KR100802013B1 - Process for preparing pegylated ursodeoxy cholic acid derivatives - Google Patents

Process for preparing pegylated ursodeoxy cholic acid derivatives Download PDF

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KR100802013B1
KR100802013B1 KR1020060075726A KR20060075726A KR100802013B1 KR 100802013 B1 KR100802013 B1 KR 100802013B1 KR 1020060075726 A KR1020060075726 A KR 1020060075726A KR 20060075726 A KR20060075726 A KR 20060075726A KR 100802013 B1 KR100802013 B1 KR 100802013B1
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김준섭
김종민
김형식
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(주)유케이케미팜
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Abstract

Pegylated UDCA(Ursodeoxy Cholic Acid) derivatives and a preparation method thereof are provided to hydrolyze PEG(Polyethyleneglycol) easily in a human body, to increase solubility for the water, and to obtain the PEG through a simple process. A method for producing pegylated UDCA derivatives comprises the steps of: making the formula 7 by dissolving polyethylene glycol monomethyl ether of the formula 3 in an organic solvent and pegylating the organic solvent by RX and a base; making the formula 8 by reacting the formula 7 in the R'X and the organic solvent or the mixed solvent; and making the formula 6 by melting the formula 8 and UDCA in the organic solvent and reacting the organic solvent with a base.

Description

페길화된 우루소데옥시 콜린산 유도체와 그의 제조방법 {process for preparing pegylated ursodeoxy cholic acid derivatives}Pegylated urosodeoxy choline acid derivatives and a method for preparing the same {process for preparing pegylated ursodeoxy cholic acid derivatives}

우루소데옥시 콜린산(이하 UDCA라 한다)은 만성 간질환의 간기능 개선제로 유용하게 쓰인다. 보통 합성된 UDCA는 여러 방법에 의해 합성되었지만 그 합성물 UDCA는 물에 대한 용해도가 극히 저조하다. 그리고 보통 아미노기를 가지는 많은 약물들이 페길레이션이 용이하므로 물에 대한 용해도를 높이기 위해 페길레이션을 하였다. 그러나 카르본산을 가지는 화합물들의 페길레이션은 어려우므로 페길레이션된 약물들은 별로 많지 않다. 조직내에 지속적이고 일정한 약물의 양을 유지하기 위하여 운반체가 약물과 천천히 쉽게 끊어짐으로써 서서히 약물이 방출되며, 또한 페길레이션된 약물이 매우 친수성이 커서 쉽게 물에 용해되어 약물의 생체이용율을 높인다. 카르본산의 페길레이션은 MeO-PEG-OH의 OH기를 술포네이트로 전환한 다음, 다시 할로겐으로 전환시킨후. 그 중간체를 카르본산을 가지는 화합물과 반응시켜야 하는 어려움이 있다.Ursodeoxycholic acid (hereinafter referred to as UDCA) is useful for improving liver function in chronic liver disease. Usually synthesized UDCA is synthesized by various methods, but its composite UDCA has extremely low solubility in water. And many drugs with amino groups are easily PEGylated, so they are PEGylated to increase their solubility in water. However, PEGylation of compounds with carboxylic acids is difficult, so there are not many PEGylated drugs. In order to maintain a constant and constant amount of drug in the tissue, the drug is slowly released from the drug by slowly breaking it with the drug, and the pegylated drug is very hydrophilic and easily dissolved in water to increase the bioavailability of the drug. Pegylation of carboxylic acid converts the OH group of MeO-PEG-OH to sulfonate and then to halogen again. There is a difficulty in reacting the intermediate with a compound having carboxylic acid.

