Process for producing Trans-2 bromoindan-1-ol

A cheap industrial method for making trans-2-bromoindan-1-ol. Trans-2-bromoindan-1-ol represented by Formula (II) is made by hydrolysing 1,2-dibromoindane represented by General Formula (I) (where the configuration of the bromine atoms on position 1 and position 2 can be trans or cis, or it can be a mixture of trans and cis isomers). Trans-2-bromoindan-1-ol represented by Formula (II) can also be made by brominating indene to synthesize 1,2-dibromoindane, and then continuously hydrolysing this 1,2-dibromoindane without isolating it. 1,2-Dibromoindane can also be made by reacting indene with hydrogen bromide in the presence of hydrogen peroxide.

TECHNICAL FIELD 
The present invention relates to an industrially useful method for making 
trans-2-bromoindan-1-ol. 
BACKGROUND ART 
Trans-2-bromoindan-1-ol is a pharmaceutical intermediate for anti-HIV 
drugs, etc., and is useful as a starting material for making 
cis-1-aminoindan-2-ol. For example, in Japanese Patent Application 
6-298619 which is a previous patent by the present applicants, it is 
stated that cis-1-aminoindan-2-ol can be obtained by reacting 
trans-2-bromoindan-1-ol under acid conditions with acetonitrile to give 
trans-1-(acetamide)-2-bromoindane, cyclizing this to make a cis-oxazoline 
derivative, and then hydrolysing. Similarly, in the method of Gagis et al. 
(J. Ore. Chem. 37, 3181 (1972)) cis-1,2-epoxyindane is obtained by 
treating trans-2-bromoindan-1-ol under basic conditions. In the 
aforementioned Japanese Patent Application 6-298619 it is shown that a 
derivative of cis-oxazoline is produced by reacting this epoxy compound 
under acid conditions with acetonitrile, and that cis-1-aminoindan-2-ol 
can be obtained by hydrolysing this. 
To date, various methods have been disclosed for making 
trans-2-bromoindan-1-ol. For example, Porter et al. (J. Am. Chem. Soc. 57, 
2022 (1935)) obtained trans-2-bromoindan-1-ol by reacting bromine water 
with indene; however, the yield was low at 31%. Similarly, Suter et al. 
(J. Am. Chem. Soc. 62, 3473 (1940)) obtained trans-2-bromoindan-1-ol with 
94% yield by saturating an aqueous solution of sodium bromide with bromine 
and then reacting with indene in the presence of a large quantity of a 
dispersant. This method gives a comparatively good yield but efficiency is 
poor, and using a 5-litre reaction vessel only 204 g of the intended 
product is obtained. Moreover, there are industrial problems in that a 
large quantity of reaction mother liquor is produced, and the fact that 
the mother liquor is a mixture of sodium bromide and hydrogen bromide 
complicates treatment after the reaction. On the other hand, Guss et al. 
(J. Am. Chem. Soc. 77, 2549 (1955)) obtained trans-2-bromoindan-1-ol with 
a yield of 59% by reacting N-bromosuccinimide with indene in water at room 
temperature for 3 hours. Although this method is comparatively efficient, 
from the economic point of view N-bromosuccinimide needs to be regenerated 
by separating out by-product succinimide and then brominating. 
As indicated above, no industrial and cheap method is known for making 
trans-2-bromoindan-1-ol. 
DISCLOSURE OF THE INVENTION 
The present invention offers an industrial and cheap method for making 
trans-2-bromoindan-1-ol. 
It has been disclosed by Dalton et al. (J. Am. Chem. Soc. 90, 5498 (1968)) 
that when an alkene is brominated in water bromine cations attack the 
carbon-carbon double bond to produce a bromonium cation intermediate, and 
this intermediate is attacked by solvated anions (OH.sup.- anions in the 
case of a reaction in water) to produce a bromhydrin. 
Thus, it is suggested that all of the prior art cited above includes this 
reaction mechanism. In the reaction of bromine water and indene of Porter 
et al., for example, Br.sup.+ OH.sup.- (produced by an equilibrium 
reaction between bromine and water) contained in the bromine water becomes 
the reaction reagent; a bromonium cation intermediate is first produced by 
Br.sup.+ attacking indene, and then trans-2-bromoindan-1-ol 
(indenebromohydrin) is produced by the action of OH.sup.-. However, 
because the concentration of Br.sup.+ OH.sup.- in water is small the 
yield is low. Similarly, Suter et al. dissolved bromine in sodium bromide 
in order to increase the concentration of Br.sup.+ OH.sup.- in the water. 
Moreover, Guss et al. used the reaction of indene with Br.sup.+ OH.sup.- 
generated from water and N-bromosuccinimide. 
The present inventors have perfected the present invention as the result of 
pursuing concerted studies focusing on the importance of the concentration 
of bromonium cations produced as an intermediate stage of the synthesis of 
trans-2-bromoindan-1-ol. 
There are 2 methods for generating bromonium cations in an indene system: 
1) Removal of the substituent group from the 1 position of a 
1-(substituted)-2-bromoindane derivative, and 
2) Br.sup.+ attack of indene. 
