JP4319292B2 - Method for producing tert-butoxycarbonyl chloride - Google Patents

Description

（式中、Ｒ¹はハロゲン原子もしくはＣ₂〜Ｃ₄アルキルを表し、Ｒ²は水素原子、メチル基、エチル基を表す。）で表されるピリジン類の存在下、-40〜0℃で反応させる事を特徴とするtert-ブトキシカルボニルクロリドの製造方法である。
また、０℃以下で反応液を水で洗浄する事を特徴とするtert-ブトキシカルボニルクロリドの製造方法である。
また、上記方法で得られたtert-ブトキシカルボニルクロリドをもちいることを特徴とするアミン類、アミノ酸類、およびアルコール類のBOC化方法である。
【０００６】
【発明の実施の形態】
Ｒ¹としては、フッ素原子、塩素原子、臭素原子等のハロゲン原子、
エチル、プロピル、イソプロピル、ブチル、イソブチル、tert-ブチル等のアルキル基が挙げられる。
本発明に使用されるピリジン類としては、具体的に２-エチルピリジン、５-エチル-２-ピコリンが挙げられる。
ベンゼン系溶媒としては、置換されていてもよいベンゼン、たとえばベンゼン、トルエン、キシレンが挙げられるがトルエンが好ましい。
反応のモル比は、tert-ブタノール１モルに対し、ホスゲン0.7〜1.5モルであり、より好ましくは0.9〜1.1 モルである。塩基は1.0〜3.0モル、好ましくは1.1〜1.3モルである。
反応温度については、-40〜0℃、好ましくは-25〜-5℃であり、その後反応の熟成を-20〜-5℃で行うと、比較的短い時間で反応を行う事が出来る。この際、温度が0℃より高くなると、BOC-クロリドが分解し、収率の低下をきたすため、好ましくない。
【０００７】
反応は tert-ブチルアルコールとホスゲンをベンゼン系溶媒に溶解し、ベンゼン系溶媒に溶解したピリジン類を滴下させ、熟成する事により行われる。
【０００８】
反応中に生じた塩基の塩酸塩は、濾別して取り除くこともできるが、工程の短縮、塩基の回収の効率上、０℃以下で水を反応溶媒に対して０．０５〜１００倍、好ましくは０．１〜１倍加え、水層を分離することによって、反応溶媒から取り除く方が有利である。水層中の塩基は、水分を除くことで再利用可能である。
【０００９】
こうして得られたベンゼン系溶媒中のBOC-クロリドは溶媒とともに、農医薬中間体等の有機中間体の保護基として使用することが出来る。
該有機中間体としてはアミン類、アミノ酸類あるいはアルコール類が挙げられ、
アミン類としては、3−ヒドロキシピロリジン、ピペラジン誘導体、アミノチアゾリルペンテン酸等、
アミノ酸としては、アラニン、フェニルアラニン、トリプトファン、グルタミン酸、バリン、4-ヒドロキシプロリン、3-ヒドロキシピロリジン、アミノフェニル酪酸等、
アルコール類としては、フェノール等のフェノール系アルコールが挙げられる。
【００１０】
【実施例】
以下に実施例を挙げ本発明を詳細に説明する。生成物についてはＭＳ、ＮＭＲ、ＨＰＬＣで同定、定量を行った。
【００１１】
比較例１（BOC-クロリドの製造）
ホスゲン20g(0.2mol)をtert-ブチルアルコール16.5g(0.22mol)含有トルエン溶液200mlに吹き込み、-20℃に冷却撹拌下、２-ピコリン19.0g(0.24mol)含有トルエン溶液60gを約１時間かけ、徐々に滴下した。その後、温度を-10℃まで上げ、ホスゲンが消失するまで約５時間熟成撹拌した。反応終了後、副生したピリジン塩酸塩を濾別して少量のトルエンで洗浄し、BOC-クロリドのトルエン溶液を収率50%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
【００１２】
実施例１（BOC-クロリドの製造）
ホスゲン16.6g(0.168mol)をtert-ブチルアルコール11.9g(0.16mol)含有トルエン溶液160mlに吹き込み、-20℃に冷却撹拌下、５-エチル-２-ピコリン23.3g(0.192mol)含有トルエン溶液50gを約１時間かけ、徐々に滴下した。その後、温度を-10℃まで上げ、ホスゲンが消失するまで約２時間熟成撹拌した。反応終了後、副生したピリジン塩酸塩を濾別して少量のトルエンで洗浄し、BOC-クロリドのトルエン溶液を収率88%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
【００１３】
実施例２（BOC-クロリドの製造）
ホスゲン16.6g(0.168mol)をtert-ブチルアルコール11.9g(0.16mol)含有メシチレン溶液160mlに吹き込み、-20℃に冷却撹拌下、５-エチル-２-ピコリン23.3g(0.192mol)含有メシチレン溶液50gを約１時間かけ、徐々に滴下した。その後、温度を-10℃まで上げ、ホスゲンが消失するまで約２時間熟成撹拌した。反応終了後、副生したピリジン塩酸塩を濾別して少量のメシチレンで洗浄し、BOC-クロリドのメシチレン溶液を収率84%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
