CN111440087A - Production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine - Google Patents
Production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine Download PDFInfo
- Publication number
- CN111440087A CN111440087A CN202010267540.1A CN202010267540A CN111440087A CN 111440087 A CN111440087 A CN 111440087A CN 202010267540 A CN202010267540 A CN 202010267540A CN 111440087 A CN111440087 A CN 111440087A
- Authority
- CN
- China
- Prior art keywords
- ethoxy
- hydroxylamine
- methoxyethoxy
- ethyl
- dichloromethane
- 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
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- TUEYHEWXYWCDHA-UHFFFAOYSA-N ethyl 5-methylthiadiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=NSC=1C TUEYHEWXYWCDHA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 55
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 8
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003039 volatile agent Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention discloses an oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy group]Ethoxy radical]Ethyl radical]The production process of hydroxylamine is characterized by that it uses tetraethylene glycol monomethyl ether as starting material, makes it produce Mitsunobu reaction with NHPI to produce compound 1, then makes it produce NH3‑CH3And obtaining the target compound 2 under the action of the OH solution. By establishing strict internal control standards for the starting raw materials and intermediates and strictly controlling the parameters of key process steps, qualified products can be stably prepared in multiple batches.
Description
Technical Field
The invention relates to a production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine.
Background
Oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy]Ethoxy radical]Ethyl radical]The English chemical name of hydroxylamine is O- [2- [2- (2-methoxy) ethoxy]ethoxy]ethyl]Hydroxylamine, Chemical Abstracts (CAS) number 1355318-41-0, having the structural formula:
no preparation method of the compound is found in the literature at present.
Disclosure of Invention
The present invention provides a process for the production of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine.
The invention provides the following technical scheme:
the production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine has the following synthetic route:
wherein NHPI is N-hydroxyphthalimide DIAD is diisopropyl azodicarboxylate; PPh3Is triphenylphosphine; DCM is dichloromethane;
s1, carrying out Mitsunobu reaction on tetraethylene glycol monomethyl ether serving as a raw material and NHPI to generate a compound 1;
s2, Compound 1 and NH3-CH3And obtaining the target compound 2 under the action of the OH solution.
Further, tetraethylene glycol monomethyl ether, NHPI, PPh3And DIAD in a 1:1.2 molar ratio: 1.2: 2.4. Dissolving tetraethylene glycol monomethyl ether with dichloromethane, cooling to 0 deg.C, and adding PPh3NHPI and DIAD, and then reacted at room temperature for 12 h.
Further, the molar ratio of the intermediate 1 to the ammonia-methanol solution (7M) in S2 is 1: 145, the intermediate 1 is added with the ammonia-methanol solution, stirred and dissolved, the reaction is heated to 40 ℃, the reaction is carried out for 12h, then the volatile matter is removed by vacuum concentration after the reaction, the remainder is dissolved by dichloromethane and filtered, the filter cake is washed twice by dichloromethane, the filtrate is combined, 1.2M hydrochloric acid is slowly dripped into the filtrate to adjust the pH value of the solution to about 4.0, the solution is kept stand and layered, the water phase is separated and washed twice by dichloromethane, then saturated sodium carbonate solution is slowly dripped into the water phase to adjust the pH value of the solution to 9.0, then dichloromethane (150M L) is used for extraction for three times, the organic phase is combined, dried by anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain the target compound.
The invention discloses an oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy group]Ethoxy radical]Ethyl radical]The production process of hydroxylamine uses tetraethylene glycol monomethyl ether as initial material, and makes it and NHPI produce Mitsunobu reaction to produce compound 1, then makes it undergo the process of NH3-CH3And obtaining the target compound 2 under the action of the OH solution. The key process step parameters are strictly controlled by establishing strict internal control standards for the starting raw materials and the intermediatesAnd qualified products can be stably prepared in multiple batches.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
Examples
The production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine has the following synthetic route:
s1 Synthesis procedure of intermediate 1
Weighing tetraethylene glycol monomethyl ether (10.0g,48.0mmol,1.0equiv.) in a 2L round-bottom flask, adding dichloromethane (1000m L), stirring to dissolve, cooling the reaction to 0 ℃, and respectively adding PPh3(15.1g, 57.6mmol,1.2equiv.), NHPI (9.5g,57.6mmol,1.2equiv.), and DIAD (22.4m L, 115.2mmol,2.4equiv.), after addition, the reaction was left at room temperature for 12 h.
