CN108503619A - The synthetic method of 1R, 2R, 3R- substituted cyclopentanone class compound - Google Patents
The synthetic method of 1R, 2R, 3R- substituted cyclopentanone class compound Download PDFInfo
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- CN108503619A CN108503619A CN201710099741.3A CN201710099741A CN108503619A CN 108503619 A CN108503619 A CN 108503619A CN 201710099741 A CN201710099741 A CN 201710099741A CN 108503619 A CN108503619 A CN 108503619A
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- compound
- synthetic method
- hours
- substituted cyclopentanone
- reaction
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 32
- -1 cyclopentanone class compound Chemical class 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 229940126214 compound 3 Drugs 0.000 claims abstract description 16
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 10
- 239000011737 fluorine Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 108010019160 Pancreatin Proteins 0.000 claims abstract description 8
- 229940055695 pancreatin Drugs 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 229940125782 compound 2 Drugs 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical class OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims 1
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 claims 1
- 229960002050 hydrofluoric acid Drugs 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 abstract description 8
- 229960000711 alprostadil Drugs 0.000 abstract description 8
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 abstract description 8
- OJZYRQPMEIEQFC-UAWLTFRCSA-N limaprost Chemical class CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(O)=O OJZYRQPMEIEQFC-UAWLTFRCSA-N 0.000 abstract description 6
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 abstract description 6
- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 0.000 abstract description 4
- 229960000345 lubiprostone Drugs 0.000 abstract description 4
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- 230000000694 effects Effects 0.000 abstract description 2
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- 150000001335 aliphatic alkanes Chemical class 0.000 abstract 1
- 238000010931 ester hydrolysis Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 18
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
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- 229910052786 argon Inorganic materials 0.000 description 3
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 3
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to a kind of 1R, 2R, the synthetic method of 3R substituted cyclopentanone class compounds includes the following steps：In organic solvent, compound 1 is reacted with halogenated alkane under the action of highly basic and cuprous salt, obtains compound 3, compound 3 pass through alkali or pancreatin effect carry out after ester hydrolysis again with fluorine reagent be deprotected to get.The synthetic method high income of the present invention, product purity is high, and cis-selectivity is good, reaction is easy to control, and post-processing is simple, is suitable for industrialized production, Alprostadil, Lubiprostone 1 and the Misoprostol and limaprost analog of high-purity can be synthesized in high yield.
Description
Technical field
The present invention relates to organic syntheses and medicinal chemistry art, more particularly to a kind of 1R, 2R, 3R- substituted cyclopentanone classes
The synthetic method of compound.
Background technology
Alprostadil also known as prostaglandin E1 are one kind in natural prostaglandins substance.Prostaglandin is present in greatly
In most mammalian tissues, basic structure is containing there are one 20 carbon fatty acids of pentamethylene and two aliphatic side chains.According to
The difference of position of double bond and substituent group can be divided into several types on pentamethylene, mainly there is four class such as E/F/A/B.Have not per one kind
Same hypotype has extensive biological effect.Wherein prostaglandin E1 has expansion blood vessel, improves microcirculation disorder, inhibits
Platelet aggregation, anti-tampon generates and the effect of artery sclerosis.In document J.Am.Chem.SOC.1988,110,4718-
The synthesis technology of Alprostadil, wherein mesosome 1R, the system of 2R- alkyl substitution -3R- alkoxy substituted cyclopentanones are described in 4126
Standby yield is very low, and cis-selectivity is relatively low, and product purity is not high, it is difficult to realize industrialization.
Invention content
Based on this, the present invention provides a kind of 1R, 2R, the new synthetic methods of 3R- substituted cyclopentanone class compounds, with this
The product yield that method is prepared is high, and purity is high, and cis-selectivity is good.
