CN105348112A - Technological synthesis method of 1-amino cyclopropyl acetylene - Google Patents
Technological synthesis method of 1-amino cyclopropyl acetylene Download PDFInfo
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- CN105348112A CN105348112A CN201510749950.9A CN201510749950A CN105348112A CN 105348112 A CN105348112 A CN 105348112A CN 201510749950 A CN201510749950 A CN 201510749950A CN 105348112 A CN105348112 A CN 105348112A
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- 0 CN(*)C(CO)C1CC1 Chemical compound CN(*)C(CO)C1CC1 0.000 description 3
- UEFJXKKWBTXRGK-UHFFFAOYSA-N CC(C)(C)C(NCCC=O)=O Chemical compound CC(C)(C)C(NCCC=O)=O UEFJXKKWBTXRGK-UHFFFAOYSA-N 0.000 description 1
- KSRPJFWFJXZJMV-UHFFFAOYSA-N CC(C)C(NC1(CC1)C=C)=O Chemical compound CC(C)C(NC1(CC1)C=C)=O KSRPJFWFJXZJMV-UHFFFAOYSA-N 0.000 description 1
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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Abstract
The invention discloses a technological synthesis method of 1-amino cyclopropyl acetylene. The method includes: taking compound 1 as the starting material, and carrying out oxidation, Corey-Fuchs reaction, and amino protection group removal so as to obtain the 1-amino cyclopropyl acetylene. The reagents and raw materials used by the method provided by the invention are cheap and easily available, and low in cost. With the advantages of high reaction safety, simple operation and high yield, the method is suitable for industrial scale-up production. (with the synthesis process shown as the specification).
Description
Technical field:
The present invention relates to the process synthetic method of the amino cyclopropyl acethlene of a kind of medicine intermediate 1-, belong to organic synthesis field.
Background technology:
The amino cyclopropyl acethlene of 1-is a kind of useful micromolecular compound, containing two active reaction sites, can pile up group as the small molecules that drug molecule is important.In recent years, the amino cyclopropyl acethlene of 1-more and more receives the concern of people, and the application on pharmaceutical activity molecule also increases gradually.2014, the patent WO2014066490 of Merck company disclosed a kind of new compound, and have good treatment neuropathic pain disfunction active, structural formula is such as formula 1; 2015, a kind of new compound disclosed in the patent WO2015056799 of Taisho company, had good anti-microbial activity, and structural formula, such as formula 2, all introduces the amino cyclopropyl acethlene of 1-.Therefore, 1-amino cyclopropyl acethlene will have a extensive future future.
At present, the report about the synthesis of 1-amino cyclopropyl acethlene is few, and document Synthesis2010, No.23,3967 – 3973 report the synthetic method of the amino cyclopropyl acethlene of 1-, as shown in following flow process.Use the method second step to insert carbonyl reaction, need dry ice to join in reaction system, reaction heats up uncontrollable rapidly, and has by product to generate, and the 3rd step Curtius rearrangement needs to use sodium azide, explosive and hypertoxic.Therefore use the method to be unfavorable for industry's enlarging production, a large amount of market requirements cannot be met.Patent WO2013169401 then also reports the synthesis of the amino cyclopropyl acethlene of 1-, but does not do substantial improvement.
Patent WO2015095227 reports another kind of synthetic method, the method is obtained by reacting the amino cyclopropyne of 1-by Seyferth-GilbertHomologation, Bestmann-Ohira reagent (1-diazo-2-oxopropyl) the dimethyl phosphonate price used is very expensive, cost improves, and is unfavorable for market competition.
Therefore, need to develop a kind of novel method to synthesize the amino cyclopropyl acethlene of 1-, the method safety, cost be low, simple to operate, can suitability for industrialized production.
Summary of the invention
The technical problem to be solved in the present invention relates to the preparation method of the amino cyclopropyl acethlene of 1-, and the method safety, cost be low, simple to operate, can suitability for industrialized production.
Preparation method of the present invention can represent by following flow process:
X is halogen, and described halogen is chlorine, bromine, iodine.