최근 연구 결과에 의하면 Poly(ethylene glycol)(이하 PEG라 한다)이 인체에 무해하며, 약물에 연결되어 있을 때 인체 내에서 쉽게 가수분해되고, 또한 물에 대한 용해도를 증가시킨다는 보고가 있다. 이에 본 발명은 종래의 비경제적인 문제점을 해결하여 전체 공정이 간단하고, 부반응이 수반되지 않는 경제적인 반응 단계를 통해 그의 PEG 화학식 6을 높은 수율로 얻을 수 있는 제조 방법을 제공하는 것을 목적으로 한다.Recent studies have reported that poly (ethylene glycol) (PEG) is harmless to humans, readily hydrolyzed in the body when connected to drugs, and also increases solubility in water. Accordingly, an object of the present invention is to provide a manufacturing method capable of obtaining the PEG formula 6 in high yield through an economic reaction step in which the entire process is simple and does not involve side reactions by solving a conventional non-economic problem.

[화학식 6][Formula 6]

Figure 112006057310815-pat00002
Figure 112006057310815-pat00002

Figure 112006057310815-pat00003
Figure 112006057310815-pat00003

Figure 112006057310815-pat00004
Figure 112006057310815-pat00004

Figure 112006057310815-pat00005
Figure 112006057310815-pat00005

Figure 112006057310815-pat00006
Figure 112006057310815-pat00006

상기 목적을 달성하기 위한 본 발명의 UDCA의 페길레이션은 여러 종류의 연결고리를 갖는 PEG와 연결시켜 물에 잘 용해되는 새로운 PEG-UDCA 프로드러그를 만드는 것이다. 본 발명의 페길레이션된 우루소데옥시 콜린산 유도체의 제조방법은 다음과 같은 단계를 포함한다.The PEGylation of the UDCA of the present invention to achieve the above object is to make a new PEG-UDCA prodrug that is well dissolved in water by connecting with PEG having various types of linkages. The method for preparing the pegylated urosodeoxy choline acid derivative of the present invention includes the following steps.

화학식 3의 폴리에틸렌 글리콜 모노메틸 에테르( MeO-PEG)를 유기용매에 녹이고 RX와 염기로 페길화 반응시켜 화학식 7을 제조하는 단계 1;Dissolving polyethylene glycol monomethyl ether (MeO-PEG) of formula 3 in an organic solvent and PEGylating RX with a base to prepare formula 7;

화학식 7을 R'X와 유기 용매의 단일 또는 혼합 용매에서 반응시켜 화학식 8을 제조하는 단계 2;Preparing Chemical Formula 8 by reacting Chemical Formula 7 in a single or mixed solvent of R′X and an organic solvent;

화학식 8과 UDCA 유도체를 유기 용매에 녹이고, 염기와 반응시켜 화학식 6을 제조하는 단계 3;Dissolving Formula 8 and the UDCA derivative in an organic solvent and reacting with a base to produce Formula 6;

Figure 112006057310815-pat00007
Figure 112006057310815-pat00007

Figure 112006057310815-pat00008
Figure 112006057310815-pat00008

Figure 112006057310815-pat00009
Figure 112006057310815-pat00009

Figure 112006057310815-pat00010
Figure 112006057310815-pat00010

상기 화학식에서 n은 38 내지 46의 정수이고, R은 메탄 술포닐, p-톨루일 또 는 트리풀루오로 아세틸이며, R'는 K, Na 또는 Li 이고, X는 할로겐으로서 클로로, 브로모 또는 요오드이다.N is an integer from 38 to 46, R is methane sulfonyl, p -toluyl or tripulo acetyl, R 'is K, Na or Li, and X is halogen as chloro, bromo or It is iodine.

단계 1에서 사용되는 유기 용매는 디메틸술폭시드(DMSO), DMF, 디메틸아세트아미드(DMAc), H2O, MeOH, EtOH, Pyridine, Acetone, 테트라히드로퓨란(THF), Dioxane, 헥사메틸포스포라미드(HMPA), CH2Cl2 또는 클로로포름(CHCl3)의 단일 또는 혼합 용매이며, 염기는 NEt3, diisopropyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diaza-bicyclo-[4.3.0]non-5-ene(DBN)중에서 선택되는 1종이상이 사용될 수 있다.The organic solvent used in step 1 is dimethyl sulfoxide (DMSO), DMF, dimethylacetamide (DMAc), H 2 O, MeOH, EtOH, Pyridine, Acetone, tetrahydrofuran (THF), Dioxane, hexamethylphosphoramide (HMPA), CH 2 Cl 2 or chloroform (CHCl 3 ) single or mixed solvent, base is NEt 3 , diisopropyl amine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, One or more selected from 5-diaza-bicyclo- [4.3.0] non-5-ene (DBN) may be used.

