CN105936626A - Preparation method of amino protection group - Google Patents
Preparation method of amino protection group Download PDFInfo
- Publication number
- CN105936626A CN105936626A CN201610222187.9A CN201610222187A CN105936626A CN 105936626 A CN105936626 A CN 105936626A CN 201610222187 A CN201610222187 A CN 201610222187A CN 105936626 A CN105936626 A CN 105936626A
- Authority
- CN
- China
- Prior art keywords
- nitrophenol
- protecting group
- preparation
- amino protecting
- chloromethyl
- 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- PJNPZIYGODMAQE-UHFFFAOYSA-N 2-(chloromethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CCl PJNPZIYGODMAQE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000006239 protecting group Chemical group 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- JIUUVBNWDONEFB-UHFFFAOYSA-N 2-(azidomethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CN=[N+]=[N-] JIUUVBNWDONEFB-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 238000007265 chloromethylation reaction Methods 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- ISUNZYFGWCNJLT-UHFFFAOYSA-N 4-nitrophenol;hydrochloride Chemical compound Cl.OC1=CC=C([N+]([O-])=O)C=C1 ISUNZYFGWCNJLT-UHFFFAOYSA-N 0.000 abstract 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- -1 trimethylsilylethoxycarbonyl Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KDQPMQNHVQVVMR-UHFFFAOYSA-N 2-methyl-4-nitrophenol Chemical compound CC1=CC([N+]([O-])=O)=CC=C1O KDQPMQNHVQVVMR-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
Description
技术领域technical field
本发明属于有机合成技术领域，涉及一种氨基保护基的制备方法。The invention belongs to the technical field of organic synthesis and relates to a preparation method of an amino protecting group.
背景技术Background technique
氨基保护基在有机合成中应用广泛，尤其是在多肽的合成中起着重要的作用，常用的氨基保护基主要分为三类：烷氧羰基类氨基保护基，酰基类氨基保护基，烷基类氨基保护基。Amino protecting groups are widely used in organic synthesis, especially play an important role in the synthesis of polypeptides. Commonly used amino protecting groups are mainly divided into three categories: alkoxycarbonyl amino protecting groups, acyl amino protecting groups, alkyl Amino-like protecting group.
烷氧羰基类氨基保护基主要有苄氧羰基（Cbz）、叔丁氧羰基（Boc）、笏甲氧羰基（Fmoc）、烯丙氧羰基（Alloc）、三甲基硅乙氧羰基（Teoc）、甲（或乙）氧羰基，这些保护基虽然应用广泛，但是也存在着缺陷，苄氧羰基（Cbz）脱除困难，如用强酸或Lewis酸脱除时，会产生苄基的碳正离子，若分子中有捕捉碳正离子的基团时，将得到相应的副产物；叔丁氧羰基（Boc）对碱稳定，但是对酸敏感，一定程度上限制了它的应用；笏甲氧羰基（Fmoc）主要的优点是对酸稳定，但是对碱过于敏感，反应副产物多。Alkoxycarbonyl amino protecting groups mainly include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Wat methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc) , A (or B) oxycarbonyl group, although these protective groups are widely used, but there are also defects. It is difficult to remove benzyloxycarbonyl (Cbz), such as when it is removed with strong acid or Lewis acid, it will produce benzyl carbocation , if there is a carbocation-capturing group in the molecule, the corresponding by-product will be obtained; tert-butoxycarbonyl (Boc) is stable to alkali, but sensitive to acid, which limits its application to a certain extent; Wat methoxycarbonyl The main advantage of (Fmoc) is that it is stable to acid, but it is too sensitive to alkali and has many reaction by-products.
