CN107325122B - Novel intermediate for preparing prostaglandins and preparation method thereof - Google Patents
Novel intermediate for preparing prostaglandins and preparation method thereof Download PDFInfo
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- CN107325122B CN107325122B CN201710012228.6A CN201710012228A CN107325122B CN 107325122 B CN107325122 B CN 107325122B CN 201710012228 A CN201710012228 A CN 201710012228A CN 107325122 B CN107325122 B CN 107325122B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 10
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims description 64
- 239000000243 solution Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 239000012279 sodium borohydride Substances 0.000 claims description 17
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 11
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 10
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 10
- 229910052987 metal hydride Inorganic materials 0.000 claims description 7
- 150000004681 metal hydrides Chemical class 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012448 Lithium borohydride Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 235000003270 potassium fluoride Nutrition 0.000 claims description 5
- 239000011698 potassium fluoride Substances 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000001879 copper Chemical class 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 3
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 3
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 claims description 3
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 15
- 238000001816 cooling Methods 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000012295 chemical reaction liquid Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- -1 sodium prostaglandins Chemical class 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYGNJYLXDRROPN-UHFFFAOYSA-N [2-(4-phenylmethoxyphenyl)-1,3-thiazol-4-yl]methanamine Chemical compound NCC1=CSC(C=2C=CC(OCC=3C=CC=CC=3)=CC=2)=N1 FYGNJYLXDRROPN-UHFFFAOYSA-N 0.000 description 2
- RJCTVFQQNCNBHG-UHFFFAOYSA-N chloromethyl-dimethyl-phenylsilane Chemical compound ClC[Si](C)(C)C1=CC=CC=C1 RJCTVFQQNCNBHG-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical compound CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- DHOBOKVTKIYNEK-UHFFFAOYSA-N chloromethyl-dimethyl-prop-1-enylsilane Chemical compound CC=C[Si](C)(C)CCl DHOBOKVTKIYNEK-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- 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
-
- 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 Table
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides a compound shown as a formula I and a preparation method thereof. The compound shown in the formula I is a novel intermediate with a novel structure and can be used for preparing prostaglandins. The synthesis of the sodium prostacyclin by using the intermediate can obviously shorten the synthesis steps of prostaglandin, improve the synthesis efficiency and obviously reduce the production cost, thereby having obvious economic benefit and social value.
Description
Technical Field
The present invention relates to the field of chemical synthesis. In particular to an intermediate with a brand-new structure for preparing prostaglandins, a preparation method and application thereof.
Background
The sodium prostacyclin is prostanoid (prostacyclin PGI) capable of being administered orally2). Has the functions of resisting platelet and expanding blood vessels, and is widely used for treating chronic arterial occlusive diseases of lower limbs clinically.
The sodium structure of prostaglandins is a racemic compound containing four stereoisomers.
Patents US5202447, JP59134787 and JP2003002885 describe synthesis methods of sodium prostaglandins (see scheme 1) starting from cyclopentadiene, with many synthetic steps and very low yields.
Route 1:
patent WO2004/005274 and JP07238046 describe another synthetic route (see route 2) in which phenol is used as a starting material, and after bromination and bromopropene protection, the product is obtained by a series of reactions such as rearrangement after reaction with furan, and the yield of the process is higher than that of route 1, but the yield of 1, 4-addition reaction is not high, and in addition, chemical substances with high toxicity such as osmium tetroxide are used for carrying out double bond cleavage oxidation, and the reaction has the disadvantages of high safety protection requirements for synthesizers, inconvenient operation and the like.
Route 2:
therefore, there is a need in the art to develop a key intermediate compound which has low production cost, efficient process, convenient operation and suitability for industrial production, and the intermediate compound can be applied to the synthesis route of the sodium prostaglandins.
Disclosure of Invention
The invention aims to provide an intermediate suitable for synthesis of sodium prostacyclin.
Another object of the present invention is to provide a method for synthesizing sodium prostacyclin using the intermediate.
In a first aspect, the present invention provides a compound of formula I:
in the formula, R1Is a silicon protecting group; wherein R is2And R3Each independently is an alkyl group having 1 to 6 carbon atoms; r4Is allyl or aryl.
In a specific embodiment, R1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base and triethyl silicon base; r2And R3Each independently is methyl or ethyl; r4Is allyl or phenyl.
