CN114085167A - Preparation method of impurity TS-3A - Google Patents
Preparation method of impurity TS-3A Download PDFInfo
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- CN114085167A CN114085167A CN202111515741.XA CN202111515741A CN114085167A CN 114085167 A CN114085167 A CN 114085167A CN 202111515741 A CN202111515741 A CN 202111515741A CN 114085167 A CN114085167 A CN 114085167A
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- Prior art keywords
- reduced pressure
- under reduced
- stirring
- impurity
- ethyl acetate
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- 239000012535 impurity Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000007787 solid Substances 0.000 claims abstract description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004821 distillation Methods 0.000 claims abstract description 8
- 239000000741 silica gel Substances 0.000 claims abstract description 8
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 8
- 238000004440 column chromatography Methods 0.000 claims abstract description 7
- 238000011068 loading method Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000005303 weighing Methods 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 4
- -1 BOC-amino Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/50—Spiro compounds
Abstract
The invention discloses a preparation method of an impurity TS-3A, relating to the technical field of chemical industry, and the technical scheme comprises the following steps: the method comprises the following steps: preparing raw materials: weighing 25.00g PM2 and 280.13g SM2, wherein PM2 is C6H9NO2SM2 is C8H14O2Putting the weighed PM2 and SM2 into a three-mouth bottle; step two: stirring: raising the temperature to 150-155 ℃, and stirring for reacting for 16 h; step three: and (3) reduced pressure distillation: the liquid obtained by the reaction was distilled under reduced pressure to remove SM2, thereby obtaining 35.50g of a black solid; step four: and (3) concentrating under reduced pressure: dissolving the residue in 150ml dichloromethane, adding 50g silica gel (100-200 mesh), mixing, and heating to 40-45 deg.CConcentrating under reduced pressure, loading the residue by dry method, and purifying by column chromatography; by PM2 (C)6H9NO2) And SM2 (C)8H14O2) Stirring at 150-155 ℃, accelerating the mixing speed of the two, purifying and separating the materials through reduced pressure distillation and reduced pressure concentration, subsequently adding ethyl acetate, filtering and drying to obtain the TS-3A solid.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a preparation method of an impurity TS-3A.
Background
TS-3A has the chemical formula of C14H23NO4, also known as 6- (BOC-amino) spiro [3.3] heptane-2-methyl formate, and TS-3A is used for preparing C12H17NO3(2- (4-butoxyphenyl) acetohydroxamic acid).
The prior art is lack of synthesis of TS-3A (6- (BOC-amino) spiro [3.3] heptane-2-methyl formate), so a preparation method of impurity TS-3A is needed.
Disclosure of Invention
The invention aims to solve the defect of lack of synthesis of TS-3A (6- (BOC-amino) spiro [3.3] heptane-2-methyl formate) in the prior art, and provides a preparation method of impurity TS-3A.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of an impurity TS-3A comprises the following steps:
the method comprises the following steps: preparing raw materials: weighing 25.00g PM2 and 280.13g SM2, wherein PM2 is C6H9NO2SM2 is C8H14O2Putting the weighed PM2 and SM2 into a three-mouth bottle;
step two: stirring: raising the temperature to 150-155 ℃, and stirring for reacting for 16 h;
step three: and (3) reduced pressure distillation: the liquid obtained by the reaction was distilled under reduced pressure to remove SM2, thereby obtaining 35.50g of a black solid;
step four: and (3) concentrating under reduced pressure: adding 150ml of dichloromethane into the residue to dissolve, adding 50g of silica gel (100-200 meshes), uniformly mixing, concentrating the mixture at 40-45 ℃ under reduced pressure, loading the residue by a dry method, and purifying by column chromatography;
step five: eluting by using 4L of mixed solution of petroleum ether and ethyl acetate, and then placing the eluent at 40-45 ℃ for decompression and concentration to obtain 15.10g of yellow solid;
step six: adding 50ml of ethyl acetate into the yellow solid, pulping, stirring for 1h, and filtering;
step seven: the filtered cake was washed with 10ml ethyl acetateThe filter cake was air-dried to give 13.10g C14H23NO4A pale yellow solid.
The above technical solution further comprises:
the volume of the three-mouth bottle is 500 ml.
The reduced pressure distillation environment is at an external temperature of 135 ℃ and a pressure of-0.095 Ma.
The drying temperature of the filter cake is 50-55 ℃, and the drying time is 30 min.
Compared with the prior art, the invention has the beneficial effects that:
in the present invention, PM2 (C) is passed6H9NO2) And SM2 (C)8H14O2) Stirring at 150-155 ℃, accelerating the mixing speed of the two, purifying and separating the materials through reduced pressure distillation and reduced pressure concentration, subsequently adding ethyl acetate, filtering and drying to obtain the TS-3A solid.
