GB2037286A - Process for the preparation of substituted malonic acid dinitriles - Google Patents
Process for the preparation of substituted malonic acid dinitriles Download PDFInfo
- Publication number
- GB2037286A GB2037286A GB7942396A GB7942396A GB2037286A GB 2037286 A GB2037286 A GB 2037286A GB 7942396 A GB7942396 A GB 7942396A GB 7942396 A GB7942396 A GB 7942396A GB 2037286 A GB2037286 A GB 2037286A
- Authority
- GB
- United Kingdom
- Prior art keywords
- substituted
- cyanogen chloride
- acetonitrile
- malonic acid
- aromatically
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 31
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical class ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 150000007960 acetonitrile Chemical class 0.000 claims abstract description 10
- 239000011541 reaction mixture Substances 0.000 claims description 6
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical class N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 7
- 239000007789 gas Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- JHQBLYITVCBGTO-UHFFFAOYSA-N 2-(4-fluorophenyl)acetonitrile Chemical compound FC1=CC=C(CC#N)C=C1 JHQBLYITVCBGTO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 description 1
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- -1 alkali metal hydrogen carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000007656 barbituric acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000004071 soot Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/04—Preparation of carboxylic acid nitriles by reaction of cyanogen halides, e.g. ClCN, with organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
Abstract
A process for the preparation of an aromatically or heteroaromatically- substituted malonic acid dinitriles which comprises introducing separately, in gaseous form, into a reactor, an appropriate aromatically- or heteroaromatically- substituted acetonitrile and cyanogen chloride, the reaction being carried out in the gas phase at a temperature of from 550 to 800 DEG C. The dinitriles may be used, inter alia, in the preparation of pharmaceuticals.
Description
SPECIFICATION
Process for the preparation of substituted malonic acid dinitriles
This invention relates to a process for the preparation of substituted ma lonic dinitriles; more particularly, it relates to a process for the preparation of aromatically or heteroaromatically - substituted malonic acid dinitriles by reacting aromatically - or heteroaromatically - substituted acetonitriles with cyanogen chloride in the gas phase at elevated temperature. The aromatically - or heteroaromatically substituted malonicacid dinitriles may be used, interalia, as starting materials for the preparation of pharmaceutically active substances, particularly barbituric acid derivatives.
It is known that phenyl malonic acid dinitrile may be prepared by reacting phenyl acetonitrile with cyanogen chloride in the gas phase in a reaction tube at temperature of from 575 to 6400C. To this end, the starting materials are introduced in liquid form and volatilised at the inlet end of the reaction tube (Ind. Eng.
Chem., Prod. Res. Div., 14 (1975), 158 to 161). Although favourable conversions are obtained in this process, the yield of pure phenyl malonic acid dinitrile amounts to only about 50%. The volume-time yield is moderate. In addition, decomposition products, particularly soot, are deposited in the reaction tube, with the result that the tube becomes blocked after a relatively short period of operation. Consequently, this process is not suitable for working on a commercial scale.
A process for the preparation of aromatically - or heteroaromatically - substituted malonic acid dinitriles by reacting aromatically - or heteroaromatically - substituted acetonitriles with cyanogen chloride in the gas phase at elevated temperature has now been found and is characterised in that the substituted acetonitrile and the cyanogen chloride are separately introduced into the reactor in gaseous form and the reaction is carried out at temperatures of from 550 to 800"C.
In this process, the yield of pure phenyl malonic acid dinitrile amounts to more than 70 %. High volume-time yields are obtained. The reactor remains free from deposits over long periods of operation. The process according to the present invention may be used with equal effect for the production of a variety of aromatically or heteroaromatically-substituted malonic acid dinitriles and is eminently suitable for working on a commercial scale.
The process according to the present invention is suitable for the preparation of aromatically - or heteroaromatically - substituted malonic acid dinitriles corresponding to the following general formula (I):
wherein R represents, in particular, a phenyl, pyridyl orthienyl radical optionally substituted one or more times by halogen, preferably fluorine or chorine.
To carry out the present process, cyanogen chloride is reacted with aromatically - heteroaromatically substituted acetonitriles corresponding to the following general formula (ill): R - CH2 - CN (II) wherein R is as defined above. Suitable aromatically- or heteroaromatically- substituted acetonitriles include, for example, phenyl acetonitrile, o-, m-, p-fluorophenyl acetonitrile, o-, m-, p-chlorophenyl acetonitrile, pyridyl-2-acetonitrile, pyridyl-3-acetonitrile, pyridyl-4-acetonitrile, thienyl-2-acetonitrile and thienyl-3-acetonitrile.
