CN1827597A - Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester - Google Patents
Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester Download PDFInfo
- Publication number
- CN1827597A CN1827597A CN 200610039441 CN200610039441A CN1827597A CN 1827597 A CN1827597 A CN 1827597A CN 200610039441 CN200610039441 CN 200610039441 CN 200610039441 A CN200610039441 A CN 200610039441A CN 1827597 A CN1827597 A CN 1827597A
- Authority
- CN
- China
- Prior art keywords
- solution
- ester
- reaction
- toluene
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention discloses a method for preparation of 1-methyl-5-p-benzoyl pyrrole-2-guaiacol acetamidoacetic acetate, which includes the following steps: (1) dehydrating and drying tolmetin sodium; (2) obtaining the mixed acid anhydride by reaction between tolmetin sodium and chloroformate; (3) produing the object product by reaction between the mixed acid anhydride and guaiacol glycinate. The process for preparing of this method is of short composited course, higher total yield rate and fine purity of the product.
Description
Technical field
The invention belongs to a kind of pharmaceutical chemicals synthetic method, specifically is 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester synthetic method.
Background technology
Amtolmetin Guacil (1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester) is a kind of NSAID (non-steroidal anti-inflammatory drug) of Sigma-Tau company of Luo Shi Subsidiary Company exploitation, be the nonacid prodrug of tolmetin, be first nitrogen protoxide release type NSAID (non-steroidal anti-inflammatory drug) in the world.This medicine is not owing to contain the acidic-group (carboxyl) in stimulating gastrointestinal road; simultaneously in metabolic process, can produce the NO that gastrointestinal tract mucosa is had provide protection; thereby Amtolmetin Guacil is all effective with administration after the meal on an empty stomach; especially good with oral curative effect under the empty stomach state; its curative effect and tolmetin are quite or better; but gastrointestinal side effect still less, takes repeatedly and also do not have obvious gastrointestinal injury several weeks.Amtolmetin Guacil is as the pain relieving of postoperative patient and the safer alternative medicine that anti-inflammatory may be the standard NSAID (non-steroidal anti-inflammatory drug).
At present, the synthetic method of Amtolmetin Guacil has following several:
(1)、US?4578481
Shortcoming: be disclosed in US4, there are some shortcomings in the method in 578,481, and is low because it is not easy in industrial scale applications and productive rate; N, N '-phosphinylidyne diimidazole price height makes condensing agent cost height with it; Make refining solvent with benzene, toxicity is too big.
As stated above, with tolmetin and N, N '-phosphinylidyne diimidazole reaction adds the ethyl aminoacetate hydrochloride again in this reaction mixture in tetrahydrofuran (THF) (THF).
Then carry out the washing of a series of complexity so that remove unreacted starting compounds, crystallization from benzene/cyclohexane again obtains 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid ethyl ester.Subsequently this compound is changed into corresponding acid.
Should acid and N, N '-phosphinylidyne diimidazole reaction and corresponding imidazolium compounds, the solution of interpolation methyl catechol in THF in this compound again.
Washing for several times, neutralizing and from benzene/cyclohexane, after the crystallization, obtaining 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester from this reaction mixture.
(2)、US?6288241?B1(CN1283185A)
Shortcoming: synthetic route long (reaction of 5 steps), total recovery is lower, and product purity is lower.Particularly the reaction system thickness stirs difficulty, is difficult to suitability for industrialized production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of new 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester, synthetic route is short, and total recovery is higher, good product purity.
Synthetic method of the present invention:
The preparation method of 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester is characterized in that may further comprise the steps:
(1), tolmetin sodium is dehydrated;
(2), the reaction of tolmetin sodium and chloro-formic ester obtains mixed acid anhydride;
(3), the reaction of mixed acid anhydride and glycine guaiacol ester generates target product.
Above-mentioned preparation method is characterized in that each step reaction condition is:
(1), tolmetin sodium is mixed reflux toluene band water, and then adding saleratus backflow band water with toluene;
(2), tolmetin sodium and chloro-formic ester are reflected at isopropylcarbinol and N-methylmorpholine as carrying out under the condition of catalyzer;
(3), mixed acid anhydride and glycine guaiacol ester are to react under the condition of antioxidant at the potassium hydroxide alkalescence aqueous solution, with the Sodium Pyrosulfite.
