CN111377821A - Method for synthesizing 4-isopropylamino-1-butanol - Google Patents
Method for synthesizing 4-isopropylamino-1-butanol Download PDFInfo
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- CN111377821A CN111377821A CN201811625097.XA CN201811625097A CN111377821A CN 111377821 A CN111377821 A CN 111377821A CN 201811625097 A CN201811625097 A CN 201811625097A CN 111377821 A CN111377821 A CN 111377821A
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- Prior art keywords
- butanol
- isopropylamino
- synthesizing
- reaction
- isopropylamine
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- IPLWOCGPIGUXOR-UHFFFAOYSA-N 4-(propan-2-ylamino)butan-1-ol Chemical compound CC(C)NCCCCO IPLWOCGPIGUXOR-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- HXHGULXINZUGJX-UHFFFAOYSA-N 4-chlorobutanol Chemical compound OCCCCCl HXHGULXINZUGJX-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000000967 suction filtration Methods 0.000 claims abstract description 7
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- 238000004821 distillation Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 230000001276 controlling effect Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 abstract description 4
- 238000000605 extraction Methods 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000005406 washing Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LRZREJLKOKQIGM-UHFFFAOYSA-N 4-(propan-2-ylamino)butyl acetate Chemical compound C(C)(C)NCCCCOC(=O)C LRZREJLKOKQIGM-UHFFFAOYSA-N 0.000 description 2
- UOABIRUEGSGTSA-UHFFFAOYSA-N 4-bromobutyl acetate Chemical compound CC(=O)OCCCCBr UOABIRUEGSGTSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical compound NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 229960003841 selexipag Drugs 0.000 description 1
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing 4-isopropylamino-1-butanol, which comprises the following steps of mixing isopropylamine, 4-chloro-1-butanol, a reaction solvent and an acid-binding agent according to a molar ratio of 10-1: 1: 0 to 20: 0-5, placing the mixture in a closed reactor, controlling the temperature to be 30-90 ℃, reacting for 5-48 hours, adding water to obtain a reaction solution, carrying out a series of reaction post-treatments such as rotary evaporation, acid regulation, washing, alkali regulation, extraction, drying, suction filtration and the like on the reaction solution, and carrying out reduced pressure distillation to obtain the 4-isopropylamino-1-butanol. The method has the advantages of easily available raw materials, few reaction steps, mild reaction conditions, few byproducts, simple and convenient operation, recyclable organic solvent, little influence on environment, simple post-treatment, high product purity and yield, and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of a 4-isopropylamino-1-butanol medical intermediate, in particular to a method for synthesizing 4-isopropylamino-1-butanol by a one-step method.
Background
4-isopropylamino-1-butanol is an important biological medicine intermediate and an important industrial raw material for preparing pulmonary hypertension drug selexipag.
The chemical name of 4-isopropylamino-1-butanol is: 4- (propan-2-ylamino) butan-1-ol CAS number: 42042-71-7, the chemical structural formula is:
4-isopropylamino-1-butanol can be prepared by reacting acetone and 4-aminobutanol in ethanol, catalyzing with platinum oxide, and adding hydrogen gas for 48 hours (see EP1400518A 1); or reacting tetrahydrofuran with acetic acid solution of hydrogen bromide to obtain 4-bromo-1-acetoxybutane, reacting 4-bromo-1-acetoxybutane with isopropylamine to obtain 4-isopropylamino-1-acetoxybutane, and hydrolyzing 4-isopropylamino-1-acetoxybutane (see CN 104829465A); however, the methods disclosed in these documents are complicated in reaction steps, severe in reaction conditions, high in raw material cost, large in reaction energy consumption, low in yield, and still need to be improved in product purity and post-treatment method. There remains a need for a better process for the preparation of 4-isopropylamino-1-butanol.
Disclosure of Invention
The invention aims to overcome the defects of complex operation, harsh reaction conditions, low yield and high cost of the existing method, and provides a preparation method of 4-isopropylamino-1-butanol, which has the advantages of mild conditions, simple and convenient operation, high efficiency and low cost.
The technical scheme of the invention is as follows: a method for synthesizing 4-isopropylamino-1-butanol comprises the following steps:
A. reaction: the method comprises the following steps of (1) mixing isopropylamine, 4-chloro-1-butanol, a reaction solvent and an acid-binding agent according to a molar ratio of 10-1: 1: 0 to 20: 0-5, placing the mixture in a closed reactor, controlling the temperature to be 30-90 ℃, reacting for 5-48 hours, and adding water to obtain a reaction solution;
B. and (3) product purification: and B, adding water into the reaction liquid obtained in the step A, adding hydrochloric acid to regulate the acid, adding an organic solvent to wash, regulating the alkali, extracting with the organic solvent, drying, performing suction filtration, and performing reduced pressure distillation to obtain the catalyst.
