CA1050023A - Process for the preparation of benzylamines - Google Patents

Process for the preparation of benzylamines

Info

Publication number
CA1050023A
CA1050023A CA194,467A CA194467A CA1050023A CA 1050023 A CA1050023 A CA 1050023A CA 194467 A CA194467 A CA 194467A CA 1050023 A CA1050023 A CA 1050023A
Authority
CA
Canada
Prior art keywords
amino
group
formula
methyl
compound
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
Application number
CA194,467A
Other languages
French (fr)
Other versions
CA194467S (en
Inventor
Johannes Keck
Gerd Kruger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE2311637A external-priority patent/DE2311637C3/en
Priority claimed from DE19732338408 external-priority patent/DE2338408C3/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Application granted granted Critical
Publication of CA1050023A publication Critical patent/CA1050023A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

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)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyridine Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a new process for the preparation of benzylamine derivatives of the general formula (I) (wherein Hal represents a chlorine or bromine atom; R1 represents a hydrogen, chlorine or bromine atom; R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and either R3 represents a cyclohexyl or hydroxy-cyclohexyl group and R4 represents a hydrogen atom or R3 represents an isopropylaminocarbonylmethyl or a morpholine-carbonylmethyl group and R4 represents a hydrogen atom or a benzyl group) and acid addition salts thereof, which process comprises reacting a compound of formula (II) (wherein R1, R4 and Hal are as hereinbefore defined and X represents a nucleophilic leaving group) with a compound of formula

Description

~56)'1)Z3 This invention relates to a new process for the preparation of benzylamine derivatives having interesting physiological properties.
British Patent Specifications 968,254 and 1,098,140 describe and claim inter alia ben~ylamines of general formula 1 \ ~ CH N'" 2 (I) Hal NH - R~

~wherein Hal represents a chlorine or brOmine atom, Rl represents a hydrogen, chlorine or bromine atom; R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and either R3 represents a cyclohexyl or hydroxy-cyclohexyl group and R4 represents a hydrogen atom or R3 represents an isopropylaminocarbonylmethyl or morpholinocarbonylmethyl group and R4 represents a hydrogen atom or a benzoyl group) and acid addition salts thereof as well as processes for their preparation.
In general the compounds of general formula I possess valuable physiological properties, in particular a secretolytic, anti~ussive and/or respiration stimulating activity.
According to the present invention, there is provided a process for the preparation of compounds of general formula I ~as hereinbefore defined) and pharmaceutically acceptable acid addition salts thereof which comprises reacting a compound of formula 1 ~ CH2 - X

