Process for the Preparation of Fluorinated Diazoalkanes

Abstract

The disclosure relates to a process for preparing a fluorinated diazoalkane in which the process is a continuous process and a ,-difluoroalkylamine is reacted with an organic nitrite in a reactor, and in which the ,-difluoroalkylamine and the organic nitrite are initially charged in separate vessels, and also to the use of the process for preparing a fluoroalkyl-substituted compound.

Claims

1. A process for preparing a fluorinated diazoalkane wherein the process is a continuous process and a ,-difluoroalkylamine is reacted with an organic nitrite in a reactor, wherein the ,-difluoroalkylamine and the organic nitrite are initially charged to separate vessels.

2. The process according to claim 1, wherein the ,-difluoroalkylamine is initially charged to a first vessel and the organic nitrite and acetic acid are initially charged conjointly to a second vessel, or the organic nitrite is initially charged to a first vessel and the ,-difluoroalkylamine and acetic acid are initially charged conjointly to a second vessel.

3. The process according to claim 1, wherein the reaction of the ,-difluoroalkylamine with the organic nitrite in the reactor is carried out at a temperature in the range of approximately 40 C. to 100 C., preferably in the range of approximately 40 C. to 80 C., preferably at a temperature in the range of approximately 55 C. to 75 C.

4. The process according to claim 2, wherein the residence time of the components ,-difluoroalkylamine, organic nitrite and acetic acid in the reactor is in a range of approximately 30 seconds to 1 hour, preferably in the range of approximately 1 min to 20 min and preferably in the range of approximately 2 min to 10 min.

5. The process according to claim 1, wherein the organic nitrite is used in a 0.5-fold to 2-fold, preferably a 1-fold to 1.5-fold and more preferably a 1-fold to 1.2-fold molar excess based on the ,-difluoroalkylamine.

6. The process according to claim 2, wherein the amount-of-substance fraction of acetic acid is in the range of approximately 1 mol % to 50 mol %, preferably in the range of approximately 5 mol % to 40 mol % and more preferably in the range of approximately 5 mol % to 10 mol %, based on the amount of substance of the ,-difluoroalkylamine.

7. The process according to claim 1, wherein the ,-difluoroalkylamine has the following general formula (1) ##STR00003## where: R is selected from the group comprising H and/or substituted or unsubstituted alkyl, aryl, arylalkyl, cyclyl, heteroaryl or heterocyclyl, X is selected from the group comprising H, F, Cl, CN, CO.sub.2R, CONR, COR, SO.sub.2R, SO.sub.2NR.sub.2 and/or substituted or unsubstituted alkyl, aryl, arylalkyl, cyclyl, heteroaryl or heterocyclyl, and R is selected, independently where applicable, from the group comprising H and/or substituted or unsubstituted alkyl, aryl, arylalkyl, cyclyl, heteroaryl or heterocyclyl.

8. Use of the process according to any one of the preceding claims for preparing a fluoroalkyl-substituted compound, especially a di- or trifluoroalkyl-substituted pyrazole, pyrazoline or cyclopropane.

9. A process for preparing a fluoroalkyl-substituted compound, especially a di- or trifluoroalkyl-substituted pyrazole, pyrazoline or cyclopropane, wherein the process comprises the steps of: a) preparing a fluorinated diazoalkane as per the process according to any one of claims 1-7, and b) reacting the fluorinated diazoalkane in a cyclopropanation reaction or with a dipolarophile in a 1,3-dipolar cycloaddition reaction.

