MXPA99002943A - Pictet-spengler reaction for the synthesis of tetrahydroisoquinolines and related heterocyclic compounds - Google Patents
Pictet-spengler reaction for the synthesis of tetrahydroisoquinolines and related heterocyclic compoundsInfo
- Publication number
- MXPA99002943A MXPA99002943A MXPA/A/1999/002943A MX9902943A MXPA99002943A MX PA99002943 A MXPA99002943 A MX PA99002943A MX 9902943 A MX9902943 A MX 9902943A MX PA99002943 A MXPA99002943 A MX PA99002943A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- created compound
- created
- formaldehyde
- lewis acid
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 230000002194 synthesizing Effects 0.000 title description 6
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 title description 4
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 title description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 41
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000002841 Lewis acid Substances 0.000 claims abstract description 12
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- NKDDWNXOKDWJAK-UHFFFAOYSA-N Dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- LOCDPORVFVOGCR-UHFFFAOYSA-N 2,4-Dithiapentane Chemical compound CSCSC LOCDPORVFVOGCR-UHFFFAOYSA-N 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L Magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 229920002866 paraformaldehyde Polymers 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- -1 aryl N-sulfonylethylamines Chemical class 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000002378 acidificating Effects 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- HFBYLYCMISIEMM-FFHNEAJVSA-N (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid Chemical class OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC HFBYLYCMISIEMM-FFHNEAJVSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CWGBFIRHYJNILV-UHFFFAOYSA-N (1,4-diphenyl-1,2,4-triazol-4-ium-3-yl)-phenylazanide Chemical compound C=1C=CC=CC=1[N-]C1=NN(C=2C=CC=CC=2)C=[N+]1C1=CC=CC=C1 CWGBFIRHYJNILV-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- CNTFLQRFLRXDMA-UHFFFAOYSA-N 3,3-dimethyl-2-(2-methylphenyl)sulfonyl-1,4-dihydroisoquinoline Chemical compound CC1=CC=CC=C1S(=O)(=O)N1C(C)(C)CC2=CC=CC=C2C1 CNTFLQRFLRXDMA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N Tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- TYPFXWHHTKMUCU-UHFFFAOYSA-N 2-methyl-N-(2-methyl-1-phenylpropan-2-yl)benzenesulfonamide Chemical compound CC1=CC=CC=C1S(=O)(=O)NC(C)(C)CC1=CC=CC=C1 TYPFXWHHTKMUCU-UHFFFAOYSA-N 0.000 description 1
- FXQNTOHRTXRWTM-UHFFFAOYSA-N 3,3-dimethyl-4H-isoquinoline Chemical compound C1=CC=C2C=NC(C)(C)CC2=C1 FXQNTOHRTXRWTM-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- 230000002292 Radical scavenging Effects 0.000 description 1
- NCVIXNVCXNGGBW-UHFFFAOYSA-N Sodium naphthalenide Chemical compound [Na+].C1=CC=CC2=C[CH][CH-]C=C21 NCVIXNVCXNGGBW-UHFFFAOYSA-N 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N Sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001066 destructive Effects 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
Abstract
A commercial scale process for the production of tetrahydroisoquinolines and related heterocyclics by reaction, in mildly acidic conditions, of aryl N-sulfonylethylamines in the presence of suitable Lewis acid, and a compound capable of in situ generation of formaldehyde. The process is further characterized by formaldehyde being generated by the reaction of the Lewis acid upon the formaldehyde generating agent, instead of being present as an initial reactant. The process further avoids the presence of initial water which destroys the Lewis acid before it can act upon the formaldehyde generating agent.
