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WO2025196119A1 - Désoxyfluoration continue de cétones à l'aide d'un dast formé in situ - Google Patents

Désoxyfluoration continue de cétones à l'aide d'un dast formé in situ

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Publication number
WO2025196119A1
WO2025196119A1 PCT/EP2025/057491 EP2025057491W WO2025196119A1 WO 2025196119 A1 WO2025196119 A1 WO 2025196119A1 EP 2025057491 W EP2025057491 W EP 2025057491W WO 2025196119 A1 WO2025196119 A1 WO 2025196119A1
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WO
WIPO (PCT)
Prior art keywords
reaction
alkyl
alkenyl
aryl
substituted
Prior art date
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Pending
Application number
PCT/EP2025/057491
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English (en)
Inventor
Michael Bersier
Simon Wagschal
Dominique Roberge
Oliver KAPPE
Christopher Hone
Dominik POLTERAUER
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Lonza AG
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Lonza AG
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Application filed by Lonza AG filed Critical Lonza AG
Publication of WO2025196119A1 publication Critical patent/WO2025196119A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a method for continuous deoxyfluorination of ketones with the fluorination reagent diethylaminosulfur trifluoride (DAST) which is prepared continuously in situ from SF 4 .
  • DAST diethylaminosulfur trifluoride
  • Umemoto et al discloses the conversion of cyclohexanone in the presence of HF-pyridine with the fluorinating agent phenylsulfur trifluoride, which was in situ generated from phenyl sulfur chlorotetrafluoride and pyridine, with a yield of 94% of 1,1-difluorocyclohexane (run 6 in table 2). Phenylsulfur trifluoride requires additional steps for its preparation likewise the preparation of HF-pyridine. The handling of pyridine is not desired. Umemoto et al. in J. AM. CHEM.
  • SOC.2010, 132, 18199–18205 discloses conversion of ethyl-4-oxocyclohexanecarboxylate with 1.5 eq FluoleadTM (4-tert- butyl-2,6-dimethylphenylsulfur trifluoride) with a yield of 81% and a of 99 / 1 ratio of geminal difluoro (called herein RCF2) / vinylfluoro (called herein RCF) (run 3 table 2). The conversion was done in the presence of 0.4 eq HF-pyridine.
  • FluoleadTM 4-tert- butyl-2,6-dimethylphenylsulfur trifluoride
  • RCF2 geminal difluoro
  • RCF vinylfluoro
  • FluoleadTM was prepared from 1-tert-butyl-3,5-dimethylbenzene by reaction with an equivalent amount of S 2 Cl 2 in acetic acid at room temperature in the presence of a catalytic amount of ZnCl2 for 4 h to produce bis(4-tert-butyl-2,6- dimethylphenyl) disulfide (2k), which then was converted by oxidation with Cl2/KF to FluoleadTM (1k). Our Ref.
  • the disclosed reactions have various disadvantages:
  • the fluorinating agent such as phenylsulfur trifluoride or FluoleadTM needs to be prepared in more than one separate steps; some procedures use pyridine of HF-pyridine which requires separate preparation and generates additional waste which needs to be treated, the handling of pyridine is in general not welcome due to its smell and potential hazardousness.
  • Other disclosures show rather high content of the undesired vinyl fluoride byproduct (RCF). For example Haycock at al. in Organic Process Research & Development 2008, 12, 1094–1103, discloses (point 2.2.
  • WO2014184561A1 discloses on page 36 in Scheme 1 a deoxyfluorination with DAST providing a mixture of RCF2 and RCF; further on on page 37 lines 12 to 18 the deoxyfluorination of ethyl 4-oxocyclohexanecarboxylate with DAST in dichloromethane, providing a mixture of desired RCF2 and undesired RCF; the inseparable and undesired vinyl fluoride impurity (RCF) requires for its separation from the desired RCF2 an oxidization and further steps.
  • RCF vinyl fluoride impurity
  • the inventors of present invention found a method for continuous deoxyfluorination of ketones as substrates which provides good results such as conversion, yield, selectivity and low amount of undesired vinyl fluoride byproduct (RCF), wherein two reactions, the preparation of the fluorinating agent DAST and the fluorination reaction of a ketone with said DAST, are continuously done consecutively and coupled to each other without interrupting the flow of the reaction mixture: at first, that is upstream relative to the fluorination rection, DAST is continuously prepared and then second, that is downstream from the DAST preparation , the fluorination takes place. In addition the method provides for shorter residence times. The risk associated with the handling of DAST is minimized.
  • RCF undesired vinyl fluoride byproduct
  • Subject of the invention is a method for deoxyfluorination of a ketone in a solvent, by exchange of the oxo residue of the ketone against two geminal fluorine atoms providing the respective difluoro compound, in a continuous flow reaction set up comprising two reactions, ⁇ a first reaction for the preparation of diethylaminosulfur trifluoride (DAST), and Our Ref.
  • DAST diethylaminosulfur trifluoride
  • LZA32043PCT 4 ⁇ a second reaction for the deoxyfluorination of the ketone by said DAST as fluorinating agent; wherein the solvent in said continuous flow reaction set up is selected from the group of dichloromethane, dichloroethane and mixtures thereof and both the first reaction and the second reaction take place in said solvent; the first reaction is done by combining SF4 continuously with a secondary amine, herein abbreviated with BASE, providing DAST; the second reaction is done by combining said DAST from the first reaction continuously with the ketone; the combining of SF 4 with BASE providing said DAST is done at a first position of said continuous flow reaction set up, which is separated from and located upstream to a second position of said continuous flow reaction set up where the combining of said DAST with the ketone takes place; with the direction of the flow of the reagents SF4 and BASE going to the first position, where the SF4 and the BASE are continuously combined with each other, providing at this first position a first position
  • Figure 1 shows the (A1) Flow Configuration for “Commercial DAST in flow, 2 feeds”, wherein commercial DAST is the fluorinating reagent, which is not generated continuously.
  • Figure 2 shows the (A2) Flow Configuration for “DAST in situ, 3 feeds”, which shows an embodiment of the continuous flow reaction set up according to the invention, with the first position where SF 4 and Et 2 NH are Our Ref. : LZA32043PCT 5 mixed to provide a first reaction mixture containing DAST which flows downstream to the second position, where said first reaction mixture is mixed with the ketone for the deoxyfluorination to take place.
  • Figure 3 shows the (A3) Flow Configuration for “DAST in situ, 2 feeds” which is an embodiment wherein SF 4 , EtNH 2 and the ketone are mixed in one position for the deoxyfluorination to take place.
  • LIST OF CITATIONS ⁇ Umemoto et al, Journal of Fluorine Chemistry (2012), 140, 17-27 ⁇ Umemoto et al., J. AM. CHEM.
  • the invention relates to a deoxyfluorination of a ketone as substrate with DAST as fluorinating reagent.
  • the reaction is a deoxyfluorination reaction.
  • deoxofluorination and deoxyfluorination are used in the prior art to describe an exchange of an oxygen atom against one or two fluorine atoms, as the case may be. In this specification these two terms are used synonymously.
  • the desired product provided by the deoxyfluorination of the invention is a compound with two geminal fluorine atoms (RCF2). These two geminal fluorine atoms are Our Ref. : LZA32043PCT 6 both bonded to the C atom of the keto residue of the ketone that if being deoxyfluorinated. So the oxygen atom of the keto residue of the substrate is exchanged against two geminal fluorine atoms. It is known in the art, that deoxyfluorination reactions of ketone as substrate might also provide the unwanted vinyl fluoro byproduct (RCF) as depicted in Scheme 0.