Specific technical solution is as follows：
A kind of 1R, 2R, the synthetic method of 3R- substituted cyclopentanone class compounds, include the following steps：
(1) in organic solvent, compound 1 is reacted with compound 2 under the action of highly basic and cuprous salt, obtains compound
3；
(2) in organic solvent, compound 3 is reacted under the action of alkali or pancreatin, obtains compound 4；
(3) in organic solvent, compound 4 is reacted with fluorine reagent, obtains compound 5 or compound 6, the compound 5
Or compound 6 is the 1R, 2R, 3R- substituted cyclopentanone class compounds；
The fluorine reagent is that hydrogen fluoride pyridine, hydrogen fluoride triethylamine, tetrabutyl ammonium fluoride (TBAF) or mass fraction are
The hydrofluoric acid of 10%-50%；
The compound 1, compound 2, compound 3, compound 4 and compound 5 are respectively provided with lower structure：
Wherein, R is selected from：C3H7,
R ' is selected from：C3H7,
Work as R ' to be selected fromWhen, the hydroxyl on cyclopentanone in the compound 5 can be with the carbonyl in R '
Base cyclization, obtains compound 6, the structural formula of the compound 6 is：
In wherein some embodiments, highly basic described in step (1) is n-BuLi, tert-butyl lithium, two silicon substrate of hexamethyl
Amido potassium (KHMDS) or bis- (trimethyl silicon substrate) lithium amide (LiHMDS)；And/or
Cuprous salt described in step (1) is cuprous cyanide, cuprous bromide, cuprous iodide or stannous chloride.
In wherein some embodiments, alkali described in step (2) is imidazoles, triethylamine, diisopropylethylamine, piperidines, two
Picoline, N-methylmorpholine, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, 1,4- bis-
Azabicyclic [2.2.2] octane (DABCO) or pyridine.
In wherein some embodiments, the time that compound 1 is reacted with compound 2 in step (1) is 2-20 hours, reaction
Temperature is -100 DEG C -0 DEG C；The reaction time of step (2) is 1-20 hours, and reaction temperature is -60 DEG C -50 DEG C；Step (3) it is anti-
It is 1-30 hours between seasonable, reaction temperature is 0 DEG C -50 DEG C.
In wherein some embodiments, the time that compound 1 is reacted with compound 2 in step (1) is 3-5 hours, reaction
Temperature is -80 DEG C~-60 DEG C；The reaction time of step (2) is 2-4 hours, and reaction temperature is 0 DEG C -40 DEG C；Step (3) it is anti-
It is 2-4 hours between seasonable, reaction temperature is 0 DEG C -10 DEG C.
In wherein some embodiments, the molar ratio of compound 1, compound 2 and cuprous salt is 1.0:1.0-5:1.0-5；
Compound 3 and the molar ratio of alkali are 1.0:0.1-5.0 or compound 3 and the molar ratio of pancreatin are 1.0:0.1-5.0；Compound 4
Molar ratio with fluorine reagent is 1.0:0.5-5.
In wherein some embodiments, the molar ratio of compound 1, compound 2 and cuprous salt is 1.0:1.5-2.5:1.5-
2.5；Compound 3 and the molar ratio of alkali are 1.0:0.2-0.4 or compound 3 and the molar ratio of pancreatin are 1.0:0.2-0.4；Change
The molar ratio for closing object 4 and fluorine reagent is 1.0:0.8-1.2.
In wherein some embodiments, the organic solvent is selected from dichloromethane, tetrahydrofuran, dimethylformamide, two
Methylacetamide, glycol dimethyl ether, 1,2- dichloroethanes, dimethyl sulfoxide (DMSO), toluene, methanol, ethyl alcohol, acetonitrile, petroleum ether, 2,
At least one of 2,2- trifluoroethanols, n-hexane, pentane and ether.
In wherein some embodiments, organic solvent described in step (1) be selected from tetrahydrofuran, n-hexane, pentane and
At least one of toluene；Organic solvent described in step (2) and step (3) is dichloromethane or toluene.
In wherein some embodiments, step (1) includes the following steps：
A, under inert gas protection, -80 DEG C~-60 DEG C will be cooled to added with the organic solvent of cuprous salt, highly basic is added dropwise
Solution stirs 1-3 hours, is warming up to 35 DEG C -40 DEG C and reacts 25-35 minutes, obtains the first reaction solution；
B, under -80 DEG C~-60 DEG C and inert gas shielding, strong base solution is added dropwise into the organic solution of compound 2,
Stirring 1-3 hours, then first reaction solution is added dropwise, it reacts 1-3 hours, then be warming up to 35 DEG C -40 DEG C and react 25-35 minutes,
It is cooled to -80 DEG C~-60 DEG C again, obtains the second reaction solution；
C, under -80 DEG C~-60 DEG C and inert gas shielding, strong base solution is added dropwise into the organic solution of compound 1,
Stirring 25-35 minutes, obtains third reaction solution, then the third reaction solution is added drop-wise in second reaction solution, at -80 DEG C
It is reacted 3-5 hours at~-60 DEG C.