The reaction temperature and the quantitative ratios between the reactants may be interdependent and may be governed by the type of reactants.
The reaction is generally carried out at temperatures of from 550 to 800"C, preferably from 600 to 700"C.
Although the reaction may be carried out under various pressures, i.e. under normal pressure or under a lower or higher pressure, it is generally advantageous to use a pressure which does not differ significantly from normal pressure.
The molar ratio between substituted acetonitrile and cyanogen chloride may be selected largely as required, i.e. it is possible to use a stoichiometric molar ratio or above or below a stoichiometric molar ratio.
In general, it is advantageous to use at least 1 mole of the acetonitrile per mole of cyanogen chloride. It is preferred to use from 1 to 10 moles and, with particular preference, from 2 to 6 moles, of the acetonitrile per mole of cyanogen chloride.
The process according to the present invention is advantageously carried out continuously. To this end, it is preferable to use a reactor of the tubular type, for example in the form of a nest of tubes.
According to the present invention, the starting materials, i.e. the substituted acetonitrile and the cyanogen chloride, are introduced separately into the reactor in gaseous form. Accordingly, on entering the reactor, the substances are above the boiling points thereof. It is generally advantageous to introduce the substances into the reactor at temperature close to the reaction temperature, i.e. at temperatures of from 550 to 800 C, preferably from 600 to 700 C.
The reaction mixture may be diluted with one or more inert gases, such as nitrogen or steam. The inert gases may be introduced together with the substituted acetonitrile and/or the cyanogen chloride or separately therefrom. It is generally preferred to use no more than 2 parts, by volume, of inert gas per part, by volume, of cyanogen chloride. The cyanogen chloride may be used either in pure form or in the form of a crude product of the type accumulating in the production of cyanogen chloride from chlorine and hydrogen cyanide.
The pure substituted malonic acid dinitrile may be recovered from the reaction mixture in various ways, for example by distillation or by alkaline extraction (Ind. Eng. Chem., Prod. Res. Div., 14(1975), 160). It is advantageous to cool the reaction mixture to temperatures below 100 C immediately it leaves the reactor.
This may be done in a conventional way, more particularly by washing the gases with liquids, preferably water. Since it is also advantageous to treat the reaction mixture with bases, immediately it is preferred to add basic substances to the washing liquids. Aqueous solutions of basic substances, particularly alkali metal hydroxides, alkali metal carbonates or alkali metal hydrogen carbonates, are preferably used for washing.
The following Examples illustrate the present invention.
Example 1
An externally heated quartz tube 1 m long and 39 mm wide was used as the reactor. 37 g (0.6 mole)/h of cyanogen chloride pre-heated to 580"C and 240 g (2.0 moles)/h of phenyl acetonitrile also pre-heated to 580"C were separately introduced into the tube in a uniform stream. The reaction temperature was 650"C. In a gas scrubber immediately following the reactor, the reaction mixture was treated with 2 litresih of a 5 % aqueous sodium hydroxide solution. The aqueous mixture flowing from the gas scrubber was extracted with dichloromethane. The unreacted phenyl acetonitrile and the extractant were recovered from the extract by distillation.The residual aqueous phase was adjusted to a pH of below 2 using concentrated aqueous hydrochloric acid and then extracted with dichloromethane. The dichloromethane was distilled off from the extract and recovered, leaving the phenyl malonic acid dinitrile as residue. The yield amounted to 63 g!h (corresponding to 74 %), based on the cyanogen chloride used. The phenyl malonic acid dinitrile had a melting point of from 64 to 65"C. It was found by gas chromatography to have a purity of more than 99 %.
Example 2
The procedure was as in Example 1, except that a quartz tube only 20 mm wide was used. 11 g (0.18 mole)/h of cyanogen chloride and 72 g (0.61 mole)/h of phenyl acetonitrile, both of which has been pre-heated to 600 C, were introduced separately into the reactor. The reaction temperature was 685 C. The yield of phenyl malonic acid dinitrile amounted to 21.2 g/h (corresponding to 83 %), based on the cyanogen chloride used. The phenyl malonic acid dinitrile had a purity of 99 %.
Example 3
The procedure was as in Example 1, except that 37 g (0.6 mole)/h of cyanogen chloride and 259 g (1.9 mole)/h of p-fluorophenyl acetonitrile, both pre-heated to 61 0C, were used. The reaction temperature was 680"C. The yield ofp-fluorophenyl malonic acid dinitrile amounted to 62 g/h (corresponding to 77 %), based on the cyanogen chloride used. The substance was found by gas chromatography to have a purity of more than 98%.