단계 1에서 반응 온도는 0 내지 40oC 이다. 온도가 0 oC 이하의 경우는 반응이 매우 느리며, 40oC 이상의 경우는 알코올과 생성물 사이에 에테르 반응이 일어날 수 있다.The reaction temperature in step 1 is 0-40 ° C. Temperature is 0 Below o C the reaction is very slow, above 40 o C an ether reaction can occur between the alcohol and the product.

단계 2에서 반응 온도는 0 내지 40oC 이다, 온도가 0 oC 이하의 경우는 반응이 매우 느리며, 40oC 이상의 경우는 알코올과 생성물 사이에 에테르 반응이 일어날 수 있다.In step 2 the reaction temperature is 0 to 40 o C, the temperature is 0 Below o C the reaction is very slow, above 40 o C an ether reaction can occur between the alcohol and the product.

유기 용매는 DMSO, DMF, DMAc, H2O, MeOH, EtOH, Pyridine, Acetone, THF, Dioxane, HMPA, CH2Cl2, 또는 CHCl3의 단일 또는 혼합용매가 사용될 수 있다.The organic solvent may be a single or mixed solvent of DMSO, DMF, DMAc, H 2 O, MeOH, EtOH, Pyridine, Acetone, THF, Dioxane, HMPA, CH 2 Cl 2 , or CHCl 3 .

단계 3에서 반응 온도는 0 내지 120oC이다. 온도가 0 oC 이하의 경우는 반응이 매우 느리며, 120oC 이상의 경우는 알코올과 생성물 사이에 에테르 반응이 일어날 수 있다.The reaction temperature in step 3 is 0-120 ° C. Temperature is 0 Below o C the reaction is very slow, above 120 o C an ether reaction can occur between the alcohol and the product.

사용되는 유기 용매는 DMSO,DMF, DMAc, H2O, MeOH, EtOH, Pyridine, Acetone, THF, Dioxane, HMPA, CH2Cl2, 또는 CHCl3의 단일 또는 혼합 용매이며, 사용되는 염기는 유기염기로는 NEt3, diisopropyl amine, DBU 또는 DBN 중에서 선택되는 1종이상이, 무기염기로는 NaHCO3, Na2CO3, NaOH, KOH, BaOH 또는 LiOH 수용액중에서 선택되는 1종이상을 0.1 내지 5N 농도로 사용하는 것이 바람직하다.The organic solvent used is a single or mixed solvent of DMSO, DMF, DMAc, H 2 O, MeOH, EtOH, Pyridine, Acetone, THF, Dioxane, HMPA, CH 2 Cl 2 , or CHCl 3 , and the base used is an organic base As the inorganic base, at least one selected from NEt 3 , diisopropyl amine, DBU, or DBN, and at least one selected from NaHCO 3 , Na 2 CO 3 , NaOH, KOH, BaOH, or LiOH aqueous solution in a concentration of 0.1 to 5 It is preferable to use as.

본 발명에 따른 반응 단계를 각각 살펴보면 먼저 아래 반응식 1과 같이 화학식 3 메틸옥시폴리에틸렌글리신(MeO-PEG)을 디클로로메탄(CH2Cl2) 용매에서 클로로메탄술포네이트(MsCl)와 트리에틸아민(Et3N)을 반응시켜 화학식 4를 얻는다.Looking at each reaction step according to the present invention, as shown in Scheme 1 below, the formula 3 methyloxypolyethylene glycine (MeO-PEG) in chloromethanesulfonate (MsCl) and triethylamine (Et) in dichloromethane (CH 2 Cl 2 ) solvent by reacting a 3 N) to obtain a formula (4).