The synthetic method of the 1R of the present invention, 2R, 3R- substituted cyclopentanone class compounds have with advantages and beneficial effects：
The present invention is by the reasonable selection to agents useful for same in each step, to the further excellent of reaction step and reaction condition
Change, obtain 1R, 2R, the new synthetic method of 3R- substituted cyclopentanone class compounds, which overcomes existing method receipts
Rate and cis-selectivity are relatively low, the not high disadvantage of product purity.The synthetic method intermediate of the present invention is stablized, and final product is received
Rate is high, and products obtained therefrom purity is high, and diastereoisomer is hardly generated in reaction process, and product can be easily separated, diastereomeric choosing
Selecting property height.
The synthetic method of the present invention, selects suitable cuprous salt reagent catalytic addition reaction, ester water is carried out with weak base or enzyme
Solution, then TBS is taken off with fluorine reagent, the method being deprotected by two steps keeps the product purity being prepared high, and impurity is few, diastereomeric
Isomers is few, and product is easily separated, is not necessarily to column chromatography for separation, reaction product can be obtained high-purity by simply recrystallizing
Sterling (99.9%HPLC) enormously simplifies the step of post-processing purified product, reduces solvent dosage, is suitable for industrial metaplasia
Production.
The synthetic method of the present invention, it is raw materials used to be easy to get, is cheap, is economic and environment-friendly, it is easy to operate, it reacts and is easy control
System has good industrial applications value.
Alprostadil, the Lubiprostone 1 of high-purity can be synthesized in high yield using the synthetic method of the present invention, and
Misoprostol and limaprost analog, and the de value height of product, wherein Misoprostol and limaprost analog
It can be used as intermediate and further synthesize Misoprostol and limaprost.
Specific implementation mode
Below in conjunction with specific embodiment to the 1R of the present invention, 2R, the synthetic methods of 3R- substituted cyclopentanone class compounds do into
The detailed elaboration of one step.
The 1R of the present invention, the synthetic route of 2R, 3R- substituted cyclopentanone class compounds are as follows：
R=C3H7；
R'=C3H7；
The synthesis of 1 prostaglandin E1 (compound 5b) of embodiment
(1) synthesis of compound 3b
Under protection of argon gas, cuprous iodide (0.50g, 5.65mmol) is added in a dry round-bottomed flask, is added
Enter tetrahydrofuran (3ml), be cooled to -78 DEG C, the hexane solution (4.2ml, 6.78mmol) of tert-butyl lithium is added dropwise, stirs
2h is slowly ramped to 40 DEG C and reacts 30 minutes, obtains the first reaction solution, for use.
Under -78 DEG C, argon gas protection, dripped into tetrahydrofuran (3ml) solution of compound 2b (2.08g, 5.65mmol)
The hexane solution (4.2ml, 6.78mmol) for adding n-BuLi stirs 2 hours at -78 DEG C；Then slowly by the first reaction solution
It is added drop-wise in reaction system, is reacted 2 hours at -78 DEG C, then be warming up to 40 DEG C and react 30 minutes, then be cooled to -78 DEG C, obtain second
Reaction solution, for use.
Under -78 DEG C, argon gas protection, uncle is added dropwise into tetrahydrofuran (3ml) solution of compound 1 (1g, 2.82mmol)
The pentane solution (1.9ml, 3.10mmol) of butyl lithium stirs 30 minutes at -78 DEG C, then it is slowly added drop-wise to second anti-
It answers in liquid, is reacted 4 hours at -78 DEG C, the reaction was complete for TLC detections, saturated ammonium chloride solution (5ml) is added, reaction is quenched, depressurize
Concentration removes solvent, and ethyl acetate (10ml), layering is added, and water phase is extracted with ethyl acetate (2*10ml), merges organic phase, is used
Saturated common salt washes (10ml), then is dried with anhydrous sodium sulfate, filters, and concentration, column chromatography obtains compound 3b (1.346g, yield
80%).1HNMR(CDCl3,400MHz):5.60 (dd, J=15.2and 5.2Hz, 1H), 5.51 (dd, J=15.6,7.6Hz,
1H), 4.13-4.01 (m, 2H), 3.66 (s, 3H), 2.61 (dd, J=18.4and 6.8Hz, 1H), 2.45 (m, 1H), 2.26
(t, J=7.6Hz, 2H), 2.2 (dd, J=18.4and 8.0Hz, 1H), 1.92 (m, 2H), 1.61-1.24 (m, 17H), 0.91
(m,21H),0.01(s,12H).MS(m/z):598(M+1).de>96%.
