CN1349982A - Prepn of lactam - Google Patents
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- CN1349982A CN1349982A CN 00129881 CN00129881A CN1349982A CN 1349982 A CN1349982 A CN 1349982A CN 00129881 CN00129881 CN 00129881 CN 00129881 A CN00129881 A CN 00129881A CN 1349982 A CN1349982 A CN 1349982A
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- lactan
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Abstract
The preparation method of lactam is characterized by using lactone and amine and/or ammonia, utilizing crystalline aluminium silicate zeolite as catalyst and making them implement amination reaction in the presence of water under the condition of gas phase to obtain the invented product.
Description
The present invention relates to a kind of method for preparing lactan, be included in (a) lactone, (b) amine and ammonia, reach under (c) the water existence, utilize the crystalline aluminosilicate zeolite, under gas phase condition, carry out amination reaction as catalyzer.The present invention uses that this catalyzer can have that reaction pressure is low, unit time productive rate height, and save advantage such as reaction times.
Lactan comprises for example 2-Pyrrolizidine ketone, N-alkyl Pyrrolizidine ketone, hexanolactam etc., mainly is the monomer as solvent or high molecular polymerization, and therefore, the preparation method of the lactan of exploitation tool economic benefit is that industrial community is required always.
For example, with Succinic Acid, Succinic anhydried, maleic acid or MALEIC ANHYDRIDE etc., carrying out hydrogenation and amination reaction can synthesize Pyrrolizidine ketone; But carry out hydrogenation and amination reaction synthesis of caprolactam with pimelinketone.In addition, also can use catalysis or uncatalyzed reaction method, make lactone and amine carry out amination reaction and beta-lactams synthesis.
About using the liquid phase reaction method of non-catalytic, be disclosed in reaction conditions for the clear 47-21420 of Japanese Patent Application, 47-20585 number and be under 200 ℃ to 300 ℃ and the 20atm to 40atm, make the reaction of the excessive methylamine aqueous solution and gamma-butyrolactone generate N-methylpyrrole pyridine ketone, wherein earlier that methylamine is soluble in water, itself and gamma-butyrolactone are reacted, and this method is preferable for the selection rate effect of N-methylpyrrole pyridine ketone.The clear 51-42107 of Japanese Patent Application number announcement is soluble in water with excessive methylamine, carries methylamine and make methylamine utilization more capable of circulation in reaction with water.Special fair 6-78304 of Japan and 7-10835 disclose and use secondary or tertiary amine to prepare the modification method of N-substituting group-2-Pyrrolizidine ketone.Yet the liquid phase reaction method of above-mentioned use non-catalytic still exists needs high top pressure operation and the low shortcomings such as (also being to increase relatively in the reaction times) of unit time productive rate, does not meet the economic benefit of industrial community preparation process; And because reaction pressure height and product viscous flow time in reactor are long, so the bigger reactor of equipment claimed, be unfavorable for reducing manufacturing cost.
About using the reaction method of catalyzer, people such as Paul G.Rodewald at first proposed in 1973 to use X zeolite (Zeolite X) as catalyzer in No. the 3775431st, United States Patent (USP), made the reaction of lactone and primary amine and the generation lactan.Yet for example to generate N-methylpyrrole pyridine ketone, even utilize a large amount of excessive methylamine (mol ratio is about more than 30), and temperature of reaction reaches 300 ℃ and pressure and reaches under the situation of 500psig, and the product productive rate of gained is still not good.
The inventor's purpose is to provide a kind of method for preparing lactan, it utilizes the crystalline aluminosilicate zeolite as catalysts, make lactone and amine and/or ammonia under gas phase condition, carry out amination reaction, can significantly reduce the working pressure of reaction and the productive rate of raising product, to overcome existing shortcoming in the prior art.
The present invention finishes in the following manner: a kind of method for preparing lactan, this lactan is as shown in the formula shown in (I), its key is that this method is included in (a) lactone, (b) amine and ammonia, reaches (c) water existence down, utilize the crystalline aluminosilicate zeolite as catalyzer, under gas phase condition, carry out amination reaction.
