CN108314627A - Benzocainum green preparation process - Google Patents
Benzocainum green preparation process Download PDFInfo
- Publication number
- CN108314627A CN108314627A CN201810384624.6A CN201810384624A CN108314627A CN 108314627 A CN108314627 A CN 108314627A CN 201810384624 A CN201810384624 A CN 201810384624A CN 108314627 A CN108314627 A CN 108314627A
- Authority
- CN
- China
- Prior art keywords
- benzocainum
- catalytic hydrogenation
- ethyl
- preparation process
- nitrobenzoate
- 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.)
- Pending
Links
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- PHWSCBWNPZDYRI-UHFFFAOYSA-N ethyl 4-nitrobenzoate Chemical compound CCOC(=O)C1=CC=C([N+]([O-])=O)C=C1 PHWSCBWNPZDYRI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019441 ethanol Nutrition 0.000 claims abstract description 8
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- CPNMAYYYYSWTIV-UHFFFAOYSA-N ethyl 2-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC=C1[N+]([O-])=O CPNMAYYYYSWTIV-UHFFFAOYSA-N 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 6
- 230000032050 esterification Effects 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960005274 benzocaine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000006097 ultraviolet radiation absorber Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of benzocainum green preparation process, including paranitrobenzoic acid is esterified to obtain ethyl p-nitrobenzoate with ethyl alcohol under the catalysis of the concentrated sulfuric acid and ethyl p-nitrobenzoate obtains benzocainum through catalytic hydrogenation.Wherein, catalytic hydrogenation carries out in water, catalytic hydrogenation temperature is 90~110 DEG C, catalytic hydrogenation pressure is 0.2~1.0MPa, the dosage of water is 3~7 times of ethyl p-nitrobenzoate weight, the weight ratio of ethyl p-nitrobenzoate and catalyst is 1: 0.001~1: 0.1, and catalyst is the Pd/C catalyst that mass fraction is 3wt%~10wt%.The catalytic hydrogenation of the present invention avoids using organic solvent, to make the preparation of entire benzocainum become friendly process, and by selecting the dosage of suitable water, can obtain preferable reaction yield and product purity.
Description
Technical field
The invention belongs to technical field of fine, and in particular to a kind of benzocainum（Ethylaminobenzoate）Green
Preparation process.
Background technology
Benzocainum（Benzocaine）It is the nickname of ethylaminobenzoate, can be used as local anesthetic, for creates
Hinder the antipruritic analgesic such as face, ulcer surface and hemorrhoid, and can be as pharmaceutical intermediate；Ultra-violet absorber can be used, is mainly used for sun-proof
Class and tanned class cosmetics, to skin safe, also have the ability to form a film on the skin to the chemical stabilization of light and air,
It simultaneously again can be as the intermediate of other ultraviolet absorbers.
Chinese patent literature CN105315168A discloses a kind of N-（4- carboethoxyphenyls）- N'- methyl-N'- benzene
Base carbonamidine intermediate（Namely benzocainum）Green preparation process, it be using paranitrobenzoic acid as raw material, first in the concentrated sulfuric acid
Catalysis under carry out esterification with ethyl alcohol and obtain ethyl p-nitrobenzoate, then obtain benzocainum through catalytic hydrogenation.
The document is mainly using the concentrated sulfuric acid of recovery processing and the ethyl alcohol of recovery processing as the material of esterification, both
Production cost can be reduced, and higher esterification yield can be obtained, can especially avoid the generation of high-salt wastewater,
Reduce pollution on the environment.
And for catalytic hydrogenation, the document does not make improvements, still using the prior art, and shows
The catalytic hydrogenation be in the organic solvent that can dissolve benzocainum（Such as ethyl alcohol, toluene etc.）Middle progress,
And since the fusing point of benzocainum only has 90 DEG C or so, the existing catalytic hydrogenation temperature is generally at 80 DEG C or so.
And since benzocainum is not soluble in water, the prior art is without using water as the catalytic hydrogenation
Solvent.
Invention content
It is an object of the invention to solve the above problems, a kind of benzene assistant card of catalytic hydrogenation without organic solvent is provided
Because of green preparation process.
Realizing the technical solution of the object of the invention is：A kind of benzocainum green preparation process, including paranitrobenzoic acid
It is esterified to obtain ethyl p-nitrobenzoate and ethyl p-nitrobenzoate through catalysis with ethyl alcohol under the catalysis of the concentrated sulfuric acid
Hydrogenation obtains benzocainum.
Applicant pass through many experiments surprisingly it has been found that, the catalysis is carried out using water as solvent and at 90 DEG C or more of temperature
Hydrogenation can be smoothed out, this is because the benzocainum generated at this temperature can become molten condition.
Therefore, the catalytic hydrogenation carries out in water, and reaction temperature is 90~110 DEG C, preferably 95 DEG C
~100 DEG C.
In addition, the dosage of water also has larger impact for the effect of the catalytic hydrogenation, the dosage of water, which is crossed, at most can
Product yield is largely effected on, and the dosage of water can then largely effect on product purity less excessively.