10. The process according to claim 9, wherein the dipolarophile has the following general formula (2) or (3) ##STR00004## where: A is selected from the group comprising substituted or unsubstituted alkyl, aryl, arylalkyl, cyclyl, heteroaryl, heterocyclyl, alkoxy, aryloxy, NR.sub.2 and/or NHR, B is selected from the group comprising CO and/or SO.sub.2, R.sub.1, R.sub.2 and R.sub.3 are each independently selected from the group comprising H, F, Cl, C.sub.1-3-alkyl, CF.sub.3, CF.sub.2H, CFH.sub.2, phenyl, COR and/or SO.sub.2R, R is selected, independently where applicable, from the group comprising C.sub.1-8-alkyl, phenyl and/or C.sub.5-6-heteroaryl, and R is selected from the group comprising H and/or substituted or unsubstituted alkyl, aryl, arylalkyl, cyclyl, heteroaryl or heterocyclyl, where in the case of the dipolarophile of formula (2) A and R.sub.1 are capable of conjointly forming a 5-, 6- or 7-membered ring which is present as ketone, lactone, lactam, sulfone, sulfonic ester, sultam, anhydride or imide.

Description

[0113] Examples and figures follow to illustrate the present disclosure.

[0114] FIG. 1 shows the preparation of a fluorinated diazoalkane, exemplified by difluoroethylamine, as per an embodiment of the process according to the disclosure.

[0115] FIG. 2 shows the preparation of a di- or trifluoroalkyl-substituted compound by preparing a fluorinated diazoalkane and subsequently reacting the fluorinated diazoalkane with a dipolarophile.

[0116] FIG. 3 shows the yields for the preparation of difluoromethyldiazomethane as per Comparative Example 72 at room temperature in FIG. 3 a) and at 55 C. in FIG. 3 b).

[0117] FIG. 4 shows the yields of difluoromethyldiazomethane as per Examples 73 to 79.

[0118] FIG. 1 shows that reacting 2,2-difluoroethylamine 1 with tert-butyl nitrite by use of acetic acid (AcOH) gives 2,2-difluoromethyldiazomethane 2. In accordance with the present disclosure, the 2,2-difluoromethyldiazomethane 2 is prepared in a continuous process in a reactor 5. In the illustrated embodiment, difluoroethylamine 1 is initially charged to a first vessel, while tert-butyl nitrite and acetic acid are initially charged conjointly to a second vessel. Before entry into the reactor 5, 2,2-difluoroethylamine 1, tert-butyl nitrite and acetic acid are mixed in the mixer 4.

[0119] The mixer 4 is embodied in FIG. 1 as a T-piece. 2,2-Difluoroethylamine 1, tert-butyl nitrite and acetic acid are each fed to the mixer 4 by a pump 3. A back pressure valve 6 is connected to the reactor 5.

[0120] FIG. 2 shows the conversion of a ,-difluoroalkylamine as per formula (1) 7 with tert-butyl nitrite by use of acetic acid (AcOH) into a 2,2-difluorinated diazoalkane 8. In accordance with the present disclosure, the fluorinated diazoalkane 8 is prepared in a continuous process in a reactor 5. In the illustrated embodiment, the ,-difluoroalkylamine 7 is initially charged to a first vessel, while tert-butyl nitrite and acetic acid are initially charged conjointly to a second vessel. The ,-difluoroalkylamine 7, tert-butyl nitrite and acetic acid are fed by a pump 3 to a T-piece mixer 4, and mixed before passing into the reactor 5. A back pressure valve 6 is connected to the reactor 5.

[0121] The fluorinated diazoalkane 8 is fed to a second T-piece mixer 4. It is likewise supplied with a dipolarophile D by a further pump 3. The fluorinated diazoalkane 8 and the dipolarophile D are mixed in the second mixer 4 and directed into a second reactor 5. A further back pressure valve 6 is connected also to the second reactor 5. The fluorinated diazoalkane 8 and the dipolarophile D undergo a 1,3-dipolar cycloaddition reaction in the second reactor 5 to form a fluoroalkyl-substituted compound.

Material:

[0122] Chloroform was dried over calcium hydride before use.