酰基类氨基保护基有邻苯二甲酰基（Pht），同一般的酰基氨基酸比较，Pht-氨基酸在接肽时不易消旋，但它对碱不稳定；再如对甲苯磺酰基（Tos），它是最稳定的氨基保护基之一，但是脱除困难。The acyl-type amino protecting group includes phthaloyl (Pht). Compared with general acyl amino acids, Pht-amino acids are not easy to racemize when they are attached to peptides, but they are unstable to alkalis; another example is p-toluenesulfonyl (Tos), It is one of the most stable amino protecting groups, but its removal is difficult.
烷基类氨基保护基有三苯甲基（Trt）、它是50年代开始用于多肽合成的，也被用于保护各种氨基，但是对酸很敏感；苄基（Bn）是应用广泛，是也最稳定的氨基保护基之一，但是脱除困难。Alkyl amino protecting groups include trityl (Trt), which was used in polypeptide synthesis in the 1950s and was also used to protect various amino groups, but it is very sensitive to acids; benzyl (Bn) is widely used and is It is also one of the most stable amino protecting groups, but it is difficult to remove.
在有机合成中选择一个氨基保护基时，必须仔细考虑到所有的反应物，反应条件及所设计的反应过程中会涉及的底物中的官能团。最好的是不保护，若需要保护，选择最容易上和脱除简单的保护基，还要从电子效应和立体效应的因素去考虑对保护的生成和去除速率的选择性。When selecting an amino-protecting group in organic synthesis, careful consideration must be given to all reactants, reaction conditions, and functional groups in the substrates that will be involved in the planned reaction. The best is no protection. If protection is required, choose the easiest protecting group to add and remove, and consider the selectivity of the generation and removal rate of protection from the factors of electronic effect and stereo effect.
本发明针对氨基保护基的稳定性和脱除条件的选择性，提供了一种新的氨基保护基，此氨基保护基本身稳定性好，容易与胺反应，同时脱除条件温和，可以在水中脱除，本氨基保护基可用于多种胺的保护。Aiming at the stability of the amino protecting group and the selectivity of the removal conditions, the present invention provides a new amino protecting group. The amino protecting group itself has good stability and is easy to react with amines. Removal, this amino protecting group can be used for the protection of various amines.
发明内容Contents of the invention
本发明提供了一种氨基保护基（NRT），如下所示：The present invention provides an amino protecting group (NRT), as follows:
一种氨基保护基（NRT）的制备方法，其技术方案如下：A preparation method of an amino protecting group (NRT), the technical scheme of which is as follows:
S1：将对硝基苯酚、多聚甲醛、无水氯化锌、浓盐酸加入到250 mL 三口瓶中，升温至60~80℃，开始通氯化氢气体，并保温反应，过滤得粗品，粗品用氯仿重结晶，得白色固体，即2-氯甲基-4-硝基苯酚，产率75%；S1: Add p-nitrophenol, paraformaldehyde, anhydrous zinc chloride, and concentrated hydrochloric acid into a 250 mL three-necked flask, raise the temperature to 60~80°C, start to flow hydrogen chloride gas, and keep it warm for reaction. Chloroform was recrystallized to obtain a white solid, namely 2-chloromethyl-4-nitrophenol, with a yield of 75%;
S2：将2-氯甲基-4-硝基苯酚与叠氮化钠加入到DMF中，反应12 h，加入水，二氯甲烷萃取，干燥，真空浓缩得红棕色液体，即2-叠氮甲基-4-硝基苯酚，产率98%；S2: Add 2-chloromethyl-4-nitrophenol and sodium azide to DMF, react for 12 h, add water, extract with dichloromethane, dry, and concentrate in vacuo to obtain a reddish-brown liquid, namely 2-azide Methyl-4-nitrophenol, yield 98%;
S3：将2-叠氮甲基-4-硝基苯酚与无机碱加入到甲苯中，反应20 min，冰浴下将三光气分批加入体系，保温反应1~2 h，室温反应10 ~12 h，过滤，真空浓缩滤液，得油状物，即得到氨基保护基（NRT），产率95.8%。S3: Add 2-azidomethyl-4-nitrophenol and inorganic base to toluene, react for 20 min, add triphosgene to the system in batches under ice bath, keep warm for 1~2 h, and react at room temperature for 10~12 h, filter, and concentrate the filtrate in vacuo to obtain an oily substance, that is, an amino protecting group (NRT), with a yield of 95.8%.
