Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-12-12
2003-01-21
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S495000
Reexamination Certificate
active
06509504
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for preparing serinol which is used as an intermediate in preparing a medical intermediate. More particularly, the present invention relates to a method for preparing serinol (2-amino-1,3-propanediol) of a high purity at high yield by reacting nitromethane with para-formaldehyde and then with sodium hydroxide as a sodium source to give 2-nitro-1,3-propanediol sodium salt and hydrogenating the sodium salt as in the following reaction in the presence of a metal or a metal-impregnated catalyst system.
Serinol (2-amino-1,3-propanediol) is an intermediate for a medicine and in particular, is used as an intermediate useful for preparing lopamidol, an X-ray contrast medium.
BACKGROUND ART
As described, in detail, in U.S. Pat. No. 4,754,079, 2-nitro-1,3-propanediol sodium salt, which is used as a raw material for serinol, can be prepared from nitromethane, paraformaldehyde, sodium methoxide and potassium hydroxide (KOH). The described preparation process in which KOH is used as a catalyst and sodium methoxide in a liquid phase (30% methanol solution) is utilized as a sodium source for 2-nitro-1,3-propanediol sodium salt, is disadvantageous in that the reaction is too complicated and the handling of the compounds is troublesome. In addition, the reaction between para-formaldehyyde and nitromethane must be carried out in a temperature range of 42 to 45° C. which is too narrow to control. Further, this process suffers from a problem of being economically unfavorable because sodium methoxide in a aligned phase is expensive compared with sodium hydroxide (NaOH) powder which is used in the present invention.
Another serinol preparation method can be referred to DE Pat. No. 2,742,981, in which 2-nitro-1,3-propanediol sodium salt is hydrogenated in a buffer acid to prepare serinol. In this method, hydrogen is absorbed in a stoichiometric amount, but the yield is merely 30 to 50% even under an ideal reaction condition. Another disadvantage of this method is that it is difficult to apply for industrial production because a Pd/C catalyst is hardly reusable.
According to U.S. Pat. No. 4,448,999, the production yield of serinol may be increased up to 74% by adopting a loop-type reactor equipped with effective cooling means and using methanol as a solvent. However, the batch reaction using a Pd/C catalyst, which is expensive and difficult to reuse, deters users from applying the method for industrial production. In addition, the catalyst must be removed vexatiously with a filter after reaction and the production yield is too low for industrial application.
U.S. Pat. No. 4,221,740 discloses the use of a Raney nickel instead of expensive Pd/C catalyst, asserting that the production yield of serinol can be increased to 64 to 87%. However, the Raney nickel catalyst is also not easy to reuse and requires a filter for its removal. In fact, the production yield is not sufficient.
Therefore, there remains a need for developing a preparation method for serinol which can be conducted even at relatively low temperatures, is economically favorable, and affords a high purity of serinol at a high production yield.
DISCLOSURE OF THE INVENTION
Accordingly, after intensive and thorough research the present inventors found that in the preparation of a 2-nitro-1,3-propanediol salt the use of sodium hydroxide (NaOH) powder as a sodium source unlike the conventional methods and the adoption of a fixed bed reactor system loaded with metals or a metal impregnated catalyst instead of using a conventional batch reactor can prevent the decrease in yield resulting from a reaction temperature rise and overcome the problems of heating para-formaldehyde for a complete dissolution. Based on these findings, the present invention, which is simple and economically favorable and can produce serinol with a purity at a high yield, became complete.
Therefore, it is an object of the present invention to provide a method for preparing serinol with a high purity at a high yield, which is simple and economically favorable.
In one embodiment of the present invention, there is provided a method for preparing serinol (2-amino-1,3-propanediol), comprising the steps of: reacting 1 equivalent of nitromethane with 1 to 10 equivalents of para-formaldehyde and then, adding 0.5 to 5 equivalents of sodium hydroxide to give 2-nitro-1,3-propanediol sodium salt; preparing a catalyst which comprises an inorganic support in which a catalytically effective metal component is impregnated at an amount of 1 to 20 wt %, said catalytically effective metal being selected from the group consisting of palladium (Pd), platinum (Pt), rhodium (Rh), iridium (Ir). ruthenium (Ru), osmium (Os) and mixtures thereof; and continuously hydrogenating the 2-nitro-1,3-propanediol sodium salt in a fixed bed reactor in which the catalyst is packed.
In one version of the embodiment, the present invention comprises of the reaction for preparing the 2-nitro-1,3-propanediol sodium salt at a temperature of 0 to 100° C. and the hydrogenation for preparing the 2-nitro-1,3-propanediol at a temperature of 0 to 150° C., a hydrogen pressure of 15 to 2,500 psig, and at a weight hourly space velocity (WHSV) of 0.1 to 10 h
−1
while feeding hydrogen/2-nitro-1,3-propanediol sodium salt at a molar ratio of 1 to 10 with a 1 to 50 wt % solution of 2-nitro-1,3-propanediol sodium salt in a solvent.
BEST MODES FOR CARRYING OUT THE INVENTION
In the present invention, nitromethane is first reacted with para-formaldehyde and the resulting compound is salted with sodium hydroxide under absence of catalysts to afford 2-nitro-1,3-propanediol sodium salt which is then allowed to undergo continuous hydrogenation when passing through a fixed bed reactor in which a catalyst comprising a metal or a metal-impregnated support is packed.
Different from conventional ones, the process for the preparation of 2-nitro-1,3-propanediol sodium salt in accordance with the present invention can be readily conducted even at relatively low temperatures. In addition, sodium hydroxide powder, which is used in the present invention, is relatively convenient to handle compared with the aqueous potassium hydroxide solution and sodium methoxide of liquid phase (30% methanol solution), which are conventionally used. In addition, the relatively cheap sodium hydroxide gives an economical advantage to the present invention.
For the preparation of the sodium salt, the amount of para-formaldehyde used preferably ranges from 1 to 10 equivalents per equivalent of nitromethane and more preferably from 1 to 5 equivalents. When the amount of para-formaldehyde is below 1 equivalent, the yield of the sodium salt is poor. On the other hand, when it is over 10 equivalents, side reactions occur.
As for sodium hydroxide, it is preferably used at an amount of 0.5 to 5 equivalents per equivalent of nitromethane and more preferably at an amount of 0.5 to 3 equivalents. Less than 0.5 equivalents of sodium hydroxide slows the reaction rate. On the other hand, greater than 5 equivalents of sodium hydroxide causes side reactions and an economical disadvantage.
The reaction temperature is set in the range of 0 to 100° C. and preferably 10 to 50° C. For instance, when the reaction is conducted at less than 0° C., the formation of the sodium salt is slow. On the other hand, when the reaction temperature exceeds 100° C., side reactions frequently occur to reduce the yield of the sodium salt yielding a colored mixture.
In accordance with the present invention, 2-nitro-1,3-propanediol sodium salt can be produced with a purity of 99.8% at a yield of 98%.
Subsequently, the 2-nitro-1,3-propanediol sodium salt is hydrogenated in the presence of a metal catalyst or a catalyst system comprising a metal-impregnated support, so as to produce serinol of a high purity at a high yield. This hydrogenation is accomplished in a continuous process using a fixed bed reactor. Therefore, the method of the present invention has an advantage over other processes using batch type processes, in production rate. In add
Chung Ki-Nam
Kim Choon-Gil
Koh Ki-Ho
Kwak Byong-Sung
Abelman ,Frayne & Schwab
Davis Brian J.
SK Corporation
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