CN102584628B - Method for synthesizing N-carboxymethyl pentamidine - Google Patents
Method for synthesizing N-carboxymethyl pentamidine Download PDFInfo
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- 229960004448 pentamidine Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 27
- 239000003513 alkali Substances 0.000 claims abstract description 20
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 15
- 239000004471 Glycine Substances 0.000 claims abstract description 14
- 230000032050 esterification Effects 0.000 claims abstract description 11
- -1 methyl ester hydrochloride Chemical class 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 238000010189 synthetic method Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 238000013517 stratification Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 6
- 150000001409 amidines Chemical class 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000002327 cardiovascular agent Substances 0.000 description 3
- 229940125692 cardiovascular agent Drugs 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- 229960004773 losartan Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 2-(6-amino-1h-indol-3-yl)acetonitrile Chemical compound NC1=CC=C2C(CC#N)=CNC2=C1 ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing N-carboxymethyl pentamidine which is shown as a formula (II). The method comprises the following steps of: performing esterification on valeronitrile and carbinol which are used as raw materials to obtain penta imidic acid methyl ester hydrochloride which is shown as a formula (I), wherein valeronitrile is shown as a formula (IV), dissociating penta imidic acid methyl ester hydrochloride to obtain penta imidic acid methyl ester alkali which is shown as a formula (V), performing amidine reaction on the penta imidic acid methyl ester alkali and glycine to obtain N-carboxymethyl pentamidine which is shown as a formula (II), wherein in the esterification, valeronitrile which is shown as the formula (IV) and carbinol are fully reacted under the action of acetylchloride to form penta imidic acid methyl ester hydrochloride, and the obtained reaction liquid A is directly used for next reaction. The method is safe and environment-friendly, and is convenient to operate, and the obtained product is high in yield and quality; and the method is suitable for industrial production.
Description
Technical field
The present invention relates to key intermediate---the synthetic method of N-carboxymethyl pentamidine of the husky smooth raw material imidazole aldehyde of industrial production cardiovascular agent network.
Background technology
N-carboxymethyl pentamidine (structure is as Suo Shi (II)) is the key intermediate of the husky smooth raw material imidazole aldehyde (compound III) of present industrial production cardiovascular agent network.Losartan because of its antihypertensive effect obvious, better tolerance, has unique curative effect and provide protection to cardiovascular disorder, has become one of the most general antihypertensive drug of Clinical practice.Along with the continuous increase of losartan demand, develop a kind of safe, convenient and be suitable for the method for industrial N-carboxymethyl pentamidine thus better synthesis imidazole aldehyde is necessary.
The synthetic route of the imidazole aldehyde (structure is as Suo Shi (III)) that current document is reported to mainly contains following four:
Route one (1, US4355040 (1982); 2, EP0403159A2 (1990); 3, SyntheticCommunications, 2971-2977,
22 (20), 1992:4, Chinese pharmaceutical chemistry magazine, 271-276,
8 (04), 1998):
Route two (5, Chinese Chemical Letters, 269-270,
20 (03), 2009):
Route three (6, J.Org.Chem., 8084-8089,
64 (22), 1999):
Route four (7, Chinese Journal of New Drugs, 1948-1950,
15 (22), 2006; 8, Guangxi light industry, 8-10,
(02), 2008; 9, CN101781255A (2010)):
In above-mentioned route, route one is longer, complicated operation, and need hydrogen chloride gas, ammonia to participate in reaction, and reaction is carried out under elevated pressure conditions, have certain danger, yield is low, is unfavorable for suitability for industrialized production.
Route two reaction have employed noble metal catalyst, and production cost is high, is unfavorable for suitability for industrialized production.
Route three reaction has more by product, and route is longer, and production cost is high.
Current industrial main employing technological line four synthesizes imidazole aldehyde (compound III), and this technique, compared with conventional art, simplifies technological process, shortens the reaction times, improves production efficiency, is the regular course of present industrial production imidazole aldehyde.
But route four also exists following obviously not enough:
The first step in A, route four leads to hydrogen chloride gas, and industrial can reaction by the vitriol oil, phosphorus trichloride etc. and concentrated hydrochloric acid or sodium-chlor obtains usually, but the method causes very large environmental pollution;
B, we find in an experiment, as dry in hydrogen chloride gas bad, can produce impurity methyl valerate, thus affect purity and the yield of imidazole aldehyde further;
The hydrogen chloride gas of C, this step reaction will arrive certain amount, just can react completely, and industrial hydrogen chloride gas measuring difficulties, high (molar ratio of bibliographical information valeronitrile and hydrogen chloride gas is 1.0: 1.37 better for operation and running cost, as [Guangxi light industry, 8-10
(02), 2008]).
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of safety, environmental protection, easy to operate, products obtained therefrom yield high quality is good, be applicable to key intermediate---the synthetic method of N-carboxymethyl pentamidine of the husky smooth raw material imidazole aldehyde of the industrial production cardiovascular agent network of suitability for industrialized production.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
The synthetic method of the N-carboxymethyl pentamidine shown in a kind of formula (II), comprise the steps: with the valeronitrile shown in formula (IV) and methyl alcohol as raw material, penta imidic acid methyl ester hydrochloride shown in formula (I) is obtained through esterification, described penta imidic acid methyl ester hydrochloride obtains penta imidic acid methyl esters alkali shown in formula (V) through free, and described penta imidic acid methyl esters alkali and glycine react the N-carboxymethyl pentamidine shown in obtained formula (II) through amidineization;
Described esterification is with the valeronitrile shown in formula (IV) and methyl alcohol for raw material, and under the effect of Acetyl Chloride 98Min., fully reaction generation penta imidic acid methyl ester hydrochloride, gained reaction solution A is directly used in next step reaction.
Further, described esterification reaction temperature is-10 ~ 15 DEG C, and reaction time of esterification is 10 ~ 20 hours.
Further, described esterification reaction temperature is-5 ~ 5 DEG C.
Further again, described esterification reaction temperature is 0 ~ 5 DEG C.
The present invention most preferably described esterification reacts 12 hours at 0 ~ 5 DEG C.
Further, in described esterification, the mol ratio of described valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three is 1: 2 ~ 5: 1 ~ 3; Be more preferably 1: 3 ~ 4: 1 ~ 2, most preferably be 1.00: 3.47: 1.42.
In the present invention, described free comprising the steps: adds benzene kind solvent in gained reaction solution A, and adding alkali lye, to be neutralized to pH value be 8 ~ 10, obtains the solution of penta imidic acid methyl esters alkali.
Further, the preferred toluene of described benzene kind solvent.Described alkali lye can use the conventional reagent such as sodium hydroxide solution.
Further, for improving product purity, described freely also comprise the steps: to add alkali lye by described reaction solution A to be neutralized to pH value be after 8 ~ 10, stratification, isolated organic layer steams except methyl acetate wherein and methyl alcohol, obtains the solution of penta imidic acid methyl esters alkali.
In the present invention, described amidineization reaction comprises the steps: to add methyl alcohol, sodium methylate and glycine in the solution of penta imidic acid methyl esters alkali, described penta imidic acid methyl esters alkali and glycine react under sodium methoxide catalyzed, regulate reaction solution pH to 6 ~ 8 after abundant reaction, be isolated to N-carboxymethyl pentamidine.In described reaction, be insoluble to the benzene kind solvents such as toluene due to glycine, therefore add methyl alcohol and increase its solvability as solvent.
Further, described amidineization temperature of reaction is 0 ~ 5 DEG C, and the amidineization reaction times is 15 ~ 20 hours.
Further, the mol ratio of the glycine that amidineization reaction uses and valeronitrile is 1.0: 1.0 ~ 1.2, and the mol ratio of sodium methylate and glycine is 0.05 ~ 0.1: 1.
The present invention is relative to the advantage of prior art: 1, avoid the environmental pollution directly passing into hydrogen chloride gas and bring.2, easy to operate, steady quality, is more suitable for industrial production.3, products obtained therefrom yield is high, purity good.
Embodiment
Following type reaction is used for illustrating the present invention.All belong within the technical scheme that the present invention protects inventing the simple replacement done or improvement etc. those skilled in that art.
The synthesis of embodiment 1N-carboxymethyl pentamidine:
In there-necked flask, add valeronitrile 30 grams (0.36mol) and anhydrous methanol 40 grams (1.25mol), mixing, cryosel bath is cooled to 0 DEG C, slowly drip the Acetyl Chloride 98Min. (0.51mol) of 40 grams, drip off, 0 ~ 5 DEG C of reaction about 12 is little is less than 2% (GC tracking) up to valeronitrile content, reaction terminates, and obtains penta imidic acid methyl ester hydrochloride solution.Gained penta imidic acid methyl ester hydrochloride solution adds toluene 150 grams, pH is regulated to be 9 with liquid caustic soda at 0 DEG C, stir 15 minutes, stratification, water layer, extract once with 50 grams of toluene, merge organic layer, 100 grams of saturated salt washings, after organic layer decompression steams methyl acetate and methyl alcohol, stand-by, this is the toluene solution of penta imidic acid methyl esters free alkali.
In above-mentioned solution, add methyl alcohol 80 grams, sodium methylate 1 gram, be chilled to 0 ~ 5 DEG C, slowly add glycine 26.3 grams (0.35mol), temperature control less than 5 DEG C, reaction about 20 is little of penta this disappearance of imidic acid methyl esters base, and sulfuric acid adjusts pH=7, underpressure distillation removing methyl alcohol, cooling, filter, obtain the N-carboxymethyl pentamidine 47.9 grams of white solid, yield: 84.2%, purity: 98.3% (in valeronitrile), fusing point: 199.2 ~ 200.8 DEG C.Hydrogen spectrum (
1h-NMR) (D
2o, 400MHz): δ 0.91 (t, 3H, J=7.2Hz), 1.38 (m, 2H), 1.66 (m, 2H), 2.52 (t, 2H, J=7.6Hz), 3.86 (s, 2H), mass spectrum (ESI-MS): 159 (M+1), infrared IR (KBr, cm
-1): 787,1334,1385,1626,2959,3354, ultimate analysis (C
7h
14n
2o
2, %) and (measured value/calculated value): C53.22/53.15, H8.92/8.98, N17.71/17.55.