Detailed Description
Example one
Firstly, adding 25.00g of PM2 and 280.13g of SM2 into a 500ml three-necked bottle, heating to 150-155 ℃, stirring for reacting for 16 hours, and stopping reaction;
secondly, distilling the reaction solution at the external temperature of 135 ℃ and the pressure of-0.095 Ma under reduced pressure to remove SM2 to obtain 35.50g of black solid, adding 150ml of dichloromethane into the residue to dissolve, adding 50g of silica gel (100-200 meshes), uniformly mixing, and concentrating the mixture under reduced pressure at the temperature of 40-45 ℃;
and thirdly, carrying out dry-process sample loading and column chromatography purification on the residues. Eluting with petroleum ether and ethyl acetate (1: 1 (V/V)) 4L, and concentrating the eluate at 40-45 deg.C under reduced pressure. 15.10g of a yellow solid was obtained;
the fourth step: to the yellow solid, 50ml of ethyl acetate was added, slurried and stirred for 1 h. Filtering, washing a filter cake by using 10ml of ethyl acetate, and drying the filter cake by blowing air at 50-55 ℃ to obtain 13.10g of light yellow solid.
The above embodiment passes through PM2 (C) during actual operation6H9NO2) And SM2 (C)8H14O2) Stirring at 150-155 ℃, accelerating the mixing speed of the two, purifying and separating the materials through reduced pressure distillation and reduced pressure concentration, subsequently adding ethyl acetate, filtering and drying to obtain 13.10g of TS-3A solid.
Example two
Firstly, adding 25.00g of PM2 and 280.13g of SM2 into a 500ml three-neck bottle, heating to 130 ℃, stirring and reacting for 20 hours, and stopping the reaction;
secondly, distilling the reaction solution at the external temperature of 135 ℃ and the pressure of-0.095 Ma under reduced pressure to remove SM2 to obtain 35.50g of black solid, adding 150ml of dichloromethane into the residue to dissolve, adding 50g of silica gel (100-200 meshes), uniformly mixing, and concentrating the mixture under reduced pressure at the temperature of 40-45 ℃;
and thirdly, carrying out dry-process sample loading and column chromatography purification on the residues. Eluting with petroleum ether and ethyl acetate (1: 1 (V/V)) 4L, and concentrating the eluate at 40-45 deg.C under reduced pressure. 15.10g of a yellow solid was obtained;
the fourth step: to the yellow solid was added 50ml of ethyl acetate, slurried and stirred for 0.5 h. Filtering, washing a filter cake by using 10ml of ethyl acetate, and drying the filter cake by blowing air at 50-55 ℃ to obtain 12.12g of light yellow solid.
The above example was carried out in practice on PM2 (C)6H9NO2) And SM2 (C)8H14O2) The PM2 (C) is caused by lower temperature in the mixing process6H9NO2) And SM2 (C)8H14O2) And the stirring time during the subsequent addition of ethyl acetate to mix with the yellow solid was too short, resulting in a yellowish solid content of 11.64g, which is a 11.14% reduction in yield compared to example one.
EXAMPLE III
Firstly, adding 25.00g of PM2 and 280.13g of SM2 into a 500ml three-necked bottle, heating to 150-155 ℃, stirring for reacting for 16 hours, and stopping reaction;
secondly, distilling the reaction solution at the external temperature of 135 ℃ and the pressure of-0.095 Ma under reduced pressure to remove SM2 to obtain 35.50g of black solid, adding 150ml of dichloromethane into the residue to dissolve, adding 25g of silica gel (100-200 meshes), uniformly mixing, and concentrating the mixture under reduced pressure at the temperature of 40-45 ℃;
and thirdly, carrying out dry-process loading on the residue, purifying by column chromatography, eluting by using petroleum ether and ethyl acetate which are 1:1(V/V)4L, and concentrating the eluent at 40-45 ℃ under reduced pressure. 15.10g of a yellow solid was obtained;
the fourth step: to the yellow solid, 50ml of ethyl acetate was added, slurried and stirred for 1 h. Filtering, washing a filter cake by using 10ml of ethyl acetate, and drying the filter cake by blowing air at 50-55 ℃ to obtain 13.10g of light yellow solid.
In the practical operation process of the embodiment, the added silica gel is low, so that the material obtained by vacuum concentration is less, and then the material is filtered and dried, so that 11.25g of TS-3A pale yellow solid can be obtained, and the content of the generated TS-3A pale yellow solid is lower compared with that of the TS-3A produced in the embodiment 1.