The present investigators first pursued studies on method 1). 
It is it known that when the substituent group on position 1 of the indane 
skeleton is a hydroxyl group it can be easily removed under acid 
conditions to produce a carbocation. For example, Suter et al. (J. Am. 
Chem. Soc. 62, 3473 (1940)) reported that cis/trans isomerization is 
produced by heating indane-1,2-diol or 2-chloro-1-indanol in an acid 
aqueous solution, and this shows that a hydroxyl group on position 1 is 
removed to produce a carbocation intermediate (equation below). 
##STR1## 
The present inventors have also discovered that 
trans-1-acetamide-2-bromoindane is produced by reacting 
trans-2-bromoindan-1-ol with acetonitrile under acid conditions (Japanese 
Patent Application 6-298619), and this indicates that acetonitrile attacks 
the carbocation produced by the removal of the hydroxyl group on position 
1 (equation below). 
##STR2## 
The present inventors have also discovered that this reaction is also 
possible when 1,2-dibromoindane is used. Thus, this results shows that 
under selected conditions a bromonium cation is produced by withdrawal of 
a bromine atom on position 1 of 1,2-dibromoindane (equation below). 
##STR3## 
As the result of investigations based on the results above, the present 
inventors have discovered that trans-2-bromoindan-1-ol represented by 
Formula (II) 
##STR4## 
can be obtained easily by hydrolysing 1,2-bromoindane represented by 
General Formula (I) 
##STR5## 
(where the bromine atoms on position 1 and position 2 in the formula can 
be in cis configuration or trans configuration or a mixture of these) 
under selected conditions. 
The present invention is explained in detail below. 
The 1,2-dibromoindane starting material can be the cis or trans isomer or a 
mixture of these. 1,2-Dibromoindane can be obtained by reacting indene 
with bromine in a suitable solvent. For example, Billups et al. (J. Ore. 
Chem. 44, 4218 (1979)) obtained 1,2-dibromoindane by brominating indene in 
ether. It is also known that the ratio of cis-1,2-dibromoindane and 
trans-1,2-dibromoindane produced in the bromination reaction depends on 
the reaction solvent. Heasley et al. (J. Org. Chem. 45, 5150 (1980)) have 
reported the percentages of the cis and trans isomers when bromination of 
indene was performed in different solvents. In the present invention, 
either isomer can be employed as starting material because no matter which 
is used the bromonium cation intermediate is produced by the removal of 
the bromine atom on position 1. 
1,2-dibromoindane is converted to the desired trans-2-bromoindan-1-ol by 
mixing in water. The reaction temperature is preferably room temperature 
to 100.degree. C., and more preferably 50.degree.-80.degree. C. When the 
temperature is lower than this the reaction progresses slowly, and when 
the temperature is higher than this the yield is lowered because the 
intended product trans-2-bromoindan-1-ol is converted to indan-1-one 
and/or indan-2-one via cis-2-bromoindan-1-ol produced by isomerization 
(equation below). 
##STR6## 
When this hydrolysis is performed in a non-uniform system of water and 
1,2-dibromoindane, which is sparingly soluble in water, a high stirring 
efficiency is preferred. An emulsion is preferably further formed in order 
to cause full contact between the organic layer and aqueous layer, and the 
addition of dispersants and/or emulsifiers is an effective measure. 
Dispersants and/or emulsifiers which can be employed include glyceryl 
fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, 
propylene glycol fatty acid esters and polyoxyethylene ethers; 
polyoxyethylene (10) octyl phenyl ether (trade name : Triton X-100) is 
ideal. The quantity of dispersant and/or emulsifier employed is preferably 
0.5-10 wt % relative to 1,2-dibromoindane, and 1 wt % to 5 wt % is more 
preferable. If the quantity of dispersant and/or emulsifier employed is 
smaller than this an adequate dispersing/emulsifying effect is not 
obtained, and more than this is economically disadvantageous. 
Also, because water-insoluble trans-2-bromoindan-1-ol separates out as the 
hydrolysis reaction progresses, it can be performed in the presence of an 
aprotic organic solvent in order to obtain an adequate stirring effect. 
When for example a solvent is employed which is insoluble in water or 
sparingly soluble in water, the reaction system becomes non-uniform and 
therefore as previously mentioned a dispersant and/or emulsifier is 
preferably used. Solvents which can be employed include chlorinated 
solvents such as dichloromethane, dichloroethane, chloroform, carbon 
tetrachloride, chlorobenzene and dichlorobenzene, etc., and hydrocarbons 
such as hexane, heptane, octane, benzene, toluene and xylene, etc. The 
quantity of these solvents employed can be decided in the light of phase 
solubility with the 1,2-dibromoindane starting material and the solubility 
of the intended trans-2-bromoindan-1-ol. Moreover, this reaction is 
preferably performed at 50.degree.-80.degree. C., and therefore when the 
boiling point of the solvent or azeotropic mixture of solvent and water at 
ordinary pressure is lower than the preferred reaction temperature it can 
be performed at increased pressure. The preferred solvents are 
chlorobenzene and dichloroethane, and more preferably chlorobenzene. 
