CN103694146A - Method for preparing 2-(2-chloro-1-ethidene)hydrazide methyl formate - Google Patents
Method for preparing 2-(2-chloro-1-ethidene)hydrazide methyl formate Download PDFInfo
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Abstract
The invention provides a method for preparing a method for preparing an aprepitant intermediate 2-(2-chloro-1-ethidene)hydrazide methyl formate. The method comprises the following steps: carrying out a condensation reaction between chloroacetonitrile and methyl hydrazinocarboxylate in a methanol/sodium methylate reaction solution by virtue of catalysis of glacial acetic acid, and performing after-treatment purification on the reaction solution by adopting acetone. The operation is simple, the purity of the obtained product is over 99%, and the method is high in yield and suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the synthetic method of antiemetic Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate.
Background technology
Aprepitant (English name aprepitant), chemistry 5-[[(2R by name, 3S)-2-[(1R)-1-[3,5-bis-(trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone, U.S. FDA in first neurokinin 1 (NK-1) receptor-blocking agent of approval listing in 2003, by with nk 1 receptor (being mainly present in central nervous system and periphery thereof) in conjunction with the effect of blocking Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.This product can be passed through hemato encephalic barrier, captures the nk 1 receptor in brain, has selectivity and high-affinity, and very low to NK-2 and NK-3 receptor affinity.Target spot (as Dopamine Receptors, the 5HT acceptor) affinity interaction of medicine of nausea and vomiting symptom that simultaneously this product is used for the treatment of chemotherapy induction to other is also very low, its reduce feel sick, the effect of vomiting is better than other drug.Its structural formula is:
Chinese Journal of Pharmaceuticals (Chinese Journal of Pharmaceuticals 2009, 40 (12), 951-953) Aprepitant graphical Synthetic Routes is disclosed, from this diagram, by number of ways, prepare the i.e. (2R of key intermediate 2, 3S)-2-[(1R)-1-[3, 5-bis-(trifluoromethyl) phenyl] oxyethyl group] after-3-(4-fluorophenyl) morpholine, need react to continue the synthetic Aprepitant that obtains with 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, therefore 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate is very important intermediate in the process of synthetic Aprepitant.
The synthetic method that discloses 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate (formula I compound) in patent (CN1261882A) is, the method adopts chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution, after glacial acetic acid catalysis, to obtain the methanol solution of target product with the condensation of carbazic acid methyl esters, and concentration of reaction solution is decompressed to the dry yellow powder shape product that obtains.Reaction formula is as follows:
Actual experiment result shows, product characteristics that this method obtains are bad, purity is on the low side, easily residual highly toxic chloromethyl cyanide and other unreacted raw material completely, affect the purity of subsequent product, aftertreatment concentrating under reduced pressure spends the night, length consuming time, energy consumption is high, is not suitable for suitability for industrialized production.
Summary of the invention
The preparation method who the invention provides a kind of Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, the method purification process is simple to operate, and the product purity obtaining reaches more than 99.9%, and yield is high, is applicable to suitability for industrialized production.
The preparation method of Aprepitant intermediate 2-provided by the invention (the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with the condensation reaction of carbazic acid methyl esters, it is characterized in that, adopt acetone to carry out aftertreatment purifying to reaction solution.
Contriver is for fear of long concentrating under reduced pressure, and other aftertreatment purification process of reaction solution has after completion of the reaction been carried out to the effects.A kind of method is to reduce the time of concentrating under reduced pressure, reaction solution concentrating under reduced pressure is removed after lower boiling methyl alcohol, just added solvent making beating, expectation is by removing by filter high boiling solvent and other impurity, select the solvent of indissoluble solution reaction product, comprise sherwood oil, isopropyl ether, acetonitrile, ethyl acetate or their mixed solvent, under room temperature, fully after making beating, filter, dry, the product purity obtaining sees the following form:
| Making beating solvent | HPLC |
| Sherwood oil | 96.2% |
| Isopropyl ether | 96.2% |
| Acetonitrile | 98.3% |
| Ethyl acetate | 97.0% |
| Methylene dichloride | 96.3% |
| Acetonitrile/sherwood oil | 97.1% |
| Acetonitrile/isopropyl ether | 96.9% |
| Acetone | 99.5% |
From upper table result, the method purifying that making beating is filtered adopts most solvents still can residual a small amount of impurity, through tlc analysis of control, finds to contain the complete carbazic acid methyl esters of unreacted in product, only has acetone making beating product purity higher, reaches more than 99%.
