KR100327787B1 - A process for the monosodium tri-hydrate of 4-amino-1-hydroxybutylidene -1,1-diphosphonic acid - Google Patents
A process for the monosodium tri-hydrate of 4-amino-1-hydroxybutylidene -1,1-diphosphonic acid Download PDFInfo
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- KR100327787B1 KR100327787B1 KR1020010009980A KR20010009980A KR100327787B1 KR 100327787 B1 KR100327787 B1 KR 100327787B1 KR 1020010009980 A KR1020010009980 A KR 1020010009980A KR 20010009980 A KR20010009980 A KR 20010009980A KR 100327787 B1 KR100327787 B1 KR 100327787B1
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- hydroxybutylidene
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- bisphosphonic acid
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- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- -1 4-amino-1-hydroxybutylidene Chemical group 0.000 title claims 4
- 238000000034 method Methods 0.000 title abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 18
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 10
- 239000000203 mixture Substances 0.000 abstract description 8
- 238000010992 reflux Methods 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 abstract 1
- 150000004684 trihydrates Chemical class 0.000 abstract 1
- 239000005457 ice water Substances 0.000 description 6
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002876 effect on osteoporosis Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
본 발명은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물 의 제조방법에 관한 것으로서, 본 발명에서는 선행기술보다 안전하고 경제성있게 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염의 제조하되 감마-아미부틸산을 포스폰화 반응을 사용하여 비스포스폰화 할 때 선행기술에서 사용하는 아인산과 삼염화인 대신에 물과 삼염화인을 사용하여 포스폰화 반응 시키고 나서, 물 혹은 진한 염산을 넣고 환류냉각 한 후 냉각시키고 감압증류하여 농축한 다음, 아세톤을 넣어 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 얻고, 이를 물에 녹이고 일정량의 수산화나트륨을 넣고 가온 한 후 서서히 냉각하여 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 제조하므로써, 종래 아인산을 사용하여 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염을 제조하고 이로부터 삼수화물을 제조하는 경우보다 안전하고 수율이 높으며 경제성이 좋고 순도가 높은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 얻을 수 있는 개선된 방법에 관한 것이다.The present invention relates to a method for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, and in the present invention, 4-amino-1-hydroxy is safer and more economical than the prior art. Preparation of oxybutylidene-1,1-bisphosphonic acid or salts thereof, wherein water and phosphorus trichloride are substituted for the phosphorous and phosphorus trichlorides used in the prior art when bisphosphonated gamma-amibutyl acid using a phosphonation reaction. After phosphonation reaction, water or concentrated hydrochloric acid was added to the mixture, and the mixture was cooled to reflux, cooled, distilled under reduced pressure, concentrated, and then acetone was added to 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. It is dissolved in water, added with a certain amount of sodium hydroxide and warmed, and then cooled slowly to prepare 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate.4-amino-1 is safer, higher yield, more economical and has higher purity than preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof and trihydrates It relates to an improved method for obtaining hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate.
Description
본 발명은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 경제적 방법으로 대기중에서 고순도 고수율로 제조하는 방법에 관한 것이다.The present invention relates to a process for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate in high purity and high yield in air in an economic manner.
골다공증 등에 탁월한 효과가 있는 것으로 나타난 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염은, 미합중국 특허 제 4,407,761호, 미합중국 특허 제 4,621,077호에 따르면, 다음과 같은 방법에 의해 얻어진다.4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof that have been shown to have an excellent effect on osteoporosis and the like, according to US Pat. No. 4,407,761 and US Pat. No. 4,621,077, Is obtained by.
먼저, 아미노카복실산을 포스폰화반응을 사용하여 비스포스폰화 한 다음, 반응 혼합물을 가열하면서 비산화 강산, 바람직하게는 진한 염산을 가해 급냉시킨다.그리고, 이 때 형성된 인 중간 생성물을 최종 생성물로 가수분해 함으로써 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 제조하게 된다.First, the aminocarboxylic acid is bisphosphonated using a phosphonation reaction, and then quenched by addition of a non-oxidizing strong acid, preferably concentrated hydrochloric acid while heating the reaction mixture, and the phosphorus intermediate formed at this time is hydrolyzed to the final product. Thus, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is produced.