Excess 1, 2-dibromoindane can also be employed (i.e. the starting material 
can be employed as a solvent). 
This hydrolysis reaction can also be performed in the presence of a solvent 
which dissolves water, 1,2-dibromoindane and trans-2-bromoindan-1-ol. When 
the quantity of solvent employed is small the reaction system becomes 
non-uniform, but a uniform reaction is possible by selecting the quantity 
of solvent. Solvents which can be employed include acetone, ethyl methyl 
ketone, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidone and 
1,3-dimethyl-2-imidazolidinone, etc. In this case the reaction can be 
performed under a reaction pressure which will allow a suitable reaction 
temperature. 
The velocity of the hydrolysis of 1,2-dibromoindane differs depending on 
pH, and it is preferably performed at a lower pH. This is not a problem, 
since hydrogen bromide is produced as a by-product as the hydrolysis 
progresses, and consequently the pH decreases steadily; however, when the 
pH at the beginning of hydrolysis is comparatively high in the acid region 
the system pH is preferably set low. 
The progress of the reaction can be followed by gas chromatography (GC) or 
liquid chromatography (HPLC), and consequently the end of the reaction can 
be decided from the quantity of 1,2-dibromoindane left and the quantity of 
trans-2-bromoindan-1-ol produced. The time required for the hydrolysis of 
1,2-dibromoindane differs with the reaction temperature, the use or 
otherwise of a dispersant, the use or otherwise of an aprotic solvent and 
the quantity of water added, and therefore the reaction is preferably 
followed by the aforementioned methods. 
The 1,2-bromoindane starting material can further be hydrolysed 
continuously with its synthesis without isolating it, to obtain the 
desired trans-2-bromoindan-1-ol. In this case, 1,2-dibromoindane can be 
synthesized by reacting indene and bromine in the presence or not in the 
presence of an aprotic solvent which does not cause bromination, and this 
can be hydrolysed under the aforementioned conditions by adding the 
desired quantity of water; or indene can be brominated while it is 
dispersed in water to synthesize 1,2-dibromoindane, and this can be 
hydrolysed in the presence or not in the presence of an aprotic solvent 
which does not cause bromination. In the case of the latter method, by 
selecting the reaction conditions the production and hydrolysis of 
1,2-dibromoindane can be performed in parallel. In addition, by performing 
bromination employing excess indene (i.e. using indene as an aprotic 
solvent) it is possible to synthesize 1,2-dibromoindane, and perform 
hydrolysis and synthesize trans-2-bromoindan-1-ol in the presence of 
unreacted indene. Hydrogen bromide is a by-product of the hydrolysis of 
1,2-dibromoindane, and addition of hydrogen bromide to indene in the 
hydrolysis of 1,2-dibromoindane can be suppressed by selecting the 
reaction conditions. 
The isolation of the intended substance after the end of the reaction will 
differ depending on whether or not an aprotic solvent is used, and the 
quantity employed. 
For example, when the reaction is performed without using aprotic solvent 
the product separates from water, and after solid separation ordinary 
clean-up methods can be used. However, when a product including oily 
by-products is filtered or centrifuged as it stands the yield of the 
desired trans-2-bromoindan-1-ol is lowered because it dissolves in the 
oily substances in the filtrate. Consequently, after ending the reaction 
an organic solvent in which trans-2-bromoindan-1-ol is comparatively 
sparingly soluble and the by-products are readily soluble is preferably 
added at a suitable temperature, and the intended product dispersed in the 
organic solvent is subjected to solid separation after removing the 
aqueous layer. In this process dichloromethane, dichloroethane and 
chlorobenzene, etc., can be used as an organic solvent. Or 
trans-2-bromoindan-1-ol can be extracted at a suitable temperature with an 
organic solvent in which it is highly soluble, and then collected by 
crystallization by an ordinary method. Ethyl acetate, propyl acetate and 
isopropyl acetate, etc., can be used as the extracting solvent. 
On the other hand, when the reaction is performed using an aprotic solvent 
the following treatment can be carried out. When a solvent is employed in 
which the solubility of trans-2-bromoindan-1-ol is comparatively small, 
solid separation of the intended product dispersed in the organic layer 
can be performed after removing the aqueous layer as described above. When 
a solvent is employed in which the solubility of trans-2-bromoindan-1-ol 
is comparatively large, if crystallization of the intended product is 
noticeable the mother liquor can be concentrated after isolating these 
crystals, and the intended product can be crystallized by an ordinary 
method. 
The present inventors next investigated the production of the 
indenebromonium cation intermediate by bromo cation (Br.sup.+) attack of 
indene. 
It is known that Br.sup.+ OH.sup.- and Br.sub.2 are produced by reaction 
between hydrogen peroxide and hydrogen bromide and that this reaction 
system has an equilibrium ((Jolles (editor) "Bromine and its compounds." 
p. 100 (1966) (equations below). 