  • RCF2 vinyl fluoro byproduct
  • the reaction is done under anhydrous conditions; preferably the residual amount of water in the reaction mixture at the beginning of the reaction is 1'000 ppm or less, more preferably 750 ppm or less, even more preferably 500 ppm or less, especially 250 ppm or less, more especially 100 ppm or less, even more especially 75 ppm or less, in particular 50 ppm or less, more in particular 25 ppm or less, even more in particular, 10 ppm or less.
  • an excess of SF 4 can be used to react this residual water to HF which no longer interacts with the reaction.
  • BASE is selected from the group consisting of R1(R2)NH and pyrrolidine; wherein R1 and R2 are identical or different and independently from each other C1-4 alkyl or benzyl;
  • Our Ref. : LZA32043PCT 7 more preferably, BASE is selected from the group consisting of dibutylamine, dipropylamine, diethylamine (Et 2 NH), dimethylamine, N-methylbutylamine, and pyrrolidine; even more preferably, BASE is selected from the group consisting of diethylamine (Et 2 NH), N-methylbutylamine, and pyrrolidine; especially, BASE is diethylamine (Et2NH).
  • the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane and mixtures thereof; more preferably, the solvent is dichloromethane or 1,2-dichloroethane.
  • the amount of solvent is chosen such that the concentration of the substrate in the solvent is from 0.001 to 5 M, more preferably from 0.01 to 3 M, even more preferably from 0.01 to 2 M.
  • the first reaction and the second reaction are done without any addition of HF to any of the two reactions.
  • the first reaction and the second reaction are done without the presence of a salt of HF with pyridine.
  • the first reaction and the second reaction are done without the presence of TEA-3HF.
  • the first reaction and the second reaction are done without the presence of a salt of HF with TEA.
  • the first reaction and the second reaction are done without any addition of a salt of HF with an organic base.
  • the first reaction and the second reaction are done without any addition of a salt of HF with a base.
  • the first reaction and the second reaction are done without the presence of an organic base except for BASE.
  • the first reaction and the second reaction are done without the presence of a base except for BASE.
  • the second reaction is done with DAST being the only fluorinating agent. Our Ref.
  • the deoxyfluorination reaction is done with DAST being the only fluorinating agent.
  • the first reaction and the second reaction are done without the presence of anyone fluorinating agent of the group phenylsulfur trifluoride, 4- tert-butyl-2,6-dimethylphenylsulfur trifluoride (also called FluoleadTM), bis(2- methoxyethyl)aminosulfur trifluoride (also called deoxo-fluor), diethylaminodifluorosulfinium tetrafuoroborate (also called XtalFluor ETM), and morpholinodifluorosulfinium tetrafluoroborate (also called XtalFluor-MTM).
  • the amount of SF 4 is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate.
  • the amount of BASE is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate. If the substrate has more than one keto residue per molecule that are intended to be deoxyfluorinated, then said equiv are molar equiv based on the molar amount of keto residues of the substrate.
  • the substrate has more than one keto residue per molecule that are intended to be deoxyfluorinated and the substrate has any further residues such as OH, C(O)H or COOH, which can react with SF 4 or with DAST, then said equiv are molar equiv based on the total molar amount of keto residues and said any further residues, which can react with SF4 or with DAST, of the substrate.
  • the molar amount of SF 4 and the molar amount of BASE are identical.
  • the first reaction is done at a reaction temperature which is herein called REACTEMP1; preferably REACTEMP1 is a predefined and chosen reaction temperature.
  • REACTEMP1 can be -25 °C, -10 °C, 0 °C, 10 °C or 20 °C.
  • Upper limits of REACTEMP1 can be 200 °C or 175 °C.
  • REACTEMP1 can be from -25 to 200 °C, preferably from -10 to 200 °C, more preferably from 0 to 200 °C, even more
  • Our Ref. : LZA32043PCT 9 preferably from 10 to 200 °C, especially from 10 to 175 °C, more especially from 15 to 175 °C, even more especially from 20 to 175 °C.
  • the second reaction is done at a reaction temperature which is herein called REACTEMP2; preferably REACTEMP2 is a predefined and chosen reaction temperature.
  • REACTEMP1 and REACTEMP2 can be different or identical.
  • Lower limits of REACTEMP2 can be -25 °C, -10 °C, 0 °C, 10 °C, 20 °C or 30 °C.
  • Upper limits of REACTEMP2 can be 200 °C or 175 °C.
  • REACTEMP2 can be from -25 to 200 °C, preferably from -10 to 200 °C, more preferably from 0 to 200 °C, even more preferably from 10 to 200 °C, especially from 10 to 175 °C, more especially from 15 to 175 °C, even more especially from 20 to 175 °C, in particular from 30 to 175 °C.
  • the continuous combining of SF 4 with BASE is preferably a continuous mixing.
  • the continuous combining of DAST from the first reaction with the substrate is preferably a continuous mixing.
  • neat SF4 is continuously combined with BASE.
  • BASE is first mixed with the solvent, and this mixture of BASE with the solvent is combined continuously with SF4; more preferably, the mixture of BASE with the solvent is a solution of the BASE in the solvent.
  • the substrate is first mixed with the solvent, and this mixture of the substrate with the solvent is combined continuously with the reaction mixture from the first reaction; more preferably, the mixture of the substrate with the solvent is a solution of the substrate in the solvent.
  • MIXDEV1 first mixing device
  • the continuous mixing in MIXDEV1 is done by continuously feeding two feeds, a first feed (FEED1) and a second feed (FEED2) FEED1 containing the BASE and FEED2 containing SF4, into and through MIXDEV1.
  • the reaction mixture exiting MIXDEV1 is called herein the first reaction mixture.
  • FEED1 contains a mixture of BASE in the solvent, more preferably a solution of BASE in the solvent.
  • MIXDEV2 is located in downstream direction relative to MIXDEV1.
  • the continuous mixing in MIXDEV2 is done by continuously feeding two feeds, the first reaction mixture and a third feed (FEED3), FEED3 containing the substrate, into and through MIXDEV2.
  • the reaction mixture exiting MIXDEV2 is called herein the second reaction mixture.
  • FEED3 contains a mixture of the substrate in the solvent, more preferably a solution of the substrate in the solvent.
  • FEED1 can be the BASE neat or can be a solution of BASE in the solvent, preferably FEED1 is a solution of BASE in the solvent.
  • FEED2 contains the SF4, preferably FEED2 is the SF4 neat.
  • FEED3 is a solution of the substrate in the solvent.
  • FEED1 consists of a solution of BASE in the solvent
  • FEED2 consists of SF 4
  • FEED3 consists of a solution of the substrate in the solvent.
  • concentration of the substrate in FEED3 is primarily limited by the solubility of the substrate in the solvent and the chosen temperature of FEED3.
  • concentration of the substrate in FEED3 is from 0.01 to 10 M, more preferably from 0.01 to 5 M, even more preferably from 0.01 to 3 M.
  • MIXDEV1 and MIXDEV2 that is the pumping or dosing of FEED1, FEED2 and FEED3 into and through MIXDEV1 and Our Ref.
  • LZA32043PCT 11 MIXDEV2 is preferably done using a back pressure regulation device BPR.
