US3755416A - Noracymethadol carbamates - Google Patents
Noracymethadol carbamates Download PDFInfo
- Publication number
- US3755416A US3755416A US00220698A US3755416DA US3755416A US 3755416 A US3755416 A US 3755416A US 00220698 A US00220698 A US 00220698A US 3755416D A US3755416D A US 3755416DA US 3755416 A US3755416 A US 3755416A
- Authority
- US
- United States
- Prior art keywords
- methyl
- compounds
- methadon
- diphenyl
- ethyl
- 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 - Lifetime
Links
- 229950008848 noracymethadol Drugs 0.000 title abstract description 5
- -1 Noracymethadol carbamates Chemical class 0.000 title description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 abstract description 6
- VWCUGCYZZGRKEE-UHFFFAOYSA-N Noracymethadol Chemical compound C=1C=CC=CC=1C(CC(C)NC)(C(OC(C)=O)CC)C1=CC=CC=C1 VWCUGCYZZGRKEE-UHFFFAOYSA-N 0.000 abstract description 4
- 208000003698 Heroin Dependence Diseases 0.000 abstract description 3
- 206010013663 drug dependence Diseases 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 34
- 230000000202 analgesic effect Effects 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 9
- 229960002069 diamorphine Drugs 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012458 free base Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229950004655 dimepheptanol Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- GJJQIGFCGLPOQK-UHFFFAOYSA-N methadone intermediate Chemical compound C=1C=CC=CC=1C(C#N)(CC(C)N(C)C)C1=CC=CC=C1 GJJQIGFCGLPOQK-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 206010020400 Hostility Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical group [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- SRGKFVAASLQVBO-DASCVMRKSA-N dexbrompheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Br)C=C1 SRGKFVAASLQVBO-DASCVMRKSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000005224 forefinger Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000754 repressing effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
Definitions
- Methadon (systematically named as dl-4,4-diphenyl- 6-dimethylamino-3-heptanone) is analgesically active with a low addiction liability. The compound, therefore, became a candidate for use in the treatment of heroin addiction since it afforded the possibility of repressing the symptoms accompanying the withdrawal of heroin from persons addicted thereto.
- An addict in the process of withdrawing from heroin is able to do so by taking a daily dose of methadon and still perform useful work and earn a living although he may become addicted to methadon in the process.
- the addict in order to support his or her habit need no longer resort to armed robbery, burglary or prostitution.
- Methadon is orally active and the daily cost for an addict has been in the neighborhood of $l$l.50 as compared to the daily cost of heroin which is said to be from $20-$60 day.
- Methadon does suffer from one drawback as a heroin treatment drug in that it can be main-lined as is heroin and is more addictive, in that it produces more euphoria, when administered by this route than when taken orally.
- Methadon was discovered in Germany during World War II and has been marketed as an analgesic since the conclusion of hostilities in most countries of the World.
- the reduction products of methadon are alcohols known as methadols and the acyl derivatives of the alcohol group are known as acymethadols. Both the methadols and acymethadols are active analgesics.
- the nor derivatives of methadon (by nor is meant compounds which have a methylamino in place of a dimethylamino group in methadon) are unstable but the nor derivatives of the methadols and acymethadols are quite stable.
- the noracymethadols are described in US. Pat. 3,021,360 issued Feb. 13, 1962.
- Alk is methyl or ethyl
- Y is O or S
- R is C -C alkyl or phenyl.
- Groups illustrative of R when it is C -C alkyl include the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, t-butyl, Z-pentyl, n-amyl, isoamyl, 3-pentyl, 3-methyl-2-butyl, 2- methyl-Z-butyl and the like.
- the compounds represented by the above formula possess two asymmetric carbon atoms. Accordingly, four different forms of each compound are possible, these consisting of two diastereoisomeric pairs, each of which can be resolved into dextroand levorotatory isomers. Since it is not possible at present to assign an absolute spatial configuration to the diastereoisomeric pairs, they have been arbitrarily designated as the uand fl-isomers, the designation on having been given to that diastereoisomeric pair or more properly, racemic pair, which has the lower solubility.
- Both on and B diastereoisomeric pairs have utility in this invention in that both are analgesically active.
- the l-isomer has the analgesic activity, the disomer being analgesically inactive.
- the unresolved a-dl or diastereoisomeric pair is useful for the same purposes in accordance with its analgesic content, the analgesic content being one-half that of the pure active l-isomer.