Example 4
The procedure was as in Example 2, except that 9.9 g (0.16 mole)/h of cyanogen chloride and 73.8 g (0.6 mole)/h of thienyl-3-acetonitrile, both pre-heated to 600 C, were used. The reaction temperature was 650do.
The yield of thienyl-3-malonic acid dinitrile amounted to 12 g/h (corresponding to 50 %), based on the cyanogen chloride used. The substance was found by gas chromatography to have a purity of more than 97 %.
Claims (10)
1. A process for the preparation of an aromatically- or heteroaromatically - substituted malonic acid dinitrile which comprises introducing separately, in gaseous form, into a reactor, an appropriate aromatically - or heteroaromatically - substituted acetonitrile and cyanogen chloride, the reaction being carried out in the gas phase at a temperature of from 550 to 800 C.
2. A process as claimed in claim 1 in which the substituted acetonitrile corresponds to the following general formula:
R - CH2 - CN wherein R represents an optionally halogen - substituted phenyl, pyridyl orthienyl radical.
3. A process as claimed in claim 1 or claim 2 in which the reaction is carried out at a temperature of from 600 to 700C.
4. A process as claimed in any of claims 1 to 3 in which from 1 to 10 moles of substituted acetonitrile are used for mole of cyanogen chloride.
5. A process as claimed in claim 4 in which from 2 to 6 moles of substituted acetonitrile are used per mole of cyanogen chloride.
6. A process as claimed in any of claims 1 to 5 in which the substituted acetonitrile and the cyanogen chloride are introduced into the reactor at temperatures close to the reaction temperature.
7. A process as claimed in any of claims 1 to 6 in which, on leaving the reactor, the reaction mixture is immediately cooled and treated with aqueous base.
8. A process as claimed in claim 1 substantially as herein described.
9. A process as claimed in claim 1 substantially as herein described with reference to any of the
Examples.
10. An aromatically or heteroaromatica lly - substituted malonic acid dinitrile when prepared by a process as claimed in any of claims 1 to 9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782854197 DE2854197A1 (en) | 1978-12-15 | 1978-12-15 | METHOD FOR PRODUCING SUBSTITUTED MALONIC ACID REDITITILE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2037286A true GB2037286A (en) | 1980-07-09 |
| GB2037286B GB2037286B (en) | 1983-04-13 |
Family
ID=6057290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7942396A Expired GB2037286B (en) | 1978-12-15 | 1979-12-07 | Process for the preparation of substituted malonic acid dinitriles |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5583742A (en) |
| AT (1) | AT362774B (en) |
| BE (1) | BE880557A (en) |
| CH (1) | CH641442A5 (en) |
| DE (1) | DE2854197A1 (en) |
| FR (1) | FR2444027A1 (en) |
| GB (1) | GB2037286B (en) |
| IT (1) | IT7951079A0 (en) |
| NL (1) | NL7907361A (en) |
| SU (1) | SU1048982A3 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1173479A (en) * | 1966-11-28 | 1969-12-10 | Little Inc A | Improvements in method for Synthesizing Malononitrile |
-
1978
- 1978-12-15 DE DE19782854197 patent/DE2854197A1/en not_active Withdrawn
-
1979
- 1979-10-03 NL NL7907361A patent/NL7907361A/en not_active Application Discontinuation
- 1979-11-19 FR FR7928483A patent/FR2444027A1/en active Granted
- 1979-12-06 SU SU792847575A patent/SU1048982A3/en active
- 1979-12-07 GB GB7942396A patent/GB2037286B/en not_active Expired
- 1979-12-11 BE BE6/47031A patent/BE880557A/en not_active IP Right Cessation
- 1979-12-13 IT IT7951079A patent/IT7951079A0/en unknown
- 1979-12-14 CH CH1111979A patent/CH641442A5/en not_active IP Right Cessation
- 1979-12-14 AT AT0789479A patent/AT362774B/en active
- 1979-12-15 JP JP16220279A patent/JPS5583742A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AT362774B (en) | 1981-06-10 |
| FR2444027B1 (en) | 1984-01-27 |
| JPS5583742A (en) | 1980-06-24 |
| GB2037286B (en) | 1983-04-13 |
| DE2854197A1 (en) | 1980-07-03 |
| NL7907361A (en) | 1980-06-17 |
| FR2444027A1 (en) | 1980-07-11 |
| CH641442A5 (en) | 1984-02-29 |
| IT7951079A0 (en) | 1979-12-13 |
| BE880557A (en) | 1980-06-11 |
| SU1048982A3 (en) | 1983-10-15 |
| ATA789479A (en) | 1980-11-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |