CA1082198A - Process for preparation of a therapeutically active compound - Google Patents
Process for preparation of a therapeutically active compoundInfo
- Publication number
- CA1082198A CA1082198A CA306,260A CA306260A CA1082198A CA 1082198 A CA1082198 A CA 1082198A CA 306260 A CA306260 A CA 306260A CA 1082198 A CA1082198 A CA 1082198A
- Authority
- CA
- Canada
- Prior art keywords
- wittig reagent
- formula
- reacted
- bromophenyl
- pyridyl
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- IDGVUIHZWDVXOQ-UHFFFAOYSA-N (4-bromophenyl)-pyridin-3-ylmethanone Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=CN=C1 IDGVUIHZWDVXOQ-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Chemical group 0.000 claims description 3
- 239000001257 hydrogen Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NBYQRBQKOIJRNX-UHFFFAOYSA-M [Br-].CN(C)C1=C(C=CC=C1)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)CC Chemical compound [Br-].CN(C)C1=C(C=CC=C1)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)CC NBYQRBQKOIJRNX-UHFFFAOYSA-M 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- WLNKGGRXEOAKBY-UHFFFAOYSA-N bis(4-bromo-2-pyridin-3-ylphenyl)methanone Chemical compound C=1C=CN=CC=1C1=CC(Br)=CC=C1C(=O)C1=CC=C(Br)C=C1C1=CC=CN=C1 WLNKGGRXEOAKBY-UHFFFAOYSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract:
A process for preparing therapeutically active compounds comprising preparation of a Wittig reagent and employing it in a reaction according to the reaction scheme:
NaOCH3 Ph3PO
A process for preparing therapeutically active compounds comprising preparation of a Wittig reagent and employing it in a reaction according to the reaction scheme:
NaOCH3 Ph3PO
Description
Astra Lakemedel AB
Sodertalje/SWEDEN
Inventor: P Bamberg RN/ACE
A novel process for preparation of a therapeutically active compound Description Techn_cal Field The present invention is related to a novel process for pre-5 paration of a therapeutically active compound.
.
An object of the invention is to provide a process enabling improved economy of production and avoiding use of chemicals that are difficult to handle.
Background Art Swedish Patent 361 663 discloses i.a. a compound of the formula '~
_ I _ ..
1~8Zl~
Br CH
~H2 N(CH3)2 10 believed to be useful as an anti-depressive agent, and a method for preparation thereof, comprising dehydration of an intermediate of the formula ~r ~ ~ II
/ ~
.,,. ' ' ' 25 The main disadvantages of the known method is that the pre-: paration of the intermediate is complicated, involving - chemicals which are difficult to handle, such as butyl lithium, and that only a low overall yield may be obtained.
30 Belgian Patent 835 802 discloses a related therapeutically ; active compound having the formula - . . , .: . . : .
.
',: ' . ' . :.. ~ :
1~8~8 J~ 111 CH
The present invention provides a process for preparation of a therapeutically active compaund of the formula Br VI
~CH
. CH3 R
-, wherein R is methyl or hydrogen, a geometrical isomer thereof or a therspcutically acceptable salt of said compound or geometrical isomer in any degree of hydration, characterized in that a Wittig reagent is :-prepared according to the following reaction scheme:
Ph3P * BrCH2CH2X ) ~Ph3 ~CH2CH2X ~ Br~3 ~h3P CH2CH2X~ B ~ 1 2 HN \ 3 .
rPh3P~3CH2CH2 ~ ~ 3 ~ CH ~ 2 (IV) : . , .
.. . . ' --` 10~ 8 Wherein Ph denotes a phenyl group, X represents Br or OPh and R is as defined above; and either the Wittig reagent of formula IV is reacted with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium methylate according to the following reaction scheme:
3PCH2CH2N ~ ~ B ~ ~ NaOCH3 ~ ~ C
O
(IV) (V) Br NaBr I CH30H + ~ C ~ ~ Ph3PO
CH
CH2N ~ 3 :, , CVI) or the Wittig reagent of formula IV is reacted with a base to form a Wittig reagent of the formula : CH
Ph3P CH C 2N \
R
: which is reacted with 4-bromophenyl-3-pyridyl-ketone.