(2) synthesis of compound 4b
At 0 DEG C, into dichloromethane (3ml) solution of compound 3b (1g, 1.68mmol) be added dropwise pancreatin (0.3g,
3h 0.50mmol) is stirred at room temperature, is then concentrated under reduced pressure and removes solvent, ethyl acetate (10ml), layering, water phase second is added
Acetoacetic ester (2*10ml) extracts, and merges organic phase, washes (10ml) with saturated common salt, is dried with anhydrous sodium sulfate, is filtered, concentration
Obtain compound 4b (933mg, yield 93%).1HNMR(CDCl3,400MHz):5.60 (dd, J=15.2and 5.2Hz, 1H),
5.51 (dd, J=15.6,7.6Hz, 1H), 4.13-4.01 (m, 2H), 2.61 (dd, J=18.4and 6.8Hz, 1H), 2.45
(m, 1H), 2.26 (t, J=7.6Hz, 2H), 2.2 (dd, J=18.4and 8.0Hz, 1H), 1.92 (m, 2H), 1.61-1.24
(m,17H),0.91(m,21H),0.01(s,12H).MS(m/z):600(M+1).de>98%.
(3) synthesis of prostaglandin E1 (compound 5b)
At 0 DEG C, 65% hydrogen fluoride pyrrole is added dropwise into dichloromethane (10ml) solution of compound 4b (1g, 1.67mmol)
3h is stirred in pyridine (1mL, 1.67mmol), and the reaction was complete for TLC detections, and reaction is quenched with saturated sodium bicarbonate solution (10ml), depressurizes
Concentration removes acetonitrile, and ethyl acetate (10ml), layering is added, and water phase is extracted with ethyl acetate (2*10ml), merges organic phase, is used
Saturated common salt washes (10ml), then is dried with anhydrous sodium sulfate, filters, and concentration obtains compound 5b with recrystallize with dichloromethane
(525.6mg, yield 85%).1HNMR(DMSO,400MHz):5.55 (dd, J=12.4and 5.2Hz, 1H), 5.42 (dd, J
=12.6,5.6Hz, 1H), 4.26-4.13 (m, 2H), 2.65 (dd, J=15.2and 6.2Hz, 1H), 2.51 (m, 1H), 2.28
(t, J=7.4Hz, 2H), 2.2 (dd, J=15.4and 7.8Hz, 1H), 1.81 (m, 2H), 1.55-1.11 (m, 17H), 0.93
(m,3H).MS(m/z):371(M+1).Purity:99.9%, de>99%.
The synthesis of 2 limaprost analog (compound 5c) of embodiment
(1) synthesis of compound 3c
Replace the 2b in embodiment 1, synthetic method identical as (1) the step of embodiment 1 with 2c.Yield, 82%.1HNMR(CDCl3,400MHz):(5.68 dd, J=15.6and 5.2Hz, 1H), 5.55 (dd, J=15.6,7.6Hz, 1H),
4.15-4.05 (m, 2H), 3.68 (s, 3H), 2.65 (dd, J=18.4and 6.8Hz, 1H), 2.46 (m, 1H), 2.28 (t, J=
7.6Hz, 2H), 2.21 (dd, J=18.4and 8.0Hz, 1H), 1.93 (m, 2H), 1.63-1.26 (m, 17H), 0.91-0.89
(m,24H),0.01(s,12H).MS(m/z):642(M+1).de>96%.