Description
REACTION OF PICTET-SPENGLER FOR THE SYNTHESIS OF TETRAHIDROISOQU INOLINES AND HETEROCICLIC COMPOUNDS
RELATIVES
Background of the Invention The present application relates to a novel synthesis for certain tetrahydroquinolines which are useful intermediates in the preparation of certain cyclic nitrones having multiple pharmaceutical utility, including, for example, the prevention of oxidizable tissue damage against free radicals. based on oxygen and the inhibition of interleuken-1. The utility of these cyclic nitrones and their advantages are best described in U.S. Patent No. 5,292,746. The reaction in Pictet-Spengler is a condensation of a β-arylethylamine with a carbonyl compound to give a tetrahydroisoquinoline, and is a specific example of the more general Mannich reaction. It has generally been accepted that the reactivity of the aromatic nucleus of the arylethylamine as well as the carbonyl reagent is significant for the success of the reaction. Whaley, W. M. & Govindachari, T.R., Organic Reactions 6: 151-190 (1951), the disclosure of which is incorporated herein by reference. Formaldehyde is routinely used, because it is cheap, reactive and effective. More importantly, Whaley and Govindachari have noted that the activation of the aromatic ring, by some form of electrophilic substitution to signal
ring closure was necessary before the reaction proceeded. The production of tetrahydroisoquinolines by means of the Pictet-Spengler condensation of unsubstituted aryl N-sulfonylethylamines was described by K. Ito and H. Tanaka in Chem. Pharm. Bull. 25 (7), 1732-1739 (1997), the description of which is incorporated herein by reference. The process conditions described the reaction in chloroform between sulfonated N-phenethylamines with aqueous formaldehyde in the presence of BF3-etherate. Because the formaldehyde was in an aqueous solution, and the water is destructive of the BF3-etherate, the BF3-etherate must be used in substantial molar excess. This procedure is feasible in a small laboratory scale, but it is very inefficient and expensive to be applicable to a synthesis on a commercial scale.
BRIEF DESCRIPTION OF THE INVENTION Applicants have created a process for the commercial scale production of tetrahydroisoquinolines and related heterocyclics by reaction, under mild acid conditions, of aryl N-sulfonylethylamines in the presence of a suitable Lewis acid, and a compound capable of in situ generation of formaldehyde. Applicants' invention is an improvement of the Ito and Tanaka process, in which the water is not present as an initial reagent (the formaldehyde used was a 37% aqueous solution). The applicant's process is also characterized by the
formaldehyde that is generated by the reaction of Lewis acid (boron trifluoroetherate) by the CH 0 generating agent, rather than being present as an initial reagent. The in situ generation of formaldehyde is advantageous because the formaldehyde reagent present is available only as a 37% aqueous solution, which requires a substantial molar excess of the Lewis acid to compensate for that which is deactivated by water. The invention describes a process for creating a compound of the formula:
wherein Ri and R2 are each independently C1 -3 alkyl or Ri and R2 together form an alkylene of C2-7, n is an integer of 0-2, R3 is hydrogen, halogen, C? ? -4, -CF3, -OCF3 and -OH, and Ts is para-toluenesulfonyl. By reacting a compound of the formula:
with a suitable Lewis acid in a solvent generating formaldehyde.
DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "suitable Lewis acid" means a strongly electrophilic compound capable of combining with another molecule to form at least one covalent bond with two electrons of the second molecule. For example, boron trifluoroetherate (BF3 «Oet2), aluminum chloride (AICI3), zinc chloride (ZnCl2), magnesium bromide (MgCl2), ferric chloride (FeCl3). The preferred Lewis acid is boron trifluoroetherate. As used herein, the term "formaldehyde generating solvent" means dimethoxy methane, paraformaldehyde, diethoxyethane, bis (methylthio) methane (CH2 (SCH3) 2). The preferred formaldehyde generating agent is dimethoxy methane. As used herein, the term "C?-3 alkyl" means methyl, ethyl, n-propyl, isopropyl. As used herein, the term "C2-7alkylene" means a straight-chain alkyl bridge of two valences, such that the same atom does not both valences. For example, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene. As used herein, the term "halogen" means fluorine, chlorine, bromine, iodine.