EXAMPLE 1

Continuous Preparation of Difluoromethyldiazomethane

[0123] A solution of difluoroethylamine (0.2 M, 4 eq) in chloroform was initially charged to a syringe. A further syringe was initially charged with a mixture of 40 mol % acetic acid (1.6 eq) and tert-butyl nitrite (0.24 M, 4.8 eq) in chloroform at room temperature (202 C.). Both solutions were syringe pumped (Chemyx Fusion V710) at a constant flow rate of 50 L/min into a micromixer (Little Things Factory, MR-LAB Type MST, volume 200 L). This micromixer also served as microreactor. The reactor had connected to it a back pressure valve (IDEX back pressure assembly) which established a pressure of 40 psi. The micromixer/microreactor was heated to a temperature of 75 C. The mixture of the reactants had a residence time of 2 minutes in the reactor.

[0124] A sample of the reaction solution was taken at the outlet of the reactor and analysed by NMR. Difluoromethyldiazomethane was obtained in a yield of about 40%.

[0125] The reaction of difluoroethylamine (4 eq) with tert-butyl nitrite (4.8 eq) was repeated using various proportions of acetic acid, temperatures and residence times in the reactor. Samples of the reaction solution were in each case taken at the output of the reactor and analysed by NMR. The conditions and yields of the individual reactions are summarised below in Table 1.

TABLE-US-00001 TABLE 1 Continuous conversion of difluoroethylamine with (1.2 eq) tert-butyl nitrite into difluoromethyldiazo-methane Reaction conditions Residence Acetic Temper- time in acid, ature, reactor, Yield, Example mol % C. min % 2 20 mol % 75 C. 2 min 30% 3 10 mol % 55 C. 2 min 11% 4 10 mol % 75 C. 8 min 15% 5 40 mol % 90 C. 2 min 27% 6 10 mol % 75 C. 2 min 29% 7 10 mol % 75 C. 4 min 23% 8* 5 mol % 55 C. 10 min 26% *a 0.8 mL capacity microreactor was additionally attached to the micromixer. The combined capacity of micromixer and microreactor was 1 mL.

[0126] It transpired that a temperature of 55 C. to 90 C., a 2 to 10 minutes' residence time for the components in the mixer/reactor and an acetic acid amount-of-substance fraction ranging from 10 mol % to 40 mol % gave good yields of difluoromethyldiazomethane.

EXAMPLE 9

Use of Said Difluoromethyldiazomethane in Cyclopropanations

[0127] Difluoromethyldiazomethane was prepared as described in Example 1. The reaction solution from the reactor was passed under argon into a 50 ml reaction flask containing 0.4 mmol of styrene (1 eq) and, by way of catalyst, 5 mol % of rhodium(II) (Rh.sub.2esp.sub.2) in 4 mL of CHCl.sub.3 and stirred at room temperature (202 C.) for 4 hours. Subsequently, the chloroform was removed under reduced pressure and the residue was purified by column chromatography. 1-Phenyl-2-difluoromethylcyclopropane was obtained in a yield of 67%.

[0128] The conversion of the reaction solution from the reactor was repeated using various styrene derivatives. The styrene derivatives used, the difluoromethyl-substituted cyclopropanes obtained and the respective yields are summarised below in Table 2.

TABLE-US-00002 TABLE 2 Conversion of difluoromethyldiazomethane with styrene derivatives into difluoromethyl-substituted cyclopropanes Ex- Yield, ample Styrene reactant Cyclopropane % 10 4-methylstyrene 1-(4-methylphenyl)-2- 68 difluoromethylcyclopropane 11 4-tert- 1-(4-tert-butylphenyl)-2- 57 butylstyrene difluoromethylcyclopropane 12 4-fluorostyrene 1-(4-fluorophenyl)-2- 42 difluoromethylcyclopropane 13 4-chlorostyrene 1-(4-chlorophenyl)-2- 56 difluoromethylcyclopropane 14 4-bromostyrene 1-(4-bromophenyl)-2- 59 difluoromethylcyclopropane 15 3-methylstyrene 1-(3-methylphenyl)-2- 60 difluoromethylcyclopropane 16 3-fluorostyrene 1-(3-fluorophenyl)-2- 52 difluoromethylcyclopropane 17 3-chlorostyrene 1-(3-chlorophenyl)-2- 34 difluoromethylcyclopropane 18 2-fluorostyrene 1-(2-fluorophenyl)-2- 49 difluoromethylcyclopropane 19 2-vinylnaphthalene 1-(2-naphthalenyl)-2- 32 difluoromethylcyclopropane 20 alpha- (2-(difluoromethyl)-1- 63 methylstyrene methylcyclopropyl)benzene 21 trans-beta- (2-(difluoromethyl)-3- 45 methylstyrene methylcyclopropyl)benzene 22 indene 1-(difluoromethyl)- 50 1,1a,6,6a-tetrahydrocyclo- propa[a]indane 23 dihydro- 1-(difluoromethyl)- 49 naphthalene 1a,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalene 24 4-vinylpyridine 1-(4-pyridyl)-2- <10 difluormethyl-cyclopropane