Preparation method of the present invention, the concrete operations condition of its each step is:
(1), with the mixture of tolmetin sodium, toluene, reflux, with toluene band water, dry this solution;
When solution temperature reaches 95-100 ℃, cool off this solution to 55-60 ℃, add potassium bicarbonate solution in batches, continuing to reflux dewaters, and reaches 105 ± 2 ℃ up to internal temperature, and ice-water bath is cooled to 5 ± 2 ℃ with this mixture;
(2), in mixture, add isopropylcarbinol and N-methylmorpholine is a catalyzer, temperature is remained on 10 ± 3 ℃, press 1-10ml/ minute speed again and drip isobutyl chlorocarbonate, allow this mixture fully react down at 10 ± 3 ℃, obtain acid anhydrides solution;
(3), the acid anhydrides drips of solution is added in the glycine methyl catechol aqueous solution of ester, dropwise, temperature be raised to room temperature, fully reaction, suspension, acid anhydrides and glycine guaiacol ester solution reaction generate target product.
Chloro-formic ester of the present invention is isobutyl chlorocarbonate or isopropyl chlorocarbonate.
The following separating step of target product process that the present invention obtains:
(1), target product is regulated pH of suspension to 6.0 ± 0.5 with dilute hydrochloric acid, heat this suspension to 70 ± 5 ℃, regulate pH to 3.5～4.5 with dilute hydrochloric acid again, carry out separatory while hot, aqueous phase discarded is added water in organic phase, temperature is remained on 70 ± 5 ℃, regulate this pH value of solution to 8.0 ± 0.5 with diluted sodium hydroxide solution, carry out separatory, aqueous phase discarded more while hot;
(2), water repetitive scrubbing organic phase, under 70 ± 5 ℃, be separated, then with diatomite cleaning toluene organic phase, cool to room temperature, put refrigerator cooling and allow its crystallization, filter, filter cake washs with cold toluene, to constant weight, get 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester crude product in 60 ℃ of following vacuum-dryings.
Operational path of the present invention is as follows:
R represents the alkyl of carbonatoms 1～4 in the formula.
More than in each step each reactant get final product by its reaction formula weight, also can be slightly excessive.
Advantage of the present invention:
Synthetic route is short, and total recovery is higher, good product purity.Be easy to suitability for industrialized production.
The glycine guaiacol ester can prepare according to literature method.
Embodiment
Example 1:
Operation steps:
In the 2000ml four-hole reaction flask of water trap, mechanical stirrer and thermometer is housed, add tolmetin sodium 100.0g (0.358mol) and 500ml toluene, open and stir, reflux is with toluene band water, and dry this solution is when internal temperature reaches 95-100 ℃, cool off this solution to 55-60 ℃, add the 11.5g potassium bicarbonate solution that is dissolved in 30ml water, continuing to reflux dewaters, and reaches 105 ± 2 ℃ up to internal temperature in batches.Ice-water bath is cooled to 5 ± 2 ℃ with this mixture, toward the isopropylcarbinol and the 0.3ml N-methylmorpholine that wherein add 24ml.Temperature is remained on 10 ± 3 ℃, drip isobutyl chlorocarbonate 45.5ml (0.400mol) with constant pressure funnel, 10min dropwises, allow this mixture react 2hr down and promptly get acid anhydrides solution at 10 ± 3 ℃, it is added drop-wise in the glycine methyl catechol ester solution that has prepared, and 5-10min dropwises.Glycine methyl catechol ester solution is by add 295ml water, the potassium hydroxide (82%) of 27g and the Sodium Pyrosulfite of 0.3g in the 2000ml flask, stirring and dissolving, temperature is controlled at 