Hal ~ NH - R4 ~wherein Rl, R4 and Hal are as hereinbefore defined and X represents a nucleophilic leaying group~ with a compound of formula \ R (III) ~7 .. , -1 -~S~23 ~ erein R2 and l~3 are as hereinbefore defined~ and if desired subsequently converting the compound of formula I thereby obtained into a pharmaceutically acceptable acid addition salt thereof Using the process according to the invention, we have prepared compounds of formula I and pharmaceutically acceptable acid addition salts thereof ~f good purity in excellent yield.
Compounds of general formula II which may be used for the process according to the invention include for example those w~erein Rl~ R4 and Hal are as hereinbefore defined and X represents an organic acyloxy group, preferably an acetoxy, butyryloxy, benzoyloxy or 4-chlorobenzoyloxy group, or a group of formula -0-S~2-R5 ~wherein R5 represents a methyl or 4-methyl-phçnyl group) with the proviso that if R4 represents a hydrogen atom, X may also represent a chlorine, bromine or iodine atom.
The reaction is preferably effected in the presence of a solvent, for example in ethanol, ether, acetone, tetrahydrofuran9 benzene, dioxane, chloroform or carbon tetrachloride, optionally in the presence of an inorganic ba~e, for example sodium carbcnate or sodium hydroxide, or a tertiary organic base, such as triethylamine or pyridine. The reaction is most preferably effected in the presence of an excess of the amine of formula III used or an 2Q excess of the tertiary organic base used which excess sexves as solvent~
The reaction may however be effected in the absence of a solvent.
The reaction temperature used is in general conveniently in the range from -70 to 200 C, depending on the reactivity of the group X in the compound of formula II.
Thus if X represents a halogen atom, the reaction is preferably carried out at temperatures from 0 to 100C, if X represents a 4-methyl-phenyl-sulfonyloxy group, the reaction is preferably carried out at temperatures from -70 to 50C, and if X represents an organic acyloxy group, the reaction is preferably carried out at temperatures from 80 to 170C.
3Q The ohtained compounds of general formula I may, if desired, be subsequently converted into their physiologically compatible acid addition salts. Acids suitable for this B~ -2-~5l:~0Z3 purpose include for examyle hydrochloric acid, hydrobromic acid, sulfuric acid, phosyhoric acid, lactic acid, citric acid and maleic acid~
The compounds of general formula II used as star~ing materials may be prepared from the corresponding benzyl alcohols (which themselves may be prepared by reduction of the corresponding aldehydes with sodium boro-hydride) by reaction with a corresponding hydrohalic acid, with a correspond-ing sulfonyl halide in the presence of sodium hydride, with a corresponding thionyl halide or with a corresponding acyl halide in the presence of pyridine~ The starting materials of general formula II obtained need not necessarily be isolated before use in the process of the invention.
It would not have been expected that the process of the present invention would be successul for the preparation of compounds of general formula I for the following reasons. Usually esters of general formula II
~wherein R4 represents a hydrogen atom) polymerize in the presence of bases such as amines of general formula III and are thus not suitable for reactions in the presence of bases (see for example Ber. dtsch. chem. Ges 27, 3509 -3525 (1894)). In addition amides and alcohols are usually formed by reacting amines with carboxylic acid esters.
The following Examples serve to illustrate the new process of the invention:
- ample 1
2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 10.0 g of 2-amino-3,5-dibromo-benzyl alcohol were dissolved in 50 ml of thionyl chloride and left to stand overnight. Subsequently, t~e solution was evaporated to dryness in vacuo at 25Co 10.1 g of N-methyl-cyclohexylamine in 50 ml of absolute ethanol were added to the residue and the mixture was refluxed for 1 hour. The solution was evaporated to dryness~
The residue was dissolved in 30 ml of ethanol and the solution was acidified wi~h ethanolic hydrochloric acid. The hydrochloride crystallized out.
Yield: 12.6 g (85.7 % of theory).
Mopo 232 to 235C (decomposition).

:10SV023 Example 2 2-Amino-N-cyclohex~1-3,5-dibromo-N-methyl-benzylamine 10.0 g of 2-amino-3,5-dibromo-benzyl alcohol were heated with 100 ml of 48% hydrobromic acid at 100C. After cooling~ the reaction mixture was diluted with water and the precipitate obtained was suction filtered and washed with water. Subsequently, the compound obtained was refluxed for 30 minutes in 8.7 g of N~methyl-cyclohexylamine and 50 ml of ethanolO The solution was evaporated to dryness. The residue was dissolved in 3~ ml of ethanol and the solution was acidified with ethanolic hydrochloric acid.
The hydrochloride crystallizedO
Yield: 9.6 g (65.8% of theory).
M.p.: 232 to 235C (decomposition).
Example 3 2-Amino-N-cyclohexyl-3?5-dibromo-N methyl-benzylamine 7O0 g of 2-amino-3,5-dibromo-benzyl alcohol and 1.4 g of sodium hydride (50% dispersion in oil) were refluxed for 6 hours in 200 ml of absolute ether and 100 ml of absolute tetrahydrofuran whilst stirring, Sub-sequently, the solution was cooled to -70C and 4.75 g of p-toluenesulfonyl chloride in 100 ml o ether were added dropwise. The sGlution was then slowly warmed to -30C and again cooled to -70C. 5.7 g of N-methyl-cyclo-hexylamine were subsequently added, the cooling bath was removed, and the reaction mixture was stirred until room temperature was reachedO Then, the mixture was extracted twice with water and the organic phase was evaporated to dryness. Purification was effected by means of column chromatography over silica gel with chloroform/ethyl acetate (10:1)= The corresponding fractions were evaporated, the residue was dissolved in ethanol and the hydrochloride was precipitated with ethanolic hydrochloric acidO
Yield: 2.8 g ~27,2% of theory) M.p,: 232 to 235C ~decomposition).
Example 4 2-Amino-3?5-dibromo-N-Ctrans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 233 to 234~5C (decompO).