[0129] As is derivable from Table 2, the process makes for an efficient synthesis of difluoromethyl-substituted cyclopropanes in good yield. In an embodiment, one requirement for this may be the continuous preparation of the difluoromethyldiazomethane in good yield in the first step. As is further derivable from Table 2, the use of heterocycles resulted in but low yields of the desired cyclopropane.

EXAMPLE 25

Preparation of Methyl 3-(Difluoromethyl)-1H-Pyrazole-5-Carboxylate

a) Preparing the Fluorinated Diazoalkane

[0130] Two stock solutions were prepared. 2,2-Difluoroethylamine (0.1 M, 2 eq) was dissolved in 9 mL of CHCl.sub.3. tBuONO (0.24 M, 2.4 eq) and 5 mol % of acetic acid (0.08 M, 0.1 eq) were likewise dissolved in 9 mL of CHCl.sub.3. Both solutions were initially charged to a syringe and added by syringe pumping at a flow rate of 50 L/min via a micromixer (Little Things Factory, MR Lab Type MST) having a capacity of 0.2 mL and a microreactor (CS Chromatographie PTFE tubing, Article No. 590515, ID=0.8 mm, length 1.6 m) having a volume of 0.8 mL. The micromixer and the microreactor were heated to 55 C. The mixture of the reactants had a residence time of 10 minutes in the microreactor.

b) Reacting the Fluorinated Diazoalkane with a Dipolarophile in a 1,3-Dipolar Cycloaddition Reaction

[0131] The downstream tube end of the reactor was directed into a flask which was initially charged with 1 eq of ethyl propiolate (0.5 mmol) dissolved in 6 mL of chloroform. On completion of the addition the reaction solution was stirred overnight at room temperature (202 C.). The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain methyl 3-(difluoromethyl)-1H-pyrazole-5-carboxylate.

[0132] The reaction was repeated with various dipolarophiles. The di- and trifluoromethyl-substituted pyrazoles obtained, the dipolarophiles and the particular fluoroalkyl groups are summarised below in Table 3.

TABLE-US-00003 TABLE 3 Preparation of various di- and trifluoromethyl- substituted pyrazoles and pyrazolines Ex- Di- or trifluoromethyl- Fluoroalkyl ample substituted pyrazole Dipolarophile group 26 ethyl 3-(difluoromethyl)-1H- propiolate CF.sub.2H pyrazole-5-carboxylate 27 tert-butyl propiolate CF.sub.2H 3-(difluoromethyl)-1H- pyrazole-5-carboxylate 28 5-benzyl-3-(difluoromethyl)- Maleimide CF.sub.2H 1,6a-dihydropyrrolo[3,4- c]pyrazole-4,6(3aH,5H)-dione 29 1-(3-(difluoromethyl)-1H- alkynyl CF.sub.2H pyrazol-5-yl)ethanone ketone 30 dimethyl 3-(difluoromethyl)- alkynyl CF.sub.2H 1H-pyrazole-4,5- diester dicarboxylate 31 tert-butyl acrylic ester CF.sub.2H 3-(difluoromethyl)-4,5- dihydro-1H-pyrazole-5- carboxylate 32 1-(3-(difluoromethyl)-4,5- vinyl ketone CF.sub.2H dihydro-1H-pyrazol-5- yl)ethanone 33 tert-butyl propiolate CF.sub.3 3-(trifluoromethyl)-1H- pyrazole-5-carboxylate 34 methyl 3-(trifluoromethyl)- propiolate CF.sub.3 1H-pyrazole-5-carboxylate 35 ethyl 3-(trifluoromethyl)- propiolate CF.sub.3 1H-pyrazole-5-carboxylate 36 1-(3-(trifluoromethyl)-1H- alkynyl CF.sub.3 pyrazol-5-yl)ethanone ketone 37 dimethyl alkynyl CF.sub.3 3-(trifluoromethyl)-1H- diester pyrazole-4,5-dicarboxylate 38 1-(3-(trifluoromethyl)-4,5- vinyl ketone CF.sub.3 dihydro-1H-pyrazol-5- yl)ethanone 39 tert-butyl acrylic ester CF.sub.3 3-(trifluoromethyl)-4,5- dihydro-1H-pyrazole-5- carboxylate

