketone, cuprous iodide or stannous chloride, because of cuprous iodide catalytic effect
Most preferably, thus it is preferred that cuprous iodide.- 60 DEG C~-20 DEG C, preferably -40 DEG C~-30 DEG C of reaction temperature.
In step 2, metal hydride is lithium borohydride, potassium borohydride, sodium borohydride.It is preferred that sodium borohydride
In step 3, azo condensing agent is that diethylazodicarboxylate, azodicarboxy dimethyl phthalate, azo-2-carboxylic acid two are different
Propyl ester, compares, preferably diisopropyl azo-2-carboxylic acid from the Activity and stabill of condensing agent.- 50 DEG C~-20 DEG C of reaction temperature,
It is preferred that -40 DEG C~-30 DEG C.
On the basis of compound shown in Formulas I in the present invention, the present invention further provides the synthesis of compound shown in Formula VII
Method, comprises the following steps：
The specific synthesis step of compound shown in Formula VII is：Compound shown in Formulas I is added in acetic acid solution and borontrifluoride
Borate ether obtains intermediate state in after 550 DEG C~70 DEG C reactions 12-24 hours by post processing, and intermediate state is dissolved in methanol and THF
Mixed liquor, adds saleratus, potassium fluoride and 30% hydrogen peroxide, and reaction solution is warming up into 50 DEG C~70 DEG C reacts 12-24 hours
Afterwards, it is post-treated to obtain Formula VII (racemic modification).
According to method of the prior art, such as patent US5202447, the patent document method, Ke Yili such as CN1680351
Beraprost sodium is obtained with compound synthesis shown in Formula VII.
Because the synthetic route of compound shown in the Formulas I of the present invention is simple, the cost for finally preparing beraprost sodium is big
For reduction.In a particular embodiment, the beraprost sodium cost that prepared by the inventive method is only the 60% of literature method.
Advantages of the present invention：
1. the present invention provides a kind of intermediate for being used to synthesize beraprost sodium of structure completely newly；
2. the synthesis step for synthesizing beraprost sodium using the intermediate is few；
3. the combined coefficient for synthesizing beraprost sodium using the intermediate is high；With
4. the production cost for synthesizing beraprost sodium using the intermediate is low.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.The reagent and raw material used in reaction are commercially available or can be according to existing
There is technology to prepare.
In the examples below, compound shown in Formula II can be closed according to prior art, such as JP07238046 methods describeds
Into.
Embodiment 1.
Formula IV：(±)-(2- acrylic epoxide -3- bromophenyls) -4- (t-Butyldimethylsilyl) epoxide -3- (2- propylene
Base dimethyl silicon substrate) methyl-cyclopentanone preparation
Under argon gas protection, addition THF (830.0ml) in dry reaction bottle, magnesium chips (24.3g, 1.0mol), iodine granule, plus
Enter a small amount of chloromethyl propylene base butyldimethylsilane to be stirred vigorously after illumination initiation reaction, keep reaction solution to flow back slightly, drip
Chlorination methylpropenyl base dimethylsilane (148.1g, 1.0mol), Formula II is obtained after being wholly absent to magnesium chips.Reaction solution cools
Added to -40 DEG C~-30 DEG C after the insulation 0.5 hour of -40 DEG C~-30 DEG C of cuprous iodide (41.3g, 0.217mol), be cooled to -80
DEG C~-75 DEG C, it is added dropwise after trim,ethylchlorosilane (121.0g, 0.98mol), continues that Formula II (83.3g, 0.197mol) is added dropwise
THF solution (85.0ml), -40 DEG C~-30 DEG C of heating is complete to reaction.Post processing：Saturated ammonium chloride is added in reaction solution molten
Liquid, adds methyl tertiary butyl ether(MTBE) and extracts three times, merge organic layer, washed successively with saturated sodium bicarbonate solution, saturated salt washing, point
Layer, organic layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure to obtain oily through silica gel chromatography
Compound (80.5g) shown in thing formula IV, yield 76%.
Embodiment 2-4：The cuprous screening experiment of halo (other conditions are with example 1)
| Inventory | Reducing agent | Yield | |
| Embodiment 2 | Formula III 17.3g, Formula II 8.3g | Protobromide ketone | 45% |
| Embodiment 3 | Formula III 17.3g, Formula II 8.3g | Cuprous cyanide | 52% |
| Embodiment 4 | Formula III 17.3g, Formula II 8.3g | Cuprous iodide | 73% |
By contrast and experiment it can be found that the effect of the cuprous use cuprous iodide of halo is much better than other halos Asias
Copper.
Embodiment 5.
Formula IV：(±)-(2- acrylic epoxide -3- bromophenyls) -4- (t-Butyldimethylsilyl) epoxide -3- (2- phenyl
Dimethyl silicon substrate) methyl-cyclopentanone preparation
Under argon gas protection, addition THF (1000.0ml) in dry reaction bottle, magnesium chips (29.2g, 1.20mol), iodine granule,
Add a small amount of chloromethyl phenyl dimethylsilane to be stirred vigorously after illumination initiation reaction, keep reaction solution to flow back slightly, chlorine is added dropwise
Aminomethyl phenyl dimethylsilane (232.0g, 1.20mol), formula III is obtained after being wholly absent to magnesium chips.Reaction solution is cooled to -40
DEG C~-30 DEG C add cuprous iodides -40 DEG C~-30 DEG C of (49.5g, 0.26mol) insulation 0.5 hour after, be cooled to -80 DEG C~-
75 DEG C, it is added dropwise after trim,ethylchlorosilane (121.0g, 0.98mol), the THF for continuing to be added dropwise Formula II (100.0g, 0.236mol) is molten
Liquid (100.0ml), -40 DEG C~-30 DEG C of heating is complete to reaction.Post processing：Saturated ammonium chloride solution is added in reaction solution, plus
Enter methyl tertiary butyl ether(MTBE) to extract three times, merge organic layer, washed successively with saturated sodium bicarbonate solution, saturated salt washing, layering has
Machine layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure to obtain grease formula IV through silica gel chromatography
Shown compound (112.5g), yield 83%.
1H-NMR(CDCl3)δ0.110-1.50(m,23H),δ2.010-2.052(d,1H),δ2.688-2.742(dd,
2H),δ3.239-3.362(dd,1H),δ3.820-3.834(m,1H),δ4.175-4.221(m,1H),δ4.465-4.508(m,
1H),δ5.077-5.106(d,1H),δ5.252-5.299(d,1H),δ5.997(m,1H),δ6.783-6.822(t,1H),δ
7.174-7.412(m,7H)。
MS(ES+)M+Na 597.09 C29H41BrO3Si2。
Embodiment 6-10. reaction temperatures screening experiment (other conditions are with example 5)
| Inventory | Reaction temperature | Yield | |
| Embodiment 6 | Formula III 17.3g, Formula II 8.3g | - 20 DEG C~-10 DEG C | 48% |
| Embodiment 7 | Formula III 17.3g, Formula II 8.3g | - 30 DEG C~-20 DEG C | 60% |
| Embodiment 8 | Formula III 17.3g, Formula II 8.3g | - 40 DEG C~-30 DEG C | 85% |
| Embodiment 9 | Formula III 17.3g, Formula II 8.3g | - 50 DEG C~-40 DEG C | 50% |
| Embodiment 10 | Formula III 17.3g, Formula II 8.3g | - 60 DEG C~-50 DEG C | 56% |
Found by contrast and experiment, be much better than other temperature in the effect reacted at -40 DEG C~-30 DEG C.
Embodiment 11.
Formula V：The bromo- 6- of (±) -2- [3- (t-Butyldimethylsilyl) epoxide -5- hydroxyls -2- (2- (acrylic dimethyl-silicons
Base) methyl)-cyclopenta] and-phenol preparation
Under argon gas protection, formula IV (64.5g, 0.12mol) is added in dry reaction bottle, methanol (685.0ml) is stirred molten
Solution, lucifuge adds four (triphenyl) phosphine palladiums (1.37g, 0.12mmol), after room temperature reaction completely.Reaction solution is cooled to -5 DEG C
~0 DEG C, sodium borohydride (7.1g, 0.15mol) is added portionwise, continues complete to TLC detection reactions in 10 DEG C~15 DEG C reactions.Afterwards
Processing：Saturated brine is added in reaction solution, methyl tertiary butyl ether(MTBE) is added and extracts three times, merge organic layer, wash, layering has
Machine layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure to obtain grease Formula V through silica gel chromatography
Shown compound (39.5g), yield 65.9%.
