CN1109017C - Preparation of 1.1-cyclohexyl oxalic amide - Google Patents
Preparation of 1.1-cyclohexyl oxalic amide Download PDFInfo
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- CN1109017C CN1109017C CN 00128111 CN00128111A CN1109017C CN 1109017 C CN1109017 C CN 1109017C CN 00128111 CN00128111 CN 00128111 CN 00128111 A CN00128111 A CN 00128111A CN 1109017 C CN1109017 C CN 1109017C
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- Prior art keywords
- cyclohexanediacetic
- cyclohexanediacetic acid
- preparation
- acid
- monoamide
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- 238000002360 preparation method Methods 0.000 title claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 34
- QJGSJXLCJRXTRY-UHFFFAOYSA-N 2-[1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid Chemical compound NC(=O)CC1(CC(O)=O)CCCCC1 QJGSJXLCJRXTRY-UHFFFAOYSA-N 0.000 claims abstract description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- -1 1-cyclohexanediacetic acid acid anhydride Chemical class 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- YQPCHPBGAALCRT-UHFFFAOYSA-N 2-[1-(carboxymethyl)cyclohexyl]acetic acid Chemical compound OC(=O)CC1(CC(O)=O)CCCCC1 YQPCHPBGAALCRT-UHFFFAOYSA-N 0.000 abstract description 8
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 229960002870 gabapentin Drugs 0.000 abstract description 3
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 2
- XNDSIASQMRYFSW-UHFFFAOYSA-N 3-oxaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)OC(=O)CC11CCCCC1 XNDSIASQMRYFSW-UHFFFAOYSA-N 0.000 abstract 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 2
- 230000003556 anti-epileptic effect Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Cyclohexanediacetic acid, monoamide is an important intermediate for synthesizing antiepileptic Gabapentin. The present invention provides a method for preparing 1, 1-cyclohexanediacetic acid, monoamide through 1, 1-cyclohexanediacetic anhydride as a raw material reacting with ammonia water or ammonia gas in presence of a benzene solvent. The benzene solvent comprises benzene, methylbenzene and dimethylbenzene, and the amount of the solvent is 2 to 10 times greater than the weight of the 1, 1-cyclohexanediacetic anhydride; the molarity of the ammonia water or the ammonia gas is 2.2 to 4 times greater than that of the 1, 1-cyclohexanediacetic anhydride, and the range of reaction temperature is from 30 to 110 DEG C. The present invention has the advantages of simple technological process, high yield and low production cost; the purity of the obtained product is more than 97%.
Description
1,1-cyclohexanediacetic acid monoamide is a kind of important intermediate of synthetic antiepileptic drug gabapentin (Gabapentin), and its structural formula is as follows:
1,1-cyclohexanediacetic acid monoamide is as follows from the preparation feedback equation of basic chemical raw materials:
Wherein 1, the method of the synthesized reference A.I.Vogel of 1-cyclohexanediacetic acid (J.Chem.Soc.1934 1758～1765), 1,1-cyclohexanediacetic acid acid anhydride synthesized reference English Patent GB 1,003,476, but this preparation method's technology is complicated, and do not provide further preparation 1, the operational path of 1-cyclohexanediacetic acid monoamide.
The purpose of this invention is to provide one simple, easily industrialized 1, the preparation method of 1-cyclohexanediacetic acid monoamide, this method product yield, purity height.
The present invention is with 1, and 1-cyclohexanediacetic acid acid anhydride is a raw material, generates 1,1-cyclohexanediacetic acid monoamide with ammoniacal liquor or ammonia gas react in the presence of benzene kind solvent.Benzene kind solvent refers to benzene,toluene,xylene herein, and quantity of solvent is 1,2～10 times of 1-cyclohexanediacetic acid acid anhydride weight; Ammoniacal liquor or ammonia are calculated as 1 with mole, 2.2～4 times of 1-cyclohexanediacetic acid acid anhydride amount, and when using ammoniacal liquor, its concentration is 10%～28%; Range of reaction temperature is 30～110 ℃.