R is conventional amino protecting group; described amino protecting group is tertbutyloxycarbonyl (Boc); benzyl (Bn), carbobenzoxy-(Cbz) (Cbz), fluorenylmethyloxycarbonyl (Fmoc); allyloxycarbonyl (Alloc); p-toluenesulfonyl (Ts), ethanoyl (Ac), trifluoroacetyl group (Tfa); pivaloyl group, trimethylsilyl ethoxycarbonyl etc.
Preparation method of the present invention is more specifically described below.However, it should be understood that the present invention is not limited to following given concrete reaction conditions (amount, temperature of reaction, reaction required time etc. as solvent, compound used therefor).
1. step a. compound 1 obtains compound 2 through oxidation
Wherein the definition of R is as front, is preferably Boc.
Described oxidation system is 4-hydroxyl-2, 2, 6, 6-tetramethyl piperidine oxide compound (4-OH-TEMPO), 4-amino-2, 2, 6, 6-tetramethyl piperidine oxide compound (4-NH2-TEMPO), 4-methyl-2, 2, 6, 6-tetramethyl piperidine oxide compound (4-Me-TEMPO) and clorox (NaClO), sodium hypobromite (NaOBr), the arbitrary combination etc. of t-butyl hypochlorate (t-BuOCl), be preferably 4-OH-TEMPO and NaClO, the molar feed ratio of 4-OH-TEMPO/NaClO and compound 1 is 0.005 ~ 0.02:1.5 ~ 2.5:1, be preferably 0.01 ~ 0.02:1.8 ~ 2:1.
Described alkali can be salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate etc., is preferably sodium bicarbonate.
Described compound 1 can obtain by following flow process synthesis, or commercially available purchase obtains.
2. step b. compound 2 is obtained by reacting compound 3 through Corey-Fuchs
Wherein the definition of X, R is as front, and X is preferably chlorine and bromine, and R is preferably Boc.
It is triphenyl phosphorus/carbon tetrabromide, triphenyl phosphorus/tetracol phenixin, triphenyl phosphorus/trichlorobromomethane that described Corey-Fuchs reacts the reagent used, triphenyl phosphorus/tetraiodo-methane, or trichoroacetic acid(TCA)/methyl-chloroformate/cuprous chloride/2,2 '-dipyridyl, trichoroacetic acid(TCA)/Vinyl chloroformate/cuprous chloride/2,2 '-dipyridyl, trichoroacetic acid(TCA)/diacetyl oxide/zinc/acetic acid, hydrazine hydrate/trichlorobromomethane/cuprous chlorides etc., are preferably triphenyl phosphorus/carbon tetrabromide and trichoroacetic acid(TCA)/diacetyl oxide/zinc/acetic acid.
Described alkali is n-Butyl Lithium (n-BuLi), di-isopropyl lithium (LDA), lithium methide (MeLi), two (trimethyl silicon based) sodium amide (NaHMDS), two (trimethyl silicon based) Lithamide (LiHMDS), methyl-magnesium-bromide, potassium tert.-butoxide etc., be preferably n-Butyl Lithium, the molar feed ratio of described alkali and compound 2 is 2 ~ 5:1, is preferably 3 ~ 4:1.
3. step c compound 3 deaminizating protecting group obtains compound 4
Wherein the definition of R is as front.
The method of described deaminizating protecting group and condition can be ordinary method and the condition of this type of reaction of this area.
The advantage of the inventive method is mainly:
1) operation is simple, and security is high, and reaction is clean, and aftertreatment is simple, and yield is high, is easy to industrial production;
2) reagent used and raw material are cheaply easy to get, and cost is low.
3) for the synthesis of similar compound provides methodology reference.
Specific embodiment:
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition is carried out usually.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20 ~ 35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.Reaction is analyzed by TLC and/or is analyzed by LC-MS, is judged the termination of reacting by the consumption of parent material.The thin-layer chromatography (TLC) analyzed carries out on the sheet glass (EMD chemical company (EMDChemicals)) of pre-coated silica gel 60F2540.25 millimeter plate, with the iodine developing on UV light (254nm) and/or silica gel, and/or heat together with alcohol phospho-molybdic acid, ninidrine solution, potassium permanganate solution or ceric sulfate solution with TLC product dyed thereby.