【００１４】
実施例３（BOC-クロリドの製造）
ホスゲン31.2g(0.315mol)をtert-ブチルアルコール22.2g(0.30mol)含有トルエン溶液300mlに吹き込み、-20℃に冷却撹拌下、５-エチル-２-ピコリン43.6g(0.360mol)含有トルエン溶液50gを約１時間かけ、徐々に滴下した。その後、-20℃で熟成を行い、ホスゲンが消失するまで約４時間熟成撹拌した。反応終了後、副生したピリジン塩酸塩を濾別して少量のトルエンで洗浄し、BOC-クロリドのトルエン溶液を収率90%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
【００１５】
実施例４（BOC-クロリドの製造）
ホスゲン15.9g(0.16mol)をtert-ブチルアルコール11.9g(0.16mol)含有トルエン溶液160mlに吹き込み、-20℃に冷却撹拌下、２-エチルピリジン 20.6g(0.192mol)含有トルエン溶液50gを約１時間かけ、徐々に滴下した。その後、温度を-10℃まで上げ、ホスゲンが消失するまで約３時間熟成撹拌した。反応終了後、副生したピリジン塩酸塩を濾別して少量のトルエンで洗浄した。BOC-クロリドのトルエン溶液を収率91%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
【００１６】
実施例５（BOC-クロリドの製造（水による塩基の除去））
ホスゲン31.2g(0.315mol)をtert-ブチルアルコール22.2g(0.30mol)含有トルエン溶液200mlに吹き込み、-5〜0℃（主に‐3℃）に冷却撹拌下、５-エチル-２-ピコリン43.6g(0.36mol)含有トルエン溶液78gを約１時間かけ、徐々に滴下した。その後、-5〜0℃（主に-2℃）で熟成を行い、ホスゲンが消失するまで約3時間熟成撹拌した。反応終了後、0℃に冷却下、冷却した水20mlを投入し、5分間攪拌すると副生した5-エチル-2-ピコリン塩酸塩が溶解する。5分間静置後、二層に分液し水層を分離する事で、ボッククロリドのトルエン溶液240.1g(21.0wt%)を収率80%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
また水層は28%苛性ソーダ水溶液55gを加え、アルカリ性(pH 13.7)にすると、二層に分液し、水層を分離する事で、回収5-エチル-2-ピコリン48.1g(純分87.5wt%、水分10.0wt%、トルエン2.5wt%)を回収率96.5%で得た。得られた回収5-エチル-2-ピコリンは共沸脱水により水分を除く事で再利用可能である。
【００１７】
実施例６（BOC-クロリドの製造（水による塩基の除去））
ホスゲン29.7g(0.30mol)をtert-ブチルアルコール22.2g(0.30mol)含有トルエン溶液200mlに吹き込み、-5〜0℃（主に‐2℃）に冷却撹拌下、2-エチルピリジン35.4g(0.33mol)含有トルエン溶液70gを約１時間かけ、徐々に滴下した。その後、-5〜0℃（主に-1℃）で熟成を行い、ホスゲンが消失するまで約3時間熟成撹拌した。反応終了後、0℃に冷却下、冷却した水20mlを投入し、5分間攪拌すると副生した2-エチルピリジン塩酸塩が溶解する。5分間静置後、二層に分液した水層を分離する事で、ボッククロリドのトルエン溶液239.2g(22.1wt%)を収率85%（対tert-ブタノール）で得た。保存は-20℃のフリーザー中で行った。
また水層は28%苛性ソーダ水溶液51gを加え、アルカリ性(pH 13.8)にすると、二層に分液し、水層を分離する事で、回収2-エチルピリジン38.9g(純分84.9wt%、水分14.1wt%、トルエン0.9wt%)を回収率93.3%で得た。また水層をトルエン20mlで再抽出する事で回収率は96.3%まで向上した。得られた回収2-エチルピリジンは共沸脱水により水分を除く事で再利用可能である。
【００１８】
実施例７（N-tert-ブトキシカルボニル-4-ヒドロキシプロリンの製造）