Embodiment 11, and 1-cyclohexanediacetic acid monoamide synthetic the steps include: 1, α, α '-dicyano-1,1-cyclohexyl diacetyl imines ammonium salt synthetic
Add 98.1 in 1000 liters of reactors and do gram pimelinketone, 226 kilograms of ethyl cyanacetates and 550 kilograms of ethanol, be cooled to-5 ℃, stir and feed 51 kilograms of ammonia down.After logical ammonia finishes, with this reactant remain on-5 ℃ 18～26 hours down, 0 ℃ 18～26 hours, room temperature 100～130 hours.Centrifuging removes and desolvates, and solid washs with small amount of ethanol, dry intermediate cyano group acid amides, the productive rate about 95% of getting.2,1,1-cyclohexanediacetic acid synthetic
Add the solution that 150 premium on currency and 450 are done the vitriol oil preparation of gram in 1000 liters of reactors, be heated to 135 ℃, stirring slowly adds 248 down in batches and does gram α, α '-dicyano-1,1-cyclohexyl diacetyl imines ammonium salt, control reaction temperature is at 135～145 ℃, after adding, temperature is raised to 200 ℃ gradually, continues reaction 30 minutes, cool to room temperature, stir and slowly add 250 premium on currency down, placed 10～15 hours, centrifuging obtains black solid, washing.The thick acid of gained is dissolved in 900 liters of 95%～70 ℃ of ethanol, adds activated carbon decolorizing and filters, and steams and removes about 650 liters of ethanol, adds～70 ℃ of hot water toward raffinate in, and to there being solid to separate out, cooling is separated out fully solid, suction filtration, dryly gets white cyclohexanediacetic acid.Productive rate about 73%.180～181 ℃ of fusing points, 181 ℃ of literature values.3,1,1-cyclohexanediacetic acid acid anhydride synthetic
Add 200 kilogram 1 in 1000 liters of reactors, 1-cyclohexanediacetic acid and 450 is done the gram diacetyl oxide, be heated to about 120 ℃, at any time the acetate that will produce in will reacting steams and removes, react after 2 hours, make water distilling apparatus into, remove residual acetic acid and excessive acetic anhydride via under reduced pressure, products obtained therefrom cyclohexanediacetic acid acid anhydride can carry out next step reaction without further processing.4,1,1-cyclohexanediacetic acid monoamide synthetic
By quantity of solvent is 1, and 2～10 of 1-cyclohexanediacetic acid acid anhydride weight is extraordinarily gone into benzene kind solvent, is heated to 30～110 ℃, add ammoniacal liquor or ammonia and be calculated as 1 with mole, 2.2～4 times of 1-cyclohexanediacetic acid acid anhydride amount reacted 3～8 hours, stopped reaction, benzene solvent is removed in cooling, separation.The ammonium salt solution that obtains is acidified to PH=3 with 1: 4 concentrated hydrochloric acid, is warming to 60 ℃, stirs reaction down 2 hours, cooling, centrifuging, washing, the dry cyclohexanediacetic acid monoamide crude product that gets.Crude product with ethyl alcohol recrystallization, activated carbon decolorizing, centrifuging, be drying to obtain finished product.
Embodiment 2
With reference to embodiment 1,1,1-cyclohexanediacetic acid monoamide synthetic
1, add 580 liters toluene in 180 kilograms of the 1-cyclohexanediacetic acid acid anhydrides, be heated to 40 ℃, drips 182 kilogram of 20% ammoniacal liquor, reaction need 8 hours.Stopped reaction, solvent toluene is removed in cooling, separation.The ammonium salt solution that obtains is acidified to PH=3 with 1: 4 concentrated hydrochloric acid, is warming to 60 ℃, stirs reaction down 2 hours, cooling, centrifuging, washing, the dry cyclohexanediacetic acid monoamide crude product that gets.Crude product with ethyl alcohol recrystallization, activated carbon decolorizing, centrifuging, be drying to obtain almost white finished product, productive rate is with 1,1-cyclohexanediacetic acid meter is about 96%, the HPLC purity assay is 97.3%.Product ultimate analysis behind recrystallization again, the result is C 60.15%; H 8.58%; N 7.06; C
10H
17NO
3Theoretical value be C 60.30%; H8.54%; N 7.04%.HPLC shows that to the standard specimen analytical results that product and user provide both main peak retention time are identical.Above analytical results shows that this product structure formula is correct.
Embodiment 31,1-cyclohexanediacetic acid monoamide synthetic
1, add 1000 liters benzene in 110 kilograms of the 1-cyclohexanediacetic acid acid anhydrides, be heated to 80 ℃, 30 kilograms of logical ammonias, reaction needs 5 hours, has a large amount of solids to generate during this period.Stopped reaction, solvent benzol is removed in cooling.The ammonium salt that obtains is handled with the method for embodiment 2, and productive rate is with 1, and 1-cyclohexanediacetic acid meter is about 94%, purity 97.1%.
Embodiment 41,1-cyclohexanediacetic acid monoamide synthetic
1, add 700 liters dimethylbenzene in 110 kilograms of the 1-cyclohexanediacetic acid acid anhydrides, be heated to 100 ℃, 30 kilograms of logical ammonias, reaction needs 3 hours, has a large amount of solids to generate during this period.Stopped reaction, solvent xylene is removed in cooling.The ammonium salt that obtains is handled with the method for embodiment 2, and productive rate is with 1, and 1-cyclohexanediacetic acid meter is about 94.6%, purity 97.2%.
Claims (6)
1. pharmaceutical intermediate 1, the preparation method of 1-cyclohexanediacetic acid monoamide is characterized in that with 1, and 1-cyclohexanediacetic acid acid anhydride is a raw material, under benzene or toluene or xylene solvent existence and 30～110 ℃ of temperature, generate 1,1-cyclohexanediacetic acid monoamide with ammonia react.