  • the BPR is located downstream from MIXDEV2.
  • the BPR provides for having a predetermined pressure in MIXDEV1 and MIXDEV2 and for maintaining this predetermined pressure in MIXDEV1 and MIXDEV2 at a constant level.
  • the first reaction and the second reaction can be done at different pressures. This can for example be realized by inserting respective pressure regulating devices between MIXDEV1 and MIXDEV2.
  • the first reaction is preferably done at a pressure which is above the vapor pressure, at REACTEMP1, of the reaction mixture of the first reaction containing all components of the reaction mixture of the first reaction except for the SF 4 , and/or above the vapor pressure of SF4 at REACTEMP1.
  • the second reaction is preferably done at a pressure which is above the vapor pressure, at REACTEMP2, of the reaction mixture of the second reaction containing all components of the reaction mixture of the second reaction except for any SF 4 which may be present in the reaction mixture of the second reaction, and/or above the vapor pressure of SF4 at REACTEMP2.
  • the first reaction and the second reaction are done under the same pressure, herein called REACPRESS.
  • REACTEMP1 and REACTEMP2 may be identical or different; if REACTEMP1 and REACTEMP2 are different, then one of the two is the higher one, called herein REACTEMPHIGHER; if REACTEMP1 and REACTEMP2 are identical then REACTEMPHIGHER is REACTEMP1; preferably REACPRESS is above the vapor pressure, at REACTEMPHIGHER, of the reaction mixture of the first reaction and the second reaction containing all components of the respective reaction mixtures of the first reaction and second reaction except for any SF 4 , and/or REACPRESS is above the vapor pressure of SF4 at REACTEMPHIGHER.
  • the first reaction and the second reaction are done under the same pressure
  • Our Ref. : LZA32043PCT 12 REACPRESS, and REACPRESS is above the vapor pressure of SF4 at REACTEMPHIGHER, that is above the vapor pressure which SF 4 has at the reaction temperature of the first reaction and of the second reaction; so SF4 is used in liquid state.
  • any reaction pressure is above the vapor pressure of any reaction mixture at any chosen reaction temperature.
  • Typical ranges for any reaction pressure can be from 0 to 200 barg, more preferably from 0 to 150 barg, even more preferably from 0 to 100 barg.
  • any reaction pressure can be from atmospheric pressure to 200 bar, more preferably from atmospheric pressure to 150 bar, even more preferably from atmospheric pressure to 100 bar.
  • the first reaction and the second reaction are done under the same pressure, REACPRESS, that is the pressure in MIXDEV1 and MIXDEV2 is the same, i.e. REACPRESS, and REACPRESS can be chosen and set by the BPR.
  • REACPRESS Suitable back pressure regulation devices BPR are known to the skilled person and are available on the market, such as from companies like Swagelok Company, Solon, Ohio, US, or Zaiput Flow Technologies, Scottsdale, Arizona, US.
  • the BPR features a small dead volume, precise pressure control and/or a large enough channel width to ensure a smooth flow without clogging.
  • respective pumps can be used for conveying anyone of FEED1, FEED2, FEED3 and/or any reaction mixture.
  • the dosing and feeding of FEED2, that is of the SF 4 gas can also be driven by its own respective vapor pressure, for example if the pressure in MIXDEV1 is below the vapor pressure of SF4 at the chosen reaction temperature in MIXDEV1.
  • each of FEED1, FEED2, FEED3, and any reaction mixture can either be gaseous or liquid.
  • any gaseous flow rate V ⁇ g and/or any liquid flow rate V ⁇ l respective flow meters or mass flow controllers can be used. Pressure and Our Ref. : LZA32043PCT 13 temperature can be measured by respective measuring devices. All such devices are know to the skilled person.
  • Mass flow controllers MFC can be used to determine and control and maintain any flow rate, be it gaseous or liquid of any of the components of the reaction mixture. For example a MFC can be used upstream before the MIXDEV, to determine and control and maintain the gaseous flow rate V ⁇ g of SF 4 .
  • N 2 can be used for cleaning and especially for drying of any devices which come into contact with any of the components of the reaction mixture.
  • the mixing devices MIXDEV1 and MIXDEV2 can be identical or different types of mixing devices and can be any suitable device with means for combining two fluid feeds or for combining a fluid feed with a gaseous feed to provide a reaction mixture. Any of the two mixing devices can further comprise means for mixing the reaction mixture. Any of the two mixing devices MIXDEV1 and MIXDEV2 can be for example a T-piece, a microreactor, a mixing device, such as a static mixing device, or any combination thereof.
  • any of the two mixing devices is a T-piece, which has two entrance channels
  • the two feeds entering the mixing device are fed each into one of the two separate entrance channels
  • the two separate entrance channels combine in the T-piece into the one exit channel of the T-piece, through which the mixed feeds, that is the reaction mixture, exits.
  • Mixing devices such as dynamic mixing devices or static mixing devices, e.g. static mixers, are well established and widespread in all fields of chemical process technology. It is characteristical for static mixing devices, in contrast to dynamic mixing devices, that only the media to be mixed are in motion. The feeds, liquid or gaseous, are mixed by their motion only, while the geometrically defined mixing elements in the static mixing devices remain fixed and in their positions.
  • the static mixing device has the form of a tube or a plate containing means that present obstacles for the flow of the reaction mixture and thereby effecting the mixing of the feeds.
  • micro reactors also called micro structured reactors, are devices in which chemical reactions take place in a confinement with typical lateral dimensions below 1 mm; the most typical form of such confinement are micro channels.
  • a micro reactor is a continuous flow reactor. Microreactors have been successfully applied in lab, pilot and production scale. E.g.
  • the micro reactor contains micro channels which are arranged in such a way as to effect the mixing of the feeds.
  • a microreactor is called a split and recombine mixer.
  • a microreactor comprises both the means for combining the two feeds and the means for mixing the obtained reaction mixture.
  • the first reaction starts when FEED1 and FEED2 are mixed in MIXDEV1; MIXDEV1 provides the first reaction mixture.
  • the time which the first reaction mixture needs for passing through MIXDEV1 is a mixing time tMix1.
  • the reaction time of the first reaction is equal to or larger than t Mix1 . If MIXDEV1 is a simply T piece then t Mix1 is rather short.
  • the first reaction mixture exiting from MIXDEV1 can be passed through a first residence device (RESDEV1) before entering MIXDEV2.
  • RESDEV1 provides for additional reaction time of the first reaction.
  • RESDEV1 is located downstream from MIXDEV1.
  • Our Ref. : LZA32043PCT 15 In one embodiment, the first reaction mixture is passed through a RESDEV1 after having passed through MIXDEV1 and before entering MIXDEV2; RESDEV1 provides for additional reaction time of the first reaction.
  • this back pressure regulation device is preferably located downstream of RESDEV1. In a preferred embodiment, no back pressure regulation device is used between MIXDEV1 and MIXDEV2
  • the time which the first reaction mixture needs for passing through RESDEV1 is a residence time t Res1 .
  • t Res1 is part or the first reaction time. If not RESDEV1 is present, t Res1 is zero.
  • RESDEV1 has a channel through which the first reaction mixture passes through, the length and the inner diameter of this channel are chosen in such a way that a desired tRes1 is provided for.
  • RESDEV1 may for example be a tube, the tube may have the shape of a coil, herein also called the first reactor coil.