In-oné embodiment the present invention provides a process for preparation of a compound of formula I or III characterized in that a Wittig reagent is prepared according to the following reaction scheme: .
?~
- , , , ~
., . , : . . :- ~ . :
. ~ .. . .. . .
:: : .: : ,,, :, ,'',," ' '': ' ' , . .' ~ ' ' ~ ':
- ~0821~8 Ph3P + BrCH2CH2Br~~~~~ ~ Ph3 ~CH2CH2Br3 B ~ ;
[Ph3 ~CH2CH2B~ B~ + 2HN 3 ~ ~Ph3P CH2CH2N H3 ] B ~ +
CH ~ H
3 \N / B ~ (IV) R/ \ H
wherein Ph denotes phenyl and R denotes CH3 or H, and reacted with 4-bromophenyl-3-pyridylketone in the presence of sodium methylate according : to the following scheme:
[Ph3PCH2CH2N ~ 3] B ~ + NaOCH3 + ~ / ~ N
, lCI -:
(IV) (V) Br Na~r ~ CH~OH t ~ ~ I ph~rO
; H
: ¦ ~ CH
CH2N;\ 3 R
; (VI) The last reaction step is suitably carried out in a solvent such as dimethylformamide, hexamethylphosphorus-~riamide or di-methylsulfoxide. The new manner of preparing the Wittig reagent has surprisingly been found to be operable and is technically advantageous.
A further advantage of the new process is that the simple reactant sodium methylate may be used as a base instead of butyl lithium often used in .
... -, - 5-,.~.,~
., . . . - . .: .
.. .. : ,: . . ' -, ~ . . : , . . . .
.
similar reactions. Butyl lithium is, as mentioned, difficult to handle and should if possible be avoided in production on a technical scale because of its strong reactivity, which i.a. may lead to self-ignition.
The therapeutically active end compound VI exists in two stereoisomeric forms, a Z-form and an E-form according to the IUPAC
nomenclature. The preferred isomer is the Z-isomer, having the configuration.
\ /
H ~ R
The preferred isomer may be obtained by isolation from an isomeric mixture of the end compound VI.
In another embodiment of the invention the Wittig reagent of formuls IV is prepared by the following reaction ~Ph3P-CH2CH20P ~ 3 ~ HN ~ ~ ~ h3P -CH-CH2N 3 ~ Br~
It is reacted with a base to form a Wittig reagent of formula Ph3P = CH-CH2N \ 3 which is then reacted with 4-bromophenyl-3-pyridyl ketone in accordance with the following reaction scheme B - 6 ~
, . .: . . .... . - : . . :
. .: .
.: - . . .. . , : -.
... ,.. , .. . . , . ., ~ .
- - .. . .. .
108Z1~8 base Ph P=CH-CH N
_ _ __ ~ 32 \ R
Ph3P=CH-CH N / 3 3r Vl I Ph3P0 lCI
:. O
,~ (V) .
wherein R represents methyl or hydrogen.
; The base with which the Wittig reagent of formula IV is reacted is preferably sodium methylate but this is not essential as other bases can be used.
Again the last reaction step, i.e. the reaction between the - Wittig reagent and the 4-bromophenyl-3-pyrityl-~etone, is carried out in a solvent such as dimethylformamide, hexamethylphosphorus-triamide or dimethylsulfoxide.
10The invention is further illustrated by the following example:
Step 1. Preparation of[Ph3~CH2CH2Br] BrG~
A mixture of triphenylphosphine (26.2 g, 0.1 mole) and 1,2-di-bromoethane (18.8 g, 0.1 m~le) in xylene (40 ml) was boiled gently for about 2.5 hours. A precipitate formed during this time. After cooling to ambient temperature the mixture was filtered and the crystals were washed with xylene yielding 29.2 g (65%) of product.
Step 2. Preparation of[m3PCH2CH2NMe2] B ~
;
A solution of 2-bromoethylenetriphenylphosphonium bromide (13.5 g, 0.03 mole) in acetonitrile (200 ml) was treated in the cold 20with dimethylamine (20 g, 0.44 mole) in 50 ml of acetonitrile. The . .
,:
108~
mixture was kept at ambient temperature over night and filtered. The crystals were washed with acetone yielding the product, mp 200-203C.
Step 3. N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allyl-amine-dihydrochloride .
To 0.14 g (2.5 mmol) of sodium methylate in 1 ml of dimethyl-formamide was added a suspension of 1,4 g t2.5 mmol) dimethylamino ethyltriphenyl-phosphonium bromide in 2 ml of dimethylformamide. After a few minutes stirring 0.66 g (2.5 mmol) 3-pyridyl-4-bromophenylketone was added in 2 ml of dimethylformamide. A brown solution was formed.
lOj The mixture was stirred at room temperature overnight and thereafter poured into ice water. The oily precipitate was extracted with ether.
The ether phase was washed with water and evaporated. The residue was stirred with ether/petroleum ether 1:2, whereby triphenyl-phospineoxide crystallized. The crystals were filtered off and the mother lye was evaporated. The residue was extracted with hexane (2 x 10 ml), and to the hexane solution was added l ml of concentrated hydrochloric acid. Two phases were formed. A mixture of ethanol/ether 1:1 was dropped in until one homogenous phase was obtained. The product then crystallized, and after cooling 0.3 g (ca 30~) thereof was isolated. M.p. 178--192C. This product gave no depression of the melting point on admixture with an authentic sample. The MMR-spectrum was identical to that of an authentic sample.
While being advantageous over previously known processes for preparing the compound of formula VI the modified processes above do not have all the advantages of the original process of the present invention.
.
18~19~3 Industrial Applicability The compound and the methods of the invention are useful in the pharmaceutical industry, especially in preparation of a compound of formula VI above in a technical scale.
,~ _ g_ - . . .
. '. ' . ~ :
Sodertalje/SWEDEN
Inventor: P Bamberg RN/ACE
A novel process for preparation of a therapeutically active compound Description Techn_cal Field The present invention is related to a novel process for pre-5 paration of a therapeutically active compound.
.
An object of the invention is to provide a process enabling improved economy of production and avoiding use of chemicals that are difficult to handle.
Background Art Swedish Patent 361 663 discloses i.a. a compound of the formula '~
_ I _ ..
1~8Zl~
Br CH
~H2 N(CH3)2 10 believed to be useful as an anti-depressive agent, and a method for preparation thereof, comprising dehydration of an intermediate of the formula ~r ~ ~ II
/ ~
.,,. ' ' ' 25 The main disadvantages of the known method is that the pre-: paration of the intermediate is complicated, involving - chemicals which are difficult to handle, such as butyl lithium, and that only a low overall yield may be obtained.
30 Belgian Patent 835 802 discloses a related therapeutically ; active compound having the formula - . . , .: . . : .
.
',: ' . ' . :.. ~ :
1~8~8 J~ 111 CH
The present invention provides a process for preparation of a therapeutically active compaund of the formula Br VI
~CH
. CH3 R
-, wherein R is methyl or hydrogen, a geometrical isomer thereof or a therspcutically acceptable salt of said compound or geometrical isomer in any degree of hydration, characterized in that a Wittig reagent is :-prepared according to the following reaction scheme:
Ph3P * BrCH2CH2X ) ~Ph3 ~CH2CH2X ~ Br~3 ~h3P CH2CH2X~ B ~ 1 2 HN \ 3 .
rPh3P~3CH2CH2 ~ ~ 3 ~ CH ~ 2 (IV) : . , .
.. . . ' --` 10~ 8 Wherein Ph denotes a phenyl group, X represents Br or OPh and R is as defined above; and either the Wittig reagent of formula IV is reacted with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium methylate according to the following reaction scheme:
3PCH2CH2N ~ ~ B ~ ~ NaOCH3 ~ ~ C
O
(IV) (V) Br NaBr I CH30H + ~ C ~ ~ Ph3PO
CH
CH2N ~ 3 :, , CVI) or the Wittig reagent of formula IV is reacted with a base to form a Wittig reagent of the formula : CH
Ph3P CH C 2N \
R
: which is reacted with 4-bromophenyl-3-pyridyl-ketone.