)23 Prepared from 2-amino-3,5-dibromo-benzyl alcohol, thionyl chloride and trans-4-amino-cyclohexanol analogously to Example lo Example 5 2-Amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 233 to 234.5C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl alcoholJ hydrobromic acid and trans-4-amino-cyclohexanol analogously to Example 2.
Example 6 2-Amino-6-chloro-N-~morpholino-carbonyl-methyl)-benzylamine M.p.: 116 to 118C.
Prepared from 2-amino-6-chloro-benzyl alcohol, thionyl chloride and sarcosine-morpholide analogously to Example lo Example 7 2-Amino-6-chloro-N-methyl-N-(mo~e_olino-carbonyl-methyl)-benzylamine M~po 116 to 118C.
Prepared from 2-amino-6-chloro-benzyl alcohol, 48% hydrobromic acid and sarcosine-morpholide analogously to Example 2.
Example 8 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine 4.2 g ~0.01 mol) of 2-amino-3,5-dibromo-benzyl ~-chlorobenzoate were refluxed with 5.7 g (0O05 mol) of N-methyl-cyclohexylamine for 2 1/2 hours (oil bath, 165C). After cooling the reaction mixture was dissolved in ether and extracted three times with waterO The organic layer was dried with sodium sulfate and evaporated. The residue was dissolved in absolute ethanol and the solution was acidified with ethanolic hydrochloric acid. The crystallization of the 2-amino-N-cyclohexyl-3J5-dibromo-N-methyl-benzylamine hydrochloride was completed by addition of ether.
Yield: 3.7 g ~89.7% of theory).
M~po 232 to 235C (decomp.).
Exam~le 9 2-Amino-N-cyclohex~1-3,5-dibromo-N-methyl-benzylamine M.p. of the hydrochloride: 232 to 235C (decomp.)~

~OS100~3 Prepar~d from 2-amino-3,5-dibromo-benzyl acetate and N-methyl-cyclohexylamine analogously to Exc~ple 8.
Example 10 2-Amino-N-cycloh xyl-3~5-dibromo-N-methyl-benzylamine .
M.p. of the hydrochloride: 232 to 235C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl butyrate and N-methyl-cyclohexylamine analogously to Example 8.
Example 11 2-Amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine M.p. of the hydrochloride: 232 to 235C (decomp.).
Prepared from 2-amino-3~5-dibromo-benzyl benzoate and N-methyl-cyclohexylamine analogously to Example 80 Example 12 2-Amino=3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 233 to 234.5C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl butyrate and trans-4-amino-cyclohexanol analogously to Example 8.
Example 13 2-Amino-3,5-dibromo-N-(trans 4-hydroxy-cyclohexyl)-benzylamine M~po of the hydrochloride: 233 to 234.5C (decompO)O
Prepared from 2-amino-3,5-dibromo-benzyl benzoate and trans-4-amino-cyclohexanol analogously to Example 8.
Example 14 2-Amino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine Mq~u: 116 to 118C.
Prepared from 2-amino-6-chloro-benzyl benzoate and sarcosine-morpholide analogously to Example 8.
Example 15 2-Benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methy~-benzylamine 2 g (0.0055 mol) of 2-benzoylamino-6-chloro-benzyl benzoate and 5 g (0.0316 mol) of sarcosine-morpholide were heated for 6 hours at 140C.
After cooling, the reaction mixture was diluted with 50 ml of water and lO~DOZ3 extracted with ethyl aceta~e. The ethyl acetate extract was washed with water and saturated potassium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue was purified by column chromatography over a silica gel column (eluent : cill~roform/me~hanol =
19~ 1.75 g of a crude product were obtained, from which 1.68 g (76% of theory) of 2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine were obtained after recrystallization from ether.
M~po 122.5 to 123C.
Example 16 2-Benzoylamino-6-chloro-N-methyl--N=-(morpholino-carbonyl-meth ~ -benzylami-ne 2.62 g (0.01 mol) of 2-benzoylamino-6-chloro-benzyl alcohol were dissolved in 50 ml of absolute ether and 10 ml of absolute tetrahydrofuran and within 5 minutes 0032 g (0.01 mol) o~ 75% sodium hydride in oil were added whilst stirring at room temperature. After stirring for 1/2 hour, the sodium salt began to appear as a gelatinous precipitate. The reaction mixture was stirred for a further hourO After standing overnight at room temperature, the suspension obtained was diluted with 150 ml of absolute ether and cooled to -50C. A solution of 1.91 g (0.01 mol) of p-toluenesulfonyl chloride in 50 ml of absolute ether were added dropwise over 15 minutes whilst stirring and the mixture was stirred for a further 2 hours at -50 to -40~C. Subse-quently, a solution of 7.9 g (0005 mol) of sarcosine-morpholide in S0 ml of absolute ether was added dropwise within 5 minutes at -50~C. The reaction mixture was stirred for a further 3 hours and the temperature was raised to 1~C. Subsequently the reaction mixture was evaporated in vacuo, the residue was dissolved in 100 ml of ethyl acetate and this solution was washed with water and 5% sodium hydrogen carbonate solution and extrac~ed twice with 2N
hydrochloric acid. The acidic extract was washed with ethyl acetate, made alkaline with concentrated ammonia and extracted three times with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate and evaporated in vacuo. The oily 2-benzoylamino-6-chloro-N-methyl-N-Cmorpholino-carbonyl-~ethyl)-benzylamine crystallized from ether.

