KR100679115B1 - Process for preparing 1-alpha-hydroxycholecalciferol derivatives - Google Patents

Process for preparing 1-alpha-hydroxycholecalciferol derivatives Download PDF

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KR100679115B1
KR100679115B1 KR1020040092207A KR20040092207A KR100679115B1 KR 100679115 B1 KR100679115 B1 KR 100679115B1 KR 1020040092207 A KR1020040092207 A KR 1020040092207A KR 20040092207 A KR20040092207 A KR 20040092207A KR 100679115 B1 KR100679115 B1 KR 100679115B1
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compound
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김준섭
조동옥
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(주)유케이케미팜
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed ring

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Abstract

본 발명은 1-알파-히드록시콜레칼시페롤 유도체를 간단한 반응 공정을 통해 높은 수율로 얻을 수 있는 제조 방법에 관한 것으로, 비타민 D3와 유사한 화학식 1의 화합물을 출발 물질로 하여 화학식 7의 1-알파-히드록시콜레칼시페롤 유도체를 제조하는 것을 특징으로 한다.The present invention is 1-alpha-of formula (VII) to the compound of formula (1) is similar to that according to the production method can be obtained in a high yield the hydroxy cholecalciferol derivative through a simple reaction step, and the vitamin D 3 in the starting material 1 It is characterized by preparing an alpha-hydroxy cholecalciferol derivative.

[화학식 1][Formula 1]

Figure 112004052449215-pat00001
Figure 112004052449215-pat00001

[화학식 7][Formula 7]

Figure 112004052449215-pat00002
Figure 112004052449215-pat00002

위 화학식에서, R1은 수소 또는 할로겐을 나타내며, R2는 H, 저급 알킬기 또는 히드록시기를 나타내고, R3는 이소프로필, t-부틸, 시클로프로필 또는 2-히드록시프로필기를 나타낸다.In the above formula, R 1 represents hydrogen or halogen, R 2 represents H, lower alkyl group or hydroxy group, and R 3 represents isopropyl, t-butyl, cyclopropyl or 2-hydroxypropyl group.

1-알파-히드록시콜레칼시페롤 유도체, 비타민 디 유도체.1-alpha-hydroxycholecalciferol derivative, vitamin di derivative.

Description

1-알파-히드록시콜레칼시페롤 유도체의 제조방법{PROCESS FOR PREPARING 1-ALPHA-HYDROXYCHOLECALCIFEROL DERIVATIVES}Process for preparing 1-alpha-hydroxycholecalciferol derivatives {PROCESS FOR PREPARING 1-ALPHA-HYDROXYCHOLECALCIFEROL DERIVATIVES}

본 발명은 1-α-히드록시콜레칼시페롤 유도체를 간단한 반응 공정을 통해 높은 수율로 얻을 수 있는 제조 방법에 관한 것이다.The present invention relates to a process for producing 1-α-hydroxycholecalciferol derivatives in high yield through a simple reaction process.

1-α-히드록시콜레칼시페롤 유도체인 알파칼시돌은 골조송증, 부갑상선 기능 저하증, 만성 신부전증, 비타민 D 저항성 구루병, 골연화증 치료제로 유용하게 사용된다.Alphacalcidol, a 1-α-hydroxycholecalciferol derivative, is useful for the treatment of osteoporosis, parathyroidism, chronic renal failure, vitamin D resistant rickets and osteomalacia.

알파칼시돌은 미국특허 제3,929,770호에 개시된 바와 같이 3-옥소-1,4,6-콜레스타트리엔을 출발물질로 하여 아래 반응식 1의 공정을 통해 제조되고 있다.Alpha calcidol is prepared through the process of Scheme 1 below using 3-oxo-1,4,6-cholestatriene as a starting material, as disclosed in US Pat. No. 3,929,770.

Figure 112004052449215-pat00003
Figure 112004052449215-pat00003

그러나, 이러한 종래의 방법은 중간체 시약으로 고가의 4-페닐-1,2,4-트리아졸린-3,5-디온을 사용하고 있으며, 또한 전체 반응이 7 단계로 복잡할 뿐 아니라, 총 수득율도 2.6 %로 매우 낮다.However, this conventional method uses expensive 4-phenyl-1,2,4-triazolin-3,5-dione as an intermediate reagent, and the overall reaction is not only complicated in seven steps, but also the total yield is obtained. Very low at 2.6%.

각 반응 단계의 문제점을 살펴보면, 먼저 화학식 Ⅱ에서 염기를 사용하여 화학식 Ⅲ을 제조할 때 화학식 Ⅲ-1이나 화학식 Ⅲ-2와 같은 부산물이 생길 수 있으며, 분리에 어려움이 있다. 또한, 화학식 Ⅲ을 소디움보로하이드라이드(NaBH4)로 환원시켜 화학식 Ⅰ을 제조하고 있으나, 이 또한 화학식 Ⅰ-1과 같은 알코올의 이성체가 나타날 수 있어, 역시 분리에 어려움이 있다. 그리고, 화학식 Ⅶ을 산화시켜 에폭시화합물인 화학식 Ⅷ을 제조하고 있는데, 여기에서도 이성체인 화학식 Ⅷ-1이 생산될 수 있어, 분리에 어려움에 있다. 마찬가지로, 화학식 Ⅷ에 리튬알루미늄하이드라이드(LAH)를 사용하여 화학식 Ⅸ를 제조하는 단계에서도 이성체인 화학식 Ⅸ-1가 제조될 수 있어, 분리가 어렵다.Looking at the problem of each reaction step, by the first formula (II) using the base in formula (III) to produce by-products such as formula (III-1) or (III-2), there is difficulty in separation. In addition, the formula (I) by reducing the formula III to sodium borohydride (NaBH 4 ) to prepare the formula (I), but also may be difficult to separate because the isomer of the alcohol, such as formula (I-1). In addition, the chemical formula (X) is prepared by oxidizing the chemical formula (X), and here, the isomer (XIV-1) may be produced, which is difficult to separate. Likewise, in the step of preparing the formula (VII) using lithium aluminum hydride (LAH) in the formula (X), the isomer of formula (X-1) may be prepared, and thus separation is difficult.