- the fi-l diastereoisomeric pair With the fi-dl diastereoisomeric pair, the fi-l isomer is the more active analgetically. As with the u-dl pair, the unresolved racemate is useful as an analgesic and in the alleviation of heroin withdrawal symptoms.
- the compounds represented by the above formula have analgesic action as measured by the method of Robbins, J. Am. Pharm. Assoc. (Sci. Ed.) 44 497 (1955).
- rats are divided into groups of four and appropriate concentrations of the analgesic under test are administered to the rats, one dose level per group of rats.
- One group of rats is used as a control group and are administered orally the medium used for administration of the analgesic itself.
- Analgesic activity in the ad ministered compounds is measured by an increase in reaction time to a painful stimulus over the reaction time of the control group of rats to the same stimulus.
- the painful stimulus consists of heat, the rats tail being grasped between the thumb and forefinger of the operator equidistant between the sides of an electrical ly-heated rod.
- Table 1 below gives the results of testing representative compounds of this invention as analgesics by the above method.
- column 1 is the Y substituent for the formula at the head of the table
- column 2 the R substituent
- column 3 the oral dose in mg./kg.
- column 4 the time of peak analgesic action, this time being that at which the analgesic response is measured
- column 5 the prolongation time in seconds for the response of the treatedgroup to the painful stimulus over the response time of the control group.
- the compounds of this invention also demonstrate their analgesic action in the mouse writhing assay described by Koster et al., Fed. Proc. Soc. Exptl. Biol. 18 412 (1969).
- the compounds of this invention are relatively nontoxic in that their analgesically elfecti-ve dose is low compared to the dose at which toxic signs appear.
- Table 2 which follows records the lethal dose for 50% of rats (LD for a-dl-ethyl N-methyl-N-(l-methyl-3,3-diphenyl-4-acetoxy-n-hexyl)carbamate.
- column 1 gives the route of administration of the compound and column 2, the LD determined from the mortality rate among groups of rats at various dose levels.
- the compounds of this invention are efiective analgesically by the oral route, this route of administration is preferred.
- the compound may be placed in empty telescoping gelatin capsules, either with or without conventional pharmaceutical extending media.
- the compounds can also be mixed with various excipients, binders, etc. and compressed into tablets.
- the compounds can also be administered intraperitoneally or subcutaneously as an aqueous suspension of the type illustrated above.
- the compounds are not soluble in water and they do not form salts which might be water soluble.
- the compounds are not suitable for intravenous injection and thus cannot be self-administered as can methadon. It is, of course, an advantage accruing to the compounds of this invention that they cannot be self-administered and are therefore not subject to street abuse as is methadon.
- a second advantage of the compounds of this invention is their comparatively long duration of action which, in some instances, is greater than six hours.
- the compounds of this invention are white crystalline solids. They are prepared in general by acylating noracetylmethadol or its propionic acid analogue. The preparation of these starting materials is set forth in US. Pat. 3,021,360.
- the acylating agent is preferably a chlorocarbonate such as ethyl chlorocar bonate, n-butyl chlorocarbonate or the like. The preparation of a compound of this invention is illustrated by the following specific example.
- EXAMPLE 1 a-l-ethyl N-methyl-N- (l-methyl-3,3-diphenyl-4-acetoxyn-hexyl)carbamate
- Eight grams of a-Z-noracetylmethadol free base obtained from the corresponding hydrochloride salt were dissolved in a mixture of 10 ml. of pyridine and 100 ml. of benzene. The mixture was cooled to about 0 C.
- 2.4 g. of ethyl chlorocarbonate in 20 ml. of benzene were added slowly with stirring to the chilled solution containing the oz-lnoracetylmethadol. After the addition had been completed, stirring was continued for about 2 more hours at about 0 C.
- the starting noracetylmethadol can be prepared by an alternate procedure in addition to that set forth in US. Pat. 3,021,360. This procedure is illustrated below.
- EMM-PLE 2 a-l-Noracetylmethadol 30 g. of a-l-acetylmethadol hydrochloride were converted to the free base and the free base mixed with 15.6 g. of diethyl azodicarboxylate in 200 ml. of n-hexane. The mixture was allowed to stand at ambient temperature overnight. The solvent was then removed in vacuo and the residual oil dissolved in 200 ml. of l N aqueous hydrochloric acid. -Ethanol was added to effect complete solution. The mixture was heated for about 4 hours at about 100 C. The reaction mixture was then cooled and extracted with ether. The ether layer was separated and discarded.