Embodiment 12.
Formula V：The bromo- 6- of (±) -2- [3- (t-Butyldimethylsilyl) epoxide -5- hydroxyls -2- (2- (pheiiyldimetliyl silicon
Base) methyl)-cyclopenta] and-phenol preparation
Under argon gas protection, formula IV (120.0g, 0.21mol) is added in dry reaction bottle, methanol (1200.0ml) is stirred molten
Solution, lucifuge, add four (triphenyl) phosphine palladiums (2.4g, 21.0mmol), room temperature reaction completely after, by reaction solution be cooled to -5 DEG C~
0 DEG C, sodium borohydride (9.9g, 0.26mol) is added portionwise, continues in 10 DEG C~15 DEG C reactions to TLC detections reaction completely, rear place
Reason, adds saturated brine in reaction solution, adds methyl tertiary butyl ether(MTBE) and extracts three times, merge organic layer, washes, and layering is organic
Layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure to obtain grease Formula V institute through silica gel chromatography
Show compound (79.5g), yield 71%.
1H-NMR(CDCl3)δ0.005-1.592(m,23H),δ1.942-1.972(m,2H),δ2.251-2.60(m,
1H),δ2.812-2.866(dd,1H),δ3.988-3.999(m,1H),δ4.011-4.292(m,1H),δ6.648-6.687(m,
1H),δ6.944-7.073(m,2H),δ7.238-7.455(m,7H)。
MS (ES+) M+Na 559.44, C26H39BrO3Si2。
Embodiment 13-17. reaction temperatures screening experiment (other conditions are with example 12)
| Inventory | Add NaBH4When reaction temperature | Yield | |
| Embodiment 13 | Formula IV 24.0g, NaBH41.98g | 5 DEG C~10 DEG C | 30% |
| Embodiment 14 | Formula IV 24.0g, NaBH41.98g | 0 DEG C~5 DEG C | 52% |
| Embodiment 15 | Formula IV 24.0g, NaBH41.98g | - 5 DEG C~0 DEG C | 70% |
| Embodiment 16 | Formula IV 24.0g, NaBH41.98g | - 10 DEG C~-5 DEG C | 62% |
| Embodiment 17 | Formula IV 24.0g, NaBH41.98g | - 15 DEG C~-10 DEG C | 52% |
Found by contrast and experiment, add NaBH4When reaction temperature be much better than in -5 DEG C~0 DEG C of effect it is other
Reaction temperature.
Embodiment 18-20. reducing agents screening experiment (other conditions are with example 12)
| Inventory | Reducing agent | Yield | |
| Embodiment 18 | Formula IV 24.0g, LiBH4 1.14g | Lithium borohydride | 44% |
| Embodiment 19 | Formula IV 24.0g, KBH4 2.81g | Potassium borohydride | 52% |
| Embodiment 20 | Formula IV 24.0g, NaBH4 1.98g | Sodium borohydride | 74% |
Found by contrast and experiment, reducing agent is much better than other reducing agents using the effect of sodium borohydride.
Embodiment 21.
Formula IV：(±)-[the bromo- 3- of 7- (2- (acrylic dimethyl silicon substrate) methyl) -2,3,3a, 8a- tetrahydrochysene -1H-8- oxygen
Miscellaneous-ring penta [a] indenyl -2- bases epoxide]-t-butyldimethyl silane preparation
Under argon gas protection, THF (600.0ml) is added in dry reaction bottle, Formula V (49.9g, 0.1mol) stirring and dissolving is added
Triphenylphosphine (27.5g, 0.105mol), is cooled to -35 DEG C~-30 DEG C, be added dropwise diisopropyl azo-2-carboxylic acid (21.3g,
THF (150.0ml) solution 0.105mol), continues complete to TLC detection reactions at -35 DEG C~-30 DEG C.Post processing：In reaction
Saturated ammonium chloride solution is added in liquid, is extracted three times with methyl tertiary butyl ether(MTBE), merges organic layer, washes successively, saturated salt washing,
Layering, organic layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure oily through silica gel chromatography
Compound (34.2g), yield 71% shown in shape thing Formula IV.