Yield: 1.3 g (32.4% of theory30
3~0~ 23 Mop~ 122.5 to 123C.
Example 17 2-Benzoylamino-6-chloro~N-methyl-N-(morpholino-carbonyl-methy ~ e M~po of the hydrochloride: 206 to 208C (decomp.).
Prepared from 2-benzoylamino-6-chloro-benzyl butyrate and sarcosine-morpholide analogously to Example 150 Example 18 2-Benzoylamino-6-chloro-N-isopropyl-N-~morpholino-carbonyl-methyl)-benzylamine M.p.: 125 to 127Co Prepared from 2-benzoylamino-6-chloro-benzyl benzoate and N-isopropyl-glycine-morpholide analogously to Example 15.
Example 19 2-Benzoylamino-4-chloro-N-methyl-N-(isopropylamino-carbonyl-methyl)-benzylamine M.p.: 140 to 142C.
Prepared from 2-benzoylamino-4-chloro-benzyl p-chloro-benzoate and sarcosine-isopropylamide analogously ~o Example 150 Example 20 2-Benzoylamino-6-bromo-N-methyl-N-~morpholinc-carbonyl-methyl)-benzylamine Mop~; 159 to 161C.
Prepared from 2-benzoylamino-6-bromo-benzyl benzoate and sarcosine-morpholide analogously to Example 15.