EQU H.sub.2 O.sub.2 +HBrBrOH+H.sub.2 O 
EQU BrOH+H.sub.2 O.sub.2 HBr+H.sub.2 O+O.sub.2 
EQU HBr+BrOHH.sub.2 O+Br.sub.2 
The present inventors have perfected the present invention as the result of 
pursuing concerted studies on the possibility that if Br.sup.+ was 
generated by reacting excess hydrogen peroxide and hydrogen bromide in the 
presence of indene, 1,2-dibromoindane could be produced when the opposing 
anion was Br and the desired trans-2-bromoindan-1-ol could be synthesized 
when the opposing anion was OH.sup.-, with the discovery that 
1,2-dibromoindane and trans-2-bromoindan-1-ol are indeed produced. 
The present invention will be explained in concrete terms. 
Hydrogen peroxide is preferably employed at 0.5-1.2 mols per mol of indene. 
Hydrogen bromide is preferably employed at 0.5-2.2 mol per mol of indene. 
Because hydrogen bromide is needed at 2 mol equivalent of indene in order 
to produce 1,2-dibromoindane, the maximum quantity produced is 0.5 mol 
equivalent of indene; and because hydrogen bromide is needed at 1 mol 
equivalent of indene for the production of trans-2-bromoindan-1-ol the 
maximum quantity produced is 1 mol equivalent of indene (equations below). 
##STR7## 
In this case, the proportions of 1,2-dibromoindane and 
trans-2-bromoindan-1-ol produced will change depending on the reaction 
temperature, the pH of the reaction system and the quantity of water (or 
concentration of hydrogen bromide in the water). Thus, the reaction 
temperature and pR affect the velocity of 1,2-dibromoindane hydrolysis: 
when the reaction temperature is preferably .ltoreq.0.degree. C. and more 
preferably -10.degree. C., and the pH is preferably .gtoreq.0.0 and more 
preferably .gtoreq.1.0, the ratio produced becomes almost those of the 
indene addition reactions; and when the temperature is higher or the pH is 
lower 1,2-dibromoindane hydrolysis is produced in parallel with the 
addition of Br.sub.2 or BrOH to indene, and consequently the proportion of 
trans-2-bromoindan-1-ol produced becomes larger. In addition, because 
there is an equilibrium in the hydrogen bromide and hydrogen peroxide 
reaction system, the quantity of water (or the hydrogen bromide 
concentration in the water) affects the percentages of Br.sub.2 and BrOH 
produced in the reaction system and therefore as a result is related to 
the proportions of the products of addition reaction. Thus, by selecting 
appropriate reaction conditions it is possible to control the ratio of 
1,2-dibromoindane and trans-2-bromoindan-1-ol. When 1,2-dibromoindane is 
desired a low reaction temperature, a pH comparatively high in the region 
0-7 and little water in the reaction system (i.e. a large concentration of 
hydrogen bromide in water) are preferred; and when trans-2-bromoindan-1-ol 
is desired a comparatively high reaction temperature, a low pH .ltoreq.0 
and a large quantity of water in the reaction system (i.e. a small 
concentration of hydrogen bromide in water) are preferred. When 
trans-2-bromoindan-1-ol is desired, trans-2-bromoindan-1-ol also can be 
obtained by hydrolysing the 1,2-dibromoindane in the mixture, by treating 
the mixture as previously described, in the previously described preferred 
conditions in the presence of water. At the same time by-product hydrogen 
bromide reacts with the remaining hydrogen peroxide, and finally produces 
trans-2-bromoindan-1-ol. 
When the present reaction is performed in the presence of water in a 
non-uniform liquid phase to give trans-2-bromoindan-1-ol, the stirring 
efficiency is preferably high, because the brominating reagent is in the 
aqueous layer and the indene is in the oil layer. Moreover, an emulsion is 
preferably formed in order to bring the organic layer and aqueous layer 
into adequate contact, and dispersants and/or emulsifiers become 
efficacious. Dispersants and/or emulsifiers which can be employed include 
glyceryl fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid 
esters, propylene glycol fatty acid esters and polyoxyethylene ethers, 
etc.; and polyoxyethylene(10) octyl phenyl ether (trade name: Triton 
X-100) is ideal. The quantity of dispersant and/or emulsifier employed is 
preferably 0.5-10 wt %, and more preferably 1 to 5 wt %, relative to 
indene. When the quantity of dispersant and/or emulsifier employed is less 
than this an adequate dispersing/emulsifying effect is not obtained, and 
more than this is economically disadvantageous. 
Water-insoluble trans-2-bromoindan-1-ol separates out when this reaction is 
performed in the presence of water, and consequently it can be performed 
in the presence of an aprotic organic solvent in order to get an adequate 
stirring effect. Because the reaction system becomes non-uniform when a 
solvent insoluble or sparingly soluble in water is employed, a dispersant 
and/or emulsifier such as those described previously is ideally employed. 