In the formula, R represents C
2-10Stretch alkyl, this stretches alkyl again can be through C
1-6Alkyl or phenyl replaces; R ' expression hydrogen atom, C
1-6Alkyl, C
1-6Hydroxyalkyl, phenyl.
The used lactone initiator of the present invention can be represented by following formula (II):
In the formula, the definition of R is with aforementioned.
Among the present invention, the C shown in the R
2-10The example of stretching alkyl comprises to be stretched ethyl, stretch propyl group, stretches butyl, stretches amyl group, stretches hexyl, stretches heptyl, stretches octyl group, stretches nonyl, stretches decyl etc.C among the R
2-10Stretching alkyl again can be through C
1-6Alkyl or phenyl replaces, as substituent C
1-6Examples of alkyl comprises methyl, ethyl, propyl group, butyl, amyl group, hexyl etc.
The better example of the used lactone of the present invention comprises beta-propiolactone, gamma-butyrolactone, γ-phenyl-gamma-butyrolactone, γ-methyl-gamma-butyrolactone, γ-phenyl-γ-methyl-gamma-butyrolactone, δ-butyrolactone, γ-Wu Neizhi, γ-Ji Neizhi, 6-caprolactone, δ-Xin Neizhi, δ-nonalactone, δ-Gui Neizhi, γ-decalactone etc., more preferably gamma-butyrolactone, γ-Ji Neizhi, 6-caprolactone.
The used amine-initiated thing of the present invention is by being selected from one-level, secondary, three grades of non-cyclic amine: C that following substituting group is replaced through 1 to 3
1-6Alkyl, C
1-6Hydroxyalkyl, phenyl.Be preferably single-, two-or three-C
1-6Alkylamine, list-, two-or three-C
1-6Alkanolamine; That example can comprise is single-, two-or three-methylamine, list-, two-or three-ethamine, Tri N-Propyl Amine, n-Butyl Amine 99, normal hexyl Amine, list-, two-or three-thanomin etc.
The present invention uses the catalyzer of crystalline aluminosilicate zeolite as amination reaction, compared to other zeolite catalyst commonly used, for example mordenite (mordenite, Na
8Al
8Si
40O
9624H
2O), Y-type zeolite etc., can have more excellent reaction effect.The mol ratio of silicon oxide and aluminum oxide is (30 to 500) in this crystalline aluminosilicate zeolite: 1, restriction index (Constraint Index) is 1 to 12, better example comprises ZSM-5, ZSM-11, ZSM-12, ZSM-22, ZSM-34, ZSM-35, ZSM-48 etc., is the best with the three-dimensional spatial structure ZSM-5 catalyzer of fine pore about 5 to 6 dusts between between pore molecular sieve (as A type zeolite, magnesium scolecite) and gross porosity molecular sieve (as faujusite, mordenite) again wherein; Therefore, amination reaction of the present invention is to belong to inhomogeneous reaction.
Lactone that amination reaction of the present invention is used and amine must be earlier be deployed into suitable proportion with as reactant with water, and amine and ammonia amount can be greater than or less than the lactone amount in the reactant, but general excessive amine and the ammonia of all using.
The mol ratio of the used lactone of the present invention and amine and/or ammonia is generally 1: 0.5 to 1: 30, is preferably 1: 1 to 1: 10.The raw materials components mole ratio (for example being increased to more than 1: 5) that improves lactone and amine and/or ammonia can shorten the reaction times, and easily purifies and separates is reacted after product and excess amine and/or ammonia; But mol ratio is crossed and is higher than the upper limit and can causes selection rate relatively poor, and mol ratio is crossed and is lower than lower limit, and then amine and ammonia are the reagent of limiting the quantity of, and the reaction after product is difficult to and excessive lactone purifies and separates.
The mol ratio of used lactone of the present invention and water is generally 1: 0.5 to 1: 20, is preferably 1: 2 to 1: 6.The mol ratio of lactone and water is if be lower than lower limit, and then the obvious variation of reaction conversion ratio and selection rate if be higher than the upper limit, though reaction is not had directly influence, can cause the purifies and separates of reaction after product need spend the more time and the energy.
