CN1793110A - Process for preparing Boc protected amino acid by (Boc) O - Google Patents

Process for preparing Boc protected amino acid by (Boc) O Download PDF

Info

Publication number
CN1793110A
CN1793110A CN 200510020085 CN200510020085A CN1793110A CN 1793110 A CN1793110 A CN 1793110A CN 200510020085 CN200510020085 CN 200510020085 CN 200510020085 A CN200510020085 A CN 200510020085A CN 1793110 A CN1793110 A CN 1793110A
Authority
CN
China
Prior art keywords
boc
amino acid
acetone
ethyl acetate
water
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.)
Pending
Application number
CN 200510020085
Other languages
Chinese (zh)
Inventor
胡先明
滕汉兵
魏海斌
邱国福
梁淑彩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wuhan University WHU filed Critical Wuhan University WHU
Priority to CN 200510020085 priority Critical patent/CN1793110A/en
Publication of CN1793110A publication Critical patent/CN1793110A/en
Pending legal-status Critical Current

Links

Abstract

The invention discloses a method that uses (Boc)<SUB>2</SUB>O to make amino acid of Boc protection. It uses acetone and water as solvent, under the existing of (Et<SUB>3</SUB>N), takes reaction to form amino acid of Boc protection. The invention has high yield, easy to produce and no pollution. The product has good homogeneity, high purity and low cost.

