CN103450071A - Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate - Google Patents
Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 9
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 title abstract 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 71
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 239000002904 solvent Substances 0.000 claims abstract description 26
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 claims abstract description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000005888 cyclopropanation reaction Methods 0.000 claims abstract description 10
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims abstract description 10
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 16
- -1 methyl chlorobromide Chemical compound 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000000463 material Substances 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 16
- 239000000543 intermediate Substances 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 208000005176 Hepatitis C Diseases 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 abstract 2
- 241000700605 Viruses Species 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- 238000009835 boiling Methods 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000010025 steaming Methods 0.000 description 15
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 5
- WSSDGZWSPMAECX-UHFFFAOYSA-N 2-azabicyclo[3.1.0]hexane Chemical class C1CNC2CC21 WSSDGZWSPMAECX-UHFFFAOYSA-N 0.000 description 4
- 241000711549 Hepacivirus C Species 0.000 description 3
- DJCBNHBQEOKLQU-UHFFFAOYSA-N toluene trihydrobromide Chemical compound Br.Br.Br.CC1=CC=CC=C1 DJCBNHBQEOKLQU-UHFFFAOYSA-N 0.000 description 3
- ITJSVDCZHCYXQE-UHFFFAOYSA-N toluene;hydroiodide Chemical class I.CC1=CC=CC=C1 ITJSVDCZHCYXQE-UHFFFAOYSA-N 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-ZDFGOMNRSA-N [2,2,3,3,4,5,5-heptadeuterio-7-methyl-6-oxo-7-(trideuteriomethyl)-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C12(C(=O)C(C(C(C1([2H])[2H])([2H])[2H])(C2(C([2H])([2H])[2H])C)[2H])([2H])[2H])CS(=O)(=O)O MIOPJNTWMNEORI-ZDFGOMNRSA-N 0.000 description 2
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- XEMRAKSQROQPBR-UHFFFAOYSA-N (trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=CC=C1 XEMRAKSQROQPBR-UHFFFAOYSA-N 0.000 description 1
- YLNQBICKVRQOED-UHFFFAOYSA-N CC(C)(C)OC(C(CC1C2C1)N2C(OC(C)(C)C=[IH])=O)=O Chemical compound CC(C)(C)OC(C(CC1C2C1)N2C(OC(C)(C)C=[IH])=O)=O YLNQBICKVRQOED-UHFFFAOYSA-N 0.000 description 1
- FXBZOXIGGXTKST-ILDUYXDCSA-N CC(C)(C)OC(N(C(C1)C1C1)[C@@H]1[IH](OC(C)(C)C)=O)=O Chemical compound CC(C)(C)OC(N(C(C1)C1C1)[C@@H]1[IH](OC(C)(C)C)=O)=O FXBZOXIGGXTKST-ILDUYXDCSA-N 0.000 description 1
- JYMFUQZGRFZLSY-JOPIAHFSSA-N CC(C)(C)O[C@](C)(C(CC=C1)N1C(OC(C)(C)C)=O)O Chemical compound CC(C)(C)O[C@](C)(C(CC=C1)N1C(OC(C)(C)C)=O)O JYMFUQZGRFZLSY-JOPIAHFSSA-N 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical class 0.000 description 1
- 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
- 208000019423 liver disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
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- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of the synthesis of anti-hepatitis C virus medicines by using medical intermediates, and particularly relates to an asymmetric synthesis method of a medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate. The asymmetric synthesis method is mainly characterized in that (2R) or (2S)-1, 2-tert-butyl dicarbonate-2, 3-pyrrole alkene is used as a raw material, methylbenzene, benzene or trihalomethylbenzene is used as a solvent, diiodomethane, chlorobromomethane, dibromomethane or diethylzinc is used as a cyclopropanation reagent, and after reaction, the compound 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate is obtained. The asymmetric synthesis method has the advantages that synthesis steps are simple, the yield is high, the cost is low, the cyclopropanation reagent is wide in selectivity, the synthesis process is simple, convenient and practical, and the like.
Description
Technical field
The invention belongs to the field of asymmetric synthesis medicine intermediate, be specifically related to medicine intermediate 2-azabicyclo [3.1.0] hexane-2 for the synthesis of anti-hepatitis C medicine, the preparation of the 3-bis-carbonic acid tert-butyl esters.