Figure 112006057310815-pat00011
Figure 112006057310815-pat00011

이어서 반응식 2와 같이 화학식 4를 아세톤과 디메틸포름아미드(DMF)에 녹이고 NaI를 가한 후, 환류시켜 화학식 5를 얻는다.Subsequently, Formula 4 is dissolved in acetone and dimethylformamide (DMF) as shown in Scheme 2, and NaI is added, followed by reflux to obtain Formula 5.

Figure 112006057310815-pat00012
Figure 112006057310815-pat00012

반응식 3과 같이 얻어진 화학식 5를 디메틸아세틸아미드(DMAc)에 녹이고 UDCA, NaHCO3와 Na2CO3를 가한 후, 가온하여 화학식 6을 얻는다.Formula 5 obtained as in Scheme 3 is dissolved in dimethylacetylamide (DMAc), and UDCA, NaHCO 3 and Na 2 CO 3 are added, followed by heating to obtain Formula 6.

Figure 112006057310815-pat00013
Figure 112006057310815-pat00013

n은 38에서 46의 정수이다.n is an integer from 38 to 46.

이하, 바람직한 실시예를 통하여 본 발명에 따른 제조 방법을 구체적으로 설명한다. 단, 이들 실시예는 본 발명의 예시일 뿐, 본 발명의 범위가 이들 만으로 한정되는 것은 아니다.Hereinafter, the manufacturing method according to the present invention will be described in detail through preferred embodiments. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited to these.

실시예 1 : 메톡시 폴리에틸렌 에틸메탄술포네이트의 제조(화학식 4)Example 1 Preparation of Methoxy Polyethylene Ethyl Methanesulfonate (Formula 4)

실온에서 폴리에틸렌 글리콜 모노메틸 에테르(MeO-PEG, 분자량:1700-2100) 30g(15.8mmol)를 질소하에서 CH2Cl2 50mL에 녹이고, Et3N 3.2g(31.6mmol)을 첨가한 후, 클로로메탄술포네이트(MsCl) 2.71g(23.7mmol)을 CH2Cl2 20mL에 녹인 용액을 0oC에서 20분간 서서히 적가한다.At room temperature, 30 g (15.8 mmol) of polyethylene glycol monomethyl ether (MeO-PEG, molecular weight: 1700-2100) was dissolved in 50 mL of CH 2 Cl 2 under nitrogen, and 3.2 g (31.6 mmol) of Et 3 N was added, followed by chloromethane. A solution of 2.71 g (23.7 mmol) of sulfonate (MsCl) in 20 mL of CH 2 Cl 2 was slowly added dropwise at 0 o C for 20 minutes.

1시간 동안 교반 후, 반응물에 물 80mL를 가하고 교반 후, 층 분리한다. CH2Cl2층을 Na2SO4로 탈수시킨 후, 여과.감압 농축하여 흰색 분말의 화학식 4(30.7g)의 생성물을 얻는다.After stirring for 1 hour, 80 mL of water was added to the reaction, and after stirring, the layers were separated. The CH 2 Cl 2 layer was dehydrated with Na 2 SO 4 , filtered and concentrated under reduced pressure to give the product of formula 4 (30.7 g) as a white powder.

1H NMR (CDCl3) δ 3.07(s, 3H), 3.34(s, 3H), 3.4-4.0(m, 170H), 4.2-4.4(m, 2H) 1 H NMR (CDCl 3 ) δ 3.07 (s, 3H), 3.34 (s, 3H), 3.4-4.0 (m, 170H), 4.2-4.4 (m, 2H)

실시예 2 : 메톡시 폴리에틸렌 에틸요오드의 제조(화학식 5)Example 2: Preparation of methoxy polyethylene ethyl iodine (Formula 5)