10 ± 3 ℃, makes toward wherein adding 82.7g (0.38mol) glycine methyl catechol ester hydrochloride.Dropwise, temperature is raised to room temperature, reaction 2hr regulates this mixture pH to 6.0 ± 0.5 with 16% dilute hydrochloric acid.Heat this suspension to 70 ± 5 ℃, regulate pH to 3.5～4.5 with 16% dilute hydrochloric acid again, carry out separatory while hot, aqueous phase discarded, in organic phase, add 250ml water, temperature is remained on 70 ± 5 ℃, regulate this pH value of solution to 8.0 ± 0.5 with rare (2N) sodium hydroxide solution, carry out separatory, aqueous phase discarded more while hot.With 2 * 250ml water washing organic phase, under 70 ± 5 ℃, be separated, then with diatomite cleaning toluene organic phase, cool to room temperature is put refrigerator cooling and is allowed its crystallization, filters, filter cake washs with 2 * 50ml cold toluene, to constant weight, get 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester crude product 135.5 grams, yield 90% in 60 ℃ of following vacuum-dryings.The crude product acetone recrystallization, 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester elaboration 127.9 grams, yield 94.4%, m.p.128.7～131.9 ℃.Ultimate analysis: C, 68.53%; H, 5.76%; N, 6.65%.Infrared spectra (KBr pressed disc method): 3318,3142,2963,1778,1652,1626,1605,1500,1480,1456,13731255 and 1153cm
-1
Example 2:
Operation steps:
In the 2000ml four-hole reaction flask of water trap, mechanical stirrer and thermometer is housed, add tolmetin sodium 100.0g (0.358mol) and 500ml toluene, open and stir, reflux is with toluene band water, and dry this solution is when internal temperature reaches 95-100 ℃, cool off this solution to 55-60 ℃, add the 11.5g potassium bicarbonate solution that is dissolved in 30ml water, continuing to reflux dewaters, and reaches 105 ± 2 ℃ up to internal temperature in batches.Ice-water bath is cooled to 5 ± 2 ℃ with this mixture, toward the isopropylcarbinol and the 0.3ml N-methylmorpholine that wherein add 24ml.Temperature is remained on 10 ± 3 ℃, drip isopropyl chlorocarbonate 46.5ml (0.41mol) with constant pressure funnel, 10-15min dropwises, allow this mixture react 2hr down and promptly get acid anhydrides solution at 10 ± 3 ℃, it is added drop-wise in the glycine methyl catechol ester solution that has prepared, and 5-10min dropwises.Glycine methyl catechol ester solution is by add 295ml water, the potassium hydroxide (82%) of 27g and the Sodium Pyrosulfite of 0.3g in the 2000ml flask, stirring and dissolving, temperature is controlled at 10 ± 3 ℃, makes toward wherein adding 82.7g (0.38mol) glycine methyl catechol ester hydrochloride.Dropwise, temperature is raised to room temperature, reaction 2hr regulates this mixture pH to 6.0 ± 0.5 with 16% dilute hydrochloric acid.Heat this suspension to 70 ± 5 ℃, regulate pH to 3.5～4.5 with 16% dilute hydrochloric acid again, carry out separatory while hot, aqueous phase discarded, in organic phase, add 250ml water, temperature is remained on 70 ± 5 ℃, regulate this pH value of solution to 8.0 ± 0.5 with rare (2N) sodium hydroxide solution, carry out separatory, aqueous phase discarded more while hot.With 2 * 250ml water washing organic phase, under 70 ± 5 ℃, be separated, then with diatomite cleaning toluene organic phase, cool to room temperature is put refrigerator cooling and is allowed its crystallization, filters, filter cake washs with 2 * 50ml cold toluene, to constant weight, get 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester crude product 138.5 grams, yield 92% in 60 ℃ of following vacuum-dryings.The crude product acetone recrystallization gets 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester elaboration 128.8 grams.