In a specific embodiment, the compound of formula I is a compound of formula Ia or Ib:
in the formula, R1、R2、R3And R4As described above.
In a second aspect, the present invention provides a process for the preparation of a compound of formula I, as shown in the following reaction scheme:
in the formula, R1、R2、R3And R4As described above.
In a specific embodiment, the method comprises the steps of:
step 1: reacting the formula III with halogenated cuprous in THF at-60 to-20 ℃ to form organic copper salt, and reacting with the formula II at-60 to-20 ℃ to obtain a formula IV;
step 2: dissolving the formula IV in methanol, removing propenyl protection by using palladium tetrakis (triphenyl) phosphine, and reducing by using metal hydride at the temperature of between 10 ℃ below zero and 0 ℃ to obtain a formula V;
and step 3: dissolving the formula V in THF, adding triphenylphosphine, adding an azo condensing agent at-50 to-20 ℃, and reacting at the same temperature to obtain a formula VI;
and 4, step 4: 9-boron bicyclo (3,3,1) -nonane (9-BBN) reacts with 3-methyl butyrate at the temperature of 10 ℃ below zero to 10 ℃, and triphenylarsine and PdCl are added2(dppf)2And formula VI, and sodium methoxide, reacting at 50-60 ℃ to obtain formula I.
In a particular embodiment of the present invention,
in the step 1, the halogenated cuprous reagent is bromized imino ketone, cuprous iodide or cuprous chloride, preferably cuprous iodide;
in step 2, the metal hydride is lithium borohydride, potassium borohydride or sodium borohydride, preferably sodium borohydride;
in step 3, the azo condensing agent is diethyl azodicarboxylate, dimethyl azodicarboxylate or diisopropyl azodicarboxylate, preferably diisopropyl azodicarboxylate.
In a preferred embodiment, the reaction temperature in step 1 is from-40 ℃ to-30 ℃.
In a preferred embodiment, the reaction temperature in step 2 is from-5 ℃ to 0 ℃.
In a preferred embodiment, the reaction temperature in step 3 is from-35 ℃ to-30 ℃.
In a third aspect, the present invention provides a process for the preparation of a compound of formula VII, said process being represented by the following reaction scheme:
in a specific embodiment, the method comprises
Reacting the compound shown in the formula I with boron trifluoride diethyl etherate at 50-70 ℃ in an acetic acid solution to obtain an intermediate state, dissolving the intermediate state in a mixed solution of methanol and THF, adding potassium bicarbonate, potassium fluoride and 30% hydrogen peroxide, and reacting at 50-70 ℃ to obtain the compound shown in the formula VII.
In a fourth aspect, the present invention provides the use of a compound of formula I according to the first aspect of the present invention for the preparation of sodium prostacyclin or an intermediate thereof.
In a fifth aspect, the present invention provides a method for preparing sodium prostacyclin, which comprises preparing a compound represented by formula VII using a compound represented by formula I according to the first aspect of the present invention, and then preparing sodium prostacyclin using a compound represented by formula VII.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor unexpectedly finds an intermediate with a brand-new structure through extensive and intensive research, and the synthesis of the sodium prostacyclin by using the intermediate can obviously shorten the synthesis step of the prostaglandin, improve the synthesis efficiency and obviously reduce the production cost, thereby having obvious economic benefit and social value. The present invention has been completed based on this finding.
Compounds of the invention and methods for their preparation
To achieve the object of the present invention, the present invention provides a compound represented by formula I:
in the formula, R1Is a silicon protecting group such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl; r2And R3Each independently an alkyl group of 1 to 6 carbon atoms, such as methyl or ethyl; r4Is allyl or aryl, for example phenyl.
Based on the fact that the structure of the compound of formula I of the present invention and the structure of sodium prostaglandins are racemic compounds comprising four stereoisomers, one skilled in the art would know that the compound of formula I of the present invention is a racemic compound. For example, in a particular embodiment, the compounds of formula I of the present invention include stereoisomers Ia and Ib
In the formula, R1、R2、R3And R4As described above.
The compound shown in the formula I can be prepared by the following method:
wherein R is1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base or triethyl silicon base, preferably tert-butyl dimethyl silicon base;
R2and R3Each independently being methyl or ethyl, preferably R2And R3Are both methyl;
R4is allyl or phenyl, preferably phenyl.