[0133] As is derivable from Table 3, the process makes for an efficient synthesis of fluoroalkyl-substituted pyrazoles and pyrazolines. In an embodiment, one requirement for this may be the continuous preparation of the fluorinated diazo compound in good yield in the first step.

EXAMPLE 40

Preparation of 3-(Phenylsulfonyl)-5-(Difluoromethyl)-4,5-Dihydro-1H-Pyrazole

a) Preparing the Fluorinated Diazoalkane

[0134] Two stock solutions were prepared. 2,2-Difluoroethylamine (0.2 M, 4 eq) was dissolved in CHCl.sub.3. tert-Butyl nitrite (0.24 M, 4.8 eq) and 5 mol % of acetic acid (0.01 M, 0.2 eq) were likewise dissolved in CHCl.sub.3. Both solutions were initially charged to a syringe and added by syringe pumping at a flow rate of 50 L/min via a micromixer (Little Things Factory, MR Lab Type MST) having a capacity of 0.2 mL and a microreactor (CS Chromatographie PTFE tubing, Article No. 590515, ID=0.8 mm, length 1.6 m) having a volume of 0.8 mL. The micromixer and the microreactor were heated to 55 C. The mixture of the reactants had a residence time of 10 minutes in the microreactor.

b) Reacting the Fluorinated Diazoalkane with a Dipolarophile in a 1,3-Dipolar Cycloaddition Reaction

[0135] The downstream tube end of the reactor was directed into a flask which was initially charged with 1 eq of phenyl vinyl sulfone (0.5 mmol) dissolved in chloroform. On completion of the addition the reaction solution was stirred for 24 hours at room temperature (202 C.). The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain 3-(phenylsulfonyl)-5-(difluoromethyl)-4,5-dihydro-1H-pyrazole.

[0136] The reaction was repeated with various vinyl sulfones. The di- and trifluoromethyl-substituted pyrazoles obtained, the vinyl sulfones used and the particular fluoroalkyl groups are summarised below in Table 4.

