CN104447205A - Method for preparing (S)-trifluoroisopropanol - Google Patents

Method for preparing (S)-trifluoroisopropanol Download PDF

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Publication number
CN104447205A
CN104447205A CN201410710672.1A CN201410710672A CN104447205A CN 104447205 A CN104447205 A CN 104447205A CN 201410710672 A CN201410710672 A CN 201410710672A CN 104447205 A CN104447205 A CN 104447205A
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CN
China
Prior art keywords
temperature
trifluoroacetone
time
reaction
trifluoroisoproanol
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CN201410710672.1A
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Chinese (zh)
Inventor
许国彬
胡燕青
樊玉平
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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Priority to CN201410710672.1A priority Critical patent/CN104447205A/en
Publication of CN104447205A publication Critical patent/CN104447205A/en
Pending legal-status Critical Current

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    • 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
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • 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
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/80—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by distillation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a method for preparing (S)-trifluoroisopropanol. The method comprises the following steps: adding potassium formate, TBAB, formic acid and a metal ruthenium complex into water, at a temperature of T1, adding trifluoroacetone to obtain a mixture, heating the mixture to a temperature of T2 and reacting for t1 time at T2, cooling the reaction system to T1 and reacting for t2 time at T1, and then heating the reaction system to T2 and reacting for the t1 time and circulating the above operations until trifluoroacetone is completely reacted. When (S)-trifluoroisopropanol is prepared, by cooling the reaction for an appropriate time, gasified trifluoroacetone is liquefied by cooling, is in full contact with a substrate and then is heated for reaction, the operations are circulated and thus the reaction conversion rate is increased.

