CN105418444A - Preparation method for N-triphenyl methyl-glycine ethyl ester - Google Patents
Preparation method for N-triphenyl methyl-glycine ethyl ester Download PDFInfo
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- CN105418444A CN105418444A CN201510899727.2A CN201510899727A CN105418444A CN 105418444 A CN105418444 A CN 105418444A CN 201510899727 A CN201510899727 A CN 201510899727A CN 105418444 A CN105418444 A CN 105418444A
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Abstract
The invention discloses a preparation method for N-triphenyl methyl-glycine ethyl ester, and mainly aims at solving the technical problems that in an original synthesis technology, the reaction time is long, the yield is low, and the cost is high. According to the technical scheme, the preparation method for N-triphenyl methyl-glycine ethyl ester is characterized by comprising the following steps that 1, h-gly-oet.hcl is prepared into trt-gly-oet, wherein the h-gly-oet.hcl is dissolved in organic solvent DMF, an aminoacyl compound triphenylchloromethane and a nucleophilic reagent N,N-diisopropylethylamine are added, and crude trt-gly-oet is obtained on the condition of regulating the pH value of the system; 2, the crude trt-gly-oet is prepared into a high-content pure product, wherein the coarse trt-gly-oet is dissolved through a certain amount of absolute ethyl alcohol, cooling crystallization is performed, vacuum suction filtering is performed, the product is washed with a petroleum ether belt, then drying is performed to obtain the pure trt-gly-oet, and a PLC process is performed. According to the preparation method, the N-triphenyl methyl-glycine ethyl ester is prepared under the technological condition and is suitable for batch production.
Description
Technical field
The present invention relates to the preparation method of a kind of N-trityl group-glycine ethyl ester.
Background technology
In currently available technology, h-gly-oet.hcl is dissolved in dcm by the syntheti c route employing method of N-trityl group-glycine ethyl ester, reflux 72 hours even a couple of days afterwards, and TLC detects its reaction process, through washing after having reacted, be concentrated into dry, add sherwood oil crystallization, purify repeatedly through recrystallization again and obtain trt-gly-oet, this method needs reflux, need to continue someone and look after the lasting TLC detection reaction process of reaction, because the cycle is long, yield is low, cost is high, and due to high temperature reflux sampling analysis also relative difficulty, and condition controls not with great difficulty stock, be not suitable for commercially producing.Another problem is, prior art divides water due to high temperature, and actual mechanical process does needs personnel's nurse continuously in 24 hours, cost increase.
Summary of the invention
The object of the invention is to overcome the complicacy in former technique, and the technical problems such as cost is high, and yield is low, provide a kind of N-preparation method of trityl group-glycine ethyl ester, the method is simple and easy to control, and yield is high, and cost is low, is suitable for large-scale production.
In order to reach foregoing invention object, the technical solution used in the present invention is: a kind of preparation method of N-trityl group-glycine ethyl ester, is characterized in that, comprise the following steps:
A, is prepared into trt-gly-oet by h-gly-oet.hcl: be dissolved in by h-gly-oet.hcl in organic solvent DMF, adds aminoacyl compound triphenylmethyl chloride, triethylamine and nucleophilic reagent DMAP afterwards, through being obtained by reacting trt-gly-oet crude product;
B, is prepared into the sterling of high-content by crude product trt-gly-oet: by crude product after a certain amount of anhydrous alcohol solution through overcooling crystallization, final vacuum suction filtration also washes product with sherwood oil band, and post-drying obtains sterling trt-gly-oet, process TLC detection reaction process.
Described the first step h-gly-oet.hcl, triphenylmethyl chloride, triethylamine with the ratio of the amount of substance of DMAP are: 1:(1.5-2.2): (1.5-2.5): (0.9-1.05).
Temperature of reaction described in the described the first step is 15-30 DEG C, and the reaction times is: 24-36 hour.
Described solvent DMF, it with the ratio of h-gly-oet.hcl is: 1gh-gly-oet.hcl adds 10ml solvent DMF.
Described solvent dehydrated alcohol, it with the ratio of crude product trt-gly-oet is: 1g crude product trt-gly-oet is dissolved in the solvent of 1.3ml; The temperature of described crystallisation by cooling is 10-20 DEG C.
Described process TLC, its developping agent used is methylene dichloride.
The implication of abbreviation used in the present invention or English full name is as follows:
H-gly-oet.hcl: glycine ethyl ester hydrochloride
Trt-gly-oet: trityl glycine ethyl ester
DMF:N, dinethylformamide
THF: tetrahydrofuran (THF)
DMAP:N, N-diisopropylethylamine
NMR: nucleus magnetic resonance (hydrogen spectrum)
HPLC: high performance liquid chromatography.
Beneficial effect of the present invention: the present invention, by h-gly-oet.hcl is directly prepared trt-gly-oet, enormously simplify technique, reduces cost, be applicable to scale operation, the trt-gly-oet yield that this technique obtains is high, and quality is also significantly improved.
Accompanying drawing explanation
Fig. 1 is product nuclear magnetic spectrum of the present invention.
Fig. 2 is product color atlas of the present invention.
Embodiment
Below in conjunction with specific examples, the present invention is described in detail, but is not to further restriction of the present invention.
Embodiment 1,
1000mlDMF is added in the there-necked flask of 2000ml, add 100gH-gly-oet.hcl afterwards, stir, be cooled to less than 10 DEG C, be added dropwise to 299.5g trityl chloride, system temperature is dropped to 5 degrees Celsius, be added dropwise to 108.7g triethylamine again, add 78.8gDMAP again, react 36 hours at 15 DEG C, add 500ml water afterwards, leave standstill after 1000ml ethyl acetate stirs and be divided into, wash 3 times again with water, saturated salt washes 2 times, process TLC (methylene dichloride), be concentrated into dry cooling crystallization afterwards and add sherwood oil grinding, gained solid dry product 251g, be crude product trt-gly-oet, afterwards by the trt-gly-oet dissolving crude product of 251g in the dehydrated alcohol of 326.3ml, being heated to 45 DEG C makes it dissolve completely, be cooled to 15 DEG C of post crystallizations afterwards, within about 2 hours, final vacuum suction filtration obtains off-white color, obtain solid after washing twice with appropriate sherwood oil band to obtain: 84g, HPLC:96.2%, correct through NMR detection architecture.See Fig. 1,2.
Embodiment 2,
1300mlDMF is added in the there-necked flask of 2000ml, add 139.6gH-gly-oet.hcl afterwards, stir, be cooled to less than 10 DEG C, be added dropwise to 515.7g trityl chloride, system temperature is dropped to 5 degrees Celsius, be added dropwise to 202.4g triethylamine again, add 119.1gDMAP again, react 24 hours at 15 DEG C, add 700ml water afterwards, leave standstill after 1500ml ethyl acetate stirs and be divided into, wash 3 times again with water, saturated salt washes 2 times, process TLC (methylene dichloride), be concentrated into dry cooling crystallization afterwards and add sherwood oil grinding, gained solid dry product 456g, be crude product trt-gly-oet, afterwards by the trt-gly-oet dissolving crude product of 456g in the dehydrated alcohol of 592.8ml, being heated to 45 DEG C makes it dissolve completely, be cooled to 15 DEG C of post crystallizations afterwards, within about 2 hours, final vacuum suction filtration obtains off-white color, obtain solid after washing twice with appropriate sherwood oil band to obtain: 161g, HPLC:95.7%, correct through NMR detection architecture.See Fig. 1,2.
Embodiment 3,
500mlDMF is added in the there-necked flask of 2000ml, add 69.8gH-gly-oet.hcl afterwards, stir, be cooled to less than 10 DEG C, be added dropwise to 306.7g trityl chloride, system temperature is dropped to 5 degrees Celsius, be added dropwise to 126.5g triethylamine again, add 64.1gDMAP again, react 24 hours at 15 DEG C, add 300ml water afterwards, leave standstill after 800ml ethyl acetate stirs and be divided into, wash 3 times again with water, saturated salt washes 2 times, process TLC (methylene dichloride), be concentrated into dry cooling crystallization afterwards and add sherwood oil grinding, gained solid dry product 182g, be crude product trt-gly-oet, afterwards by the trt-gly-oet dissolving crude product of 182g in the dehydrated alcohol of 236.6ml, being heated to 45 DEG C makes it dissolve completely, be cooled to 10 DEG C of post crystallizations afterwards, within about 2 hours, final vacuum suction filtration obtains off-white color, obtain solid after washing twice with appropriate sherwood oil band to obtain: 79g, HPLC:93.2%, correct through NMR detection architecture.See Fig. 1,2.
Embodiment 4:
1000mlDMF is added in the there-necked flask of 2000ml, add 100gH-gly-oet.hcl afterwards, stir, be cooled to less than 10 DEG C, be added dropwise to 270g trityl chloride, system temperature is dropped to 5 degrees Celsius, be added dropwise to 145g triethylamine again, add 84gDMAP again, react 24 hours at 15 DEG C, add 700ml water afterwards, leave standstill after 1500ml ethyl acetate stirs and be divided into, wash 3 times again with water, saturated salt washes 2 times, process TLC (methylene dichloride), be concentrated into dry cooling crystallization afterwards and add sherwood oil grinding, gained solid dry product 332g, be crude product trt-gly-oet, afterwards by the trt-gly-oet dissolving crude product of 332g in the dehydrated alcohol of 431.6ml, being heated to 45 DEG C makes it dissolve completely, be cooled to 20 DEG C of post crystallizations afterwards, within about 2 hours, final vacuum suction filtration obtains off-white color, obtain solid after washing twice with appropriate sherwood oil band to obtain: 120g, HPLC:97.04% is correct through NMR detection architecture.See Fig. 1,2.
Claims (6)
1. a preparation method for N-trityl group-glycine ethyl ester, is characterized in that, comprise the following steps:
A, h-gly-oet.hcl is prepared into trt-gly-oet: be dissolved in by h-gly-oet.hcl in organic solvent DMF, add aminoacyl compound triphenylmethyl chloride, triethylamine and nucleophilic reagent DIPEA afterwards, through being obtained by reacting trt-gly-oet crude product;
B, is prepared into the sterling of high-content by crude product trt-gly-oet: by crude product after a certain amount of anhydrous alcohol solution through overcooling crystallization, vacuum filtration also washes product with sherwood oil band, and post-drying obtains sterling trt-gly-oet, process TLC detection reaction process.
2. the preparation method of a kind of N-trityl group-glycine ethyl ester according to claim 1, it is characterized in that, in described step a, h-gly-oet.hcl, triphenylmethyl chloride, triethylamine with the ratio of the amount of substance of DIPEA are: 1:(1.5-2.2): (1.5-2.5): (0.9-1.05).
3. the preparation method of a kind of N-trityl group-glycine ethyl ester according to claim 1, is characterized in that, in described step a, described temperature of reaction is 15-30 DEG C, and the reaction times is: 24-36 hour.
4. the preparation method of a kind of N-trityl group-glycine ethyl ester according to claim 1, is characterized in that, in described step a, described solvent DMF with the interpolation ratio of h-gly-oet.hcl is: 1gh-gly-oet.hcl adds 10ml solvent DMF.
5. the preparation method of a kind of N-trityl group-glycine ethyl ester according to claim 1, it is characterized in that, in described step b: described solvent dehydrated alcohol, it with the ratio of crude product trt-gly-oet is: 1g crude product trt-gly-oet is dissolved in the solvent of 1.3ml; The temperature of described crystallisation by cooling is 10-20 DEG C.
6. the preparation method of a kind of N-trityl group-glycine ethyl ester according to claim 1, is characterized in that, in step b, its developping agent used of process TLC detection reaction process is methylene dichloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108341840A (en) * | 2017-01-21 | 2018-07-31 | 深圳华润九新药业有限公司 | The preparation method of Ceftaroline Fosamil |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2994692A (en) * | 1954-08-18 | 1961-08-01 | Roussel Uclaf | Process of preparing nu-trityl peptides |
| CN1251037A (en) * | 1996-03-20 | 2000-04-19 | 哈佛学院董事及会员团体 | Triaryl methane compounds for sickle cell disease |
-
2015
- 2015-12-09 CN CN201510899727.2A patent/CN105418444A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2994692A (en) * | 1954-08-18 | 1961-08-01 | Roussel Uclaf | Process of preparing nu-trityl peptides |
| CN1251037A (en) * | 1996-03-20 | 2000-04-19 | 哈佛学院董事及会员团体 | Triaryl methane compounds for sickle cell disease |
Non-Patent Citations (2)
| Title |
|---|
| HERNANDEZ, O.等: "SYNTHESIS AND CHARACTERIZATION OF 4-DIMETHYLAMINO-K-TRIPHENYLMETHYLPYRIDINIUM CHLORIDE, A POSTULATED INTERMEDIATE IN THE TRITYLATION OF ALCOHOLS", 《TETRAHEDRON LETTERS》 * |
| JEFF J.-H. WANG等: "Stereospecific Synthesis of Tetradeuterated (R)- and (S)-ifosfamide", 《JOURNAL OF LABELLED COMPOUNDS AND RODIOPHARMACEUTICALS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108341840A (en) * | 2017-01-21 | 2018-07-31 | 深圳华润九新药业有限公司 | The preparation method of Ceftaroline Fosamil |
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Application publication date: 20160323 |