It will be appreciated by those skilled in the art that the compounds of formula IV, formula V, formula VI and formula I above are racemates.
In a specific embodiment, the method of synthesis of the compounds of formula I of the present invention comprises:
step 1: under the protection of argon, after organic copper salt is formed between the formula III and halogenated cuprous in THF at-60 ℃ to-20 ℃, the formula II is added at-60 ℃ to-20 ℃, and after complete reaction, the formula IV is obtained through post-treatment.
Step 2: dissolving formula IV in methanol under the protection of argon, adding palladium tetrakis (triphenyl) phosphine at room temperature to react and remove propenyl protection, adding metal hydride at-10-0 ℃ to completely reduce, and carrying out post-treatment to obtain formula V.
And step 3: dissolving the formula V in THF under the protection of argon, adding triphenylphosphine, cooling to-50-20 ℃, adding azo condensing agent, reacting completely at the same temperature, and post-treating to obtain the formula VI.
And 4, step 4: adding 9-BBN into THF under the protection of argon, cooling to-10 deg.C, adding 3-methyl butyrate THF solution, heating to side chain reagent, adding triphenylarsine and PdCl2(dppf)2And (3) continuing adding the THF solution of the formula VI, adding sodium methoxide, heating to 50-60 ℃ for reacting for 16-24 hours, and carrying out aftertreatment after complete reaction to obtain the formula I.
The method comprises the following steps:
in the step 1, the halogenated cuprous reagent is bromized imino ketone, cuprous iodide or cuprous chloride, and cuprous iodide is preferred because the catalytic effect of cuprous iodide is the best. The reaction temperature is-60 ℃ to-20 ℃, preferably-40 ℃ to-30 ℃.
In step 2, the metal hydride is lithium borohydride, potassium borohydride or sodium borohydride. Preference is given to sodium borohydride
In step 3, the azo condensing agent is diethyl azodicarboxylate, dimethyl azodicarboxylate or diisopropyl azodicarboxylate, and diisopropyl azodicarboxylate is preferable from the viewpoint of the activity and stability of the condensing agent. The reaction temperature is-50 ℃ to-20 ℃, preferably-40 ℃ to-30 ℃.
On the basis of the compound shown in the formula I, the invention further provides a synthesis method of the compound shown in the formula VII, which comprises the following steps:
the specific synthetic steps of the compound shown in the formula VII are as follows: adding a compound shown in formula I and boron trifluoride diethyl etherate into an acetic acid solution, reacting at 550-70 ℃ for 12-24 hours, carrying out post-treatment to obtain an intermediate state, dissolving the intermediate state into a mixed solution of methanol and THF, adding potassium bicarbonate, potassium fluoride and 30% hydrogen peroxide, heating the reaction solution to 50-70 ℃ for reacting for 12-24 hours, and carrying out post-treatment to obtain a racemate shown in formula VII.
Sodium prostaglandins can be synthesized from compounds of formula VII by methods known in the art, for example, in the patent documents US5202447, CN 1680351.
The compound shown in the formula I has a simple synthetic route, so that the cost for finally preparing the sodium prostacyclin is greatly reduced. In a specific embodiment, the sodium prostacyclin prepared by the method of the invention costs only 60% of the literature methods.
The invention has the advantages that:
1. the invention provides an intermediate with a brand-new structure for synthesizing sodium prostaglandins;
2. the synthesis steps of synthesizing the sodium prostacyclin by using the intermediate are few;
3. the synthesis efficiency of synthesizing the sodium prostacyclin by using the intermediate is high; and
4. the intermediate is used for synthesizing the sodium prostacyclin, and the production cost is low.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The reagents and starting materials used in the reaction are commercially available or can be prepared according to the prior art.
In the following examples, the compounds of formula II can be synthesized according to the prior art, for example as described in JP 07238046.
Example 1.