실온에서 메톡시 폴리에틸렌 에틸메탄술포네이트 30.7g(15.5mmol)를 질소하에서 아세톤 100mL와 디메틸포름아미드(DMF) 50mL의 혼합용매에 녹인 후, NaI 4.65g(31.0mmol)을 첨가하고 반응 혼합물을 5.5시간 동안 환류시킨다. 반응 온도를 실온까지 낮춘 후, 물 50Ml에 Na2S2O3 3.7g을 녹인 용액을 반응물에 가하고 CH2Cl2 100mL로 2회 추출한다. 합해진 CH2Cl2층을 물 30mL로 3회 세척하고 Na2SO4로 탈수시킨 후, 여과.감압 농축하여 미백색 결정의 화학식 5(31.8g)의 생성물을 얻는다.At room temperature, 30.7 g (15.5 mmol) of methoxy polyethylene ethylmethanesulfonate was dissolved in a mixed solvent of 100 mL of acetone and 50 mL of dimethylformamide (DMF) under nitrogen, followed by addition of 4.65 g (31.0 mmol) of NaI and the reaction mixture for 5.5 hours. Reflux for a while. After the reaction temperature was lowered to room temperature, a solution of 3.7 g of Na 2 S 2 O 3 dissolved in 50 Ml of water was added to the reaction, followed by extraction twice with 100 mL of CH 2 Cl 2 . The combined CH 2 Cl 2 layers were washed three times with 30 mL of water, dehydrated with Na 2 SO 4 , filtered and concentrated under reduced pressure to give the product of formula 5 (31.8 g) as white crystals.

1H NMR (CDCl3) δ 3.2-3.4(t, 2H), 3.38(s, 3H), 3.4-4.0(m, 170H) 1 H NMR (CDCl 3 ) δ 3.2-3.4 (t, 2H), 3.38 (s, 3H), 3.4-4.0 (m, 170H)

실시예 3 : 메톡시 폴리에틸렌 UDCA 카보네이트의 제조(화학식 6)Example 3 Preparation of Methoxy Polyethylene UDCA Carbonate (Formula 6)

메톡시 폴리에틸렌 에틸요오드 5g(2.48mmol)을 디메틸아세트아미드(DMAc) 50mL에 녹이고 UDCA 974mg(2.48mmol), NaHCO3 313mg(3.72mmol) 그리고 Na2CO3 394mg (3.72mmol)을 차례로 가한 후, 반응 온도를 90~100oC에서 12시간 동안 교반한다. 반응물의 온도를 실온까지 낮춘 후, 물 50mL 와 CH2Cl2 100mL를 가한다. 층 분리 후, 물층을 CH2Cl2 100mL로 2회 재 추출하고 합해진 CH2Cl2 용액을 물 30mL로 3회 세척하고 Na2SO4로 탈수시킨 후, 여과.감압 농축한다. 농축물에 이소프로필에테르를 가하여 백색 결정의 화학식 6(4.81g)의 생성물을 얻는다. (평균 분자량 : 2290)5 g (2.48 mmol) of methoxy polyethylene ethyl iodine was dissolved in 50 mL of dimethylacetamide (DMAc), 974 mg (2.48 mmol) of UDCA, 313 mg (3.72 mmol) of NaHCO 3 and 394 mg (3.72 mmol) of Na 2 CO 3 were added in this order. Stir the temperature at 90-100 ° C. for 12 h. After the reaction was cooled to room temperature, 50 mL of water and 100 mL of CH 2 Cl 2 were added. After layer separation, the water layer was re-extracted twice with 100 mL of CH 2 Cl 2, the combined CH 2 Cl 2 solution was washed three times with 30 mL of water, dehydrated with Na 2 SO 4, and then filtered and concentrated under reduced pressure. Isopropyl ether is added to the concentrate to give the product of formula 6 (4.81 g) as white crystals. (Average molecular weight: 2290)

1H NMR (CDCl3) δ 0.65(s, 3H), 0.8-1.0(m, 6H), 1.0-2.4(m, 28H), 3.35(s, 3H), 3.0-3.5(m,2H), 3.4-4.0(m, 170H), 4.0-4.3(m, 2H) 1 H NMR (CDCl 3 ) δ 0.65 (s, 3H), 0.8-1.0 (m, 6H), 1.0-2.4 (m, 28H), 3.35 (s, 3H), 3.0-3.5 (m, 2H), 3.4 -4.0 (m, 170H), 4.0-4.3 (m, 2H)

우루소데옥시 콜린산(UDCA)은 만성 간질환의 간기능 개선제로 유용하게 쓰인다. 보통 합성된 UDCA는 여러 방법에 의해 합성되었지만 UDCA는 물에 대한 용해도가 극히 저조하다.Urusodeoxy choline (UDCA) is a useful agent for improving liver function in chronic liver disease. Usually synthesized UDCA is synthesized by various methods, but UDCA has very low solubility in water.