Another kind method, reaction finishes directly in reaction solution, to add solvent crystallization afterwards, and crystallization mode is stirring and crystallizing under room temperature, and the selection result of crystallization solvent sees the following form:
| Solvent | Crystallization state | HPLC |
| Sherwood oil | Wall built-up, separate out solid and be clamminess | 94.0% |
| Isopropyl ether | Wall built-up, separate out solid and be clamminess | 95.3% |
| Ether | Wall built-up, separate out solid and be clamminess | 95.5% |
| Normal hexane | Wall built-up, separate out solid and be clamminess | 93.9% |
| Normal heptane | Wall built-up, separate out solid and be clamminess | 93.5% |
| Methyl tertiary butyl ether | Wall built-up, separate out solid and be clamminess | 95.0% |
| Acetone | Light yellow crystalline powder | 99.8% |
By above-mentioned experiment screening, surprisingly find, the product purity that other reaction solvent crystallization except acetone obtains is on the low side, through thin-layer chromatographic analysis contrast, finds to contain chloromethyl cyanide and carbazic acid methyl esters in product, because chloromethyl cyanide is liquid, so the product of separating out is clamminess.And employing adds the method for acetone crystallization, product is being adopted to thin-layer chromatographic analysis contrast discovery, in product, there is no chloromethyl cyanide and carbazic acid methyl esters, filtrate is carried out to thin-layer chromatographic analysis discovery, in filtrate, contain chloromethyl cyanide, but there is no carbazic acid methyl esters, and generation another one impurity, from above-mentioned phenomenon, acetone has occurred to react with the carbazic acid methyl esters in reaction solution, consider to generate schiff bases, and this product is dissolved in acetone, thereby has reached the effect of removing carbazic acid methyl esters in reaction solution.In addition, chloromethyl cyanide is easily molten in acetone, but target product 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate is insoluble, thereby chloromethyl cyanide has been removed in separation.
Result based on above-mentioned two kinds of methods, contriver has surprisingly found that the reaction solution that acetone can obtain with the condensation reaction of carbazic acid methyl esters chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis carries out purifying fast and effectively, further study the purification effect of other ketones solvents, the results are shown in following table:
| Solvent | Volume | Temperature | Result |
| Acetone | 50ml | Room temperature | Separate out a large amount of |
| Butanone | 50ml | 15℃ | Separate out a small amount of |
| Pentanone | 50ml | 10℃ | Separate out minute quantity |
| Octanone | 50ml | -5-0℃ | Separate out minute quantity |
| Methylacetone | 50ml | -5-0℃ | Separate out minute quantity |
| 4-methyl-2 pentanone | 100ml | Room temperature | Do not separate out |
| Dimethyl diketone | 100ml | Room temperature | Do not separate out |
| Diacetylmethane | 100ml | Room temperature | Do not separate out |
| Cyclopropanone | 100ml | Room temperature | Do not separate out |
| Cyclopentanone | 100ml | Room temperature | Do not separate out |
As seen from the above table, target product 2-(the chloro-1-ethylidene of 2-) the solvability difference of hydrazides methyl-formiate in ketones solvent is larger, and only the solvability in acetone is minimum, so acetone is the optimum solvent for purification of target product.
The method that adopts acetone to carry out aftertreatment purifying to reaction solution can, for after reaction solution is concentrated, add acetone making beating and filter, or add acetone crystallization in reaction solution.Further optimize, the temperature while adopting acetone aftertreatment is-10 ~ 30 ℃, preferably 20 ~ 30 ℃, 20 ~ 30 ℃ is room temperature range, after experiment, finds that this temperature range purity and yield reach maximum value, and without cooling or heating operation, save energy, is applicable to suitability for industrialized production.Acetone used is 10 ~ 50:1 with the volume mass ratio of chloromethyl cyanide, and preferred 20 ~ 30:1 in addition, adopts when adding the method for acetone crystallization in reaction solution, and the consumption of acetone and the volume ratio of methyl alcohol are 1 ~ 3:1.
While adding the method for acetone making beating after adopting reaction solution concentrated, beating time preferably 0.5 ~ 4 hour; Employing is when adding the method for acetone crystallization in reaction solution, and crystallization mode is stirring and crystallizing, and churning time is 0.5 ~ 4 hour.
The preparation method of a kind of Aprepitant intermediate 2-provided by the invention (the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, the method adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with the condensation reaction of carbazic acid methyl esters, reaction solution adopts acetone to carry out aftertreatment purifying, simple to operate, more than the product purity obtaining reaches 99 %, and yield is high, be applicable to suitability for industrialized production.
Below in conjunction with the embodiment of embodiment, the present invention will be further described.
Embodiment
embodiment mono-
under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
Concentrating under reduced pressure reaction solution, near dry, adds 1000ml acetone, stirring at room making beating 30min, filter, obtain faint yellow solid, 50 ℃ of forced air dryings of solid, obtain 70.1g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 93.1%, HPLC purity 99.8%.
embodiment bis-
under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
Concentrating under reduced pressure reaction solution, near dry, adds 500ml acetone, and stirring at room making beating 2min, filters, and obtains faint yellow solid, and 50 ℃ of forced air dryings of solid, obtain 69.5g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 93.0%, HPLC purity 99.5%.
embodiment tri-
Under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
In above-mentioned reaction solution, drip 500ml acetone, stir on dropping limit, limit, after dripping ,-10 ~ 0 ℃ are continued stirring and crystallizing, start crystallization, insulated and stirred 40 ~ 60min after 1h, filter, obtain faint yellow solid, 50 ℃ of forced air dryings of solid, obtain 38.1g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 50.6%, HPLC purity 99.93%.
embodiment tetra-
Under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
In above-mentioned reaction solution, drip 1000ml acetone, stir on dropping limit, limit, and-10 ~ 0 ℃ of stirring and crystallizing after dripping, start crystallization after 0.5h, and insulated and stirred 40 ~ 60min filters, and obtains faint yellow solid, 50 ℃ of forced air dryings of solid.Obtain 72.0g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.6%, HPLC purity 99.85%.
embodiment five
Under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
In above-mentioned reaction solution, drip 2000ml acetone, stir on dropping limit, limit, and after dropwising, 20 ~ 30 ℃ are continued stirring and crystallizing, start crystallization after 0.5h, continues insulated and stirred 40 ~ 60min and filter, and obtains faint yellow solid, 50 ℃ of forced air dryings of solid.Obtain 71.8g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.3%, HPLC purity 99.97%.
embodiment six
Under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
In reaction solution, drip 1500ml acetone, stir on dropping limit, limit, and 20 ~ 30 ℃ of stirring and crystallizing after dripping, start crystallization after 1h, and 20 ~ 30 ℃ of insulation 40 ~ 60min, filter, and obtain faint yellow solid, 50 ℃ of forced air dryings of solid.Obtain 72.4g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 96.1%, HPLC purity 99.80%.
embodiment seven
Under nitrogen protection, in 1000ml there-necked flask, add successively chloromethyl cyanide 50g(0.67mol), 200ml methyl alcohol, is cooled to 0 ℃.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room 30 minutes.Add 1.06ml Glacial acetic acid, then to the 250ml methanol solution that drips 39g (0.43mol) carbazic acid methyl esters in gained mixture.Dropwise, continue to stir 30 minutes.
In reaction solution, drip 1000ml acetone, stir on dropping limit, limit, and 20 ~ 30 ℃ of stirring and crystallizing after dripping, start crystallization after 1h, and 20 ~ 30 ℃ of insulation 40 ~ 60min, filter, and obtain faint yellow solid, 50 ℃ of forced air dryings of solid.Obtain 71.5g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.0%, HPLC purity 99.96%.
Claims (10)
1. the preparation method of Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with the condensation reaction of carbazic acid methyl esters, it is characterized in that, adopt acetone to carry out aftertreatment purifying to reaction solution.
2. method according to claim 1, is characterized in that, the method for described aftertreatment purifying can, for after reaction solution is concentrated, add acetone making beating and filter, or add acetone crystallization in reaction solution.
3. method according to claim 1, is characterized in that, the method for described aftertreatment purifying for to add acetone crystallization in reaction solution.
4. method according to claim 1, is characterized in that, the temperature while adopting acetone aftertreatment is-10 ~ 30 ℃.
5. method according to claim 4, is characterized in that, the temperature while adopting acetone aftertreatment is 20 ~ 30 ℃.
6. method according to claim 1, is characterized in that, acetone is 10 ~ 50:1 with the volume mass ratio of chloromethyl cyanide.
7. method according to claim 1, is characterized in that, acetone is 20 ~ 30:1 with the volume mass ratio of chloromethyl cyanide.
8. method according to claim 3, is characterized in that, the volume ratio of acetone and methyl alcohol is 1 ~ 3:1.
9. method according to claim 1, is characterized in that, described aftertreatment purification process is that while adding the method for acetone making beating after reaction solution concentrates, beating time is 0.5 ~ 4 hour.
10. according to the method described in claim 1 or 3, it is characterized in that, described aftertreatment purification process is that while adding the method for acetone crystallization in reaction solution, crystallization mode is stirring and crystallizing, and churning time is 0.5 ~ 4 hour.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112684028A (en) * | 2020-12-04 | 2021-04-20 | 中山奕安泰医药科技有限公司 | Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142819A (en) * | 1993-12-17 | 1997-02-12 | 麦克公司 | Morpholine and thiomorpholine tachykinin receptor antagonists |
| CN1147254A (en) * | 1994-03-04 | 1997-04-09 | 麦克公司 | Prodrugs of morpholine tachykinin receptor antagonists |
| WO2009001203A2 (en) * | 2007-06-27 | 2008-12-31 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of aprepitant |
| CN102295611A (en) * | 2010-05-24 | 2011-12-28 | 成都地奥制药集团有限公司 | Synthetic method for medicines of neurokinin 1 receptor antagonists |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142819A (en) * | 1993-12-17 | 1997-02-12 | 麦克公司 | Morpholine and thiomorpholine tachykinin receptor antagonists |
| CN1147254A (en) * | 1994-03-04 | 1997-04-09 | 麦克公司 | Prodrugs of morpholine tachykinin receptor antagonists |
| WO2009001203A2 (en) * | 2007-06-27 | 2008-12-31 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of aprepitant |
| CN102295611A (en) * | 2010-05-24 | 2011-12-28 | 成都地奥制药集团有限公司 | Synthetic method for medicines of neurokinin 1 receptor antagonists |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112684028A (en) * | 2020-12-04 | 2021-04-20 | 中山奕安泰医药科技有限公司 | Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate |
| CN112684028B (en) * | 2020-12-04 | 2022-05-17 | 中山奕安泰医药科技有限公司 | Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate |
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