CN104926704A - Nitrogen heterocyclic propane compound and preparation method thereof - Google Patents
Nitrogen heterocyclic propane compound and preparation method thereof Download PDFInfo
- Publication number
- CN104926704A CN104926704A CN201410098898.0A CN201410098898A CN104926704A CN 104926704 A CN104926704 A CN 104926704A CN 201410098898 A CN201410098898 A CN 201410098898A CN 104926704 A CN104926704 A CN 104926704A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- preparation
- triazo
- nitrogen heterocyclic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a nitrogen heterocyclic propane compound and a preparation method thereof. The nitrogen heterocyclic propane compound is an intermediate for synthesis of a diphenyl amino propanol compound. (S)-1-(diphenyl-4-yl)-3-chloropropane-2-ol as a raw material is subjected to a reaction in an alkali to obtain a diphenyl epoxypropane compound, then the diphenyl epoxypropane compound is subjected to a reaction with sodium azide, then after reduction, the product is subjected to a reaction with an acid anhydride, then the product is subjected to a Mitsunobu reaction to obtain the nitrogen heterocyclic propane compound. The preparation method is simple in preparation route reaction mechanism, mild in reaction conditions and low in cost, can obtain the stable product, and is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to nitrogen heterocycle propane compound of Biphenylmethyl replacement and preparation method thereof.
Background technology
The invention provides a kind of ethylenimine compounds, is the intermediate of synthesis benzidino-propanol compound.Its structural formula of benzidino-propanol compound is as follows:
, wherein, * represents to have chirality.Now, the compound of this structural formula can have the compound of pharmaceutical active or the intermediate of pharmaceutically active compound for the synthesis of many.As worked as R in structural formula
1during for hydrogen or tertbutyloxycarbonyl, its chemical name is 3-biphenyl-R-2-aminopropanol or N-tertbutyloxycarbonyl-R-biphenylalanine, and its structural formula is as follows respectively:
，
，
They are two important intermediate compounds of synthetic drugs activeconstituents nep inhibitor, specifically can see patent WO2013026773.
Ethylenimine compounds provided by the invention prolongs reaction by light and prepares, and light prolongs reaction and relates to following route at document Highly regioselective ring-opening of trisubstituted aziridines by sulfurstabilised carbanions Issue 4 Pages 451-453 2009:
，
In the present invention light prolong reaction lacked vinyl compared to documents raw material and product, Cheng Huan is more stable in institute, more economically.
Prepare through reduction reaction after the propylene oxide compound that the raw material that light provided by the invention prolongs reaction is replaced by Biphenylmethyl and reaction of sodium azide generate trinitride.Although the reaction through reducing after the propylene oxide compound that in prior art, known phenyl replaces and reaction of sodium azide, the reaction effect that the reaction scheme that the present invention's xenyl replacement phenyl obtains also can obtain.
Ethylenimine compounds provided by the invention, its syntheti c route reaction mechanism is simple, and reaction conditions is gentle, and cost is low, can obtain stable product, is applicable to suitability for industrialized production.
Summary of the invention
The invention provides a kind of ethylenimine compounds, especially there is the ethylenimine compounds of optical purity, especially the ethylenimine compounds of R configuration.Its syntheti c route reaction mechanism is simple, and reaction conditions is gentle, and cost is low, can obtain stable product, is applicable to suitability for industrialized production.
Ethylenimine compounds provided by the invention, except nitrogen-containing hetero cyclopropane moiety, is also replaced by Biphenylmethyl.Its structural formula is as follows:
，
Wherein, R
1for hydrogen, tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, to nitrobenzyloxycarbonyl, * represents to have optical configuration.
The route of nitrogen heterocycle propane compound synthesis benzidino-propanol compound provided by the invention is as follows:
，
In this reaction scheme, nitrogen heterocycle propane compound can prepare benzidino-propanol compound through hydrolysis after first open loop in glacial acetic acid.
Ethylenimine compounds provided by the invention is preferably as follows the compound of structure:
，
。
Nitrogen heterocycle propane compound provided by the invention prolongs reaction preparation through light, and route is as follows:
, wherein, R
1for hydrogen, tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, to nitrobenzyloxycarbonyl.
It is as follows that described light prolongs the preferred reaction scheme of reaction:
。
Described light prolongs the combination that reaction reagent is phosphorus reagent and dialkyl group azodicarboxylate.
Wherein, described phosphorus reagent is phosphorane class or phosphine class.Described phosphorane class is (cyanogen methylene radical) tributyl phosphorane or (cyanogen methylene radical) trimethylammonium phosphorane; Described phosphine class is triphenylphosphine.
Wherein, described dialkyl group azodicarboxylate is diisopropyl azo-2-carboxylic acid or diethylazodicarboxylate.
Described light prolongs the raw material type I compound of reaction by triazo-compound preparation after reduction, or prepares with protecting group on anhydride reaction further,
，
Prepared through hydrogen-palladium charcoal reduction by triazo-compound such as formula I-1 compound, route is as follows:
，
Formula I-2 compound reacts Boc protecting group with aceticanhydride by triazo-compound and prepares after hydrogen-palladium charcoal reduces, and reaction scheme is as follows:
。
Described triazo-compound is prepared by biphenyl propylene oxide compound and reaction of sodium azide, and reaction scheme is as follows:
。
Described biphenyl propylene oxide compound is by (S)-1-(biphenyl-4-base)-3-chloropropane-2-alcohol prepared under alkali effect, and reaction scheme is as follows:
。
The synthetic method of ethylenimine compounds of the present invention, its reaction scheme is as follows:
，
Wherein, R
1for hydrogen, tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, to nitrobenzyloxycarbonyl.
The synthetic method of ethylenimine compounds of the present invention, a preferred reaction scheme is:
。
The invention provides a kind of ethylenimine compounds, its syntheti c route reaction mechanism is simple, and reaction conditions is gentle, and cost is low, can obtain stable product, is applicable to suitability for industrialized production.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, ethylenimine compounds provided by the invention and preparation method thereof is described in detail.It is to be appreciated that these embodiments describe just for further describing feature of the present invention, instead of the restriction to the scope of the invention or the claims in the present invention scope.
Embodiment 1:
，
24.65g(S is added in 500ml four-hole bottle)-1-(biphenyl-4-base)-3-chloropropane-2-alcohol, 370ml toluene, 4.8g sodium hydroxide, be warming up to 70 ~ 75 DEG C, insulation reaction 6h, TLC detection reaction terminates (He:EA=3:1), be cooled to 25 ~ 30 DEG C, add 200ml water, stir 30 minutes, layering, water layer toluene 150ml extracts once, merge organic layer, saturated sodium-chloride 150ml washs once, 50 ~ 55 DEG C are evaporated to dry, add new toluene 120ml, gac 1g, be warming up to 60 ~ 65 DEG C, insulated and stirred 60 minutes, filter, filtrate is cooled to 30 ~ 35 DEG C, stir 1h, be cooled to 10 ~ 15 DEG C and stir 2h, filter, obtain epoxide 19.3g, yield 92%.
1HNMR（400MHz CDCl
3）δ：7.37-7.61（9H），3.10-3.30(1H)，2.92-2.98(2H)，2.62-2.86(2H)
Mass：211.1(M+H)+
α
D 25+59.70 （C=0.01g/ml，CH
2Cl
2）
Embodiment 2:
，
10.0 g biphenyl propylene oxide compound are added, 5.0 g NaN in 500ml four-hole bottle
3, 1 ml TEA, 200 ml methyl alcohol.React 18 hours at 20 ~ 25 DEG C, some board monitoring reaction substantially completely (HE:EA=3:1).Concentrate and steam 100 ml methyl alcohol, then add 150 mL water.Filter, 100 ml water washings, filter cake 150ml acetic acid ethyl dissolution, the saturated NaCl washing of 100 ml, anhydrous sodium sulfate drying.Filtration, concentrated doing to obtain 11 g gray solid.Cross post to be separated, EA/HE=1/10 rinses, and obtains 6g white solid, yield 60%.
1HNMR（400MHz CDCl
3）δ：7.31-7.62(9H)，4.06-4.09(1H)，3.34-3.48(2H)，2.87-2.90(2H)，2.02-2.03(1H)
Mass：254.1(M+H)+
α
D 25-55.30 （C=0.01g/ml，CH
2Cl
2）
TEA is triethylamine, and HE is normal heptane, and EA is ethyl acetate.
Embodiment 3:
，
In 100ml four-hole bottle, add 3.9 g triazo-compounds, add 50 ml methyl alcohol, 1 g 10% Pd/C (containing 65% moisture).With hydrogen exchange three times, then in normal pressure, react 18 hours at 20 ~ 25 DEG C.Point board monitoring, reacts completely, adds 3.5 g aceticanhydrides, 1.7 g TEA.React 1 hour at 20 ~ 25 DEG C.Point board monitoring, reacts completely, is heated to 50 ~ 55 DEG C of dissolved solidss, filters, by 15 ml methanol wash.Concentrated dry, obtain white solid 4 5.1 g, yield 100%.
Embodiment 4:
，
1.92 g PPh are added in 100ml four-hole bottle
3, 10 ml THF, are cooled to-5 DEG C.1.48 g diisopropyl azo-2-carboxylic acids are dripped at 10 DEG C.At 0 DEG C, drip 2.0 g formula I-2 compound/20 ml THF, then rise to 20 DEG C of reactions 18 hours.Concentrated dry, with silica column purification, EA/HE=1/10 rinses and obtains 1.4 g white solids, yield 74%.
1HNMR（400MHz CDCl
3）δ：7.36-7.62(9H)，2.98-3.04(1H)，2.67-2.78(2H)，2.35-2.37(1H)， 2.08-2.09(1H)，1.40-1.56(9H)
Mass：310.2(M+H)+
α
D 25-37.96 （C=0.01g/ml，CH
2Cl
2）
Embodiment 5:
，
3.84 g PPh are added in 100ml four-hole bottle
3, 20ml THF, is cooled to-5 DEG C.2.96g diisopropyl azo-2-carboxylic acid is dripped at 10 DEG C.At 0 DEG C, drip formula I-1 compound 4.0 g/40 ml THF, then rise to 20 DEG C of reactions 15 hours.Concentrated dry, with silica column purification, EA/HE=1/8 rinses and obtains 2.8 g white solids, yield 75%.
Embodiment 6:
，
2.83 g PPh are added in 100ml four-hole bottle
3, 30 ml THF, are cooled to-5 DEG C.2.28 g diisopropyl azo-2-carboxylic acids are dripped at 10 DEG C.Formula I (R is dripped at 0 DEG C
1for methylsulfonyl) compound 3.0 g/30 ml THF, then rise to 20 DEG C of reactions 18 hours.Concentrated dry, with silica column purification, EA/HE=1/10 rinses and obtains 1.5 g white solids, yield 53%.
Embodiment 7:
，
2.88 g PPh are added in 250ml four-hole bottle
3, 30 ml toluene, are cooled to-5 DEG C.2.32g diisopropyl azo-2-carboxylic acid is dripped at 10 DEG C.Formula I (R is dripped at 0 DEG C
1for p-toluenesulfonyl) compound 3.81 g/30 ml toluene, then rise to 20 DEG C of reactions 18 hours.Concentrated dry, with silica column purification, EA/HE=1/10 rinses and obtains 2.6g white solid, yield 72%.
Embodiment 8:
，
2.88 g PPh are added in 250ml four-hole bottle
3, 40 ml toluene, are cooled to-5 DEG C.2.32g diisopropyl azo-2-carboxylic acid is dripped at 10 DEG C.Formula I (R is dripped at 0 DEG C
1for to nitrobenzyloxycarbonyl) compound 4.06g/40 ml toluene, then rise to 20 DEG C of reactions 18 hours.Concentrated dry, with silica column purification, EA/HE=1/10 rinses and obtains 2.8g white solid, yield 72%.
Claims (10)
1. an ethylenimine compounds, its structural formula is:
，
Wherein, R
1for hydrogen, tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, to nitrobenzyloxycarbonyl, * represents to have optical configuration.
2. ethylenimine compounds according to claim 1, its structural formula is:
，
。
3. a preparation method for ethylenimine compounds, is characterized in that, prolongs reaction prepare by type I compound through light,
，
Wherein, R
1for hydrogen, tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, to nitrobenzyloxycarbonyl.
4. preparation method according to claim 3, is characterized in that, described type I compound is prepared with anhydride reaction after reduction by triazo-compound,
。
5. preparation method according to claim 3, is characterized in that, formula I-1 compound is prepared after reduction by triazo-compound,
。
6. preparation method according to claim 3, is characterized in that, formula I-2 compound is reacted with aceticanhydride after reduction by triazo-compound to be prepared,
。
7. the preparation method according to claim 4,5 or 6, is characterized in that, described triazo-compound is prepared by biphenyl propylene oxide compound and reaction of sodium azide,
。
8. preparation method according to claim 7, is characterized in that, described biphenyl propylene oxide compound is by (S)-1-(biphenyl-4-base)-3-chloropropane-2-alcohol prepared under alkali effect,
。
9. a biphenyl propylene oxide compound, its structural formula is:
。
10. a triazo-compound, its structural formula is:
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410098898.0A CN104926704B (en) | 2014-03-18 | 2014-03-18 | Aziridine class compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410098898.0A CN104926704B (en) | 2014-03-18 | 2014-03-18 | Aziridine class compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104926704A true CN104926704A (en) | 2015-09-23 |
| CN104926704B CN104926704B (en) | 2019-03-05 |
Family
ID=54114162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410098898.0A Active CN104926704B (en) | 2014-03-18 | 2014-03-18 | Aziridine class compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926704B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108238981A (en) * | 2016-12-23 | 2018-07-03 | 宁波爱诺医药科技有限公司 | A kind of preparation method of LCZ-696 key intermediates |
| CN113387829A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯（深圳）科技有限公司 | Preparation method of shakubiqu |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863361A (en) * | 2012-10-17 | 2013-01-09 | 湖北美天生物科技有限公司 | Chiral catalytic synthesis method of thiamphenicol |
| WO2013026773A1 (en) * | 2011-08-19 | 2013-02-28 | Dsm Ip Assets B.V. | Synthesis of r-biphenylalaninol |
| WO2014032627A1 (en) * | 2012-08-31 | 2014-03-06 | Zhejiang Jiuzhou Pharmaceutical Co., Ltd | New process |
-
2014
- 2014-03-18 CN CN201410098898.0A patent/CN104926704B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013026773A1 (en) * | 2011-08-19 | 2013-02-28 | Dsm Ip Assets B.V. | Synthesis of r-biphenylalaninol |
| WO2014032627A1 (en) * | 2012-08-31 | 2014-03-06 | Zhejiang Jiuzhou Pharmaceutical Co., Ltd | New process |
| CN102863361A (en) * | 2012-10-17 | 2013-01-09 | 湖北美天生物科技有限公司 | Chiral catalytic synthesis method of thiamphenicol |
Non-Patent Citations (5)
| Title |
|---|
| JIAXI XU: "A new and expeditious asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic acids from chiral amino alcohols", 《TETRAHEDRON: ASYMMETRY》 * |
| MAITÉ SYLLA-IYARRETA VEITÍA等: "Synthesis of novel N-protected b3-amino nitriles: study of their hydrolysis involving a nitrilase-catalyzed step", 《TETRAHEDRON: ASYMMETRY》 * |