Technical background
The whole world approximately has 200,000,000 people to infect hepatitis C virus (HCV) at present, has HCV the infected of 70% finally can cause chronic hepatopathy.At western developed country, the third liver has become the major reason of liver transplantation.Treatment hepatitis C medicine becomes the focus of medical scientific research personnel research, 2-azabicyclo [3.1.0] hexane compounds becomes important intermediate (WO2013004290A1, WO2012075439A1, the WO2011075439 of numerous these kind new medicines, WO2011079118, WO2010099527, WO2010117635, US20090068140, US20100160403, US20090068140, US6395767, WO2004052850).Patent WO2004052850 discloses a class for suppressing Dipeptidyl peptidases medicines structure M4.Patent WO2010099527 discloses the structural formula M of novel hepatitis C medicine
1, M
2, patent WO2010117635 discloses hepatitis C pharmaceutical intermediate formula M
3, 2-azabicyclo [3.1.0] hexane compounds is these newtype drug key intermediates.
Stephen Hanessian in 1997, the people such as Ulrich Reinhold have delivered the method for asymmetric synthesis [Angew.Chem.Inf.Ed.Engl.1997,36, No.17] of 2-azabicyclo [3.1.0] hexane compounds: with organometallic compound LiHMDS, Me
3snCH
2react with Al, generate non-corresponding isomer A
2and A
3.Separating-purifying goes out compd A
2after again with LiEt
3bH, TFA reacting generating compound A
4(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane.And compd A
6(1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane, need separating-purifying to go out compd A
3after again with LiEt
3bH, D-10-camphorsulfonic acid (CSA) and tetrabutylammonium fluoride reaction obtain the compd A of optical configuration for (3S, 5S)
5after, then generate A with the TFA effect
6(as follows).This synthesis technique complexity, step is tediously long, and by product is many, and the purification difficulty is large.Cost is high, and ultimate yield is low, is not suitable for extensive compound probability production.
Within 2005, patent US20050090539 has reported with compd B
1with zinc ethyl, (3R)-2-azabicyclo [3.1.0] hexane compounds B that chloroiodomethane reaction has obtained
2.The cyclopropanation reagents selectivity of the method report is single, the intermediate B obtained
2and product B
3stereoselectivity poor, with this ethyl ester class chemical combination B
2synthesize final drug molecule (as M as intermediate
1and M
2) optical activity low, need to further split.
Within 2011, patent WO2011075439A1 has reported with compound 1b.2 and zinc ethyl, and the chloroiodomethane reaction has obtained compound 1b.3.But although the ring third of the method report is changed the relatively front relatively good ICH of a kind of method of reagent stereoselectivity
2cl is relatively expensive and stability is relatively poor.
For fear of the shortcoming and defect of above-mentioned three kinds of methods, the present invention proposes four kinds of 2-azabicyclos [3.1.0] hexane tert-butyl ester
1[comprise (1S, 3R, 5S)
1, (1R, 3R, 5R)
1, (1S, 3S, 5S)
1, (1R, 3S, 5R)
1] synthetic method.It is characterized in that: the compound of 1 times of amount (5R)
2or (5S)
2, the amount of thing is unit, lower same,
The zinc ethyl of doubly measuring with 2-4, the cyclopropanation reagents Z that 2-5 doubly measures and solvent S react 19-24 hour under-25 to-10 ℃ ℃, reaction solution washs respectively through aqueous citric acid solution and saturated sodium bicarbonate aqueous solution, again through column chromatography (sherwood oil: ethyl acetate=30: 1) after separating-purifying, obtain respectively compound (1S, 3R, 5S)
1(1R, 3R, 5R)
1be perhaps (1S, 3S, 5S)
1(1R, 3S, 5R)
1, reaction formula is as follows,
Wherein, Z is that cyclopropanation reagents is selected from methylene iodide, methyl chlorobromide and methylene bromide, and S is that solvent is selected from benzene, toluene, three toluene halides, wherein halogen is selected from fluorine, chlorine, bromine and iodine.
Summary of the invention
The object of the present invention is to provide the method for asymmetric synthesis of a kind of 2-azabicyclo [3.1.0] hexane class medicine intermediate.The method has the advantages such as synthesis step is easy, and productive rate is high, and cost is low, and cyclopropanation reagents is selected wide, and synthesis technique is simple and easy to do.