Solvents which can be employed include chlorinated solvents such as 
dichloromethane, dichloroethane, chloroform, carbon tetrachloride, 
chlorobenzene and dichlorobenzene, etc., and hydrocarbons such as hexane, 
heptane, octane, benzene, toluene and xylene, etc. It is also possible to 
perform the addition reactions under conditions for 1,2-dibromoindane 
hydrolysis. In this event the reaction temperature is preferably 
50.degree.-80.degree. C., and therefore it can be performed under 
increased pressure when the boiling point of the solvent or azeotropic 
mixture of water and solvent at ordinary pressure is lower than the 
preferred reaction temperature. The preferred solvents are chlorobenzene 
and dichloroethane, and chlorobenzene is more preferred. 
On the other hand this reaction can be performed in the presence of a 
solvent which dissolves water, indene and trans-2-bromoindan-1-ol. When 
the quantity of solvent employed is small the reaction system becomes 
non-uniform, but a uniform reaction is possible by selecting the quantity 
of solvent. Solvents which can be employed include dimethylformamide, 
dimethyl sulphoxide, N-methylpyrrolidone and 
1,3-dimethyl-2-imidazolidinone, etc. In this case the reaction can be 
performed under a reaction pressure which will allow a suitable reaction 
temperature. 
As described previously, the present reaction is efficacious in 
synthesizing 1,2-dibromoindane by reacting indene and bromine, and then 
hydrolysing this 1,2-dibromoindane in a continuous process. Thus, because 
hydrogen bromide is a by-product in the hydrolysis of 1,2-dibromoindane, 
the desired trans-2-bromoindan-1-ol can be made continuously by adding an 
almost equimolar quantity of indene to the hydrogen bromide in the 
reaction mixture, and bringing about the action of the hydrogen bromide 
and an almost equimolar quantity of hydrogen peroxide. 
Moreover, continuous manufacture from indene is possible. For example, the 
process below is possible. Firstly 1 mol of 1,2-dibromoindane is produced 
by adding 1 mol of bromine to 2 mol of indene in the presence or in the 
absence of water (Equation (1) below). 
##STR8## 
Then 1 mol of trans-2-bromoindan-1-o1 and 1 mol of hydrogen bromide are 
produced by progressive hydrolysis of 1,2-dibromoindane by heating and 
stirring in the presence of water (Equation 2 below). 
##STR9## 
Finally 1 mol of hydrogen peroxide is added to bring about the production 
of trans-2-bromoindan-1-ol or 1,2-dibromoindane, and when 
1,2-dibromoindane is produced this can be hydrolysed at a set temperature 
to produce trans-2-bromoindan-1-ol (Equation 3 below). 
##STR10## 
Overall, 2 mol of 2-trans-2-bromoindan-1-ol are produced by employing 2 mol 
of indene and 1 mol each of bromine and hydrogen peroxide (Equation 4 
below). 
##STR11## 
The optimum forms for carrying out the invention

The invention is explained in even more detail below by means of 
embodiments. 
Embodiment 1 
Synthesis of trans-2-bromoindan-1-ol (II) by hydrolysis of 
1,2-dibromoindane (I) (added dispersant) 
50 ml of water, 5.0 g of 1,2-dibromoindane (trans: cis=84:16; 0.18 mol) and 
0.2 g of Triton X-100 were put into a 100-ml 3-mouthed flask, and were 
emulsified by stirring together with a magnetic stirrer. Mixing was 
continued for 6 hours at 50.degree.-60.degree. C. Soft yellow 
semi-crystalline particles precipitated. By cooling to room temperature, 
filtering at decreased pressure and then washing with water, 4.26 g of 
moist crude crystals were obtained. These were dispersed in 10 ml of 
dichloromethane, and washed by mixing at 0.degree. C. The crystals were 
filtered at decreased pressure, followed by washing with a small quantity 
of dichloromethane (0.degree. C.) and then drying, to obtain 2.64 g of 
pale yellow crystals of trans-2-bromoindan-1-ol (yield 68.4%; HPLC purity 
96.5%). 
Embodiment 2 
Synthesis of trans-2-bromoindan-1-ol (II) by hydrolysis of 
1,2-dibromoindane (continuous synthesis from bromination of indene, use of 
equimolar quantities of indene and bromine, added dispersant) 
50 ml of water, 2.44 g of indene (content 95 wt %; 0.02 mol) and 0.2 g of 
Triton X-100 were put into a 100-ml 3-mouthed flask and emulsified by 
stirring together with a magnetic stirrer. At 50-60.degree. C., 3.2 g of 
bromine (0.02 mol) was added dropwise, followed by mixing at the same 
temperature for 6 hours. The semicrystalline precipitate was collected by 
filtration and treated as in Embodiment 1, to obtain 2.89 g of pale yellow 
crystals of trans-2-bromoindan-i-ol (yield based on indene 67.8%; HPLC 
purity 97.2%). 