Formula IV: preparation of (+ -) - (2-propenyloxy-3-bromophenyl) -4- (tert-butyldimethylsilyl) oxy-3- (2-propenyldimethylsilyl) methyl-cyclopentanone
Under the protection of argon, THF (830.0ml), magnesium chips (24.3g, 1.0mol) and small iodine particles are added into a dry reaction bottle, a small amount of chloromethyl propenyl butyl dimethyl silane is added, the mixture is stirred vigorously and irradiated to initiate the reaction, slight reflux is kept on the reaction liquid, chloromethyl propenyl dimethyl silane (148.1g, 1.0mol) is added dropwise until the magnesium chips completely disappear, and the formula II is obtained. Cooling the reaction liquid to-40-30 ℃, adding cuprous iodide (41.3g, 0.217mol) and preserving the temperature at-40-30 ℃ for 0.5 h, cooling to-80-75 ℃, dropwise adding trimethylchlorosilane (121.0g, 0.98mol), continuously dropwise adding THF solution (85.0ml) of formula II (83.3g, 0.197mol), and heating to-40-30 ℃ until the reaction is complete. And (3) post-treatment: adding a saturated ammonium chloride solution into the reaction solution, adding methyl tert-butyl ether for extraction for three times, combining organic layers, washing with a saturated sodium bicarbonate solution, washing with saturated saline, layering, drying and concentrating the organic layer to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain an oily substance (80.5g) shown in formula IV, wherein the yield is 76%.
Examples 2 to 4: cuprous halide screening assay (otherwise conditions same as example 1)
| Feed amount | Reducing agent | Yield of | |
| Example 2 | Formula III17.3g, formula II 8.3g | Brominating imino ketone | 45％ |
| Example 3 | Formula III17.3g, formula II 8.3g | Cuprous cyanide | 52％ |
| Example 4 | Formula III17.3g, formula II 8.3g | Cuprous iodide | 73％ |
Compared with the experimental results, the effect of using cuprous iodide for halogenated cuprous is far better than that of other halogenated cuprous.
Example 5.
Formula IV: preparation of (+ -) - (2-propenyloxy-3-bromophenyl) -4- (tert-butyldimethylsilyl) oxy-3- (2-phenyldimethylsilyl) methyl-cyclopentanone
Under the protection of argon, THF (1000.0ml), magnesium chips (29.2g, 1.20mol) and small iodine particles are added into a dry reaction bottle, a small amount of chloromethyl phenyl dimethyl silane is added, the mixture is stirred vigorously and irradiated to initiate the reaction, the reaction liquid is kept refluxing slightly, chloromethyl phenyl dimethyl silane (232.0g, 1.20mol) is added dropwise until the magnesium chips completely disappear, and the formula III is obtained. Cooling the reaction liquid to-40-30 ℃, adding cuprous iodide (49.5g, 0.26mol) and preserving the temperature at-40-30 ℃ for 0.5 h, cooling to-80-75 ℃, dropwise adding trimethylchlorosilane (121.0g, 0.98mol), continuously dropwise adding a THF solution (100.0ml) of formula II (100.0g, 0.236mol), and heating to-40-30 ℃ until the reaction is complete. And (3) post-treatment: adding a saturated ammonium chloride solution into the reaction solution, adding methyl tert-butyl ether for extraction for three times, combining organic layers, washing with a saturated sodium bicarbonate solution, washing with saturated saline, layering, drying and concentrating the organic layer to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain an oily substance (112.5g) shown in formula IV, wherein the yield is 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),δ7.174-7.412(m,7H)。
MS(ES+)M+Na 597.09 C29H41BrO3Si2。
Examples 6-10 reaction temperature screening experiments (otherwise identical to example 5)
| Feed amount | Reaction temperature | Yield of | |
| Example 6 | Formula III17.3g, formula II 8.3g | -20℃～-10℃ | 48％ |
| Example 7 | Formula III17.3g, formula II 8.3g | -30℃～-20℃ | 60％ |
| Example 8 | Formula III17.3g, formula II 8.3g | -40℃～-30℃ | 85％ |
| Example 9 | Formula III17.3g, formula II 8.3g | -50℃～-40℃ | 50％ |
| Example 10 | Formula III17.3g, formula II 8.3g | -60℃～-50℃ | 56％ |
The results of comparative experiments show that the effect of the reaction at the temperature of between 40 ℃ below zero and 30 ℃ below zero is far better than that of other temperatures.
Example 11.