이와 같은 종래 방법의 문제점을 고려할 때, 1-α-히드록시콜레칼시페롤 유도체를 제조하는 과정에서 반응 단계를 줄이고, 부반응을 억제하여 공정 수율을 극대화할 수 있는 알파칼시돌 유도체 제조방법의 개발이 요구되고 있다.In view of the problems of the conventional method, in the process for preparing 1-α-hydroxycholecalciferol derivatives, the process of preparing an alpha calcidol derivative capable of maximizing the process yield by reducing the reaction step and suppressing side reactions Development is required.

본 발명에서는 종래의 문제점을 해결하여, 전체 공정이 간단하고 부반응이 수반되지 않은 경제적인 반응 단계를 통해 1-α-히드록시콜레칼시페롤 유도체를 고수율로 얻을 수 있는 제조 방법을 제공하는 것을 목적으로 한다.The present invention is to solve the problems of the prior art, to provide a production method capable of obtaining a high yield of 1-α-hydroxy cholecalciferol derivatives through an economic reaction step is simple, the whole process is not accompanied by side reactions The purpose.

상기 목적을 달성하기 위한 본 발명의 1-α-히드록시콜레칼시페롤 유도체의 제조방법은,Method for producing a 1-α-hydroxy cholecalciferol derivative of the present invention for achieving the above object,

화학식 1의 화합물을 SO2 가스를 이용하여 디엔을 고리화하여 화학식 2의 화합물을 제조하고;Preparing a compound of Formula 2 by cyclizing the diene using SO 2 gas;

화학식 2의 화합물을 보호기 R4를 갖는 화합물과 반응시켜 화학식 3의 화합물을 제조하고;Reacting a compound of Formula 2 with a compound having protecting group R 4 to produce a compound of Formula 3;

화학식 3의 화합물을 염기 하에서 환류하여 화학식 4의 화합물을 제조하고;Refluxing the compound of formula 3 under a base to prepare a compound of formula 4;

화학식 4의 화합물을 산화하여 화학식 5의 화합물을 제조하고;Oxidizing a compound of Formula 4 to produce a compound of Formula 5;

화학식 5의 화합물을 이성질화하여 화학식 6의 화합물을 제조하고;Isomerizing the compound of formula 5 to produce the compound of formula 6;

화학식 6의 화합물을 탈보호화 반응시켜 화학식 7의 화합물을 제조하는 단계를 포함한다.Deprotecting the compound of Formula 6 to produce a compound of Formula 7.

Figure 112004052449215-pat00004
Figure 112004052449215-pat00004

Figure 712006003006982-pat00026
Figure 712006003006982-pat00026

Figure 712006003006982-pat00027
Figure 712006003006982-pat00027

Figure 112004052449215-pat00007
Figure 112004052449215-pat00007

Figure 112004052449215-pat00008
Figure 112004052449215-pat00008

Figure 112004052449215-pat00009
Figure 112004052449215-pat00009

Figure 112004052449215-pat00010
Figure 112004052449215-pat00010

위 화학식에서, R1은 수소 또는 할로겐을 나타내며, R2는 H, 저급 알킬기 또는 히드록시기를 나타내고, R3는 이소프로필, t-부틸, 시클로프로필 또는 2-히드록시프로필기를 나타내고, 그리고 R4는 보호기를 나타낸다.In the above formula, R 1 represents hydrogen or halogen, R 2 represents H, lower alkyl group or hydroxy group, R 3 represents isopropyl, t-butyl, cyclopropyl or 2-hydroxypropyl group, and R 4 is It represents a protecting group.

본 발명에서는 비타민 D3와 유사한 화학식 1의 화합물을 출발 물질로 함으로써, 전체 공정이 간단하고 반응 공정 중 부 반응을 수반하지 않는 경제적인 방법으로 목적 화합물을 제조할 수 있도록 한 것을 특징으로 한다.In the present invention, by using a compound of formula (1) similar to vitamin D 3 as a starting material, it is possible to prepare the target compound in an economical way that the entire process is simple and does not involve side reactions during the reaction process.

다음 반응식 2는 본 발명의 방법에 따라 화학식 1의 화합물을 출발물질로 하여 화학식 7의 1-α-히드록시콜레칼시페롤 유도체를 제조하는 전체 반응 공정을 나 타낸 것이다.The following Reaction Scheme 2 illustrates the entire reaction process for preparing the 1-α-hydroxycholecalciferol derivative of the formula (7) as a starting material according to the method of the present invention.

Figure 712006003006982-pat00028
Figure 712006003006982-pat00028

위 반응식에서, R1은 수소 또는 할로겐으로서 H, F, Cl 또는 Br을 나타내며, R2는 H, 저급 알킬기 또는 히드록시기를 나타내고, R3는 이소프로필, t-부틸, 시클로프로필 또는 2-히드록시프로필기를 나타내고, 그리고 R4는 실릴이나 에테르와 같은 보호기를 나타낸다.In the above scheme, R 1 represents H, F, Cl or Br as hydrogen or halogen, R 2 represents H, lower alkyl group or hydroxy group, R 3 represents isopropyl, t-butyl, cyclopropyl or 2-hydroxy A propyl group, and R 4 represents a protecting group such as silyl or ether.