TABLE-US-00004 TABLE 4 Preparation of various di- and trifluoromethylsulfonyl-substituted pyrazoles and pyrazolines Di- or Fluoro- Ex- trifluoromethylsulfonyl- Dipolaro- alkyl ample substituted pyrazole phile group 41 3-(methylsulfonyl)-5- vinyl CF.sub.3 (trifluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 42 3-(ethylsulfonyl)-5- vinyl CF.sub.3 (trifluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 43 3-(benzylsulfonyl)-5- vinyl CF.sub.3 (trifluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 44 3-(phenylsulfonyl)-5- vinyl CF.sub.3 (trifluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 45 3-((4-methylphenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 46 3-((4-fluorophenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 47 3-((4-chlorophenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 48 3-((4-bromophenyl)sulfonyl)-5- vinyl CF.sub.3 (trifluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 49 3-((4-methoxyphenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 50 3-((3-methylphenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 51 3-((2-methylphenyl)sulfonyl)- vinyl CF.sub.3 5-(trifluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 52 3-(methylsulfonyl)-5- vinyl CF.sub.2H (difluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 53 3-(ethylsulfonyl)-5- vinyl CF.sub.2H (difluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 54 3-(benzylsulfonyl)-5- vinyl CF.sub.2H (difluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 55 3-(phenylsulfonyl)-5- vinyl CF.sub.2H (difluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 56 3-((4-methylphenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 57 3-((4-fluorophenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 58 3-((4-chlorophenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 59 3-((4-bromophenyl)sulfonyl)-5- vinyl CF.sub.2H (difluoromethyl)-4,5-dihydro- sulfone 1H-pyrazole 60 3-((4-methoxyphenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 61 3-((3-methylphenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 62 3-((2-methylphenyl)sulfonyl)- vinyl CF.sub.2H 5-(difluoromethyl)-4,5- sulfone dihydro-1H-pyrazole 63 3-(methylsulfonyl)-5-(methyl)- vinyl branched 5-(trifluoromethyl)-4,5- sulfone alkyl dihydro-1H-pyrazole 64 3-(phenylsulfonyl)-5-(methyl)- vinyl branched 5-(trifluoromethyl)-4,5- sulfone alkyl dihydro-1H-pyrazole 65 3-(methylsulfonyl)-5- vinyl branched phenethyl-5-(trifluoromethyl)- sulfone alkyl 4,5-dihydro-1H-pyrazole 66 3-(methylsulfonyl)-5-(phenyl)- vinyl branched 5-(trifluoromethyl)-4,5- sulfone alkyl dihydro-1H-pyrazole 67 3-(methylsulfonyl)-5-(4- vinyl branched methylphenyl)-5- sulfone alkyl (trifluoromethyl)-4,5-dihydro- 1H-pyrazole 68 3-(methylsulfonyl)-5-(4- vinyl branched fluorophenyl)-5- sulfone alkyl (trifluoromethyl)-4,5-dihydro- 1H-pyrazole

[0137] As is derivable from Table 4, the process makes for an efficient synthesis of fluoroalkyl-substituted and sulfonyl-substituted pyrazoles and pyrazolines. In an embodiment, one requirement for this may be the continuous preparation of the fluorinated diazo compound in good yield in the first step.

EXAMPLE 69

Preparation of 3-(Phenylsulfonyl)-5-(Difluoromethyl)-4,5-Dihydro-1H-Pyrazole

a) Preparing the Fluorinated Diazoalkane

[0138] Two stock solutions were prepared. 2,2-Difluoroethylamine (0.4 M, 4 eq) was dissolved in CHCl.sub.3. tert-Butyl nitrite (0.48 M, 4.8 eq) and 5 mol % of acetic acid (0.16 M, 0.2 eq) were likewise dissolved in CHCl.sub.3. Both solutions were initially charged to a syringe and added by syringe pumping at a flow rate of 50 L/min via a micromixer (Little Things Factory, MR Lab Type MST) having a capacity of 0.2 mL and a microreactor (CS Chromatographie PTFE tubing, Article No. 590515, ID=0.8 mm, length 1.6 m) having a volume of 0.8 mL. The micromixer and the microreactor were heated to 55 C. The mixture of the reactants had a residence time of 10 minutes in the microreactor.

b) Reacting the Fluorinated Diazoalkane with a Dipolarophile in a 1,3-Dipolar Cycloaddition Reaction in a Second Microreactor

[0139] A third stock solution was prepared: phenyl vinyl sulfone (0.1 M, 1 eq) was dissolved in CHCl.sub.3. This solution was initially charged to a syringe and added by syringe pumping at a flow rate of 50 L/min together with the downstream tubing end of the first reactor connected to a second micromixer (Little Things Factory, MR Lab Type MST) and a microreactor (CS Chromatographie PTFE tubing, Article No. 590515, ID=0.8 mm, length 2.6 m) having a capacity of 1.3 mL. The micromixer and the microreactor were heated to 55 C. The downstream tubing end of the second reactor was connected to a back pressure valve (20 psi) and then directed into a round bottom flask. On completion of the addition of the reactants into the micromixers/microreactors, the collected reacted solution was desolventised under reduced pressure and the residue was purified by column chromatography to obtain 3-(phenylsulfonyl)-5-(difluoromethyl)-4,5-dihydro-1H-pyrazole.