Formula V: preparation of (+ -) -2-bromo-6- [3- (tert-butyldimethylsilyl) oxy-5-hydroxy-2- (2- (propenyl-dimethylsilyl) methyl) -cyclopentyl ] -phenol
Under the protection of argon, formula IV (64.5g, 0.12mol) and methanol (685.0ml) were added to a dry reaction flask, stirred and dissolved, and then protected from light, tetrakis (triphenyl) phosphine palladium (1.37g, 0.12mmol) was added, and the reaction was completed at room temperature. The reaction solution is cooled to-5 ℃ to 0 ℃, sodium borohydride (7.1g, 0.15mol) is added in batches, and the reaction is continued at 10 ℃ to 15 ℃ until the TLC detection reaction is complete. And (3) post-treatment: adding saturated saline water into the reaction solution, adding methyl tert-butyl ether for extraction for three times, combining organic layers, washing, demixing, drying and concentrating the organic layer to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain a compound shown as the formula V (39.5g) as an oily substance with the yield of 65.9%.
Example 12.
Formula V: preparation of (+ -) -2-bromo-6- [3- (tert-butyldimethylsilyl) oxy-5-hydroxy-2- (2- (phenyldimethylsilyl) methyl) -cyclopentyl ] -phenol
Under the protection of argon, adding formula IV (120.0g, 0.21mol) and methanol (1200.0ml) into a dry reaction bottle, stirring for dissolving, keeping out of the sun, adding palladium tetrakis (triphenyl) phosphine (2.4g, 21.0mmol), after the reaction is completed at room temperature, cooling the reaction liquid to-5 ℃ -0 ℃, adding sodium borohydride (9.9g, 0.26mol) in batches, continuing to react at 10 ℃ -15 ℃ until the TLC detection reaction is completed, performing post-treatment, adding saturated saline into the reaction liquid, adding methyl tert-butyl ether for extraction three times, combining organic layers, washing with water, layering, drying and concentrating the organic layers to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain a compound shown in formula V (79.5g) with the yield of 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。
Examples 13-17 reaction temperature screening experiment (otherwise the same as example 12)
| Feed amount | Adding NaBH4Time reaction temperature | Yield of | |
| Example 13 | Formula IV24.0g, NaBH41.98g | 5℃～10℃ | 30％ |
| Example 14 | Formula IV24.0g, NaBH41.98g | 0℃～5℃ | 52％ |
| Example 15 | Formula IV24.0g, NaBH41.98g | -5℃～0℃ | 70％ |
| Example 16 | Formula IV24.0g, NaBH41.98g | -10℃～-5℃ | 62％ |
| Example 17 | Formula IV24.0g, NaBH41.98g | -15℃～-10℃ | 52％ |
Through comparison experiment results, the NaBH is added4The effect of the reaction temperature of-5 ℃ to 0 ℃ is far better than that of other reaction temperatures.
Examples 18 to 20 reducing agent screening test (otherwise, the same conditions as in example 12)
| Feed amount | Reducing agent | Yield of | |
| Example 18 | Formula IV24.0g, LiBH4 1.14g | Lithium borohydride | 44％ |
| Example 19 | Formula IV24.0g, KBH4 2.81g | Potassium borohydride | 52％ |
| Example 20 | Formula IV24.0g, NaBH4 1.98g | Sodium borohydride | 74％ |
The results of comparative experiments show that the effect of the reducing agent adopting sodium borohydride is far better than that of other reducing agents.
Example 21.
Formula VI: preparation of (+ -) - [ 7-bromo-3- (2- (propenyldimethylsilyl) methyl) -2,3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-2-yloxy ] -tert-butyldimethylsilane
THF (600.0ml) is added into a dry reaction bottle under the protection of argon, formula V (49.9g, 0.1mol) is stirred, dissolved and added with triphenylphosphine (27.5g, 0.105mol), the temperature is reduced to minus 35 ℃ to minus 30 ℃, a THF (150.0ml) solution of diisopropyl azodicarboxylate (21.3g, 0.105mol) is added dropwise, and the reaction is continued at minus 35 ℃ to minus 30 ℃ until TLC detection reaction is complete. And (3) post-treatment: adding a saturated ammonium chloride solution into the reaction solution, extracting three times by using methyl tert-butyl ether, combining organic layers, sequentially washing by water, washing by using saturated salt water, layering, drying and concentrating the organic layer to obtain an oily substance, purifying the oily substance by using a silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain an oily substance (34.2g) of the compound shown in the formula VI, wherein the yield is 71%.