1H-NMR spectrum is on ten thousand Ruian-Mo Qiuli-VX400 (VarianMercury-VX400) instrument, records under 400MHz operation.
The abbreviation used in the present invention has this area conventional sense, as: DCM represents methylene dichloride, and DMSO represents dimethyl sulfoxide (DMSO).TMS represents trimethyl silicon based, TBS represents t-Butyldimethylsilyl, TBDPS represents that tert-butyl diphenyl is silica-based, TIPS represents triisopropylsilyl, DBU represents 1,8-diazabicylo 11 carbon-7-alkene, and DMAP represents DMAP, DiBALH represents diisobutyl aluminium hydride, and LDA represents lithium diisopropyl amido etc.
Embodiment 1
Add compound 1A (7g, 0.037mol, 1eq) and methylene dichloride (50mL) in 500mL there-necked flask, add 4-OH-TEMPO (0.06g, 0.37mmol, 0.01eq), add saturated NaHCO
3the aqueous solution (200mL), is cooled to 0 DEG C, drips the 10%NaClO aqueous solution (50g, 0.067mol, 1.8eq), is naturally warming up to room temperature, reaction 1h.Add water 100mL, dichloromethane extraction (150mL*2), merges organic phase, and wash once with water (200mL), and concentrated organic phase, obtaining compound 2A is faint yellow solid (6.3g, yield: 91%, purity: 94.2%)
1HNMR(400MHz,CDCl
3):δ=9.181(s,1H),5.142(t,1H),1.483(m,2H),1.413(s,9H),1.270(m,2H)ppm;ESI/MS:m/z=186(M+H)+.
Embodiment 2
Add triphenylphosphine (45.4g, 0.17mol, 4eq) and DCM (255g) in 250mL there-necked flask, reaction solution is cooled to 0 ~ 5 DEG C, adds CBr
4(28.6g, 0.086mol, 2eq), solution colour, by the colourless look that reddens, has solid to separate out after 20min.Divide 4 batches and add compound 2A (8g, 0.043mol, 1eq), heat release is obvious, 0 DEG C of reaction 0.5h.Solids removed by filtration, after concentrated, brush silica gel, leacheate is concentrated obtains faint yellow solid 13.7g.
1HNMR(400MHz,CDCl
3):δ=6.687(s,1H),1.453(s,9H),1.288(m,2H),1.253(m,2H)ppm;ESI/MS:m/z=342(M+H)+.
Be added to by this faint yellow solid in THF (270mL), be cooled to-78 DEG C, drip 2.5Mn-BuLi/hexane solution (53mL, 0.130mol, 3eq) ,-78 DEG C of reaction 30min, are slowly warming up to-40 DEG C, reaction 30min.Slowly drip water (100mL) at-40 DEG C, be slowly warming up to room temperature, be extracted with ethyl acetate (100mL*2), concentrated dryly obtain solid.Join in solid by normal heptane (20g), stir 30min, filter, dry, obtaining compound 3A is white solid (6.6g, yield: 84%, purity: 94.1%)
1HNMR(400MHz,CDCl
3):δ=5.002(s,1H),1.461(s,9H),1.199(m,2H),1.095(m,2H)ppm;ESI/MS:m/z=182(M+H)+.
Embodiment 3
Compound 3A (2.9g, 0.016mol, 1eq) and 7.1MHCl/MTBE solution (25mL, 0.178mol, 11eq) is added, stirred overnight at room temperature in 100mL there-necked flask.Filter, filter cake MTBE (10mL) drip washing, collect solid and dry, obtain compound 4 for white solid (1.7g, 90%, purity: 99%)
1HNMR(400MHz,CDCl
3):δ=9.082(s,3H),3.562(s,1H),1.331(t,2H),1.126(t,2H)ppm;ESI/MS:m/z=82(M+H)+.
Embodiment 4
Add compound 1B (10g, 0.058mol, 1eq) and methylene dichloride (50mL) in 500mL there-necked flask, add 4-Me-TEMPO (0.2g, 1.2mmol, 0.02eq), add saturated NaHCO
3the aqueous solution (300mL), is cooled to 0 DEG C, drips the 10%NaClO aqueous solution (86g, 0.116mol, 2eq), is naturally warming up to room temperature, reaction 1h.Add water 100mL, dichloromethane extraction (150mL*2), merges organic phase, and wash once with water (200mL), and concentrated, obtaining compound 2B is faint yellow solid (8.8g, yield: 89%, purity: 95.1%)
1hNMR (400MHz, CDC1
3): δ 9.154 (s, 1H), 5.482 (br, 1H), 1.479 (m, 2H), 1.365 (s, 9H), 1.298 (m, 2H) .ESI/MS:m/z=170 (M+H)+.
Embodiment 5
Add triphenylphosphine (45.5g, 0.189mol, 4eq) and DCM (200g) in 250mL there-necked flask, reaction solution is cooled to 0 ~ 5 DEG C, adds CBr
4(30.7g, 0.094mol, 2eq), solution colour, by the colourless look that reddens, stirs 30min.Divide 4 batches and add compound 2B (8g, 0.047mol, 1eq), heat release is obvious, 0 DEG C of reaction 0.5h.Solids removed by filtration, after concentrated, brush silica gel, leacheate is concentrated obtains faint yellow solid 14.7g (ESI/MS:m/z=326 (M+H)+).Add in 200mLTHF by this faint yellow solid, be cooled to-78 DEG C, drip 2.5Mn-BuLi/hexane solution (72mL, 0.18mol, 4eq) ,-78 DEG C of reaction 30min, are slowly warming up to-40 DEG C, reaction 30min.Slowly drip water (100mL) at-40 DEG C, be slowly warming up to room temperature, be extracted with ethyl acetate (150mL*2), concentrated dryly obtain solid.Join in solid by normal heptane (30g), stir 30min, filter, dry, obtaining compound 3B is white solid (5.9g, yield: 76%, purity: 96.3%)
1HNMR(400MHz,CDCl
3):δ=9.141(br,1H),4.859(s,1H),1.359(s,9H),1.134-1.028(m,4H);ppm;ESI/MS:m/z=166(M+H)+.
Embodiment 6
Add compound 3B (5g, 0.03mol, 1eq) and methylene dichloride (60mL) in 100mL there-necked flask, drip TFA (10g, 0.09mol, 3eq), stirred overnight at room temperature.Add DCM (40mL), drip saturated sodium bicarbonate aqueous solution, adjust ph is to 8-9, be separated organic phase, aqueous phase DCM extraction (100mL*1), merges organic phase, wash once (100mL*1) with saturated common salt, concentrated, concentration residue is dissolved in MTBE, drips 7MHCl*/MTBE solution (12mL), stir 1h, be cooled to room temperature, filter, collect filter cake, dry, obtain compound 4 for white solid (3.1g, yield: 87%, purity: 98.1%)
1HNMR(400MHz,CDCl
3):δ=9.082(s,3H),3.562(s,1H),1.331(t,2H),1.126(t,2H)ppm;ESI/MS:m/z=82(M+H)+.
Embodiment 7
Compound 2A (2g is added in 100mL there-necked flask, 0.011mol, 1eq) with DMF (20mL), trichoroacetic acid(TCA) (2.6g, 0.016mol, 1.5eq) is dripped under room temperature, sodium trichloroacetate (3g is added in three batches under room temperature, 0.015mol, 1.6eq), room temperature reaction 4h.Be cooled to 0 DEG C, drip diacetyl oxide (2.2g, 0.022mol, 2eq), be slowly warming up to room temperature, room temperature reaction 1h.Add acetic acid (25mL), be cooled to 0 DEG C, add zinc powder (1.4g, 0.02mol, 2eq), be warming up to 55 ~ 60 DEG C, reaction 1h.Slow cooling is to room temperature, and add water (200mL), and filter, MTBE extracts (50mL*2), merges organic phase, saturated common salt washing (30mL*1), and concentrated organic phase, brush silica gel, concentrate eluant, obtains faint yellow solid 2.4g.(ESI/MS:m/z=253(M+H)+)。
Joined in 100mL there-necked flask by 2.4g solid, add THF (30mL), be cooled to-30 DEG C, drip 1.6M lithium methide/diethyl ether solution (18mL, 0.03mol, 3eq), low-temp reaction 1h, is slowly warming up to room temperature.Drip aqueous ammonium chloride solution (100mL), extraction into ethyl acetate (50mL*2), merge organic phase and concentrate to obtain solid, normal heptane (10g) is joined in solid, stir 30min, filter, dry, obtaining compound 3A is white solid (1.5g, yield: 77%, purity: 95.2%)
1HNMR(400MHz,CDCl
3):δ=5.002(s,1H),1.461(s,9H),1.199(m,2H),1.095(m,2H)ppm;ESI/MS:m/z=182(M+H)+.
Embodiment 8
Add triphenylphosphine (11.3g, 0.044mol, 4eq) and DCM (255g) in 250mL there-necked flask, reaction solution is cooled to 0 ~ 5 DEG C, adds CI
4(11.4g, 0.022mol, 2eq), stirs 30min.Divide 4 batches and add compound 2A (2g, 0.011mol, 1eq), heat release is obvious, 0 DEG C of reaction 0.5h.Solids removed by filtration, after concentrated, brush silica gel, leacheate is concentrated obtains yellow solid 4.3g.ESI/MS:m/z=436(M+H)+。
Be added to by this faint yellow solid in THF (50mL), be cooled to-78 DEG C, drip 2.5Mn-BuLi/hexane solution (13mL, 0.033mol, 3eq) ,-78 DEG C of reaction 30min, are slowly warming up to-40 DEG C, reaction 30min.Slowly drip water (50mL) at-40 DEG C, be slowly warming up to room temperature, be extracted with ethyl acetate (50mL*2), concentrated dryly obtain solid.Join in solid by normal heptane (10g), stir 30min, filter, dry, obtaining compound 3A is white solid (1.55g, yield: 79%, purity: 94.6%)
1HNMR(400MHz,CDCl
3):δ=5.002(s,1H),1.461(s,9H),1.199(m,2H),1.095(m,2H)ppm;ESI/MS:m/z=182(M+H)+.
Embodiment 9
Add triphenylphosphine (11.3g, 0.044mol, 4eq) and DCM (255g) in 250mL there-necked flask, reaction solution is cooled to 0 ~ 5 DEG C, adds CCl
4(11.4g, 0.022mol, 2eq), stirs 30min.Divide 4 batches and add compound 2A (2g, 0.011mol, 1eq), heat release is obvious, 0 DEG C of reaction 0.5h.Solids removed by filtration, after concentrated, brush silica gel, leacheate is concentrated obtains faint yellow solid 2.5g.ESI/MS:m/z=253(M+H)+。
Be added to by this faint yellow solid in THF (50mL), be cooled to-78 DEG C, drip 2.5Mn-BuLi/hexane solution (13mL, 0.033mol, 3eq) ,-78 DEG C of reaction 30min, are slowly warming up to-40 DEG C, reaction 30min.Slowly drip water (50mL) at-40 DEG C, be slowly warming up to room temperature, be extracted with ethyl acetate (50mL*2), concentrated dryly obtain solid.Join in solid by normal heptane (10g), stir 30min, filter, dry, obtaining compound 3A is white solid (1.45g, yield: 74%, purity: 95.1%)
1HNMR(400MHz,CDCl
3):δ=5.002(s,1H),1.461(s,9H),1.199(m,2H),1.095(m,2H)ppm;ESI/MS:m/z=182(M+H)+.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (7)
1. a process synthetic method for the amino cyclopropyl acethlene of 1-, is characterized in that comprising the following step:
1) chemical combination 1 obtains compound 2 through oxidation;
2) compound 2 is obtained by reacting compound 3 through Corey-Fuchs;
3) compound 3 deaminizating protecting group obtains compound 4;
Wherein, R is conventional amino protecting group; X is halogen.
2. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1; it is characterized in that; described amino protecting group is tertbutyloxycarbonyl (Boc); benzyl (Bn); carbobenzoxy-(Cbz) (Cbz); fluorenylmethyloxycarbonyl (Fmoc); allyloxycarbonyl (Alloc); p-toluenesulfonyl (Ts); ethanoyl (Ac); trifluoroacetyl group (Tfa), pivaloyl group, trimethylsilyl ethoxycarbonyl etc.Be preferably tertbutyloxycarbonyl (Boc).
3. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1, it is characterized in that, described halogen is chlorine, bromine, iodine, is preferably chlorine and bromine.
4. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1, it is characterized in that, in step 1, described oxidation system is 4-hydroxyl-2,2,6,6-tetramethyl piperidine oxide compound (4-OH-TEMPO), 4-amino-2,2,6,6-tetramethyl piperidine oxide compound (4-NH
2-TEMPO), 4-methyl-2,2,6,6-tetramethyl piperidine oxide compound (4-Me-TEMPO) and clorox (NaClO), sodium hypobromite (NaOBr), the arbitrary combination etc. of t-butyl hypochlorate (t-BuOCl), be preferably 4-OH-TEMPO and NaClO system, the molar feed ratio of 4-OH-TEMPO/NaClO and compound 1 is 0.005 ~ 0.02:1.5 ~ 2.5:1, is preferably 0.01 ~ 0.02:1.8 ~ 2:1.
5. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1, is characterized in that: described alkali can be salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate etc., is preferably sodium bicarbonate.
6. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1, it is characterized in that, in step 2, it is triphenyl phosphorus/carbon tetrabromide that described Corey-Fuchs reacts the reagent used, triphenyl phosphorus/tetracol phenixin, triphenyl phosphorus/trichlorobromomethane, triphenyl phosphorus/tetraiodo-methane, or trichoroacetic acid(TCA)/methyl-chloroformate/cuprous chloride/2, 2 '-dipyridyl, trichoroacetic acid(TCA)/Vinyl chloroformate/cuprous chloride/2, 2 '-dipyridyl, trichoroacetic acid(TCA)/diacetyl oxide/zinc/acetic acid, hydrazine hydrate/trichlorobromomethane/cuprous chloride etc., be preferably triphenyl phosphorus/carbon tetrabromide and trichoroacetic acid(TCA)/diacetyl oxide/zinc/acetic acid.
7. the process synthetic method of the amino cyclopropyl acethlene of a kind of 1-as claimed in claim 1, it is characterized in that, in step 2, described alkali is n-Butyl Lithium (n-BuLi), di-isopropyl lithium (LDA), lithium methide (MeLi), two (trimethyl silicon based) sodium amide (NaHMDS), two (trimethyl silicon based) Lithamide (LiHMDS), methyl-magnesium-bromide, potassium tert.-butoxides etc., are preferably n-Butyl Lithium, the molar feed ratio of described alkali and compound 2 is 2 ~ 5:1, is preferably 3 ~ 4:1.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1942467A (en) * | 2004-04-20 | 2007-04-04 | 默克公司 | 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
WO2014099586A1 (en) * | 2012-12-17 | 2014-06-26 | Merck Sharp & Dohme Corp. | 4-pyridinonetriazine derivatives as hiv integrase inhibitors |
WO2015095227A2 (en) * | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN1942467A (en) * | 2004-04-20 | 2007-04-04 | 默克公司 | 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
WO2014099586A1 (en) * | 2012-12-17 | 2014-06-26 | Merck Sharp & Dohme Corp. | 4-pyridinonetriazine derivatives as hiv integrase inhibitors |
WO2015095227A2 (en) * | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
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