EXAMPLE 70

Gramwise Preparation of 3-(Phenylsulfonyl)-5-(Difluoromethyl)-4,5-Dihydro-1H-Pyrazole

a) Preparing the Fluorinated Diazoalkane

[0140] Two stock solutions were prepared. 2,2-Difluoroethylamine (0.4 M, 4 eq) was dissolved in CHCl.sub.3. Tert-Butyl nitrite (0.48 M, 4.8 eq) and 5 mol % acetic acid (0.02 M, 0.2 eq) were likewise dissolved in CHCl.sub.3. Altogether 50 mL of both stock solutions (corresponding to 20 mmol of 2,2-difluoroethylamine) were prepared. Compared with the preparation of 3-(phenylsulfonyl)-5-(difluoromethyl)-4,5-dihydro-1H-pyrazole as per Example 40, the amine solution had twice the concentration. Both solutions were initially charged at room temperature (202 C.) to a syringe and added by syringe pumping at a flow rate of 50 L/min via a micromixer (Little Things Factory, MR Lab Type MST) having a capacity of 0.2 mL and a microreactor (CS Chromatographie PTFE tubing, Article No. 590515, ID=0.8 mm, length 1.6 m) having a volume of 0.8 mL. The micromixer and the microreactor were heated to 55 C. The mixture of the reactants had a residence time of 10 minutes in the microreactor.

[0141] At a flow rate of 50 L/min, the addition time for the 50 mL volumes used in both cases was altogether 16.6 hours.

b) Reacting the Fluorinated Diazoalkane with a Dipolarophile in a 1,3-Dipolar Cycloaddition Reaction

[0142] The downstream tube end of the reactor was directed into a flask which was initially charged with 1 eq of phenyl vinyl sulfone (5 mmol) dissolved in chloroform. On completion of the addition the reaction solution was stirred for a further 24 hours at room temperature (202 C.). The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain 1.08 g of 3-(phenylsulfonyl)-5-(difluoromethyl)-4,5-dihydro-1H-pyrazole.

[0143] The amount of product obtained shows that fluorinated diazoalkane was made in gram amounts for the synthesis of step b). The gramwise preparation of 3-(phenylsulfonyl)-5-(difluoromethyl)-4,5-dihydro-1H-pyrazole required an addition time of about 17 hours. Yet the continuously prepared fluorinated diazoalkane did not accumulate, ensuring process safety even at the high concentrations, volumes and reaction times used.

COMPARATIVE EXAMPLE 71

Preparation of 2,2-Difluoromethyldiazomethane by Conjoint Initial Charging of Reactants

[0144] In a comparative experiment, difluoroethylamine and tert-butyl nitrite were initially charged conjointly at room temperature. Difluoroethylamine (1 eq) in chloroform was initially charged to a 50 mL flask. 5 mol % of acetic acid and tert-butyl nitrite (1.2 eq) were added and the reaction mixture was stirred at room temperature (202 C.). Samples of the reaction solution were taken at regular intervals and analysed by NMR. Table 5 below contains data points from this experiment and indicates the amount-of-substance fraction of amine and of diazo compound in the initially charged solution.

TABLE-US-00005 TABLE 5 Amine and diazo compound amount-of- substance fractions on conjoint initial charging of starting materials Diazo Time Amine compound 30 min 93% 2% 120 min 72% 4% 180 min 26% 3%

[0145] As is derivable from Table 5, within just three hours, the amount of substance decreased significantly for the difluoroethylamine reactant. The desired diazo compound was only formed to a minimal extent. It is believed that a background reaction led to premature consumption of the amine and hence to a reduction in the yield of diazo compound. This experiment shows that the conjoint initial charging of all three starting materialsamine, nitrite and acetic acidto one vessel at room temperature is unsuitable for above 2 hour addition times into the microreactor.