  • Additional t Res1 means additional first reaction time, in which the first reaction can take place.
  • the first reaction time is equal to or larger than the sum of t Mix1 and t Res1 .
  • Dimensional limitation of the inner diameter of MIXDEV1 and of RESDEV1 may be required primarily in connection with the use of SF 4 in gaseous state; this may for example be the case in small scale reactions, that is for example in lab scale reactions.
  • the inner diameter of MIXDEV1 and/or RESDEV1 that is the inner diameter of any channel in MIXDEV1 and/or RESDEV1, through which the first reaction mixture passes, should be rather small, such as 2 mm or less, preferably 1 mm or less.
  • the inner diameter of MIXDEV1 and/or RESDEV1, that is the inner diameter of any channel in MIXDEV1 and/or RESDEV1, through which the first reaction mixture passes is 2 mm or less, preferably 1 mm or less.
  • the handling of SF4 in liquid state is easier to be realized on industrial scale than in the lab. When both the feed of SF 4 and the feed of the substrate are in Our Ref.
  • the second reaction starts when the first reaction mixture, provided by MIXDEV1, and FEED3 are mixed in MIXDEV1; MIXDEV1 provides the second reaction mixture.
  • the time which the second reaction mixture needs for passing through MIXDEV2 is a mixing time t Mix2 .
  • the reaction time of the second reaction is equal to or larger than t Mix2 .
  • the second reaction mixture exiting from MIXDEV2 can be passed through a second residence device (RESDEV2); preferably the second reaction mixture exiting from MIXDEV2 passes through a RESDEV2 before passing through any other device, so MIXDEV2 and RESDEV2 are directly connected with each other.
  • RESDEV2 provides for additional reaction time of the second reaction.
  • RESDEV2 is located downstream from MIXDEV2. Preferably, RESDEV2 is in downstream direction the next device after MIXDEV2.
  • the second reaction mixture is passed through a RESDEV2 after having passed through MIXDEV2 and before entering any other device.
  • this BPR is preferably located downstream of RESDEV2.
  • the time which the second reaction mixture needs for passing through RESDEV2 is a residence time t Res2 .
  • t Res2 is part or the second reaction time. If not RESDEV2 is present, tRes2 is zero.
  • RESDEV2 has a channel through which the second reaction mixture passes through, the length and the inner diameter of this channel are chosen in such a way that a desired tRes2 is provided for.
  • RESDEV2 may for example be a tube, the tube may have the shape of a coil, herein also called the first reactor coil.
  • Additional tRes2 means additional second reaction time, in which the second reaction can take place.
  • Our Ref. : LZA32043PCT 17 In the case that RESDEV2 is used then the second reaction time is equal to or larger than the sum of t Mix2 and t Res2 .
  • the inner diameter of MIXDEV2 and/or RESDEV2, that is the inner diameter of any channel in MIXDEV2 and/or RESDEV2, through which the second reaction mixture passes, is 2 mm or less, preferably 1 mm or less.
  • the product is isolated from the second reaction mixture existing MIXDEV2, or, if present, exiting RESDEV2; methods and means for isolation are known to the skilled person.
  • the product is isolated from the second reaction mixture after a BPR located downstream of MIXDEV2.
  • the second reaction mixture is separated in a separation device (SEPDEV) into a gaseous stream and a liquid stream, or into a more hydrophobic and a more hydrophilic stream, as the case may be.
  • SEPDEV separation device
  • SEPDEV is a membrane separator.
  • SEPDEV separates any residual SF4 from the reaction mixture.
  • the time which the second reaction mixture needs for passing through a SEPDEV is a separation time tSep. tSep is part of the reaction time of the second reaction.
  • a SEPDEV is located downstream after MIXDEV2.
  • a SEPDEV is located downstream after RESDEV2.
  • a SEPDEV can be located upstream before a BPR or downstream after a BPR.
  • a SEPDEV is located downstream after a BPR,
  • the product may be in the gaseous stream or in the liquid stream or in both of these two streams, likewise the product may be in the hydrophilic stream or in the hydrophobic stream or in both streams.
  • the second reaction mixture is passed through a separation device SEPDEV which is located downstream of MIXDEV2, the RESDEV2 (if present) and the BPR (if present).
  • SEPDEV which is a membrane separator comprising a hydrophobic membrane to separate the second reaction mixture into a hydrophilic stream, which will be retained by the membrane, and a hydrophobic stream, which can pass through the membrane.
  • the separation device SEPDEV is a membrane separator comprising a hydrophobic membrane.
  • the hydrophobic stream contains primarily the solvent and any dissolved compounds such as residual substrate and the product.
  • the first reaction time can be defined as the time during which the first reaction mixture passes from the point of mixing of the SF4 with FEED1 in MIXDEV1 on through a RESDEV1, if a RESDEV1 is used, and on into MIXDEV2, until the first reaction mixture is mixed with the FEED3.
  • the second reaction may or may not be end in a SEPDEV, where some components in the reaction mixture of the second reaction are separated from the second reaction mixture.
  • the reaction mixture of the second reaction and therewith the reaction therein is quenched.
  • This quenching can be done by any suitable means. Suitable means are for examples mixing the reaction mixture with a suitable base, preferably aqueous Our Ref. : LZA32043PCT 19 base, such as aqueous NaOH or NaCO3.
  • This quenching is preferably done after any RESDEV2, after any BPR and after any SEPDEV.
  • the second reaction time during which the second reaction can occur, can be defined as at least the time during which the second reaction mixture passes from the point of mixing of the first reaction mixture with FEED3 in MIXDEV2 on through a RESDEV2, if a RESDEV2 is used, and on into a SEPDEV, if a SEPDEV is used, and on into to a quenching, if a quenching is done.
  • a quenching is done and terminates the second reaction, so the reaction time of the second reaction preferably is the time from the mixing of the first reaction mixture with FEED3 in MIXDEV3 until the quenching.
  • the second reaction time can be defined as the time during which the second reaction mixture passes from the point of mixing of the first reaction mixture with FEED3 in MIXDEV2 on through a RESDEV2, if a RESDEV2 is used, and on through the BPR, and further on through a SEPDEV, if SEPDEV is used and is located downstream after BPR, and further on until the quenching.
  • the first reaction time that is the reaction time of the first reaction, is from 0.01 to 60 min, more preferable from 0.01 to 50 min, even more preferably from 0.01 to 40 min.
  • the first reaction time is equal to or larger than the sum of t Mix1 and any t Res1 .
  • the first reaction time can for example be larger than the sum of tMix1 and any t Res1 if a passage through connecting tubes or pipes between MIXDEV1 and RESDEV1 contribute to the first reaction time.
  • the RESDEV1 is a reactor coil.
  • tRes1 is calculated based on the liquid flow rate V ⁇ l.
  • the second reaction time that is the reaction time of the second reaction, is from 0.01 to 120 min, more preferable from 0.01 to 90 min, even more preferably from 0.01 to 60 min.
  • the second reaction time is equal to or larger than the sum of t Mix2 , t Res2 and any t Sep .
  • the second reaction time can for example be larger than the sum of t Mix2 , tRes2 and any tSep if a passage through connecting tubes or pipes between MIXDEV2 and RESDEV2 contribute to the second reaction time.
  • RESDEV2 is the reactor coil.
  • tRes2 is calculated based on the liquid flow rate V ⁇ l .
  • C 2-n alkenylene comprises unbranched or branched C2-n alkenylene with n > 2.