Embodiment 2-10
Change the esterification raw material dosage in embodiment 1 and condition, thus the product result obtained is as shown in table 1.
Table 1
Claims (8)
1. the synthetic method of the N-carboxymethyl pentamidine shown in a formula (II), described synthetic method comprises the steps: with the valeronitrile shown in formula (IV) and methyl alcohol as raw material, penta imidic acid methyl ester hydrochloride shown in formula (I) is obtained through esterification, described penta imidic acid methyl ester hydrochloride obtains penta imidic acid methyl esters alkali shown in formula (V) through free, and described penta imidic acid methyl esters alkali and glycine react the N-carboxymethyl pentamidine shown in obtained formula (II) through amidineization;
It is characterized in that: described esterification is with the valeronitrile shown in formula (IV) and methyl alcohol for raw material, under the effect of Acetyl Chloride 98Min., fully reaction generation penta imidic acid methyl ester hydrochloride, gained reaction solution A is directly used in next step reaction; Esterification reaction temperature is 0 ~ 5 DEG C; The mol ratio of described valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three is 1:3 ~ 4:1 ~ 2; The mol ratio of the glycine that amidineization reaction uses and valeronitrile is 1.0:1.00 ~ 1.20, and the mol ratio of sodium methylate and glycine is 0.05 ~ 0.1:1.
2. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 1, is characterized in that: the mol ratio of sodium methylate and glycine is 0.05:1; The mol ratio of described valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three is 1:3.47:1.42.
3. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 1 or 2, is characterized in that: reaction time of esterification is 10 ~ 20 hours.
4. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 1 or 2, it is characterized in that: described free comprising the steps: adds benzene kind solvent in gained reaction solution A, and adding alkali lye, to be neutralized to pH value be 8 ~ 10, obtains the solution of penta imidic acid methyl esters alkali shown in formula (V).
5. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 4, is characterized in that: described benzene kind solvent is toluene.
6. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 4, it is characterized in that: described freely also comprise the steps: to add alkali lye by described reaction solution A to be neutralized to pH value be after 8 ~ 10, stratification, isolated organic layer steams except methyl acetate wherein and methyl alcohol, obtains the solution of penta imidic acid methyl esters alkali.
7. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 4, it is characterized in that: described amidineization reaction comprises the steps: to add methyl alcohol, sodium methylate and glycine in the solution of penta imidic acid methyl esters alkali, described penta imidic acid methyl esters alkali and glycine react under sodium methoxide catalyzed, regulate reaction solution pH to 6 ~ 8 after abundant reaction, be isolated to the N-carboxymethyl pentamidine shown in formula (II).
8. the synthetic method of N-carboxymethyl pentamidine as claimed in claim 7, it is characterized in that: amidineization temperature of reaction is 0 ~ 5 DEG C, the amidineization reaction times is 15 ~ 20 hours.
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| CN201110457673.6A CN102584628B (en) | 2011-12-30 | 2011-12-30 | Method for synthesizing N-carboxymethyl pentamidine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4355040A (en) * | 1979-11-12 | 1982-10-19 | Takeda Chemical Industries, Ltd. | Hypotensive imidazole-5-acetic acid derivatives |
| CN1027504C (en) * | 1989-06-14 | 1995-01-25 | 史密丝克莱恩比彻姆公司 | Process for the preparation of imidazolyl-alkenoic acids |
| CN101781255A (en) * | 2010-02-09 | 2010-07-21 | 江苏德峰医药化工有限公司 | Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole |
-
2011
- 2011-12-30 CN CN201110457673.6A patent/CN102584628B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4355040A (en) * | 1979-11-12 | 1982-10-19 | Takeda Chemical Industries, Ltd. | Hypotensive imidazole-5-acetic acid derivatives |
| CN1027504C (en) * | 1989-06-14 | 1995-01-25 | 史密丝克莱恩比彻姆公司 | Process for the preparation of imidazolyl-alkenoic acids |
| CN101781255A (en) * | 2010-02-09 | 2010-07-21 | 江苏德峰医药化工有限公司 | Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole |
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Effective date of registration: 20141119 Address after: 310012 No. 140, Wensanlu Road, Zhejiang, Hangzhou Applicant after: ZHEJIANG INTERNATIONAL STUDIES University Address before: 226221 Qidong City, Jiangsu Province along the River Fine Chemical Park Applicant before: Jiangsu Coben Medical Chemical Co.,Ltd. Applicant before: HANGZHOU COBEN PHARMACEUTICAL Co.,Ltd. |
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Granted publication date: 20150422 |