In-oné embodiment the present invention provides a process for preparation of a compound of formula I or III characterized in that a Wittig reagent is prepared according to the following reaction scheme: .
?~
- , , , ~
., . , : . . :- ~ . :
. ~ .. . .. . .
:: : .: : ,,, :, ,'',," ' '': ' ' , . .' ~ ' ' ~ ':
- ~0821~8 Ph3P + BrCH2CH2Br~~~~~ ~ Ph3 ~CH2CH2Br3 B ~ ;
[Ph3 ~CH2CH2B~ B~ + 2HN 3 ~ ~Ph3P CH2CH2N H3 ] B ~ +
CH ~ H
3 \N / B ~ (IV) R/ \ H
wherein Ph denotes phenyl and R denotes CH3 or H, and reacted with 4-bromophenyl-3-pyridylketone in the presence of sodium methylate according : to the following scheme:
[Ph3PCH2CH2N ~ 3] B ~ + NaOCH3 + ~ / ~ N
, lCI -:
(IV) (V) Br Na~r ~ CH~OH t ~ ~ I ph~rO
; H
: ¦ ~ CH
CH2N;\ 3 R
; (VI) The last reaction step is suitably carried out in a solvent such as dimethylformamide, hexamethylphosphorus-~riamide or di-methylsulfoxide. The new manner of preparing the Wittig reagent has surprisingly been found to be operable and is technically advantageous.
A further advantage of the new process is that the simple reactant sodium methylate may be used as a base instead of butyl lithium often used in .
... -, - 5-,.~.,~
., . . . - . .: .
.. .. : ,: . . ' -, ~ . . : , . . . .
.
similar reactions. Butyl lithium is, as mentioned, difficult to handle and should if possible be avoided in production on a technical scale because of its strong reactivity, which i.a. may lead to self-ignition.
The therapeutically active end compound VI exists in two stereoisomeric forms, a Z-form and an E-form according to the IUPAC
nomenclature. The preferred isomer is the Z-isomer, having the configuration.
\ /
H ~ R
The preferred isomer may be obtained by isolation from an isomeric mixture of the end compound VI.
In another embodiment of the invention the Wittig reagent of formuls IV is prepared by the following reaction ~Ph3P-CH2CH20P ~ 3 ~ HN ~ ~ ~ h3P -CH-CH2N 3 ~ Br~
It is reacted with a base to form a Wittig reagent of formula Ph3P = CH-CH2N \ 3 which is then reacted with 4-bromophenyl-3-pyridyl ketone in accordance with the following reaction scheme B - 6 ~
, . .: . . .... . - : . . :
. .: .
.: - . . .. . , : -.
... ,.. , .. . . , . ., ~ .
- - .. . .. .
108Z1~8 base Ph P=CH-CH N
_ _ __ ~ 32 \ R
Ph3P=CH-CH N / 3 3r Vl I Ph3P0 lCI
:. O
,~ (V) .
wherein R represents methyl or hydrogen.
; The base with which the Wittig reagent of formula IV is reacted is preferably sodium methylate but this is not essential as other bases can be used.
Again the last reaction step, i.e. the reaction between the - Wittig reagent and the 4-bromophenyl-3-pyrityl-~etone, is carried out in a solvent such as dimethylformamide, hexamethylphosphorus-triamide or dimethylsulfoxide.
10The invention is further illustrated by the following example:
Step 1. Preparation of[Ph3~CH2CH2Br] BrG~
A mixture of triphenylphosphine (26.2 g, 0.1 mole) and 1,2-di-bromoethane (18.8 g, 0.1 m~le) in xylene (40 ml) was boiled gently for about 2.5 hours. A precipitate formed during this time. After cooling to ambient temperature the mixture was filtered and the crystals were washed with xylene yielding 29.2 g (65%) of product.