또한, 미합중국 특허 제 4,922,007호에 따르면, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산의 제조시, 비스포스폰화 반응 혼합물은 균질하지 않고 부분적 응고가 발생하였는데, 이를 해결하기 위하여 용매로 메탄설폰산을 사용하였다. 또한 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 분리하여 일나트륨 형태로 전환시키는 추가의 단계를 줄이고, 1단계로 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 제조할 수 있도록 하였다.In addition, according to US Pat. No. 4,922,007, in the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, the bisphosphonated reaction mixture was not homogeneous and partial coagulation occurred, which was solved. Methanesulfonic acid was used as a solvent. It also reduces the additional step of separating and converting 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid to monosodium form, and in one step 4-amino-1-hydroxybutylidene- 1,1-bisphosphonic acid monosodium trihydrate was prepared.
한편, 미합중국 특허 제 5,019,651호에 따르면, 가수분해 과정에서 농염산이나 물을 사용하지 않고 pH가 조절된 물을 사용하여 고가의 유리장치를 스테인레스 스틸로 대처가능하도록 하였으며, 이에 따라 압력제한성이 사라져 가수분해 과정에서 압력을 가하여 가수분해 시간을 단축할 수 있도록 하였다.On the other hand, according to US Patent No. 5,019,651, the use of pH-controlled water without using hydrochloric acid or water in the hydrolysis process enables expensive glass apparatus to cope with stainless steel. Pressure was applied during decomposition to shorten the hydrolysis time.
하지만 최근까지 개발된 방법으로 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨을 생산하는 경우, 반응 중에 삼염화인을 넣는 과정에서 염화수소가스가 대량으로 발생하여 작업자의 안전성을 보장 하기 힘들며, 비교적 고가의 아인산을 사용해야 한다. 또한, 방응 도중 계속해서 질소기류 중에서 반응을 해야하며, 공기 중에서 반응시키면 순도가 낮아져 정제과정이 필요하게 되고, 이로 인해 수득량이 현저히 떨어지는 문제점을 들어낸다.However, in the case of producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium by the method developed until recently, a large amount of hydrogen chloride gas is generated in the process of adding phosphorus trichloride during the reaction. It is difficult to guarantee safety and relatively expensive phosphorous acid should be used. In addition, the reaction must be continued in the nitrogen stream during the reaction, and when reacted in the air, the purity is lowered, the purification process is required, thereby causing a problem that the yield is significantly reduced.
이에 따라, 경제적인 문제점이 있어 대량으로 생산하기 곤란하다. 또한, 대량 생산할 경우 제품의 순도를 보장할 수 없으며, 정제 과정을 거치게 되면 수득량이 현저히 떨어지게 된다는 문제점이 있다.Accordingly, there is an economic problem, it is difficult to produce in large quantities. In addition, if the mass production can not guarantee the purity of the product, there is a problem that the yield is significantly reduced through the purification process.
따라서, 본 발명의 목적은 종래에 비하여 대량생산이 가능하여 경제성 있고 안전하면서 수율과 순도가 높은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물의 제조방법을 제공하는 데 있다.Accordingly, an object of the present invention is a method for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, which is economical, safe, and has high yield and purity compared to the prior art. To provide.
본 발명은 감마-아미노부틸산을 물과 삼염화인의 혼합물과 반응시키는 단계와; 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염의 회수하는 단계와; 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 물에 넣어 가온하여 녹이고, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 몰량의 0.9∼1.0배에 해당하는 수산화나트륨을 첨가하는 단계와; 반응물을 소정의 온도까지 상승시켰다가 서서히 냉각시키는 단계를 포함하는 것을 특징으로 하는 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물의 제조방법이다.The present invention comprises the steps of reacting gamma-aminobutyl acid with a mixture of water and phosphorus trichloride; Recovering 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a salt thereof; 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is added to water and dissolved by heating, and 0.9 to molar amount of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is dissolved. Adding sodium hydroxide corresponding to 1.0-fold; The method of preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, comprising the step of raising the reaction to a predetermined temperature and then gradually cooling the reaction.
상기 반응중 인중간체가 생성되며, 상기 인중간체를 용해시키는 용매로 메탄설폰산을 사용함으로써, 반응 혼합물을 균질하게 할 수 있다.Intermediates are produced during the reaction, and the reaction mixture can be homogenized by using methanesulfonic acid as a solvent for dissolving the intermediates.
그리고, 상기 반응은 공기 중에서 수행할 수 있다.In addition, the reaction may be performed in air.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서 먼저 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 제조하기 위해서는, 물과 메탄설폰산 혼합용액에 감마-아미노부틸산을 용해시킨 후 삼염화인을 넣어 반응시킨다. 그런 다음, 반응물을 냉각하고 삼염화인을 넣고, 추가로 메탄설폰산을 더 넣어 반응시킨다. 반응이 완료되면, 물을 넣고 환류 냉각한 후 감압농축한다.In the present invention, in order to prepare 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, gamma-aminobutyl acid is dissolved in a mixture of water and methanesulfonic acid, and then phosphorus trichloride is added to the reaction. Let's do it. Then, the reaction is cooled, phosphorus trichloride is added, and further methanesulfonic acid is added to react. After the reaction was completed, the mixture was poured into water, reflux cooled, and concentrated under reduced pressure.
한편, 다른 방법으로는, 물과 삼염화인을 넣고 반응시킨 후 감마-아미노부틸산을 용해시키고, 삼염화인을 넣어 반응시킨다. 반응이 완료되면, 진한 염산을 넣은 후 환류 냉각하고 감압농축한다.On the other hand, after water and phosphorus trichloride are added and reacted, gamma-aminobutyl acid is dissolved and phosphorus trichloride is added and reacted. After the reaction was completed, the mixture was added with concentrated hydrochloric acid, cooled to reflux, and concentrated under reduced pressure.
이렇게 감압농축시킨 후 물을 넣어 희석하고 아세톤을 넣어 냉각방치하면, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산이 얻어진다.After concentration under reduced pressure like this, water is added to dilute, and acetone is added to stand for cooling, whereby 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is obtained.
이 과정에서 아인산 대신에 물과 삼염화인을 사용하므로, 반응이 격렬하지 않아 반응의 안전성을 향상시킬 수 있으며, 전체 반응에서 선행기술에서 사용한 질소기류를 사용하지 않고 특정의 압력 조건없이 상온의 공기중에서 실시할수 있으며, 고가의 아인산을 사용하지 않아 합성원가를 줄일 수 있다.In this process, since water and phosphorus trichloride are used instead of phosphorous acid, the reaction is not violent and the safety of the reaction can be improved.In the entire reaction, without using a nitrogen stream used in the prior art and in a specific air condition without specific pressure conditions It is possible to reduce the synthesis cost by not using expensive phosphorous acid.
본 발명에 따르면, 이렇게 얻어진 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 물에 용해시키고, 수산화나트륨을 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 몰량의 0.9∼1.0배를 넣어 서서히 교반하면서 소정의 온도까지 가온한 후 서서히 냉각하여 방치하면, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물이 침전된다. 그런 다음, 침전된 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 여과한 후 건조한다.According to the present invention, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid thus obtained is dissolved in water, and sodium hydroxide 4-amino-1-hydroxybutylidene-1,1 When 0.9-1.0 times the molar amount of bisphosphonic acid is added, the mixture is warmed to a predetermined temperature while gradually stirring, and then cooled slowly and left to stand, and 4-amino-1-hydroxybutylidene-1,1-monophosphonic acid monosodium trihydrate Cargo settles. The precipitated 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate is then filtered and dried.
이 과정에서 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 몰량의 0.9∼1.0배의 수산화나트륨을 넣어 반응시킴으로써, 선행기술에서 용액의 pH를 4.3으로 맞추거나 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산의 몰량과 동량의 수산화나트륨을 넣는 방법보다 순도를 높이며, 수산화나트륨을 넣은 후 용액을 가열하였다가 서서히 냉각하는 방법을 이용하여 수득율을 높일 수 있다.In this process, by adding 0.9 to 1.0 times the amount of sodium hydroxide of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in the reaction, the pH of the solution is adjusted to 4.3 or 4-amino in the prior art. Yield is increased by adding a molar amount of -1-hydroxybutylidene-1,1-bisphosphonic acid and the same amount of sodium hydroxide, and heating the solution after adding sodium hydroxide to gradually cool the yield. It can increase.
이와 같이, 본 발명에서는 고가의 아인산 대신 물과 삼염화인을 사용함으로써, 반응이 격렬하지 않을 뿐 아니라, 질소기류를 사용하지 않고, 공기중에서 반응해도 생성물의 순도를 보장할 수 있는 방법으로 4-아미노-1하이드록시부틸리덴-1,1-비스포스폰산의 일나트륨 삼수화물을 제조할 수 있다.As described above, in the present invention, by using water and phosphorus trichloride instead of expensive phosphorous acid, the reaction is not violent, and 4-amino is used to ensure the purity of the product even when reacting in air without using a nitrogen stream. Monosodium trihydrate of -1 hydroxybutylidene-1, 1-bisphosphonic acid can be prepared.