Examples 22 to 24 screening experiment of azo condensing agent reducing agent (other conditions are the same as in example 21)
| Feed amount | Condensing agent | Yield of | |
| Example 22 | Formula V25.0 g condensing agent 9.2g | Azanedicarboxylic acid diethyl ester | 41％ |
| Example 23 | Formula V25.0 g condensing agent 7.7g | Azoic dicarboxylic acid dimethyl ester | 50％ |
| Example 24 | Formula V25.0 g condensing agent 10.7g | Diisopropyl azodicarboxylate | 74％ |
The results of comparative experiments show that the condensing agent adopts diisopropyl azodicarboxylate which has far better effect than other condensing agents.
Example 25.
Formula VI: preparation of (+ -) - [ 7-bromo-3- (2- (phenyldimethylsilyl) methyl) -2,3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-2-yloxy ] -tert-butyldimethylsilane
THF (600.0ml) was added to a dry reaction flask under argon protection, formula V (67.4g, 0.126mol) was stirred to dissolve triphenylphosphine (34.6g, 0.132mol), and the temperature was reduced to-35 ℃ to-30 ℃. Diisopropyl azodicarboxylate (26.7g, 0.132mol) in THF (150.0ml) was added dropwise and the reaction was continued at-35 ℃ to-30 ℃ until completion of TLC detection. And (3) post-treatment: adding a saturated ammonium chloride solution into the reaction solution, extracting for three times by using methyl tert-butyl ether, combining organic layers, sequentially washing by water, washing by using saturated salt water, layering, drying and concentrating the organic layer to obtain an oily substance, purifying the oily substance by using a silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain an oily substance (55.4g) of the compound shown in the formula VI, wherein the yield is 85%.
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),δ6.759-6.777(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。
Examples 26-30 reaction temperature screening experiments (otherwise identical to example 25)
| Feed amount | Reaction temperature | Yield of | |
| Example 26 | Formula V25.0 g condensing agent 10.7g | -20℃～-10℃ | 66％ |
| Example 27 | Formula V25.0 g condensing agent 10.7g | -30℃～-20℃ | 64％ |
| Example 28 | Formula V25.0 g condensing agent 10.7g | -35℃～-30℃ | 85％ |
| Example 29 | Formula V25.0 g condensing agent 10.7g | -45℃～-35℃ | 72％ |
| Example 30 | Formula V25.0 g condensing agent 10.7g | -60℃～-45℃ | 51％ |
The comparison experiment shows that the reaction temperature is between-35 ℃ and-30 ℃ with the optimal effect.
Example 31.
Formula I: preparation of (+ -) -4- [2- (tert-butyldimethylsilyl) oxy-3- (2- (tert-butyldimethylsilyl) methyl) -2,3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-7-yl ] -butyric acid methyl ester
Under the protection of argon, a THF solution (300.0ml) (0.5mol/L) of 9-boron bicyclo (3,3,1) -nonane (9-BBN) is added into a dry reaction bottle, and the reaction solution is cooled to 0-10 ℃. Maintaining the anhydrous and oxygen-free operation condition, adding a THF (15.0ml) solution of methyl 3-butenoate (15.1g, 0.15mol), slowly heating to 25-30 ℃ and reacting for 2-3 hours. Triphenylarsone (3.06g, 0.01mol), PdCl were added2(dppf)2(2.93g, 4.0mmol) and stirring, adding THF (518.0ml) solution of formula VI (48.2g, 0.1mmol) and sodium methoxide (8.1g, 0.15mol), heating to 50-60 deg.C, reacting for 10-12 hours, and detecting by TLC that the reaction is complete. Cooling the reaction liquid to 0-10 deg.c, adding methyl tert-butyl ether for dilution, adding saturated salt water, stirring to separate layers, and using the water layerA small amount of methyl tertiary butyl ether is stripped and the organic layers are combined. Washing with water, washing with saturated saline, drying the organic layer with anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain oily substance. The oil was purified by silica gel column chromatography, and the objective product was collected and concentrated under reduced pressure to give an oil of the compound represented by formula I (34.1g) in 67.8% yield.