Example 3:
In the 2000ml four-hole reaction flask of water trap, mechanical stirrer and thermometer is housed, add tolmetin sodium 100.0g (0.358mol) and 500ml toluene, open and stir, reflux is with toluene band water, and dry this solution is when internal temperature reaches 95-100 ℃, cool off this solution to 55-60 ℃, add the 10-12.5g potassium bicarbonate solution that is dissolved in 30ml water, continuing to reflux dewaters, and reaches 105 ± 2 ℃ up to internal temperature in batches.Ice-water bath is cooled to 5 ± 2 ℃ with this mixture, toward the isopropylcarbinol and the 0.2-0.5mlN-methylmorpholine that wherein add 20-30ml.Temperature is remained on 10 ± 3 ℃, drip isobutyl chlorocarbonate 40.5-48.5ml with constant pressure funnel, 10-15min dropwises, allow this mixture react 2hr down and promptly get acid anhydrides solution at 10 ± 3 ℃, it is added drop-wise in the glycine methyl catechol ester solution that has prepared, and 5-10min dropwises.Glycine methyl catechol ester solution is Sodium Pyrosulfite or the vat powder by the potassium hydroxide (82%) that adds 295ml water, 25-30g in the 2000ml flask or 15-17 gram sodium hydroxide and 0.2-0.5g, stirring and dissolving, temperature is controlled at 10 ± 3 ℃, makes toward wherein adding 80-84g glycine methyl catechol ester hydrochloride.Dropwise, temperature is raised to room temperature, reaction 2hr regulates this mixture pH to 6.0 ± 0.5 with dilute hydrochloric acid.Heat this suspension to 70 ± 5 ℃, regulate pH to 3.5～4.5 with dilute hydrochloric acid again, carry out separatory while hot, aqueous phase discarded, in organic phase, add 250-280ml water, temperature is remained on 70 ± 5 ℃, regulate this pH value of solution to 8.0 ± 0.5 with diluted sodium hydroxide solution, carry out separatory, aqueous phase discarded more while hot.With 2 * 250ml water washing organic phase, under 70 ± 5 ℃, be separated, then with diatomite cleaning toluene organic phase, cool to room temperature is put refrigerator cooling and is allowed its crystallization, filters, filter cake washs with 2 * 50ml cold toluene, to constant weight, get 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester crude product 130-139 gram in 60 ℃ of following vacuum-dryings.The crude product acetone recrystallization gets 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester elaboration 120-129 gram.
Claims (5)
1, the preparation method of 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester is characterized in that by following reaction scheme preparation and may further comprise the steps:
R represents the alkyl of carbonatoms 1～4 in the formula,
(1), tolmetin sodium is dehydrated;
(2), the reaction of tolmetin sodium and chloro-formic ester obtains mixed acid anhydride;
(3), the reaction of mixed acid anhydride and glycine guaiacol ester generates target product.
2, preparation method according to claim 1 is characterized in that its each step reaction condition is:
(1), tolmetin sodium is mixed reflux toluene band water, and then adding saleratus backflow band water with toluene;
(2), tolmetin sodium and chloro-formic ester are reflected at isopropylcarbinol and N-methylmorpholine as carrying out under the condition of catalyzer;
(3), mixed acid anhydride and glycine guaiacol ester are to react under the condition of antioxidant at the potassium hydroxide alkalescence aqueous solution, with the Sodium Pyrosulfite.
3, preparation method according to claim 1 and 2 is characterized in that the concrete operations condition of its each step is:
(1), with the mixture of tolmetin sodium, toluene, reflux, with toluene band water, dry this solution; When solution temperature reaches 95-100 ℃, cool off this solution to 55-60 ℃, add potassium bicarbonate solution in batches, continuing to reflux dewaters, and reaches 105 ± 2 ℃ up to internal temperature, and ice-water bath is cooled to 5 ± 2 ℃ with this mixture;
(2), in mixture, add isopropylcarbinol and N-methylmorpholine is a catalyzer, temperature is remained on 10 ± 3 ℃, press 1-10ml/ minute speed again and drip isobutyl chlorocarbonate, allow this mixture fully react down at 10 ± 3 ℃, obtain acid anhydrides solution;
(3), the acid anhydrides drips of solution is added in the glycine methyl catechol aqueous solution of ester, dropwise, temperature be raised to room temperature, fully reaction, suspension, acid anhydrides and glycine guaiacol ester solution reaction generate target product.
4, according to claim 1,2 or 3 described preparation methods, it is characterized in that: described chloro-formic ester is isobutyl chlorocarbonate or isopropyl chlorocarbonate.