Description

A kind of usefulness (Boc) 2O prepares the amino acid whose method of Boc protection
Technical field
The invention discloses a kind of usefulness (Boc) 2O prepares the amino acid whose method of Boc protection, especially prepares the L-aspartic acid of Boc protection and the method for L-L-glutamic acid.
Background technology
The common ground of L-aspartic acid ammonia and L-L-glutamic acid is: they all contain carboxyl functional group on side chain.They are the most cheap amino acid that is easy to get in the natural amino acid, are often used as chiral raw material Just because of this and design more synthetic useful intermediates.Utilizing them to synthesize when design, people usually need amino is protected, and selecting rational blocking group to come amino protected also becomes the difficult problem that people face often.Boc has been widely used in the synthetic design as a kind of better protecting base, in synthesizing in particular for peptide.Yet up to the present, when the L-aspartic acid ammonia of preparation Boc protection and L-L-glutamic acid, people or use special reagent, as: Boc-ODSP, Boc-N 3Deng, or need expend the too many time (＞12h), or need control the pH value of reaction solution, and often can not obtain better yield.
Summary of the invention
The purpose of this invention is to provide a kind of usefulness (Boc) 2O prepares the amino acid whose method of Boc protection.This method is cheap, and is easy and simple to handle, the yield height of product.
For achieving the above object, technical scheme provided by the invention is: a kind of usefulness (Boc) 2O prepares the amino acid whose method of Boc protection, is solvent with acetone and water, triethylamine (Et 3N) exist down, amino acid and tert-Butyl dicarbonate reaction make the amino acid of Boc protection.
Above-mentioned amino acid and tert-Butyl dicarbonate 0-40 ℃, stir under reaction 0.5-4 hour.
The consumption volume ratio of above-mentioned acetone and water is 0.1-1: 1-0.1, preferred 2: 1.
After above-mentioned amino acid and the tert-Butyl dicarbonate reaction, boil off organic solvent-acetone; Ether or ethyl acetate extraction.
After boiling off organic solvent-acetone, or behind ether or the ethyl acetate extraction, the aqueous solution that obtains transfers pH value to 2-3 with dilute hydrochloric acid, uses ethyl acetate extraction, and collected organic layer is with saturated common salt washing, anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains ethyl acetate and sherwood oil crystallization.
Described amino acid is L-aspartic acid ammonia or L-L-glutamic acid.
The applicant uses (Boc) cheap and easy to get 2O is that reagent comes L-aspartic acid ammonia and L-L-glutamic acid are carried out amido protecting, several solvent systems of having selected forefathers to use always, and used mineral alkali (NaOH) and organic bases (Et respectively 3N) compare (table 1).
Table 1
Solvent system Scale (mmol) Alkali (2eq) Reagent (1.1eq) Time (h) Productive rate (%)
H 2O 20 NaOH (Boc) 2O 12 45
Dioxane/H 2O (2∶1) 20 NaOH (Boc) 2O 12 53
Tetrahydrofuran (THF)/H 2O (2∶1) 20 NaOH (Boc) 2O 12 49
Dioxane/H 2O (2∶1) 20 Et 3N (Boc) 2O 12 66
Tetrahydrofuran (THF)/H 2O (2∶1) 20 Et 3N (Boc) 2O 12 61
The result shows: these solvent systems all can not obtain a satisfied productive rate, but the applicant finds to use the effect of organic bases will be significantly better than using mineral alkali NaOH.
The another kind of solvent system of applicant's warp a large amount of experimental studies discovery employing is that the mixed solvent of acetone and water is used as solvent system, and uses organic bases Et 3During N, not only yield greatly improves, and the reaction times shorten greatly, even and amplify charging capacity, also influence result's (table 2) hardly.
Table 2
Raw material Solvent system Scale (mmol) Time (h) Productive rate (%)
The L-aspartic acid Acetone/H 2O (2∶1) 20 4 87
The L-aspartic acid Acetone/H 2O (2∶1) 100 4 83
L-L-glutamic acid Acetone/H 2O (2∶1) 20 4 91
L-L-glutamic acid Acetone/H 2O (2∶1) 100 4 88
Therefore, the present invention selects the mixed solvent of acetone and water for use, with (Boc) 2O prepares the amino acid of other Boc protections, and also receive beyond thought effect: for example, selecting other amino acid for use is substrate, still uses Et 3N is used as the amino acid that alkali prepares the Boc protection, its yield height, reaction times short (table 3).
Advantage of the present invention:
1. use (Boc) cheap and easy to get 2O is used for amino acid whose Boc protection as reagent.
2. improved the productive rate of Boc-L-aspartic acid and Boc-L-L-glutamic acid greatly.
3. shortened the reaction times greatly.
4. use lower boiling organic solvent-acetone to help aftertreatment.
5. very simple, the good uniformity of pollution-free products obtained therefrom of operation, purity height.
6. be applicable to also that high yield prepares the amino acid of other Boc protections fast.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described further:
Embodiment one
L-aspartic acid (20mmol) is added in the flask, add water 4ml, acetone 40ml stirs adding 2 normal (CH down 3) 3N, controlled temperature add (Boc) under 0 ℃ of stirring 2O (22mmol), and continue to stir 0.5h, pressure reducing and steaming acetone, with ethyl acetate to water layer extraction (4 * 60ml), with water layer with rare HCl accent pH value behind 2-3, ethyl acetate extraction (4 * 60ml), merge organic layer, with the saturated common salt washing (2 * 10ml), anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains comes crystallization with ethyl acetate and sherwood oil (1: 2, volume ratio), promptly gets Boc-L-aspartic acid (yield is 60%).
Embodiment two
L-L-glutamic acid (20mmol) is added in the flask, add water 20ml, acetone 40ml stirs adding 2 normal Et down 3N, controlled temperature add (Boc) under 25 ℃ of stirrings 2O (22mmol), and continue to stir 4h, pressure reducing and steaming acetone, with ether to the water layer extraction (3 * 10ml), transfer pH value behind 2-3 with rare HCl water layer, ethyl acetate extraction (4 * 60ml), merge organic layer, with saturated common salt wash (2 * 10ml), anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains comes crystallization with ethyl acetate and sherwood oil (1: 2, volume ratio), promptly gets Boc-L-paddy winter propylhomoserin (yield is 90%).
Embodiment three
L-proline(Pro) (20mmol) is added in the flask, add water 40ml, acetone 4ml stirs adding 1.5 normal (CH down 3) 3N, controlled temperature add (Boc) under 40 ℃ of stirrings 2O (22mmol), and continue to stir 0.5h, pressure reducing and steaming acetone, the aqueous solution that obtains transfers pH value behind 2-3 with rare HCl, ethyl acetate extraction (4 * 60ml), with saturated common salt wash (2 * 10ml), anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains comes crystallization with ethyl acetate and sherwood oil (1: 2, volume ratio), promptly gets Boc-L-proline(Pro) (yield is 73%).
Embodiment four
L-L-Ala (20mmol) is added in the flask, add water 20ml, acetone 40ml stirs adding 1.5 normal Et down 3N, controlled temperature add (Boc) under 25 ℃ of stirrings 2O (22mmol), and continue to stir 4h, pressure reducing and steaming acetone, with ether to the water layer extraction (3 * 10ml), transfer pH value behind 2-3 with rare HCl water layer, ethyl acetate extraction (4 * 60ml), merge organic layer, with saturated common salt wash (2 * 10ml), anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains comes crystallization with ethyl acetate and sherwood oil (1: 2, volume ratio), promptly gets Boc-L-L-Ala (yield is 93%).
Condition and method by embodiment four are carried out other amino acid whose protection experiments, result such as table 3.
Table 3
Product Productive rate (%) m.p.[℃]；[α] D 20 Time (h) Data in literature m.p.[ ]; [α] D 20
The Boc-L-aspartic acid 87 111-114； -5.5，c＝1.0(MeOH) 4 117-119； -5，c＝1.0(MeOH)
Boc-L-L-glutamic acid 91 110-113； -15.5，c＝1.0(MeOH) 4 108-109； -16.0，c＝1.0(MeOH)
The Boc-L-L-Ala 93 80-82； -25.3，c＝2.1(AcOH) 4 80-81； -24，c＝2.1(AcOH)
The Boc-L-leucine 93 70-72； -25.7，c＝1.0(AcOH) 4 75； -27，c＝1(AcOH)(a)
The Boc-L-proline(Pro) 95 126-129； -61.7，c＝2.0(AcOH) 4 132-133 -60，c＝2(AcOH)
The Boc-L-methionine(Met), DCHA (b) 96 135-137； +15.0，c＝1.0(DMF) 4 137-138； +16.8，c＝1(DMF) (a)
The Boc-L-Serine, DCHA 92 137-139； +12.6，c＝2.8(MeOH) 4 139-140； +13，c＝3(MeOH)
The Boc-L-Threonine, DCHA 95 146-148； -4.7，c＝1.0(AcOH) 4 151-152； -3.0，c＝1.0(AcOH)
The Boc-L-phenylalanine, DCHA 95 208-210； +28.6，c＝1.0(MeOH) 4 213-214； +30，c＝1(MeOH)
The Boc-L-Xie Ansuan, DCHA 92 134-137； -3.7，c＝1.0(AcOH) 4 138-140； -1，c＝4(AcOH)
The Boc-D-phenylglycine 93 84-86 -143，c＝1.0(EtOH) 4 85-88 -148，c＝1.0(EtOH)
The Boc-glycine 94 82-84 4 87-88
a[α] 578 20
B DCHA: dicyclohexyl amine salt (Dicyclohexylammonium salt)
The result shows: the present invention is applicable to that also high yield prepares the amino acid of other Boc protections fast.