  • Any alkenylene can Our Ref. : LZA32043PCT 22 have one or more unsaturated bonds depending on the size and connectivity of its carbon scaffold.
  • ⁇ Propylene is n-propylene or isopropylene.
  • the endocyclic atoms of the cyclic ketone are also called ring atoms herein.
  • the ketone, that is the substrate is a non-cyclic ketone or a cyclic ketone.
  • the substrate is an unsubstituted or substituted cyclic ketone.
  • any cyclic ketone being the substrate and mentioned herein comprises 0 to n-3 endocyclic heteroatoms Y4, with n being the number of ring atoms of the cyclic ketone including the C atom of the endocyclic keto residue of the cyclic ketone, preferably up to n-4 endocyclic heteroatoms Y4 in case that n > 5; more preferably, the cyclic ketone comprises 0, 1 or 2 endocyclic heteroatoms Y4, with Y4 being O, S or N; this possibility for the cyclic ketone of having endocyclic hetreoatoms expressly applies also for example in case that said cyclic ketone is said to be selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctan
  • a cyclohexanone with an endocyclic carbon atom exchanged against NH is a piperidinone and is comprised in the definition of the cyclic ketone of this invention.
  • Any endocyclic N of the cyclic ketone can be unsubstituted or substituted, in case of any saturated endocyclic N of the cyclic ketone any said saturated endocyclic N
  • Our Ref. : LZA32043PCT 23 is preferably substituted, more preferably by a residue R5, R5 is a protecting group which is stable under reaction conditions, with R5 being as defined herein, also with all its embodiments.
  • the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated.
  • the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL.
  • any cyclic ketone mentioned herein can be bridged by 1, 2 or 3 atoms selected from C or N; in case that the bridge contains N and the N is a saturated N, then the N is preferably substituted, more preferably by R5; R5 is a protecting group which is stable under reaction conditions, with R5 begin also as defined herein, also with all its embodiments.
  • the substrate is an unsubstituted or substituted cyclic ketone, which is saturated or monounsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL.
  • the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL;
  • R100 is selected from the group consisting of oxo, OH, C1-22 alkyl, C2-22 alkenyl, F, Cl, Br, I, CN, NO2, O-C 1-6 alkyl, O-C 2-6 alkenyl, Our Ref.
  • LZA32043PCT 24 C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C 1-6 alkyl, C(O)-O-C 2-6 alkenyl, O-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; with C1-6 alkyl, C2-6 alkenyl, C1-22 alkyl, C2-22 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments.
  • the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic aryl residue called FUSEDARYL, wherein FUSEDARYL is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; with R100 as defined herein, also with all its embodiments.
  • any cyclic ketone mentioned herein is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone.
  • the ketone that is the substrate, is a cyclic ketone and is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone; Our Ref.
  • the ketone that is the substrate, is a non-cyclic ketone and is a compound of formula (NCK), wherein R200 and R201 are identical or different and independently from each other selected from the group consisting of C1-22 alkyl, C2-22 alkenyl, cycloalkyl, and aryl; with C 1-22 alkyl, C 2-22 alkenyl, cycloalkyl, and aryl as defined herein, also with all their embodiments.
  • NCK compound of formula
  • Any aryl mentioned herein is, independently from any other aryl, ⁇ a 5 or 6 membered monocyclic aryl residue, ⁇ a bicyclic aryl residue formed by a 5 or 6 membered ring fused with a 6 membered ring, or ⁇ a 5 or 6 membered non-aromatic ring, any 5 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, any 6 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, and any aryl is unsubstituted or substituted by one or more identical or different substituents R110, with R110 as defined herein, also with all its embodiments.
  • R110 mentioned herein, independently from any other R110, is selected from the group consisting of oxo, OH, C 1-6 alkyl, C 2-6 alkenyl, F, Cl, Br, I, CN, NO2, Our Ref. : LZA32043PCT 27 O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C 1-6 alkyl, C(O)-C 2-6 alkenyl, COOH, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl; with C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments.
  • Any heteroatom Y2 mentioned herein is, independently from any other Y2, selected from the group consisting of O, S, and saturated or unsaturated N, said saturated N is unsubstituted or substituted, preferably substituted by R5.
  • Any Y1 mentioned herein is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, C(O), (O-CH 2 -CH 2 ) 1-20 -O, (O-propylene)1-20-O, (O-CH 2 -CH 2 ) 1-20 -O-C(O)-C 1-6 alkylene-C(O)-O, (O-propylene) 1-20 -O-C(O)-C 1-6 alkylene-C(O)-O, O-C(O)-C1-6 alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C 1-6 alkylene-C(O)-(O
  • Any C1-22 alkyl mentioned herein and any C2-22 alkenyl mentioned herein is, independently from any other C 1-22 alkyl and C 2-22 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of oxo, OH, F, Cl, Br, I, NO 2 , O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C 1-6 alkyl, C(O)-O-C 2-6 alkenyl, Our Ref.
  • LZA32043PCT 28 O-R5, S-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; with C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments.
  • Any C 1-6 alkyl mentioned herein and any C 2-6 alkenyl mentioned herein is, independently from any other C1-6 alkyl and C2-6 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of oxo, OH, F, Cl, Br, I, NO2, O-C 1-4 alkyl, O-C 2-3 alkenyl, C(O)H, C(O)-C1-4 alkyl, C(O)-C2-3 alkenyl, COOH, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5.
  • R5 mentioned herein is a protecting group which is stable under reaction conditions
  • any R5 mentioned herein is a protecting group for protecting OH, SH, NH or NH2, which is stable under reaction conditions; such protecting groups are known to the skilled person.
  • R5 is Fmoc, Boc, benzoyl, Cbz, C(O)-C1-10 alkyl, TBDMS (tert-Butyldimethylsilyl), triisopropylsilyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert- Butyl), more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6 alkyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert- Butyl), more preferably Fmoc, Boc, be
  • LZA32043PCT 29 more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6 alkyl, Bn (Benzyl), or Alloc (Allyloxycarbonyl); ⁇ if SH is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C 1-2 alkyl, C(O)- C1-10 alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), Acm (Acetamidomethyl), or Trt, more preferably Fmoc, Boc, benzoyl, Cbz, C 1-2 alkyl, C(O)-C 1-6 alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), or Acm (Acetamidomethyl).
  • R5 is Boc, benzoyl, Cbz, Fmoc, C(O)- C1-6 alkyl or Bn (Benzyl).
  • any cyclic keton and/or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond; more preferably, any cyclic keton and/or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond which is not conjugated with the double bond of the endocyclic keto residue which is deoxyfluorinated.
  • any Y1 mentioned herein is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene) 1-20 -O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O-propylene) 1-20 -O-C(O)-C 1-6 alkylene-C(O)-O, O-C(O)-C 1-6 alkylene-C(O)-(O-CH 2 -CH 2 ) 1-20 -O, and O-C(O)-C1-6 alkylene-C(O)-(O-propylene)1-20-O.
