CN102516040A - Industrialized production method of phenylalkyl chloromethyl ether - Google Patents
Industrialized production method of phenylalkyl chloromethyl ether Download PDFInfo
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- CN102516040A CN102516040A CN2011103347937A CN201110334793A CN102516040A CN 102516040 A CN102516040 A CN 102516040A CN 2011103347937 A CN2011103347937 A CN 2011103347937A CN 201110334793 A CN201110334793 A CN 201110334793A CN 102516040 A CN102516040 A CN 102516040A
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- methyl ether
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Abstract
The invention provides an industrialized production method of phenylalkyl chloromethyl ether. According to the invention, phenylalkyl alcohol is adopted as a raw material; polymerized formaldehyde is added to phenylalkyl alcohol; industrial HCL gas is delivered into the mixture while stirring, and a target compound is produced. The molar ratio of phenylalkyl alcohol to polymerized formaldehyde is 1:1-3, a reaction time is 2-5h, and a reaction temperature of 15-30 DEG C. Compared to prior arts, with the production method provided by the invention, a reaction solvent is eliminated, a reaction condition is mild (wherein room temperature is adopted), an equipment condition is simple, product quality is stable, and production cost is reduced. Therefore, the method is more suitable for large-scale industrialized productions. The invention is also suitable for a method for preparing substituted phenylalkyl chloromethyl ether by using a raw material of substituted phenylalkyl alcohol which is in a liquid state under room temperature.
Description
Technical field
The invention belongs to the organic chemistry synthesis technical field, relate to a kind of working method of pharmaceutical-chemical intermediate, especially a kind of industrialized preparing process of new preparation benzene alkyl chloride methyl ether.
Background technology
Benzene alkyl chloride methyl ether is one type of important pharmaceutical-chemical intermediate.Especially the benzyl chloride methyl ether is mainly used in forward position medicine synthetic important intermediate such as hepatitis B virus resisting medicine Entecavir, treatment postoperative ileus new drug alvimopan.Along with the listing and the extensive application of these new drugs, the consumption of benzyl chloride methyl ether just increased thereupon in the last few years.Therefore, the benzyl chloride methyl ether has very wide application prospect in field of medicine and chemical technology.
The preparation method of the benzyl chloride methyl ether of existing bibliographical information mainly contains: the benzyl chloride methyl ether in formalin, add method that feeding hydrogen chloride gas phenylcarbinol, cooling conditions under prepares the benzyl chloride methyl ether be well-known (reference Organic Syntheses-VOL.52,16-18).But this method needs strict controlled temperature below 10 ℃; Reaction times reaches 7-9 hour, because the long-time use of hydrochloric acid gas, thereby environment has been caused a large amount of pollutions; In addition, contain portion water in the reaction gained thick product, under the situation of distillation purifying, be difficult to be applied in the anhydrous response or the like.More than these factors all limited the application of benzyl chloride methyl ether in suitability for industrialized production.
In addition, in document Bulletin de la societe chimique de France (1986), 2; Narrated the preparation method of benzyl chloride methyl ether among the 245-52; Mainly be to be solvent with the methylene dichloride, add phenylcarbinol, Paraformaldehyde 96, feed HCL gas and react.Reaction finishes, layering, and drying is steamed and is removed dichloromethane solvent, obtains the thick product of purity 90%, yield 80%.But this condition is only applicable to the lab scale reaction, and when being amplified to the 10L reaction, decomposition has taken place product in the still-process, and purity drops to 80%, so method is not suitable for large-scale industrial production yet.
Again for example, at document Bioorganic & Medicinal Chemistry Letters (2011), 21, also mentioned among the 2400-02 and used trimethylchlorosilane to prepare the method for benzyl chloride methyl ether.But this method is operated very complicated in last handling process; Trimethylchlorosilane decomposes the impurity such as trimethyl silanol that produce needs underpressure distillation just can remove; And this process can cause product to decompose slowly; Cause the downgrade of product, and the also increase accordingly of the cost of reaction raw materials, so method is not suitable for large-scale industrial production yet.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the prior art with not enough, provide a kind of easy to operate, cost is low, be fit to the new process for producing of the benzene alkyl chloride methyl ether of suitability for industrialized production.Particularly, the inventor has determined the industrialized preparing process that does not adopt reacted benzyl chloride methyl ether under any solvent, the room temperature through test of many times.
The present invention produces gained benzyl chloride methyl ether product water cut and is lower than 0.1%, need not can satisfy general anhydrous response through complicated dehydration operation; Product purity is high, need not the underpressure distillation purifying and promptly can be applicable to the condensation reaction in the industrial production; Overall yield of reaction has significantly reduced production cost up to 95%, has reduced the pollution to environment.
For realizing above-mentioned purpose, the invention discloses following technical scheme:
A kind of industrialized preparing process of benzene alkyl chloride methyl ether is characterized in that under solvent-free condition, and with compound (I) and polymerization formaldehyde hybrid reaction, cooling is stirred down and fed industrial HCl gas, and reaction obtains compound (II);
Wherein said compound I is the phenyl alkanol, and R is the alkyl of C1-C3;
Said polymerization formaldehyde is trioxymethylene or Paraformaldehyde 96;
Described compound (I) is 1 with the mol ratio of polymerization formaldehyde: 1-3; Preferred compound (I) is 1 with the mol ratio of polymerization formaldehyde: 1-1.5.
Said range of reaction temperature is 10-30 ℃, preferred 20-25 ℃.
Said reaction time range is 2-5 hour, preferred 3-4 hour.
The present invention is equally applicable to being that the substituted-phenyl alkyl alcohol of liquid is the method for feedstock production substituted-phenyl alkyl chloride methyl ether under the room temperature.
The concrete step of the present invention is following:
In the exsiccant retort, add compound (I), polymerization formaldehyde, stir; At the uniform velocity feed HCl gas (industrial steel cylinder air feed, purity＞99%), temperature control 10-30 ℃; React stopped reaction after 2-5 hour, reaction solution is standing demix in jar, discards lower floor; The supernatant liquid body is benzene alkyl chloride methyl ether (II), adds the 5%-10% Calcium Chloride Powder Anhydrous, the airtight preservation of inflated with nitrogen.
The benzyl chloride methyl ether that the present invention produces is tabulated as follows compared with prior art:
The industrialized preparing process of benzene alkyl chloride methyl ether disclosed by the invention has following positively effect:
1, the double solvent of doing of benzene feedstock alkyl alcohol in reaction process; Solvents such as methylene dichloride, formalin have been cut off; Aftertreatment only needs layering can obtain specification product, operates very easyly, and has reduced three waste discharge in the production process, has reduced the pollution to environment.
2, the time that feeds HCl gas in the reaction process shortened to 2-5 hour by original 7-9 hour, had significantly shortened the time of ventilation, thus reduced gaseous waste discharging, reduced pollution to environment.
3, high, the steady quality of the thick product purity of reaction gained need not distillation purifying and promptly can be applicable to general anhydrous response.
4, owing to cut off reaction solvent, shortened the reaction times, simplified factor such as aftertreatment, therefore, reaction cost significantly reduces.Through repeatedly industrial production checking, the present invention is applicable to large-scale commercial prodn fully.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should understand these embodiment only be used to the present invention is described and be not used in the restriction scope of the present invention.Wherein phenylcarbinol, phenylethyl alcohol, 3-phenyl-1-propyl alcohol, Paraformaldehyde 96 all have commercially availablely, below elaborate as follows with preferred embodiment.
Embodiment 1
The production of phenmethyl monochloromethyl-ether
In exsiccant 100L retort, add phenylcarbinol 34.56kg (320mol), Paraformaldehyde 96 10.56kg (352mol), stir, at the uniform velocity feed HCl gas (industrial steel cylinder air feed, purity＞99%), 15 ℃ of temperature controls reacted 3.5 hours.Reaction finishes, reaction solution is left standstill 1 hour in jar after, divide sub-cloud a small amount of muddy liquid; Upper strata pale yellow oily liquid body is product, heavy 47.6kg, and purity is 92.1% (HPLC); Yield 95%; Add 5% (product weight) Calcium Chloride Powder Anhydrous, product water cut 0.08%, inflated with nitrogen, airtight preservation.
1H-NMR(400HZ，CDCl
3)δ：4.81(2H，s)，5.46(2H，s)，7.38-7.51(5H，m)。
Embodiment 2
The production of phenmethyl monochloromethyl-ether
In exsiccant 100L retort, add phenylcarbinol 34.56kg (320mol), trioxymethylene 10.56kg (960mol), stir, at the uniform velocity feed HCl gas (industrial steel cylinder air feed, purity＞99%), 15 ℃ of temperature controls reacted 4 hours.Reaction finishes, and filters, will filtrate in jar, leave standstill 1 hour after; Divide sub-cloud a small amount of muddy liquid, upper strata pale yellow oily liquid body is product, heavy 42.5kg; Purity is 90.1% (HPLC), and yield 85% adds 8% (product weight) Calcium Chloride Powder Anhydrous; Product water cut 0.06%, inflated with nitrogen, airtight preservation.
Embodiment 3
The production of hydrocinnamyl monochloromethyl-ether
In exsiccant 20L glass reaction still, add 3-phenyl-1-propyl alcohol 6.8kg (50mol), Paraformaldehyde 96 1.65kg (55mol), stir, at the uniform velocity feed HCl gas (industrial steel cylinder air feed, purity＞99%), 30 ℃ of temperature controls reacted 5 hours.Reaction finishes, reaction solution is left standstill 1 hour in jar after, divide sub-cloud a small amount of muddy liquid; Upper strata pale yellow oily liquid body is product, heavy 8.2kg, and purity is 92.1% (HPLC); Add 8% (product weight) Calcium Chloride Powder Anhydrous, product water cut 0.1%, inflated with nitrogen, airtight preservation.
1H-NMR(400HZ，CDCl
3)δ：1.8(2H，m)，2.77(2H，t)，3.37(2H，t)，5.46(2H，s)，7.27-7.41(5H，m)。
Embodiment 4 reference implementations example
The production of Entecavir intermediate E N-PT-1
Under the nitrogen protection, drop into 3.4kg (in 92%) benzyl chloride methyl ether (method preparation of the present invention) and 20Kg anhydrous tetrahydro furan to the dry low-temp reaction jar of 100L, temperature is-50 ℃ in the control.Slowly at the uniform velocity drip the cyclopentadiene sodium solution, after dropwising, close a jar mouth, keep-78 ℃ under the logical nitrogen protection and stir 1h, for use.
Under nitrogen protection, the borine crystal of Weighing is added in the retort, add 20 kilograms of anhydrous tetrahydro furans; Close a jar mouth, keep-78 ℃ of stirring reaction 2h under the logical nitrogen protection, the borine crystal is blended; Add in the THF suspension-s of borine then last one go on foot cyclopentadiene sodium and chloromethyl benzyl oxide reaction mixture, add in-78 ℃ of stirring reactions 2 hours, then; Naturally be warming up to-10 ℃ of stirring reactions 16 hours, reaction is finished, and controls Nei Wen-10 ℃; Slowly dropping sodium solution is controlled interior temperature and is lower than 0 ℃ in the dropping process.After dropwising, 3h slowly rises to room temperature (25 ℃), insulation reaction 2h.With reaction solution suction 100L extractor, and in extractor, add the aqueous solution of 0.25kg Sodium Metabisulfite, stirring reaction 30 minutes.Suction 12Kg ETHYLE ACETATE in extractor, standing demix behind the stirring 10min is emitted water layer and a small amount of emulsion layer, and organic layer is emitted, and water layer is drawn back in the jar, in jar, adds 6Kg ETHYLE ACETATE (recovery), stirs standing demix after 5 minutes.Organic layer is refunded in the extractor, suction saturated aqueous common salt 14Kg in extractor, agitator treating 5min leaves standstill, and emits water layer, and organic layer is put into bucket, 7Kg anhydrous magnesium sulfate drying 30min.Organic layer filters, and filter cake washes with THF, in 40 ℃ down the decompression rotation be concentrated into dried bullion.With the silica gel of ten times of amounts of bullion dress post, with sherwood oil: the ETHYLE ACETATE volume ratio be 7: 1 be that elutriant carries out column chromatography purification, product 1.4Kg.
1H-NMR (400HZ, CDCl
3) δ: 2.11 (0H, s), 2.26 (H, dd), 2.69 (H, dd), 2.85 (H, m), 3.30 (H, t), 3.54 (H, m), 4.29 (H, m), 4.51 (2H, s), 5.55 (H, m), 5.72 (H, m), (5H's 7.24-7.35 m), is consistent with bibliographical information.
Claims (4)
1. the industrialized preparing process of a benzene alkyl chloride methyl ether is characterized in that under solvent-free condition, and with compound (I) and polymerization formaldehyde hybrid reaction, cooling is stirred down and fed industrial HCl gas, and reaction makes compound (II);
Wherein R is C
1-C
3Alkyl.
2. the described working method of claim 1, wherein said polymerization formaldehyde is trioxymethylene or Paraformaldehyde 96.
3. the described working method of claim 1, wherein said compound (I) is 1 with the mol ratio of polymerization formaldehyde: 1-3.
4. the described working method of claim 1, the wherein said reaction times is 2-5 hour; Temperature of reaction is 15-30 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103347937A CN102516040A (en) | 2011-10-31 | 2011-10-31 | Industrialized production method of phenylalkyl chloromethyl ether |
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| CN2011103347937A CN102516040A (en) | 2011-10-31 | 2011-10-31 | Industrialized production method of phenylalkyl chloromethyl ether |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016160945A1 (en) | 2015-03-31 | 2016-10-06 | Concert Pharmaceuticals, Inc. | Deuterated vx-661 |
| CN110357766A (en) * | 2019-06-05 | 2019-10-22 | 南京康立瑞生物科技有限公司 | It is a kind of to prepare chloromethyl ether compound preparation process and its Preparation equipment |
-
2011
- 2011-10-31 CN CN2011103347937A patent/CN102516040A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| COONOR, D. S. ET AL.: "Benzyl chloromethyl ether", 《ORG. SYNTH.》 * |
| FRANCOIS SOUCY ET AL.: "A Novel and Efficient Synthesis of a Highly Active Analogue of clasto-Lactacystin a-Lactone", 《J.AM.CHEM.SOC.》 * |
| MITSUHIRO TAKEDA ET AL.: "Detection of the Sulfhydryl Groups in Proteins with Slow Hydrogen Exchange Rates and Determination of Their Proton/Deuteron Fractionation Factors Using the Deuterium-Induced Effects on the 13Cb NMR Signals", 《J.AM.CHEM.SOC.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016160945A1 (en) | 2015-03-31 | 2016-10-06 | Concert Pharmaceuticals, Inc. | Deuterated vx-661 |
| CN110357766A (en) * | 2019-06-05 | 2019-10-22 | 南京康立瑞生物科技有限公司 | It is a kind of to prepare chloromethyl ether compound preparation process and its Preparation equipment |
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Application publication date: 20120627 |