4-ヒドロキシプロリン3.9g(30mmol)を水30mlに溶解し、0℃に冷却攪拌下、ボッククロリドトルエン溶液31.5g(15.6wt%, 36mmol)を添加する。次に0℃で28%NaOH水溶液9.4g(66mmol)を約1時間かけて滴下し、0℃で3時間熟成攪拌した。反応液についてHPLC分析を行なうと、N-tert-ブトキシカルボニル-4-ヒドロキシプロリンの生成率は86.2%であった。反応終了後、反応液を分液し、得られた水層(pH8)は10%KHSO₄35mlを用いてpH2.5とする。この水溶液は酢酸エチル（計400ml）を用いて3回抽出し、得られた酢酸エチル層は硫酸マグネシウムにより脱水し、ろ過、濃縮した。濃縮液はヘキサン30mlを加え攪拌する事で結晶化した。得られた結晶はろ過し、30℃で3時間ポンプ乾燥する事でN-tert-ブトキシカルボニル-4-ヒドロキシプロリン5.6g(純度99.6%、m.p.124-125℃)、収率81%で得た。
【００１９】
実施例８（N-tert-ブトキシカルボニル-4-ヒドロキシプロリンの製造）
4-ヒドロキシプロリン3.9g(30mmol)を水30mlに溶解し、8%NaOH水溶液33.0g(66mmol) を添加する。次に0℃に冷却攪拌下、ボッククロリドトルエン溶液31.7g(15.5wt%, 36mmol)を20分かけて滴下し、0℃で3時間熟成攪拌した。反応液についてHPLC分析を行なうと、N-tert-ブトキシカルボニル-4-ヒドロキシプロリンの生成率は75.1%であった。反応終了後、反応液を分液し、得られた水層(PH8)は10%KHSO₄35mlを用いてPH2.5とする。この水溶液は酢酸エチル（計400ml）を用いて3回抽出し、得られた酢酸エチル層は硫酸マグネシウムにより脱水し、ろ過、濃縮した。濃縮液はヘキサン30mlを加え攪拌する事で結晶化した。得られた結晶はろ過し、30℃で3時間ポンプ乾燥する事でN-tert-ブトキシカルボニル-4-ヒドロキシプロリン4.9g(純度99.7%、m.p.124-125℃)、収率70%で得た。
【００２０】
実施例９（N-tert-ブトキシカルボニル-3-ヒドロキシピロリジンの製造）
4-ヒドロキシプロリン13.1g(100mmol)とメシチルオキシド0.49g(5mmol)をジグライム50mlに混和し、窒素気流下、155℃で4時間加熱還流を行なう。得られた反応液はウイドマー型精留管を用い、ジグライムを蒸留回収する（0.4KPa / 30〜35℃）。この3-ヒドロキシピロリジンが主成分である残留物に28%NaOH水溶液14.3g(100mmol)を添加し、4〜6℃に冷却攪拌下、ボッククロリドトルエン溶液93.4g(19.0wt%, 130mmol)を15分かけて滴下し、4〜6℃で3時間熟成攪拌した。反応終了後、反応液を分液し、得られたトルエン層は濃縮し、アイソパーG 50mlを加え攪拌する事で結晶化した。得られた結晶はろ過し、室温で3時間減圧乾燥する事で、N-tert-ブトキシカルボニル-3-ヒドロキシピロリジン16.1g(純度99.5%、m.p.62-63℃)を4-ヒドロキシプロリンより収率86%で得た。
【００２１】
実施例１０（N-tert-ブトキシカルボニル-3-ヒドロキシピロリジンの製造）
4-ヒドロキシプロリン26.2g(200mmol)とメシチルオキシド0.98g(10mmol)をジグライム90mlに混和し、窒素気流下、150℃で4時間加熱還流を行なう。得られた反応液を0℃に冷却し、塩酸ガスで飽和したイソプロパノール溶液10mlを滴下すると塩が析出し、これをろ過、ポンプ乾燥する事で3-ヒドロキシピロリジン塩酸塩（22.97g、収率93.8%）を得た。
この3-ヒドロキシピロリジン塩酸塩の半量11.48g(983mmol)に4〜6℃で、28%NaOH水溶液28.0g(196mmol)を添加し、4〜6℃に冷却攪拌下、ボッククロリドトルエン溶液116.0g(15.3wt%, 130mmol)を15分かけて滴下し、4〜6℃で3時間熟成攪拌した。反応終了後、反応液を分液し、得られたトルエン層は濃縮した。この濃縮液にアイソパーG 50mlを加え攪拌する事で結晶化した。得られた結晶はろ過し、室温で3時間減圧乾燥する事で、N-tert-ブトキシカルボニル-3-ヒドロキシピロリジン15.3g(純度99.7%、m.p.61-62℃)を4-ヒドロキシプロリンより収率81.9%で得た。
【００２２】
【発明の効果】
本発明によれば、短時間、高収率でBOC-クロリドを製造する事が出来、またベンゼン系の溶媒を用いるため工業的規模でのBOC-クロリドの製造方法に適している。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing tert-butoxycarbonyl chloride (BOC-chloride), which is often used as a protecting group in the synthesis of organic compounds such as agricultural pharmaceutical intermediates, and also relates to a method for producing an organic intermediate using the same. .