步骤S1中，4-硝基苯酚与多聚甲醛的摩尔比为1:2；反应温度为60~80℃，优选反应温度为70℃；反应时间为5~10 h，优选反应时间为6 h。In step S1, the molar ratio of 4-nitrophenol to paraformaldehyde is 1:2; the reaction temperature is 60-80°C, preferably 70°C; the reaction time is 5-10 h, preferably 6 h .
步骤S2中，2-氯甲基-4-硝基苯酚与叠氮化钠的摩尔比为1:1.5~3.5，优选摩尔比为1:2；反应温度为20~60℃，优选反应温度为40℃；反应时间为10~12 h。In step S2, the molar ratio of 2-chloromethyl-4-nitrophenol to sodium azide is 1:1.5~3.5, the preferred molar ratio is 1:2; the reaction temperature is 20~60°C, the preferred reaction temperature is 40°C; the reaction time is 10~12 h.
步骤S3中，所述的溶剂为甲苯、乙腈、DMF、四氢呋喃、1,4-二氧六环中的一种或多种，优选溶剂为甲苯；2-叠氮甲基-4-硝基苯酚与三光气的摩尔比为3:1；所述的无机碱为K2CO3、NaOH、KOH中的一种或多种，优选为K2CO3。In step S3, the solvent is one or more of toluene, acetonitrile, DMF, tetrahydrofuran, and 1,4-dioxane, preferably the solvent is toluene; 2-azidomethyl-4-nitrophenol The molar ratio to triphosgene is 3:1; the inorganic base is one or more of K 2 CO 3 , NaOH, KOH, preferably K 2 CO 3 .
本发明的合成如下所示：Synthesis of the present invention is as follows:
NRT作为一种新型的氨基保护基，可用于保护各种胺（R-NH2，R-NH-R’），之后将R或R’基团进行修饰，最后将保护基（NRT）在三苯基膦作用下，将保护基脱除，反应机理如下：As a new type of amino protecting group, NRT can be used to protect various amines (R-NH 2 , R-NH-R'), and then modify the R or R' group, and finally the protecting group (NRT) in three Under the action of phenylphosphine, the protecting group is removed, and the reaction mechanism is as follows:
NRT很容易与胺反应生成化合物NRT-1，化合物NRT-1对酸碱都不敏感，稳定性好，待R基团修饰完毕，得到化合物NRT-2，最后保护基（NRT）的脱除是在三苯基膦作用下将叠氮还原为氨基，此步反应可以在水中进行，适合于各种胺、氨基酸及多肽的合成，保护基（NRT）易上易下，反应产率高。NRT is easy to react with amine to generate compound NRT-1. Compound NRT-1 is not sensitive to acid and alkali and has good stability. After the modification of R group is completed, compound NRT-2 is obtained. The final removal of the protecting group (NRT) is Under the action of triphenylphosphine, azide is reduced to amino group. This reaction can be carried out in water. It is suitable for the synthesis of various amines, amino acids and polypeptides. The protecting group (NRT) is easy to get on and off, and the reaction yield is high.
本发明的氨基保护基（NRT）在丙谷二肽的合成中进行了应用，反应如下：Amino protecting group (NRT) of the present invention has been applied in the synthesis of glucodipeptide, and reaction is as follows:
本发明的有益效果：Beneficial effects of the present invention:
由于当前应用的一些氨基保护基，存在稳定性差、对酸碱过于敏感、脱除困难等缺陷，本发明涉及合成了一种新型的氨基保护基（NRT），保护基（NRT）可用于保护胺、氨基酸、多肽，对酸碱不敏感，稳定性好，可在水中脱除保护基，产率高，在多肽合成、核苷合成中有较大的潜在应用价值。Due to the disadvantages of some amino protecting groups currently used, such as poor stability, too sensitive to acid and alkali, and difficulty in removal, the present invention relates to the synthesis of a new type of amino protecting group (NRT), which can be used to protect amines , amino acids, polypeptides, insensitive to acid and alkali, good stability, can remove protecting groups in water, high yield, and has great potential application value in polypeptide synthesis and nucleoside synthesis.