Example 32.
Formula I: preparation of (+ -) -4- [2- (tert-butyldimethylsilyl) oxy-3- (2- (phenyldimethylsilyl) methyl) -2,3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-7-yl ] -butyric acid methyl ester
Under the protection of argon, a THF solution (300.0ml) (0.5mol/L) of 9-boron bicyclo (3,3,1) -nonane (9-BBN) is added into a dry reaction bottle, and the reaction solution is cooled to 0-10 ℃. A solution of methyl 3-butenoate (15.1g, 0.15mol) in THF (15.0ml) was added while maintaining anhydrous and oxygen-free operating conditions. Slowly heating to 25-30 ℃ for reaction for 2-3 hours. Triphenylarsone (3.06g, 0.01mol), PdCl were added2(dppf)2(2.93g, 4.0mmol), and stirred. A solution of formula VI (51.77g, 0.1mmol) in THF (518.0ml) and sodium methoxide (8.1g, 0.15mol) were added and the reaction was allowed to warm to 50 ℃ to 60 ℃ for 10-12 hours and the reaction was complete by TLC. Cooling the reaction liquid to 0-10 ℃, adding methyl tert-butyl ether for dilution, adding saturated brine, stirring for layering, carrying out back extraction on a water layer by using a small amount of methyl tert-butyl ether, and combining organic layers. Washing with water, washing with saturated saline, drying the organic layer with anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain oily substance. The oil was purified by silica gel column chromatography, and the desired product was collected and concentrated under reduced pressure to give an oil of the compound represented by formula I (43.6g) in 80.9% yield.
1H-NMR(CDCl3)δ0.306-1.240(m,23H),δ1.187-1.912(m,2H),δ2.027(d,1H),δ2.231-2.242(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。
Example 33.
Formula VII: preparation of (+ -) -4- [ 2-hydroxy-3-hydroxymethyl-2, 3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-7-yl ] -butyric acid methyl ester
Dissolving formula I (25.2g, 0.05mol) and 46.5% boron trifluoride ether solution (43.8g, 0.3mol) in acetic acid (163.0ml), stirring, heating to 50-55 deg.C, reacting for 20-24 hr, and detecting by TLC that the reaction is complete. Cooling to room temperature, pouring the reaction liquid into ice water, stirring for 0.5 hour, adding methyl tert-butyl ether, completely extracting, combining organic layers, washing with saturated sodium bicarbonate solution to pH6-7, layering, drying the organic layer with anhydrous magnesium sulfate, and filtering. Concentrating the filtrate to dryness to obtain an oily substance, transferring the oily substance into a reaction bottle, adding potassium bicarbonate (30.0g, 0.3mol), potassium fluoride (17.5g, 0.3mol), methanol (163.0ml) and THF (163.0ml), stirring and mixing, adding 30% hydrogen peroxide (57.0g, 0.5mol), heating to 55-60 ℃, reacting for 4-6 hours, and detecting by TLC to complete the reaction. And cooling the reaction liquid to room temperature, adding sodium sulfite in batches to quench hydrogen peroxide, filtering, leaching a small amount of methyl tert-butyl ether in a filter cake, merging filtrate, concentrating the filtrate under reduced pressure to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain a white solid compound shown as a formula VII (7.4g), wherein the yield is 48.3%.
Example 34.
