CN116621721A - Preparation method of nondiamide - Google Patents
Preparation method of nondiamide Download PDFInfo
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- CN116621721A CN116621721A CN202310392093.6A CN202310392093A CN116621721A CN 116621721 A CN116621721 A CN 116621721A CN 202310392093 A CN202310392093 A CN 202310392093A CN 116621721 A CN116621721 A CN 116621721A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 117
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- VVWPSAPZUZXYCM-UHFFFAOYSA-N 9-methoxy-9-oxononanoic acid Chemical compound COC(=O)CCCCCCCC(O)=O VVWPSAPZUZXYCM-UHFFFAOYSA-N 0.000 claims abstract description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 14
- 150000003947 ethylamines Chemical class 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 239000000376 reactant Substances 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 230000035484 reaction time Effects 0.000 claims description 12
- -1 nonanediamide compound Chemical class 0.000 claims description 11
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical group [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 claims description 10
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical group [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 3
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- FJXWKBZRTWEWBJ-UHFFFAOYSA-N nonanediamide Chemical compound NC(=O)CCCCCCCC(N)=O FJXWKBZRTWEWBJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 38
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- 230000008034 disappearance Effects 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 238000009987 spinning Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 241000186427 Cutibacterium acnes Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GHLZUHZBBNDWHW-UHFFFAOYSA-N nonanamide Chemical compound CCCCCCCCC(N)=O GHLZUHZBBNDWHW-UHFFFAOYSA-N 0.000 description 2
- LJAGLQVRUZWQGK-UHFFFAOYSA-N oxecane-2,10-dione Chemical compound O=C1CCCCCCCC(=O)O1 LJAGLQVRUZWQGK-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 201000004700 rosacea Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- DJKLLZJDRPGBPJ-UHFFFAOYSA-N 9-amino-9-oxononanoic acid Chemical compound NC(=O)CCCCCCCC(O)=O DJKLLZJDRPGBPJ-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010027146 Melanoderma Diseases 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 206010039792 Seborrhoea Diseases 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001535 azelaic acid derivatives Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- SXJVFQLYZSNZBT-UHFFFAOYSA-N nonane-1,9-diamine Chemical compound NCCCCCCCCCN SXJVFQLYZSNZBT-UHFFFAOYSA-N 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 230000037312 oily skin Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940055019 propionibacterium acne Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicine synthesis, and discloses a preparation method of a nondiamide compound, which comprises the following steps: (1) The method has the advantages that azelaic acid monomethyl ester, namely the compound I, is used as an initial reactant to react with 2-halogenated ethylamine to obtain a compound II, (2) the compound II and formate are used as reaction raw materials, methanol is used as a solvent, and the compound III is obtained through one-step reaction, namely the nonane diamide MEA.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a nondiamide compound.
Background
The nondiamide MEA is a novel sebum balancing agent and is suitable for nursing oily and seborrheic skin. Azelaic acid amide MEA is an azelaic acid derivative, has the same biological activity as azelaic acid, but has no defects of difficult dissolution in water/oil, damage to an emulsifying system, difficult exertion of effect, high irritation and the like inherent in azelaic acid. The nondiamide MEA efficacy includes: 1. helps the oily skin, seborrheic skin and black spot multiple skin to keep the balance of grease secretion; 2. cosmeceutical products useful for treating acne and comedo are effective against propionibacterium acnes, corynebacterium acnes and staphylococcus epidermidis; 3. has good whitening effect, and can be used for treating color spots and chloasma; 4. the synergistic use with pyridoxine and zinc can inhibit 5-alpha reductase; 5. has good exfoliating (exfoliating) effect; 6. can be used for treating rosacea (erythema and papulopustular rosacea).
The following two synthetic methods are reported for nondiamide MEA:
the method comprises the following steps: azelaic anhydride reacts directly with ethanolamine to form an amide (Organic Preparation and Procedures Internationgal,2013, vol.45, #4, p.314-320).
The second method is as follows: the hydroxyl groups of ethanolamine are first attached with protecting groups and then reacted with acid chlorides to give amides (WO 2007/88999,2007, A1)
Of the two methods, azelaic anhydride in the first method is difficult to synthesize and has low yield. The hydroxyl of the ethanolamine in the second method is connected with a protecting group and the deprotection process is quite complicated, which is not beneficial to industrial production.