본 발명에 따른 반응 단계를 각각 살펴보면, 먼저 아래 반응식 3과 같이 비 타민 D3 유도체인 화학식 1의 화합물을 SO2 가스를 이용하여 디엔을 고리화하여 화학식 2의 화합물을 제조한다. 고리화 반응은 화학식 1의 화합물을 0 내지 40 ℃에서 물과 유기용매의 혼액에 녹인 후, SO2 가스 존재 하에서 교반하여 화학식 2를 제조하는 것으로 이루어진다. 유기용매로는 벤젠, 톨루엔, 크실렌 등의 일반적인 유기용매를 사용할 수 있다. 고리화 반응 후 잔존하는 이산화황을 질소나 아르곤 등의 비활성 기체를 폭기함으로써 제거할 수 있다.Looking at each reaction step according to the present invention, first, the compound of formula 1, which is a vitamin D 3 derivative as shown in Scheme 3 below to cyclize the diene using SO 2 gas to prepare a compound of formula (2). The cyclization reaction consists of dissolving the compound of Formula 1 in a mixture of water and an organic solvent at 0 to 40 ° C., followed by stirring in the presence of SO 2 gas to produce Formula 2. As the organic solvent, a general organic solvent such as benzene, toluene, xylene or the like can be used. Sulfur dioxide remaining after the cyclization reaction can be removed by aeration of an inert gas such as nitrogen or argon.

Figure 712006003006982-pat00029
Figure 712006003006982-pat00029

이어서, 반응식 4와 같이, 비타민 D3 유도체의 SO2 고리화물인 화학식 2의 화합물을 보호기 R4로 보호하여 화학식 3의 화합물을 제조한다. 반응이 염기 하에서 진행될 경우 이에 사용되는 염기로는, 유기 염기로서 트리에틸아민, 피리딘, 디메틸아미노피리딘, 이미다졸 등의 일반적인 유기 염기와, 무기 염기로서 탄산칼륨, 탄산수소칼륨, 탄산나트륨, 탄산수소나트륨, 수산화나트륨, 수산화칼륨, 수산화리튬 등의 일반적인 무기 염기가 모두 가능하다. 보호기 R4로서는 t-부틸디메틸실릴, t-부틸디페닐실릴, 트리메틸실릴 또는 트리에틸실릴과 같은 실릴기나 테트라히드로 피라닐 또는 에톡시에틸과 같은 에테르기를 사용할 수 있다. 반응 온도는 0 내지 40 ℃가 적당하며, 용매로는 디클로로메탄, 테트라히드로퓨란, 디옥산, 디메틸포름아미드, 에틸아세테이트 등의 일반적인 유기용매를 단독 또는 혼합하여 사용할 수 있다. 한편, 산 촉매 반응의 경우에는, 메틸렌클로라이드나 클로로포름과 같은 유기용매 중에서 산으로는 무수 염산, P-톨루엔 술폰산, 또는 피리디늄 P-톨루엔 술폰산 등을 디히드로피란이나 에틸비닐에테르 등의 보호기를 사용할 수 있다.Subsequently, as in Scheme 4, the compound of Formula 2, which is a SO 2 cyclide of the vitamin D 3 derivative, is protected with a protecting group R 4 to prepare a compound of Formula 3. As the base used for the reaction when the reaction proceeds under a base, general organic bases such as triethylamine, pyridine, dimethylaminopyridine and imidazole as organic bases, and potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate as inorganic bases General inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide are possible. As the protecting group R 4 , silyl groups such as t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl or triethylsilyl or ether groups such as tetrahydro pyranyl or ethoxyethyl can be used. The reaction temperature is suitably 0 to 40 ° C. As a solvent, general organic solvents such as dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, and ethyl acetate may be used alone or in combination. On the other hand, in the case of acid catalysis, hydrochloric anhydride, P-toluene sulfonic acid, or pyridinium P-toluene sulfonic acid may be used as an acid in an organic solvent such as methylene chloride or chloroform to use a protecting group such as dihydropyran or ethyl vinyl ether. Can be.

Figure 712006003006982-pat00030
Figure 712006003006982-pat00030

아래 반응식 5에서 보는 바와 같이, 화학식 4의 화합물은 화학식 3을 염기 하에서 환류하여 제조된다. 반응에 사용되는 염기로는 유기 염기로서 트리에틸아민, 피리딘 등의 일반적인 유기 염기와, 무기 염기로서 탄산칼륨, 탄산수소칼륨, 탄산나트륨, 탄산수소나트륨, 수산화나트륨, 수산화칼륨, 수산화리튬 등의 일반적인 무기 염기가 모두 가능하다. 반응 온도는 60 내지 100 ℃가 적당하며, 유기용매로서 메탄올, 에탄올, 이소프로판올 등의 일반적인 알코올 용매를 단독 또는 혼합하여 사용할 수 있다.As shown in Scheme 5 below, the compound of Formula 4 is prepared by refluxing Formula 3 under a base. Examples of the base used for the reaction include general organic bases such as triethylamine and pyridine as organic bases, and general inorganic bases such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide. All bases are possible. The reaction temperature is suitably 60 to 100 ° C, and a general alcohol solvent such as methanol, ethanol, isopropanol or the like can be used alone or as a mixture.