이에 따라, 아인산을 사용하지 않고, 반응을 공기중에서 수행함으로써, 반응시간을 줄이면서도 수득율을 높일 수 있으며, 작업자의 안전을 도모하고, 원가를 절감할 수 있다.Accordingly, by performing the reaction in air without using phosphorous acid, the yield can be increased while reducing the reaction time, and the safety of the operator can be reduced and the cost can be reduced.
한편, 본 발명에 따르면 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산의 결정화 과정에서 감압농축과 희석 단계로 총부피와 아세톤의 비율을 조절함으로써 수득율을 높일 수 있다. 그리고, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물 결정화 과정에서는, 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 일정량의 물에 녹이고 수산화나트륨의 양을 조절한 후 결정화 전에 용액의 온도를 높였다가 서서히 낮추는 방법을 이용하여 순도를 높이고 수득율을 증가시킬 수 있다.On the other hand, according to the present invention it is possible to increase the yield by controlling the ratio of total volume and acetone in the concentration under reduced pressure during the crystallization process of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. In the 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate crystallization process, a certain amount of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is added. After dissolving in water and adjusting the amount of sodium hydroxide, it is possible to increase the purity and increase the yield by increasing the temperature of the solution before crystallization and then gradually lowering it.
다음에서는 본 발명을 용이하게 실시할 수 있는 실시예를 설명한다.The following describes an embodiment in which the present invention can be easily implemented.
실시예 1Example 1
2L 플라스크에 기계적 교반기, 열전쌍, 적가펀넬 및 환류 응축기를 장치한다. 물 40.5g(2.25몰)을 넣고 얼음 물 중탕에서 메탄설폰산 125㎖를 서서히 적가한다. 감마-아미노부틸산 100g(1몰)을 넣고 맑은 용액이 될 때까지 강하게 교반한 후 얼음물 중탕에서 삼염화인 103g(0.75몰)을 서서히 적가한다. 40∼80℃ 바람직하게는 60℃에서 30분간 숙성시킨 후 용액을 얼음물 중탕에서 냉각시킨다. 삼염화인 330g(2.4몰)을 얼음물 중탕에서 서서히 적가하고, 추가로 메탄설폰산 100㎖를 서서히 넣는다. 이어서 반응물을 서서히 65℃로 가열하고 그 온도에서 8∼10시간 동안 숙성시킨다. 8시간 이후부터 반응물을 박층막크로마토그래프로 조사하여 반응의 종료를 확인하고 종료됐으면 반응물을 얼음물 중탕에서 냉각시키고 물 250㎖를 서서히 적가한다. 반응물을 100℃로 가열하여 8시간동안 숙성시킨다. 냉각한 후 감압농축하고, 10L 플라스크에 반응물을 옮기고 물을 넣어 희석한 후 아세톤을 넣어 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 침전시킨다. 침전물을 여과한 후 건조하여 246g을 얻는다. (수율 92%, 순도 99.2%)A 2 L flask is equipped with a mechanical stirrer, thermocouple, dropping funnel and reflux condenser. Add 40.5 g (2.25 moles) of water and slowly add dropwise 125 ml of methanesulfonic acid in an ice water bath. Add 100 g (1 mol) of gamma-aminobutyl acid, stir vigorously until a clear solution, and then slowly add dropwise 103 g (0.75 mol) of phosphorus trichloride in an iced water bath. After aging at 40 to 80 ° C., preferably at 60 ° C. for 30 minutes, the solution is cooled in an iced water bath. 330 g (2.4 mol) of phosphorus trichloride is slowly added dropwise in an ice-water bath, and 100 ml of methanesulfonic acid is slowly added thereto. The reaction is then slowly heated to 65 ° C. and aged at that temperature for 8-10 hours. After 8 hours, the reaction was irradiated with a thin layer chromatography to confirm the completion of the reaction. When finished, the reaction was cooled in an ice water bath and 250 ml of water was slowly added dropwise. The reaction is heated to 100 ° C. and aged for 8 hours. After cooling, the mixture was concentrated under reduced pressure, the reaction was transferred to a 10L flask, diluted with water, and then diluted with acetone to precipitate 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. The precipitate is filtered off and dried to give 246 g. (Yield 92%, Purity 99.2%)
실시예 2Example 2