Disclosure of Invention
Therefore, it is necessary to provide a preparation method of a nonanamide compound, which solves the problems that the existing nonanamide MEA is difficult to synthesize and the yield is low.
In order to achieve the above object, the present invention provides the following technical solutions. The invention provides a preparation method of a nondiamide compound, which comprises the following steps:
(1) The monomethyl azelate, namely the compound I, is used as an initial reactant to react with 2-halogenated ethylamine to obtain a compound II,
(2) The compound II and formate are used as reaction raw materials, methanol is used as solvent, the compound III is obtained by one-step reaction, namely the nonanamide MEA,
the reaction formula is as follows:
wherein X is halogen element.
In some embodiments, the organic solvent is one or more of alcohols, organic amines, and alicyclic hydrocarbons during the synthesis of compound II from compound I.
In some embodiments, the alcohol is methanol during the synthesis of compound II from compound I.
In some embodiments, in step (1), the molar ratio of monomethyl azelate to 2-haloethylamine is from 1:1.1 to 1:2, the reaction temperature is from 35 ℃ to 65 ℃, and the reaction time is from 2h to 8h.
In some embodiments, in step (1), the molar ratio of monomethyl azelate to 2-haloethylamine is from 1:1.3 to 1:1.5, the reaction temperature is from 40 ℃ to 60 ℃, and the reaction time is from 2h to 3h.
The settings of the feed ratio, the reaction temperature and the reaction time will affect the yield and purity of the compound, wherein the molar ratio of monomethyl azelate to 2-halogenated ethylamine is preferably 1:1.3-1:1.5, the reaction temperature is 40-60 ℃, and the reaction time is 2-3 h, so that the purity of the prepared compound can reach more than 95%, and the yield of the compound in the step (1) can reach more than 80%.
In some embodiments, the 2-haloethylamine is selected from 2-bromoethylamine hydrobromide or 2-chloroethylamine hydrochloride.
In some embodiments, step (1) adds an organic base as an acid-binding agent. The acid binding agent is capable of neutralizing the acid generated in step (1), thereby promoting the reaction of step (1).
In some embodiments, the acid-binding agent may be triethylamine, DIEA or pyridine, and the molar ratio of monomethyl azelate (compound I) to acid-binding agent is 1:2.0-1:3, preferably 1:2.3-1:2.5.
In some embodiments, after the reaction of step (1) is completed, the solvent is distilled off under reduced pressure, water is added for dissolution, acid is added for adjusting the pH, and then the compound II is obtained through extraction and rotary evaporation. In the step (1), the reaction conditions are controlled to ensure that the reaction product is single, and the purity of the reaction product can reach more than 95 percent through simple acid regulation and extraction without more purification treatment.
In some embodiments, in step (2), the molar ratio of compound II to formate is 1:0.95-1:2.05, the reaction temperature is 35℃to 65℃and the reaction time is 4h to 10h.
In some embodiments, in step (2), the molar ratio of compound II to formate is 1:1-1:2, the reaction temperature is 40 ℃ to 60 ℃, and the reaction time is 5h to 6h.
The setting of the feed ratio, the reaction temperature and the reaction time will affect the yield and purity of the compound, wherein the molar ratio of the compound II to the formate is preferably 1:1-1:2, the reaction temperature is 40-60 ℃, and the reaction time is 5-6 h, so that the purity of the prepared compound can reach more than 98%, and the yield of the compound in the step (2) can reach more than 80%.
In some embodiments, the formate is potassium formate or sodium formate.
In some embodiments, in step (2), after the reaction of compound II with formate is completed, the methanol solvent is distilled off under reduced pressure, water is added, and the nonylenediamide compound is precipitated.
In the step (2), the reaction conditions are controlled to ensure that the reaction product is single, and the reaction product is precipitated by simple water addition without more purification treatment, so that the purity of the product is more than 98.5 percent.
In some embodiments, the water is cooled to 10-20 ℃.
The technical scheme has the following beneficial effects:
in the invention, azelaic acid monomethyl ester is used as a raw material to obtain a high-yield and high-purity nonanamide compound MEA through two reactions, the total yield of the two reaction steps can be more than 70%, and a compound with the purity of more than 95% can be obtained by simple extraction and precipitation of an intermediate product compound II and a final reaction product compound III by adding water.