Step 2. Preparation of[m3PCH2CH2NMe2] B ~
;
A solution of 2-bromoethylenetriphenylphosphonium bromide (13.5 g, 0.03 mole) in acetonitrile (200 ml) was treated in the cold 20with dimethylamine (20 g, 0.44 mole) in 50 ml of acetonitrile. The . .
,:
108~
mixture was kept at ambient temperature over night and filtered. The crystals were washed with acetone yielding the product, mp 200-203C.
Step 3. N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allyl-amine-dihydrochloride .
To 0.14 g (2.5 mmol) of sodium methylate in 1 ml of dimethyl-formamide was added a suspension of 1,4 g t2.5 mmol) dimethylamino ethyltriphenyl-phosphonium bromide in 2 ml of dimethylformamide. After a few minutes stirring 0.66 g (2.5 mmol) 3-pyridyl-4-bromophenylketone was added in 2 ml of dimethylformamide. A brown solution was formed.
lOj The mixture was stirred at room temperature overnight and thereafter poured into ice water. The oily precipitate was extracted with ether.
The ether phase was washed with water and evaporated. The residue was stirred with ether/petroleum ether 1:2, whereby triphenyl-phospineoxide crystallized. The crystals were filtered off and the mother lye was evaporated. The residue was extracted with hexane (2 x 10 ml), and to the hexane solution was added l ml of concentrated hydrochloric acid. Two phases were formed. A mixture of ethanol/ether 1:1 was dropped in until one homogenous phase was obtained. The product then crystallized, and after cooling 0.3 g (ca 30~) thereof was isolated. M.p. 178--192C. This product gave no depression of the melting point on admixture with an authentic sample. The MMR-spectrum was identical to that of an authentic sample.
While being advantageous over previously known processes for preparing the compound of formula VI the modified processes above do not have all the advantages of the original process of the present invention.
.
18~19~3 Industrial Applicability The compound and the methods of the invention are useful in the pharmaceutical industry, especially in preparation of a compound of formula VI above in a technical scale.
,~ _ g_ - . . .
. '. ' . ~ :
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparation of a therapeutically active compound of the formula VI
wherein R is methyl or hydrogen, a geometrical isomer thereof or a therapeutically acceptable salt of said compound or geometrical isomer in any degree of hydration, characterized in that a Wittig reagent is prepared according to the following reaction scheme:
(IV) wherein Ph denotes a phenyl group, X represents Br or OPh and R is as defined above; and either the Wittig reagent of formula IV is reacted with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium methylate according to the following reaction scheme:
Br? + NaOCH3 + (V) NaBr + CH3OH + + PH3PO
(VI) or the Wittig reagent of formula IV is reacted with a base to form a Wittig reagent of the formula which is reacted with 4-bromophenyl-3-pyridyl-ketone.
wherein R is methyl or hydrogen, a geometrical isomer thereof or a therapeutically acceptable salt of said compound or geometrical isomer in any degree of hydration, characterized in that a Wittig reagent is prepared according to the following reaction scheme:
(IV) wherein Ph denotes a phenyl group, X represents Br or OPh and R is as defined above; and either the Wittig reagent of formula IV is reacted with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium methylate according to the following reaction scheme:
Br? + NaOCH3 + (V) NaBr + CH3OH + + PH3PO
(VI) or the Wittig reagent of formula IV is reacted with a base to form a Wittig reagent of the formula which is reacted with 4-bromophenyl-3-pyridyl-ketone.
2. A process according to claim 1 wherein X is a bromine atom.
3. A process according to claim 1 wherein X is a phenoxy group.
4. A process according to claim 1 wherein the Wittig reagent of formula IV is reacted with sodium methylate to form a Wittig reagent of the formula which is then reacted with 4-bromophenyl-3-pyridyl-ketone.
5. A process according to claim 1, 3 or 4 wherein the reaction between the Wittig reagent and 4-bromophenyl-3-pyridyl-ketone is carried out in an organic solvent.