| NICOLA K. JOBSON等: "Design and synthesis of (2R,3S)-iodoreboxetine analogues for SPECT imaging of the noradrenaline transporter", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| ROBERT CHENEVERT等: "Chemoenzymatic Synthesis of Chiral β-Azidoalcohols.Application to the Preparation of Chiral Aziridines and Aminoalcohols", 《TETRAHEDROM:ASYMMETRY》 * |
| SANTIAGO CARBALLARES等: "Highly regioselective ring-opening of trisubstituted aziridines by sulfur-stabilised carbanions", 《CHEMCOMM》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108238981A (en) * | 2016-12-23 | 2018-07-03 | 宁波爱诺医药科技有限公司 | A kind of preparation method of LCZ-696 key intermediates |
| CN113387829A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯（深圳）科技有限公司 | Preparation method of shakubiqu |
| CN113387829B (en) * | 2020-03-13 | 2023-04-07 | 凯特立斯（深圳）科技有限公司 | Preparation method of shakubiqu |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104926704B (en) | 2019-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103121999A (en) | Method for synthesizing tyrosine kinase inhibitor PCI-32765 | |
| CN105601524B (en) | The preparation of LCZ696 key intermediates | |
| CN102985416A (en) | Process of preparing a thrombin specific inhibitor | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN108947894A (en) | Novel biaryl structure chirality N- methylpyridoxal catalyst and its synthesis and application | |
| CN101563312A (en) | Process for producing intermediate of asenapine synthesis | |
| CN103124557A (en) | Pure erlotinib | |
| CN101952246B (en) | A one-pot process for preparing 3-(2,2,2-trimethylhydrazinium)propionate dihydrate | |
| ITMI20121390A1 (en) | PROCEDURE FOR THE PREPARATION OF 2-CYANOPHENYLBORONIC ACID AND ITS ESTERS, INTERMEDIATE OF THE PERAMPANEL OR E2040 | |
| CN104926704A (en) | Nitrogen heterocyclic propane compound and preparation method thereof | |
| CN101302207B (en) | Preparation of 3-o-alkyl-5,6-o-(1-methyl ethylidine)-l-ascorbic acid and preparation of 5,6-o-(1- methyl ethylidine)-l- ascorbic acid | |
| CN106543018A (en) | The method for preparing scheme for lacosamide | |
| BRPI0709209A2 (en) | hydride reduction process for preparation of quinolone intermediates | |
| CN105148988A (en) | Chiral pyridoxal catalysts and synthetic method therefor and application thereof | |
| PT2488497E (en) | Process for manufacturing 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid | |
| CN114014863B (en) | Preparation method of bone marrow protective agent traasiril | |
| CN108084438A (en) | A kind of phenyl T10 cage-type silsesquioxanes and its synthetic method and application | |
| CN104672179B (en) | Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| EP4081503A1 (en) | A process for the synthesis of melphalan | |
| JPWO2004110972A1 (en) | (2R) -2-Propyloctanoic acid production method and intermediate | |
| CN102153518A (en) | Preparation method of Gefitinib | |
| JPH09507225A (en) | Method for producing isocyanate | |
| CN108440374A (en) | A kind of preparation method of acemetacin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 310018 Heke science and technology center, No. 500 QiaoXin Road, Xiasha street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee after: Zhejiang Jiuzhou biomedical Co.,Ltd. Address before: 310051 fifth floor, building 4, No. 88, Jiangling Road, Binjiang District, Hangzhou, Zhejiang Patentee before: ZHEJIANG JIUZHOU PHARMA SCIENCE & TECHNOLOGY Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210924 Address after: 215537 No. 18, Tonglian Road, Bixi street, Changshu, Suzhou, Jiangsu Patentee after: Ruibo (Suzhou) Pharmaceutical Co.,Ltd. Address before: 310018 Heke science and technology center, No. 500 QiaoXin Road, Xiasha street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee before: Zhejiang Jiuzhou biomedical Co.,Ltd. |
|
| TR01 | Transfer of patent right |