In the invention, the reaction temperature and reaction conditions of the monomethyl azelate and the 2-halogenated ethylamine in the step (1) are controlled so that the product is a single-end ammonolysis product of the monomethyl azelate, and in the step (2), the methyl alcohol is used as a solvent, the compound II and formate are subjected to substitution reaction first, and then the thermal decomposition of the ester occurs, so that the high-purity and high-yield nonanediamide compound MEA is prepared.
Description of the terms
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the statement "comprising … …" or "comprising … …" does not exclude the presence of additional elements in a process, method, article or terminal device comprising the element. Further, herein, "greater than," "less than," "exceeding," and the like are understood to not include the present number; "above", "below", "within" and the like are understood to include this number.
As used herein, "room temperature" and "normal temperature" refer to ambient temperatures ranging from about 10deg.C to about 40deg.C. In some embodiments, "room temperature" or "ambient temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" or "ambient temperature" refers to a temperature from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" or "normal temperature" refers to 10 ℃, 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, and the like.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
Drawings
FIG. 1 is a nuclear magnetic resonance chart of a nonylenediamide MEA prepared in example 1.
FIG. 2 is a MS mass spectrum of the nonandiamide MEA prepared in example 1.
Detailed Description
In order to describe the technical content, constructional features, achieved objects and effects of the technical solution in detail, the following description is made in detail with reference to specific embodiments.
Example 1:
12.65g (0.125 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 15.37g (0.075 mol) of 2-bromoethylamine hydrobromide were successively charged into a 100mL single-necked flask equipped with a mechanical stirrer, and the mixture was heated to 60℃and reacted at this temperature for 3 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolving, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain about 13g of white product (compound II), the purity is more than 95%, and the yield is 88.38%.
The above white product (compound II) and 4.62g (0.055 mol) of potassium formate, 50g of methanol were mixed, and the mixture was heated to 60℃and reacted at this temperature for 6 hours. The reaction was checked by TLC for the extent of reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), taking the spot of the product (compound II) disappeared as the end point of the reaction, after completion of the reaction, methanol was distilled off under reduced pressure at 60 ℃, 50g of water was added, cooling to 10-20 ℃, the product (compound III) was precipitated, filtered and washed with ice water, and dried to give 8.5g of a white powder of the product (compound III) with a purity of 98.3%, a yield of 83.17% in step (2), and a total yield of 73.5%.
The reaction formula is as follows
Example 2:
a500 mL single-port flask equipped with a mechanical stirrer, a thermometer was equipped with 58.18g (0.575 mol) of triethylamine, 120g of methanol, 50.50g (0.250 mol) of monomethyl azelate, and 66.58g (0.325 mol) of 2-bromoethylamine hydrobromide in this order, and the mixture was heated to 60℃and reacted at this temperature for 3 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain about 60g of white product (compound II), the purity is more than 95%, and the yield is 81.58%.
The above white product (compound II) and 23.13g (0.275 mol) of potassium formate, 250g of methanol were mixed, and the mixture was heated to 60℃and reacted at this temperature for 6 hours. The reaction was checked by TLC for the extent of reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), taking the spot of the product (compound II) disappeared as the end point of the reaction, after completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 50g of water was added, cooled to 10-20℃to precipitate the product (compound III), filtered and washed with ice water, dried to give 44.59g of a white powder of the product (compound III) with a purity of 98.5%, a yield of 94.53%, and a total yield of 77.1%.
Example 3:
a100 mL single-necked flask equipped with a mechanical stirrer was charged with 11.6g (0.115 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 13.33g (0.065 mol) of 2-bromoethylamine hydrobromide in this order, and the mixture was heated to 60℃and reacted at this temperature for 2 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain white product (compound II) with purity of more than 95% and yield of 89.73%.
Example 4:
25.3g (0.25 mol) of triethylamine, 40.0g of methanol, 20.20g (0.1 mol) of monomethyl azelate, and 30.75g (0.15 mol) of 2-bromoethylamine hydrobromide were successively charged into a 250mL single-necked flask equipped with a mechanical stirrer, and the mixture was heated to 40℃and reacted at this temperature for 3 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain about 26.5g of white product (compound II), purity is more than 95%, yield is 90.07%.
Example 5:
10.12g (0.1 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 11.3g (0.055 mol) of 2-bromoethylamine hydrobromide were successively charged into a 100mL single-necked flask equipped with a mechanical stirrer, and the mixture was heated to 65℃and reacted at this temperature for 2 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain white product (compound II) with purity of more than 90% and yield of 82.94%.
Example 6:
a100 mL single-port flask equipped with a mechanical stirring, thermometer was successively charged with 15.18 g (0.15 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 20.5g (0.1 mol) of 2-bromoethylamine hydrobromide, and the mixture was heated to 60℃and reacted at this temperature for 3 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain about 12.4g of white product (compound II), purity is more than 90%, and yield is 84.30%.
Comparative example 1:
12.65g (0.125 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 30.75g (0.15 mol) of 2-bromoethylamine hydrobromide were successively charged into a 100mL single-necked flask equipped with a mechanical stirrer, and the mixture was heated to 60℃and reacted at this temperature for 3 hours. The reaction proceeds by TLC (developing agent is petroleum ether/ethyl acetate (volume ratio 4:1), spot disappearance of azelaic acid monomethyl ester is used as reaction end point, after the reaction is finished, methanol is distilled off under reduced pressure at 60 ℃, water is added for dissolution, phosphoric acid is added for 85% after stirring and dissolution, pH value is adjusted to 5-6, dichloromethane is added for extraction of mixed solution, and extract is dried by spinning at 50 ℃ to obtain white product (compound II) with purity less than 85% and yield 89.06%.
Comparative example 2:
12.65g (0.125 mol) of triethylamine, 20.0g of methanol, 10.10g (0.050 mol) of monomethyl azelate, and 10.25g (0.05 mol) of 2-bromoethylamine hydrobromide were successively charged into a 100mL single-necked flask equipped with a mechanical stirrer, and the mixture was heated to 60℃and reacted at this temperature. The reaction was checked by TLC for progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), and as a result, monomethyl azelate was not completely reacted.
Example 7
14.7g (0.05 mol, purity greater than 95%) of compound II and 4.2g (0.05 mol) of potassium formate were taken, 50g of methanol were mixed, and the mixture was heated to 60℃and reacted at this temperature for 5 hours. The reaction was checked by TLC for the extent of reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), with the disappearance of the spots of the product (Compound II) as the end point of the reaction, after completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 50g of water was added, cooled to 10-20℃to precipitate the product (Compound III), filtered and washed with ice water, dried to give 10.4g of a white powder of the product (Compound III) with a purity of 97.2% and a yield of 89.99%.
Example 8
29.4g (0.1 mol, purity greater than 95%) of compound II and 16.8g (0.2 mol) of potassium formate were taken, 100g of methanol were mixed, and the mixture was heated to 40℃and reacted at this temperature for 6 hours. The reaction was checked by TLC for the extent of reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), with the disappearance of the spots of the product (Compound II) as the end point of the reaction, after completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 100g of water was added, cooled to 10-20℃to precipitate the product (Compound III), filtered and washed with ice water, and dried to give 22.1g of a white powder of the product (Compound III) with a purity of 95.2% and a yield of 95.6%.
Example 9
14.7g (0.05 mol, purity greater than 95%) of compound II and 4.0g (0.0476 mol) of potassium formate were taken, 50g of methanol were mixed, and the mixture was heated to 35℃and reacted at this temperature for 10 hours. The reaction was checked by TLC for the extent of reaction (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), and the spot of the product (Compound II) disappeared as the end point of the reaction after the completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 50g of water was added, cooled to 10-20℃to precipitate the product (Compound III), filtered and washed with ice water, and dried to give 9.6g of a white powder of the product (Compound III) with a purity of 92.8% and a yield of 83.07%.
Example 10
14.7g (0.05 mol, purity greater than 95%) of compound II and 8.61g (0.1025 mol) of potassium formate were taken, 50g of methanol were mixed, and the mixture was heated to 65℃and reacted at this temperature for 4 hours. The reaction was checked by TLC for the extent of reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), with the disappearance of the spots of the product (Compound II) as the end point of the reaction, after completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 50g of water was added, cooled to 10-20℃to precipitate the product (Compound III), filtered and washed with ice water, dried to give 9.8g of a white powder of the product (Compound III) with a purity of 88.5% and a yield of 84.80%.
Comparative example 3
14.7g (0.05 mol, purity greater than 95%) of compound II and 3.8g (0.045 mol) of potassium formate were taken, 50g of methanol were mixed, and the mixture was heated to 60℃and reacted at this temperature for 5 hours. The reaction was checked by TLC for reaction progress (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), methanol was distilled off under reduced pressure at 60 ℃, 50g of water was added, cooling was carried out to 10-20 ℃, the product (compound III) was precipitated, filtered and washed with ice water, and dried to give 8.7g of a white powder of the product (compound III) with a purity of 84.3% and a yield of 75.28%.
Comparative example 4
14.7g (0.05 mol, purity greater than 95%) of compound II and 10.5g (0.125 mol) of potassium formate were taken, 50g of methanol were mixed, and the mixture was heated to 60℃and reacted at this temperature for 5 hours. The reaction was checked by TLC for the extent of reaction (developing solvent petroleum ether/ethyl acetate (volume ratio 4:1), and the spot of the product (Compound II) disappeared as the end point of the reaction after the completion of the reaction, methanol was distilled off under reduced pressure at 60℃and 50g of water was added, cooled to 10-20℃to precipitate the product (Compound III), filtered and washed with ice water, and dried to give 9.5g of a white powder of the product (Compound III) with a purity of 83.4% and a yield of 82.20%.
In the invention, the reaction temperature and reaction conditions of the monomethyl azelate and the 2-halogenated ethylamine in the step (1) are controlled so that the product is a single-end ammonolysis product of the monomethyl azelate, and in the step (2), methanol is used as a solvent, the compound II and formate are subjected to substitution reaction firstly, and then the thermal decomposition of the ester occurs, so that the high-purity and high-yield nonane diamide compound MEA is prepared.
While the embodiments have been described above, other variations and modifications will occur to those skilled in the art once the basic inventive concepts are known, and it is therefore intended that the foregoing description and drawings illustrate only embodiments of the invention and not limit the scope of the invention, and it is therefore intended that the invention not be limited to the specific embodiments described, but that the invention may be practiced with their equivalent structures or with their equivalent processes or with their use directly or indirectly in other related fields.
Claims (10)
1. A process for the preparation of a nondiamide compound, comprising the steps of:
(1) The monomethyl azelate, namely the compound I, is used as an initial reactant to react with 2-halogenated ethylamine to obtain a compound II,
(2) The compound II and formate are used as reaction raw materials, methanol is used as solvent, the compound III is obtained by one-step reaction, namely the nonanediamide compound,
the reaction formula is as follows:
wherein X is halogen element.
2. The process for the preparation of a nonyldiamide compound according to claim 1, characterized in that in step (1), the molar ratio of monomethyl azelate to 2-halogenated ethylamine is 1:1.1-1:2, the reaction temperature is 35 ℃ to 65 ℃ and the reaction time is 2h to 8h.
3. The process for the preparation of a nonyldiamide compound according to claim 2, characterized in that in step (1), the molar ratio of monomethyl azelate to 2-halogenated ethylamine is 1:1.3-1:1.5, the reaction temperature is 40-60 ℃ and the reaction time is 2-3 h.
4. The process for producing a nonyldiamide compound according to claim 1, wherein the 2-haloethylamine is 2-bromoethylamine hydrobromide or 2-chloroethylamine hydrochloride.
5. The method for producing a nondiamide compound according to claim 1, wherein an organic base is added as an acid-binding agent in step (1).
6. The process for producing a nondiamide compound according to claim 1, wherein in the step (2), the molar ratio of the compound II to formate is 1:0.95 to 1:2.05, the reaction temperature is 35 ℃ to 65 ℃ and the reaction time is 4h to 10h.
7. The process for producing a nonyldiamide compound according to claim 6, wherein in the step (2), the molar ratio of the compound II to the formate is 1:1 to 1:2, the reaction temperature is 40 ℃ to 60 ℃, and the reaction time is 5h to 6h.
8. The method for producing a nondiamide compound according to claim 1, characterized in that the formate is potassium formate or sodium formate.
9. The process for producing a nonylenediamide compound according to claim 1, wherein in the step (2), after the completion of the reaction between the compound II and the formate, the methanol solvent is distilled off under reduced pressure, and water is added for cooling, whereby the nonylenediamide compound is precipitated.
10. The method for producing a nondiamide compound according to claim 9, characterized in that water is cooled to 10-20 ℃.
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