5,, it is characterized in that the following separating step of target product process that obtains according to claim 1 or 3 described methods:
(1), target product is regulated pH of suspension to 6.0 ± 0.5 with dilute hydrochloric acid, heat this suspension to 70 ± 5 ℃, regulate pH to 3.5～4.5 with dilute hydrochloric acid again, carry out separatory while hot, aqueous phase discarded is added water in organic phase, temperature is remained on 70 ± 5 ℃, regulate this pH value of solution to 8.0 ± 0.5 with diluted sodium hydroxide solution, carry out separatory, aqueous phase discarded more while hot;
(2), water repetitive scrubbing organic phase, under 70 ± 5 ℃, be separated, then with diatomite cleaning toluene organic phase, cool to room temperature, put refrigerator cooling and allow its crystallization, filter, filter cake washs with cold toluene, to constant weight, get 1-methyl-5-toluoyl pyrroles-2-ethanoylaminoethanoic acid guaiacol ester crude product in 60 ℃ of following vacuum-dryings.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100394418A CN100390144C (en) | 2006-03-29 | 2006-03-29 | Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100394418A CN100390144C (en) | 2006-03-29 | 2006-03-29 | Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1827597A true CN1827597A (en) | 2006-09-06 |
| CN100390144C CN100390144C (en) | 2008-05-28 |
Family
ID=36946178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100394418A Expired - Fee Related CN100390144C (en) | 2006-03-29 | 2006-03-29 | Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100390144C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435527A (en) * | 2013-09-03 | 2013-12-11 | 张家港市信谊化工有限公司 | Preparation method of non-steroid anti-inflammatory drug tolmetin |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1210673B (en) * | 1982-02-26 | 1989-09-20 | Medosan Ind Biochimi | PYROLACETIC STARCHES ANTI-INFLAMMATORY ACTIVITY |
| EP1024807B1 (en) * | 1997-08-08 | 2003-04-16 | MEDOSAN RICERCA S.r.l. | Use of the compound 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate for the production of an anti-inflammatory drug with prevention of gastric hypersecretion and renal impairment |
-
2006
- 2006-03-29 CN CNB2006100394418A patent/CN100390144C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435527A (en) * | 2013-09-03 | 2013-12-11 | 张家港市信谊化工有限公司 | Preparation method of non-steroid anti-inflammatory drug tolmetin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100390144C (en) | 2008-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2011216176B2 (en) | Methods of synthesizing and isolating N-(bromoacetyl)-3,3-dinitroazetidine and a composition including the same | |
| WO2006136087A1 (en) | Preparation method of pregabalin and its intermediate and the said intermediate | |
| CN102329277A (en) | Method for preparing Parecoxib | |
| CN108586399B (en) | Synthesis method of feloxicib | |
| CN114195661B (en) | Preparation method of milobalin benzenesulfonate | |
| CN103539744A (en) | Method for preparing 3-(3, 5-dichlorophenyl)-2, 4-imidazolidinedione | |
| CN101585519A (en) | Method for preparing <15>N-hydroxylamine hydrochloride by hydrolyzing <15>N-nitromethane | |
| EP2046750A2 (en) | Process for the preparation of montelukast | |
| CN1827597A (en) | Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester | |
| CN1817859A (en) | Synthesis of tenuazonic acid and iso-tenuazonic acid | |
| AU2003206755B2 (en) | Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds | |
| CN111072552B (en) | Preparation method of cilnidipine | |
| CN1173928C (en) | Process for preparing (1R,2S,4R)-(-)-2-[(2'-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1] heptane and pharmaceutically acceptable acid addition salts thereof | |
| WO2004073585A2 (en) | Methode of manufacturing glimepiride and the respective intermediate | |
| CN102267961A (en) | Method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate | |
| CN113683527B (en) | Preparation method of trifloxystrobin | |
| US7498432B2 (en) | Method of synthesis of 1, 4, 7, 10, 13, 16, 21, 24-octaazabicyclo [8.8.8] hexacosane (1) and 1, 4, 7, 10, 13, 16, 21, 24-octaazabicyclo [8.8.8] hexacosa, 4, 6, 13, 15, 21, 23-hexaene (2) | |
| CN108675950A (en) | A kind of synthetic method of 2- alkenyls Benzazole compounds | |
| CN110066233B (en) | Preparation method of mono-substituted amine compound | |
| JP4833419B2 (en) | Production of cyclic acids | |
| CN1966504A (en) | Guanine one-pot synthesis method | |
| CN110803994A (en) | Synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-ethyl hexanoate | |
| JPH10101627A (en) | Production of 3-amino-4,4,4-trihalocrotonate compound | |
| CN1686998A (en) | Method for preparing ortho-chloromandelic acid | |
| WO2006122444A1 (en) | Preparation method of chloramine phosphorus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080528 Termination date: 20120329 |