Embodiment 3 
Synthesis of trans-2-bromoindane-1-ol (II) by indene-hydrogen 
bromide-hydrogen peroxide reaction (added dispersant) 
237 ml of water, 173.9 g of indene (92 wt %; 1.38 mol), 2.8 g of Triton 
X-100 and 262.0 g of hydrogen bromide (47 wt %; 1.52 mol, 1.1 mol/mol 
indene) were put into a 1000-ml 3-mouthed flask, and emulsified by 
stirring together with a magnetic stirrer. The emulsion was stirred at 
60.degree. C. as 147.2 g of hydrogen peroxide (35 wt %; 1.52 mol, 1.1 
mol/mol indene) was added dropwise over 4 hours and 20 minutes. After 
stirring for 2 hours at the same temperature, stirring was continued at 
room temperature overnight. 200 ml of dichloromethane was added to the 
reaction mixture, and after stirring at room temperature for 1 hour it was 
filtered at decreased pressure. The wet crystals were dried, to obtain 
246.1 g of pale yellow crystals of trans-2-bromoindan-1-ol (yield 83.9%; 
GC purity 97.0%). 
Embodiment 4 
Synthesis of trans-2-bromoindan-1-ol (II) by hydrolysis of 
1,2-dibromoindane (I) (continuous synthesis from bromination of indene, 
employment of excess indene, added dispersant) 
43.5 g of indene (92 wt %; 0.345 mol), 0.7 g of Triton X-100 and 100 ml of 
water were put into a 500-ml 3-mouthed flask, and mixed by stirring. 
Mixing was continued at 60.degree. C. as 27.5 g of bromine (0.172 mol, 0.5 
mol/mol of indene) was added dropwise over approximately 3 hours. After 
this, stirring at 60.degree. C. was continued. The reaction mixture was 
extracted with ethyl acetate directly after dropwise addition of bromine, 
and after mixing for a further 1 hour. Yields of trans-2-bromoindan-1-ol 
were calculated from the hydrogen bromide concentrations in the aqueous 
phase (by gravimetric titration using silver nitrate), and the quantity of 
indene in the extraction layer was found by GC by means of a calibration 
line and used to calculate percent conversion. 
______________________________________ 
After After mixing 
adding Br 
for 1 hr 
______________________________________ 
Indene conversion (%) 
48.7 48.5 
Yield of product (II) (%) 
30.1 40.9 
1,2-dibromoindane (%) 
11.2 10.6 
remaining 
______________________________________ 
From the results above the facts below are clear. 
1) On mixing at 60.degree. C. for 1 hour after adding bromine approximately 
80% of the bromoindane is converted to the intended 
trans-2-bromoindan-1-ol. 
2) The rate of production of 1,2-dibromoindane is extremely rapid because 
over half of the bromine added is consumed by the end of dropwise addition 
of bromine. 
3) By the end of dropwise addition of bromine approximately 60% of the 
1,2-dibromoindane produced has been converted to trans-2-bromoindan-1-ol. 
Embodiment 5 
Synthesis of 1,2-dibromoindane by bromination of indene, and synthesis of 
trans-2-bromoindan-1-ol by hydrolysis of this 1,2-dibromoindane/-synthesis 
of trans-2-bromoindan-1-ol from indene by by-product hydrogen bromide and 
hydrogen peroxide (added dispersant) 
1200 ml of water and 5.6 g of Triton X-100 were put into a 2000-ml 
4-mouthed flask, and stirred to form a dispersion. 330.5 g of indene (88 
wt %; 2.50 mol) was added and stood overnight. The mixture was then mixed 
at 60.degree.-70.degree. C. while 200.0 g of bromine (1.25 mol) was added 
dropwise, requiring 4 hours. The solution became a yellow emulsion which 
included trans-2-bromoindan-1-ol crystals and indene. After mixing at the 
same temperature for an hour, 139.0 g of hydrogen peroxide (35 wt %; 1.43 
mol) was added dropwise over 3.5 hours. After dropwise addition a slurry 
formed which included yellow crystals. Mixing was continued at 60.degree. 
C. for 1 hour, followed by stirring during cooling for 18 hours. 400 ml of 
dichloromethane was added to the reaction liquor, and after mixing it was 
filtered under decreased pressure. The cake was washed with 200 ml of 
water and 160 ml of dichloromethane, and then dried under decreased 
pressure to obtain 410.6 g of white crystals of trans-2-bromoindan-1-ol 
(yield 77.1%). 
Embodiment 6 
Synthesis of 1,2-dibromoindane by bromination of indene, and synthesis of 
trans-2-bromoindan-1-ol by hydrolysis of this 1,2-dibromoindane/synthesis 
of trans-2-bromoindan-1-ol from indene by by-product hydrogen bromide and 
hydrogen peroxide (use of chlorobenzene, added dispersant) 
160 ml of water, 60.0 g of indene (95 wt %; 0.49 mol) and 1.12 g of Triton 
X-100 were put into a 500-ml 3-mouthed flask, and mixed as they were 
heated to 60.degree. C. 80 ml of chlorobenzene was added, and 41.2 g of 
bromine (0.258 mol) was added dropwise over 1 hour at 
60.degree.-63.degree. C. when the chlorobenzene layer was sampled, diluted 
with ethyl acetate and analysed by GC, the composition below emerged. 