Therefore, the dosage of the water is 3~7 times, preferably 4.5~5.5 times of ethyl p-nitrobenzoate weight.
The catalytic hydrogenation pressure is 0.2~1.0MPa, preferably 0.5~0.7MPa.
In the catalytic hydrogenation, the weight ratio of ethyl p-nitrobenzoate and catalyst is 1: 0.001~1: 0.1,
Preferably 1: 0.01~1: 0.05.
The catalyst is the Pd/C catalyst that mass fraction is 3wt%~10wt%.
The condition of the esterification and the prior art are essentially identical, for example reaction temperature is generally at 78 DEG C or more, still
It no more than 100 DEG C, is preferred with 78 DEG C~90 DEG C, is more best with 78 DEG C~82 DEG C；The alkyd of esterification（Absolute ethyl alcohol with
Paranitrobenzoic acid）Molar ratio is 1: 1~10: 1, preferably 3: 1~7: 1, more preferable 5: 1~6: 1；In esterification catalyst with
The molar ratio of paranitrobenzoic acid is 1: 1~1: 6, preferably 1: 2~1: 5, more preferable 1: 3~1: 4.
The good effect that the present invention has：（1）The catalytic hydrogenation of the present invention avoids using organic solvent, whole to make
The preparation of a benzocainum becomes friendly process.（2）The catalytic hydrogenation of the present invention passes through the dosage of the suitable water of selection, energy
Enough obtain preferable reaction yield and product purity.
Specific implementation mode
（Embodiment 1）
The benzocainum green preparation process of the present embodiment has steps of：
1. by the commercial anhydrous ethyl alcohol of 80g under stirring（1.74mol）With the paranitrobenzoic acid of 50g（0.30mol）It is added to anti-
It answers in device, the concentrated sulfuric acids of the 10g after dehydration is then slowly added dropwise（0.10mol）【Referring to Chinese patent literature
CN105315168A embodiments 1】, 15min drips off, after dripping off stirring be warming up to 80 ± 2 DEG C, back flow reaction 6h.
After reaction, first air-distillation goes out ethyl alcohol, and when temperature is steamed to 100 ± 2 DEG C, stopping is heated, stratification, upper layer
Material（Concentrated sulfuric acid layer）It is applied to next batch.
Lower layer's material is cooled to 60 ± 2 DEG C, it is 8 to adjust pH value with the aqueous sodium carbonate of 5wt%, multiple after stirring 0.5h
Survey pH, stratification.
2. by lower layer's material（About 58g）60 ± 2 DEG C of temperature control, is then added with stirring in the water of 290g, add 1g,
The Pd/C catalyst of 5wt%, add first with nitrogen displacement three times, logical hydrogen is to 0.6MPa under then stirring, and at 98 ± 2 DEG C
At a temperature of carry out catalytic hydrogenation, when pressure no longer declines, after catalytic hydrogenation, keep the temperature 2h, filter while hot, will
It after filtrate is cooled to 40 DEG C, filters, centrifugation, filter cake obtains the white powder benzocainum of 48.5g after 60~70 DEG C dry, pure
Degree is 99.6%（HPLC）, two step yields are 98.2%.
（2~embodiment of embodiment 5）
The step of each embodiment, is 1. same as Example 1, the difference is that 2. step, is specifically shown in Table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| Water | 290g | 290g | 290g | 400g | 180g |
| Pd/C catalyst | 1g、5wt% | 1g、5wt% | 1g、5wt% | 2g、5wt% | 0.5g、5wt% |
| Catalytic hydrogenation pressure | 0.6MPa | 0.7MPa | 0.5MPa | 0.6MPa | 0.6MPa |
| Catalytic hydrogenation temperature | 98±2℃ | 95±2℃ | 100±2℃ | 98±2℃ | 98±2℃ |
| Benzocainum | 48.5g | 48.7g | 48.1g | 47.6g | 48.5g |
| Yield | 98.2% | 98.6% | 97.4% | 96.4% | 98.2% |
| Purity | 99.6% | 99.6% | 99.7% | 99.7% | 99.3% |
（1~comparative example of comparative example 3）
The step of each comparative example, is 1. same as Example 1, the difference is that 2. step, is specifically shown in Table 2.
Table 2
| Embodiment 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | |
| Water | 290g | 290g | 100g | 500g |
| Catalytic hydrogenation temperature | 98±2℃ | 80±2℃ | 98±2℃ | 98±2℃ |
| Benzocainum | 48.5g | 18.3g | 46.2g | 36.2g |
| Yield | 98.2% | 37.0% | 93.5% | 73.3% |
| Purity | 99.6% | 81.1% | 95.8% | 99.1% |
Claims (9)
1. a kind of benzocainum green preparation process, including paranitrobenzoic acid are esterified under the catalysis of the concentrated sulfuric acid with ethyl alcohol
It obtains ethyl p-nitrobenzoate and ethyl p-nitrobenzoate obtains benzocainum through catalytic hydrogenation, it is characterised in that：Institute
It states catalytic hydrogenation to carry out in water, catalytic hydrogenation temperature is 90~110 DEG C.