Amination reaction temperature of the present invention is 180 to 400 ℃, is preferably 220 to 320 ℃.The selection rate of reaction generally can increase with temperature and improve, but temperature except the lactan of gained, also can produce non-required by product when surpassing 400 ℃; When temperature is lower than 180 ℃, then be difficult for reacting.
Because the acidity of above-mentioned crystalline aluminosilicate zeolite is strong than aluminium sesquioxide, reactivity is also stronger, so amination reaction of the present invention can carry out under the pressure range of not destroying the catalyzer configuration.The general reaction pressure of using is 0atm to 10atm, is preferably 1atm to 5atm.Pressure boost can improve the transformation efficiency of lactone a little, but compared to other factors experimental result is influenced, and its effect is not remarkable.
Amination reaction of the present invention can carry out in fixed-bed reactor, fluid bed reactor or other gas phase inhomogeneous reaction device.If use fixed-bed reactor, then above-mentioned crystalline aluminosilicate zeolite catalyst must be made the preferable form of intensity, and for example particulate state, ingot shape etc. are so that fill.
The visual different lactones of gas space flow velocity (GHSV) of amination reaction of the present invention and the reaction of amine and/or ammonia and determine, be generally 20 (hour)
-1To 100000 (hour)
-1, be preferably 2000 (hour)
-1To 50000 (hour)
-1Gas space flow velocity if greater than 100000 (hour)
-1, then reaction is incomplete, and transformation efficiency is relatively poor; If less than 20 (hour)
-1,, and be easy to generate non-required by product then because of long duration of contact with catalyzer.
The present invention will further specify as follows with reference to the following example, but these embodiment only are used to illustrate the present invention, and be not to be used to limit the scope of the invention.
[embodiment]
Lactone that following embodiment and comparative example are used and amine and/or ammonia are known compound, or can be prepared by known method.
In the certain hour of reaction back,, form ester conversion rate and lactan selection rate in calculating according to following formula (1) and (2) with HP-6890 gas chromatograph analysis outlet effluent through the condensation collecting reaction product.
Embodiment 1
Getting ZSM-5 catalyzer 40ml filling is in the reactor of 26mm in internal diameter, reactant gamma-butyrolactone, methylamine, and water with weight ratio parallel feeding in 10: 4: 6, and make after the parallel feeding gas space flow velocity keep 5050 (hour)
-1, under 280 ℃, carry out amination reaction.Collect and assay products, the gamma-butyrolactone transformation efficiency is 99.4%, and N-methyl-2-Pyrrolizidine ketone selection rate is 99.0%.
Comparative example 1
Use reactor and the catalyzer identical with embodiment 1, but reactant only be gamma-butyrolactone and methylamine with weight ratio parallel feeding in 1: 18, and make after the parallel feeding gas space flow velocity keep 80000 (hour)
-1, under 280 ℃, carry out amination reaction.Collect and assay products, the gamma-butyrolactone transformation efficiency is 35.0%, and N-methyl-2-Pyrrolizidine ketone selection rate is 50.0%.
Embodiment 2
Except reactant gamma-butyrolactone, methylamine, and the feed weight ratio of water be 10: 5: 8, all the other preparation conditions (comprising reactor, catalyzer, charging flow velocity, temperature of reaction) are all identical with embodiment 1.Collect and assay products, the gamma-butyrolactone transformation efficiency is 99.7%, and N-methyl-2-Pyrrolizidine ketone selection rate is 99.9%.
Embodiment 3 to 8
Except filling different ZSM catalyst series, all the other preparation conditions (comprising reactor, reaction-ure feeding ratio, charging flow velocity, temperature of reaction) are all identical with embodiment 2.Collect and assay products, the results are shown in table 1.