Preferably, the acid-binding agent in step a is selected from any one of isopropylamine, triethylamine, potassium carbonate and sodium carbonate.
Preferably, the reaction solvent in step a is selected from one or more of isopropylamine, ethyl acetate, acetone, butanone, tetrahydrofuran, dichloromethane and acetonitrile.
Preferably, the molar ratio of the isopropylamine to the 4-chloro-1-butanol in the step A is 8-2: 1.
further preferably, the molar ratio of the isopropylamine to the 4-chloro-1-butanol in the step A is 4-3: 1.
preferably, the temperature in the step A is 40-80 ℃.
Further preferably, the temperature in the step A is 60-70 ℃.
Preferably, the reaction time in the step A is 10-30 hours.
Further preferably, the reaction time in the step A is 17-24 hours.
Preferably, the extractant in step B is selected from one or more of benzene, toluene, xylene, ethyl acetate, n-butyl acetate, tetrahydrofuran, dichloromethane and acetonitrile.
In order to improve the purity of the 4-isopropylamino-1-butanol, after the 4-isopropylamino-1-butanol is obtained by reduced pressure distillation, water is added repeatedly, hydrochloric acid is added for regulating acid, an organic solvent is added for washing, alkali regulation is carried out, the organic solvent is used for extraction, filtration after drying and reduced pressure distillation operation are carried out, and the qualified 4-isopropylamino-1-butanol can be obtained.
The technical scheme of the invention has the following beneficial effects:
the method has the advantages of easily obtained raw materials, few reaction steps, mild reaction conditions, few byproducts, simple and convenient operation, recyclable organic solvent, little influence on environment, simple post-treatment, high product purity and yield, and suitability for industrial production.
Detailed description of the preferred embodiments
The following embodiments are better to explain the present invention. The scope of the invention is not limited to the following examples.
Example 1
Synthesis of 4-isopropylamino-1-butanol:
13.78g (0.12mol) of 4-chloro-1-butanol and 30g (0.51mol) of isopropylamine are added into a 100ml closed reactor, the mixture is heated to 65 ℃ by an oil bath and reacted for 19 hours at 65 ℃, organic solvent is removed by rotary evaporation of reaction liquid, hydrochloric acid is added to adjust the acidity to 2, the mixture is washed by dichloromethane solution, the water phase is added with sodium hydroxide to adjust the alkalinity to 11, dichloromethane is added to extract for three times, organic phases are combined, anhydrous sodium sulfate is added to dry the mixture, suction filtration is carried out, organic solvent is removed by rotary evaporation of filtrate, and a yellow transparent oily product, namely 4-isopropylamino-1-butanol, the weight is 10.1g, and the yield is 73.2 percent.
Example 2
Synthesis of 4-isopropylamino-1-butanol:
27.55g (0.25mol) of 4-chloro-1-butanol and 60g (1.01mol) of isopropylamine are added into a 100ml triangular flask, the mixture is heated to 70 ℃ by an oil bath and reacted for 17 hours at 70 ℃, water is added, then organic solvent is removed by rotary evaporation, hydrochloric acid is added to adjust the pH value of the mixture to 2, the mixture is washed by dichloromethane, sodium hydroxide is added into an aqueous phase to adjust the pH value of the aqueous phase to 11, dichloromethane is added into the aqueous phase to extract the aqueous phase for three times, organic phases are combined, anhydrous sodium sulfate is added to dry the mixture, suction filtration is carried out, filtrate is subjected to rotary evaporation to remove the organic solvent, and a yellow transparent oily product, namely the 4-isopropylamino-1-.
Example 3
Synthesis of 4-isopropylamino-1-butanol:
275.5g (0.25mol) of 4-chloro-1-butanol and 600g (10.15mol) of isopropylamine are added into a 2000ml triangular flask, the mixture is heated to 60 ℃, the temperature is 70 ℃ for reaction for 17 hours, water is added, the organic solvent is removed by rotary evaporation, hydrochloric acid is added to adjust the pH value to 2, the mixture is washed by dichloromethane, the water phase is added with sodium hydroxide to adjust the pH value to 11, dichloromethane is added into the water phase for extraction for three times, the organic phase is combined, anhydrous sodium sulfate is added for drying, suction filtration is carried out, the organic solvent is removed by rotary evaporation of the filtrate, and a yellow transparent oily product, namely the 4-isopropylamino-1-butanol, the weight is 213.5 g.