  • a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene) 1-20 -O, (O-CH2-CH2)
  • the ketone, that is the substrate is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone; wherein each cyclododecanone, cyclododecenone, cycloundecanone, cyclobutanone; wherein each cyclododecan
  • any mentioned cycloalkyl residue is, independently from an other cycloalkyl residue, a 4, 5, 6, or 7 membered cycloalkyl residue, a 4 membered cycloalkyl residue contains 0 or 1 endocyclic heteroatom Y3, a 5 membered cycloalkyl residue contains 0, 1 or 2 identical or different endocyclic heteroatoms Y3, a 6 and a 7 membered cycloalkyl residue contain 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y3, any heteroatom Y3 is, independently from any other Y3, selected from the group consisting of O, S, and N, said N is unsubstituted or substituted, preferably substituted by R5, any cycloalkyl residue, independently from any other cycloalkyl residue, is unsubstituted or substituted by one or more identical or different substituents R110; any mentioned aryl is
  • LZA32043PCT 34 O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C 1-6 alkyl, C(O)-O-C 2-6 alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl;
  • any mentioned heteroatom Y2 is, independently from any other Y2, selected from the group consisting of O, S, and saturated or unsaturated N, said saturated N is unsubstituted or substituted, preferably substituted by R5;
  • any mentioned Y1 is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene) 1-20 -O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O
  • any mentioned C1-6 alkyl and any mentioned C2-6 alkenyl is, independently from any other C 1-6 alkyl and C 2-6 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of F, Cl, Br, I, NO 2 , O-C1-4 alkyl, O-C2-3 alkenyl, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5;
  • R5 is a protecting group for protecting OH, SH, NH or NH2, which is stable under reaction conditions, also as defined herein in its embodiments.
  • Non-limiting examples for the substrate are
  • our Ref. : LZA32043PCT 36 In one embodiment, the substrate is not . In one embodiment, the substrate is not .
  • GC-MS analysis was performed using a Shimadzu GCMS-QP2010 SE, using an RTX-5MS column (30 m ⁇ 0.25 mm ⁇ 0.25 ⁇ m) and helium as carrier gas (40 cm/sec linear velocity).
  • the injector temperature was set to 280 °C. After 1 min at 50 °C, the oven temperature was increased by 25 °C/min to 300 °C and then kept at 300 °C for 3 min.
  • the mass detector was a quadrupole with pre rods and electron impact ionization.
  • Material of Construction (MoC) SF4 is in general not very corrosive but as SF4 gets in contact with water, even in form of moisture, HF is immediately formed. So, a similar material of construction (MoC) as when working with HF has to be used. Therefore, wetted parts must be made out of PEEK, PTFE, PFA, PP, FEP, stainless steel or FFKM. Glass-made material cannot be used. Additionally, it is highly recommended to check all the material for corrosion regularly and perform daily leak tests before starting the system. To prevent corrosion, it must be ensured that the system is flushed by N 2 before starting the SF 4 line to remove traces of moisture in the system, which could lead to HF formation. In this way a longer lifetime of the instruments can be achieved.
  • LZA32043PCT 47 for safety reasons. Before using the pumping systems, they were calibrated by pumping for a specified time and checking the mass balance. All pumps were found to dose within ⁇ 3%. A 6-port valve with a 5 mL sample loop having an inject position and a load position was used for the FEED2, the reagent feed (DAST). The solvent was either pumped by syringe pump 2 directly into a mixing device (MIXDEV), a T- piece, this happened in the load position of the sample loop, or first through the 5 mL sample loop containing DAST and then into the T-piece for mixing with the substrate feed, this happened in the inject position of the sample loop.
  • MIXDEV mixing device
  • FEED1 containing the substrate, was pumped by a syringe pump 1 through a check valve (Upchurch, CV-3321, IDEX Corporation, US), to prevent backflow, into the syringe pump 1.
  • the two liquid feeds were mixed in the MIXDEV, the T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a residence device (RESDEV), a reactor coil.
  • RESDEV 0.8 mm i.d., 16 mL volume
  • a coil heater Syrris Asia, UK
  • BPR adjustable back pressure regulator
  • the reaction mixture subsequently passed into a separating device (SEPDEV), a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any formed gases in the reaction, and a hydrophobic stream, which passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds.
  • SEPDEV separating device
  • SEP-10 Zaiput Flow Technologies, US
  • a hydrophobic membrane Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK
  • the hydrophilic (gaseous) stream was diluted via a T-piece with water (300 ⁇ L/min) and then collected in a stirred first quench bottle containing aqueous NaOH (5 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH).
  • the hydrophobic (liquid) stream was forwarded to a 4-way valve (4-way valve PEEK bulkhead single "T" Flow, IDEX Corporation, US).
  • One outlet was a short Our Ref. : LZA32043PCT 48 tubing for sampling.
  • Another outlet was connected via a T-piece to dilute the hydrophobic (liquid) stream with water (200 ⁇ L/min) into a stirred second quench bottle containing aqueous NaOH (5 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH).
  • the headspace of that second quench bottle was connected into the first quench bottle from the gaseous stream (again collection under the surface of the aqueous NaOH).
  • the headspace of this first quench bottle was connected to a third quench bottle containing aqueous NaOH (10 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH).
  • This third quench bottle was connected to a tubing going to the back of the fume cupboard (not shown in Figure 1).
  • the surface of the aqueous NaOH in any of the three bottles is depicted with a wavy line.
  • the dilution of both of the gaseous stream and the liquid stream with water served the purpose to prevent NaF formation and precipitation in the tubing, which can lead to clogging.
  • the water was dosed via respective pumps, which are not shown in Figure 1.
  • the quench bottles were stirred by magnetic stirrers and if necessary cooled with an ice bath (also not shown in Figure 1).
  • the pressure limit of the pumps was set to 4 bar to prevent pushing the liquid back to the mass flow controller MFC for the gaseous feed. Above 4 bar pressure, the pumps would turn-off automatically for safety reasons. Before using the pumping systems, they were calibrated by pumping for a specified time and checking the mass balance. All pumps were found to dose within ⁇ 3%.
  • Our Ref. : LZA32043PCT 49 For optimization studies and small-scale experiments, a 6-port valve with a 5 mL sample loop having an inject position and a load position was used for the substrate feed (this sample loop is not shown in Figure 2, it was inserted between the check valve after syringe pump 2 and MIXDEV2).
  • the FEED3 (solvent) was either pumped by the syringe pump 2 directly into a second mixing device, MIXDEV2, a T-piece, this happened in the load position of the sample loop, or first through said 5 mL sample loop and then into MIXDEV2 for mixing the substrate feed with the reaction stream, this happened in the inject position of the sample loop.
  • MIXDEV2 a second mixing device
  • MIXDEV2 a T-piece
  • This valve was connected to a 3-way valve (stainless steel), which was connected to a bottle of N2 (6.0, air liquide) to flush the whole system.
  • a line pressure regulator LPR
  • KPR1FJC412A20000 KPR1FJC412A20000, Swagelok Company, US
  • MFC mass flow controller
  • a check valve wetted material: SS, Kalrez®, Fitok Group, US
  • MIXDEV1 a T- piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a first residence device, RESDEV1, a reactor coil 1.
  • RESDEV1 (0.8 mm i.d., 1.6 mL volume) was placed into a heated water bath on a magnetic stirrer. After RESDEV1 the reaction mixture was mixed with a liquid feed, the FEED 3, containing the substrate from syringe pump 2 using MIXDEV2, a T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a second residence device RESDEV2, a reactor coil 2 (0.8 mm i.d., 16 mL volume) heated by a coil heater (Syrris Asia, UK). The liquid feed from syringe pump 2 was connected as described above with Our Ref.