______________________________________ 
Component Composition (GC area %) 
______________________________________ 
Indene 54.4 
1,2-Dibromoindane 
16.7 
Trans-2-bromoindan-1-o1 
25.1 
______________________________________ 
From the results above it is evident that approximately half of the indene 
was consumed and approximately 60% of the 1,2-dibromoindane produced by 
bromination was converted to the desired trans-2-bromoindan-1-ol. 
Moreover, on mixing at the same temperature for 2 hours 45 minutes, white 
crystals of trans-2-bromoindan-1-ol separated out in the chlorobenzene 
layer. Then 23.5 g of hydrogen peroxide (35 wt %; 0.242 mol) was added at 
61.degree.-62.degree. C., which required 1 hour 45 minutes, followed by 
mixing for a further 2 hours at the same temperature. The reaction mixture 
was cooled to 30.degree. C., which required ca. 2 hours, being mixed as it 
cooled. The lower slurry layer was isolated, cooled to 5.degree. C., and 
then filtered under decreased pressure. The cake was washed with 20 ml of 
chlorobenzene and then dried under decreased pressure to obtain 81.87 g of 
white crystals of trans-2-bromoindan-1-ol (yield 78.2%). 
Embodiment 7 
Synthesis of 1,2-dibromoindane by bromination of indene, and synthesis of 
trans-2-bromoindan-1-ol by hydrolysis of this 1,2-dibromoindane/synthesis 
of trans-2-bromoindan-1-ol from indene by by-product hydrogen bromide and 
hydrogen peroxide (no added dispersant) 
160 ml of water and 60.0 g of indene (95 mol%; 0.49 mol) were put into a 
500-ml 4-mouthed flask, and mixed as they were heated to 63.degree. C. 
40.1 g of bromine (0.25 mol) was added dropwise at 60.degree.-63.degree. 
C., requiring 30 minutes. On standing, 2 layers separated; the lower layer 
(organic layer) was transparent pale orange and no crystals could be 
observed. On mixing for a further 1 hour 15 minutes at 60.degree. C., 
crystals of trans-2-bromoindan-1-ol were seen in the organic layer. Then 
23.55 g of hydrogen peroxide (35 wt %; 0.24 mol) was added dropwise, 
requiring 25 minutes. After mixing for 3.5 hours at the same temperature, 
mixing was continued during air cooling overnight. 80 ml of chlorobenzene 
was added to the reaction mixture which included sticky semi-crystals, and 
mixed for 30 minutes. The slurry was filtered under decreased pressure at 
18.degree. C., and the cake was washed with a small quantity of 
chlorobenzene, and dried under decreased pressure. 52.14 g of white 
crystals of trans-2-bromoindan-1-ol (yield 49.9%) was obtained. 
Embodiment 8 
Synthesis of 1,2-dibromoindane by bromination of indene, and synthesis of 
trans-2-bromoindan-1-ol by hydrolysis of this 1,2-dibromoindane/synthesis 
of trans-2-bromoindan-1-ol from indene by by-product hydrogen bromide and 
hydrogen peroxide (use of ortho-dichlorobenzene, no added dispersant) 
100 ml of water and 0.70 g of Triton X-100 were put into a 300-ml 4-mouthed 
flask, and mixed as 80 ml of ortho-dichlorobenzene and 60.0 g of indene 
(95 wt %; 0.491 mol) were added. At 20.degree. C., 41.54 g of bromine 
(0.259 mol) was added with strong stirring and air cooling over 
approximately 5 minutes. After dropwise addition the temperature of the 
reaction mixture became 52.degree. C. After mixing at 60.degree. C. for 13 
hours, 23.8 g of hydrogen peroxide (35 wt %; 0.245 mol) was added dropwise 
at the same temperature, requiring 3 hours, followed by mixing for a 
further 3 hours at 60.degree. C. and then separation into an aqueous layer 
and a slurry layer. The aqueous layer was extracted with 120 ml of 
ortho-dichlorobenzene, and the extract layer was bulked with the earlier 
slurry layer. The warm slurry layer was cooled gradually to 20.degree. C. 
under stirring, the crystals which came down were isolated by 
centrifugation and washed with 30 ml of ortho-dichlorobenzene. The wet 
crystals were dried at 65.degree.-70.degree. C. under decreased pressure 
to obtain 72.18 g of white crystals of trans-2-bromoindan-1-ol (yield 
69.0%). 
Embodiment 9 
Synthesis of a mixture of 1,2-dibromoindane (I) and trans-2-bromoindan-1-ol 
(II) by indene-hydrogen bromide-hydrogen peroxide reaction 
21.6 g of indene (88 wt %; 0.164 mol), 16.9 g of water, 31.0 g of hydrogen 
bromide (47 wt %, 0.18 mol) and 9 ml of chlorobenzene were put into a 
100-ml 3-mouthed flask and mixed as they were cooled to -10.degree. C. At 
this time the pH was 4.13. 17.5 g of hydrogen peroxide (35 wt %; 0.18 mol) 
was added dropwise at -9.degree. to -11.degree. C., requiring 1 hour 15 
minutes. At this time the pH was -0.71. After finishing dropwise addition 
mixing was performed at the same temperature, and the surface area ratio 
of 1,2-dibromoindane (I) and trans-2-bromoindan-1-ol (II) was traced by 
HPLC and changes in indene concentration were traced by GC surface areas. 