2. according to claim 11, the preparation method of 1-cyclohexanediacetic acid monoamide, it is characterized in that described 1, among the preparation method of 1-cyclohexanediacetic acid acid anhydride raw material, α wherein, α '-dicyano-1, the synthetic employing of 1-cyclohexyl diacetyl imines ammonium salt is cooled to pimelinketone, ethyl cyanacetate and alcohol mixture subzero-5 ℃ in advance, logical again ammonia, 1, the acetate that will produce during the synthetic employing of 1-cyclohexanediacetic acid acid anhydride will be reacted at any time steams and removes.
3. according to claim 11, the preparation method of 1-cyclohexanediacetic acid monoamide, the consumption of the described benzene of its feature or toluene or xylene solvent is 1,2～10 times of 1-cyclohexanediacetic acid acid anhydride weight.
4. according to claim 11, the preparation method of 1-cyclohexanediacetic acid monoamide, the described ammonia of its feature refers to ammoniacal liquor or ammonia, is calculated as 1 with mole, 2.2～4 times of 1-cyclohexanediacetic acid acid anhydride amount.
5. according to claim 41, the preparation method of 1-cyclohexanediacetic acid monoamide, the described ammoniacal liquor of its feature, concentration is 10%～28%.
6. according to claim 11, the preparation method of 1-cyclohexanediacetic acid monoamide, the described reaction times of its feature is 3～8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00128111 CN1109017C (en) | 2000-12-01 | 2000-12-01 | Preparation of 1.1-cyclohexyl oxalic amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00128111 CN1109017C (en) | 2000-12-01 | 2000-12-01 | Preparation of 1.1-cyclohexyl oxalic amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1297885A CN1297885A (en) | 2001-06-06 |
| CN1109017C true CN1109017C (en) | 2003-05-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00128111 Expired - Fee Related CN1109017C (en) | 2000-12-01 | 2000-12-01 | Preparation of 1.1-cyclohexyl oxalic amide |
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| CN (1) | CN1109017C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019752A1 (en) * | 2005-08-19 | 2007-02-22 | Nhwa Pharma. Corporation | Process for the preparation of gabapentin hydrochloride |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL144066A0 (en) * | 2001-06-28 | 2002-04-21 | Bromine Compounds Ltd | Process for the preparation of 1,1-cyclohexane diacetic monoamide |
| ITMI20032165A1 (en) * | 2003-11-11 | 2005-05-12 | Zambon Spa | GABAPENTINE PREPARATION PROCESS |
| CN100427452C (en) * | 2006-12-29 | 2008-10-22 | 浙江大学 | Method of preparing 1,1-cyclohexanepentanedioic acid by catalyst-free hydrolyzing alpha,alpha'-dicyano-1,1-1,1-cyclohexanediacetylimide ammonium salt in near-critical water medium |
| CN101475466B (en) * | 2009-01-04 | 2011-06-22 | 曹桂东 | Preparation method of 1,1-cyclohexanediacetic acid |
| CN101717330B (en) * | 2009-11-09 | 2012-09-05 | 浙江大学 | Method for utilizing dilute sulphuric acid to catalyze and hydrolyze alpha,alpha'-dicyano-1,1-cyclohexanediacetamide to prepare 1,1-cyclohexanediacetic acid |
| CN102690207B (en) * | 2012-05-31 | 2014-03-26 | 湖北楚阳科技股份有限公司 | Gabapentin synthesizing method |
| CN103333081A (en) * | 2013-06-27 | 2013-10-02 | 南通泰通化学科技有限公司 | Preparation method of 1,1-cyclohexanediacetic acid mono amide |
| CN104402752A (en) * | 2014-11-28 | 2015-03-11 | 太仓运通生物化工有限公司 | Preparation method of 1,1'-cyclohexyl monoamide |
| CN104402744A (en) * | 2014-11-28 | 2015-03-11 | 太仓运通生物化工有限公司 | Preparation method for gabapentin |
| CN109232508B (en) * | 2018-10-24 | 2022-05-27 | 河北三川化工有限公司 | Preparation method of 1, 1-cyclohexyl diacetic anhydride |
| CN112592289B (en) * | 2020-12-15 | 2022-09-20 | 内蒙古永太化学有限公司 | Preparation method of gabapentin intermediate |
| CN115850109B (en) * | 2022-09-14 | 2025-02-18 | 河北三川化工有限公司 | CAM preparation process and application thereof |
-
2000
- 2000-12-01 CN CN 00128111 patent/CN1109017C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019752A1 (en) * | 2005-08-19 | 2007-02-22 | Nhwa Pharma. Corporation | Process for the preparation of gabapentin hydrochloride |
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| CN1297885A (en) | 2001-06-06 |
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