[0002]
[Prior art]
Conventionally, BOC-chloride is produced by using tert-butyl alcohol and phosgene in an ether solvent, pyridine or 2- or 3-picoline as a base, a reaction temperature of -25 to -15 ° C, and an aging temperature of -15. A method of obtaining BOC-chloride in a yield of 80 to 85% by carrying out at -5 ° C (JP-A-10-114715) is known.
[0003]
[Problems to be solved by the invention]
When BOC is introduced as a protective group for an agricultural pharmaceutical intermediate, BOC ₂ O is used. However, since BOC ₂ O is expensive, a method capable of forming BOC at a lower cost has been demanded.
The production method of BOC-chloride with ether solvent is known, but since it is industrially dangerous and difficult to recover with ether solvent, BOC in a more industrially advantageous solvent (for example, toluene etc.) -Chloride synthesis was desired. However, it was found that when pyridine or 2- or 3-picoline described in JP-A-10-114715 was used as a base, the yield of BOC-chloride was significantly reduced in a toluene solvent.
[0004]
[Means for Solving the Problems]
As a result of examining the above problems in detail, the present inventors have found out the conditions under which a target product can be easily obtained with a yield equivalent to or higher than that in the past even when using an industrially easy-to-use benzene solvent. It came to be completed.
[0005]
That is, the present invention relates to tert-butyl alcohol and phosgene in a benzene solvent with the formula [I]
[Formula 4]

(Wherein R ¹ represents a halogen atom or C _{2 to} C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group, or an ethyl group) in the presence of pyridines represented by −40 to 0 ° C. A method for producing tert-butoxycarbonyl chloride, characterized by reacting.
Further, the present invention is a method for producing tert-butoxycarbonyl chloride, wherein the reaction solution is washed with water at 0 ° C. or lower.
Further, the present invention is also a method for BOC formation of amines, amino acids, and alcohols characterized by using tert-butoxycarbonyl chloride obtained by the above method.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
R ¹ is a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom,
Alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like can be mentioned.
Specific examples of pyridines used in the present invention include 2-ethylpyridine and 5-ethyl-2-picoline.
Examples of the benzene-based solvent include optionally substituted benzene, such as benzene, toluene, and xylene, with toluene being preferred.
The molar ratio of the reaction is 0.7 to 1.5 moles of phosgene, more preferably 0.9 to 1.1 moles per mole of tert-butanol. The base is 1.0 to 3.0 mol, preferably 1.1 to 1.3 mol.
The reaction temperature is −40 to 0 ° C., preferably −25 to −5 ° C. If the reaction is then aged at −20 to −5 ° C., the reaction can be performed in a relatively short time. At this time, if the temperature is higher than 0 ° C., BOC-chloride is decomposed and the yield is lowered, which is not preferable.
[0007]
The reaction is carried out by dissolving tert-butyl alcohol and phosgene in a benzene solvent, dropping pyridines dissolved in the benzene solvent, and aging.
[0008]
The hydrochloride of the base generated during the reaction can be removed by filtration. However, in terms of shortening the process and recovering the base, water is 0.05 to 100 times the reaction solvent at 0 ° C. or less, preferably It is advantageous to remove from the reaction solvent by adding 0.1 to 1 times and separating the aqueous layer. The base in the aqueous layer can be reused by removing moisture.
[0009]
The BOC-chloride in the benzene solvent thus obtained can be used together with the solvent as a protective group for organic intermediates such as agricultural pharmaceutical intermediates.
Examples of the organic intermediate include amines, amino acids, and alcohols.
Examples of amines include 3-hydroxypyrrolidine, piperazine derivatives, aminothiazolylpentenoic acid,
As amino acids, alanine, phenylalanine, tryptophan, glutamic acid, valine, 4-hydroxyproline, 3-hydroxypyrrolidine, aminophenylbutyric acid, etc.
Examples of alcohols include phenolic alcohols such as phenol.
[0010]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples. The product was identified and quantified by MS, NMR, and HPLC.
[0011]
Comparative Example 1 (Production of BOC-chloride)
20 g (0.2 mol) of phosgene was blown into 200 ml of toluene solution containing 16.5 g (0.22 mol) of tert-butyl alcohol, and 60 g of toluene solution containing 19.0 g (0.24 mol) of 2-picoline was cooled to -20 ° C over about 1 hour. , Gradually dropped. Thereafter, the temperature was raised to −10 ° C., and the mixture was aged and stirred for about 5 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene to obtain a toluene solution of BOC-chloride in a yield of 50% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
[0012]
Example 1 (Production of BOC-chloride)
16.6 g (0.168 mol) of phosgene was blown into 160 ml of toluene solution containing 11.9 g (0.16 mol) of tert-butyl alcohol, and 50 g of toluene solution containing 23.3 g (0.192 mol) of 5-ethyl-2-picoline was cooled and stirred at -20 ° C. Was gradually added dropwise over about 1 hour. Thereafter, the temperature was raised to −10 ° C., and the mixture was aged and stirred for about 2 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was separated by filtration and washed with a small amount of toluene to obtain a BOC-chloride toluene solution in a yield of 88% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
[0013]
Example 2 (Production of BOC-chloride)
16.6 g (0.168 mol) of phosgene was blown into 160 ml of mesitylene solution containing 11.9 g (0.16 mol) of tert-butyl alcohol, and 50 g of mesitylene solution containing 23.3 g (0.192 mol) of 5-ethyl-2-picoline was cooled to -20 ° C and stirred. Was gradually added dropwise over about 1 hour. Thereafter, the temperature was raised to −10 ° C., and the mixture was aged and stirred for about 2 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was filtered off and washed with a small amount of mesitylene to obtain a mesitylene solution of BOC-chloride in a yield of 84% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
[0014]
Example 3 (Production of BOC-chloride)
31.2 g (0.315 mol) of phosgene was blown into 300 ml of a toluene solution containing 22.2 g (0.30 mol) of tert-butyl alcohol, and 50 g of toluene solution containing 43.6 g (0.360 mol) of 5-ethyl-2-picoline was cooled and stirred at −20 ° C. Was gradually added dropwise over about 1 hour. Thereafter, aging was carried out at −20 ° C., and the mixture was aged and stirred for about 4 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene to obtain a toluene solution of BOC-chloride in a yield of 90% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
[0015]
Example 4 (Production of BOC-chloride)
15.9 g (0.16 mol) of phosgene was blown into 160 ml of toluene solution containing 11.9 g (0.16 mol) of tert-butyl alcohol, and about 1 of 50 g of toluene solution containing 20.6 g (0.192 mol) of 2-ethylpyridine was cooled and stirred at -20 ° C. It was gradually added dropwise over time. Thereafter, the temperature was raised to −10 ° C., and the mixture was aged and stirred for about 3 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene. A toluene solution of BOC-chloride was obtained in 91% yield (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
[0016]
Example 5 (Production of BOC-chloride (removal of base with water))
31.2 g (0.315 mol) of phosgene was blown into 200 ml of a toluene solution containing 22.2 g (0.30 mol) of tert-butyl alcohol, and cooled to -5 to 0 ° C. (mainly −3 ° C.) with stirring and 5-ethyl-2-picoline 43.6 78 g of toluene solution containing g (0.36 mol) was gradually added dropwise over about 1 hour. Thereafter, aging was performed at −5 to 0 ° C. (mainly −2 ° C.), and the mixture was aged and stirred for about 3 hours until phosgene disappeared. After completion of the reaction, with cooling to 0 ° C., 20 ml of cooled water is added and stirred for 5 minutes to dissolve by-produced 5-ethyl-2-picoline hydrochloride. After standing for 5 minutes, the solution was separated into two layers and the aqueous layer was separated to obtain 240.1 g (21.0 wt%) of a toluene solution of box chloride in a yield of 80% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
The aqueous layer is 55% of 28% sodium hydroxide aqueous solution and made alkaline (pH 13.7), and it is separated into two layers, and the aqueous layer is separated to recover 48.1 g of recovered 5-ethyl-2-picoline (pure 87.5 wt. %, Moisture 10.0 wt%, toluene 2.5 wt%) was obtained at a recovery rate of 96.5%. The obtained recovered 5-ethyl-2-picoline can be reused by removing water by azeotropic dehydration.