Figure 712006003006982-pat00031
Figure 712006003006982-pat00031

이어서, 화학식 4의 화합물을 유기용매에 용해시켜 화학식 5의 화합물을 제조한다. 이러한 반응식 6에서는 산화촉매제로 N-메틸모폴린-N-옥사이드, 그리고 산화제로서 셀레늄 디옥사이드, 셀렌산 등을 사용할 수 있다. 반응 용매로는 메탄올, 에탄올, 디클로로메탄, 에틸렌디클로라이드 등의 일반적인 유기용매를 단독 또는 혼합하여 사용할 수 있으며, 반응 온도는 60 내지 100 ℃가 적당하다.Subsequently, the compound of formula 4 is dissolved in an organic solvent to prepare a compound of formula 5. In this Scheme 6, N-methylmorpholine-N-oxide as an oxidation catalyst, selenium dioxide, selenic acid, etc. may be used as an oxidizing agent. As the reaction solvent, a general organic solvent such as methanol, ethanol, dichloromethane, ethylene dichloride, or the like may be used alone or in combination. The reaction temperature is preferably 60 to 100 ° C.

Figure 112004052449215-pat00015
Figure 112004052449215-pat00015

다음으로, 화학식 5의 화합물을 이성질화하여 화학식 6의 화합물을 생성하는 반응식 7의 단계는 화학식 5의 화합물을 유기용매에 용해시켜 암소에서 파장 λ=300∼400 ㎚, 바람직하게는 긴파장 λ=365 ㎚ 근방의 빛을 조사하여 진행된다. 반응 지시약으로 안트라센을 사용할 수 있으며, 반응 용매로는 메탄올, 에탄올과 같 은 알코올, 벤젠이나 톨루엔과 같은 불포화 고리 용매 등의 일반적인 유기용매를 단독 또는 혼합하여 사용할 수 있다. 또한, 반응에 소량의 염기로서 트리에틸아민, 디이소프로필에틸아민, 그리고 피리딘 등의 일반적인 유기 염기와, 무기 염기로서 탄산칼륨, 탄산수소칼륨, 탄산나트륨, 탄산수소나트륨, 수산화나트륨, 수산화칼륨, 수산화리튬 등의 일반적인 무기 염기를 모두 사용할 수 있다. 반응에 사용되는 염기의 양은 0.01 내지 0.5 당량이 바람직하며, 반응 온도는 0 내지 40 ℃가 적당하다.Next, the step of Scheme 7 in which isomerization of the compound of formula 5 to produce the compound of formula 6 is carried out by dissolving the compound of formula 5 in an organic solvent in a dark wavelength λ = 300 to 400 nm, preferably long wavelength λ = It proceeds by irradiating light of 365 nm vicinity. Anthracene may be used as the reaction indicator, and as the reaction solvent, general organic solvents such as alcohols such as methanol and ethanol and unsaturated ring solvents such as benzene and toluene may be used alone or in combination. In addition, general organic bases such as triethylamine, diisopropylethylamine, and pyridine as a small amount of base in the reaction, and potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, hydroxide as inorganic bases All general inorganic bases, such as lithium, can be used. The amount of base used in the reaction is preferably 0.01 to 0.5 equivalents, and the reaction temperature is suitably 0 to 40 ° C.

Figure 112004052449215-pat00016
Figure 112004052449215-pat00016

이어서, 다음 반응식 8에서 보듯이 화학식 6의 탈보호기 반응에 의해 화학식 7의 유도체를 얻을 수 있다. 탈보호 시약으로는 p-톨루엔술폰산(p-TsOH), 염화수소(HCl, gas), n-테트라부틸암모늄 플루오라이드(nBu4NF), 암모늄 플루오라이드(NH4F) 등을 사용할 수 있다. 반응 온도는 20 내지 80 ℃가 적당하며, 반응 용매는 테트라히드로퓨란, 디옥산 등의 일반적인 유기용매를 단독 또는 혼합하여 사용할 수 있다. 제조된 화학식 7의 화합물은 에틸에테르와 n-헥산, 또는 n-펜탄 등의 혼합 용액으로 재결정하여 순수한 화합물을 얻을 수 있다.Subsequently, a derivative of Formula 7 may be obtained by a deprotection group reaction of Formula 6, as shown in Scheme 8 below. As the deprotection reagent, p-toluenesulfonic acid (p-TsOH), hydrogen chloride (HCl, gas), n-tetrabutylammonium fluoride (nBu 4 NF), ammonium fluoride (NH 4 F) and the like can be used. 20-80 degreeC of reaction temperature is suitable, and a reaction solvent can be used individually or in mixture of common organic solvents, such as tetrahydrofuran and a dioxane. The prepared compound of Formula 7 may be recrystallized with a mixed solution of ethyl ether and n-hexane or n-pentane to obtain a pure compound.

Figure 112004052449215-pat00017
Figure 112004052449215-pat00017

이하, 바람직한 실시예를 통하여 본 발명에 따른 제조 방법을 구체적으로 설명한다. 단, 이들 실시예는 본 발명의 예시일 뿐, 본 발명의 범위가 이들만으로 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: t-부틸-(3-{2-[1-(1,5-디메틸헥실)-7a-메틸옥타히드로인덴-4-일리덴메틸]-에틸리덴}-4-메틸렌시클로헥실옥시)-디메틸실란(화학식 4)의 제조 Example 1 t-butyl- (3- {2- [1- (1,5-dimethylhexyl) -7a-methyloctahydroindene-4-ylidenemethyl] -ethylidene} -4-methylenecyclohex Preparation of siloxy) -dimethylsilane (Formula 4)

화학식 1의 비타민 D3 30 g을 상온에서 톨루엔 300 ㎖와 정제수 300 ㎖에 녹이고 SO2 가스를 폭기시키면서 5 시간 동안 교반하였다. 반응액에 질소 가스를 폭기하여 남아있는 SO2 가스를 제거하였다. 반응액에 포화식염수 300 ㎖와 에틸에테르 300 ㎖를 가하여 교반하고, 수용액 층을 에틸에테르 300 ㎖로 재추출하였다. 에틸에테르 혼합 용액을 합해서 포화식염수 200 ㎖로 탈수시킨 후, 황산나트륨 100 g으로 건조시켰다.30 g of vitamin D 3 of Formula 1 was dissolved in 300 ml of toluene and 300 ml of purified water at room temperature and stirred for 5 hours while aeration of SO 2 gas. Nitrogen gas was aerated in the reaction solution to remove the remaining SO 2 gas. 300 ml of saturated brine and 300 ml of ethyl ether were added to the reaction mixture, followed by stirring. The aqueous layer was reextracted with 300 ml of ethyl ether. The combined mixture of ethyl ethers was dehydrated with 200 ml of saturated brine, and dried over 100 g of sodium sulfate.