COMPARATIVE EXAMPLE 72

Preparation of 2,2-Difluoromethyldiazomethane by Conjoint Initial Charging of Starting Materials

[0146] In further comparative experiments in the batch mode, 162 mg (2 mmol) of 2,2-difluoroethylamine, 2.4 mmol of tert-butyl nitrite (1.2 eq) and 0.2 mmol of acetic acid (5 mol %) in 2 ml of CDCl.sub.3 were in each case initially charged conjointly. ,,-Trifluorotoluene was added as internal standard and the reaction vessels were sealed. A comparative batch was stirred at room temperature (202 C.) and samples were taken after 30, 60, 120 and 180 minutes. Further comparative batches were stirred at 55 C. for 5, 15, 30, 60, 120 and 180 minutes and, after the particular reaction time, briefly cooled in an ice bath before a sample was taken and analysed by NMR.

[0147] FIGS. 3a) and 3 b) show the respective yields of difluoromethyldiazomethane and the residual amounts of difluoroethylamine for the experiments at 55 C. and at room temperature. As is derivable from FIG. 3 a), the amount of the difluoroethylamine decreased rapidly at 55 C. while merely small amounts of difluoromethyldiazomethane were formed. The highest yield of 15% was obtained after a reaction time of 15 minutes. At room temperature, merely traces of difluoromethyldiazomethane were detected, while the starting amount of difluorethylamine likewise decreased to about 70% after 2 hours.

[0148] This shows that on conjoint initial charging of the amine, nitrite and acetic acid starting materials to one vessel at 55 C., the maximum yield of difluoromethyl diazomethane was 15% after 15 minutes. If all starting materials were charged together at room temperature, only traces of difluoromethyl diazomethane were formed. Both at room temperature and at 55 C., the reactants decompose under these conditions.

[0149] This illustrates that neither at elevated temperatures nor at room temperature sufficiently high yields for an industrial production can be achieved if the starting materials ,-difluoroalkylamine and nitrite are initially charged together in a vessel. A continuous process, on the other hand, makes it possible to achieve consistently high yields over a prolonged period of time, which, for example, enable further chemical transformations.

EXAMPLES 73-79

Preparation of Difluoromethyldiazomethane by Continuous Flow

[0150] 0.2 M of 2,2-difluoroethylamine was dissolved in anhydrous devolatilised CHCl.sub.3. In a further vessel, 0.24 M of tert-butyl nitrite and 0.08 M of acetic acid were dissolved in anhydrous devolatilised CHCl.sub.3. Both solutions were filled into syringes, introduced into a syringe pump (Chemyx Fusion V710) and connected via PTFE tubing to a micromixer having an internal volume of 200 L (Little Things Factory, MR-LAB Type MST). The micromixer likewise served as microreactor, a back pressure valve (IDEX back pressure assembly) creating a pressure of 20 psi. At the outlet, the particular reaction mixture was removed and analysed as a whole by NMR.

[0151] Samples using 10, 20 or 40 mol % of acetic acid were transported at respectively constant flow rates of 13, 25 or 50 L/min into the reactor, which was preheated to temperatures of 55 C., 75 C. and 90 C. The particular examples are summarised below in Table 6.

TABLE-US-00006 TABLE 6 Examples 73-79 Ex- Flow rate Temperature Acetic acid ample [L/min] [ C.] [mol %] 73 50 55 10 74 50 75 10 75 25 75 10 76 13 75 10 77 50 75 20 78 50 75 40 79 50 90 40

[0152] FIG. 4 shows the respectively obtained yields of difluoromethyldiazomethane reported in % on the Y-axis. As is derivable from FIG. 4, in contradistinction to the batch reaction, a yield of more than 10% was obtained continuously in all experiments. The reaction mixture may further be added directly to subsequent reactions. Scalability is obtainable by adding the volume flow across a longer period, or by parallelising the microreactors.