2. benzocainum green preparation process according to claim 1, it is characterised in that：Catalytic hydrogenation temperature is 95
DEG C~100 DEG C.
3. benzocainum green preparation process according to claim 1 or 2, it is characterised in that：The dosage of the water is pair
3~7 times of ethyl nitrobenzoate weight.
4. benzocainum green preparation process according to claim 3, it is characterised in that：The dosage of the water is to nitro
4.5~5.5 times of ethyl benzoate weight.
5. the benzocainum green preparation process according to one of Claims 1-4, it is characterised in that：The catalytic hydrogenation
Reaction pressure is 0.2~1.0MPa.
6. benzocainum green preparation process according to claim 5, it is characterised in that：The catalytic hydrogenation pressure
For 0.5~0.7MPa.
7. the benzocainum green preparation process according to one of Claims 1-4, it is characterised in that：The catalytic hydrogenation
In reaction, the weight ratio of ethyl p-nitrobenzoate and catalyst is 1: 0.001~1: 0.1.
8. benzocainum green preparation process according to claim 7, it is characterised in that：Ethyl p-nitrobenzoate with urge
The weight ratio of agent is 1: 0.01~1: 0.05.
9. benzocainum green preparation process according to claim 7 or 8, it is characterised in that：The catalyst is quality
Score is the Pd/C catalyst of 3wt%~10wt%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810384624.6A CN108314627A (en) | 2018-04-26 | 2018-04-26 | Benzocainum green preparation process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810384624.6A CN108314627A (en) | 2018-04-26 | 2018-04-26 | Benzocainum green preparation process |
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| Publication Number | Publication Date |
|---|---|
| CN108314627A true CN108314627A (en) | 2018-07-24 |
Family
ID=62896167
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810384624.6A Pending CN108314627A (en) | 2018-04-26 | 2018-04-26 | Benzocainum green preparation process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110156618A (en) * | 2019-05-31 | 2019-08-23 | 常州瑞曦生物科技有限公司 | A kind of preparation process of ethylaminobenzoate |
| CN110343051A (en) * | 2019-07-23 | 2019-10-18 | 常州永和精细化学有限公司 | The preparation method of p-aminobenzoic acid Arrcostab |
| CN110590585A (en) * | 2019-09-25 | 2019-12-20 | 浙江优创材料科技股份有限公司 | Process for preparing benzocaine by solvent-free hydrogenation |
| CN111732521A (en) * | 2020-06-16 | 2020-10-02 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl p-aminobenzoate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315168A (en) * | 2015-11-27 | 2016-02-10 | 常州永和精细化学有限公司 | Environment-friendly preparation process of N-(4-ethoxy carbonyl phenyl)-N'-methyl-N'-phenyl formamidine intermediate |
| CN105481707A (en) * | 2015-12-08 | 2016-04-13 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl-4-dimethylaminobenzoate intermediate benzocaine |
| CN106699579A (en) * | 2016-11-18 | 2017-05-24 | 陕西高华知本化工科技有限公司 | Synthesis method of benzocaine |
| CN206646049U (en) * | 2017-04-10 | 2017-11-17 | 上海迅凯新材料科技有限公司 | Serialization catalytic hydrogenation produces and catalyst regeneration device |
-
2018
- 2018-04-26 CN CN201810384624.6A patent/CN108314627A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315168A (en) * | 2015-11-27 | 2016-02-10 | 常州永和精细化学有限公司 | Environment-friendly preparation process of N-(4-ethoxy carbonyl phenyl)-N'-methyl-N'-phenyl formamidine intermediate |
| CN105481707A (en) * | 2015-12-08 | 2016-04-13 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl-4-dimethylaminobenzoate intermediate benzocaine |
| CN106699579A (en) * | 2016-11-18 | 2017-05-24 | 陕西高华知本化工科技有限公司 | Synthesis method of benzocaine |
| CN206646049U (en) * | 2017-04-10 | 2017-11-17 | 上海迅凯新材料科技有限公司 | Serialization catalytic hydrogenation produces and catalyst regeneration device |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110156618A (en) * | 2019-05-31 | 2019-08-23 | 常州瑞曦生物科技有限公司 | A kind of preparation process of ethylaminobenzoate |
| CN110343051A (en) * | 2019-07-23 | 2019-10-18 | 常州永和精细化学有限公司 | The preparation method of p-aminobenzoic acid Arrcostab |
| CN110590585A (en) * | 2019-09-25 | 2019-12-20 | 浙江优创材料科技股份有限公司 | Process for preparing benzocaine by solvent-free hydrogenation |
| CN110590585B (en) * | 2019-09-25 | 2022-08-23 | 浙江优创材料科技股份有限公司 | Process for preparing benzocaine by solvent-free hydrogenation |
| CN111732521A (en) * | 2020-06-16 | 2020-10-02 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl p-aminobenzoate |
| CN111732521B (en) * | 2020-06-16 | 2021-04-20 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl p-aminobenzoate |
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Application publication date: 20180724 |