Structural formula of the present invention and synthetic method are as follows.
Reaction equation is as follows:
Wherein, Z is that cyclopropanation reagents is selected from methylene iodide, methyl chlorobromide and methylene bromide, and S is that solvent is selected from benzene, toluene, three toluene halides, wherein halogen is selected from fluorine, chlorine, bromine and iodine.
The preparation method of a class intermediate of the present invention specifically, the compound of 1 times of amount (5R)
2or (5S)
2amount of substance is unit, the zinc ethyl of doubly measuring with 2-4, the cyclopropanation reagents Z that 2-5 doubly measures and solvent S react 19-24 hour under-25 to-10 ℃ ℃, reaction solution washs respectively through aqueous citric acid solution and saturated sodium bicarbonate aqueous solution, again through column chromatography (sherwood oil: ethyl acetate=30: 1) obtain respectively compound (1S, 3R, 5S) after separating-purifying
1(1R, 3R, 5R)
1be perhaps (1S, 3S, 5S)
1(1R, 3S, 5R)
1, the method for synthetic compound of the present invention is simple to operate, and yield is greater than 70%.
Embodiment
Following specific embodiment is used for further illustrating the present invention.
Synthetic example
Embodiment 1:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1synthetic
The compound (5R) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the toluene of 75.0mL under nitrogen protection, be cooled to-20 ℃ after the methylene iodide of (99.4g, 371.2mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 18 hours, be added drop-wise in the lemon aqueous acid of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate aqueous solution washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, finally by silica gel column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain 15.7g compound (1R, 3R, 5R)
1, fusing point is 130-132 ℃, and 1.7g compound (1S, 3R, 5S)
1, fusing point is 131-133 ℃, overall yield 66%.
Compound (1R, 3R, 5R)
1nuclear magnetic data (
1hNMR, 500MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm0.87-0.88 (m, 1H, CH), 0.88-0.89 (m, 1H, CH), 0.894-0.898 (m, 1H, CH), 1.43-1.45 (m, 9H, CH
3), 1.45-1.49 (m, 9H, CH
3), 2.00 (t, 1H, J=3.05, CH), 2.47-2.53 (m, 1H, CH), 3.52-3.55 (m, 1H, CH), 4.36-4.39 (m, 1H, CH).
Compound (1S, 3R, 5S)
1nuclear magnetic data (
1hNMR, 500MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm0.87-0.88 (m, 1H, CH), 0.88-0.89 (m, 1H, CH), 0.894-0.898 (m, 1H, CH), 1.43-1.45 (m, 9H, CH
3), 1.45-1.49 (m, 9H, CH
3), 1.97 (t, 1H, J=3.05, CH), 2.54-2.61 (t, 1H, CH), 3.40-3.43 (m, 1H, CH), 4.62-4.91 (m, 1H, CH).
Embodiment 2:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (20.0g, 74.3mmol) in the four-hole boiling flask of 500mL
2, add the benzene of 70.0mL under nitrogen protection, be cooled to-22 ℃ after the methylene iodide of (79.6g, 297.2mmol), drip the toluene solution of (148.6mL) 1.1M zinc ethyl.React after 25 hours, be added drop-wise in the aqueous citric acid solution of (170.5mL) 0.95M, separate (70.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(12.6g) with (1S, 3R, 5S)
1(1.4g), overall yield 67%.
Embodiment 3:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (30.0g, 111.5mmol) in the four-hole boiling flask of 500mL
2, add the phenylfluoroform of 80.0mL under nitrogen protection, be cooled to-17 ℃ after the methyl chlorobromide of (42.8g, 334.5mmol), drip the toluene solution of (222.0mL) 1.1M zinc ethyl.React after 18 hours, be added drop-wise in the aqueous citric acid solution of (255.0mL) 0.95M, separate (80.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(19.7g) with (1S, 3R, 5S)
1(2.2g), overall yield 70%.
Embodiment 4:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (30.0g, 111.5mmol) in the four-hole boiling flask of 500mL
2, add the toluene tribromide of 80.0mL under nitrogen protection, be cooled to-10 ℃ after the methylene bromide of (95.8g, 557.5mmol), drip the toluene solution of (222.0mL) 1.1M zinc ethyl.React after 72 hours, be added drop-wise in the aqueous citric acid solution of (255.0mL) 0.95M, separate (80.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(18.9g) with (1S, 3R, 5S)
1(2.1g), overall yield 67%.