Embodiment 22-24. azo condensing agent reducing agent screening experiments (other conditions are with example 21)
| Inventory | Condensing agent | Yield | |
| Embodiment 22 | Formula V 25.0g condensing agents 9.2g | Diethylazodicarboxylate | 41% |
| Embodiment 23 | Formula V 25.0g condensing agents 7.7g | Azodicarboxy dimethyl phthalate | 50% |
| Embodiment 24 | Formula V 25.0g condensing agents 10.7g | Diisopropyl azo-2-carboxylic acid | 74% |
Found by contrast and experiment, condensing agent is much better than other condensations using the effect of diisopropyl azo-2-carboxylic acid
Agent.
Embodiment 25.
Formula IV：(±)-[the bromo- 3- of 7- (2- (pheiiyldimetliyl silicon substrate) methyl) -2,3,3a, 8a- tetrahydrochysene -1H-8- oxa-s -
Ring penta [a] indenyl -2- bases epoxide]-t-butyldimethyl silane preparation
Under argon gas protection, THF (600.0ml) is added in dry reaction bottle, Formula V (67.4g, 0.126mol) stirring and dissolving adds
Enter triphenylphosphine (34.6g, 0.132mol), be cooled to -35 DEG C~-30 DEG C.Dropwise addition diisopropyl azo-2-carboxylic acid (26.7g,
THF (150.0ml) solution 0.132mol), continues complete to TLC detection reactions at -35 DEG C~-30 DEG C.Post processing：In reaction
Saturated ammonium chloride solution is added in liquid, is extracted three times with methyl tertiary butyl ether(MTBE), merges organic layer, washes successively, saturated salt washing,
Layering, organic layer, which is dried, is concentrated to give grease, and grease collects target product, be concentrated under reduced pressure oily through silica gel chromatography
Compound (55.4g), yield 85% shown in shape thing Formula IV.
1H-NMR(CDCl3)δ0.275-0.868(m,23H),δ2.157-2.189(m,2H),δ2.20-2.30(m,1H),
δ3.570-3.591(dd,1H),δ3.904-3.912(d,1H),δ5.35-5.40(t,1H),δ6.566-6.604(t,1H),δ
6.759-6.777(d,1H),δ7.112-7.132(d,1H),δ7.373-7.394(t,3H),δ7.533-7.557(d,2H)。
MS (ES+) M+Na 541.18, C26H37BrO2Si2。
Embodiment 26-30. reaction temperatures screening experiment (other conditions are with example 25)
| Inventory | Reaction temperature | Yield | |
| Embodiment 26 | Formula V 25.0g condensing agents 10.7g | - 20 DEG C~-10 DEG C | 66% |
| Embodiment 27 | Formula V 25.0g condensing agents 10.7g | - 30 DEG C~-20 DEG C | 64% |
| Embodiment 28 | Formula V 25.0g condensing agents 10.7g | - 35 DEG C~-30 DEG C | 85% |
| Embodiment 29 | Formula V 25.0g condensing agents 10.7g | - 45 DEG C~-35 DEG C | 72% |
| Embodiment 30 | Formula V 25.0g condensing agents 10.7g | - 60 DEG C~-45 DEG C | 51% |
Found by contrast experiment, -35 DEG C~-30 DEG C effects of reaction temperature use are optimal.
Embodiment 31.
Formulas I：(±) -4- [2- (t-Butyldimethylsilyl) epoxides -3- (2- (t-Butyldimethylsilyl) methyl) -2,
3,3a, 8a- tetrahydrochysene -1H-8- oxa-s-ring penta [a] indenyl -7- bases]-methyl butyrate preparation
Under argon gas protection, the THF solution of bicyclic (3,3, the 1)-nonane (9-BBN) of 9- boron is added in dry reaction bottle
(300.0ml) (0.5mol/L), 0 DEG C~10 DEG C are cooled to by reaction solution.Anhydrous and oxygen-free operating condition is kept, 3-butenoic acid is added
THF (15.0ml) solution of methyl esters (15.1g, 0.15mol), is to slowly warm up to 25 DEG C~30 DEG C and reacts 2-3 hours.Add triphen
Arsine (3.06g, 0.01mol), PdCl2(dppf)2(2.93g, 4.0mmol), stirring, continuously adds Formula IV (48.2g, 0.1mmol)
THF (518.0ml) solution, sodium methoxide (8.1g, 0.15mol) is warming up to 50 DEG C~60 DEG C, reacts 10-12 hour, and TLC is examined
Survey reaction complete.Reaction solution is cooled to 0 DEG C~10 DEG C, added after methyl tertiary butyl ether(MTBE) dilution, saturated brine, stirring point is added
Layer, water layer is carried with a small amount of methyl tertiary butyl ether is counter, merges organic layer.Washing, saturated salt washing, organic layer anhydrous magnesium sulfate is dried,
Filtering, filtrate decompression is concentrated to give grease.Grease collects target product, be concentrated under reduced pressure to obtain oily through silica gel chromatography
Compound (34.1g) shown in thing Formulas I, yield 67.8%.
Embodiment 32.
Formulas I：(±) -4- [2- (t-Butyldimethylsilyl) epoxides -3- (2- (pheiiyldimetliyl silicon substrate) methyl) -2,3,
3a, 8a- tetrahydrochysene -1H-8- oxa-s-ring penta [a] indenyl -7- bases]-methyl butyrate preparation
Under argon gas protection, the THF solution of bicyclic (3,3, the 1)-nonane (9-BBN) of 9- boron is added in dry reaction bottle
(300.0ml) (0.5mol/L), 0 DEG C~10 DEG C are cooled to by reaction solution.Anhydrous and oxygen-free operating condition is kept, 3-butenoic acid is added
THF (15.0ml) solution of methyl esters (15.1g, 0.15mol).25 DEG C~30 DEG C are to slowly warm up to react 2-3 hours.Add triphen
Arsine (3.06g, 0.01mol), PdCl2(dppf)2(2.93g, 4.0mmol), stirring.Continuously add Formula IV (51.77g,
THF (518.0ml) solution 0.1mmol), sodium methoxide (8.1g, 0.15mol) is warming up to 50 DEG C~60 DEG C reaction 10-12 small
When, TLC detection reactions are complete.Reaction solution is cooled to 0 DEG C~10 DEG C, adds after methyl tertiary butyl ether(MTBE) dilution, adds saturated salt
Water, stirring layering, water layer is carried with a small amount of methyl tertiary butyl ether is counter, merges organic layer.Washing, saturated salt washing, the anhydrous sulphur of organic layer
Sour magnesium is dried, and filtering, filtrate decompression is concentrated to give grease.Grease collects target product through silica gel chromatography, depressurizes dense
Contract to obtain compound (43.6g) shown in grease Formulas I, yield 80.9%.
1H-NMR(CDCl3)δ0.306-1.240(m,23H),δ1.187-1.912(m,2H),δ2.027(d,1H),δ
2.231-2.242(m,2H),δ2.313-2.351(t,2H),δ2.453(m,1H),δ2.542(m,1H),δ3.488-3.509
(d,1H),δ3.644(s,3H),δ3.868-3.878(d,1H),δ6.617-6.654(t,1H),δ6.727-6.745(d,1H),
δ6.788-6.807(d,1H),δ7.362-7.385(m,3H),δ7.536-7.559(dm,2H)。
MS (ES+) M+Na 561.24, C31H46O4Si2。
Embodiment 33.
Formula VII：(±) -4- [2- hydroxyl -3- methylols -2,3,3a, 8a- tetrahydrochysene -1H-8- oxa-s-[a] indenyl of ring penta -7-
Base]-methyl butyrate preparation
By Formulas I (25.2g, 0.05mol), 46.5% boron trifluoride ether solution (43.8g, 0.3mol) is dissolved in acetic acid
In (163.0ml), agitating and heating is warming up to 50 DEG C~55 DEG C and reacted 20-24 hours, and TLC detection reactions are complete.It is cooled to room temperature,
Reaction solution is poured into frozen water and stirred 0.5 hour, adds after methyl tertiary butyl ether extraction completely, merges organic layer, unsaturated carbonate hydrogen
Sodium solution is washed till pH6-7, and layering, organic layer anhydrous magnesium sulfate is dried, filtering.Filtrate is concentrated to dryness to obtain grease, by grease
Be transferred in reaction bulb add saleratus (30.0g, 0.3mol), potassium fluoride (17.5g, 0.3mol), methanol (163.0ml) and
THF (163.0ml), after stirring mixing, adds 30% hydrogen peroxide (57.0g, 0.5mol), is warming up to 55 DEG C~60 DEG C reaction 4-6
After hour, TLC detection reactions are complete.Reaction solution is cooled to room temperature, sodium sulfite, which is added portionwise, is quenched hydrogen peroxide, filtered,
Filter cake a small amount of methyl tertiary butyl ether elution, merging filtrate is concentrated under reduced pressure to obtain grease, and grease collects mesh through silica gel chromatography
Product is marked, be concentrated under reduced pressure to obtain compound (7.4g) shown in white solid Formula VII, yield 48.3%.
Embodiment 34.
Formula VII：(±) -4- [2- hydroxyl -3- methylols -2,3,3a, 8a- tetrahydrochysene -1H-8- oxa-s-[a] indenyl of ring penta -7-
Base]-methyl butyrate preparation
By Formulas I (51.8g, 0.1mol), 46.5% boron trifluoride ether solution (87.5g, 0.6mol) is dissolved in acetic acid
In (326.0ml), agitating and heating is warming up to 50 DEG C~55 DEG C and reacted 20-24 hours, and TLC detection reactions are complete.It is cooled to room temperature,
Reaction solution is poured into frozen water and stirred 0.5 hour, adds after methyl tertiary butyl ether extraction completely, merges organic layer.Unsaturated carbonate hydrogen
Sodium solution is washed till pH6-7, and layering, organic layer anhydrous magnesium sulfate is dried, filtering.Filtrate is concentrated to dryness to obtain grease, by grease
Be transferred in reaction bulb add saleratus (60.1g, 0.6mol), potassium fluoride (34.9g, 0.6mol), methanol (326.0ml) and
THF (326.0ml), after stirring mixing, adds 30% hydrogen peroxide (113.4g, 1.0mol), is warming up to 55 DEG C~60 DEG C reaction 4-6
After hour, TLC detection reactions are complete.Reaction solution is cooled to room temperature, sodium sulfite, which is added portionwise, is quenched hydrogen peroxide, filtered,
Filter cake a small amount of methyl tertiary butyl ether elution, merging filtrate is concentrated under reduced pressure to obtain grease, and grease collects mesh through silica gel chromatography
Product is marked, be concentrated under reduced pressure to obtain compound (20.6g) shown in white solid Formula VII, yield 67.2%.
1H-NMR(CDCl3)δ1.254-2.340(m,7H),δ2.532-2.660(m,4H),δ3.382-3.422(t,
1H),δ3.646(s,3H),δ3.733-3.778(m,1H),δ3.913-3.952(t,1H),δ4.094(dd,1H),δ5.087-
5.139(dm,1H),δ6.762-6.800(t,1H),δ6.935-6.953(d,1H),δ7.009-7.027(d,1H)。
MS (ES+) M+Na 329.13, C17H22O5。
Embodiment 35.
Inventor is according to patent US5202447, and the patent document method such as CN1680351 is closed using compound shown in Formula VII
Into beraprost sodium, the yield of final beraprost sodium is 12%.
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. the compound shown in Formulas I：
In formula, R1For silicon-based protecting group；Wherein R2And R3It is each independently the alkyl of 1~6 carbon atom；R4For pi-allyl or virtue
Base.
2. compound as claimed in claim 1, it is characterised in that R1For t-Butyldimethylsilyl, tert-butyl diphenyl silicon
Base, triethyl group silicon substrate；R2And R3Each stand alone as methyl or ethyl；R4For pi-allyl or phenyl.