Claims (7)

1. one kind with (Boc) 2O prepares the amino acid whose method of Boc protection, and it is characterized in that: with acetone and water is solvent, triethylamine (Et 3N) exist down, amino acid and tert-Butyl dicarbonate reaction make the amino acid of Boc protection.
2. method according to claim 1 is characterized in that: amino acid and tert-Butyl dicarbonate 0-40 ℃, stir under reaction 0.5-4 hour.
3. method according to claim 1 and 2 is characterized in that: the consumption volume ratio of acetone and water is 0.1-1: 1-0.1.
4. method according to claim 3 is characterized in that: the consumption volume ratio of acetone and water is 2: 1.
5. method according to claim 1 and 2 is characterized in that: after amino acid and the tert-Butyl dicarbonate reaction, boil off organic solvent-acetone; Ether or ethyl acetate extraction.
6. method according to claim 5 is characterized in that: after boiling off organic solvent-acetone, or behind ether or the ethyl acetate extraction, the aqueous solution that obtains transfers pH value to 2-3 with dilute hydrochloric acid, uses ethyl acetate extraction, collected organic layer, with saturated common salt washing, anhydrous Na 2SO 4After the drying, filter evaporate to dryness, the product that obtains ethyl acetate and sherwood oil crystallization.
7. method according to claim 1 and 2 is characterized in that: described amino acid is L-aspartic acid ammonia or L-L-glutamic acid.
CN 200510020085 2005-12-20 2005-12-20 Process for preparing Boc protected amino acid by (Boc) O Pending CN1793110A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200510020085 CN1793110A (en) 2005-12-20 2005-12-20 Process for preparing Boc protected amino acid by (Boc) O

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200510020085 CN1793110A (en) 2005-12-20 2005-12-20 Process for preparing Boc protected amino acid by (Boc) O

Publications (1)

Publication Number Publication Date
CN1793110A true CN1793110A (en) 2006-06-28

Family

ID=36804774

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200510020085 Pending CN1793110A (en) 2005-12-20 2005-12-20 Process for preparing Boc protected amino acid by (Boc) O

Country Status (1)