Embodiment 5:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the benzene of 75.0mL under nitrogen protection, be cooled to-15 ℃ after the methyl chlorobromide of (38.3g, 300.0mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 60 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(15.9g) with (1S, 3R, 5S)
1(1.8g), overall yield 67%.
Embodiment 6:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the toluene tribromide of 75.0mL under nitrogen protection, be cooled to-19 ℃ after the methylene iodide of (38.9g, 220.0mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 58 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(16.2g) with (1S, 3R, 5S)
1(1.8g), overall yield 68%.
Embodiment 7:(1R, 3R, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3R, 5R)
1(1S, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3R, 5S)
1synthetic
The compound (5R) that adds (20.0g, 74.3mmol) in the four-hole boiling flask of 500mL
2, add three toluene iodides of 70.0mL under nitrogen protection, be cooled to-25 ℃ after the chloroiodomethane of (72.4g, 410.0mmol), drip the toluene solution of (148.0mL) 1.1M zinc ethyl.React after 42 hours, be added drop-wise in the aqueous citric acid solution of (170.0mL) 0.95M, separate (70.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1R, 3R, 5R)
1(13.0g) with (1S, 3R, 5S)
1(1.4g), overall yield 69%.
Embodiment 8:(1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1
The compound (5S) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the toluene of 75.0mL under nitrogen protection, be cooled to-23 ℃ after the methylene iodide of (99.4g, 371.2mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 18 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(15.9g) fusing point is 129-131 ℃ and (1R, 3S, 5R)
1(1.8g) fusing point is 130-132 ℃, overall yield 67%.
Compound (1S, 3S, 5S)
1nuclear magnetic data (
1hNMR, 500MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm0.87-0.88 (m, 1H, CH), 0.88-0.89 (m, 1H, CH), 0.894-0.898 (m, 1H, CH), 1.43-1.45 (m, 9H, CH
3), 1.45-1.49 (m, 9H, CH
3), 2.02 (t, 1H, J=3, CH), 2.57-2.61 (t, 1H, CH), 3.55-3.53 (m, 1H, CH), 4.36-4.39 (m, 1H, CH).
Compound (1R, 3S, 5R)
1nuclear magnetic data (
1hNMR, 500MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm0.87-0.88 (m, 1H, CH), 0.88-0.89 (m, 1H, CH), 0.894-0.898 (m, 1H, CH), 1.43-1.45 (m, 9H, CH
3), 1.45-1.49 (m, 9H, CH
3), 2.00 (m, 1H, J=3, CH), 2.54-2.57 (t, 1H, CH), 3.40-3.53 (m, 1H, CH), 4.36-4.49 (m, 1H, CH).
Embodiment 9:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (20.0g, 74.3mmol) in the four-hole boiling flask of 500mL
2, add the benzene of 70.0mL under nitrogen protection, be cooled to-25 ℃ after the methylene iodide of (96.4g, 360.2mmol), drip the toluene solution of (148.0mL) 1.1M zinc ethyl.React after 25 hours, be added drop-wise in the aqueous citric acid solution of (170.0mL) 0.95M, separate (70.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(12.6g) with (1R, 3S, 5R)
1(1.4g), overall yield 67%.
Embodiment 10:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the phenylfluoroform of 75.0mL under nitrogen protection, be cooled to-22 ℃ after the methylene iodide of (111.8g, 417.6mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 30 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(16.5g) with (1R, 3S, 5R)
1(1.8g), overall yield 70%.
Embodiment 11:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the trichlorotoluene zotrichloride of 75.0mL under nitrogen protection, be cooled to-20 ℃ after the methylene bromide of (74.5g, 278.4mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 35 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(16.9g) with (1R, 3S, 5R)
1(1.9g), overall yield 71%.
Embodiment 12:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add three toluene iodides of 75.0mL under nitrogen protection, be cooled to-18 ℃ after the methyl chlorobromide of (47.5g, 371.2mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 65 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(16.8g) with (1R, 3S, 5R)
1(1.9g), overall yield 71%.