~ ~ -

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (I) (wherein Hal represents a chlorine or bromine atom; R1 represents a hydrogen, chlorine or bromine atom; R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and either R3 represents a cyclohexyl or hydroxy cyclohexyl group and R4 represents a hydrogen atom or R3 represents an iso-propylaminocarbonylmethyl or a morpholino-carbonylmethyl group and R4 represents a hydrogen atom or a benzoyl group) and pharmaceutically acceptable acid addition salts thereof, which process comprises reacting a compound of formula (II) (wherein R1, R4 and Hal are as hereinbefore defined and X represents a nucleophilic leaving group) with a compound of formula (III) (wherein R2 and R3 are as hereinbefore defined) and if desired subsequently converting the compound of formula I thereby obtained into a pharmaceutically acceptable acid addition salt thereof.
2. A process as claimed in claim 1 wherein a compound of formula II
[wherein R1, R4 and Hal are as defined in claim 1 and X represents an organic acyloxy group or a group of formula -O-SO2-R5 (wherein R5 represents a methyl or a 4-methyl-phenyl group) with the proviso that if R4 represents a hydrogen atom, X may additionally represent a chlorine, bromine or iodine atom] is reacted with a compound of formula III as defined in claim 1.
3. A process as claimed in claim 1 or claim 2 wherein a compound of formula II as defined in claim 1 (wherein X represents an acetoxy, butyryloxy, benzoyloxy or 4-chlorobenzoyloxy group) is reacted with a compound of formula III as defined in claim 1.
4. A process as claimed in claim 1 wheerein the reaction is effected in the presence of a solvent.
5. A process as claimed in claim 4 wherein the solvent comprises ethanol, ether, acetone, tetrahydrofuran, benzene, dioxane, chloroform or tetrahydrofuran.
6. A process as claimed in claim 1 wherein the reaction is effected in the presence of an inorganic or a tertiary organic base.
7. A process as claimed in claim 6 wherein the organic base comprises sodium carbonate or sodium hydroxide.
8. A process as claimed in claim 6 wherein the tertiary organic base comprises triethylamine or pyridine.
9. A process as claimed in any of claims 1, 4 and 6 wherein an excess of the compound of formula III or an excess of the tertiary organic base is used which excess serves as solvent.
10, A process as claimed in any of claims 1, 4 and 6 wherein the reaction is effected at temperatures from -70 to 50°C.
11. A process according to claim 1 in which Hal is a bromine atom in the 3-position, R1 is a bromine atom in the 5-position, R2 represents a methyl group, R3 represents a cyclohexyl group and R4 represents a hydrogen atom.
12. A process for the preparation of 2-amino-N-cyclohexy1-3,5-dibromo-N-methyl-benzylamine and its hydrochloride which comprises reacting 2-amino-3,5-dibromobenzyl chloride, 2-amino-3,5-dibromohenzyl bromide, 2-amino-3,5-dibromobenzyl p-toluenesulfonate, 2-amino-3,5-dibromobenzyl p-chlorobenzoate, 2-amino-3,5-dibromobenzyl acetate, 2-amino-3,5-dibromobenzyl butyrate or 2-amino-3,5-dibromobenzyl benzoate with N-methylcyclohexylamine and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
13. A process according to claim 1 in which Hal is a bromine atom in the 3-position, R1 is a bromine atom in the 5-position, R2 represents a methyl group, R3 represents a trans-4-hydroxycyclohexyl group and R4 represents a hydrogen atom.
14. A process for the preparation of 2-amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamine and its hydrochloride which comprises reacting 2-amino-3,5-dibromobenzyl chloride, 2-amino-3,5-dibromobenzyl bromide, 2-amino-3,5-dibromobenzyl butyrate or 2-amino-3,5-dibromobenzyl benzoate with trans-4-aminocyclohexanol and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
15. A process according to claim 1 in which Hal is a chlorine atom in the 6-position, R1 represents a hydrogen atom, R2 represents a methyl group, R3 represents a morpholinocarbonylmethyl group and R4 represents a benzoyl group.
16. A process for the preparation of 2-benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine and its hydrochloride which comprises reacting 2-benzoylamino-6-chlorobenzyl benzoate, 2-benzoylamino-6-chlorobenzyl-p-toluenesulfonate or 2-benzoylamino-6-chlorobenzyl butyrate with sarcosine morpholide and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
CA194,467A 1973-03-09 1974-03-08 Process for the preparation of benzylamines Expired CA1050023A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE2311637A DE2311637C3 (en) 1973-03-09 1973-03-09 Process for the preparation of 2-aminobenzylamines
DE19732338408 DE2338408C3 (en) 1973-07-28 Process for the preparation of 2-amino-benzylamines
DE19732338409 DE2338409A1 (en) 1973-03-09 1973-07-28 2-Aminobenzylamine derivs prepn. - by direct amination of 2-aminobenzyl derivs, used as secretolytics and anti-tussives

Publications (1)

Publication Number Publication Date
CA1050023A true CA1050023A (en) 1979-03-06

Family

ID=27185122

Family Applications (1)