건조된 에틸에테르 혼합 용액을 여과, 농축하고 농축물을 상온에서 디메틸포름아미드 250 ㎖와 에틸아세테이트 100 ㎖에 용해시켰다. 용해된 반응 용액에 이미다졸 11.163 g을 상온에서 녹이고, 다시 0 ℃에서 t-부틸디메틸실릴 클로라이드 13.322 g을 가하여 교반하였다. 상온으로 온도를 올린 후, 약 2 시간 가량 교반하고, 에틸에테르 1 ℓ를 가하였다. 다시 증류수 50 ㎖로 각 5 회 세척 후, 포화식염수 200 ㎖로 탈수시키고, 탈수된 에틸에테르 용액 혼합액에 황산나트륨 100 g을 가하여 건조시켰다.The dried ethyl ether mixture was filtered and concentrated, and the concentrate was dissolved in 250 ml of dimethylformamide and 100 ml of ethyl acetate at room temperature. 11.163 g of imidazole was dissolved in the dissolved reaction solution at room temperature, and 13.322 g of t-butyldimethylsilyl chloride was further added and stirred at 0 ° C. After raising the temperature to room temperature, the mixture was stirred for about 2 hours, and 1 liter of ethyl ether was added thereto. After washing each time 5 times with 50 ml of distilled water, it was dehydrated with 200 ml of saturated brine, and 100 g of sodium sulfate was added to the dehydrated ethyl ether solution mixture and dried.

건조물을 여과, 농축하고 농축물을 99.5 % 에탄올 300 ㎖에 녹인 후, 탄산수소나트륨 29.4 g을 가해 2 시간 동안 환류 교반하였다. 상온으로 식힌 후, 셀라이트로 여과하고 에틸에테르 200 ㎖로 세척하였다. 여과된 혼합 용액을 농축하고, 에틸에테르 300 ㎖와 증류수 300 ㎖를 가하여 추출한 후, 수용액층을 에틸에테르 300 ㎖로 재추출하였다. 에틸에테르 혼합 용액을 합해서 포화식염수 200 ㎖로 탈수시킨 후, 황산나트륨 100 g으로 건조시켰다. 건조된 에틸에테르 혼합 용액을 여과, 농축하고, 농축물을 칼럼크로마토그래피하여 순수한 표제 화합물(화학식 4) 38.8 g(정량적)을 얻었다.The dried product was filtered, concentrated, and the concentrate was dissolved in 300 ml of 99.5% ethanol, and then 29.4 g of sodium hydrogen carbonate was added thereto, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the mixture was filtered through celite and washed with 200 ml of ethyl ether. The filtered mixed solution was concentrated, extracted with 300 ml of ethyl ether and 300 ml of distilled water, and the aqueous layer was reextracted with 300 ml of ethyl ether. The combined mixture of ethyl ethers was dehydrated with 200 ml of saturated brine, and dried over 100 g of sodium sulfate. The dried ethyl ether mixed solution was filtered, concentrated, and the concentrate was subjected to column chromatography to give 38.8 g (quantitative) of the pure title compound (Formula 4).

1H NMR(CDCl3) δ0.10-0.11(6H, d), 0.60(3H, s), 0.90-0.94(15H, m), 0.95-0.97(3H, d), 1.17-1.19(3H, m), 1.14-1.60(3H, m), 1.63-1.73(3H, m), 1.88-1.93(7H, m), 2.18(4H, m), 2.26-2.33(1H, dd), 2.47-2.50(1H, dd), 2.66-2.71(1H, dd), 2.87-2.91(1H, dd), 3.87-3.90(1H, m), 4.66(1H, s), 4.95(1H, s), 5.86-5.90(1H, d), 6.48-6.52(1H, d) 1 H NMR (CDCl 3 ) δ 0.10-0.11 (6H, d), 0.60 (3H, s), 0.90-0.94 (15H, m), 0.95-0.97 (3H, d), 1.17-1.19 (3H, m ), 1.14-1.60 (3H, m), 1.63-1.73 (3H, m), 1.88-1.93 (7H, m), 2.18 (4H, m), 2.26-2.33 (1H, dd), 2.47-2.50 (1H) , dd), 2.66-2.71 (1H, dd), 2.87-2.91 (1H, dd), 3.87-3.90 (1H, m), 4.66 (1H, s), 4.95 (1H, s), 5.86-5.90 (1H , d), 6.48-6.52 (1H, d)

실시예 2: 5-(t-부틸디메틸실란일옥시)-3-{2-[1-(1,5-디메틸헥실)-7a-메틸옥타히드로인덴-4-일리덴]에틸리덴}-2-메틸렌시클로헥산올(화학식 5)의 제조 Example 2 : 5- (t-butyldimethylsilanyloxy) -3- {2- [1- (1,5-dimethylhexyl) -7a-methyloctahydroinden-4-ylidene] ethylidene}- Preparation of 2-methylenecyclohexanol (Formula 5)