Embodiment 13:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (20.0g, 74.3mmol) in the four-hole boiling flask of 500mL
2, add the toluene tribromide of 70.0mL under nitrogen protection, be cooled to-12 ℃ after the methyl chlorobromide of (23.7g, 185.6mmol), drip the toluene solution of (148.0mL) 1.1M zinc ethyl.React after 72 hours, be added drop-wise in the aqueous citric acid solution of (170.0mL) 0.95M, separate (70.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(12.7g) with (1R, 3S, 5R)
1(1.4g), overall yield 67%.
Embodiment 14:(1R, 3R, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (20.0g, 74.3mmol) in the four-hole boiling flask of 500mL
2, add three toluene iodides of 70.0mL under nitrogen protection, be cooled to-10 ℃ after the chloroiodomethane of (68.5g, 389.6mmol), drip the toluene solution of (148.0mL) 1.1M zinc ethyl.React after 52 hours, be added drop-wise in the aqueous citric acid solution of (170.0mL) 0.95M, separate (70.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(12.9g) with (1R, 3S, 5R)
1(1.4g), overall yield 68%.
Case of comparative examples 1:(1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1S, 3S, 5S)
1(1R, 3S, 5R)-2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters (1R, 3S, 5R)
1synthetic
The compound (5S) that adds (25.0g, 92.8mmol) in the four-hole boiling flask of 500mL
2, add the toluene of 75.0mL under nitrogen protection, be cooled to-20 ℃ after the chloroiodomethane of (99.4g, 371.2mmol), drip the toluene solution of (185.6mL) 1.1M zinc ethyl.React after 14 hours, be added drop-wise in the aqueous citric acid solution of (213.0mL) 0.95M, separate (75.0mL * 2) saturated sodium bicarbonate washing for organic phase, after anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains white solid, column chromatography (sherwood oil: ethyl acetate=30: 1) separate and obtain compound (1S, 3S, 5S)
1(13.9g) fusing point is 129-131 ℃ and (1R, 3S, 5R)
1(1.3g) fusing point is 130-132 ℃, overall yield 58%.
Any those skilled in the art, without departing from the spirit and scope of the present invention, should make various modifications and change.Therefore protection scope of the present invention should be considered as appended claims limited range.
Claims (1)
1. a medicine intermediate 2-azabicyclo [3.1.0] hexane-2, the 3-bis-carbonic acid tert-butyl esters
1the method of asymmetric synthesis of (its structural formula general formula is as follows) is characterized in that: the compound of 1 times of amount (5R)
2or (5S)
2, material
Amount is unit, lower same, the zinc ethyl of doubly measuring with 2-4, the cyclopropanation reagents Z that 2-5 doubly measures and solvent S react 19-24 hour under-25 to-10 ℃, reaction solution is respectively through aqueous citric acid solution and saturated sodium bicarbonate aqueous solution washing, again through column chromatography (sherwood oil: ethyl acetate=30: 1) obtain respectively compound (1R, 3S, 5R) after separating-purifying
1(1S, 3R, 5R)
1be perhaps (1S, 3R, 5S)
1(1R, 3S, 5S)
1, reaction formula is as follows,
Wherein, Z is that cyclopropanation reagents is selected from methylene iodide, methyl chlorobromide and methylene bromide, and S is that solvent is selected from benzene, toluene, three toluene halides, wherein halogen is selected from fluorine, chlorine, bromine and iodine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106928124A (en) * | 2015-12-30 | 2017-07-07 | 上海现代制药股份有限公司 | The preparation method of onglyza intermediate |
| CN114057627A (en) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | Preparation method of hepatitis C and neocorolla drug intermediate and salt thereof |
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| WO2004052850A2 (en) * | 2002-12-09 | 2004-06-24 | Bristol-Myers Squibb Company | Methods and compounds producing dipeptidyl peptidase iv inhibitors and intermediates thereof |
| CN102741242A (en) * | 2009-12-16 | 2012-10-17 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
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| WO2004052850A2 (en) * | 2002-12-09 | 2004-06-24 | Bristol-Myers Squibb Company | Methods and compounds producing dipeptidyl peptidase iv inhibitors and intermediates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106928124A (en) * | 2015-12-30 | 2017-07-07 | 上海现代制药股份有限公司 | The preparation method of onglyza intermediate |
| CN106928124B (en) * | 2015-12-30 | 2021-07-30 | 上海现代制药股份有限公司 | Preparation method of saxagliptin intermediate |
| CN114057627A (en) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | Preparation method of hepatitis C and neocorolla drug intermediate and salt thereof |
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