CN1850785A - N,N-dibasic glycine 3,7-dimethyl n-octyl ester, and its preparing method and use - Google Patents

N,N-dibasic glycine 3,7-dimethyl n-octyl ester, and its preparing method and use Download PDF

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CN1850785A
CN1850785A CN 200610035728 CN200610035728A CN1850785A CN 1850785 A CN1850785 A CN 1850785A CN 200610035728 CN200610035728 CN 200610035728 CN 200610035728 A CN200610035728 A CN 200610035728A CN 1850785 A CN1850785 A CN 1850785A
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dimethyl
monooctyl ester
glycine
dibasic
ester
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王子元
李伟杰
林佩玉
肖叶玉
李谷平
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Shantou University
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Abstract

This invention relates to n,n-bi substitution glycine-3,7-dimethyl ortho oct ester preparation method and its application. Its structure formula is shown as formula I, its preparation method is that chloracetyl chloride is reacted with 3,7-dimethyl-1-octanol for 1-3 hours at room temperature, then they reacted with excess 33 percent dimethylamine agueous solution for 1-3 hours at room temperature to synthesize object I, whole yield is 74-83 percent. The n, n-bi substitution glycine-3,7-dimethyl ortho oct ester related in this invention can be used as one kind of skin penetrating agent.

Description

N, N-dibasic glycine-3,7-dimethyl n monooctyl ester and its production and application
Technical field
The present invention relates to N, N-dibasic glycine-3, the application of transdermal agent in 7-dimethyl n monooctyl ester and preparation method thereof and conduct preparation medicine or the makeup.
Background technology
N, N-disubstituted glycine ester are the novel biodegradable transdermal agents of a class.Experimental study shows: N, N-N-methylsarcosine ester in the last of the ten Heavenly stems and N, the N-N-methylsarcosine-(E)-3,7-dimethyl-2, the drug effect that 6-octadiene ester promotes the medicine INDOMETHACIN to absorb through skin is several times (the 1. Li Wei outstanding person of Azone (1-positive dodecyl aza cyclohepta ketone-2), Xu Zunle, Wang Bo, Zhongshan University's journal (natural science edition), 2003,42 (6), 44-46,50; 2. Li Wei outstanding person, Xu Zunle, chemical research and application, 2005,17 (6), 762-765).This compounds can be applicable to creme, paste and the liniment in medicine, the makeup, strengthens the osmotic absorption effect of medicine to skin, strengthens drug effect; Also can be applicable in the plant nutrition liquid, strengthen the absorption of plant nutritive medium.Potential application prospect is widely arranged.
The US4980378 patent disclosure (CH 3) 2NCH 2CO 2(CH 2) nCH 3(n=5,7,9,11,13) and (C 2H 5) 2NCH 2CO 2(CH 2) 11CH 3Synthetic method Deng compound.Its method is: chloroacetyl chloride and high fatty alcohol room temperature reaction 16 hours in the presence of triethylamine and anhydrous chloroform, make chloracetate, and obtain N with excessive decil ethereal solution or diethylamine reaction then, N-disubstituted glycine ester, productive rate are 72%～94%.Its shortcoming is that the chloroform give solvent is used in the reaction of the 1st step, and triethylamine is made acid binding agent, and the reaction times is longer; The 2nd step reaction is with the diethyl ether solution of 1mol/L dimethylamine, operates dangerously, is difficult to industrialization.We studies show that, chloroform is unfavorable for chloroacetyl chloride and high fatty alcohol acylation reaction at room temperature, and chloroform toxicity is big; Though triethylamine plays acid binding agent, acidylate the reaction times increase on the contrary.
CN1091122 has improved N, the synthetic method of N-N-methylsarcosine ester in the last of the ten Heavenly stems.This method is: at solvent-free or toluene is under the solvent, chloroacetyl chloride and 1-decanol adopt solid-liquid phase transfer catalysis method reaction 4h～10h synthesis of chloroacetic acid ester in the last of the ten Heavenly stems, obtain N with excessive dimethylamine gas reaction 2h then, N-N-methylsarcosine ester in the last of the ten Heavenly stems, productive rate are 80.8%～86.1%.Its shortcoming is that the building-up reactions cost increases complex operation.Show: the 1st step reaction is made phase-transfer catalyst with TBAI or PEG-400, and pasty state is stirred into earlier in decyl alcohol, alkali and mixture of catalysts heating, is cooled to just to splash into chloroacetyl chloride after the room temperature and carry out acylation reaction; Catalyzer TBAI is somewhat expensive, and PEG-400 makes phase-transfer catalyst, and the reaction times is long partially; The reaction of the 2nd step feeds dimethylamine gas with cryosel and bathes in the refrigerative reaction system, needs to increase dimethylamine gas and takes place and transport unit, and will make solvent with toluene.