6. A process according to claim 1, 3 or 4 wherein the reaction between the Wittig reagent and 4-bromophenyl-3-pyridyl-ketone is carried out in dimethyl formamide, hexamethylphosphornstriamide or dimethylsul-foxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7707707-1 | 1977-07-04 | ||
| SE7707707A SE409861B (en) | 1977-07-04 | 1977-07-04 | A NEW PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE PYRIDINE ASSOCIATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1082198A true CA1082198A (en) | 1980-07-22 |
Family
ID=20331764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA306,260A Expired CA1082198A (en) | 1977-07-04 | 1978-06-27 | Process for preparation of a therapeutically active compound |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5414976A (en) |
| AT (1) | AT365171B (en) |
| CA (1) | CA1082198A (en) |
| CH (1) | CH641163A5 (en) |
| DK (1) | DK295378A (en) |
| ES (1) | ES471302A1 (en) |
| FI (1) | FI64581C (en) |
| IT (1) | IT1105226B (en) |
| NL (1) | NL7807246A (en) |
| NO (1) | NO782304L (en) |
| SE (1) | SE409861B (en) |
| SU (1) | SU923366A3 (en) |
| WO (1) | WO1979000023A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7909514L (en) * | 1979-11-16 | 1981-05-17 | Astra Laekemedel Ab | NEW HALOPHENYL-PYRIDYL-ALLYLAMINE DERIVATIVES |
| FI20090389A7 (en) * | 2009-10-23 | 2011-04-24 | Kone Corp | Method of manufacturing an elevator |
| FI122066B (en) * | 2009-12-31 | 2011-08-15 | Kone Corp | A method of making a lift |
| FI20100223A0 (en) * | 2010-05-28 | 2010-05-28 | Kone Corp | Procedure and lift arrangement |
| FI20106273L (en) * | 2010-12-01 | 2012-06-02 | Kone Corp | Elevator arrangement and method |
| EP2636629B1 (en) * | 2012-03-06 | 2015-05-06 | KONE Corporation | A method and an elevator arrangement |
| US9388020B2 (en) * | 2012-03-06 | 2016-07-12 | Kone Corporation | Method and an elevator arrangement |
-
1977
- 1977-07-04 SE SE7707707A patent/SE409861B/en unknown
-
1978
- 1978-06-26 CH CH329979A patent/CH641163A5/en not_active IP Right Cessation
- 1978-06-26 WO PCT/SE1978/000009 patent/WO1979000023A1/en not_active Ceased
- 1978-06-27 CA CA306,260A patent/CA1082198A/en not_active Expired
- 1978-06-29 DK DK782953A patent/DK295378A/en not_active Application Discontinuation
- 1978-06-30 FI FI782115A patent/FI64581C/en not_active IP Right Cessation
- 1978-06-30 IT IT50123/78A patent/IT1105226B/en active
- 1978-06-30 ES ES471302A patent/ES471302A1/en not_active Expired
- 1978-07-03 NO NO782304A patent/NO782304L/en unknown
- 1978-07-04 JP JP8182078A patent/JPS5414976A/en active Pending
- 1978-07-04 NL NL7807246A patent/NL7807246A/en not_active Application Discontinuation
- 1978-07-04 AT AT0483778A patent/AT365171B/en not_active IP Right Cessation
-
1979
- 1979-08-03 SU SU792798502A patent/SU923366A3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FI782115A7 (en) | 1979-01-05 |
| IT7850123A0 (en) | 1978-06-30 |
| ES471302A1 (en) | 1979-09-01 |
| CH641163A5 (en) | 1984-02-15 |
| SE409861B (en) | 1979-09-10 |
| ATA483778A (en) | 1981-05-15 |
| FI64581C (en) | 1983-12-12 |
| JPS5414976A (en) | 1979-02-03 |
| AT365171B (en) | 1981-12-28 |
| IT1105226B (en) | 1985-10-28 |
| NL7807246A (en) | 1979-01-08 |
| FI64581B (en) | 1983-08-31 |
| DK295378A (en) | 1979-01-05 |
| WO1979000023A1 (en) | 1979-01-25 |
| SU923366A3 (en) | 1982-04-23 |
| NO782304L (en) | 1979-01-05 |
| SE7707707L (en) | 1979-01-05 |
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| MKEX | Expiry |