JP5305421B2 - ジアミン誘導体の製造方法 - Google Patents
ジアミン誘導体の製造方法 Download PDFInfo
- Publication number
- JP5305421B2 JP5305421B2 JP2010542969A JP2010542969A JP5305421B2 JP 5305421 B2 JP5305421 B2 JP 5305421B2 JP 2010542969 A JP2010542969 A JP 2010542969A JP 2010542969 A JP2010542969 A JP 2010542969A JP 5305421 B2 JP5305421 B2 JP 5305421B2
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- Prior art keywords
- toluenesulfonic acid
- compound
- molar equivalent
- acid monohydrate
- added
- Prior art date
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- 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
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Description
[1](a)溶媒中、式(B)
(b)冷却下で、当該混合液にp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物を追加する工程であって、
ここで、該追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物は、工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物との総モル当量が、工程(a)の式(B)で表される化合物に対して1モル当量以上になるような量で追加され、次いで、
(c)晶析することにより式(A)
を包含する、式(A)で表される化合物の製造方法;
[2] 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物が、式(B)で表される化合物に対して0.5モル当量以上1.0モル当量未満である、[1]に記載の方法;
[3] 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物が、式(B)で表される化合物に対して0.8モル当量以上1.0モル当量未満である、[1]または[2]に記載の方法;
[4] 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物と工程(b)で追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物の総モル当量が、工程(a)の式(B)で表される化合物に対して1.0モル当量以上3.0モル当量以下である、[1]〜[3]のいずれか1に記載の方法;
[5] 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物と工程(b)で追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物の総モル当量が、工程(a)の式(B)で表される化合物に対して1.0モル当量以上1.2モル当量以下である、[1]〜[4]のいずれか1に記載の方法;
[6] 溶媒が、アルコールまたは含水アルコールである、[1]〜[5]のいずれか1に記載の方法;
[7] 溶媒が、含水エタノールである、[1]〜[6]のいずれか1に記載の方法;
[8] 含水エタノールの含水率が、0%超50%以下である、[1]〜[7]のいずれか1に記載の方法;
[9] p−トルエンスルホン酸 一水和物を用いる、[1]〜[8]のいずれか1に記載の方法;
[10] 溶媒の量が、化合物Bに対して5倍〜30倍(V/W)である、[1]〜[9]のいずれか1に記載の方法;
[11] 工程(a)の加温温度が60℃〜80℃である、[1]〜[10]のいずれか1に記載の方法;
[12] 工程(b)の冷却温度が−20℃〜40℃である、[1]〜[11]のいずれか1に記載の方法、
に関する。
化合物Bは、特許文献1〜8に記載の方法に準じて合成した。
N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド(150g)、エタノール(735ml)、水(315ml)の混液にTsOH・H2O(49.5g)を加えて70℃に加熱した。溶解液をフィルター濾過し、フィルターを15%含水エタノール(300ml)とエタノール(150ml)で洗浄した。次いで濾過母液と洗浄液の混液を徐冷し、TsOH・H2O(7.8g)とエタノール(2100ml)を加えた。10℃で1時間攪拌後、結晶を濾取し、標題化合物を188.9g得た。
化合物Aを晶析する条件(含水率10%のエタノール、10℃)においてTsOH・H2Oの量を変動させた場合の、化合物Aの溶解度を測定した。具体的には、含水率10%のエタノール10mlに化合物A、化合物BまたはTsOH・H2Oを以下の組み合わせで加えて、10℃でスラリー攪拌し、結晶を濾取した後の濾過母液に含まれる化合物Aの含量をHPLC(カラム:Shiseido CAPCELL PAK CN UG120(4.6×250mm)、カラム温度:40℃、流速:1.0ml/min.、移動相:アセトニトリル:0.02M リン酸緩衝液(pH 7.0)=30:70)で測定した。
化合物Bを溶媒に溶解する条件(含水率30%のエタノール、70℃)においてTsOH・H2Oの量を変動させた場合の、化合物Bの安定性を測定した。具体的には、化合物B 1.0gに含水率30%のエタノール7mlとTsOH・H2Oを以下の組み合わせで加え、70℃で溶解させ、一定時間毎に化合物Bの含量をHPLC「カラム:Shiseido CAPCELL PAK CN UG120(4.6×250mm)、カラム温度:40℃、流速:1.0ml/min.、移動相:アセトニトリル:0.02M リン酸緩衝液(pH7.0)=30:70」で測定した。