As used herein, the term "C? -4 alkyl" means a straight or branched chain alkyl of from one to four carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. As used herein, the term "C 1 -C 4 alkoxy" means a straight or branched alkoxy group of one to four carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy. The present invention is a useful part of a multi-step synthesis for the creation of certain nitrones useful in the prevention of damage to oxidizable tissues and which are described in the U.S. Patent. , No. 5,292,746. More particularly, this synthesis can be carried out as follows:
BF3? Et2 DMM
Oxidation
In the above scheme, the tosylated amine [2] can be prepared, as indicated by Ito and Tanaka, in the presence of three molar equivalents of triethylamine (NEt3). The tosylated amine can then be converted to the relative tetrahydroisoquinoline or heterocyclic [3] as described by the present invention. This compound, as is known, can then be subjected to alkaline conditions to give the dihydro analogue [4], Remers, W. A. et al., J. Org. Chem., 36, 1232-1240 (1971) or treated with sodium naphthalenide in DME to give the cyclic amine without protection [5], Heathcock et al., J. Org. Chem., 54: 7, 1548-1562 (1989). The compound [4] or [5] can then be oxidized to a nitron [6], for example, by application of sodium tungstate (NaWO) as described in "Synthesis and Radical Scavenging Activity of 3,3-Dialkil-3" , 4-Dihydro-lsoquinoline-2-Oxides ", Bioorganic & Medicinal Chemistry Letters, in presses), Berotas, R.C. , and collaborators. The following examples are given to illustrate in greater detail the practice of the invention, but should not be construed as limiting in any way. Example 1 To a solution of 1,1-dimethyl-2-phenyl-ethylamine (3.56 g, 0.019 mol), methylene chloride (CH2Cl2, 20 mL) and trethylamine (Et3N, 8.01 mL, 0.058 mol) in nitrogen atmosphere was added para-toluenesulfonyl chloride (TsCI, 4.39 g, 0.023 mol). The mixture was stirred at room temperature for 12 hours while monitored by chromatography. The reaction mixture was divided between
Methylene chloride (100 mL) and water (100 mL) and the organic layer was separated and dried over sodium sulfate. The drying agent was filtered and the filtrate was concentrated to give 5.73 g of N-toluenesulfonyl-1,1-dimethyl-2-phenyl-ethylamine (yield = 99%). IR (Kbr, cm-1) 3443.3283, 131 1, 1097; H1-NMR (300 Mhz, CDCl 3) d 7.72 (m, 2H), 7.21 -7.35 (m, 7H), 4.50 (bs, 1 H),
2. 83 (s, 2H), 2.40 (s, 3H), 1 .18 (s, 6H); C13-NMR (75 Mhz, CDCl 3) ppm 142.8, 140.6, 136.6, 130.8, 129.4, 128.2,
126. 9, 126.7, 56.9, 49.0, 27.4, 21.5; MS m / z (M +) calc'd 303.4, observed 304. Analysis calc'd for C? 7H? NO2S: C, 67.30; H, 6.98; N, 4.62. Found:
C, 67.23; H, 6.90; N, 4.55.
Example 2 To a mixture of N-toluensu-Ionyl-1, 1-dimethyl-2-phenylethylamine (8.30 g, 0.027 mol) in dimethoxymethane (50 mL) under nitrogen atmosphere was added boron trifluoroetherate (BF3 «OEt2, 9.9 mL, 0.081 mol). The mixture was stirred at room temperature for 12 hours while monitored by gas chromatography. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), separated, and the organic layer was washed with saturated sodium bicarbonate (2 x 100 mL) and dried over sodium sulfate (Na 2 SO 4). The drying agent was filtered and the filtrate was concentrated at 40 ° / 50 torr to give 8.55 g of N-toluenesulfonyl-3,3-dimethyl-1, 2,3,4-tetrahydroisoquinoline (yield = 99%).
I R (KBr, crtT1) 3441, 2984, 1338, 1 159; H1-NMR (300 Mhz, CDCl3) d 7.65 (m, 2H), 7.05-7.25 (m, 7H), 4.59 (s, 2H),
2. 39 (s, 3H), 1.40 (s, 6H); C13-NMR (75 Mhz, CDCl 3) ppm 142.7, 139.7, 134.5, 133.6, 129.4, 128.1,
127. 2, 126.9, 126.4, 125.4, 58.1, 46.9, 44.9, 27.7, 21.4; MS m / z (M +) calc'd 315.4, observed 315. Anal. Calcd for C? 8H2i NO2S: C, 68.54; H, 6.71; N, 4.44. Found: C,
68. 14; H, 6.70; N, 4.37.
Example 3 To a mixture of potassium hydroxide (KOH, 30 g) and methanol (CH 3 OH, 60 mL) under nitrogen atmosphere was added N-toluenesulfoni I-3,3-dimethyl-1, 2,3,4-tetrahydroisoquinoline (4.0 g, 0.013 mol). The reaction mixture was heated to reflux for 17 hours and the reaction was followed by gas chromatography. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and 10% HCl was slowly added until a pH = 7 was obtained. The aqueous mixture was extracted methylene chloride (3 x 100 mL) and the organic layers were combined and stirred with charcoal and sodium sulfate Na2SO4). The solution was filtered through celite and the filtrate was concentrated (25 ° / 150 torr) to give 3,3-dimethyl-3,4-dihydroisoquinoline (1.79 g, yield = 90%). IR (clean, crn "1) 3389, 2966, 1628; H1-N MR (300 Mhz, CDCl3) d 8.23 (s, 1 H), 7.40-7.15 (m, 4H), 2.72 (s, 2H), 1 .25 (s, 6H);
C13-N MR (75 Mhz, CDCl 3) ppm 157.4, 135.6, 131 .0, 128.0, 127.5, 127.0,
126. 9, 54.7, 37.9, 28.0; MS m / z (M +) calc'd 159.3, observed 159.