실시예 1에서 제조한 화학식 4의 화합물 38.8 g을 상온에서 에틸렌디클로라이드 500 ㎖에 녹이고, N-메틸모폴린-N-옥사이드 32.88 g을 메틸렌클로라이드 500 ㎖에 녹인 용액을 혼합 용액에 가하였다. 약 10 분 동안 100 ℃에서 가열 환류 후, 셀렌산 11.26 g을 메탄올 500 ㎖에 녹인 용액을 반응액에 가하고, 약 40 분 동안 100 ℃에서 가열 환류하였다. 반응 후, 반응 용액을 농축하고 에틸에테르 500 ㎖를 가하였다. 포화 탄산수소나트륨 용액 300 ㎖로 세척하고 포화식염수 200 ㎖로 탈수시킨 후, 황산나트륨 100 g으로 건조시켰다. 건조된 에틸에테르 혼합 용액을 여과, 농축하고, 농축물을 칼럼크로마토그래피하여 순수한 표제 화합물(화학식 5) 13.83 g(34.5 %)을 얻었다.38.8 g of the compound of formula 4 prepared in Example 1 was dissolved in 500 ml of ethylenedichloride at room temperature, and a solution of 32.88 g of N-methylmorpholine-N-oxide in 500 ml of methylene chloride was added to the mixed solution. After heating to reflux at 100 ° C. for about 10 minutes, a solution of 11.26 g of selenic acid dissolved in 500 mL of methanol was added to the reaction solution, and heated to reflux at 100 ° C. for about 40 minutes. After the reaction, the reaction solution was concentrated and 500 ml of ethyl ether was added. It was washed with 300 ml of saturated sodium hydrogen carbonate solution, dehydrated with 200 ml of saturated brine, and dried over 100 g of sodium sulfate. The dried ethyl ether mixed solution was filtered, concentrated, and the concentrate was subjected to column chromatography to give 13.83 g (34.5%) of the pure title compound (Formula 5).

1H NMR(CDCl3) δ0.11-0.14(6H, d), 0.58(3H, s), 0.83-0.91(15H, m), 0.92-0.94(3H, d), 1.11-1.16(3H, m), 1.30-1.37(6H, m), 1.45-1.57(4H, m), 1.68-1.73(3H, m), 1.90-1.96 (3H, m), 1.99-2.08(2H, m), 2.40-2.45(1H, dd), 2.54-2.59(1H, dd), 2.86-2.90(1H, dd), 4.20-4.23(1H, m), 4.52(1H, br s), 4.96(1H, s), 5.09(1H, s), 5.85-5.89(1H, d), 6.51-6.55(1H, d). 1 H NMR (CDCl 3 ) δ 0.11-0.14 (6H, d), 0.58 (3H, s), 0.83-0.91 (15H, m), 0.92-0.94 (3H, d), 1.11-1.16 (3H, m ), 1.30-1.37 (6H, m), 1.45-1.57 (4H, m), 1.68-1.73 (3H, m), 1.90-1.96 (3H, m), 1.99-2.08 (2H, m), 2.40-2.45 (1H, dd), 2.54-2.59 (1H, dd), 2.86-2.90 (1H, dd), 4.20-4.23 (1H, m), 4.52 (1H, br s), 4.96 (1H, s), 5.09 ( 1H, s), 5.85-5.89 (1H, d), 6.51-6.55 (1H, d).

실시예 3: 1-α히드록시 비타민 D3(화학식 8)의 제조 Example 3 Preparation of 1-αhydroxy Vitamin D 3 (Formula 8)

Figure 112004052449215-pat00018
Figure 112004052449215-pat00018

실시예 2에서 제조한 화학식 5의 화합물 13.83 g을 상온에서 99.5 %의 에탄올 600 ㎖와 톨루엔 1200 ㎖의 혼액에 녹이고, 안트라센 4.02 g과 트리에틸아민 0.66 ml를 0 ℃에서 가하고, 아르곤 가스를 1시간 동안 폭기하였다. 차광된 환경에서 긴 파장 λ=365 ㎚ 근방의 자외선을 상온에서 50 시간 동안 조사, 교반하였. 반응 후 여과, 감압 농축하고, 농축 화합물을 칼럼크로마토그래피하여 안트라센이 포함된 혼합 생성물을 얻었다.13.83 g of the compound of formula 5 prepared in Example 2 was dissolved in a mixture of 600 ml of 99.5% ethanol and 1200 ml of toluene at room temperature, 4.02 g of anthracene and 0.66 ml of triethylamine were added at 0 ° C., and argon gas was added for 1 hour. Aerated during. Ultraviolet light in the vicinity of a long wavelength λ = 365 nm was irradiated and stirred at room temperature for 50 hours in a shielded environment. After the reaction, the mixture was filtered and concentrated under reduced pressure, and the concentrated compound was subjected to column chromatography to obtain a mixed product containing anthracene.

이 혼합 생성물을 테트라히드로퓨란 500 ㎖에 녹이고, 1 M 농도의 테트라부틸암모늄 플루오라이드 60 ㎖를 가하여 60 ℃에서 40 분 동안 가열 환류하였다. 반응 혼합물을 농축 후, 농축물을 칼럼크로마토그래피하여 표제 화합물(화학식 8) 6.84 g을 얻었다.This mixed product was dissolved in 500 ml of tetrahydrofuran, and 60 ml of 1 M tetrabutylammonium fluoride was added and heated to reflux for 40 minutes at 60 deg. After the reaction mixture was concentrated, the concentrate was subjected to column chromatography to give 6.84 g of the title compound (Formula 8).