The volatiles were removed by concentration under reduced pressure and dried under vacuum directly to the next step.
S2 Synthesis Process of target product 2
To the crude product obtained above was added ammonia-methanol solution (7M in CH)3OH, 1L), stirring to dissolve, heating the reaction to 40 ℃, and reacting for 12 hours.
Concentrating under reduced pressure to remove volatile substances, dissolving the residues with dichloromethane (200M L), filtering, washing the filter cake twice with dichloromethane (50M L), combining the filtrates, slowly dropwise adding 1.2M hydrochloric acid into the filtrate to adjust the pH of the solution to about 4.0, standing for layering, separating an aqueous phase, washing the aqueous phase twice with dichloromethane (100M L), then slowly dropwise adding a saturated sodium carbonate solution into the aqueous phase to adjust the pH of the solution to about 9.0, extracting with dichloromethane (150M L) for three times, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to obtain the target compound 2 (light yellow oily liquid) with qualified purity.
The mass of the obtained compound 2 was weighed to 6.9g, and the yield was 65%.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. The production process of the oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine is characterized in that the synthetic route is as follows:
wherein NHPI is N-hydroxyphthalimide DIAD is diisopropyl azodicarboxylate; PPh3Is triphenylphosphine; DCM is dichloromethane;
s1, carrying out Mitsunobu reaction on tetraethylene glycol monomethyl ether serving as a raw material and NHPI to generate a compound 1;
s2, Compound 1 and NH3-CH3And obtaining the target compound 2 under the action of the OH solution.
2. Oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy ] as claimed in claim 1]Ethoxy radical]Ethyl radical]The production process of hydroxylamine is characterized by that it uses tetraethylene glycol monomethyl ether, NHPI and PPh3And DIAD in a 1:1.2 molar ratio: 1.2: 2.4.
3. oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy ] as claimed in claim 2]Ethoxy radical]Ethyl radical]The production process of hydroxylamine is characterized by that the tetraglycol monomethyl ether is dissolved by adopting dichloromethane, then cooled to 0 deg.C, then respectively added into PPh3NHPI and DIAD, and then reacted at room temperature for 12 h.
4. A process for the production of oxo- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine as claimed in claim 1 wherein the molar ratio of intermediate 1 to ammonia-methanol solution (7M) in S2 is 1: 145.
5. the process for producing oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine as claimed in claim 1, wherein the intermediate 1 is dissolved in ammonia-methanol solution in S2 by stirring, and the reaction is heated to 40 ℃ and reacted for 12 hours.
6. The process for producing oxy- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine as claimed in claim 5, wherein the reaction is followed by concentrating under reduced pressure to remove volatiles, dissolving the residue in dichloromethane, suction filtration, washing the filter cake twice with dichloromethane, combining the filtrates, adding hydrochloric acid slowly dropwise to the filtrate to adjust the pH of the solution to about 4.0, standing for layering, separating the aqueous phase, washing the aqueous phase twice with dichloromethane, then adding saturated sodium carbonate solution slowly dropwise to the aqueous phase to adjust the pH of the solution to 9.0, extracting three times with dichloromethane (150m L), combining the organic phases, drying over anhydrous magnesium sulfate, suction filtration, and concentrating under reduced pressure to obtain the objective compound 2 of acceptable purity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010267540.1A CN111440087A (en) | 2020-04-08 | 2020-04-08 | Production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010267540.1A CN111440087A (en) | 2020-04-08 | 2020-04-08 | Production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111440087A true CN111440087A (en) | 2020-07-24 |
Family
ID=71650067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010267540.1A Pending CN111440087A (en) | 2020-04-08 | 2020-04-08 | Production process of oxygen- [2- [2- [2- (2-methoxyethoxy) ethoxy ] ethyl ] hydroxylamine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111440087A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008083346A1 (en) * | 2006-12-28 | 2008-07-10 | Ambrx, Inc. | Phenazine and quinoxaline substituted amino acids and polypeptides |
-
2020
- 2020-04-08 CN CN202010267540.1A patent/CN111440087A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008083346A1 (en) * | 2006-12-28 | 2008-07-10 | Ambrx, Inc. | Phenazine and quinoxaline substituted amino acids and polypeptides |
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| PB01 | Publication | ||
| PB01 | Publication | ||
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Application publication date: 20200724 |