2L 플라스크에 기계적 교반기, 열전쌍, 적가펀넬 및 환류 응축기를 장치한다. 물 162g(9몰)을 넣고 얼음 물 중탕에서 삼염화인 412g(3몰) 40∼80℃ 바람직하게는 60℃에서 30분간 숙성시킨 후 용액을 얼음물 중탕에서 냉각시킨다. 감마-아미노부틸산 100g(1몰)을 넣고 맑은 용액이 될 때까지 강하게 교반한 후 얼음물 중탕에서 삼염화인 330g(2.4몰)을 서서히 적가한다. 이어서 반응물을 서서히 100℃로 가열하고 그 온도에서 15∼20시간 동안 숙성시킨다. 이때 반응물은 고형화되므로 최대한 강하게 교반해주어야 한다. 15시간 이후부터 반응물을 박층막크로마토그래프로 조사하여 반응의 종료를 확인하고 종료됐으면 반응물을 얼음물 중탕에서 냉각시키고 진한 염산 250㎖를 서서히 적가한다. 반응물을 100℃로 가열하여 8시간동안 숙성시킨다. 냉각한 후 활성탄을 넣어 탈색시킨다. 감압농축하고, 10L 플라스크에 반응물을 옮기고 물을 넣어 희석한 후 아세톤을 넣어 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산을 침전시킨다. 침전물을 여과한 후 건조하여 174g을 얻는다. (수율 70%, 순도 99.3%)A 2 L flask is equipped with a mechanical stirrer, thermocouple, dropping funnel and reflux condenser. 162 g (9 mol) of water were added and aged at 412 g (3 mol) of phosphorus trichloride in an ice water bath at 40 to 80 ° C, preferably at 60 ° C for 30 minutes, and the solution was cooled in an ice water bath. Add 100 g (1 mol) of gamma-aminobutyl acid, stir vigorously until a clear solution, and slowly add dropwise 330 g (2.4 mol) of phosphorus trichloride in an ice-water bath. The reaction is then slowly heated to 100 ° C. and aged at that temperature for 15-20 hours. At this time, the reactants are solidified and must be stirred as strongly as possible. After 15 hours, the reaction was irradiated with a thin layer chromatography to confirm the completion of the reaction. When finished, the reaction was cooled in an iced water bath and 250 ml of concentrated hydrochloric acid was slowly added dropwise. The reaction is heated to 100 ° C. and aged for 8 hours. After cooling, activated carbon is decolorized. Concentrate under reduced pressure, transfer the reaction to a 10 L flask, dilute with water, add acetone to precipitate 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. The precipitate is filtered off and dried to give 174 g. (Yield 70%, Purity 99.3%)
실시예 3Example 3
상기 실시예 1에서 얻은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 267g(1몰)을 374㎖의 물에 넣고 반응물의 온도를 올려 완전히 녹인다. 반응물에 수산화나트륨 38g(0.95몰)을 물 267g에 녹인 용액을 교반하면서 서서히 넣어준다. 가볍게 교반하면서 반응물을 80∼95℃, 바람직하게는 90℃로 서서히 가열한 후 서서히 온도를 낮추고 냉각 방치한다. 생성된 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물을 여과한 후 60℃에서 일정량이 될 때까지 건조하여 302g을 얻는다. (수율 93%, 순도 99.5%)267 g (1 mol) of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid obtained in Example 1 was added to 374 ml of water, and the reactant was heated to dissolve completely. Slowly add a solution of 38 g (0.95 mol) of sodium hydroxide to 267 g of water. The reaction is slowly heated to 80-95 ° C., preferably 90 ° C., with gentle stirring, then the temperature is gradually lowered and left to cool. The resulting 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate was filtered and dried at 60 ° C. until constant, yielding 302 g. (Yield 93%, Purity 99.5%)
이상에서 설명한 바와 같이, 본 발명에 따르면 종래와는 달리 아인산을 사용하지 않고 물과 삼염화인을 사용하여 대기중에서 반응시킴으로써 단시간에 고수율과 고순도의 목적물을 제조할 수가 있어서, 대량이 생산이 가능하며 경제성 있고 안전하면서도 고수율로 순도가 높은 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산일나트륨 삼수화물을 제조할 수 있는 효과가 있다As described above, according to the present invention, unlike the related art, by using water and phosphorus trichloride in the atmosphere without using phosphorous acid, the target product can be manufactured in high yield and purity in a short time, so that mass production is possible. Economical, safe, high-purity 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate can be produced
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| KR100246809B1 (en) * | 1992-07-21 | 2000-04-01 | 헤르베르트 포우퀘트, 만프레트 베버 | Novel acyclic amidine-group-containing diphosphonic acid derivatives, process for producing them and medicaments containing these compounds |
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