본 발명에 의거 UDCA의 물에 대한 용해도를 높인 친수성이 강한 페길레이션된 UDCA를 제공할 수 있다. According to the present invention, a hydrophilic PEGylated UDCA having a high solubility in water can be provided.

Claims (8)

하기 화학식 6으로 표시되는 분자량 2090~2490의 우루소데옥시 콜린산 유도체.Urusodeoxy choline acid derivatives having a molecular weight of 2090 to 2490 represented by the following formula (6). [화학식 6][Formula 6]
Figure 112006057310815-pat00014
Figure 112006057310815-pat00014
 상기 화학식에서 n은 38 내지 46의 정수이다.N is an integer of 38 to 46 in the above formula. 화학식 3의 폴리에틸렌 글리콜 모노메틸 에테르( MeO-PEG)를 유기용매에 녹이고 RX와 염기로 페길화 반응시켜 화학식 7을 제조하는 단계 1;Dissolving polyethylene glycol monomethyl ether (MeO-PEG) of formula 3 in an organic solvent and PEGylating RX with a base to prepare formula 7; 화학식 7을 R'X와 유기 용매의 단일 또는 혼합 용매에서 반응시켜 화학식 8을 제조하는 단계 2; 및Preparing Chemical Formula 8 by reacting Chemical Formula 7 in a single or mixed solvent of R′X and an organic solvent; And 화학식 8과 UDCA 를 유기 용매에 녹이고, 염기와 반응시켜 화학식 6을 제조하는 단계 3을 포함하며,Dissolving Formula 8 and UDCA in an organic solvent and reacting with a base to produce Formula 6; 단계 1에서 사용되는 유기 용매는 디메틸술폭시드(DMSO), 디메틸포름아미드(DMF), 디메틸아세트아미드(DMAc), H2O, MeOH, EtOH, Pyridine, Acetone, 테트라히드로퓨란(THF), Dioxane, 헥사메틸포스포라미드(HMPA), CH2Cl2, 또는 클로로포름(CHCl3)의 단일 또는 혼합 용매이며, 사용되는 염기는 NEt3 , diisopropyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU),1,5-diaza- bicyclo-[4.3.0]non-5-ene(DBN)중에서 선택되는 1종이상이고,The organic solvent used in step 1 is dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), H 2 O, MeOH, EtOH, Pyridine, Acetone, tetrahydrofuran (THF), Dioxane, Single or mixed solvent of hexamethylphosphoramide (HMPA), CH 2 Cl 2 , or chloroform (CHCl 3 ); the base used is NEt 3 , diisopropyl amine, 1,8-diazabicyclo [5.4.0] undec-7 at least one selected from -ene (DBU), 1,5-diazabicyclo- [4.3.0] non-5-ene (DBN), 단계 2에서 사용되는 유기 용매는 디메틸술폭시드(DMSO), 디메틸포름아미드(DMF), 디메틸아세트아미드(DMAc), H2O, MeOH, EtOH, Pyridine, Acetone, 테트라히드로퓨란(THF), Dioxane, 헥사메틸포스포라미드(HMPA), CH2Cl2, 또는 클로로포름(CHCl3)의 단일 또는 혼합 용매이며,The organic solvent used in step 2 is dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), H 2 O, MeOH, EtOH, Pyridine, Acetone, tetrahydrofuran (THF), Dioxane, Single or mixed solvent of hexamethylphosphoramide (HMPA), CH 2 Cl 2 , or chloroform (CHCl 3 ), 단계 3에서 사용되는 유기 용매는 디메틸술폭시드(DMSO), 디메틸포름아미드(DMF), 디메틸아세트아미드(DMAc), H2O, MeOH, EtOH, Pyridine, Acetone, 테트라히드로퓨란(THF), Dioxane, 헥사메틸포스포라미드(HMPA), CH2Cl2, 또는 클로로포름(CHCl3)의 단일 또는 혼합 용매이며, 사용되는 염기는 유기염기로는 NEt3, diisopropyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) 또는 1,5-diaza- bicyclo-[4.3.0]non-5-ene (DBN)중에서 선택되는 1종이상, 무기염기로는 NaHCO3, Na2CO3, NaOH, KOH, BaOH 또는 LiOH 수용액 중에서 선택되는 1종이상임을 특징으로 하는 페길화된 우루소데옥시 콜린산 유도체의 제조방법.The organic solvent