具体实施方式detailed description
实施例1：Example 1:
2-氯甲基-4-硝基苯酚的制备：将4-硝基苯酚（13.9 g，0.1 mol）、多聚甲醛（6.0 g，0.2mol）、无水氯化锌（0.1 g）、100 mL浓盐酸加入到250 mL三口瓶中，升温至70℃开始通氯化氢气体，并保温反应6 h，过滤，用氯仿重结晶，得14.0 g白色固体，收率75%。Preparation of 2-chloromethyl-4-nitrophenol: 4-nitrophenol (13.9 g, 0.1 mol), paraformaldehyde (6.0 g, 0.2 mol), anhydrous zinc chloride (0.1 g), 100 Add mL of concentrated hydrochloric acid into a 250 mL three-neck flask, raise the temperature to 70°C and start to pass hydrogen chloride gas, and keep it warm for 6 h, filter, and recrystallize with chloroform to obtain 14.0 g of white solid with a yield of 75%.
2-叠氮甲基-4-硝基苯酚：将2-氯甲基-4-硝基苯酚（5.6 g，0.03 mol）与叠氮化钠（3.9 g，0.06 mol）加入到30 mL的DMF中，40℃反应12 h，冷却至室温，加入80 mL水，二氯甲烷萃取，干燥，真空浓缩得红棕色液体5.7 g，产率98%。2-Azidomethyl-4-nitrophenol: Add 2-chloromethyl-4-nitrophenol (5.6 g, 0.03 mol) with sodium azide (3.9 g, 0.06 mol) to 30 mL of DMF , reacted at 40°C for 12 h, cooled to room temperature, added 80 mL of water, extracted with dichloromethane, dried, and concentrated in vacuo to obtain 5.7 g of reddish-brown liquid with a yield of 98%.
氨基保护基（NRT）制备：将2-叠氮甲基-4-硝基苯酚（2.91 g，0.015 mol）与K2CO3（6.2 g，0.045 mol）加入到甲苯中，反应20 min，冰浴下将三光气（1.48 g，0.005 mol）分批加入体系，保温反应1~2 h，室温反应12 h，过滤，真空浓缩滤液，得油状物3.6 g，即得到氨基保护基，产率95%。Preparation of amino protecting group (NRT): Add 2-azidomethyl-4-nitrophenol (2.91 g, 0.015 mol) and K 2 CO 3 (6.2 g, 0.045 mol) into toluene, react for 20 min, and store on ice Under the bath, triphosgene (1.48 g, 0.005 mol) was added to the system in batches, kept for 1-2 h, and reacted at room temperature for 12 h, filtered, and the filtrate was concentrated in vacuo to obtain 3.6 g of an oily substance, namely the amino protecting group, with a yield of 95% %.