Example 4
Synthesis of 4-isopropylamino-1-butanol:
4.8kg (44.2mol) of 4-chloro-1-butanol and 10.4kg (175.9mol) of isopropylamine are added into a 50L triangular flask, the mixture is heated to 60 ℃ and reacted at 70 ℃ for 17 hours, water is added, then the organic solvent is removed by rotary evaporation, hydrochloric acid is added to adjust the pH value of the mixture to 2, the mixture is washed by dichloromethane, sodium hydroxide is added into an aqueous phase to adjust the pH value of the aqueous phase to 11, dichloromethane is added into the aqueous phase to extract the aqueous phase for three times, the organic phases are combined, anhydrous sodium sulfate is added to dry the mixture, suction filtration is carried out, the organic solvent is removed by rotary evaporation of filtrate, and a yellow transparent oily product, namely the 4-isopropylamino-1-.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A method for synthesizing 4-isopropylamino-1-butanol, comprising the steps of:
A. reaction: the method comprises the following steps of (1) mixing isopropylamine, 4-chloro-1-butanol, a reaction solvent and an acid-binding agent according to a molar ratio of 10-1: 1: 0 to 20: 0-5, placing the mixture in a closed reactor, controlling the temperature to be 30-90 ℃, reacting for 5-48 hours, and adding water to obtain a reaction solution;
B. and (3) product purification: and B, adding water into the reaction liquid obtained in the step A, adding hydrochloric acid to regulate the acid, adding an organic solvent to wash, regulating the alkali, extracting with the organic solvent, drying, performing suction filtration, and performing reduced pressure distillation to obtain the catalyst.
2. The method for synthesizing 4-isopropylamino-1-butanol according to claim 1, wherein the acid-binding agent in step A is selected from one of isopropylamine, triethylamine, potassium carbonate and sodium carbonate.
3. The method for synthesizing 4-isopropylamino-1-butanol according to claims 1 and 2, wherein the reaction solvent in step a is one or more selected from isopropylamine, ethyl acetate, acetone, butanone, tetrahydrofuran, dichloromethane and acetonitrile.
4. The method for synthesizing 4-isopropylamino-1-butanol according to claim 4, wherein the molar ratio of isopropylamine to 4-chloro-1-butanol in step A is 8-2: 1.
5. the method for synthesizing 4-isopropylamino-1-butanol according to claim 4, wherein the molar ratio of isopropylamine to 4-chloro-1-butanol in step a is 4 to 3: 1.
6. the method for synthesizing 4-isopropylamino-1-butanol according to any one of claims 1 to 5, wherein the temperature in step A is 40 to 80 ℃.
7. The method for synthesizing 4-isopropylamino-1-butanol according to claim 6, wherein the temperature in step A is 60 to 70 ℃.
8. The method for synthesizing 4-isopropylamino-1-butanol according to any one of claims 1 to 7, wherein the reaction time in step A is 10 to 30 hours.
9. The method for synthesizing 4-isopropylamino-1-butanol according to claim 8, wherein the reaction time in step A is 17 to 24 hours.
10. The method for synthesizing 4-isopropylamino-1-butanol according to any one of claims 1 to 9, wherein the organic solvent in step B is one or more selected from benzene, toluene, xylene, ethyl acetate, n-butyl acetate, tetrahydrofuran, dichloromethane and acetonitrile.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811625097.XA CN111377821A (en) | 2018-12-28 | 2018-12-28 | Method for synthesizing 4-isopropylamino-1-butanol |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811625097.XA CN111377821A (en) | 2018-12-28 | 2018-12-28 | Method for synthesizing 4-isopropylamino-1-butanol |
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| CN111377821A true CN111377821A (en) | 2020-07-07 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1173867A (en) * | 1995-09-01 | 1998-02-18 | 伊莱利利公司 | Indolyl neuropeptide Y receptor antagonists |
| CN104829465A (en) * | 2015-02-13 | 2015-08-12 | 上海适济生物科技有限公司 | Method for preparing 4-isopropamide group-1-butanol |
| WO2017060827A1 (en) * | 2015-10-07 | 2017-04-13 | Lupin Limited | An imrpoved process for the preparation of selexipag or its pharmaceutically acceptable salts |
-
2018
- 2018-12-28 CN CN201811625097.XA patent/CN111377821A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1173867A (en) * | 1995-09-01 | 1998-02-18 | 伊莱利利公司 | Indolyl neuropeptide Y receptor antagonists |
| CN104829465A (en) * | 2015-02-13 | 2015-08-12 | 上海适济生物科技有限公司 | Method for preparing 4-isopropamide group-1-butanol |
| WO2017060827A1 (en) * | 2015-10-07 | 2017-04-13 | Lupin Limited | An imrpoved process for the preparation of selexipag or its pharmaceutically acceptable salts |
Non-Patent Citations (1)
| Title |
|---|
| KUZNETSOV, S. G. 等: "Formation of polymethyleneammonium rings. I. Synthesis and transformations of some esters of diphenyl-acetic acid", OBSHCHEI KHIM. * |
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