______________________________________ 
Time (hr) 0 1.5 2.5 3.5 5.5 
______________________________________ 
I:II 92:8 90:10 90:10 89:11 88:12 
Indene 70.0 59.0 60.0 54.9 53.3 
______________________________________ 
Mixing was continued for 5.5 hours at the same temperature. At this time 
the pH was -0.31. The temperature was raised to 15.degree. C. over 15 
minutes. Mixing was continued for 30 minutes at this temperature and when 
HPLC and GC analyses were performed the HPLC surface area ratio (I):(II) 
was 86:14, and the percentage surface area accounted for by indene on GC 
was 43. When similar analyses were performed after mixing overnight (ca. 
13 hours) at 16.degree.-21.degree. C. the HPLC (I):(II) surface area ratio 
was 82:18 and the percentage surface area of indene on GC was 32%. At this 
time pH was 1.33. After mixing at 21.degree. C. for 1.5 hours the 
temperature was raised to 60.degree. C., and on analysis after 3.5 hours 
the HPLC (I):(II) surface area ratio was 79:21 and the percentage surface 
area of indene on GC was 25%. When analysed when mixed while cooling from 
60.degree. C. the HPLC (I):(II) surface area ratio was 63:37 and the 
percentage surface area of indene was 13%. The pH at this time was 1.40. 
From the results above the following facts are clear. 
(1) At -10.degree. C. while pH is low (pH&lt;0) the (I):(II) ratio is almost 
constant. Indene is also consumed in the reaction. This means that at low 
temperatures below 0.degree. C. the addition of BrOH and Br.sub.2 to 
indene progresses but the hydrolysis of (II) is extremely slow. 
(2) At room temperature hydrolysis proceeds more rapidly than at 
.ltoreq.0.degree. C. As the reaction proceeds the pH rises and the 
velocity tends to decrease. 
(3) At the same pH the velocity of the hydrolysis reaction is markedly 
greater at 60.degree. C. than at room temperature. 
The reaction mixture was filtered under decreased pressure, washed with 5 
ml and 10 ml of chlorobenzene and then dried at 40.degree. C. under 
decreased pressure, to obtain 26.7 g of white crystals of 
trans-2-bromoindan-1-ol (II) (yield 76.5%). Purity by the GC surface area 
percentage method was 100.0%. 
Embodiment 10 
Synthesis of a mixture of 1,2-dibromoindane (I) and trans-2-bromoindan-1-ol 
(II) by indene-hydrogen bromide-hydrogen peroxide reaction 
21.6 g of indene (88 wt %; 0.164 mol), 17.5 g of hydrogen peroxide (35 wt 
%; 0.18 mol) and 9 ml of chlorobenzene were put into a 100-ml 3-mouthed 
flask and mixed as they were cooled. At this time the pH was 4.06. 31.0 g 
of hydrogen bromide (47 wt %, 0.18 mol) was added dropwise at -9.degree. 
to -11.degree. C. over 1 hour 20 minutes. The surface area ratio of (I) 
and (II) in HPLC analysis was 95:5, and the surface area percentage of 
indene in GC was 53. A further 31.0 g of hydrogen bromide (47 wt %, 0.18 
mol) was added dropwise over 1 hour 20 minutes at the same temperature. At 
this time the pH was -0.21. The surface area ratio of (I) and (II) in HPLC 
analysis was 94:6, and the surface area percentage of indene in GC was 22. 
On analysis after mixing for 1 hour at the same temperature the HPLC 
surface area ratio (I):(II) was 94:6, and the percentage surface area 
accounted for by indene on GC was 2.8. At this time the pH was 0.03. When 
analyses were performed after mixing overnight the HPLC (I):(II) surface 
area ratio was 93:7 and the percentage surface area of indene on GC was 
2.6. 
From the results above the following facts are clear. 
1) When the hydrogen bromide concentration is large (when the quantity of 
water in the system is small) the velocity of the indene addition 
reactions becomes large. 
2) When the hydrogen bromide concentration is large the ratio of the indene 
addition reaction products (I) and (II) changes, with the percentage of 
(I) becoming larger. 
3) As in Embodiment 9, the hydrolysis of (I) is extremely slow at 
-10.degree. C. 
The reaction mixture was mixed for a further 9 hours at 60.degree. C. and 
after stirring under cooling overnight the crystals that came down were 
filtered out under decreased pressure, washed with 5 ml of water and 10 ml 
of chlorobenzene and then dried at 40.degree. C. under decreased pressure, 
to obtain 27.3 g of white crystals of trans-2-bromoindan-1-ol (II) (yield 
78.1%). 
The Possibility of industrial utilization 
By means of the present invention trans-2-bromoindan-1-ol can be 
manufactured industrially cheaply and simply with good yield, by using 
1,2-dibromoindane as the starting material.