Table 1
| Embodiment | Catalyst mode | The butyrolactone transformation efficiency | N-methyl-2-Pyrrolizidine ketone selection rate |
| Embodiment 2 | ????ZSM-5 | ????99.7％ | ??????????99.9％ |
| Embodiment 3 | ????ZSM-11 | ????98.0％ | ??????????83.7％ |
| Embodiment 4 | ????ZSM-12 | ????97.6％ | ??????????81.3％ |
| Embodiment 5 | ????ZSM-22 | ????98.2％ | ??????????78.0％ |
| Embodiment 6 | ????ZSM-34 | ????96.6％ | ??????????75.0％ |
| Embodiment 7 | ????ZSM-35 | ????97.9％ | ??????????69.3％ |
| Embodiment 8 | ????ZSM-48 | ????98.1％ | ??????????64.4％ |
Embodiment 9 to 11
Except changing the gas with various space flow speed, all the other preparation conditions (comprising reactor, catalyzer, reaction-ure feeding ratio, temperature of reaction) are all identical with embodiment 2.Collect and assay products stable back, the results are shown in table 2.
Table 2
| Embodiment | Gas space flow velocity (hour) -1 | The butyrolactone transformation efficiency | N-methyl-2-Pyrrolizidine ketone selection rate |
| Embodiment 2 | ????5050 | ????99.7％ | ?????????99.9％ |
| Embodiment 9 | ????7200 | ????99.3％ | ?????????93.7％ |
| Embodiment 10 | ????3000 | ????100％ | ?????????99.9％ |
| Embodiment 11 | ????1000 | ????100％ | ?????????97.5％ |
Comparative example 2
Except filling mordenite 40ml as the catalyzer, all the other preparation conditions (comprising reactor, reaction-ure feeding ratio, charging flow velocity, temperature of reaction) are all identical with embodiment 2.Collect and assay products, the gamma-butyrolactone transformation efficiency is 97.5%, and N-methyl-2-Pyrrolizidine ketone selection rate is 58.0%.
Embodiment 12
Use reactor and the catalyzer identical with embodiment 1, but reactant gamma-butyrolactone and water is with weight ratio parallel feeding in 1.2: 1, ammonia also adopts the continous way charging with flow rate control device simultaneously, always make after the parallel feeding gas space flow velocity keep 3300 (hour)
-1, under 300 ℃, carry out amination reaction.Collect and assay products, the gamma-butyrolactone transformation efficiency is 96.0%, and 2-Pyrrolizidine ketone selection rate is 90.0%.
Comparative example 3
Use reactor and the catalyzer identical with embodiment 1, but reactant only be gamma-butyrolactone and ammonia with weight ratio parallel feeding in 1: 2, and make after the parallel feeding gas space flow velocity keep 2700 (hour)
-1, under 300 ℃, carry out amination reaction.Collect and assay products, the gamma-butyrolactone transformation efficiency is 20.0%, and 2-Pyrrolizidine ketone selection rate is 65.0%.
Comparative example 4
Reactor, reaction-ure feeding ratio, and temperature of reaction all identical with embodiment 12, but filling mordenite 40ml is as catalyzer, and always make after the parallel feeding gas space flow velocity keep 2700 (hour)
-1Collect and assay products, the gamma-butyrolactone transformation efficiency is 80.0%, and 2-Pyrrolizidine ketone selection rate is 40.0%.
Embodiment 13
Use reactor and the catalyzer identical with embodiment 1, but reactant is gamma-butyrolactone, dimethylamine, reaches water with weight ratio parallel feeding in 10: 7: 11, flow rate control device adopts the continous way charging, and make after the parallel feeding gas space flow velocity keep 1000 (hour)
-1, under 280 ℃, carry out amination reaction.Collect and assay products, product has 10% methyl alcohol, and the gamma-butyrolactone transformation efficiency is 98.0%, and N-methyl-2-Pyrrolizidine ketone selection rate is 88.0%.
Embodiment 14
Except reactant is gamma-butyrolactone, Trimethylamine 99, reaches water with the weight ratio 10: 9.3: 11, all the other preparation conditions (comprising reactor, catalyzer, charging flow velocity, temperature of reaction) are all identical with embodiment 13.Collect and assay products, product has 8% methyl alcohol, and the gamma-butyrolactone transformation efficiency is 95.0%, and N-methyl-2-Pyrrolizidine ketone selection rate is 79.0%.
Comparative example 5
Except filling Y-type zeolite 40ml as the catalyzer, all the other preparation conditions (comprising reactor, reaction-ure feeding ratio, charging flow velocity, temperature of reaction) are all identical with embodiment 13.Collect and assay products, product has 6.6% methyl alcohol, and the gamma-butyrolactone transformation efficiency is 95.0%, and N-methyl-2-Pyrrolizidine ketone selection rate is 51.0%.