Description

The method of preparation (S)-Trifluoroisoproanol
Technical field
The present invention relates to pharmaceutical intermediate field, be specifically related to the method that one prepares (S)-Trifluoroisoproanol.
Background technology
The bitopertin that Roche and Japanese Subsidiary Company CHUGAI thereof research and develop jointly is a kind of oral small molecules Gly T1 inhibitor; its chemical name is: [4-(the fluoro-5-trifluoromethylpyridin of 3--2-base)-piperazine-1-base]-[5-methylsulfonyl-2-(2; 2; the fluoro-1-methyl-ethoxy of 2-tri-)-phenyl]-ketone; structure is such as formula shown in (A5); it has potential treatment schizophrenia, comprises negative symptoms and the controlled positive symptom of appropriateness
PCT application WO 2008107334 discloses the preparation method of formula (A5) compound, and it comprises compound a) compound of formula (A3) and the compound of (S)-Trifluoroisoproanol formula (B1) being obtained by reacting formula (A4); And b) the compound coupling of the compound of formula (A4) and formula (C3) is obtained formula (A5) compound,
(S)-Trifluoroisoproanol is the intermediate of formula (A5) compound, at present the method for preparation (the S)-Trifluoroisoproanol of report, there is following defect:
1. use bread yeast to the asymmetric reduction of trifluoroacetone, obtain (S)-Trifluoroisoproanol with bread yeast as the bio-transformation of catalyzer, the method operation key point difficulty controls, long reaction time, purity is low, and Main By product is ethanol, purification difficult.
2. use metal catalyst to prepare (S)-Trifluoroisoproanol to the asymmetric hydrogenation of trifluoroacetone, the method uses water as reaction solvent, and aftertreatment is obtained by underpressure distillation.But due to the boiling point of (S)-Trifluoroisoproanol low (53-56 DEG C), underpressure distillation is easily taken away, if air distillation, elapsed time is long, and (S)-Trifluoroisoproanol amount of collecting is few, and yield is low.
Summary of the invention
In the process of preparation (S)-Trifluoroisoproanol, because the boiling point of trifluoroacetone is low, only there is 20-21 DEG C, so under needing to be stored at the condition of low temperature, be liquid state.But preparation (S)-Trifluoroisoproanol generally needs 25-40 DEG C of reaction, and namely in reaction process, trifluoroacetone is gaseous phase, therefore can be suspended in more than reaction liquid level, cause reaction insufficient, low conversion rate.
The present invention is intended to improve reaction conversion ratio by improving synthetic method, thus improves yield.
The method of preparation (S)-Trifluoroisoproanol, it comprises: potassium formiate, TBAB, formic acid and metal Ru complex compound are added to the water, at T1 temperature, add trifluoroacetone, then mixture is heated to T2 temperature and reacts the t1 time at T2 temperature, then cooling reaction system reacts the t2 time to T1 temperature at T1 temperature, and then reacting by heating system reacts the t1 time to T2 temperature at T2 temperature, cyclical operation like this, until trifluoroacetone reacts completely.
Described T1 temperature is-10-5 DEG C, is preferably 0-5 DEG C.
The described t1 time is more than 3 hours, preferred 5-15 hour.
Described T2 temperature is 25-40 DEG C, preferred 30-35 DEG C.
The described t2 time is more than 30 minutes, preferred 1-1.5 hour.
Described metal Ru complex compound, its structure is such as formula shown in (1)
After trifluoroacetone reacts completely, aftertreatment comprises: first lower the temperature to reaction system, then adds methylene dichloride and extracts three times at about 15 DEG C, the dichloromethane layer of collection, the dichloromethane solution of air distillation obtains (S)-Trifluoroisoproanol.
The concentration of the dichloromethane solution of described (S)-Trifluoroisoproanol is 75.0mg/mL to 85.0mg/mL.
The present invention is when preparing (S)-Trifluoroisoproanol, and by lowering the temperature to reaction in good time, object makes the trifluoroacetone of gasification through cooling liquid, more fully contact with substrate, then temperature reaction, with this cyclical operation, thus improves reaction conversion ratio.
Post-reaction treatment is also carried out some and is improved, and by first lowering the temperature to reaction system, with dichloromethane extraction, the dichloromethane layer of collection then obtains (S)-Trifluoroisoproanol dichloromethane solution through distillation again.Yield is increased to about 80% by original about 21-40%.
(S) dichloromethane solution of-Trifluoroisoproanol is stablized, and can preserve, uses as the compound reagent of one.
Term " reacts completely " and refers to that described reactions steps is reacted to a certain degree as reaction raw materials consumption is approximately greater than 90% after testing, be greater than 95%, or reaction raw materials disappears substantially after testing.Can by conventional method as detection reaction degree such as thin layer chromatography (TLC), high performance liquid chromatography method (HPLC), vapor-phase chromatographies (GC).The present invention can adopt HPLC to monitor level of response, when peak area is less than 10%, be less than 5% or be less than 1% time visual response complete.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
Term " about " or " approximately " typically refer within 10% of specified value or scope, suitably within 5% or within 3%.Or for those of ordinary skills, term " about " or " approximately " represent within the scope of the acceptable standard error of mean value.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, mmol represents mmole, and h represents hour, and g represents gram, and ml represents milliliter, GC (gas-chromatography).
TBAB is Tetrabutyl amonium bromide,
Embodiment 1 synthesizes S-Trifluoroisoproanol
Metal Ru complex compound (0.084g, 0.13mmol), potassium formiate (13.77g, 164mmol), TBAB (1.29g, 1.6mmol), water (45mL) and formic acid (0.38g, 8mmol) add in the decomposition tank of 80mL, be cooled to 0-5 DEG C of stirring.Adding trifluoroacetone (9.2g) to decomposing in tank, being warming up to 30 DEG C of stirring reactions.At 30 DEG C of reaction about 10h, be transferred to cryostat, be cooled to 0 DEG C and stir 1-1.5h, and then be warming up to 30 DEG C of continuation stirring reactions.With this cyclical operation, reaction 37.5h sampling is sent in GC and is controlled, and trifluoroacetone reacts completely.Reaction system is cooled to about 0 DEG C, adds methylene dichloride at about 15 DEG C extractions three times (27mL*3), combined dichloromethane layer toward reaction solution.Dichloromethane layer is 50-60 DEG C of air distillation, collect the dichloromethane solution that cut obtains the S-Trifluoroisoproanol of 88mL, the purity of sample presentation GC detection S-Trifluoroisoproanol is 97.89%, ee value is 96.6%, the concentration of S-Trifluoroisoproanol in methylene dichloride is 83.23mg/mL, and yield is 80%.
Comparative example 1 synthesizes S-Trifluoroisoproanol
Ru complex compound (0.084g is added in the 300mL autoclave that tetrafluoroethylene magneton is housed, 0.13mmol), potassium formiate (13.77g, 164mmol), Tetrabutyl amonium bromide (1.29g, 0.05mmol), after water (45mL) and formic acid (0.38g, 0.1mmol); Add trifluoroacetone (9.2g, 80mmol), be airtightly warming up to 30 DEG C of stirring reaction 37.5h.Reaction terminates, and add dichloromethane extraction, distillation yield cut obtains the dichloromethane solution yield 40% of S-Trifluoroisoproanol.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.