The contriver has systematically studied N, and the synthetic method of N-disubstituted glycine ester and intermediate chloracetate thereof makes the preparation method of this compounds be more suitable in suitability for industrialized production (1. Li Wei outstanding person, Lu Yu, Xu Zunle, fine-chemical intermediate, 2005,35 (5), 41-42; 2. Li Wei outstanding person, Lu Yu, Xu Zunle, chemical reagent, 2005,27 (9), 565-567; 3. Li Wei outstanding person, Lu Yu, Xu Zunle, fine chemistry industry, 2005,22 (11), 859-861; 4. Li Wei outstanding person, Xu Zunle, chemical research and application, 2005,17 (6), 762-765).
Summary of the invention
The object of the present invention is to provide N, N-dibasic glycine-3,7-dimethyl n monooctyl ester, the application in its preparation method and conduct preparation medicine or the makeup.
N provided by the present invention, N-dibasic glycine-3,7-dimethyl n monooctyl ester comprises N, N-N-methylsarcosine-3,7-dimethyl n monooctyl ester, N, N-diethyl glycine-3,7-dimethyl n monooctyl ester and N, N-bicine N--3,7-dimethyl n monooctyl ester, its general structure is suc as formula shown in the I:
Figure A20061003572800061
Wherein R represents CH 3, C 2H 5Or CH 2CH 2OH.
General formula of the present invention is the compound N of I, N-dibasic glycine-3, and the synthetic route of 7-dimethyl n monooctyl ester is:
Figure A20061003572800062
The processing step of its preparation method is:
(1). at room temperature, 3, splash into chloroacetyl chloride in 7-dimethyl-1-octanol and carry out acylation reaction; 3, the mol ratio of 7-dimethyl-1-octanol and chloroacetyl chloride is 1.0: 1.0～1.0: 1.3, is preferably 1.0: 1.1; the acylation reaction time is 1～3h, after the acylation reaction, and the saturated NaHCO of reaction solution 3Transfer to weakly alkaline, tell organic layer, water layer merges organic layer with ether or ethyl acetate extraction, through washing, drying, removes solvent under reduced pressure, and residue gets Mono Chloro Acetic Acid-3 through column chromatography, 7-dimethyl n monooctyl ester.
(2). at room temperature, Mono Chloro Acetic Acid-3, adding excessive general formula in the 7-dimethyl n monooctyl ester is R 2The compound of NH, reaction 1～3h tells organic layer, and water layer merges organic layer with ether or dichloromethane extraction, and drying removes solvent under reduced pressure, and residue gets target compound through column chromatography, Mono Chloro Acetic Acid-3 wherein, 7-dimethyl n monooctyl ester and R 2The mol ratio of NH is 1.0: 1.0～1.0: 2.5, R 2R among the NH gets the group identical with the R of general formula I.
Among the above-mentioned preparation method, 3, the optimum mole ratio of 7-dimethyl-1-octanol and chloroacetyl chloride is 1.0: 1.1, Mono Chloro Acetic Acid-3,7-dimethyl n monooctyl ester and R 2The optimum mole ratio of NH is 1.0: 2.0.
Among the above-mentioned preparation method, R 2R in the NH formula gets the group identical with the R of general formula I, and promptly the R when general formula I gets CH 3The time, R 2R among the NH also gets CH 3, R 2NH is 33% dimethylamine agueous solution; When the R of general formula I gets C 2H 5, R 2R among the NH also gets C 2H 5, R 2NH is a diethylamine; When R gets CH 2CH 2During OH, R 2NH is a diethanolamine.
The menthol derivative of general formula I of the present invention is as the application of transdermal agent.Can be used for preparing the transdermal agent in medicine or the makeup.
With the diclofenac sodium is drug model, the rat skin is a biological film model, we have carried out Compound I medicine have been oozed active simultaneous test through skin is short, experimental result shows: contain 2.0% N, N-diethyl glycine-3,7-dimethyl n monooctyl ester has good in the short activity of oozing of skin to the medicine diclofenac sodium, it is 3 times of blank group through the short effect of oozing of skin.N involved in the present invention, N-dibasic glycine-3,7-dimethyl n monooctyl ester can be used as a class transdermal agent, can be used for creme, paste, liniment and patch in medicine, the makeup, promotes absorbing through skin of medicine, strengthens drug effect.
Embodiment
Embodiment 1: invent described compound and synthetic, and with N, N-N-methylsarcosine-3,7-dimethyl n monooctyl ester is an example.
(1) Mono Chloro Acetic Acid-3,7-dimethyl n monooctyl ester synthetic
In the 100mL there-necked flask, place 43.42g 3,7-dimethyl-1-octanol at room temperature, splashes into the 23.8mL chloroacetyl chloride while stirring, after dropping liquid is intact, at room temperature continues to stir 2h.The saturated NaHCO of reaction solution 3Solution transfers to weakly alkaline, tells organic layer, and water layer merges organic layer with ether or ethyl acetate extraction, with saturated common salt washing, anhydrous Na 2SO 4Dried overnight, steaming desolventizes, and with the chloroform give eluent, column chromatography (silica gel is 100～300 orders) steams and removes eluent, gets colourless liquid 61.96g, and productive rate is 96.2%.The spectroscopic data of product is as follows:
1H?NMR(CDCl 3，400MHz)，δ：0.83(d，J＝5.6Hz，6H)，0.87(d，J＝5.2Hz，3H)，1.11～1.13(m，2H)，1.21～1.26(m，4H)，1.45～1.51(m，3H)，1.65～1.83(m，1H)，4.04(s，2H)，4.18～4.19(m，2H)。
(2) N, N-N-methylsarcosine-3,7-dimethyl n monooctyl ester synthetic
13.92g Mono Chloro Acetic Acid-3 adds 20.4mL 33% dimethylamine agueous solution in the 7-dimethyl n monooctyl ester, at room temperature stirring reaction 2h tells organic layer, and water layer merges organic layer with ether or ethyl acetate extraction, uses anhydrous Na 2SO 4Drying, steaming desolventizes, and makes eluent with ethyl acetate, and column chromatography (silica gel is 100～300 orders) steams and removes eluent, gets weak yellow liquid 12.40g, and productive rate is 85.9%.Product 1H NMR and ESI-MS spectrum are as follows:
1H?NMR(CDCl 3，400MHz)，δ：0.83(d，J＝6.8Hz，6H)，0.89(d，J＝6.4Hz，3H)，1.00～1.09(m，2H)，1.14～1.31(m，4H)，1.33～1.50(m，3H)，1.53～1.65(m，1H)，2.28(s，6H)，3.08(s，2H)，4.04～4.14(m，2H)。ESI-MS，m/z(％)：244([M+H] +，100)。
Embodiment 2: invent described compound and synthetic, and with N, N-diethyl glycine-3,7-dimethyl n monooctyl ester is an example.
(1) Mono Chloro Acetic Acid-3,7-dimethyl n monooctyl ester synthetic with embodiment 1.
(2) N, N-diethyl glycine menthol ester synthetic
14.09g Mono Chloro Acetic Acid-3 adds the 15.6mL diethylamine in the 7-dimethyl n monooctyl ester, at room temperature stirring reaction 2h concentrates, and makes eluent with ethyl acetate, and column chromatography (silica gel is 100～300 orders) steams and removes eluent, gets yellow liquid 13.81g, and productive rate is 84.8%.Product 1H NMR and ESI-MS spectrum are as follows:
1H?NMR(CDCl 3，400MHz)，δ：0.79(d，J＝6.4Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.99(t，J＝6.8Hz，6H)，1.06～1.10(m，2H)，1.18～1.23(m，4H)，1.34～1.48(m，3H)，1.56～1.62(m，1H)，2.59(q，J＝7.2Hz，4H)，3.24(s，2H)，3.97～4.10(m，2H)。ESI-MS，m/z(％)：272([M+H] +，100)。
Embodiment 3: that invents described compound oozes activity test through skin is short, with N, and N-diethyl glycine-3,7-dimethyl n monooctyl ester is an example.
(1). the diclofenac sodium typical curve
Precision takes by weighing diclofenac sodium 2g, places the 100mL volumetric flask, is settled to scale with 70% dissolve with ethanol solution, and vibration shakes up, and is standby.Precision is measured reference liquid 25,50,75,100,125 μ L place the 100mL volumetric flask, are settled to scale with pH 7.4 phosphate buffered saline buffers, obtain concentration and be followed successively by 5,10,15,20,25 μ g/mL solution, is that the 276nm place measures solution absorbency with ultraviolet spectrophotometer at wavelength, gets typical curve equation: C (μ g/mL)=31.847A-1.070, r=0.9996.
(2) .1% diclofenac sodium solution
Make the ethanolic soln that contains 1% diclofenac sodium by the ethanol of diclofenac sodium and 70%.
(3). contain 2.0%N, N-diethyl glycine-3, the diclofenac sodium solution of 7-dimethyl n monooctyl ester
By the ethanolic soln and the N that contain 1% diclofenac sodium, N-diethyl glycine-3,7-dimethyl n monooctyl ester is made the ethanolic soln of the diclofenac sodium that contains 2.0% transdermal agent.
(4). the preparation of rat skin in vitro
Put to death the hairiness rat and slough the hair of its belly, separate intact skin at belly, the removal subcutis is washed 2～3 times with physiological saline, and is standby.
(5). external drug transdermal absorption test
Medicine carries out on TT-18 type transdermal instrument through the skin absorption test.Mouse skin stratum corneum is fixed between supply chamber and the reception chamber towards supply chamber, and effective infiltrating area of skin is 2.55cm 2, add 5mL pH in the receiving chamber and be 7.4 phosphate buffer soln as acceptable solution, place the circulator bath of (37 ± 0.1) ℃, magnetic stirs in the receiving chamber.Add 1mL in the supply chamber and discharge liquid.In the 6h, quantitatively take out 50 μ L acceptable solutions from receiving chamber at interval at different time, while is 7.4 phosphate buffer soln to the pH of the additional equivalent of receiving chamber, the acceptable solution that takes out is measured its absorbancy with ultraviolet spectrophotometer at the 276nm place, and calculate unit surface accumulation transit dose Q (μ g/mL), experimental result sees the following form:
Table. diclofenac sodium in vitro tests unit surface accumulation transit dose Q (μ g/mL)
Show through data processed result: N, N-diethyl glycine menthol ester promote that the medicine diclofenac sodium is 3 times of blank group through the skin assimilation effect.

Claims (8)

1. the N of structural formula such as general formula I, N-dibasic glycine-3,7-dimethyl n monooctyl ester:
Wherein R represents CH 3, C 2H 5Or CH 2CH 2OH.
2. N according to claim 1, N-dibasic glycine-3,7-dimethyl n monooctyl ester, this compound is N, N-N-methylsarcosine-3,7-dimethyl n monooctyl ester.
3. N according to claim 1, N-dibasic glycine-3,7-dimethyl n monooctyl ester, this compound is N, N-diethyl glycine-3,7-dimethyl n monooctyl ester.
4. N according to claim 1, N-dibasic glycine-3,7-dimethyl n monooctyl ester, this compound is N, N-bicine N--3,7-dimethyl n monooctyl ester.
5. as claim 1 general formula the N of I, N-dibasic glycine-3, the preparation method's of 7-dimethyl n monooctyl ester concrete steps are:
(1). at room temperature, 3, splash into chloroacetyl chloride in 7-dimethyl-1-octanol and carry out acylation reaction; 3, the mol ratio of 7-dimethyl-1-octanol and chloroacetyl chloride is 1.0: 1.0～1.0: 1.3, and the acylation reaction time is 1～3h; after the acylation reaction, the saturated NaHCO of reaction solution 3Solution transfers to weakly alkaline, tells organic layer, and water layer merges organic layer with ether or ethyl acetate extraction, through washing, drying, removes solvent under reduced pressure, and residue gets Mono Chloro Acetic Acid-3 through column chromatography, 7-dimethyl n monooctyl ester;
(2). at room temperature, Mono Chloro Acetic Acid-3, adding excessive general formula in the 7-dimethyl n monooctyl ester is R 2The compound of NH, reaction 1～3h tells organic layer, and water layer merges organic layer with ether or dichloromethane extraction, through washing, drying, removes solvent under reduced pressure, and residue gets target compound I through column chromatography, Mono Chloro Acetic Acid-3 wherein, 7-dimethyl n monooctyl ester and R 2The mol ratio of NH is 1.0: 1.0～1.0: 2.5, R 2R among the NH gets the group identical with the R of general formula I.
6. N as claimed in claim 5, N-dibasic glycine-3, the preparation method of 7-dimethyl n monooctyl ester is characterized in that 3, the mol ratio of 7-dimethyl-1-octanol and chloroacetyl chloride is 1.0: 1.1.
7. N as claimed in claim 5, N-dibasic glycine-3, the preparation method of 7-dimethyl n monooctyl ester is characterized in that Mono Chloro Acetic Acid-3,7-dimethyl n monooctyl ester and R 2The mol ratio of NH is 1.0: 2.0.
8. N as claimed in claim 1, N-dibasic glycine-3,7-dimethyl n monooctyl ester is as the application of transdermal agent.
CN 200610035728 2006-06-01 2006-06-01 N,N-dibasic glycine 3,7-dimethyl n-octyl ester, and its preparing method and use Pending CN1850785A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108250093A (en) * 2016-12-29 2018-07-06 韩山师范学院 Compound Dahpe and its preparation method and application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108250093A (en) * 2016-12-29 2018-07-06 韩山师范学院 Compound Dahpe and its preparation method and application
CN108250093B (en) * 2016-12-29 2021-01-12 韩山师范学院 Compound Dahpe and preparation method and application thereof

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