Application Number Title Priority Date Filing Date
CA194,467A Expired CA1050023A (en) 1973-03-09 1974-03-08 Process for the preparation of benzylamines

Country Status (14)

Country Link
JP (1) JPS5523820B2 (en)
AT (1) AT329020B (en)
BG (1) BG21852A3 (en)
CA (1) CA1050023A (en)
CH (1) CH605617A5 (en)
CS (1) CS180004B2 (en)
DE (1) DE2338409A1 (en)
ES (1) ES423393A1 (en)
FI (1) FI60550C (en)
HU (1) HU167188B (en)
NL (1) NL7401880A (en)
NO (1) NO138406C (en)
SE (1) SE434942B (en)
SU (1) SU512697A3 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924295A (en) * 2012-10-09 2013-02-13 石家庄东方药业有限公司 Bromhexine hydrochloride crystal as well as preparation method and application of crystal
CN103145564A (en) * 2013-03-15 2013-06-12 湖北美林药业有限公司 Bromhexine hydrochloride compound and pharmaceutical composition thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53114748U (en) * 1977-02-21 1978-09-12

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924295A (en) * 2012-10-09 2013-02-13 石家庄东方药业有限公司 Bromhexine hydrochloride crystal as well as preparation method and application of crystal
CN103145564A (en) * 2013-03-15 2013-06-12 湖北美林药业有限公司 Bromhexine hydrochloride compound and pharmaceutical composition thereof

Also Published As

Publication number Publication date
CH605617A5 (en) 1978-09-29
JPS505338A (en) 1975-01-21
NO138406C (en) 1978-08-30
FI60550C (en) 1982-02-10
DE2338408A1 (en) 1975-03-13
FI60550B (en) 1981-10-30
NL7401880A (en) 1974-09-11
ES423393A1 (en) 1976-05-16
JPS5523820B2 (en) 1980-06-25
DE2338408B2 (en) 1976-05-20
BG21852A3 (en) 1976-09-20
HU167188B (en) 1975-08-28
DE2338409A1 (en) 1975-02-13
AT329020B (en) 1976-04-26
CS180004B2 (en) 1977-12-30
NO740820L (en) 1974-09-10
SU512697A3 (en) 1976-04-30
ATA68274A (en) 1975-07-15
SE434942B (en) 1984-08-27
NO138406B (en) 1978-05-22

Similar Documents

Publication Publication Date Title
US4315007A (en) 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines
EP1497274B1 (en) Terphenyl derivatives, preparation thereof, compositions containing same
TW304193B (en)
JPH0780871B2 (en) Novel 4-benzyl-1- (2H) -phthalazinone-derivative and process for producing the same
IE52079B1 (en) N-substituted omega-(2-oxo-4-imidazolin-1-yl)alkanoic acids,salts and esters thereof,process for producing the same and pharmaceutical preparations containing the same
US3903137A (en) Choline sulfonate derivatives
JPS62116583A (en) Purine derivative
CA1050023A (en) Process for the preparation of benzylamines
TWI281920B (en) Cephalosporin intermediates
US2605285A (en) Urea derivatives and their preparation
JPS6354363A (en) quinoline derivative
JP3285421B2 (en) 2-Amino-N-[[[4- (aminocarbonyl) pyrimidin-2-yl] amino] alkyl] pyrimidine-4-carboxamide derivative, its production and application to medicine
JPS6355512B2 (en)
US3407210A (en) Aminoethyl-benzofurans and derivatives thereof
JPS5959664A (en) Anthranilic acid esters
JPH02145572A (en) N-substituted amides
EP0196910B1 (en) Benzo[a]phenazine derivatives
US2674615A (en) 1-arylcycloalkane 1-thiocar-boxylates
US2798072A (en) Substituted benzamidopiperidinopropanes
JPH03215488A (en) Pyrimidobenzimidazole derivative
JPH03294277A (en) piperidine derivatives
CA1052790A (en) Process for the preparation of 2-amino-benzylamines
JP3538889B2 (en) Method for producing alkylthioacetamide
CA1050543A (en) Process for the preparation of 2-acylamino-benzylamines
JP2810747B2 (en) Method for producing pyridine derivative