used in step 3 is dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), H 2 O, MeOH, EtOH, Pyridine, Acetone, tetrahydrofuran (THF), Dioxane, A single or mixed solvent of hexamethylphosphoramide (HMPA), CH 2 Cl 2 , or chloroform (CHCl 3 ), and the bases used are organic bases such as NEt 3 , diisopropyl amine, 1,8-diazabicyclo [5.4.0 ] undec-7-ene (DBU) or at least one selected from 1,5-diazabicyclo- [4.3.0] non-5-ene (DBN), inorganic bases include NaHCO 3 , Na 2 CO 3 , A method for producing a pegylated urosodeoxy choline acid derivative, characterized in that at least one selected from NaOH, KOH, BaOH or LiOH aqueous solution. [화학식 3][Formula 3]
Figure 112007068153251-pat00019
Figure 112007068153251-pat00019
 [화학식 7][Formula 7]
Figure 112007068153251-pat00020
Figure 112007068153251-pat00020
 [화학식 8][Formula 8]
Figure 112007068153251-pat00021
Figure 112007068153251-pat00021
 [화학식 6][Formula 6]
Figure 112007068153251-pat00022
Figure 112007068153251-pat00022
 상기 화학식에서 n은 38 내지 46의 정수이고, R은 메탄 술포닐, p-톨루일 또는 트리풀루오로 아세틸이며, R'는 K, Na 또는 Li 이고, X는 할로겐으로서 클로로, 브로모 또는 요오드이다.Wherein n is an integer from 38 to 46, R is acetyl, m-sulfonyl, p -toluyl, or trifulo, R 'is K, Na or Li, and X is halogen, chloro, bromo or iodine to be. 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR950031082A (en) * 1994-05-13 1995-12-18 루이스 베르나소코니 Novel derivatives of ursodeoxycholic acid and pharmaceutical ingredients comprising the same
KR960000918A (en) * 1994-06-20 1996-01-25 유서홍 Method for preparing ursodeoxycholic acid
KR960037050A (en) * 1995-04-21 1996-11-19 서홍석 Angiogenesis inhibitors containing derivatives of ursodeoxycholic acid
JPH11199598A (en) 1998-01-08 1999-07-27 Yokohama Kokusai Bio Kenkyusho:Kk Ursodeoxycholic acid derivative and its production
JP2001261696A (en) 2000-03-15 2001-09-26 Mitsubishi-Tokyo Pharmaceuticals Inc Tertiary amine salt of ursodeoxycholic acid and method for producing ursodeoxycholic acid using the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR950031082A (en) * 1994-05-13 1995-12-18 루이스 베르나소코니 Novel derivatives of ursodeoxycholic acid and pharmaceutical ingredients comprising the same
KR960000918A (en) * 1994-06-20 1996-01-25 유서홍 Method for preparing ursodeoxycholic acid
KR960037050A (en) * 1995-04-21 1996-11-19 서홍석 Angiogenesis inhibitors containing derivatives of ursodeoxycholic acid
JPH11199598A (en) 1998-01-08 1999-07-27 Yokohama Kokusai Bio Kenkyusho:Kk Ursodeoxycholic acid derivative and its production
JP2001261696A (en) 2000-03-15 2001-09-26 Mitsubishi-Tokyo Pharmaceuticals Inc Tertiary amine salt of ursodeoxycholic acid and method for producing ursodeoxycholic acid using the same

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