Example four
Firstly, adding 25.00g of PM2 and 280.13g of SM2 into a 500ml three-necked bottle, heating to 150-155 ℃, stirring for reacting for 16 hours, and stopping reaction;
secondly, distilling the reaction solution at an external temperature of 105 ℃ and a pressure of-0.065 Ma under reduced pressure to remove SM2 to obtain 35.50g of black solid, adding 150ml of dichloromethane into the residue to dissolve, adding 50g of silica gel (100-200 meshes), uniformly mixing, and concentrating the mixture under reduced pressure at a temperature of 40-45 ℃;
and thirdly, carrying out dry-process sample loading and column chromatography purification on the residues. Eluting with petroleum ether and ethyl acetate (1: 1 (V/V)) 4L, and concentrating the eluate at 40-45 deg.C under reduced pressure. 15.10g of a yellow solid was obtained;
the fourth step: to the yellow solid, 50ml of ethyl acetate was added, slurried and stirred for 1 h. Filtering, washing a filter cake by using 10ml of ethyl acetate, and drying the filter cake by blowing air at 50-55 ℃ to obtain 9.31g of light yellow solid.
In the practical operation process of the above embodiment, in the process of concentrating the reaction solution, due to the change in the reaction conditions, the yield of the concentrated solution generated by concentration is reduced, and further 16.20g of a light yellow solid, which is subsequently generated, contains a part of white block-shaped substances, and the content of the white block-shaped substances is weighed to be 7.63g, so that the content of the obtained TS-3A solid is reduced by 34.58% compared with that in the first embodiment.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (4)
1. The preparation method of the impurity TS-3A is characterized by comprising the following steps:
the method comprises the following steps: preparing raw materials: weighing 25.00g PM2 and 280.13g SM2, wherein PM2 is C6H9NO2SM2 is C8H14O2Putting the weighed PM2 and SM2 into a three-mouth bottle;
step two: stirring: raising the temperature to 150-155 ℃, and stirring for reacting for 16 h;
step three: and (3) reduced pressure distillation: the liquid obtained by the reaction was distilled under reduced pressure to remove SM2, thereby obtaining 35.50g of a black solid;
step four: and (3) concentrating under reduced pressure: adding 150ml of dichloromethane into the residue to dissolve, adding 50g of silica gel (100-200 meshes), uniformly mixing, concentrating the mixture at 40-45 ℃ under reduced pressure, loading the residue by a dry method, and purifying by column chromatography;
step five: eluting by using 4L of mixed solution of petroleum ether and ethyl acetate, and then placing the eluent at 40-45 ℃ for decompression and concentration to obtain 15.10g of yellow solid;
step six: adding 50ml of ethyl acetate into the yellow solid, pulping, stirring for 1h, and filtering;
step seven: the filtered cake was washed with 10ml of ethyl acetate and the cake was dried by air blowing to give 13.10g C14H23NO4A pale yellow solid.
2. The method for preparing the impurity TS-3A according to claim 1, wherein the volume of the three-mouth bottle is 500 ml.
3. The method for preparing the impurity TS-3A according to claim 1, wherein the reduced pressure distillation environment is an external temperature of 135 ℃ and a pressure of-0.095 Ma.
4. The preparation method of the impurity TS-3A, according to claim 1, characterized in that the drying temperature of the filter cake is 50-55 ℃, and the drying time is 30 min.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111515741.XA CN114085167A (en) | 2021-12-13 | 2021-12-13 | Preparation method of impurity TS-3A |
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| CN202111515741.XA CN114085167A (en) | 2021-12-13 | 2021-12-13 | Preparation method of impurity TS-3A |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110072857A (en) * | 2016-10-13 | 2019-07-30 | 葛兰素史密斯克莱知识产权发展有限公司 | The disubstituted cyclobutanone of 1,3- or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitor |
| CN112313208A (en) * | 2018-04-17 | 2021-02-02 | 泰普斯特医疗公司 | Bicyclic carboxamides and methods of use thereof |
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2021
- 2021-12-13 CN CN202111515741.XA patent/CN114085167A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110072857A (en) * | 2016-10-13 | 2019-07-30 | 葛兰素史密斯克莱知识产权发展有限公司 | The disubstituted cyclobutanone of 1,3- or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitor |
| CN112313208A (en) * | 2018-04-17 | 2021-02-02 | 泰普斯特医疗公司 | Bicyclic carboxamides and methods of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| BRYAN C. N. M. JONES 等: "(.+-.)-N9-(2-(Hydroxymethyl)spiro[3.3]hept-6-yl)adenine. The First Biologically Active Saturated Analog of Adenallene with Axial Dissymmetry", J. ORG. CHEM., vol. 60, no. 20, pages 6277 - 6280 * |
| DMYTRO S. RADCHENKO 等: "Cyclobutane-Derived Diamines: Synthesis and Molecular Structure", J. ORG. CHEM., vol. 75, no. 17, pages 5941 - 5952, XP055601119, DOI: 10.1021/jo101271h * |
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