얻어진 화합물을 다시 상온에서 에틸에테르 43 ㎖에 녹이고, 노말 펜탄 480 ㎖를 가하여 0 ℃에서 교반하고, 14 시간 동안 차광된 환경에 방치하였다. 침전물을 여과, 감압 건조하여 순수한 표제 화합물(화학식 8) 5.37(50.3 %) g을 얻었다.The obtained compound was again dissolved in 43 ml of ethyl ether at room temperature, 480 ml of normal pentane was added thereto, stirred at 0 ° C, and left for 14 hours in a shaded environment. The precipitate was filtered off and dried under reduced pressure to give 5.37 g (50.3%) of the title compound (Formula 8).

1H NMR(CDCl3) δ0.57(3H, s), 0.88-0.96(8H, m), 1.15(3H, m), 1.29- 1.36(6H, m), 1.45-1.58(7H, m), 1.68-1.71(2H, m), 1.91-2.07(4H, m), 2.32-2.37(1H, dd), 2.60-2.64(1H, dd), 2.82-2.87(1H, dd), 4.25(1H, m), 4.45(1H, m), 5.02(1H, s), 5.34(1H, s), 6.01-6.05 (1H, d), 6.38-6.42(1H, d) 1 H NMR (CDCl 3 ) δ 0.57 (3H, s), 0.88-0.96 (8H, m), 1.15 (3H, m), 1.29-1.36 (6H, m), 1.45-1.58 (7H, m), 1.68-1.71 (2H, m), 1.91-2.07 (4H, m), 2.32-2.37 (1H, dd), 2.60-2.64 (1H, dd), 2.82-2.87 (1H, dd), 4.25 (1H, m ), 4.45 (1H, m), 5.02 (1H, s), 5.34 (1H, s), 6.01-6.05 (1H, d), 6.38-6.42 (1H, d)

이상에서 살펴 본 바와 같이, 본 발명에 따른 1-α-히드록시콜레칼시페롤 유도체의 제조 방법에서는 종래 기술의 문제점을 해결하기 위하여 비타민 D3와 유사한 화학식 1의 화합물을 출발 물질로 함으로써 반응 단계를 줄이고 부반응을 최소화하는 경제적인 반응 공정을 통해 목적 화합물인 화학식 7 및 화학식 8의 화합물을 높은 수율로 제조할 수 있다.As described above, in the method for preparing a 1-α-hydroxycholecalciferol derivative according to the present invention, in order to solve the problems of the prior art, a reaction step is performed by using a compound of formula 1 similar to vitamin D 3 as a starting material. Through the economic reaction process to reduce the side reaction and minimize side reactions can be prepared in a high yield of the compounds of the general formula (7) and formula (8).

Claims (18)