  • LZA32043PCT 50 the 6-port valve, the check valve and optionally the sample loop (not shown in Figure 2).
  • RESDEV2 the flow of the reaction mixture then passed through an adjustable back pressure regulator (BPR) (20 bar max, Zaiput Flow Technologies, US) pressurized by compressed air to 2.5 barg.
  • BPR adjustable back pressure regulator
  • the reaction mixture passed into a separating device, SEPDEV, a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any residual amount of SF 4 , and a hydrophobic stream, which passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds.
  • a hydrophobic membrane Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK
  • a 6-port valve with a 5 mL sample loop (for dosing the substrate) having an inject position and a load position was used for the liquid feed FEED1 (this sample loop is not shown in Figure 3, it was inserted between the check valve after the Our Ref. : LZA32043PCT 51 syringe pump and MIXDEV).
  • the solvent was either pumped directly into a mixing device, MIXDEV, a T-piece, this happened in the load position of the sample loop, or first through the 5 mL sample loop and then into MIXDEV for mixing the liquid feed with the gaseous feed, this happened in the inject position of the sample loop.
  • MFC mass flow controller
  • the gaseous flow was mixed with the liquid flow from the syringe pump in the MIXDEV, the T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a residence device, RESDEV, a reactor coil (0.8 mm i.d., 16 mL volume) heated by a coil heater (Syrris Asia, UK).
  • RESDEV the flow of the reaction mixture then passed through an adjustable back pressure regulator (BPR) (20 bar max, Zaiput Flow Technologies, US) pressurized by compressed air to 2.5 barg.
  • BPR adjustable back pressure regulator
  • the reaction mixture subsequently passed into a separating device (SEPDEV), a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any residual amount of SF4, and a hydrophobic stream, which Our Ref. : LZA32043PCT 52 passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds.
  • SEPDEV separating device
  • SEP-10 Zaiput Flow Technologies, US
  • a hydrophobic membrane Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 ⁇ m pore size, 47 mm circle (100 pcs), Whatman plc, UK
  • Cyclohexanone (0.948 g, 10 mmol) and 4-fluorotoluene (0.551 g, 5 mmol) were dissolved in DCM (20 mL), resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of 4-fluorotoluene.
  • DCM dimethyl methacrylate
  • FEED2 second feed solution
  • DAST reagent
  • FEED2 was the gaseous SF 4 and was fed as described in (A2).
  • the feed solution FEED3 containing the substrate was prepared in a volumetric flask. Cyclohexanone (0.237 g, 2.5 mmol) and 4-fluorotoluene (0.138 g, 1.25 mmol) were dissolved in DCM (5 mL), resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of 4-fluorotoluene.
  • the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position.
  • a solution of cyclohexanone (0.5 M) and 4-fluorotoluene (0.25 M) in DCM is fed into the syringe pump 2.
  • the system was flushed with N2 (15 mLn/min) for 20 min, and then, the syringe pump 1 and syringe pump 2 were started (1 + 1 mL/min) and the whole system was flushed for 20 min with DCM.
  • the heating baths for RESDEV1, the reactor coil 1, (1.6 mL internal volume) and RESDEV2, the reactor coil 2, (16 mL internal volume) were heated to and kept at 70 °C. After reaching a temperature of 70 °C in the reactor coils, the 3-way valve was turned and FEED2 containing SF 4 gas was started.
  • the gaseous flow rate V ⁇ g was set to 25 mLn/min and the mixing with DCM (liquid flow rates V ⁇ l,1 of 0.666 mL/min and V ⁇ l,2 of 0.333 mL/min) continued for 4 min.
  • the gaseous flow rate V ⁇ g was reduced to 8.2 mLn/min (1 equiv SF4 compared to base) and FEED1 was started by changing from DCM to the Our Ref. : LZA32043PCT 55 FEED1 solution.
  • the system was left to equilibrate until all gas was dissolved after MIXDEV1 (no N 2 traces left, t Res1 1.5 min).
  • MIXDEV1 no N 2 traces left, t Res1 1.5 min.
  • the 6-way valve was turned to the inject position and the FEED3 loaded sample loop was fed into RESDEV2, the reactor coil 2, (t Res2 16 min) via MIXDEV2. After 20 minutes, which corresponds to 1.25 x residence times, steady state was assumed, and sampling was started.
  • the 4-way valve was turned, and the outlet tubing was placed into 4 mL vials containing quench solution and a stirring bar.
  • the following order of samples was collected, each sample was collected for 30 sec if not otherwise stated: 1) NaOH 5% 2) aq. sat. solution of NaHCO3 3) sampling into an FEP NMR liner without a quench 4) NaOH 5%: sampling for 2 min 30 sec 5) NaOH 5%
  • the sample 3) in the FEP NMR liner was analyzed by NMR analysis ( 1 H and 19 F).
  • the system was flushed with N 2 (15 mL n /min) for 20 min, and then, the syringe pump was started (1.5 mL/min) and the whole system was flushed for 20 min with DCM.
  • RESDEV the reactor coil, (16 mL internal volume) was heated to and kept at 70 °C. After reaching a temperature of 70 °C in the reactor coil, the 3-way valve was turned and FEED2 containing SF4 gas was started.
  • the gaseous flow rate V ⁇ g was set to 25 mLn/min and the mixing with DCM (liquid flow rate V ⁇ l,1 of 1 mL/min) continued for 4 min.
  • the (B4) Fluorination Procedure is similar to the (B3) Fluorination procedure, instead of creating DAST in situ by a reaction between Et 2 NH and SF 4 , no Et 2 NH Our Ref. : LZA32043PCT 58 was used but Et3N, thereby SF4 itself was the fluorinating agent, no DAST is generated in situ.
  • the (B4) Fluorination Procedure was done with the (A3) Flow Configuration with the following differences to (A3) Flow Configuration: ⁇ the sample loop for the liquid FEED1 (which is not shown in Figure 3) was not inserted between the check valve after the syringe pump and MIXDEV, but between the syringe pump and the check valve; ⁇ the residence device, RESDEV, was not a reactor coil with 16 mL volume, but with 4.6 ml volume; ⁇ the heating of RESDEV was not done with a coil heater (Syrris Asia, UK), but RESDEV was placed in a heated water bath on a magnetic stirrer; ⁇ after RESDEV the flow of the reaction mixture did not enter directly into the BPR, but between RESDEV and BPR the flow of the reaction mixture passed thorough an inline NMR analysis (ca.1 ml internal volume) (not shown in Figure 3); The feed solution FEED1 containing the substrate was prepared in a volumetric flask.
  • Cyclohexanone (245 mg, 2.5 mmol), triethylamine (253 mg, 2.5 mmol, 1 equiv) and trifluorotoluene (183 mg, 1.25 mmol) were dissolved in ethyl acetate (5 mL, resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of trifluorotoluene). After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position.
  • the system was flushed with N 2 (15 mL n /min) for 20 min, and then, the EtOAc pump was started (0.50 mL/min) and the whole system was flushed for 15 min.
  • the heating bath for the reactor coil (4.6 mL internal volume) was heated to and kept at 50 °C. After reaching in the heating bath the temperature of 50 °C, the 3-way valve was turned and SF4 feed FEED2 was started.
  • the gaseous flow rate V ⁇ g was set to 25 mL n /min and the mixing with EtOAc (liquid flow rate V ⁇ l of 0.5 mL/min) continued for 4 min.