Formula VII: preparation of (+ -) -4- [ 2-hydroxy-3-hydroxymethyl-2, 3,3a,8 a-tetrahydro-1H-8-oxa-cyclopenta [ a ] indenyl-7-yl ] -butyric acid methyl ester
Dissolving formula I (51.8g, 0.1mol) and 46.5% boron trifluoride ether solution (87.5g, 0.6mol) in acetic acid (326.0ml), stirring, heating to 50-55 deg.C, reacting for 20-24 hr, and detecting by TLC that the reaction is complete. Cooling to room temperature, pouring the reaction liquid into ice water, stirring for 0.5 hour, adding methyl tertiary butyl ether, completely extracting, and combining organic layers. The saturated sodium bicarbonate solution was washed to pH6-7, the layers were separated, the organic layer was dried over anhydrous magnesium sulfate, and filtered. Concentrating the filtrate to dryness to obtain an oily substance, transferring the oily substance into a reaction bottle, adding potassium bicarbonate (60.1g, 0.6mol), potassium fluoride (34.9g, 0.6mol), methanol (326.0ml) and THF (326.0ml), stirring and mixing, adding 30% hydrogen peroxide (113.4g, 1.0mol), heating to 55-60 ℃, reacting for 4-6 hours, and detecting by TLC to complete the reaction. And cooling the reaction liquid to room temperature, adding sodium sulfite in batches to quench hydrogen peroxide, filtering, leaching a small amount of methyl tert-butyl ether in a filter cake, merging filtrate, concentrating the filtrate under reduced pressure to obtain an oily substance, purifying the oily substance by silica gel column chromatography, collecting a target product, and concentrating under reduced pressure to obtain a white solid compound shown as a formula VII (20.6g), wherein the yield is 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。
Example 35.
The inventors synthesized sodium diphosprostate from a compound represented by formula VII according to the methods of patent documents such as US5202447, CN1680351, etc., and finally obtained sodium diphosprostate in a yield of 12%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (7)
1. A preparation method of sodium prostacyclin is characterized by comprising the steps of preparing a compound shown as a formula VII by using a compound shown as a formula I, and then preparing sodium prostacyclin by using a compound shown as a formula VII;
wherein, the compound of formula I:
in the formula, R1Is a silicon protecting group; wherein R is2And R3Each independently is an alkyl group having 1 to 6 carbon atoms; r4Is allyl or aryl;
a compound represented by formula VII:
the preparation method of the compound shown in the formula I is shown as the following reaction scheme:
the preparation of the compound of formula VII is shown in the following reaction scheme:
2. the method of claim 1, wherein R is1Is tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base and triethyl silicon base; r2And R3Each independently is methyl or ethyl; r4Is allyl or phenyl.
3. The process according to claim 1 or 2, wherein the compound of formula I is a compound of formula Ia or Ib:
in the formula, R1、R2、R3And R4As claimed in claim 1 or 2.
4. The method of claim 1, comprising the steps of:
step 1: reacting the formula III with halogenated cuprous in THF at-60 to-20 ℃ to form organic copper salt, and reacting with the formula II at-60 to-20 ℃ to obtain a formula IV;
step 2: dissolving the formula IV in methanol, removing propenyl protection by using palladium tetrakis (triphenyl) phosphine, and reducing by using metal hydride at the temperature of between 10 ℃ below zero and 0 ℃ to obtain a formula V;
and step 3: dissolving the formula V in THF, adding triphenylphosphine, adding an azo condensing agent at-50 to-20 ℃, and reacting at the same temperature to obtain a formula VI;
and 4, step 4: 9-boron bicyclo (3,3,1) -nonane (9-BBN) reacts with 3-methyl butyrate at the temperature of 10 ℃ below zero to 10 ℃, and triphenylarsine and PdCl are added2(dppf)2And formula VI, and sodium methoxide, reacting at 50-60 ℃ to obtain formula I.
5. The method according to claim 4,
in the step 1, the halogenated cuprous reagent is cuprous bromide, cuprous iodide or cuprous chloride;
in step 2, the metal hydride is lithium borohydride, potassium borohydride or sodium borohydride;
in step 3, the azo condensing agent is diethyl azodicarboxylate, dimethyl azodicarboxylate or diisopropyl azodicarboxylate.
6. The method according to claim 5,
the halogenated cuprous reagent is cuprous iodide;
the metal hydride is sodium borohydride;
the azo condensing agent is diisopropyl azodicarboxylate.
7. The method of claim 1, comprising
Reacting the compound shown in the formula I with boron trifluoride diethyl etherate at 50-70 ℃ in an acetic acid solution to obtain an intermediate state, dissolving the intermediate state in a mixed solution of methanol and THF, adding potassium bicarbonate, potassium fluoride and 30% hydrogen peroxide, and reacting at 50-70 ℃ to obtain the compound shown in the formula VII.
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| 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 |
| 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 |
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| GB0215757D0 (en) * | 2002-07-08 | 2002-08-14 | Cascade Biochem Ltd | Benzoprostacyclin intermediates methods for their preparation and products derived therefrom |
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| 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 |
| 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 |
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