上述虽然对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，所属领域技术人员应该明白，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。Although the specific implementation of the present invention has been described above, it is not a limitation to the protection scope of the present invention. Those skilled in the art should understand that on the basis of the technical solution of the present invention, those skilled in the art can do it without creative work. Various modifications or deformations are still within the protection scope of the present invention.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610222187.9A CN105936626B (en) | 2016-04-12 | 2016-04-12 | A kind of preparation method of amino protecting group |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610222187.9A CN105936626B (en) | 2016-04-12 | 2016-04-12 | A kind of preparation method of amino protecting group |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105936626A true CN105936626A (en) | 2016-09-14 |
| CN105936626B CN105936626B (en) | 2017-11-03 |
Family
ID=57152020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610222187.9A Expired - Fee Related CN105936626B (en) | 2016-04-12 | 2016-04-12 | A kind of preparation method of amino protecting group |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105936626B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699491A (en) * | 2016-12-01 | 2017-05-24 | 浙江工业大学 | Method for preparing azide compound through azidation based on C-H activated anilines |
| CN112723986A (en) * | 2020-12-24 | 2021-04-30 | 衢州康鹏化学有限公司 | Preparation method of p-chloromethyl styrene |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011001330A (en) * | 2009-06-22 | 2011-01-06 | Sumitomo Seika Chem Co Ltd | Method for producing 4-nitrophenyl chloroformate |
-
2016
- 2016-04-12 CN CN201610222187.9A patent/CN105936626B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011001330A (en) * | 2009-06-22 | 2011-01-06 | Sumitomo Seika Chem Co Ltd | Method for producing 4-nitrophenyl chloroformate |
Non-Patent Citations (2)
| Title |
|---|
| JAYENDRA Z. PATEL ET AL.: "Loratadine analogues as MAGL inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 岳荣耀等: "两种新的恶嗪类化合物的合成与结构表征", 《化学试剂》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699491A (en) * | 2016-12-01 | 2017-05-24 | 浙江工业大学 | Method for preparing azide compound through azidation based on C-H activated anilines |
| CN112723986A (en) * | 2020-12-24 | 2021-04-30 | 衢州康鹏化学有限公司 | Preparation method of p-chloromethyl styrene |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105936626B (en) | 2017-11-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3004147C (en) | Crystal form, preparation method and intermediate of dihydropyrido ring compound | |
| ES2715082T3 (en) | Production method of a synthetic pentapeptide | |
| US20140046022A1 (en) | Fluorene compound | |
| JP7063409B1 (en) | How to remove the Fmоc group | |
| JPWO2019198834A1 (en) | Method for producing leuprorelin | |
| CN105936626B (en) | A kind of preparation method of amino protecting group | |
| AR091075A1 (en) | PROCESS TO PREPARE MONOCICLIC DERIVATIVES OF HETEROARIL-CICLOALQUIL-DIAMINA | |
| CN105237496A (en) | A new method for synthesizing N-tert-butoxycarbonylpiperazine | |
| US9790170B2 (en) | Method for preparing lacosamide | |
| CN108017593B (en) | A simple and efficient method for synthesizing 1-oxo-4,5-diazepane | |
| TW202233574A (en) | Method for producing peptide, reagent for forming protective group, and fused polycyclic compound | |
| CN109369779B (en) | Synthetic method of taltirelin | |
| EP2821389A1 (en) | Production method for compound comprising amino group and/or hydroxyl group | |
| WO2023033016A1 (en) | Arginine derivative | |
| ES2252633T3 (en) | NEW SYNTHESIS PROCEDURE OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE BASES. | |
| US20230021514A1 (en) | Etelcalcetide intermediate and method for synthesizing etelcalcetide | |
| TW202328164A (en) | Method for producing ganirelix or salt thereof | |
| JPWO2015198505A1 (en) | Method for producing synthetic pentapeptide | |
| SI21506A (en) | Procedure of preparation of perindopril | |
| CN105713068A (en) | Method for preparing key intermediate of imidapril and derivative thereof | |
| AU684763B2 (en) | Process for the preparation of an alpha-amino acid amide | |
| CN101809022B (en) | Novel method for the synthesis of anticancer (poly)aminoalkylaminoacetamide derivatives of epipodophyllotoxin | |
| JP2016065050A (en) | Octreotide production method | |
| US10407389B2 (en) | Method for the preparation of H-Arg(MIS)-OH | |
| JP5982720B2 (en) | Method for producing histidyl-prolinamide derivative using solid polymer support |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171103 Termination date: 20180412 |