(2) synthesis of compound 4c
Replace the 3b in embodiment 1, synthetic method identical as (2) the step of embodiment 1 with 3c.Yield, 95%.1HNMR(CDCl3,400MHz):5.67 (dd, J=15.6and 5.2Hz, 1H), 5.54 (dd, J=15.6,7.6Hz, 1H),
4.15-4.05 (m, 2H), 2.63 (dd, J=18.4and 6.8Hz, 1H), 2.45 (m, 1H), 2.27 (t, J=7.6Hz, 2H),
2.20 (dd, J=18.4and 8.0Hz, 1H), 1.92 (m, 2H), 1.62-1.26 (m, 17H), 0.91-0.89 (m, 24H),
0.01(s,12H).MS(m/z):628(M+1).de>96%.
(3) synthesis of limaprost analog (compound 5c)
Replace the 4b in embodiment 1, synthetic method identical as (3) the step of embodiment 1 with 4c.Yield, 90%.1HNMR(CDCl3,400MHz):5.60 (dd, J=15.2and 4.8Hz, 1H), 5.50 (dd, J=15.2,7.8Hz, 1H),
4.18-4.11 (m, 2H), 2.88 (dd, J=18.8and 6.2Hz, 1H), 2.43 (m, 1H), 2.20 (t, J=7.6Hz, 2H),
2.11 (dd, J=18.0and 8.0Hz, 1H), 1.88 (m, 2H), 1.61-1.22 (m, 17H), 0.92-0.82 (m, 6H).MS
(m/z):399(M+1).Purity:99.9%, de>99%.
The synthesis of 3 Misoprostol analog (compound 5d) of embodiment
(1) synthesis of compound 3d
Replace the 2b in embodiment 1, synthetic method identical as (1) the step of embodiment 1 with 2d.Yield, 82%.1HNMR(CDCl3,400MHz):5.58 (dd, J=15.0and 5.2Hz, 1H), 5.49 (dd, J=15.0,7.2Hz, 1H),
4.11-4.00 (m, 2H), 3.65 (s, 3H), 2.60 (dd, J=17.6and 6.8Hz, 1H), 2.43 (m, 1H), 2.24 (t, J=
7.6Hz, 2H), 2.18 (dd, J=17.6and 8.0Hz, 1H), 1.91 (m, 2H), 1.59-1.23 (m, 16H), 0.88-0.90
(m,24H),0.01(s,12H).MS(m/z):628(M+1).de>96%.
(2) synthesis of compound 4d
Replace the 3b in embodiment 1, synthetic method identical as (2) the step of embodiment 1 with 3d.Yield, 96%.1HNMR(CDCl3,400MHz):5.57 (dd, J=15.0and 5.2Hz, 1H), 5.48 (dd, J=15.0,7.2Hz, 1H),
4.10-4.00 (m, 2H), 2.60 (dd, J=17.6and 6.8Hz, 1H), 2.42 (m, 1H), 2.23 (t, J=7.6Hz, 2H),
2.17 (dd, J=17.6and 8.0Hz, 1H), 1.90 (m, 2H), 1.57-1.23 (m, 16H), 0.87-0.90 (m, 24H),
0.01(s,12H).MS(m/z):628(M+1).de>96%.
(3) synthesis of Misoprostol analog (compound 5d)
Replace the 4b in embodiment 1, synthetic method identical as (3) the step of embodiment 1 with 4d.Yield, 93%.1HNMR(CDCl3,400MHz):5.51 (dd, J=15.2and 5.2Hz, 1H), 5.32 (dd, J=15.2,7.6Hz, 1H),
4.13-4.04 (m, 2H), 2.65 (dd, J=17.2and 6.4Hz, 1H), 2.41 (m, 1H), 2.28 (t, J=8.0Hz, 2H),
2.11 (dd, J=17.2and 8.0Hz, 1H), 1.94 (m, 2H), 1.53-1.31 (m, 16H), 0.84-0.72 (m, 6H).MS
(m/z):385(M+1).Purity:99.9%, de>99%.
The synthesis of 4 Lubiprostone 1 of embodiment (compound 6)
(1) synthesis of compound 3e
Replace the 2b in embodiment 1, synthetic method identical as (1) the step of embodiment 1 with 2e.Yield, 83%.1HNMR(CDCl3,400MHz):4.16-4.08 (m, 2H), 3.66 (s, 3H), 2.62 (dd, J=18.4and 6.8Hz, 1H),
2.47 (m, 1H), 2.29 (t, J=7.8Hz, 2H), 2.23 (t, J=7.6Hz, 2H), 2.18 (dd, J=18.4and 8.0Hz,
1H),1.92(m,2H),1.59–1.21(m,17H),0.86-0.90(m,21H),0.01(s,12H)。MS(m/z):535(M+
1).de>96%.