試験例1および試験例2の結果をふまえ、高温下で化合物Bを溶解するときには、分解が促進するp−トルエンスルホン酸過剰状態を回避し、晶析のときには低温下でp−トルエンスルホン酸過剰状態にして化合物Aの溶解度を下げれば、結果として工程(a)の収率向上に繋がると考え、この考えを反映したp−トルエンスルホン酸分割法を試行した。
*2:対化合物B
TsOH・H2Oを分割添加することで化合物Bのロットが異なっても再現性よく化合物Aが高い収率で得られることが判明した。
Claims (12)
- (a)溶媒中、式(B)
(b)冷却下で、当該混合液にp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物を追加する工程であって、
ここで、該追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物は、工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物との総モル当量が、工程(a)の式(B)で表される化合物に対して1モル当量以上になるような量で追加され、次いで、
(c)晶析することにより式(A)
を包含する、式(A)で表される化合物の製造方法。 - 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物が、式(B)で表される化合物に対して0.5モル当量以上1.0モル当量未満である、請求項1に記載の方法。
- 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物が、式(B)で表される化合物に対して0.8モル当量以上1.0モル当量未満である、請求項1または請求項2に記載の方法。
- 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物と工程(b)で追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物の総モル当量が、工程(a)の式(B)で表される化合物に対して1.0モル当量以上3.0モル当量以下である、請求項1〜3のいずれか1項に記載の方法。
- 工程(a)のp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物と工程(b)で追加されるp−トルエンスルホン酸またはp−トルエンスルホン酸 一水和物の総モル当量が、工程(a)の式(B)で表される化合物に対して1.0モル当量以上1.2モル当量以下である、請求項1〜3のいずれか1項に記載の方法。
- 溶媒が、アルコールまたは含水アルコールである、請求項1〜5のいずれか1項に記載の方法。
- 溶媒が、含水エタノールである、請求項1〜6のいずれか1項に記載の方法。
- 含水エタノールの含水率が、0%超50%以下である、請求項1〜7のいずれか1項に記載の方法。
- p−トルエンスルホン酸 一水和物を用いる、請求項1〜8のいずれか1項に記載の方法。
- 溶媒の量が、化合物Bに対して5倍〜30倍(V/W)である、請求項1〜9のいずれか1項に記載の方法。
- 工程(a)の加温温度が60℃〜80℃である、請求項1〜10のいずれか1項に記載の方法。
- 工程(b)の冷却温度が−20℃〜40℃である、請求項1〜11のいずれか1項に記載の方法。
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WO2010104106A1 (ja) | 2009-03-13 | 2010-09-16 | 第一三共株式会社 | 光学活性なジアミン誘導体の製造方法 |
WO2015129603A1 (ja) * | 2014-02-25 | 2015-09-03 | 第一三共株式会社 | 活性化血液凝固第X因子(FXa)阻害剤の高純度結晶 |
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CA2747427C (en) | 2015-10-13 |
EP2371830A1 (en) | 2011-10-05 |
TW201028428A (en) | 2010-08-01 |
EP2371830A4 (en) | 2012-07-11 |
EG26766A (en) | 2014-08-18 |
KR101463653B1 (ko) | 2014-11-19 |
EP2371830B1 (en) | 2013-10-02 |
HK1162467A1 (en) | 2012-08-31 |
BRPI0923109A8 (pt) | 2016-06-07 |
CN102256984B (zh) | 2014-09-03 |
WO2010071121A1 (ja) | 2010-06-24 |
BRPI0923109A2 (pt) | 2016-02-02 |
IL213614A (en) | 2015-10-29 |
RU2464271C1 (ru) | 2012-10-20 |
JPWO2010071121A1 (ja) | 2012-05-31 |
CN102256984A (zh) | 2011-11-23 |
ES2437346T3 (es) | 2014-01-10 |
US20110275821A1 (en) | 2011-11-10 |
US8404847B2 (en) | 2013-03-26 |
ZA201104236B (en) | 2012-02-29 |
TWI439464B (zh) | 2014-06-01 |
SI2371830T1 (sl) | 2014-01-31 |
MY150973A (en) | 2014-03-31 |
HRP20131109T1 (hr) | 2014-01-31 |
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