  • Soc.2010, 132, 18199–18205 discloses conversion of ethyl-4-oxocyclohexanecarboxylate with 1.5 eq FluoleadTM with a yield of 81% and a of 99 / 1 ratio of RCF2 / RCF (run 3 table 2). The conversion was done in the presence of 0.4 eq HF-pyridine.
  • FluoleadTM requires additional steps: it was prepared from 1-tert-butyl-3,5-dimethylbenzene by reaction with an equivalent amount of S2Cl2 in acetic acid at room temperature in the presence of a catalytic amount of ZnCl 2 for 4 h to produce bis(4-tert-butyl-2,6- dimethylphenyl) disulfide (2k), which then was converted by oxidation with Cl2/KF to FluoleadTM (1k). Also the preparation of HF-pyridine requires additional separate process steps, and the handling of pyridine in production is not desired. Haycock at al. in Organic Process Research & Development 2008, 12, 1094– 1103, discloses (2.2.
  • WO2014184561A1 discloses on page 36 in Scheme 1 a deoxyfluorination with DAST providing a mixture of RCF2 and RCF; further on on page 37 lines 12 to 18 the deoxyfluorination of ethyl 4-oxocyclohexanecarboxylate with DAST in dichloromethane, providing a mixture of desired RCF2 and undesired RCF; the inseparable and undesired vinyl fluoride impurity (RCF) requires for its separation from the desired RCF2 an oxidization and further steps.
  • RCF vinyl fluoride impurity
  • WO2022040487A1 discloses as L15 -> L16 on scheme page 126 and in [355]: L15 (1.95 g, 8.01 mmol, 1.0 equiv) was converted in DCM with DAST providing L16 as a yellow oil. (2.0 g, yield: 94%). It is an isolated yield after a flash chromatography. Our Ref. : LZA32043PCT 70 None about any elimination (vinyl) is said, no purity is given. The combined assay yield in example 43 is 98%, with an isolated yield of RCF2 84%.
  • WO2015025962A1 discloses in example 165 the conversion of 5,6,8,9- tetrahydro-7H­ benzo[7]annulen-7-one with bis (2-methoxyethyl) aminosulfur trifluoride as fluorinating reagent with purification by silica gel column chromatography without solvent gradient, which will not separate RCF2 from RCF; the yield was 84%, no information about purity are given.
  • Comparative Example 2a and Comparative Example 2b Comparative Example 2a shows the results of (B4) Fluorination Procedure as described above: direct fluorination of cyclohexanone with SF4 in the presence of Et3N, no presence of Et2NH and therefore no in situ generation of DAST. Fluorination with SF4 provides predominantly RCF compared to Example 1. Comparative Example 2b was done according to Comparative Example 2a with the sole difference that DCM was used instead of EtOAc. Comparative Example 3 Comparative Example 3 shows the results of (B1) Fluorination Procedure exemplified with cyclohexanone using the setup (A1) "Commercial DAST in flow, 2 feeds", with the sole difference that EtOAc was used as solvent instead of DCM.
  • Comparative Example 6 shows the results of (B3) Fluorination Procedure exemplified with cyclohexanone using the setup (A3), "DAST in situ, 2 feeds". Simultaneous generation of DAST in situ together with the fluorination reaction itself (only one MIXDEV and only one RESDEV), lowers the conversion and the yield of RCF2 considerably compared to Example 1, where the in situ generation of DAST is done first (in MIXDEV1 and RESDEV1) and separately from the ensuing fluorination reaction (in MIXDEV2 and RESDEV2). 73

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de désoxyfluoration continue de cétones avec un réactif de fluoration à base de difluorure de diéthylaminosoufre (DAST) qui est préparé en continu in situ à partir de SF4.
PCT/EP2025/057491 2024-03-22 2025-03-19 Désoxyfluoration continue de cétones à l'aide d'un dast formé in situ Pending WO2025196119A1 (fr)

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EP1275631A2 (fr) * 1997-09-29 2003-01-15 Air Products And Chemicals, Inc. Fluorination avec trifluorides d'aminosoufre
US6686509B2 (en) 2001-02-22 2004-02-03 Mitsui Chemicals, Inc. Process for producing α, α-difluorocycloalkane compound
WO2004050619A1 (fr) 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour le traitement de la maladie d'alzheimer
WO2008022791A1 (fr) * 2006-08-21 2008-02-28 Bayer Schering Pharma Aktiengesellschaft Méthode de désoxofluoration de cétones à grande échelle
WO2014184561A1 (fr) 2013-05-15 2014-11-20 The University Court Of The University Of Aberdeen Composés de fluoro-perhexiline et leur utilisation thérapeutique
WO2015025962A1 (fr) 2013-08-23 2015-02-26 富山化学工業株式会社 Composé amidine ou sel associé
CN110372572A (zh) 2019-08-23 2019-10-25 苏州汉德创宏生化科技有限公司 一种4,4-二氟哌啶-1-甲酰氯的合成方法
WO2020198368A1 (fr) 2019-03-26 2020-10-01 Neuropore Therapies, Inc. Composés et compositions utilisés en tant que modulateurs de la signalisation tlr
WO2022040487A1 (fr) 2020-08-21 2022-02-24 Reyoung Corporation Conjugés de triptolide et leurs utilisations
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1275631A2 (fr) * 1997-09-29 2003-01-15 Air Products And Chemicals, Inc. Fluorination avec trifluorides d'aminosoufre
US6686509B2 (en) 2001-02-22 2004-02-03 Mitsui Chemicals, Inc. Process for producing α, α-difluorocycloalkane compound
WO2004050619A1 (fr) 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour le traitement de la maladie d'alzheimer
WO2008022791A1 (fr) * 2006-08-21 2008-02-28 Bayer Schering Pharma Aktiengesellschaft Méthode de désoxofluoration de cétones à grande échelle
WO2014184561A1 (fr) 2013-05-15 2014-11-20 The University Court Of The University Of Aberdeen Composés de fluoro-perhexiline et leur utilisation thérapeutique
WO2015025962A1 (fr) 2013-08-23 2015-02-26 富山化学工業株式会社 Composé amidine ou sel associé
WO2020198368A1 (fr) 2019-03-26 2020-10-01 Neuropore Therapies, Inc. Composés et compositions utilisés en tant que modulateurs de la signalisation tlr
CN110372572A (zh) 2019-08-23 2019-10-25 苏州汉德创宏生化科技有限公司 一种4,4-二氟哌啶-1-甲酰氯的合成方法
WO2022040487A1 (fr) 2020-08-21 2022-02-24 Reyoung Corporation Conjugés de triptolide et leurs utilisations
CN115850156A (zh) 2022-12-15 2023-03-28 上海泰坦科技股份有限公司 一种双氟化合物的纯化方法

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L'HEUREUX ET AL., JOURNAL OF ORGANIC CHEMISTRY, vol. 75, no. 10, 2010, pages 3401 - 3411
MARCUS BAUMANN ET AL: "The Use of Diethylaminosulfur Trifluoride (DAST) for Fluorination in a Continuous-Flow Microreactor", SYNLETT, vol. 2008, no. 14, 1 August 2008 (2008-08-01), pages 2111 - 2114, XP055035994, ISSN: 0936-5214, DOI: 10.1055/s-2008-1078026 *
PRICE ET AL., TETRAHEDRON LETTERS, vol. 46, 2005, pages 5005 - 5007
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