Example 4 To a stirred solution of naphthalene (5.8 g, 0.045 mol) in dimethoxyethane (50 mL) was added sodium metal (1.09 g, 0.039 mol). The mixture was stirred for four (4) hours until a dark green color persisted. To this was added N-toluenesulfonyl-3,3-dimethyl-1, 2,3,4-tetrahydroisoquinoline (5.0 g, 0.016 mol) in 20 mL of dimethoxymethane. The reaction was monitored by gas chromatography. When the reaction was complete ("2 hours), the mixture was quenched with saturated sodium chloride (70 mL). The mixture was partitioned between ethyl acetate (250 mL) and 10% HCl (250 mL) and the organic layer was discarded. 10% sodium hydroxide was added to the aqueous layer until a pH = 7 was obtained. The aqueous layer was further extracted over methylene chloride (2 x 100 mL), dried over magnesium sulfate, filtered and concentrated (25 ° C). C / 150 torr) to produce 2.2 g (86%) of 3,3-dimetiI-1, 2,3,4-tetrahydroisoquinoline. IR (clean, cm'1) 3043, 2897, 744; H1-NMR (300 Mhz, CDCl3) d 7.14-7.00 (m, 4H), 4.02 (s, 2H), 2.61 (s, 2H), 1.58 (bs, 1 H), 1.19 (s, 6H) ); C 13 NMR (75 Mhz, CDCl 3) 134.5, 134.4, 129.5, 125.9, 125.6, 125.5, 48.6, 44.3, 41.5, 27.7; MS m / z (M +) calc'd 161 .24, observed161.
Claims (32)
- CLAIMS 1. A process to create a compound of the formula: wherein Ri and R2 are each independently alkyl of Cr C3 or R (and R2 together form C2-C7 alkylene, n is an integer of 0-2, R3 is hydrogen, halogen, d-4 alkyl, C1 alkoxy -4, -CF3, -OCF3, and OH, and Ts is para-toluenesulfonyl, reacting a compound of the formula: with suitable Lewis acid in a solvent generating formaldehyde.
- 2. The process of Claim 1 wherein the Lewis acid is selected from the group consisting of boron trifluoroetherate (BF3 »OEt2), aluminum chloride, zinc chloride, magnesium bromide, ferric chloride (FeCI3).
- 3. The process of Claim 2 wherein the Lewis acid is boron trifluoroetherate.
- 4. The process of Claim 1 wherein the solvent generating formaldehyde is selected from the group consisting of dimethoxymethane, para-formaldehyde, diethoxyethane, bis (methylthio) methane.
- 5. The process of Claim 4 wherein the solvent generating formaldehyde is dimethoxymethane.
- 6. The process of Claim 1 wherein R ^ and R2 are each C1-3 alkyl.
- 7. The process of Claim 1 wherein R3 is hydrogen.
- 8. The process of Claim 1 wherein n is 1.
- 9. The process of Claim 1 wherein n is 0.
- 10. The process of Claim 1 wherein R3 is hydrogen, n is 1 and R, and R2 is each methyl. eleven .
- The process of Claim 1 wherein R3 is hydrogen, n is 1, and Ri and R2 combined are - (CH2) 5- or - (CH2) 4-.
- 12. The process of Claim 1 wherein the created compound is:
- 13. The process of Claim 1 wherein the created compound is:
- 14. The process of Claim 1 wherein the created compound is:
- 15. The process of Claim 1 wherein the created compound is:
- 16. The process of Claim 1 wherein the created compound is:
- 17. The process of Claim 1 wherein the created compound is:
- 18. The process of Claim 1 wherein the created compound is:
- 19. The process of Claim 1 wherein the created compound is:
- 20. The process of Claim 1 wherein the created compound is: twenty-one .
- The process of Claim 1 wherein the created compound is:
- 22. The process of Claim 1 wherein the created compound is:
- 23. The process of Claim 1 wherein the created compound is:
- 24. The process of Claim 1 wherein the created compound is:
- 25. The process of Claim 1 wherein the created compound is:
- 26. The process of Claim 1 wherein the created compound is:
- 27. The process of Claim 1 wherein the created compound is:
- 28. The process of Claim 1 wherein the created compound is:
- 29. The process of Claim 1 wherein the created compound is:
- 30. The process of Claim 1 wherein the created compound is:
- 31. The process of Claim 1 wherein the created compound is:
- 32. The process of Claim 1 wherein the created compound is:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/722,588 | 1996-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99002943A true MXPA99002943A (en) | 2000-02-02 |
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