Country Link
CN (1) CN1793110A (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102381999A (en) * 2011-09-14 2012-03-21 杭州澳赛诺化工有限公司 Synthetic method of L-aspartate-4-methyl ester-1-benzyl ester
CN104276964A (en) * 2014-11-04 2015-01-14 崇州合瑞科技有限公司 Preparation method of Boc-glycine
CN104276966A (en) * 2014-11-04 2015-01-14 崇州合瑞科技有限公司 Preparation method of Boc-L-aspartic acid
CN104326943A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-serine
CN104326960A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-proline
CN104326944A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-threonine
CN106187819A (en) * 2016-07-04 2016-12-07 宜兴市前成生物有限公司 A kind of preparation method of BOC L asparagine
CN108084057A (en) * 2017-12-25 2018-05-29 常州吉恩药业有限公司 A kind of industrialized preparing process of high-quality N- tertbutyloxycarbonyls-L-Leu crystallization
CN108794352A (en) * 2018-06-20 2018-11-13 南京肽业生物科技有限公司 A kind of new method of Boc Amino acid synthesis
CN112661672A (en) * 2020-12-30 2021-04-16 山东金城柯瑞化学有限公司 Crystallization method of Boc-amino acid

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102381999A (en) * 2011-09-14 2012-03-21 杭州澳赛诺化工有限公司 Synthetic method of L-aspartate-4-methyl ester-1-benzyl ester
CN104276964A (en) * 2014-11-04 2015-01-14 崇州合瑞科技有限公司 Preparation method of Boc-glycine
CN104276966A (en) * 2014-11-04 2015-01-14 崇州合瑞科技有限公司 Preparation method of Boc-L-aspartic acid
CN104326943A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-serine
CN104326960A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-proline
CN104326944A (en) * 2014-11-04 2015-02-04 崇州合瑞科技有限公司 Method for preparing Boc-L-threonine
CN106187819A (en) * 2016-07-04 2016-12-07 宜兴市前成生物有限公司 A kind of preparation method of BOC L asparagine
CN108084057A (en) * 2017-12-25 2018-05-29 常州吉恩药业有限公司 A kind of industrialized preparing process of high-quality N- tertbutyloxycarbonyls-L-Leu crystallization
CN108794352A (en) * 2018-06-20 2018-11-13 南京肽业生物科技有限公司 A kind of new method of Boc Amino acid synthesis
CN112661672A (en) * 2020-12-30 2021-04-16 山东金城柯瑞化学有限公司 Crystallization method of Boc-amino acid

Similar Documents

Publication Publication Date Title
CN1793110A (en) Process for preparing Boc protected amino acid by (Boc) O
CA2754698C (en) Methods and intermediates for preparing pharmaceutical agents
CN100352801C (en) Synthesis method of L-n-valaine
CN107129444A (en) High-purity (S) -2- t-butoxycarbonyl aminos -3-（4- carbamyl -2,6- 3,5-dimethylphenyls）The preparation method of propionic acid
CN106831951A (en) A kind of purification process of oxytocin
CN100591649C (en) Method of preparing R-(+)-3-chlorophenylpropanol
CN101486481A (en) Method for coproduction of ammonia sulfate and superfine light calcium carbonate from fluorgypsum
CN104193634B (en) A kind of separation of ammonia guanidine-acetic acid and the method for ammonium chloride mixed crystal
CN102040561B (en) Method for synthesizing benzotriazole ultraviolet absorber
CN104370791A (en) Purifying method of levetiracetam
CN105440012A (en) Lenalidomide and lenalidomide intermediate preparation method
CN106732770A (en) In a mild condition by CO2It is converted into the catalyst and method of cyclic carbonate
CN107602661B (en) Preparation method of polaprezinc
CN102234309B (en) Preparation method of peptide with a C-terminal of fluoride methyl ketone
CN105254575B (en) A kind of synthetic method of sulphadiazine
CN106905254A (en) A kind of preparation method of 5 phenyl 1H tetrazoles
CN107216332A (en) The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5
CN111269158A (en) Preparation method of α -hydroxy acid ester compound
CN106946724B (en) The synthetic method of monoamine base inhibitor class intermediate 2- acetylaminohydroxyphenylarsonic acid 2- benzyl malonic acid mono ethyl ester
CN105712919A (en) Application of amide condensing agent in vildagliptin synthetic method
CN102993256B (en) The trimethyl silicon based method in uncle position that the complete trimethyl silicon based protection of a kind of selectively removing is sugared
CN101007772B (en) Synthesis method of chiral norvaline
CN108640912A (en) A kind of industrially scalable preparation method of Pidotimod
CN108456143A (en) Asymmetry prepares (S) -3- aminomethyl -5- methylhexanoic acids
CN103922985B (en) A kind of synthetic method of azetidinone

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication
BOC Protected Amino Acids