[0017]
Example 6 (Production of BOC-chloride (removal of base with water))
29.7 g (0.30 mol) of phosgene was blown into 200 ml of a toluene solution containing 22.2 g (0.30 mol) of tert-butyl alcohol, and 35.4 g (0.33 of 2-ethylpyridine) was cooled and stirred at -5 to 0 ° C (mainly -2 ° C). mol) -containing toluene solution (70 g) was gradually added dropwise over about 1 hour. Thereafter, aging was performed at -5 to 0 ° C (mainly -1 ° C), and the mixture was aged and stirred for about 3 hours until phosgene disappeared. After completion of the reaction, 20 ml of cooled water is added while cooling to 0 ° C., and stirred for 5 minutes to dissolve the by-produced 2-ethylpyridine hydrochloride. After standing for 5 minutes, the aqueous layer separated into two layers was separated to obtain 239.2 g (22.1 wt%) of a toluene solution of box chloride in a yield of 85% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.
In addition, the aqueous layer is made alkaline (pH 13.8) by adding 51 g of 28% caustic soda aqueous solution, and it is separated into two layers, and the aqueous layer is separated to recover 38.9 g of recovered 2-ethylpyridine (pure content 84.9 wt%, moisture 14.1 wt%, toluene 0.9 wt%) was obtained with a recovery rate of 93.3%. The recovery rate was improved to 96.3% by re-extracting the aqueous layer with 20 ml of toluene. The obtained recovered 2-ethylpyridine can be reused by removing water by azeotropic dehydration.
[0018]
Example 7 (Production of N-tert-butoxycarbonyl-4-hydroxyproline)
3.9 g (30 mmol) of 4-hydroxyproline is dissolved in 30 ml of water, and 31.5 g (15.6 wt%, 36 mmol) of a box chloride toluene solution is added with cooling and stirring at 0 ° C. Next, 9.4 g (66 mmol) of 28% NaOH aqueous solution was added dropwise at 0 ° C. over about 1 hour, and the mixture was aged and stirred at 0 ° C. for 3 hours. When the reaction mixture was analyzed by HPLC, the production rate of N-tert-butoxycarbonyl-4-hydroxyproline was 86.2%. After completion of the reaction, the reaction solution is separated, and the resulting aqueous layer (pH 8) is adjusted to pH 2.5 using 35 ml of 10% KHSO ₄ . This aqueous solution was extracted three times with ethyl acetate (total 400 ml), and the resulting ethyl acetate layer was dehydrated with magnesium sulfate, filtered and concentrated. The concentrate was crystallized by adding 30 ml of hexane and stirring. The obtained crystals were filtered and pump-dried at 30 ° C. for 3 hours to obtain 5.6 g of N-tert-butoxycarbonyl-4-hydroxyproline (purity 99.6%, mp 124-125 ° C.) in a yield of 81%.
[0019]
Example 8 (Production of N-tert-butoxycarbonyl-4-hydroxyproline)
3.9 g (30 mmol) of 4-hydroxyproline is dissolved in 30 ml of water, and 33.0 g (66 mmol) of 8% NaOH aqueous solution is added. Next, 31.7 g (15.5 wt%, 36 mmol) of a box chloride toluene solution was added dropwise over 20 minutes with stirring at 0 ° C., and the mixture was aged and stirred at 0 ° C. for 3 hours. When the reaction mixture was analyzed by HPLC, the production rate of N-tert-butoxycarbonyl-4-hydroxyproline was 75.1%. After completion of the reaction, the reaction solution is separated, and the obtained aqueous layer (PH8) is adjusted to PH2.5 using 35 ml of 10% KHSO ₄ . This aqueous solution was extracted three times with ethyl acetate (total 400 ml), and the resulting ethyl acetate layer was dehydrated with magnesium sulfate, filtered and concentrated. The concentrate was crystallized by adding 30 ml of hexane and stirring. The obtained crystals were filtered and pump-dried at 30 ° C. for 3 hours to obtain 4.9 g of N-tert-butoxycarbonyl-4-hydroxyproline (purity 99.7%, mp 124-125 ° C.) in a yield of 70%.