Embodiment 15
Except reactant is gamma-butyrolactone, ethamine, reaches water with the weight ratio 10: 7: 13.6, all the other preparation conditions (comprising reactor, catalyzer, charging flow velocity, temperature of reaction) are all identical with embodiment 13.Collect and assay products, the gamma-butyrolactone transformation efficiency is 98.0%, and N-ethyl-2-Pyrrolizidine ketone selection rate is 79.0%.
Embodiment 16
Except reactant is gamma-butyrolactone, triethylamine, reaches water with the weight ratio 10: 16.4: 14.6, all the other preparation conditions (comprising reactor, catalyzer, charging flow velocity, temperature of reaction) are all identical with embodiment 13.Collect and assay products, product has 13% ethanol, and the gamma-butyrolactone transformation efficiency is 95.0%, and N-ethyl-2-Pyrrolizidine ketone selection rate is 68.0%.
Embodiment 17
Except reactant is gamma-butyrolactone, thanomin, reaches water with the weight ratio 7: 5: 6, all the other preparation conditions (comprising reactor, catalyzer, charging flow velocity, temperature of reaction) are all identical with embodiment 13.Collect and assay products, the gamma-butyrolactone transformation efficiency is 92.0%, and N-(β-ethyl)-2-Pyrrolizidine ketone selection rate is 69.0%.
Can find by the foregoing description and comparative example,, then can cause bad reaction conversion ratio and selection rate, prove that water is necessary reactant of the present invention if water ratio in reactant is crossed low or very caused and do not have (comparative example 1 and comparative example 3).If use known mordenite or Y-type zeolite as catalyzer (comparative example 2, comparative example 4 and comparative example 5), then can't improve the selection rate of lactan, prove that crystalline aluminosilicate zeolite of the present invention can impel the unit time productive rate to improve.
In addition, compared with prior art, use the amination liquid phase reaction of non-catalytic, the condition that forms lactan is to change along with the kind of used amine, but all must under high pressure just react, use crystalline aluminosilicate zeolite catalyst rule of the present invention under lower pressure, to obtain required lactan rapidly.
Under determined spirit and scope without prejudice to claim, the present invention's upgrading and variation in addition.
Claims (15)
1, a kind of method for preparing lactan, this lactan is characterized in that as shown in the formula shown in (I) this method is included in (a) lactone, (b) amine and ammonia, reaches under (c) the water existence, utilize the crystalline aluminosilicate zeolite as catalyzer, carry out amination reaction in gas phase:
[in the formula, R represents C
2-10Stretch alkyl, this stretches alkyl again can be through C
1-6Alkyl or phenyl replaces; R ' expression hydrogen atom, C
1-6Alkyl, C
1-6Hydroxyalkyl, phenyl];
Wherein this lactone is to represent with following formula (II):
[in the formula, R defines with aforementioned];
This amine is for being selected from one-level, secondary, three grades of non-cyclic amines that following substituting group replaces through 1 to 3: hydrogen atom, C
1-6Alkyl, C
1-6Hydroxyalkyl, phenyl.
2, the method for preparing lactan as claimed in claim 1 is characterized in that this lactone is beta-propiolactone, gamma-butyrolactone, δ-butyrolactone, γ-Wu Neizhi, γ-Ji Neizhi, 6-caprolactone, δ-Xin Neizhi, δ-nonalactone, δ-Gui Neizhi, γ-decalactone.
3, the method for preparing lactan as claimed in claim 1, it is characterized in that this amine for single-, two-or three-C
1-6Alkylamine, list-, two-or three-C
1-6Alkanolamine.
4, the method for preparing lactan as claimed in claim 1, it is characterized in that this amine for single-, two-or three-methylamine, list-, two-or three-ethamine, list-, two-or three-thanomin.
5, the method for preparing lactan as claimed in claim 1 is characterized in that the mol ratio of silicon oxide and aluminum oxide in this crystalline aluminosilicate zeolite is (30 to 500): 1.