- the aqueous layer was made basic with dilute ammonium hydroxide and a-l-noracetylmethadol free base prepared in the above reaction was extracted into ether.
- the aqueous basic layer was again extracted with ether and the ether layers combined.
- the ether layers were then washed with water and dried. Removal of the solvent in vacuo yielded about 30 g. of an oil.
- the oil was dissolved in ether and the ethereal solution saturated with dry gaseous hydrogen chloride.
- the hydrochloride salt of a-l-noracetylmethadol thus prepared was separated by filtration and crystallized from an ethyl acetate-ether solvent mixture.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22069872A | 1972-01-25 | 1972-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3755416A true US3755416A (en) | 1973-08-28 |
Family
ID=22824588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00220698A Expired - Lifetime US3755416A (en) | 1972-01-25 | 1972-01-25 | Noracymethadol carbamates |
Country Status (22)
-
0
- BE BE794390D patent/BE794390A/xx unknown
-
1972
- 1972-01-25 US US00220698A patent/US3755416A/en not_active Expired - Lifetime
- 1972-01-25 ES ES410947A patent/ES410947A1/es not_active Expired
-
1973
- 1973-01-16 ZA ZA730327A patent/ZA73327B/xx unknown
- 1973-01-17 IL IL41308A patent/IL41308A/xx unknown
- 1973-01-18 AU AU51225/73A patent/AU472051B2/en not_active Expired
- 1973-01-19 PH PH14262*UA patent/PH9470A/en unknown
- 1973-01-22 SE SE7300839A patent/SE376414B/xx unknown
- 1973-01-22 DE DE2303021A patent/DE2303021A1/de active Pending
- 1973-01-22 GB GB309173A patent/GB1374943A/en not_active Expired
- 1973-01-23 IE IE104/73A patent/IE37137B1/xx unknown
- 1973-01-24 DD DD168422A patent/DD103892A5/xx unknown
- 1973-01-24 FR FR7302473A patent/FR2181688B1/fr not_active Expired
- 1973-01-24 CH CH98773A patent/CH554847A/fr not_active IP Right Cessation
- 1973-01-24 HU HUEI458A patent/HU166566B/hu unknown
- 1973-01-24 SU SU1878951A patent/SU474138A3/ru active
- 1973-01-24 AT AT57873A patent/AT320663B/de not_active IP Right Cessation
- 1973-01-25 AR AR246281A patent/AR196511A1/es active
- 1973-01-25 CS CS579A patent/CS164223B2/cs unknown
- 1973-01-25 RO RO7300073606A patent/RO62268A/ro unknown
- 1973-01-25 JP JP48010624A patent/JPS4881840A/ja active Pending
- 1973-01-25 NL NL7301122A patent/NL7301122A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE794390A (fr) | 1973-07-23 |
| CS164223B2 (enrdf_load_stackoverflow) | 1975-11-07 |
| NL7301122A (enrdf_load_stackoverflow) | 1973-07-27 |
| AT320663B (de) | 1975-02-25 |
| JPS4881840A (enrdf_load_stackoverflow) | 1973-11-01 |
| ES410947A1 (es) | 1976-05-16 |
| ZA73327B (en) | 1974-08-28 |
| AR196511A1 (es) | 1974-02-06 |
| FR2181688A1 (enrdf_load_stackoverflow) | 1973-12-07 |
| AU5122573A (en) | 1974-07-18 |
| FR2181688B1 (enrdf_load_stackoverflow) | 1976-07-02 |
| IE37137L (en) | 1973-07-25 |
| AU472051B2 (en) | 1976-05-13 |
| DD103892A5 (enrdf_load_stackoverflow) | 1974-02-12 |
| HU166566B (enrdf_load_stackoverflow) | 1975-04-28 |
| RO62268A (fr) | 1977-10-15 |
| SE376414B (enrdf_load_stackoverflow) | 1975-05-26 |
| IE37137B1 (en) | 1977-05-11 |
| GB1374943A (en) | 1974-11-20 |
| DE2303021A1 (de) | 1973-08-09 |
| IL41308A (en) | 1975-04-25 |
| PH9470A (en) | 1975-12-16 |
| IL41308A0 (en) | 1973-03-30 |
| CH554847A (fr) | 1974-10-15 |
| SU474138A3 (ru) | 1975-06-14 |
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