(2) synthesis of compound 4e
Replace the 3b in embodiment 1, synthetic method identical as (2) the step of embodiment 1 with 3e.Yield, 97%.1HNMR(CDCl3,400MHz):4.15-4.08 (m, 2H), 2.61 (dd, J=18.4and 6.8Hz, 1H), 2.45 (m, 1H),
2.28 (t, J=7.8Hz, 2H), 2.23 (t, J=7.6Hz, 2H), 2.17 (dd, J=18.4and 8.0Hz, 1H), 1.91 (m,
2H),1.58–1.21(m,17H),0.85-0.90(m,21H),0.01(s,12H).MS(m/z):521(M+1).de>96%.
(3) synthesis of Lubiprostone 1 (compound 6)
At 0 DEG C, into acetonitrile (10ml) solution of compound 4e (1g, 1.92mmol), the hydrogen fluoride pyridine of dropwise addition 65% is molten
Liquid (1mL, 1.67mmol) stirs 3h, and the reaction was complete for TLC detections, and reaction is quenched with saturated sodium bicarbonate solution (10ml), depressurizes
Concentration removes acetonitrile, and ethyl acetate (10ml), layering is added, and water phase is extracted with ethyl acetate (2*10ml), merges organic phase, is used
Saturated common salt washes (10ml), then is dried with anhydrous sodium sulfate, filters, is dissolved in after concentration in 4mL isobutyl acetates, stirs
Dissolving, is cooled to 0 DEG C, and the normal heptane of 40mL is added dropwise, and stirs 2h, white solid is slowly precipitated, and filters, is dried under reduced pressure, obtains white
The compound 6 (682.4mg, 91%) of color solid.1HNMR(CDCl3,400MHz):10.8 (s, 1H), 3.36d, J=15.2and
5.2Hz,1H),2.61-2.45(m,5H),2.28(m,3H),1.91(m,6H),1.58–1.21(m,12H),0.85-0.90(m,
3H).MS(m/z):391(M+1).Purity:99.9%, de>99%.
Each technical characteristic of embodiment described above can be combined arbitrarily, to keep description succinct, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, it is all considered to be the range of this specification record.
Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention
Range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of 1R, 2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that include the following steps：
(1) in organic solvent, compound 1 is reacted with compound 2 under the action of highly basic and cuprous salt, obtains compound 3；
(2) in organic solvent, compound 3 is reacted under the action of alkali or pancreatin, obtains compound 4；
(3) in organic solvent, compound 4 is reacted with fluorine reagent, obtains compound 5 or compound 6, the compound 5 or change
Conjunction object 6 is the 1R, 2R, 3R- substituted cyclopentanone class compounds；
The fluorine reagent is the hydrogen that hydrogen fluoride pyridine, hydrogen fluoride triethylamine, tetrabutyl ammonium fluoride or mass fraction are 10%-50%
Fluoric acid；
The compound 1, compound 2, compound 3, compound 4 and compound 5 are respectively provided with lower structure：
Wherein, R is selected from：C3H7,
R ' is selected from：C3H7,
Work as R ' to be selected fromWhen, the hydroxyl on cyclopentanone in the compound 5 can with the carbonyl in R ' at
Ring, obtains compound 6, and the structural formula of the compound 6 is：
2. 1R according to claim 1,2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that step
Suddenly highly basic described in (1) is n-BuLi, tert-butyl lithium, potassium hexamethyldisilazide or bis- (trimethyl silicon substrate) lithium amides；
And/or
Cuprous salt described in step (1) is cuprous cyanide, cuprous bromide, cuprous iodide or stannous chloride.
3. 1R according to claim 1,2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that step
Suddenly alkali described in (2) be imidazoles, triethylamine, diisopropylethylamine, piperidines, lutidines, N-methylmorpholine, sodium hydroxide,
Lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, 1,4- diazabicylos [2.2.2] octane or pyridine.
4. according to the synthetic method of claim 1-3 any one of them 1R, 2R, 3R- substituted cyclopentanone class compound, feature
It is, the time that compound 1 is reacted with compound 2 in step (1) is 2-20 hours, and reaction temperature is -100 DEG C -0 DEG C；Step
(2) reaction time is 1-20 hours, and reaction temperature is -60 DEG C -50 DEG C；The reaction time of step (3) is 1-30 hours, reaction
Temperature is 0 DEG C -50 DEG C.
5. 1R according to claim 4,2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that step
Suddenly the time that compound 1 is reacted with compound 2 in (1) is 3-5 hours, and reaction temperature is -80 DEG C~-60 DEG C；Step (2) it is anti-
It is 2-4 hours between seasonable, reaction temperature is 0 DEG C -40 DEG C；The reaction time of step (3) be 2-4 hour, reaction temperature for 0 DEG C-
10℃。
6. according to the synthetic method of claim 1-3 any one of them 1R, 2R, 3R- substituted cyclopentanone class compound, feature
It is, the molar ratio of compound 1, compound 2 and cuprous salt is 1.0:1.0-5:1.0-5；Compound 3 and the molar ratio of alkali are
1.0:0.1-5.0 or compound 3 and the molar ratio of pancreatin are 1.0:0.1-5.0；Compound 4 and the molar ratio of fluorine reagent are
1.0:0.5-5。
7. 1R according to claim 6,2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that change
The molar ratio for closing object 1, compound 2 and cuprous salt is 1.0:1.5-2.5:1.5-2.5；Compound 3 and the molar ratio of alkali are 1.0:
0.2-0.4 or compound 3 and the molar ratio of pancreatin are 1.0:0.2-0.4；Compound 4 and the molar ratio of fluorine reagent are 1.0:
0.8-1.2。
8. according to the synthetic method of claim 1-3 any one of them 1R, 2R, 3R- substituted cyclopentanone class compound, feature
It is, the organic solvent is selected from dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetylamide, glycol dinitrate
Ether, 1,2- dichloroethanes, dimethyl sulfoxide (DMSO), toluene, methanol, ethyl alcohol, acetonitrile, petroleum ether, 2,2,2- trifluoroethanols, n-hexane,
At least one of pentane and ether.
9. 1R according to claim 8,2R, the synthetic method of 3R- substituted cyclopentanone class compounds, which is characterized in that step
Suddenly organic solvent described in (1) is selected from least one of tetrahydrofuran, n-hexane, pentane and toluene；Step (2) and step
(3) organic solvent described in is dichloromethane or toluene.
10. special according to the synthetic method of claim 1-3 any one of them 1R, 2R, 3R- substituted cyclopentanone class compound
Sign is that step (1) includes the following steps：
A, under inert gas protection, -80 DEG C~-60 DEG C will be cooled to added with the organic solvent of cuprous salt, strong base solution are added dropwise,
Stirring 1-3 hours is warming up to 35 DEG C -40 DEG C and reacts 25-35 minutes, obtains the first reaction solution；
B, under -80 DEG C~-60 DEG C and inert gas shielding, strong base solution is added dropwise into the organic solution of compound 2, stirs
1-3 hours, then first reaction solution is added dropwise, it reacts 1-3 hours, then be warming up to 35 DEG C -40 DEG C and react 25-35 minutes, then drop
Temperature obtains the second reaction solution to -80 DEG C~-60 DEG C；
C, under -80 DEG C~-60 DEG C and inert gas shielding, strong base solution is added dropwise into the organic solution of compound 1, stirs
25-35 minutes, third reaction solution is obtained, then the third reaction solution is added drop-wise in second reaction solution, -80 DEG C~-60
It is reacted 3-5 hours at DEG C.
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| US10253011B1 (en) * | 2018-07-13 | 2019-04-09 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
| CN111351867A (en) * | 2018-12-21 | 2020-06-30 | 南京正大天晴制药有限公司 | Analysis method for determining substances related to lubiprostone test sample |
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| CN102050771A (en) * | 2009-11-05 | 2011-05-11 | 沈阳万爱普利德医药科技有限公司 | Method for preparing prostaglandin derivative |
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| US10253011B1 (en) * | 2018-07-13 | 2019-04-09 | Chirogate International Inc. | Lubiprostone crystals and methods for preparing the same |
| CN111351867A (en) * | 2018-12-21 | 2020-06-30 | 南京正大天晴制药有限公司 | Analysis method for determining substances related to lubiprostone test sample |
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