Claims (10)

1. prepare the method for (S)-Trifluoroisoproanol, it comprises: potassium formiate, TBAB, formic acid and metal Ru complex compound are added to the water, at T1 temperature, add trifluoroacetone, then mixture is heated to T2 temperature and reacts the t1 time at T2 temperature, then cooling reaction system reacts the t2 time to T1 temperature at T1 temperature, and then reacting by heating system reacts the t1 time to T2 temperature at T2 temperature, cyclical operation like this, until trifluoroacetone reacts completely.
2. the method for claim 1, described T1 temperature is-10-5 DEG C, is preferably 0-5 DEG C.
3. the method for claim 1, the described t1 time is more than 3 hours, preferred 5-15 hour.
4. the method for claim 1, described T2 temperature is 25-40 DEG C.
5. method as claimed in claim 4, described T2 temperature is 30-35 DEG C.
6. the method for claim 1, the described t2 time is more than 30 minutes, preferred 1-1.5 hour.
7. the method for claim 1, described metal Ru complex compound, its structure is such as formula shown in (1)
8. the method for claim 1, after trifluoroacetone reacts completely, aftertreatment comprises: first lower the temperature to reaction system, then adds methylene dichloride and extracts three times at about 15 DEG C, the dichloromethane layer collected, the dichloromethane solution of air distillation obtains (S)-Trifluoroisoproanol.
9. method as claimed in claim 7, the concentration of the dichloromethane solution of described (S)-Trifluoroisoproanol is 75.0mg/mL to 85.0mg/mL.
10. the method for claim 1, it comprises: metal Ru complex compound (0.084g, 0.13mmol), potassium formiate (13.77g, 164mmol), TBAB (1.29g, 1.6mmol), water (45mL) and formic acid (0.38g, 8mmol) add in the decomposition tank of 80mL, be cooled to 0-5 DEG C of stirring, add trifluoroacetone (9.2g) to decomposing in tank, be warming up to 30 DEG C of stirring reactions, at 30 DEG C of reaction about 10h, be transferred to cryostat, be cooled to 0 DEG C and stir 1-1.5h, and then be warming up to 30 DEG C of continuation stirring reactions, with this cyclical operation, react completely to trifluoroacetone, reaction system is cooled to about 0 DEG C, methylene dichloride is added about 15 DEG C of extractions three times toward reaction solution, combined dichloromethane layer, dichloromethane layer is 50-60 DEG C of air distillation, collect cut.
CN201410710672.1A 2014-11-27 2014-11-27 Method for preparing (S)-trifluoroisopropanol Pending CN104447205A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001104795A (en) * 1999-10-13 2001-04-17 Mitsubishi Chemicals Corp Ruthenium catalyst composition
CN101500974A (en) * 2006-07-27 2009-08-05 弗·哈夫曼-拉罗切有限公司 Asymmetric hydrogenation of 1,1,1-trifluoroacetone
EP2399895A2 (en) * 2010-06-28 2011-12-28 Kanto Kagaku Kabushiki Kaisha Process for producing optically active aliphatic fluoroalcohol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001104795A (en) * 1999-10-13 2001-04-17 Mitsubishi Chemicals Corp Ruthenium catalyst composition
CN101500974A (en) * 2006-07-27 2009-08-05 弗·哈夫曼-拉罗切有限公司 Asymmetric hydrogenation of 1,1,1-trifluoroacetone
EP2399895A2 (en) * 2010-06-28 2011-12-28 Kanto Kagaku Kabushiki Kaisha Process for producing optically active aliphatic fluoroalcohol

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Application publication date: 20150325