[0020]
Example 9 (Production of N-tert-butoxycarbonyl-3-hydroxypyrrolidine)
14.1 g (100 mmol) of 4-hydroxyproline and 0.49 g (5 mmol) of mesityl oxide are mixed with 50 ml of diglyme and heated under reflux at 155 ° C. for 4 hours under a nitrogen stream. The resulting reaction solution is recovered by distillation using a Widmer type rectification tube (0.4 KPa / 30 to 35 ° C.). To this residue containing 3-hydroxypyrrolidine as a main component, 14.3 g (100 mmol) of a 28% NaOH aqueous solution was added, and 93.4 g (19.0 wt%, 130 mmol) of a box chloride toluene solution was added to the mixture at 4 to 6 ° C. with cooling and stirring. The solution was added dropwise over a period of time, and aged and stirred at 4 to 6 ° C. for 3 hours. After completion of the reaction, the reaction solution was separated, and the resulting toluene layer was concentrated and crystallized by adding 50 ml of Isopar G and stirring. The obtained crystals were filtered and dried under reduced pressure at room temperature for 3 hours to obtain 16.1 g of N-tert-butoxycarbonyl-3-hydroxypyrrolidine (purity 99.5%, mp 62-63 ° C.) from 4-hydroxyproline in a yield of 86. Obtained in%.
[0021]
Example 10 (Production of N-tert-butoxycarbonyl-3-hydroxypyrrolidine)
4-Hydroxyproline (26.2 g, 200 mmol) and mesityl oxide (0.98 g, 10 mmol) are mixed with 90 ml of diglyme, and heated under reflux at 150 ° C. for 4 hours under a nitrogen stream. The obtained reaction solution was cooled to 0 ° C., and 10 ml of an isopropanol solution saturated with hydrochloric acid gas was added dropwise to precipitate a salt, which was filtered and pump-dried to give 3-hydroxypyrrolidine hydrochloride (22.97 g, yield 93.8). %).
Half of 11.48 g (983 mmol) of 3-hydroxypyrrolidine hydrochloride was added at 4-6 ° C., 28.0 g (196 mmol) of 28% NaOH aqueous solution was added, and cooled to 4-6 ° C., 116.0 g of bock chloride toluene solution ( 15.3 wt%, 130 mmol) was added dropwise over 15 minutes, and the mixture was aged and stirred at 4-6 ° C. for 3 hours. After completion of the reaction, the reaction solution was separated, and the resulting toluene layer was concentrated. The concentrated solution was crystallized by adding 50 ml of Isopar G and stirring. The obtained crystals were filtered and dried under reduced pressure at room temperature for 3 hours to obtain 15.3 g of N-tert-butoxycarbonyl-3-hydroxypyrrolidine (purity 99.7%, mp 61-62 ° C.) from 4-hydroxyproline in a yield of 81.9. Obtained in%.
[0022]
【The invention's effect】
According to the present invention, BOC-chloride can be produced in a high yield in a short time, and since a benzene-based solvent is used, it is suitable for a production method of BOC-chloride on an industrial scale.

Claims (3)

tert-Butyl alcohol and phosgene in a benzene-based solvent selected from benzene, toluene and xylene in the formula [I]

(In the formula, R ¹ represents C _{2 to} C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group or an ethyl group) and is reacted at −40 to 0 ° C. in the presence of pyridines. A method for producing tert-butoxycarbonyl chloride, which is characterized. tert-Butyl alcohol and phosgene in a benzene-based solvent selected from benzene, toluene and xylene in the formula [I]

(Wherein R ¹ represents C _{2 to} C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group or an ethyl group) and is reacted at −40 to 0 ° C. in the presence of pyridines. A method for producing tert-butoxycarbonyl chloride, characterized in that the reaction solution is washed with water at 0 ° C. or lower. The method for producing tert-butoxycarbonyl chloride according to claim 1 or 2, wherein the pyridine is 5-ethyl-2-picoline or 2-ethylpyridine.