3. compound as claimed in claim 1 or 2, it is characterised in that compound shown in Formulas I is with change shown in following formula I a or Ib
Compound：
In formula, R1、R2、R3And R4As claimed in claim 1 or 2.
4. the preparation method of compound shown in Formulas I, methods described is as shown in following reaction process：
In formula, R1、R2、R3And R4As claimed in claim 1 or 2.
5. preparation method as claimed in claim 3, it is characterised in that the described method comprises the following steps：
Step 1：Formula III with halo is cuprous is formed in THF in -60 DEG C~-20 DEG C reactions after organic copper salt, then at -60 DEG C~-
20 DEG C are reacted to obtain formula IV with Formula II；
Step 2：Formula IV is dissolved in methanol, is protected with four (triphenyl) phosphine palladiums removing acrylic, in using metallic hydrogen at -10 DEG C~0 DEG C
Compound reduces to obtain Formula V；
Step 3：Formula V is dissolved in THF, adds triphenylphosphine, and azo condensing agent is added in -50 DEG C~-20 DEG C, and under synthermal
React to obtain Formula IV；
Step 4：Bicyclic (3,3, the 1)-nonane (9-BBN) of 9- boron is in -10 DEG C~10 DEG C with after the completion of the reaction of 3- methyl butyrates, adding
Triphenylarsine, PdCl2(dppf)2, Formula IV, sodium methoxide, react to obtain Formulas I in 50 DEG C~60 DEG C.
6. preparation method as claimed in claim 6, it is characterised in that
In step 1, halo cuproine is protobromide ketone, cuprous iodide or stannous chloride, preferably cuprous iodide；
In step 2, metal hydride is lithium borohydride, potassium borohydride or sodium borohydride, preferably sodium borohydride；
In step 3, azo condensing agent is diethylazodicarboxylate, azodicarboxy dimethyl phthalate or azo-2-carboxylic acid's diisopropyl
Ester, preferably diisopropyl azo-2-carboxylic acid.
7. the preparation method of compound shown in Formula VII, it is characterised in that methods described is as shown in following reaction process：
8. preparation method as claimed in claim 7, it is characterised in that methods described includes
Compound shown in Formulas I and BFEE are obtained into intermediate state in 50 DEG C~70 DEG C reactions in acetic acid solution, it is middle
State is dissolved in methanol and THF mixed liquor, is added saleratus, potassium fluoride and 30% hydrogen peroxide, is reacted in 50 DEG C~70 DEG C
Compound shown in Formula VII.
9. the purposes of compound shown in the Formulas I as described in claim any one of 1-3, it is characterised in that for preparing shellfish prostatitis
Parathyrine sodium or its intermediate.
10. a kind of preparation method of beraprost sodium, it is characterised in that methods described is any using claim 1-3
Compound shown in preparation of compounds of formula VII shown in Formulas I described in, then prepares shellfish prostate using compound shown in Formula VII
Plain sodium.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4474802A (en) * | 1982-01-20 | 1984-10-02 | Toray Industries, Inc. | 5,6,7-Trinor-4,8-inter-m-phenylene prostaglandin I2 derivatives useful in anti-ulcer, hypotensive and platelet aggregation inhibiting compositions |
| WO2004005274A1 (en) * | 2002-07-08 | 2004-01-15 | Johnson Matthey Public Limited Company | Benzoprostacyclin intermediates and methods for their preparation |
| CN100379746C (en) * | 2002-12-11 | 2008-04-09 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing the antiviral agent [1s-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one |
-
2017
- 2017-01-06 CN CN201710012228.6A patent/CN107325122B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4474802A (en) * | 1982-01-20 | 1984-10-02 | Toray Industries, Inc. | 5,6,7-Trinor-4,8-inter-m-phenylene prostaglandin I2 derivatives useful in anti-ulcer, hypotensive and platelet aggregation inhibiting compositions |
| WO2004005274A1 (en) * | 2002-07-08 | 2004-01-15 | Johnson Matthey Public Limited Company | Benzoprostacyclin intermediates and methods for their preparation |
| CN100379746C (en) * | 2002-12-11 | 2008-04-09 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing the antiviral agent [1s-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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