6, the method for preparing lactan as claimed in claim 1 is characterized in that the restriction index (Constraint Index) of this crystalline aluminosilicate zeolite is 1 to 12.
7, as any described method for preparing lactan in the claim 1 to 6, it is characterized in that this crystalline aluminosilicate zeolite is to be selected from ZSM-5, ZSM-11, ZSM-12, ZSM-22, ZSM-34, ZSM-35, ZSM-48.
8, the method for preparing lactan as claimed in claim 7 is characterized in that this crystalline aluminosilicate zeolite is ZSM-5.
9, the method for preparing lactan as claimed in claim 1, the raw materials components mole ratio that it is characterized in that this lactone and amine and/or ammonia is 1: 0.5 to 1: 30.
10, the method for preparing lactan as claimed in claim 1, the raw materials components mole ratio that it is characterized in that this lactone and water is 1: 0.5 to 1: 20.
11, the method for preparing lactan as claimed in claim 1 is characterized in that this amination reaction temperature is between 180 ℃ to 400 ℃.
12, the method for preparing lactan as claimed in claim 1 is characterized in that this amination reaction pressure is between the 0atm to 10atm.
13, the method for preparing lactan as claimed in claim 1, the feed gas space flow speed that it is characterized in that this amination reaction be 20 (hour)
-1To 100000 (hour)
-1Between.
14, the method for preparing lactan as claimed in claim 1 is characterized in that this amination reaction is to carry out in fixed-bed reactor or fluid bed reactor.
15, a kind of lactan is characterized in that by the method for claim 1 prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00129881 CN1120151C (en) | 2000-10-24 | 2000-10-24 | Prepn of lactam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00129881 CN1120151C (en) | 2000-10-24 | 2000-10-24 | Prepn of lactam |
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| Publication Number | Publication Date |
|---|---|
| CN1349982A true CN1349982A (en) | 2002-05-22 |
| CN1120151C CN1120151C (en) | 2003-09-03 |
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ID=4593817
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|---|---|---|---|
| CN 00129881 Expired - Lifetime CN1120151C (en) | 2000-10-24 | 2000-10-24 | Prepn of lactam |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8304413B2 (en) | 2008-06-03 | 2012-11-06 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| US8741936B2 (en) | 2005-05-10 | 2014-06-03 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
| US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
| CN108774172A (en) * | 2018-08-20 | 2018-11-09 | 铜仁学院 | A kind of preparation method of caprolactam and N substitution caprolactams |
| US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
| CN109851543A (en) * | 2019-01-24 | 2019-06-07 | 浙江华海药业股份有限公司 | A method of preparing pregabalin lactams |
-
2000
- 2000-10-24 CN CN 00129881 patent/CN1120151C/en not_active Expired - Lifetime
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10010536B2 (en) | 2005-05-10 | 2018-07-03 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
| US8741936B2 (en) | 2005-05-10 | 2014-06-03 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
| US9527816B2 (en) | 2005-05-10 | 2016-12-27 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
| US8969347B2 (en) | 2008-06-03 | 2015-03-03 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| US9290450B2 (en) | 2008-06-03 | 2016-03-22 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| US8304413B2 (en) | 2008-06-03 | 2012-11-06 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| USRE47142E1 (en) | 2008-06-03 | 2018-11-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| US10376497B2 (en) | 2012-10-02 | 2019-08-13 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US9675593B2 (en) | 2012-10-02 | 2017-06-13 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US10898474B2 (en) | 2012-10-02 | 2021-01-26 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US10544161B2 (en) | 2014-04-02 | 2020-01-28 | Intermune, Inc. | Anti-fibrotic pyridinones |
| CN108774172A (en) * | 2018-08-20 | 2018-11-09 | 铜仁学院 | A kind of preparation method of caprolactam and N substitution caprolactams |
| CN109851543A (en) * | 2019-01-24 | 2019-06-07 | 浙江华海药业股份有限公司 | A method of preparing pregabalin lactams |
| CN109851543B (en) * | 2019-01-24 | 2023-07-07 | 浙江华海药业股份有限公司 | Method for preparing S-pregabalin lactam |
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|---|---|
| CN1120151C (en) | 2003-09-03 |
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