화학식 1의 화합물을 SO2 가스 존재 하에 디엔을 고리화하여 화학식 2의 화합물을 제조하고;The compound of formula 1 is cyclized to a diene in the presence of SO 2 gas to prepare a compound of formula 2; 화학식 2의 화합물을 t-부틸디메틸실릴 보호기를 갖는 화합물과 반응시켜 화학식 3의 화합물을 제조하고;Reacting a compound of formula 2 with a compound having a t-butyldimethylsilyl protecting group to prepare a compound of formula 3; 화학식 3의 화합물을 탄산칼륨, 탄산수소칼륨, 탄산나트륨 또는 탄산수소나트륨 하에서 환류하여 화학식 4의 화합물을 제조하고;Preparing a compound of formula 4 by refluxing the compound of formula 3 under potassium carbonate, potassium hydrogencarbonate, sodium carbonate or sodium hydrogencarbonate; 화학식 4의 화합물을 N-메틸모폴린-N-옥사이드 촉매 존재 하에서 셀레늄 디옥사이드 또는 셀렌산을 산화제로 사용하여 화학식 5의 화합물을 제조하고;The compound of formula 4 is prepared using selenium dioxide or selenic acid as oxidant in the presence of an N-methylmorpholine-N-oxide catalyst; 화학식 5의 화합물을 에탄올 또는 메탄올과 톨루엔의 혼액에 용해시켜 암소에서 파장 λ=300∼400 ㎚의 빛을 조사하여 이성질화하여 화학식 6의 화합물을 제조하고;Dissolving the compound of Formula 5 in a mixture of ethanol or methanol and toluene and isomerizing it by irradiating with light having a wavelength of λ = 300 to 400 nm in the dark to prepare a compound of Formula 6; 화학식 6의 화합물을 유기용매 중 60 ℃에서 40 분간 가열 환류하여 탈보호화 반응시켜 화학식 7의 화합물을 제조하고;The compound of formula 6 was heated to reflux for 40 minutes at 60 ° C. in an organic solvent to deprotection to prepare a compound of formula 7; 화학식 7의 화합물을 에틸에테르, n-헥산, n-펜탄, 또는 이들의 혼합 용매로 재결정하는 단계를 포함하는, 1-α-히드록시콜레칼시페롤 유도체의 제조 방법.A method for preparing a 1-α-hydroxycholecalciferol derivative, comprising recrystallizing a compound of Formula 7 with ethyl ether, n-hexane, n-pentane, or a mixed solvent thereof. [화학식 1][Formula 1]
Figure 712006003006982-pat00019
Figure 712006003006982-pat00019
 [화학식 2][Formula 2]
Figure 712006003006982-pat00032
Figure 712006003006982-pat00032
 [화학식 3][Formula 3]
Figure 712006003006982-pat00033
Figure 712006003006982-pat00033
 [화학식 4][Formula 4]
Figure 712006003006982-pat00022
Figure 712006003006982-pat00022
 [화학식 5][Formula 5]
Figure 712006003006982-pat00023
Figure 712006003006982-pat00023
 [화학식 6][Formula 6]
Figure 712006003006982-pat00024
Figure 712006003006982-pat00024
 [화학식 7][Formula 7]
Figure 712006003006982-pat00025
Figure 712006003006982-pat00025
 위 화학식에서, R1은 수소, R2는 수소, R3는 이소프로필, 그리고 R4는 t-부틸디메틸실릴기를 나타낸다.In the above formula, R 1 is hydrogen, R 2 is hydrogen, R 3 is isopropyl, and R 4 is t-butyldimethylsilyl group. 제 1 항에 있어서, 화학식 1의 화합물의 고리화 반응은 화학식 1의 화합물을 물과 유기용매의 혼액에 녹인 후, SO2 가스 존재 하에서 교반하여 이루어지는 것을 특징으로 하는 방법.The method according to claim 1, wherein the cyclization reaction of the compound of Formula 1 is performed by dissolving the compound of Formula 1 in a mixture of water and an organic solvent and then stirring in the presence of SO 2 gas. 제 1 항 또는 제 2 항에 있어서, 화학식 1의 화합물의 고리화 반응은 0 내지 40 ℃에서 실시되는 것을 특징으로 하는 방법.The process according to claim 1 or 2, wherein the cyclization reaction of the compound of formula (1) is carried out at 0 to 40 ° C. 제 1 항 또는 제 2 항에 있어서, 화학식 1의 화합물의 고리화 반응 후 잔존하는 이산화황을 비활성 기체를 폭기하여 제거하는 단계를 더욱 포함하는 것을 특징으로 하는 방법.The process according to claim 1 or 2, further comprising aeration of the sulfur dioxide remaining after the cyclization of the compound of formula (1). 제 1 항에 있어서, 화학식 2의 화합물과 t-부틸디메틸실릴 보호기를 갖는 화합물과의 반응이 염기의 존재 하에 유기용매 중에서 진행되는 것을 특징으로 하는 방법.A process according to claim 1, wherein the reaction of the compound of formula (2) with a compound having a t-butyldimethylsilyl protecting group proceeds in an organic solvent in the presence of a base. 삭제delete 제 1 항에 있어서, 화학식 2의 화합물과 t-부틸디메틸실릴 보호기를 갖는 화합물과의 반응이 산 촉매 중에서 진행되는 것을 특징으로 하는 방법.A process according to claim 1, wherein the reaction of the compound of formula (2) with a compound having a t-butyldimethylsilyl protecting group proceeds in an acid catalyst. 제 1 항 또는 제 7 항에 있어서, 화학식 2의 화합물과 t-부틸디메틸실릴 보호기를 갖는 화합물과의 반응이, 화학식 2의 화합물을 메틸렌클로라이드 또는 클로로포름 중에서 무수 염산, P-톨루엔 술폰산, 또는 피리디늄 P-톨루엔 술폰산 존재 하에 디히드로피란 또는 에틸비닐에테르과 반응시키는 것임을 특징으로 하는 방법.The reaction of the compound of formula (2) with a compound having a t-butyldimethylsilyl protecting group according to claim 1 or 7, wherein the compound of formula (2) is reacted with hydrochloric anhydride, P-toluene sulfonic acid, or pyridinium in methylene chloride or chloroform. Reacting with dihydropyran or ethylvinylether in the presence of P-toluene sulfonic acid. 제 1 항에 있어서, 화학식 2의 화합물과 t-부틸디메틸실릴 보호기를 갖는 화합물과의 반응이 0 내지 40 ℃에서 진행되는 것을 특징으로 하는 방법.The method of claim 1, wherein the reaction of the compound of Formula 2 with a compound having a t-butyldimethylsilyl protecting group proceeds at 0 to 40 ° C. 제 1 항에 있어서, 화학식 3의 화합물로부터 화학식 4의 화합물을 제조하는 반응이 알코올 용매 단독 또는 혼액 중 60 내지 100 ℃에서 진행되는 것을 특징으로 하는 방법.The method of claim 1, wherein the reaction for preparing the compound of formula 4 from the compound of formula 3 is carried out at 60-100 ° C. in alcohol solvent alone or in a mixture. 삭제delete 제 1 항에 있어서, 화학식 4의 화합물의 산화가 유기용매 중 60 내지 100 ℃에서 진행되는 것을 특징으로 하는 방법.The method of claim 1, wherein the oxidation of the compound of formula 4 is carried out at 60 to 100 ℃ in an organic solvent. 삭제delete 제 1 항에 있어서, 화학식 5의 화합물의 이성질화 반응 지시약으로 안트라센을 사용하는 것을 특징으로 하는 방법.The method of claim 1, wherein anthracene is used as an indicator for isomerization of the compound of formula (5). 제 1 항에 있어서, 화학식 5의 화합물의 이성질화 반응에 유기 또는 무기 염기가 0.01 내지 0.5 당량의 양으로 첨가되는 것을 특징으로 하는 방법.A process according to claim 1, wherein an organic or inorganic base is added to the isomerization of the compound of formula 5 in an amount of 0.01 to 0.5 equivalents. 제 1 항에 있어서, 화학식 5의 화합물의 이성질화 반응이 0 내지 40 ℃에서 진행되는 것을 특징으로 하는 방법.The method of claim 1, wherein the isomerization reaction of the compound of formula 5 is carried out at 0 to 40 ℃. 제 1 항에 있어서, 화학식 6의 화합물의 탈보호화 반응 시약으로 p-톨루엔술폰산(p-TsOH), 염화수소(HCl, gas), n-테트라부틸암모늄 플루오라이드(nBu4NF) 또는 암모늄 플루오라이드(NH4F)가 사용되는 것을 특징으로 하는 방법.The deprotection reaction reagent of the compound of formula 6, wherein p-toluenesulfonic acid (p-TsOH), hydrogen chloride (HCl, gas), n-tetrabutylammonium fluoride (nBu 4 NF) or ammonium fluoride ( NH 4 F) is used. 삭제delete
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